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Carbon-carbon bond formation : reactions of alkenyltrimethylstannanes mediated by copper(I) salts Yee, James Gee Ken 2000

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CARBON-CARBON BOND FORMATION. REACTIONS OF ALKENYLTRIMETHYLSTANNANES MEDIATED BY COPPER(I) SALTS  BY JAMES G E E K E N Y E E B. Sc., University of Calgary, 1995  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF T H E REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in T H E F A C U L T Y OF GRADUATE STUDIES (Department of Chemistry)  We accept this thesis as conforming to the required standard  T H E UNIVERSITY OF BRITISH COLUMBIA July, 2000 © James G. K. Yee,<3(?CO  UBC  Special Collections - Thesis Authorisation Form  I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f the requirements f o r a n advanced degree a t the U n i v e r s i t y o f B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and study. I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y purposes may be g r a n t e d b y the head o f my department o r b y h i s o r h e r r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t copying o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l gain s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n .  Department o f The U n i v e r s i t y o f B r i t i s h Columbia Vancouver, Canada  http://www.library.ubc.ca/spcoll/thesauth.html  21/07/00 12:56  11  ABSTRACT  The work in this thesis is described in two sections. In the first section, the conjugate addition of alkenyltrirnethylstannane functions to a,p-alkynic esters mediated by copper(I) chloride are discussed. A n experimental protocol employing copper(I) chloride and acetic acid in A^A^-dimethylforaiamide was developed to effect the stereoselective conversion of the precursors 80 and 178-185 into the monocyclic compounds 81 and bicyclic compounds 186-193, respectively.  The intramolecular copper(I)-mediated conjugate  addition of aryltrimethyl  stannane functions to a,(3-alkynic esters was also explored. A variety of bicyclic compounds of general structure 89 that each incorporate an aromatic ring were prepared by this method. a,f3-Alkynic aldehydes and a,(3-alkynic ketones were shown to function as viable Michael acceptors in the conversion of 233 and 235 into 236-237 and 238-239, respectively.  The  catalytic nature of the copper(I) chloride in the reaction was also demonstrated. In the second part of this thesis, the copper(I) chloride-mediated oxidative coupling of alkenyltrimethylstannane and aryltrimethylstannane functions is discussed. The intermolecular homocoupling of f3-trirnethylstannyl-a,P-unsaturated ketones 100 produced the structurally unusual diketones 101 upon the treatment of the precursors with copper(I) chloride.  The  synthesis of the 5-, 6-, and 7-membered ring compounds 105, 107, 109, 111, and 113 from the precursors 104, 106, 108, 110, and 112, respectively, was accomplished by use of the intramolecular variant of the coupling reaction. The scope of the methodology was extended to include the formation of 9-membered and 10-membered ring compounds of general structure  115.  Ill  Me Sn 3  COpMe R C0 Me 2  R = H, Me, o r O M e X = O or C ( C 0 E t ) 2  Q  8  ,R  Me  100  "SnMe  3  C(=0)R  SnMe  3  SnMe  3  233 R = H 235 R = Me SnMe  9  236,237 R = H 238,239 R = Me 3  .0.  SnMe  SnMe  3  3  108  SnMe  SnMe  3  E = C0 Et 2  112  n =  3  E = C0 Et 2  113  1  or 2 R  E = C0 Et 2  115  2  iv  TABLE OF CONTENTS  ABSTRACT  ii  T A B L E OF CONTENTS  iv  LIST OF TABLES  viii  LIST OF FIGURES  xi  LIST OF G E N E R A L PROCEDURES  xii  LIST OF ABBREVIATIONS ACKNOWLEDGEMENTS I.  xiii  xvi  INTRODUCTION  1  1. General  1  2. Background  2  2.1 General background  2  2.2 Oxidative homocoupling of alkenyltrimethylstannanes  7  2.3 Intramolecular conjugate addition  12  3. Proposals  16  3.1 Intramolecular conjugate addition of alkenyltrimethylstannane functions to a,(3-alkynic esters to form monocycles  16  3.2 Intramolecular conjugate addition of alkenyltrimethylstannane functions to a,f3-alkynic esters to form bicycles  17  3.3 Intramolecular conjugate addition of aryltrimethylstannane functions to a,f3-alkynic esters to form bicycles incorporating an aromatic ring  18  3.4 Limitations, extentions, and mechanistic considerations....  19  3.4.1 Mechanistic considerations  19  3.4.2 Intramolecular conjugate addition of alkenyltrimethystannane functions to a,(3-alkynic aldehydes and a,p-alkynic ketones  22  3.5 Intermolecular oxidative homocoupling of (3-trimethylstannyl a, ^unsaturated ketones mediated by copper(I) chloride  23  3.6 Oxidative intramolecular couplings of bisaryltrimethylstannanes mediated by copper(I) chloride  24  3.7 Intramolecular oxidative coupling of bisalkenyltrimethylstannanes to produce 9- and 10-membered rings  26  II. RESULTS AND DISCUSSION 1. Intramolecular conjugate additions of alkenyltrimethylstannanes to Michael acceptors mediated by copper(I) salts  27  27  1.1 Introductory remarks  27  1.2 Intramolecular conjugate additions to form monocycles  29  1.2.1 Preparation of acyclic cyclization precursors  29  1.2.2 Copper(I) chloride-mediated cyclizations  35  1.3 Intramolecular cyclizations to form bicyclic compounds....  44  1.3.1 Preparation of cyclization precursors  44  1.3.2 Copper(I)-mediated cyclizations  48  1.4 Copper(I)-mediated intramolecular cyclizations of aryltrimethylstannane functions to a,(3-alkynic esters  54  1.4.1 Preparation of cyclization precursors  54  1.4.2 Copper(I)-mediated cyclizations of aryltrimethylstannane functions to a,(3-alkynic esters  59  1.5 Limitations, extensions, and mechanistic considerations  64  1.5.1 Effect of varying solvents and additives  64  1.5.1.1 Development of the use of an in situ proton source 1.5.1.2 Use of catalytic amounts of CuCl in the conjugate addition reaction 1.5.2 Preparation of a,(3-alkynic ketone and aldehyde precursors  64 67 71  1.5.3 Cyclization of oc,|3-alkynic ketone and aldehyde precursors 1.6 Summary 2. Intermolecular and intramolecular oxidative coupling of alkenyl- and aryltrimethylstannanes mediated by copper(I) chloride  72 77  79  2.1 Introductory remarks  79  2.2 Intermolecular coupling of P-trimethylstannyla,(3-unsaturated ketones mediated by copper(I) chloride....  80  2.2.1 Preparation of P-trimethylstannyla,(3-unsaturated ketones  80  2.2.2 Copper(I) salt mediated coupling  81  2.3 Intramolecular copper(I)-mediated coupling of aryltrimethylstannane functions to aryltrimethylstannane and alkenyltrimethylstannane functions  83  2.3.1 Preparation of cyclization precursors  83  2.3.2 Copper(I) chloride-mediated cyclizations  86  2.4 Intramolecular oxidative coupling of bisalkenyltrimethylstannanes to formbicyclo[7.3.0]dodecane and bicyclo[8.3.0]tridecane derivatives  92  2.4.1 Preparation of cyclization precursors  92  2.4.2 Copper(I)-mediated cyclizations  98  2.5 Summary  III. EXPERIMENTAL 1. General  105  107 107  1.1 Data acquisition, presentation, and techniques  107  1.2 Solvents and reagents  110  2. Intramolecular conjugate additions to form monocycles  112  2.1 Preparation of cyclization precursors  112  2.2 Copper(I)-mediated cyclizations  126  vii  3. Intramolecular conjugate additions to form bicyclic compounds  135  3.1 Preparation of cyclization precursors  135  3.2 Copper(I)-mediated conjugate additions  161  4. Copper (I)-mediated intramolecular conjugate additions of aromatic stannanes to a,P-alkynic ester functions  173  4.1 Preparation of precursors  173  4.2 Copper(I)-mediated conjugate additions  194  5. Extensions and limitations  203  5.1 Effect of solvents and additives  203  5.2 Preparation of acetylenic aldehyde and ketone precursors...  208  5.3 Copper(I) mediated cyclizations  211  6. Intermolecular coupling of P-trimethylstannyl-a,P-unsaturated ketones mediated by copper(I) chloride 6.1 Intermolecular copper(I)-mediated couplings  7. Intramolecular coupling of aryltrimethylstannanes to aryltrimethylstannane and alkenyltrimethylstannanes  216 216  221  7.1 Preparation of coupling precursors  221  7.2 Intramolecular couplings mediated by copper(I) chloride...  235  8. Intramolecular oxidative coupling of bisalkenyltrimefhylstannanes to form bicyclo[7.3.0]dodecane and bicyclo[8.3.0]tridecane derivatives  235  8.1 Preparation of coupling precursors  235  8.2 Intramolecular oxidative couplings mediated by copper(I) chloride  263  IV. R E F E R E N C E S A N D F O O T N O T E S  271  LIST O F T A B L E S Table 1.  Synthesis of the bicycles 67  15  Table 2.  Synthesis of the dienes 144 and 145  35  Table 3.  Synthesis of the cyclization precursors 178-184  47  Table 4.  Synthesis of the bicycles 186-193  49  Table 5.  Synthesis of the bicycles 224-228  60  Table 6.  Synthesis of the diene 158  67  Table 7.  Synthesis of the diene 156  68  Table 8.  Synthesis of the iodides 246a-246d and stannanes 247-250....  80  Table 9.  Synthesis of the diketones 251-254  81  Table 10.  Synthesis of the tricycles 105,107, and 109  87  Table 11.  Synthesis of the tricycles 113 and 263-266  88  Table 12.  Synthesis of the distannanes 293-298  97  Table 13.  Synthesis of the bicyclic dienes 299-304  99  Table 14.  *H nmr (400 MHz, CDC1 ) data for the ester 144: 3  C O S Y (200 MHz) and NOED experiments  128  ix  Table 15.  Table 16.  Table 17.  Table 18.  Table 19.  H nmr (400 M H z , CDC1 ) data for the silyl ether 155: N O E D experiments  131  *H nmr (400 M H z , CDC1 ) data for the ester 156: N O E D experiments  132  *H nmr (400 M H z , CDC1 ) data for the diester 158: N O E D experiments  134  H nmr (400 M H z , CDC1 ) data for the diester 187: C O S Y (200 MHz) and N O E D experiments  162  *H nmr (400 M H z , C D ) data for the diester 188: N O E D experiments  164  *H nmr (400 M H z , CDC1 ) Data for the diester 198: NOED experiments  167  H nmr (400 M H z , CDC1 ) data for the diester 190: C O S Y and N O E D experiments  169  *H nmr (400 M H z , CDC1 ) data for the diester 191: C O S Y and N O E D experiments  171  *H nmr (400 M H z , CDC1 ) data for the diester 192: C O S Y and NOED experiments  172  *H nmr (400 M H z , CDC1 ) data for the ester 224: N O E D experiments  195  *H nmr (400 M H z , CDC1 ) data for the ester 225: N O E D experiments  196  l  3  3  3  X  3  6  Table 20.  Table 21.  Table 22.  Table 23.  Table 24.  Table 25.  Table 26.  6  3  X  3  3  3  3  3  J  H nmr (400 M H z , CDC1 ) data for the triester 226: 3  N O E D experiments  198  Table 27.  Table 28.  Table 29.  Table 30.  Table 31.  Table 32.  *H nmr (400 M H z , CDC1 ) data for the triester 227: N O E D experiments  199  H nmr (400 M H z , C D ) data for the triester 228: N O E D experiments  201  3  l  6  1 3  6  C nmr (128.5 M H z , C D ) data for the triester 228: 6  6  H M B C and H M Q C experiments  202  *H nmr (200 M H z , CDC1 ) data for the ester 145: N O E D experiments  204  *H nmr (400 M H z , CDC1 ) data for the aldehdye 237: N O E D experiments  213  3  3  J  H nmr (400 M H z , CDC1 ) data for the aldehyde 236: 3  N O E D experiments  Table 33.  r  213  H nmr (400 M H z , CDC1 ) data for the ketone 238: 3  N O E D experiments  Table 34.  Table 35.  Table 36.  215  *H nmr (200 M H z , CDC1 ) data for the diester 299: C O S Y experiment  265  *H nmr (400 M H z , CDC1 ) data for the diester 300: N O E D and C O S Y experiments  267  ' H n m r (400 M H z , CDC1 ) data for the diester 301: N O E D and C O S Y experiments.  269  3  3  3  LIST O F FIGURES Figure 1.  Catalytic cycle of the Stifle coupling reaction  3  Figure 2.  Effect of copper(I) salts in the Stifle reaction  4  Figure 3.  NOED experiments on 144 and 145  36  Figure 4.  NOED experiments on 155  41  Figure 5.  NOED experiments on 156 and 157  42  Figure 6.  NOED experiments on 158  43  Figure 7.  NOED experiments on 187,188,190-192, and 157  52  Figure 8.  NOED experiments on 224 and 225  61  Figure 9.  NOED experiments on 228  62  Figure 10.  NOED experiments on 236 and 237  74  Figure 11.  N O E D experiments on 238  75  Figure 12.  Steric interactions in 265 and 266  90  xu  LIST OF GENERAL PROCEDURES General Procedure 1:  CuCl-mediated intramolecular conjugate addition of alkenyltrimethylstannanes to alkynic esters  126  Protection of terminal alkynes with te^butyldimethylsilylcMoride  135  General Procedure 3:  Conversion of THP ethers into alkyl bromides..  138  General Procedure 4:  Preparation of 2-trimethylstannylbenzyl alcohol derivatives  173  Conversion of benzyl alcohol derivatives into benzyl bromides  176  Copper(I)-mediated intermolecular coupling of P-trimethylstannyl-a,P-unsaturated ketones.  216  Protection of terminal alkynes with te^butyldimethylsilylcMoride  229  Copper(I)-mediated intermolecular oxidative coupling of bisalkenyltrimethylstannanes  263  General Procedure 2:  General Procedure 5: General Procedure 6: General Procedure 7: General Procedure 8:  xiii  LIST O F ABBREVIATIONS a  -  1,2 relative position  Ac  -  acetyl  anal.  -  analysis  APT  -  attached proton test  (3  -  1,3 relative position  Bn  -  benzyl  bp  -  boiling point  br  -  broad  Bu  -  butyl  °C  -  degrees Celsius  calcd.  -  calculated  cm  -  centimeter  COSY -  ( H- H) - homonuclear correlation spectroscopy  C-x  -  carbon number x  d  -  doublet  8  -  chemical shift in parts per million from tetramethylsilane  A  -  heat  1  1  DIBAL -  dnsobutylaluminum hydride  DMF  -  A/,iV-dimethylformamide  DMI  -  l,3-dimethyl-2-imidazolidinone  DMPU -  iV.iV'-dimethylpropyleneurea  DMS  dimethyl sulfide  -  DMSO -  dimethyl sulfoxide  E  -  entgegen (configuration)  ed.  -  edition  Ed.  -  editor  e.g.  -  exempli gratia (for example)  equiv  -  equivalent(s)  Et  ethyl  g  gram  gc  gas-liquid chromatography  h  hour(s)  HMPA -  hexamethylpho sphoramide  H-x  hydrogen number x  -  Hz  Hertz  IR  infrared  J  coupling constant in hertz  Jsa-n -  n bond coupling for tin and proton nuclei in Hertz  LDA  lithium diisopropylamide  R  -  m  multiplet  m  meta  M  molar  Me  methyl  mg  milUgram(s)  MHz  -  megahertz  min  minute(s)  mL  milhliter(s)  \xL  microliter(s)  mm  millimeter (s)  mmol  -  millirnole(s)  mol.  molecular  mp  melting point  NMP  -  Af-methylpyrro lidone  nmr  nuclear magnetic resonance  noed  nuclear Overhauser effect difference  0  ortho  Pg  page(s)  P  para  PCC  -  pyridinium chlorochromate  Ph  -  phenyl  ppm  -  parts per million  PPTS  -  pyridinium /?-toluenesulfonate  Pr  -  propyl  q  -  quartet  rt  -  room temperature  s  -  singlet  t  -  triplet  t  -  tertiary  TBAF -  tetrabutylarnmonium fluoride  TBS  -  te^butyldimethylsilyl  tert  -  tertiary  THF  -  tetrahydrofuran  tic  -  thin layer chromatography  TMEDA-  N, N, N', JV'-tetramethy leneethy lenediamine  -ve  -  negative  Z  -  zusammen (configuration)  •  -  coordination or complex  xvi  ACKNOWLEDGEMENTS  I would like to take this opportunity to thank my graduate research supervisor Dr. Edward Piers for his guidance and for the opportunity to join his research group. The contribution of all members of the Piers research group, who have made my stay a pleasurable and exciting experience, is gratefully acknowledged. For hstening to me chatter incessantly and inanely over many years, the patience of A l Kaller, Serge Boulet, Rob Britton, Shawn Walker, Elizabeth Cheu, Alex Wong, Gay Yuyitung, and Krystyna Skupinska is particularly noted. The assistance of the support staff at the U B C chemistry department is acknowledged. A special thanks goes to Patricia Gladstone who was not only a mentor and a labmate but also a best friend. The extraordinary support and encouragement  from Ipi Yuyitung is also  immensely appreciated. Lastly, this thesis is dedicated to my parents for always being there.  1  I. I N T R O D U C T I O N  1. General  Research in the area of synthetic organic chemistry can be generally divided into two central themes.  In the first theme, the research is target-based and a particular  substance is synthesized from simple, commercially available starting materials.  By  performing a sequence of transformations that modify or combine various existing fragments, more complex structures are obtained until the desired final product or target is made. The targets chosen for synthesis may be of industrial value, such as monomers or plant growth hormones, of medicinal value, or simply chosen for esthetic reasons. The final products of the synthesis may also serve to confirm constitutional and stereochemical assignments.  For products that exhibit interesting pharmacological or  biological activity, the process often culminates in the total synthesis of a natural product or an analog thereof.  This involves the construction of molecules that exist in nature  from terrestrial or marine origin. In order to construct a structurally complex substance, a series of reactions, each employing a substrate and a reagent to perform the desired conversion, must be employed.  Consequently, the second major theme of synthetic organic chemistry is  concerned with discovering and developing new reagents and methods for synthesis. Such methodological studies, leading to new protocols for the construction and manipulation of the bonds between carbon and other elements, are of major interest to the practicing organic chemist. A desirable chemical transformation is a reaction that is high yielding, occurs under mild reaction conditions, and employs cheap, non-hazardous starting materials and reagents.  For certain reactions, a high degree of chemo selectivity, regio selectivity,  enantioselectivity, or diastereoselectivity may be required. Many transformations that presently exist or that synthetic organic chemists may desire to carry out are inefficient or  2 simply not possible with known procedures. A great deal of effort is spent on developing new reagents and synthetic methods to satisfy some of these goals. As new protocols and reactions are developed, unique or more efficient access to potentially valuable compounds becomes possible. In particular, an important application of newly developed reactions is the synthesis of natural products or analogs, in the hopes of discovering new or more effective therapeutic agents. Another use of new processes is the application of the methodology to large-scale industrial chemical preparations. Also important, in this era of environmental responsibility, is the search for environmentally safer alternatives to known reactions and industrial procedures that employ toxic reagents and produce unwanted byproducts or hazardous effluent. A n enormous amount of time and resources is spent finding viable and better alternatives to existing processes. Alongside the discovery and use of a reaction is the mechanistic understanding that underlies the transformation.  Methodological studies provide the scope and  limitations of a reaction, with respect to both the substrate and the reagent, and, in some instances, may give insight into the mechanistic pathway that may be involved. Indeed, a greater understanding of how a reaction occurs can often lead to proposing and developing reaction conditions that improve and expand the usefulness of the process. Thus, the practicing organic chemist is supplied with a rationale to attempt alternative conditions in the laboratory to achieve a more desirable outcome.  2. Background  2.1 General Background  One of the most well known transition metal-mediated organic transformations is the Stille coupling reaction.  1  Formulated in general terms as shown in equation 1, the  reaction cross-couples a tetraorganostananne (RSnR's) with an appropriate electrophile (R"-X) and is catalyzed by a palladium(0) complex. The structure of the organostananne partner that participates in the reaction can be quite varied and may incorporate alkenyl, alkynyl, allyl, aryl, and benzyl groups. Alkyl groups transfer at the slowest rate and  3 hence act as the nontransferable or dummy ligands (R ) when a ligand (R) that 1  participates at a faster rate is present.  2  The electrophile is often an alkenyl halide or  alkenyl triflate but acid chlorides, allyl halides, aryl halides, benzyl halides, and aryl triflates have been used as well. A n illustrative example is given in equation 2 .  la  Pd(0) RSnR'g  R-R"  R"-X  +  XSnR'  3  (1)  SiMe, OTf  Pd(Ph ) /LiCI 3  4  (2) SiMe,  2  1  90%  The Stille reaction is thought to proceed via a pathway displayed in a general manner in Figure l .  l a  The reaction is believed to be initiated by the (reversible) loss of a  pair of ligands from the tetracoordinate palladium(0) species (PdL ) to form a 4  coordinatively unsaturated species (Pdl^). In the presence of the appropriate electrophile Pdl_ R-R"  +  4  2_Lfl  reductive elimination  cis-trans isomerization  R"-X oxidative addition  RSnR'  transmetalation XSnR'  Figure 1. Catalytic cycle of the Stille coupling reaction  3  3  4 (R"-X), an oxidative addition of the PdL>2 to the C - X bond produces a palladium(II) complex.  The  palladium(II)  species  undergoes  a  transmetalation  with  the  tetraorganostannane (RSnR' ) to form the bis(organo)palladium(II) species (R-Pd(L2)-R") 3  and a triorganostannyl-X side-product. This transmetalation step is considered to be the rate limiting step in the catalytic cycle of the Stille reaction. A cis-trans isomerization, followed by a rapid reductive elimination, yields the cross-coupled product (R-R") and results in the regeneration of the coordinatively unsaturated palladium(0) catalyst to participate further in the catalytic cycle. A n important advance in Stille coupling chemistry was the discovery that copper(I) salts (CuCl, CuBr, Cul) accelerate the reaction rate of the coupling process, often by a thousand fold or more.  3  The copper(I) salt is thought to have two major  influences. The first is that the copper(I) salt acts as a ligand scavenger to help form the coordinatively unsaturated palladium(O) species (PdL^). solvents such as  In addition, in highly polar  N-dimethylformamide (DMF) and JV-methylpyrrolidone (NMP), a  reversible tin-copper transmetalation occurs which produces an organocopper(I) derivative (vide infra). palladium(II)  The organocopper(I) species (RCu) transmetalates with the  species (R"-Pd(L2.)-X) to form the bis(organo)palladium complex L  L  R-Pd-X  "R-Pd-X  L  A  L  RSnR'3 il  B  Figure 2. Effect of copper(I) salts in the Stille reaction  (R-PdLrR") (pathway B i n ' Figure 2) at a rate faster than the palladium-tin transmetalation (pathway A in Figure 2). The end result is that the two step process  5 (pathway B) occurs at a rate faster than the one step transmetalation of the palladium(II) complex (R-PdL2-X) and the tetraorganostannane (RSnR'3) (pathway A). In studies involving the use of the intramolecular variant of the Stille reaction for 4  the synthesis of substituted bis(alkylidene)cyclopentanes utilizing copper(I) salts as a cocatalyst, Piers and Wong made a valuable discovery: the cyclization was found to 5  proceed rapidly and smoothly in the absence of any palladium catalyst. For example, in the conversion of 4 into 5 (equation 3), the yield of the transformation improved remarkably from 52% under "standard" Stille reaction conditions (Pd(Ph P) (5 mol %), 3  4  L i C l (2 equiv), 105 °C, 1.5 h, DMF) to 81% when copper(I) chloride was employed alone (equation 3).  This method was recently exploited by Corey in the total synthesis of  5b  aegiceradienol (9). In this case, the internal Stille coupling of the alkenylstannane6  alkenylbromide 7 failed under traditional palladium catalysis but successfully gave 8 when treated with copper(I) chloride. The key steps in the synthesis are shown below in Scheme 1. C0 Et 2  CuCI (2.5 eq) 5 min, 60 °C DMF 81  %  (3) C0 Et 2  (Me Sn) Pd(Ph ) LiCl 3  3  2  SnMe,  4  THF reflux  TBSO  CuCI 1 DMF, 60 °C  HO'  9  55 % over 3 steps  Scheme 1.  TBSO  6 Since the initial report by Piers, several instances of copper(I) salt mediated couplings have appeared in the literature. A n important advance was reported by Allred and Liebeskind, who showed that copper(I) thiophene-2-carboxylate (CuTC) effectively 7  carries out intermolecular cross couplings of alkenyl- and aryl iodides with alkenyl- and aryltributylstannanes in N M P . A n example of this process is shown below in equation 4.  (4)  11 More detailed investigations, by Liebeskind, Piers, and others,  into the  mechanism of the copper(I) halide co-catalyst effect in the Stille cross-coupling reaction and of the copper(I) chloride mediated cross-coupling processes, led to the suggestion that these reactions proceed via a common initial intermediate. coworkers,  33  by employing  119  Liebeskind and  S n nmr spectroscopy, showed that, in polar solvents,  copper(I) iodide reacts with phenyltributyltin to produce tributyltin iodide and, presumably, a phenylcopper(I) species. Furthermore, in studies related to the copper(I) effect in Stille reactions, it was shown that the rate of the coupling was retarded by the addition of Bu SnCl to the reaction mixture. These two observations, as well as similar 7  3  evidence provided by other research groups, led to the conclusion that the copper(I) 3  halide  participates  in  the  reversible  transmetalation  with  the  alkenyl-  or  aryltrialkylstannane to produce, in each case, an organocopper(I) species and a triorganohalide as the co-product (equations 5 and 6). This would be consistent with the shift of the equilibrium (left) toward the stannane with added Bu SnCl and, as a result, 3  the beneficial effect of the added copper(I) salt would be lessened or annulled.  + 13  CuCI  + 14  7  CuCl  ^=  B u S n C I (6)  +  15  3  16  Aside from the rate enhancing effects observed in the Stille cross-coupling reaction, the organocopper(I) species derived from reaction of alkenylstannanes with copper(I) salts has been found in the Piers laboratory, under certain conditions, to react in two other synthetic operations: the oxidative homocoupling of bisalkenylstannanes and the intramolecular conjugate addition of alkenyltrialkylstannanes to Michael acceptors, each mediated by copper(I) salts.  2.2 Oxidative Homocoupling of Alkenyltrimethylstannanes A n important observation made by Piers and Wong during mechanistic investigations related to the copper(I) chloride-mediated intramolecular coupling of alkenylstannane and alkenyl halide functions was that minor amounts of a dimerized product, resulting from the homocoupling of two alkenyltrimethylstannane moieties, were produced.  For example, in a control experiment (equation 7),  5b  in which the  stannane 17 was treated with 2.1 equiv of CuCl in warm D M F , a low yield (14%) of the homocoupled product 19 was obtained.  The remainder of the isolated material was  recovered starting material 17 (15%) and the protiodestannylated product 18 (42%). COoMe C0 Me  CuCl DMF  2  SnMe 17  3  C0 Me 2  C0 Me 2  (7)  60 °C 1 0 min 15%  42%  C0 Me 14% 19 2  This key observation was investigated further by Piers and coworkers, with the 8  aim of determining the generality of this new homocoupling protocol. It was found that a wide variety of alkenyltrimethylstannanes bearing allylic alcohol, a,P-unsaturated ester and a,p-unsaturated aldehyde functions are amenable to this copper(I) mediated process (equations 8, 9, 10, and 12). In the case of a, ^unsaturated esters, the coupling reactions  8 were shown to be stereo specific, since the configurational integrity of the double bond remained intact. Examples are shown in the conversions of the esters 20 and 22 into the dienes 21 and 23, respectively (equations 8 and 9). In general, it was found that superior yields are obtained from substrates that possess the alkenyltrimethylstannane function on the P carbon of a,(3-unsaturated aldehydes or esters.  Alkenyltributylstannanes also  undergo this transformation as shown by the conversion of the stannane 26 into the diene 25 in a moderate yield (51%) (equation 11).  CuCI  27  OHC  28 The mechanistic details of the copper(I) chloride-mediated oxidative coupling of alkenyltrialkylstannanes remain elusive. From quantitative determinations of the copper metal produced in the reaction, it was found that 2 mols of copper metal are produced for each mol of diene that is produced in the reaction. * A reasonable mechanistic pathway 81  9 would involve transmetalation of the organotrialkylstananne moiety in 29 (vide supra) to produce the corresponding organocopper(I) species 30 and the triorganostannyl halide (R3S11X). Disproportionation of 30 would produce the copper(II) intermediate 31 and one equivalent of Cu(0).  A subsequent reductive elimination of Cu(0) from 31 would  yield the coupled product 32 (Scheme 2).  A X u  /^/SnRj + 2 CuCI  1  2 R SnCI + 2 3  30  29  .Cu"V  32 + Cu  31 + Cu  c  c  Scheme 2.  This coupling method has been expanded by Piers and Romero to include the intramolecular coupling of bisalkenyltrimethylstanannes.  9  This powerful cyclization  method was demonstrated to form an impressive array of 4- to 8-membered rings. For example, the distannanes 32 and 34 were converted into the 6- and 8-membered ring bicycles 33 and 35, respectively, in excellent yields when the substrates were treated with 5 equiv of copper(I) chloride in warm D M F (equations 13 and 14).  C0 Me  CuCI (5 equiv) DMF, 60 °C  2  SnMe 32  SnMe 3  3  82%  C0 Me 2  CD 33  I  (13)  10  CuCI (5 equiv) DMF, 60 °C  s  SnMe  3  SnMe  34  Et0 Q 2  (14)  Et0 C 2  87% 3  35  Piers and Kaller investigated the possibility of using the oxidative homocoupling of alkenyltrimethylstannanes in a methylenecyclopentene annulation sequence.  10  In this  study, a series of cyclopentene derivatives was formed in moderate to good yields. A highlight of the method developed is the formation of the bicyclic systems 39-41 from the monocyclic precursors 36-38, respectively (equation 15). OAc  SnMe  OAc  CuCI (5 equiv) DMF, 60 °C  (15)  3  SnMe 36 n =1 37 n= 2 38 n=3 3  39 40 41  n = 1, 67 % n = 2, 82 % n = 3, 42 %  It should be noted that other protocols have been developed to accomplish the homocoupling of organotrialkylstannanes. The most noteworthy is the copper(II) nitratemediated coupling of organostannanes.  Kyler and coworkers, for example, employed  copper(II) nitrate to oxidatively homocouple aryl-, alkynyl-, and alkenylstannanes to produce an assortment of unsaturated systems (equation 16 and 17).  The exact  11  mechanistic details of this process are unclear.  Cu(N0 ) -3H 0 THF, rt, 30 min 3  Ph-  -SnBu;  2  2  50%  42  2  (16)  43  Cu(N0 ) -3H 0 THF, rt, 10 min 3  -SnBu,  -Ph  Ph-  2  (17)  67% 45  44  Since this initial report, Crisp and Glink reported the dimerization of certain alkenylstannanes facilitated by copper(II) nitrate (equation 18) in T H F .  Zhang and  12  coworkers reported the single example of a copper(II)-mediated coupling of an a-tributylstannyl  a,|3-unsaturated  ester (equation  19)  13  Finally,  a  series of  11 P-trimethylstannyl a,(3-unsaturated ketones and esters were reported to undergo copper(II) nitrate-mediated couplings by Quayle and coworkers.  14  One example reported  is given in equation 20 where the conversion of the alkenyltributylstannane 50 proceeded to give the corresponding dimerized product 51 in a moderate yield (58%). Cu(N0 ) -3H 0 THF, rt, 1 h 3  C0 Et 2  Bu Sn  5  NHAc  3  2  2  2  AcHN  (18)  NHAc  EtQ C  %  2  47  46 SnBu 48  ,C0 Et  2  Cu(N0 ) -3H 0 THF, rt, 10 min 3  3  C0 Me  Me0 C,  C0 Me  2  3  2  SPh C 0 M e 2  2  58%  3  (19)  2  49  Cu(N0 ) -3H 0 THF, rt  COoMe SnBu 50  2  58%  2  PhS  2  (20) Me0 C 2  SPh 51  Palladium salts have recently been reported by Liebeskind and Riesinger to mediate the coupling process. '  15 16  Stannylquinones of general structure 52 were found to  dimerize to give the corresponding 2,2'-bisquinones 53 in moderate to good yields (65-80%) when treated with PdCl2(PPh ) and copper(I) iodide in the presence of air. 3  R  1  II  n-J  o3  rs  i  PdCI (PPh ) Cul, NMP, air 2  SnBu  2  3  2  (21)  3  O 52 Lastly, silver salts, in particular silver(I) triflate, have been reported by Tius and Kawakami to mediate the coupling of two alkenyltrimethylstannane functions.  17  The  alkenylstannane 54 upon treatment with 1.1 equiv of silver(I) triflate in CH2CI2 resulted in the formation of the dimer 55 in good yield (79%) (equation 22).  12 AgOTf P  h  _ _ A A _  S  n  M  e  P  3  h  oy/o  Ph  (22)  79 % 54  55  2.3 Intramolecular Conjugate Addition The synthetic usefulness of organocopper(I) derivatives, formed from the transmetalation of organostannanes with copper(I) salts, has been further demonstrated in their ability to participate in intramolecular conjugate additions. Although the ability of organocopper(I)  reagents  to  add  mtermolecularly,  a,p-unsaturated carbonyl systems is well known, conjugate addition of unstabilized carbanions published literature.  19  18  in  a  conjugate  sense,  to  reports on the intramolecular  to Michael acceptors is a rarity in the  The primary reason for this scarcity is the inherent difficulty in  forming a reactive carbanion-like centre in the presence of an electron deficient n system, such as a carbonyl functionality or a Michael acceptor, where competing 1,2 and 1,4 modes of addition may operate. A few reports have emerged regarding intramolecular conjugate additions of non-stabilized carbanions and several deserve mention here.  20  By employing a bis(cuprate) addition-spiroannulation strategy, Wender and White produced the spiro system 57 from the (3-chloro enone 56 in a moderate (56%) yield (equation 23).  21  In this case, the order of addition of the alkenyl (sp ) centre and the 2  primary (sp ) centre of the bis(cuprate) to the unsaturated enone is not known. This type 3  of reaction was applied to form a variety of spiro compounds in moderate to excellent yields (39-94%).  0  Li  2  PhSCu  (23) THF, -20 °C  56  56%  In studies by Cooke and Widener,  57 22  the intramolecular conjugate additions of  alkenyl centres to unsaturated acylphosphoranes, mediated by BuLi, were performed. Treatment of the terminal alkenyl iodide 58 with BuLi, to effect a halogen-metal  13  exchange, followed by quenching the addition product with water, resulted in an excellent yield (87%) of the cyclized product 59 (equation 24).  1. ^ .BuLi, ^ ' ' THF "" -78 °C  I  l  k ^ ^ x ^ / C O R  87%  58 23  (24)  //  2  2  In another report by Cooke,  ^COR  2. H 0  R = -C(PPh )C0 Et 3  L J  59  the conjugate addition of unstabilized primary  carbanion functions to a,(3-alkynic esters were reported.  In a specific example, the  primary iodide 60 was treated with B u L i and trimethylsilyl chloride (TMSC1) to provide the cyclobutane derivative 61 in a moderate yield (equation 25). The presence of the TMSC1 as a trap for the intermediate allenoate was found to be essential, as the yield of the cyclization was very poor (11%) in its absence.  ^SiMe  n-BuLi, Me SiCI 3  ==  CO^Bu  THF, -78 °C 48%  60  = <  3  t  CQ Bu  (25)  2  61  In a study by Danheiser and coworkers, the conjugate addition of primary 24  carbanionic species, formed from the reaction of primary iodides with activated zinc dust, to a variety of Michael acceptors (a,(3-unsaturated esters, enones, and alkynoates) were achieved. In one example, involving treatment of the a,(3-alkynic ester 62 with zinc dust in THF, the a,(3-unsaturated  ester 63 was obtained in a moderate yield (66%)  (equation 26).  C0 Me 2  62  ,C0 Me 2  Zn dust THF, rt 5 days 66%  (26)  63  Finally, the conjugate addition of alkenyl systems to a,p-unsaturated sulfones in the synthesis of a series of ds-fused bicyclic ethers was reported by Fuchs and Lee.  25  In  this study, halogen-metal exchange of the alkenyl bromides of general structure 64 with  14 £-BuLi resulted in the formation of the cyclic ethers 65 in moderate to good yields as mixtures of diastereomers (equation 27). Br  (27)  64a n = 1, R = H 64b n = 1, R = Me 64c n = 0, R = H  65a 86 % 65b 75 % 65c 45 %  Piers and coworkers have used organocopper(I)  intermediates  to  effect  intramolecular conjugate additions of alkenyl functions to a,(3-unsaturated ketones (enones).  A series of ds-fused bicyclo[4.3.0]nonenones 67 can be prepared efficiently  26  via this method by the formation of the five membered rings under mild conditions (equation 28). In this work, copper(I) chloride in D M F or copper(I) cyanide in warm (60 °C) dimethyl sulfoxide (DMSO) were found to be effective protocols for accomplishing these reactions (Table 1). In some instances in which the (3-positions of the enones were sterically hindered (R = Et, /-Pr, or CH=CH ), the use of copper(I) 2  2  cyanide was found to give results superior to those derived from the use of copper(I) chloride.  For example, when R = H and R = /-Pr, the application of the reaction 1  2  protocol employing copper(I) cyanide gave a good yield (73%) (entry 6) of the cyclized adduct. The same conversion proved to be inefficient under the conditions employing copper(I) chloride in D M F (entry 5). O O  CuCl, DMF, rt or C u C N , D M S O , 60 °C  R ^^-SnMe Me 66  3  Me  R  67  (28)  15 Table 1. Synthesis of the bicycles 67  3 b c  Entry  R  R  1  H  H  CuCI  96  2  H  Me  CuCI  81  3  H  Et  CuCI  48  4  H  Et  CuCN  91  5  H  j-Pr  CuCI  15  6  H  j-Pr  CuCN  73  7  H  CH=CH  2  CuCI  6  8  H  CH=CH  2  CuCN  60  9  Me  H  CuCI  85  10  Me  Me  CuCI  90  1  Copper Source  2  3  % Yield  b  c  C  Reaction conditions: CuCI (2.5 equiv), D M F , rt, or C u C N (2.5 equiv), D M S O , 60 °C. Unless otherwise stated, isolated yield of the purified product. Glc yields of desired product in crude reaction mixtures. In manner similar to that described above, the syntheses of tricyclic compounds of  general structure 69 were reported by Piers and coworkers.  27  The intramolecular  conjugate addition of cyclic alkenyltrimethylstannane functions to a,(3-unsaturated ketones utilizing copper(r) cyanide in warm D M S O was described (equation 29). By the formation of the central five-membered ring, the functionalized tricyclic ketones 69 were synthesized in excellent yields (80-94%). O CuCN DMSO 60 °C n = 1,2 m = 1,2 R = H, Me R = H, Me  (29)  1  m  *SnMe  3  2  68 Finally, intramolecular conjugate additions of alkenyltrimethylstannane functions to a,(3-alkynic esters mediated by copper(I) chloride were achieved by Eva Boehringer in Dr. Piers' laboratory.  28  In this work, 2.5 equiv of copper(I) chloride in D M F was utilized  16 in the formation of symmetrical 4-6 membered monocycles with good to excellent yields (74-95%) (equation 30).  Bicyclo[4.2.0]octane and bicyclo[3.2.0]heptane structures,  arising from the formation of a four membered ring, were also synthesized in good yields (equation 31). The reader is refered to Introduction section 3.4.1 for a discussion on the proposed mechanism of this transformation. C0 R 2  ° 2  C  Me Sn  C u C l (2.5 equiv) DMF, 0 °C  R  3  (30) C0 R 2  C0 R 7 3 n = 1, 9 5 % 74 n = 2, 94 % 75 n = 3, 74 % 2  7 0 n = 1, R = Me 71 n = 2, R = Et 72 n = 3, R = Me SnMe  . ^CU Me 3  2  C u C l (2.5 equiv) o D  M  F  )  0  C  y^C0 Me 2  (31) OH 78 n = 1, 73 % 79 n = 2, 75 %  76 n = 1 77 n = 2  3. Proposals 3.1  Intramolecular  conjugate  addition of alkenyltrimethylstannane  functions  to  q,(3-alkynic esters to form monocycles  The scope and utility of the copper(I)-mediated cyclization protocol broadened significantly with the discovery of the intramolecular conjugate addition reaction of alkenyltrimethylstannane functions to a,(3-alkynic esters by Piers and Boehringer (see previous section).  However, only four successful examples of the formation of  monocyclic ring structures were presented and, of these, three of the carbocycles synthesized were symmetrical in nature (equation 30). To explore further the generality of the reaction, a series  of cyclization precursors  80 and 82, incorporating  17 alkenyltrimethylstannane and a,p-alkynic ester moieties in the same molecular construct, would be prepared and subjected to the intramolecular conjugate addition protocol (equations 32 and 33).  In this manner, the flexibility of the reaction to form  unsymmetrical 4- to 6-membered monocycles could be explored. For a discussion on the proposed mechanistic pathway of the reaction, the reader is referred to Introduction section 3.4.1. C0 R  C0 R  2  2  Me Sn>  CuCI  3  (32)  n = 1,2,3 80  81 C0 R  1  2  C0 R 2  .C0 R  1  2  CuCI  Me Sn  (33)  3  R0 C 2  3.2  Intramolecular  conjugate  83  addition of alkenyltrimethylstannane  functions  to  a,(3-alkynic esters to form bicycles  In the previous study by Piers and coworkers describing the synthesis of bicyclic systems via the copper(I)-initiated internal conjugate addition of alkenyl functions to a,P-alkynic esters,  283  two successful examples were presented in which good yields were  reported (equation 31). It was proposed to undertake a study to determine whether the reaction could be extended to include the synthesis of bicyclic ring systems of general structure 85 (equation 34). To accomplish this, the cyclizations of a series of precursors 84 were envisaged in which the chain length of the appendage, terminating with an a,(3alkynic ester moiety, and the size of the preexisting ring structure in the cyclization precursors could be varied. The result, should the copper(I)-mediated transformations of  18 R0 C  C0 R  2  2  CuCl  n K) SnMe  C0 R 3  (34)  m  n = 1,2, or 3 m = 1, 2, or 3  2  C0 R 2  85  84  84 into 85 prove to be successful, would be the synthesis of a series of bicyclic structures which incorporate 4- to 7-membered rings and various functionality to serve as a handle in future synthetic manipulations.  The configuration associated with the exocyclic  double bond in the bicycles is predicted to be trans by analogy with the previous examples of bicycle and monocycle formation (see Introduction section 3.4.1, pg. 19).  3.3 Intramolecular conjugate addition of aryltrimethylstannane functions to a,ft-alkynic esters to form bicycles incorporating an aromatic ring  As a result of the mechanistic investigations into the "copper effect" in the Stille and related  coupling protocols,  aryltrialkylstannanes to undergo (Introduction section 2.1, pg. 6).  it was  determined  that  a reversible transmetalation  it  was  possible  for  with copper(I) salts  Analogous to the conjugate addition reaction of  alkenyltrimethylstannane functions to a,(3-alkynic esters mediated by copper(I) chloride discussed previously, it was hypothesized that aryltrimethylstannanes should behave in a similar manner (i.e. copper-tin transmetalation followed by internal conjugate addition, see Introduction section 3.4.1).  To test this premise, two model systems of general  structure 86, which contain an ether linkage (X = O) or a malonate unit ( X = C(C0 R)2), 2  would be prepared and the intramolecular conjugate additions mediated by copper(I) chloride would be investigated (equation 35).  CuCl (35) X = O or C ( C 0 R ) 2  86  C0 R  2  2  87  19 Should the initial test cases to form the aromatic bicyclic compounds 87 prove to be successful, a series of cyclization precursors 88 would be tested to expand the generality and scope of the reaction (equation 36).  88  89  R = H, alkyl, or O M e  3.4 Limitations, extensions and mechanistic considerations  3.4.1 Mechanistic considerations The proposed mechanistic pathway for the conjugate addition reaction of alkenyltrimethylstannane functions to a,(3-alkynic esters was first postulated in work by Piers and Boehringer (Scheme 3).  28b  In this proposal, using the conversion of the  stannane 72 to the diene 75 as an illustrative example, an initial copper-tin transmetalation of the alkenyltrimethylstannane 72 with copper(I) chloride results in the formation of the copper(III) intermediate 91. The intermediate 91 can proceed to form, via the elimination of Me SnCl, the expected copper(I) intermediate 92. This hypothesis 3  differs slightly from the "simple" copper-tin transmetalation postulated in previous studies (see equation 5, pg. 6). Support for the formation of the copper(III) intermediate 91 was supplied by the 29  observation that, if the cyclization reaction was allowed to proceed for a relatively short period of time (7 min), a mixture (ratio -2:1, respectively, by gas-liquid chromatography) of the diene 75 and the a-trimethylstannane 90 was obtained after aqueous workup (equation 37).  When the reaction time was extended to 60 min, the diene 75 was  produced exclusively. This would suggest that two competing intramolecular conjugate additions in a cis manner  30  across the triple bond of the a,P-alkynic ester in the  intermediates 91 and 92 was taking place to form the cyclized adducts 93 and 94,  20 Me0 C> 2  f^SnMe  COoMe  2.5 equiv CuCI DMF, 0 °C  3  C0 Me 2  SnMe COoMe  C0 Me 2  72  75 7 min: 60 min:  - Me SnCI 3  "^^SnMe  Cu(SnMe )CI 3  a  C0 Me 2  90 1 (glc ratio) 0 % (isolated yield)  2 74%  II  (37) 3  II  ^ " C u + Me SnCI 3  72  92  Cu(SnMe )CI 3  - Me SnCI 3  "E  + Me SnCI 3  E = C0 Me  93  2  + CuCI  + CuCI  94  CuCI  workup (- CuCI)  E.  SnMe  3  •E  90  75  Scheme 3.  respectively (Scheme 3).  A subsequent reductive elimination of CuCI from the  intermediate 93 allows for the formation of the a-trimethylstannyl ester 90. It is then  21 reasonable to suggest that a second copper-tin transmetalation between 90 and 94 would take place which, based on the disappearance of the stannane 90 upon prolonged reaction times, would lie largely toward the alkenylcopper(I) species 94.  Eventually, the  a-copper(I) adduct 94 is formed from both cyclization pathways and, lastly, protonation of 94 upon aqueous workup provides the conjugated (.E^-diene 75.  A premature  quench of the reaction mixture would result in the isolation of the observed a-trimethylstannyl ester 87. Upon further examination of the proposed mechanism, it may be noted that copper(I) chloride is regenerated in the sequence of events leading to the formation of the a-stannyl ester 90. This led to the speculation that, under the appropriate conditions, the copper(I) chloride (or another copper(I) salt derived therefrom) may be used under catalytic conditions. For this requirement to be satisfied, the alkenylcopper(I) species 94 C0 Me 2  + Me SnCI 3  + XY  Me SnCI + 3  + CuY i  C0 Me 94  C0 Me  2  2  95  I i  t  to participate in transmetalation/ cyclization rxn  CuCl +  + XY C0 Me 2  95 Scheme 4.  and/or the a-stannyl ester 90 must be intercepted with a suitable in situ quench and, in doing so, regenerate a copper(I) salt that would be capable of participating in the transmetalation and cyclization events (Scheme 4).  In addition, for this concept to be  viable, the intramolecular cyclization process must obviously transpire at a rate faster  22 than that of the intermolecular quench. Otherwise, an undesired acyclic product arising from the premature quenching of the alkenylcopper species 91 or 92 would be produced. To examine this intriguing possibility of employing the copper(I) salt in a catalytic fashion, a variety of additives ( X Y , e.g. acetic acid) that may perform the twofold function of quenching the alkenylcopper(I) species 94 and regenerating a copper(I) salt (CuY) would be investigated (Scheme 4).  3.4.2 Intramolecular conjugate  addition of alkenyltrimethylstannane functions to  a,(3-alkynic aldehydes and a,(3-alkynic ketones Up to the present, a,(3-unsaturated ketones and a,P-alkynic esters have been the only Michael acceptors that have been examined in the Piers laboratory with respect to the intramolecular conjugate addition of alkenyltrimethylstannane functions mediated by copper(I) salts. It was of interest to ascertain whether or not other Michael acceptors that contain the carbon-carbon triple bond subunit are amenable to the cyclization protocols developed.  To explore this possibility, it was proposed that two test substrates, the  a,(3-alkynic ketone 96 and the a,(3-alkynic aldehyde 98 would be synthesized and subjected to the copper(r) salt mediated process to form the bicycles 97 and 99, respectively. The stereochemical outcome of the conjugate addition with respect to the newly formed double bond is uncertain. However, by analogy to previous studies with a,(3-alkynic esters, the E configuration of the double bond would be expected (see previous section). C0 R 2  C0 R 2  CuCI  (38)  96  O 97  23 C0 R 2  C0 R 2  CuCl  H SnMe  3  (39) H  O  98  O 99  3.5 Intermolecular oxidative homocoupling of p-trimethylstannyl a,B-unsaturated ketones mediated by copper(D chloride  Although a considerable number of examples of alkenyltrialkylstannane intermolecular couplings have been reported recently, there still remains some uncertainty as to which functional groups are tolerated by the copper(I) chloridemediated protocol.  It has been shown that a variety of P-trimethylstannyl  a,P-unsaturated ester and P-trimethylstannyl a,P-unsaturated aldehyde precursors undergo the copper(I)-induced coupling process (see Introduction section 2.2, pg. 7). However, P-trimethylstannyl a,P-unsaturated ketones had not been shown to react with copper(I) chloride to produce the corresponding homocoupled product and a short study to further explore this aspect of the reaction was to be undertaken. A series of P-trimethylstannyl a,P-unsaturated ketones of general structure 100 would be prepared and subjected to the copper(I) chloride-mediated process to produce, if successful, the corresponding highly conjugated diketones 101 (equation 40).  O  o  CuCl (40) R = H or Me n = 1 or2  n  100 101  o  24 3.6 Oxidative intramolecular couplings of bisarvltrimethvlstannanes  mediated by  copper(I) chloride  Since  several  reports  of  the  oxidative  homocoupling  reactions  of  alkenyltrialkylstannanes had appeared in the literature (see Introduction section 2.2, pg. 7), it was proposed that arylstannanes, since they should possess properties similar to those of alkenylstannanes, should undergo similar homocoupling processes mediated by copper(I) chloride.  Indeed, concurrent with this work, the mteraiolecular oxidative  coupling of aryltrimethylstannanes was discovered.  31  In one example of this process, it  was found that treatment of trimethylstannylbenzene (102) with 2.5 equiv of copper(I) chloride in D M F resulted in the isolation of biphenyl (103) in good yield (68%). s b  n  M M  6  CuCI (2.5 equiv) DMF, rt, 1.5 h  3  (41)  68%  103 It was proposed in collaboration with Dr. Patricia Gladstone, a postdoctoral research fellow in Dr. Piers' laboratory, that the copper(I)-mediated intramolecular coupling of bisaryltrimethylstannane functions may offer a viable synthetic route to 5-, 6-, and 7-membered ring compounds. bisaryltrimethylstannanes  104,  To test the proposed methodology, a series of  106,  and  108,  in  which  each  of  the  two  aryltrimethylstannane functions in the precursors are connected together via an ether linkage, would be subjected to the oxidative copper(I) chloride-mediated coupling protocol (equations 42, 43, and 44).  SnMe  3  -CL  104  SnMe  3  CuCI  (42)  25  CuCl SnMe  (43)  3  CuCl  SnMe  SnMe  3  (44)  3  109  108  If the synthesis of the seven membered ring 109 proved to be successful, it was proposed that the methodology would then be extended to encompass the synthesis of the carbocyclic ring structures of general structure 111 (equation 45).  The scope of the  reaction would be explored by the addition of substituents (alkyl or methoxy) located on each of the aromatic rings.  (45) SnMe  3  R  H H  R  R = H, Alkyl, o r O M e Lastly,  an  example  involving  a  "mixed"  alkenyltrimethylstannane coupling would be attempted.  aryltrimethylstannane  and  It was envisaged that the  distannane 112 would be transformed into the tricycle 113 upon treatment with copper(I) chloride (equation 46). E  CuCl  E  (46)  E = C0 Et 2  SnMe  3  112  SnMe  3  113  26 3.7 Intramolecular oxidative coupling of bisalkenyltrimethylstannanes to produce 9- and 10-membered rings  With the successful development of the intramolecular oxidative coupling protocol of bisalkenyltrialkylstannane functions to form 4- to 8-membered rings, it 9  seemed only logical to extend the scope of the copper(I)-mediated reaction to include the formation of 9- and 10-membered carbocycles.  With this in mind, the substrates of  general structure 114, which incorporate two alkenyltrimethylstannane moieties, would be subjected to the copper(I)-mediated coupling process to form the medium ring bicycles 115 (equation 47). The configuration of the exocyclic diene in the final products 115 is likely to be E based on the analogous stereo specific intermolecular coupling of alkenyltrialkylstannanes (see Introduction section 2.2, pg. 7).  (47) R  E = C0 Et R= H,C0 Me, or C H 0 - A l k y l n = 1 or 2 2  114  2  2  R  115  27  II. RESULTS AND DISCUSSION  1.  Intramolecular conjugate additions of alkenyl- and aryltrimethylstannane  functions to a.B-alkynic Michael acceptors mediated by copper(I) salts 1.1 Introductory remarks  In this study, we desired a synthetic pathway to the substrates necessary for the cyclization studies that was easily adaptable to future changes. With this in mind, it was envisaged that the a,(3-alkynic ester functionality would be installed, in each case, at the end of the synthesis. In this manner, we could take advantage of the ability to easily change the pendant Michael acceptor and assess its potential in the methodology. For example, in the synthesis of the substrates of general structure 116, a deconjugationalkylation strategy involving cyclic P-trimethylstannyl a,(3-unsaturated esters would be 32  employed and is shown in the brief retro synthesis in Scheme 5. With access to esters 117 with different ring sizes and acyclic alkylating agents 117a, the capacity to rapidly R0 C 2  n  SnMe 116  R  SnMe 116a  3  R = ester, ketone,  TBS 3  C0 R  •TBS  2  + SnMe  Br-  3  117a  Scheme 5. synthesize an assortment of alkenyltrimethylstannane precursors 117 and to assess the flexibility of the cyclization methodology is readily apparent. Through various functional  28 group manipulations, the alkyne termini contained in 116a can be altered to synthesize not only a,(3-alkynic esters but also a,|3-alkynic ketones and a,(3-alkynic aldehydes for investigations into the limitations and extensions of the copper(I)-mediated methodology. Concise syntheses of the aryltrimethylstananne precursors 118 and 119 employing malonate alkylations and Williamson etherifications were planned as shown in the retro synthetic pathways  summarized in Scheme 6.  The series  0-trimethylstannylbenzyl  alcohols  suitable  123  and,  by  a  of  substituted  functional  group  interconversion, the o-trimethylstannylbenzyl bromides 121 can be accessed by use of directed ortho-metalation  33  (DoM) of the benzyl alcohols 124.  The  malonate  dialkylation, ether formation, and D o M reactions together impart to the overall synthetic pathway a great deal of flexibility. SnMe  SnMe  3  3  C0 Me 2  119 Scheme 6.  29 1.2 Intramolecular conjugate additions to form monocvcles  1.2.1 Preparation of acyclic cyclization precursors The synthesis of the cyclization precursor 129 (Scheme 7) began with the Swern oxidation  of  34  4-trimethylstannylpent-4-en-l-ol  (125)  35  to  the  corresponding  aldehyde 126 with oxalyl chloride, D M S O , and txiethylarnine in methylene chloride. Because the acquired aldehyde 126 was found to be quite unstable (significant decomposition of the material was observed after several hours at room temperature), the crude product of the oxidation reaction was immediately subjected to the two-step onecarbon homologation protocol developed by Corey and Fuchs.  36  Thus, treatment of the  crude aldehyde 125 with carbon tetrabromide and triphenylphosphine in methylene chloride afforded the dibromoolefin 127 in excellent overall yield (90%) from the alcohol 125. Me Sn 3  Swern oxidation  OH  O Me Sn 3  125  H  126  1) LDA, T H F 2) C I C 0 E t 2  X0 Et 2  129 Scheme 7.  The proposed structure of the dibromoolefin 127 was confirmed by the spectroscopic data. For example, the IR spectrum of 127 showed a tin-methyl rocking absorption at 770 cm" . 1  The H nmr spectrum indicated the presence l  of a  30 trimethylstannyl function as a 9 proton singlet located at 8 0.14, with satellite peaks (/ = 52.0 Hz) arising from tin-proton coupling, three alkenyl protons (a one proton singlet at 8 5.19,  3  /  S n  -H  = 69.4 Hz, a one proton singlet at 8 5.67, / s - H = 148.0 Hz, and a one 3  n  proton triplet at 8 6.45, / = 7.0 Hz), and two methylene groups (a 2 proton multiplet at 8 2.12-2.20 and a 2 proton triplet at 8 2.35, / = 7.6 Hz, spectrum contained the expected 7 signals.  3  / n-H S  = 69.4 Hz). The  1 3  C nmr  A high resolution mass spectrometric  measurement on the (M -Me) fragment confirmed the molecular formula of 127. +  Conversion of the dibromoalkene 127 to the alkyne 128 was accomplished by the treatment of 127 with crushed magnesium metal in refluxing THF, a protocol developed by Hijfte and coworkers  3 7  Because the resultant alkyne 128 was found to be volatile and  also produced an extremely sharp noxious odour, it was decided that the product, after purification by flash column chromatography on silica gel, would be immediately converted to the alkynoate 129 without characterization. A modified literature acylation procedure, employing Uthium diisopropylamide (LDA) and ethyl chloroformate, served 38  to convert 128 to ethyl 6-trimethylstannylhept-6-en-2-ynoate (129). The overall yield of the two-step process was 79% from the dibromoalkene 127. The structure of ethyl 6-trimethylstannylhept-6-en-2-ynoate (129) was confirmed by an analysis of the spectroscopic (*H nmr, C nmr, and IR) data. The *H nmr spectrum 1 3  indicated the presence of a Me Sn function as a 9 proton singlet located at 8 0.14 with 3  satellite peaks (/ = 53.1 Hz), two methylene groups (a 2 proton triplet at 8 2.40, / = 7.5 Hz, and a 2 proton triplet at 8 2.52, / = 7.5 Hz, 7 - H = 50.7 Hz), and the ethyl ester 3  Sn  function (a 3 proton triplet at 8 1.28, / = 7.2 Hz, and a 2 proton quartet at 8 4.20, / = 7.2 Hz). The  1 3  C nmr spectrum contained the expected 10 signals. In the IR spectrum,  the presence of the alkyne function was indicated by the absorption at 2236 cm" and the 1  carbonyl function was shown by the absorption at 1713 cm" . In addition, the molecular 1  formula of 129 was confirmed by a high resolution mass spectrometric measurement on the (M -Me) fragment. +  In a reaction sequence analogous to that employed to synthesize the stannane 129, as described above, the cyclization precursor 131 was synthesized in four steps from 5-trimethylstannylhex-5-en-l-ol (130) in an overall yield of 72% (equation 48). The 35  structure of 129 was confirmed by analyses of the K nmr, l  1 3  C nmr, and IR spectra.  31 Notable in the *H nmr spectrum were the signals due to the Me Sn function (a 9 proton 3  singlet at 8 0.12,  2  / s n - H  = 52.6 Hz), three methylene groups (a 2 proton multiplet centred  at 8 1.65, a 2 proton triplet at 8 2.28, / = 7.1 Hz, and a 2 proton triplet at 8 2.35, J = 7.6 Hz,  3  /S„-H  =  63.9 Hz), and two alkenyl protons (a 1 proton multiplet at 8 5.15-5.20,  Jsn-H = 70.4 Hz, and a 1 proton multiplet at 8 5.65-5.70, Jsn-a = 150.0 Hz). In addition, the  1 3  C nmr spectrum displayed the expected 11 signals. The molecular formula of 131  was confirmed by a high resolution mass spectrometric measurement on the (M -Me) +  fragment. 1) Swern oxidation Me Sn 3  (48)  C0 Et 2  A n alternative synthetic route to prepare the stannane 131 is illustrated in Scheme 8. Monosilylation of commercially available 1,6-heptadiyne (132) was achieved by treatment of this material with methyllithium (MeLi) in T H F at -20 °C, followed by quenching the resultant hthium acetylide with ^-butyldimethylsilyl chloride (TBSC1). 1) MeLi, T H F 2) TBSCI TBS  133  |Me SnCu-Me S, •THF, MeOH 3  Me Sn  TBAF Me Sn  3  3  1) LDA, T H F „ 2) C I C 0 E t 2  131 Scheme 8.  2  32 The acquired TBS-capped acetylene 133 was converted to the alkenyltrimethylstannane 10  134 by the treatment of 133 with the organocopper reagent Me SnCu-Me2S in T H F in 35  3  the presence of methanol. As a result of the extreme difficulty in separating the starting material 133 from the stannane 134 by column chromatography, the mixture of 133 and 134, obtained after flash column chromatography of the crude product on silica gel, was treated with with tetrabutylammonium fluoride (TBAF) in THF. The resultant mixture 39  of 132 and 135 could be separated by chromatography on silica gel. To complete the synthetic sequence, acylation of the terminal alkyne function of 135 by sequential 38  treatment with L D A and ethyl chloroformate provided 131 in a four-step overall yield of 20% from the diyne 132. The material obtained by this synthetic route was found to be spectroscopically identical with the material synthesized previously (vide supra). A route essentially identical with that shown in Scheme 8 was employed to synthesize the six-membered ring cyclization precursor 137 in four steps from commercially available octa-l,7-diyne (136) with an overall yield of 28% (equation 49). The proposed structure of ethyl 8-trimethylstannnylnon-8-en-2-ynoate supported by spectroscopic data.  (137) was  For example, the *H nmr spectrum of 137 showed  resonances corresponding to the Me Sn function, four methylene groups, two alkenyl 3  protons, and the ethyl ester moiety. The  1 3  C nmr spectrum displayed the expected 12  signals and a high resolution mass spectrometric measurement on the (M -Me) fragment +  confirmed the molecular formula of C M ^ C ^ S n . 1) MeLi; TBSCI 2) Me SnCu-Me2S, MeOH Me Sn 3  3  3) T B A F 4) LDA; C I C 0 E t  136  2  137  Methyl 4-bromobut-2-ynoate (140) was required for the projected synthesis of the cyclization precursor 143 (Scheme 10). The former substance was prepared in two steps from commercially available tetrahydro-2-(2-propynyloxy)-2/7-pyran (138) (Scheme 9). Sequential treatment of 138 with B u L i and methyl chloroformate  38  in T H F at -78 °C  provided the a,(3-alkynic ester 139 in an excellent yield (99%). Following a modified literature procedure, the tetrahydropyranyl ether function in 139 was converted directly 40  to the bromide by treatment of this material with triphenylphosphine dibromide in  33 methylene chloride.  The required alkylating agent 140 was obtained in very good  yield (87%). •j  1) BuLi, T H F , - 7 8 °C 2)CIC0 Me 2  THPCX  -C0 Me 2  THPCX  138  139 PPh , Br , , CH CI 3  1  2  2  2  C0 Me 2  140 Scheme 9.  The identity of the bromide 140 was confirmed by an analysis of the spectroscopic data. The presence of the alkyne moiety was indicated by the C-C triple bond stretch in the IR spectrum at 2245 cm" , the bromide function by the C-Br stretching 1  absorption located at 625 cm" , and the carbonyl group was shown by the absorption at 1  1718 cm" . In the *H nmr spectrum, signals for the methylene group (a 2 proton singlet at 1  8 3.93), and the methyl ester function (a 3 proton singlet at 8 3.77) were present. In addition, the expected 5 signals were present in the  1 3  C nmr spectrum  Lastly, the  molecular formula of CsHsC^Br was confirmed by a high resolution mass measurement on the molecular ion. With the bromide 140 in hand, the cyclization precursor 143 could readily be prepared from ethyl (Z)-3-trimethylstannylbut-2-enoate (141).  41  The latter material was  prepared by reaction of ethyl but-2-ynoate with lithium trimethylstannyl(cyano)cuprate according  to  a  literature  procedure.  38  Treatment  32  of  141  with  L D A and  hexamethylphosphoramide (HMPA) in THF, followed by quenching the resulting enolate anion 142 with the bromide 140, afforded, after an aqueous work-up, a mixture of 143 and a substantial amount of a brown, intractable material. Flash chromatography of this material afforded 143 in moderate yield (58%). Nevertheless, sufficient quantities for use in this study were prepared in this fashion.  34 LDA, H M P A  Et0 C. 2  THF,  -78  °C  v  u  2 t t  • Me Sn3  Me Sn  CH  3  3  141  C0 Me 2  140 C0 Et  .C0 Me  2  2  Me Sn 3  143  Scheme 10. The proposed structure of methyl 5-ethoxycarbonyl-6-trimethylstarrriylhept-6-en2-ynoate (143) formed from the deconjugation-alkylation reaction was confirmed by the spectroscopic ( H nmr, l  1 3  C nmr, and IR) data.  For instance, in the IR spectrum, the  presence of the alkyne moiety was indicated by the C-C triple bond absorption located at 2241 cm" , the carbonyl functions by the strong absorption band located at 1718 cm" , and 1  1  the Me Sn moiety by the absorption at 773 cm" . Notable in the H nmr spectrum were 1  X  3  the resonances ascribed to the Me Sn function (a 9 proton singlet at 8 0.11, / s - H = 2  3  n  52.9 Hz), the methine proton (a 1 proton triplet at 8 3.43, / = 7.5 Hz,  3  /  S n  -H  = 58.2 Hz), a  set of diastereotopic methylene protons (a 1 proton doublet of doublets at 8 2.51, J - 7.5, 17.2 Hz, mutually coupled to a 1 proton doublet of doublets at 8 2.88, J = 7.5, 17.2 Hz), and two vinylic protons (two 1 proton multiplets centred at 8 5.40 and 8 5.83). 1 3  C nmr spectrum contained the 12 resonances expected for 143.  The  Lastly, a high  resolution mass measurement on the (M -Me) fragment confirmed the molecular formula +  of the stannane 143. Having completed the syntheses of the desired cyclization precursors 129, 131, 137, and 143, we could now investigate the copper(I)-mediated conjugate addition processes.  35 1.2.2 Copper(I) chloride-mediated cyclizations To begin the study, ethyl 6-trimethylstannylliept-6-en-2-ynoate subjected to a reaction protocol developed previously for the  (129)  was  copper(I)-mediated  cyclization of alkenyltrimethylstannane functions to a,f3-alkynic esters  28  (Table 2,  entry 1). After treatment of 129 with 2.5 equiv of copper(I) chloride in dry D M F at 0 °C for 15 min, quenching the dark red reaction mixture with aqueous ammonium chlorideammonia, and subsequent purification of the crude product by flash column chromatography, the cyclobutane derivative 144 was obtained in a modest yield (64%). Not unexpectedly (see Introduction section 3.4.2, pg. 22), the major side product in the reaction was determined to be the a-trimethylstannyl ester 145 in an isolated yield of 18%.  In addition, by thin layer chromatographic (tic) analysis, uncharacterized polar  material was detected in the crude reaction mixture. C0 Et 2  CuCl C 0 E t (2.5 equiv)  C0 Et 2  X— S n M e  3  2  Me Sn 3  DMF, 0°C, 15 min 129  (50) H 144  H 145  Table 2. Synthesis of the dienes 144 and 145 Entry  Reaction Conditions  3  % Yield  b  % Yield  144  145  1  CuCl (2.5 equiv), D M F , 0 °C, 15 min  64  18  2  CuCl (2.5 equiv), D M F , 0 °C, 1 h  60  6  3  CuCl (2.5 equiv), D M F , 0 °C, 15 min, then 1 M HC1  77  0  4  CuCl (2.5 equiv), A c O H (5 equiv), D M F , 0 °C, 15 min  85  0  b  (pH 8) was used in the workup in each case. Isolated yield of purified products.  NH4CI-NH3  The proposed structure of the diene 144 was confirmed by the spectral ( H nmr, X  13  C nmr, and IR) data. In the IR spectrum of 144, the carbonyl function was indicated by  the absorption located at 1713 cm" . In the *H nmr spectrum, resonances due to two 1  methylene groups (a 2 proton multiplet centred at 8 2.73 and a 2 proton triplet of doublets  36 at 8 3.02, / = 8.0, 2.5 Hz), three alkenyl proton signals (a 1 proton singlet at 8 4.94, a 1 proton multiplet centred at 8 5.38, and a 1 proton multiplet centred at 8 5.87), and the ethyl ester function (a 3 proton triplet at 8 1.26, / = 7.1 Hz, and a 2 proton quartet at 8 4.15, / = 7.1 Hz) were present. In addition, the (^-configuration of the newly formed a,(3-unsaturated ester function in 144 was confirmed by suitable nuclear Overhauser enhancement difference (nOed) experiments.  42  Thus, irradiation of the resonance  attributable to the olefinic methine proton, located at 8 5.87, resulted in an enhancement in the resonance due to the proximal vinylic proton at 8 5.38. Confinriing the results from the first nOed experiment, the reverse nOe enhancement was also observed. The remainder of the nOed experiments carried out on 144 are summarized in Figure 3. In the  1 3  C nmr spectrum, the expected 13 resonances were shown and, in an A P T  experiment, two negative signals at 8 14.3 and 108.3 could be attributed to the trimethylstannyl group and the lone sp methine carbon, respectively. 2  The molecular  formula of 144 was confirmed with a H R M S measurement on the molecular ion.  8 4.88 145  144 Figure 3. NOed experiments on 144 and 145  The constitution and configuration of the minor product 145 was determined with various spectroscopic aids. In the IR spectrum, the carbonyl function was shown by the absorption at 1699 cm" and the presence of the trimethylstannyl function was indicated 1  by the tin-methyl rocking absorption located at 772 cm" . The H nmr spectrum exhibited 1  X  signals due to the presence of the Me Sn moiety (a 9 proton singlet at 8 0.25, 3  3  / s n - H  =  56.2 Hz), two methylene groups (a 2 proton multiplet centred at 8 2.62 and a 2 proton multiplet centred at 8 2.95), two alkenyl protons (a 1 proton singlet at 8 4.88 and a 1 proton triplet at 8 5.18, / = 2.7 Hz), and the ethyl ester function (a 3 proton triplet at  37 8 1.26, J =1.1 Hz and a 2 proton quartet at 8 4.14, / =7.1 Hz). A nOed experiment, in which irradiation of the signal located at 8 5.18 enhanced the resonances attributable to the gerninal proton at 8 4.88 and the Me Sn group, determined the (Z)-configuration of 3  the exocyclic tetrasubstituted double bond. The corresponding reverse nOed effects were also observed (Figure 3).  Lastly, a H R M S measurement on the (M -Me) fragment +  confirmed the molecular formula of 145. It was found that increasing the duration of the reaction from 15 min to 1 h (Table 2, entry 2), a modification shown in previous studies to eliminate related a-stannylated  side  products,  successfully  28b  reduced  the  production  of  the  a-trimethylstannyl ester 145 to 6% but, unfortunately, simutaneously diminished the yield of the desired cyclized product 144 to 60%. In addition, tic analyses showed that a considerable amount of polar material was present in the crude product. It appeared that by allowing the reaction to proceed for extended periods of time, competitive decomposition of reaction intermediates and/or reaction products was occurring in the reaction mixture. This poor outcome forced us to abandon this strategy. It was surmised that a successful reaction protocol would require a suitable quenching agent and, furthermore, it was our belief that a proton source more acidic than the aqueous ammonium chloride-ammonia (pH 8) employed in the workup would be required to protiodestannylate the a-trimethylstannyl ester 145 formed in the reaction pathway (Scheme 11). This notion was supported by related work in our laboratory which had shown that the a-trimethylstannyl function of alkyl (Z)- and (E)-2,3bis(trimethylstannyl)-2-alkenoates 146, 147, and 149 can be selectively removed by hydrochloric acid-mediated  and copper(I)  (equations 51 and 52, respectively). R  1  W  Me Sn 3  protiodestannylations  43  C0 R  R  SnMe  Me Sn  2  SnMe  1  W  3  chloride-catalyzed  C0 R  3  146  3  H  r  i  D  H  M  R  n  F  2  1  Me Sn  Me Sn  /  \  3  149  2  R  SnMe  2  148  CuCI, H 0  R"  2  3  (51) C0 R  3  147 R * p 0  W  H  DMF  C0 R  v  M e s S {  (  2  ) = \  (52) H  150  38 Indeed, the presence of the undesired stannane 145 was completely curtailed with a simultaneous increase in the isolated yield of 144 to a satisfactory 77% when aqueous 1 M H Q was added after the reaction had been allowed to proceed for 15 min (Table 2, entry 3).  The hydrochloric acid appeared to serve well in the capacity to  protiodestannylate the a-trimethylstannyl ester 145 and to quench the a-copper(I) intermediate 151 (Scheme 11). This alternative protiodestarmylation/quenching strategy led to the development of an experimental protocol employing the use of an in situ proton source (acetic acid) in the reaction pot (see Discussion section 1.5.1, pg. 64, for additional details). C0 Et  C0 Et  2  ,C0 Et 2  129a  Jr-S  2  nMe  Cu  3  151  145 HCI C0 Et 2  +  CuCl or Me SnCI 3  144 Scheme 11. A n excellent yield (85%) of (£)-l-ethoxycarbonylmethylidene-2-methylidene cyclobutane (144) was obtained when the alkenyltrimethylstannane 129 was treated with 2.5 equiv of CuCl and 5 equiv of acetic acid at 0 °C in dry D M F for 15 min (Table 2, entry 4). More satisfyingly, no other detectable products, including the geometric isomer of 144, were seen by tic or *H nmr analysis of the crude reaction mixtures. It is clear from this result that the intramolecular cyclization process is faster  than the  intermolecular quench of the acyclic species 129a by acetic acid. Motivated by these key observations and by having prepared the cyclobutane derivative 144 in a very satisfactory yield, it was decided to test the next cyclization precursor in the study.  39 Surprisingly, when the 5 membered ring precursor 131 was subjected to the initially employed reaction conditions (Table 2, entry 1), the reaction failed. Tic analyses of the crude product after aqueous workup showed the presence of only minor amounts of the product 153 (Scheme 12) and a great deal of colored polar material (equation 53). CuCI complex mixture  C0 B 2  131  (53)  ™F 15 min  The polar material, containing several compounds by tic analysis, was isolated as one fraction after flash column chromatography of the crude product. However, a *H nmr spectrum of the acquired mixture did not provide any useful information to identify the products formed. To further complicate matters, the isolated traces of the desired product 153 proved to be unstable and polymerized upon standing in a freeezer over a period of a couple  of  days.  However,  the  slow  rate  at  which  the  product  153  decomposed/polymerized did not account for the low yield of 153 nor for the formation of large amounts of yellow polar material during the relatively short reaction times (15 min). The attempted conversion of 131 into 153 under these reaction conditions was not investigated further. Gratifyingly, when the modified reaction conditions (Table 2, entry 4) with acetic acid present in the reaction mixture were employed, the desired cyclized product 153 was formed in -80% yield (Scheme 12). Apparently, the increase in the efficiency of the transformation was due to the relatively rapid protonation of the intermediate copper(I) species 152 by the acetic acid, thus precluding extensive decomposition of this intermediate.  However, as mentioned previously, the diene 153 was prone to  polymerization/decomposition and a suitable analytical sample could not be obtained. In the hopes of obtaining a stable derivative for characterization purposes, it was decided to reduce 153 to the corresponding alcohol. Treatment of the crude product of the cyclization process with dnsobutylaluminum hydride (DIBAL) in T H F yielded the 44  allylic alcohol 154. Disappointingly, this product also proved to be unstable and polymerized over several days to give a hard, plastic-like substance.  Not to be  discouraged, a stable derivative which could be stored for extended periods of time was  40 obtained by conversion of the alcohol 154 into the TBS ether 155. Thus, treatment of 154 with TBSC1  39  in the presence of imidazole formed the ether 155 in excellent overall  yield (84%) from the stannane 131 (Scheme 12). CuCl (2.5 equiv) A c O H (5 equiv)  Me Sn 3  DMF, 0 °C, 15 min  C0 Et 2  131  OTBS  152  JBSC^ imidazole CHpClp  DIBAL, T H F -78 °C-> 0°C  155  154  153  Scheme 12.  The structure of the TBS ether 155 was corrfirmed by an analysis of spectrometric data. Notable in the IR spectrum was the presence of a C-C double bond stretching absorption at 1628 cm" . In the H nmr spectrum, resonances due to four methylene 1  X  groups (a 2 proton multiplet at 8 1.60-1.75, a 4 proton multiplet at 8 2.30-2.42, and a 2 proton doublet at 8 4.25, / = 6.2 Hz), three alkenyl protons (two 1 proton singlets at 8 4.82 and 5.27 and a 1 proton multiplet centred at 8 5.90), and the ^-butyldimethylsilyl ether moiety (a 6 proton singlet at 8 0.06 and a 9 proton singlet at 8 0.89) were seen. In addition, the  1 3  C nmr spectrum of 155 displayed the expected 11 signals and the  molecular formula of Ci4H 60Si was confirmed by a high resolution mass spectrometric 2  measurement on the molecular ion. The (£)-configuration of the exocyclic double bond was confirmed by a series of nOed experiments which are summarized in Figure 4. Serving as additional confirmation to the nOe effects already gathered, a negative or "relay" nOe was also observed as illustrated below. 45  41  The superiority of the modified cyclization procedure, employing acetic acid, to form a 6-membered ring was exemplified in the conversion of the precursor 137 to the cyclic diene 156 (equation 54). It was found that treatment of the stannane 137 under "standard" conditions (2.5 equiv CuCl, 5 equiv AcOH, D M F , 0 °C, 15 min) resulted in CuCl (2.5 equiv), 0  Me Sn  _Et *  A  c  0  H  (  5 e c  l  u i v  )'  DMF, 0 °C, 15 min  C0 Et 2  ^ J r^^T  3  (54)  —  137  156 C0 Et 2  157 the formation of 156 in an excellent isolated yield (87%). In stark contrast, subjection of 137 to the experimental conditions that did not employ acetic acid in the reaction pot resulted in a 48% isolated yield of the a-trimethylstannyl ester 157 and an inseparable  42 mixture of the cyclized product 156 and the starting material 137 in a -1:1 ratio (equation 55). The structural assignment for 156 was fully supported by the spectroscopic data collected. For example, the ER spectrum clearly showed the C=C bond stretch due to the exocyclic methylene at 1636 cm" and the carbonyl absorption at 1714 cm" . Notable in 1  1  the H nmr spectrum were the signals for three alkenyl protons (three 1 proton multiplets X  centred at 8 4.70, 5.03, and 5.83), and four methylene groups (a 4 proton multiplet at 8 1.60-1.75, and two 2 proton broad unresolved multiplets at 8 2.30 and 2.60).  The  molecular formula of 156 was confirmed by a high resolution mass measurement on the molecular ion. Finally, the (£)-configuration of the trisubstituted olefin bearing the ethyl ester function was confirmed by a series of nOed experiments summarized in Figure 5.  8 4.78  8 4.72  156  157  Figure 5. NOed experiments on 156 and 157  The constitution and configuration of the minor product 157 was confirmed by the spectrometric data ( H nmr and ER). J  The ER spectrum showed the presence of the  trimethylstannyl function by the absorption at 774 cm" and the alkenyl functions by the 1  stretching absorptions at 1604 and 1635 cm" . 1  The H nmr spectrum displayed :  resonances due to the trimethylstannyl function (a 9 proton singlet at 8 0.14,  2  / s n - H  =  53.1 Hz), four methylene groups (two 2 proton multiplets centred at 8 2.41 and 2.25 and a four proton multiplet centred at 8 1.67), and two alkenyl signals (two 1 proton multiplets centred at 8 4.79 and 4.72). The molecular formula of 157 was confirmed by a H R M S measurement on the (M -Me) fragment. +  The (Z)-configuration of the double bond was  confirmed by a series of nOed experiments summarized in Figure 5.  43 Lastly, the acyclic precursor 143 was subjected to the copper(I)-mediated cyclization protocol without the addition of the acetic acid.  Disappointingly, after  purification of the crude product by flash column chromatography on silica gel, a moderate yield (52%) of 158 was obtained. However, upon switching to the modified reaction conditions employing 5 equiv of acetic acid (equation 56), the yield of 158 improved to 85%.  Also isolated was a very minor amount (-5%) of unidentifed  protiodestannylated starting material.  Me Sn.  ™ I  r2  ™  M 2  A  3  C0 Me j A 2  ( - equiv), (5 equiv), DMF, 0 °C, 15 min  C  u  c  C  0  I  2  5  H  (56) Et0 C 2  143  158  The spectroscopic data collected fully support the proposed structure of 158. In the IR spectrum, the carbonyl stretching absorption band at 1734 cm" and the C=C 1  double bond stretch at 1665 cm" could be seen clearly. The H nmr spectrum showed 1  :  signals due to the methylene protons (a 1 proton doublet of doublets at 8 3.22, / = 2.5, 18.1 Hz, mutually coupled to a 1 proton doublet of doublets at 8 3.38, / = 2.8, 18.1 Hz), the cyclobutane methine proton (a 1 proton multiplet centred at 8 3.80), and the three alkenyl protons (a 1 proton singlet at 8 5.25, a 1 proton doublet at 8 5.50, J = 2.5 Hz, and a 1 proton doublet of doublets at 8 5.92, / = 2.5, 2.5 Hz). By a series of nOed experiments summarized in Figure 6, the trisubstituted double bond in the diester 158 was determined to possess an (^-configuration. C0 Me 2  I*.  8 5.50  Et0 C 2  158 Figure 6. NOed experiments on 158  8 5.92  44 The positive impact of the new protocol developed for the cyclization of alkenyltrimethylstannane functions to a,P-alkynic esters can be seen clearly in the increased efficiency of the transformations, especially in the conversion of 143 to 158 and 137 to 156.  These impressive results to form the stereodefined 4-, 5-, and  6-membered ring compounds 144 and 158, 153, and 156, respectively, prompted us to apply this vastly improved protocol (2.5 equiv CuCI, 5 equiv A c O H , D M F , 0 °C, 15 min) in future studies relating to the intramolecular conjugate addition of alkenyl- and aryltrimethylstannane functions to a,(3-alkynic esters.  A discussion of a mechanistic  pathway somewhat modified from that proposed previously can be found in Discussion 28  section 1.5.1.  1.3 Intramolecular cyclizations to form bicyclic compounds  1.3.1 Preparation of cyclization precursors In order to prepare a series of bicyclic cyclization precursors of general structure 116b, we required the alkylating agents 140, 159, and 160-162 and the cyclic (3-trimethylstannyl a,P-unsaturated esters 163-165. Collectively, these substances could  R0 C 2  140  nK) SnMe  C0 Me 2  160 n = 1 161 n = 2 162 n = 3  3  116b  163 n = 1, R = Me 164 n = 2, R = Et 165 n = 3, R = Me Chart 1.  45 be employed in a number of deconjugation-alkylation reactions.  Of the electrophiles  shown in Chart 1, the preparation of the propargylic bromide 140 was described in section 1.2.1. The remaining compounds were prepared as described below. Each of the bromides 160-162 were synthesized as illustrated in Scheme 13. Silylation of the terminal alkynes 166-168 was, in each case, achieved by reaction of 46  the substrate with M e L i in THF, followed by quenching the resultant Uthium acetylide with  TBSC1.  10  Reaction  of each  of the resultant  169-171 with  products  triphenylphosphine dibromide in methylene chloride as described by Sonnet,  40  effected  the conversion of the THPO function into the corresponding bromide. Thus, the bromides 160-162 were formed in two step yields of 70%, 55%, and 53% from the alkynes 166168, respectively. The spectral data (*H nmr,  1 3  C nmr, and IR) obtained from the silyl  ethers 169-171 and the bromides 160-162 were fully consistent with their assigned structures  and their  molecular formulae  were  confirmed  by suitable  HRMS  measurements. H 1) MeLi, T H P O o ^ ^ THF ^ ' n 2)TBSCI |  ,T*S  T  H  P  Q . r  166n = 1 167 n =2 168 n = 3  y  ^ r " '  ^ n  C H 2 C  ^  2  2 T  B  r  ^ r)  T  B  S  ^  n  169n = 1 170 n = 2 171 n = 3  160 n = 1 161 n = 2 162 n = 3  Scheme 13. The iodide 159 was prepared from the known alkynoate 172 by a standard 47  removal of the THP group with pyridinium /?-toluenesufonate (PPTS) in methanol,  46  followed by treatment of the resultant alcohol with triphenylphosphine diiodide and imidazole.  48  The overall yield of 159 was 79%.  The iodide 159 exhibited spectral  characteristics identical with those reported previously. -C0 Me 2  THPO.  1  )  p  p  T  S  i  M  e  0  47  COoMe  H  (57)  2) P P h - l , Imid 3  2  172  173X = OH 159 X = I  Reaction of each of the enol triflates 174, (trimethylstannyl)(cyano)cuprate  38  in  THF  28b  • 28b <10 175, and 176 with Uthium  provided  Z8b  1U  the  known  cyclic  46 alkenyltrimethylstannanes  163-165 in isolated yields of 92%, 93%, and 76%,  49  respectively (equation 58). The spectroscopic data derived from the esters 163-164  28b  and 165 were in full accord with those previously reported. 10  Li[(Me Sn)(CN)Cu] THF 3  OTf  „«oc  C0 R 2  (58)  SnMe 163 n = 1, R = Me 164 n = 2, R = Et 165 n = 3, R = Me 3  174 n = 1, R = Me 175 n = 2, R = Et 176 n = 3, R = Me  The cyclization precursors 178-180, 182, and 184 were prepared as shown in Scheme 14 and in Table 3, entries 1-3, 5, and 7. The deconjugation-alkylation of the 32  esters 163-165 with L D A and H M P A (or DMPU) in THF, followed by quenching the derived enolate with the appropriate bromide 160, 161, or 162, provided the alkylated substances 115. The silyl functions in 116a were removed with T B A F in THF to give the terminal alkynes 177 and, lastly, the terminal ester function was installed by the sequential treatment of the alkynes 177 with L D A and methyl chloroformate to provide the cyclization precursors 178-180, 182, and 184. The moderate three step overall R0 C  C0 R  2  2  1) LDA, H M P A or D M P U , T H F  ,«) S  n  M  e  3  TBS  2) 160,161, or 162 n = 1 or 3, R = Me n = 2, R = Et  163-165  TBAF  11) LDA, T H F  SnMe 178-180 182, 184  C0 Me 2  2)CIC0 Me 2  3  Scheme 14. yields (33%, 35%) of 179 and 182 (Table 3, entries 2 and 5) were mainly due to difficulties arising from the elimination of HBr from the homopropargylic bromide 161 in  47 the deconjugation-alkylation step. On the other hand, for reasons which are not readily apparent, alkylation of the alkenylstannane 165 with the bromide 162 was also an inefficient process (-35%, see Experimental pg. 160) and, as a result, the overall yield of 184 from 165 was only 22% (Table 3, entry 7).  Despite these problems, sufficient  quantities of the cyclization precursors to test the proposed methodology were prepared in this manner. Lastly, treatment of ethyl 2-trimethylstannylcyclohex- 1-enecarboxylate (164) with L D A and D M P U , followed by the addition of the propargylic bromide 140 or the primary alkyl iodide 159, supplied the expected alkylated substances 181 and 183, respectively (equation 59 and Table 3, entries 4 and 6).  Et0 C 2  1) LDA, DMPU, T H F 'SnMe, 2) 140 or 159  (59)  SnMe 181,183  C0 Me 2  3  164 Table 3. Synthesis of the cyclization precursors 178-184  a  b  0  Entry  Substrate  n  m  Product  Procedure  1  163  1  1  178  A  55  2  163  1  2  179  A  33  3  163  1  3  180  A  65  4  164  2  1  181  B  51  5  164  2  2  182  A  35  6  164  2  3  183  B  58  7  165  3  3  184  A  22  3  % Yield  b  c  c  Procedure A - following the reaction sequence illustrated in Scheme 14. Procedure B - following the reaction sequence illustrated in equation 59. Isolated (overall) yields of purified products from the substrates 163-165. Elimination of the homopropargylic bromide alkylating agents was a major side reaction in the deconjugation-alkylation step. In each case, the spectral data collected for the diesters 178-184 were in full  accord with their assigned structures. Using methyl 5-(l-methoxycarbonyl-2-trimethyl stannylcyclopent-2-en-l-yl)pent-2-ynoate (179) as an example, the ER spectrum indicated the presence of the alkynic function by the C-C triple bond stretching absorption at  48 2239 cm" , the carbonyl functions by the strong C=0 stretching absorption band centred 1  at 1718 cm" , and the Me Sn function by the tin-methyl rocking absorption at 770 cm" . 1  1  3  In the H nmr spectrum, resonances due to the Me Sn moiety (a 9 proton singlet at 8 0.13, :  3  2  -/sn-H  = 54.3 Hz), four methylene groups (8 protons displayed as a 2 proton multiplet at  8 1.68-1.78, a 3 proton multiplet at 8 2.15-2.30, a 2 proton multiplet at 8 2.36-2.45, and a 1 proton multiplet at 8 2.47-2.56), the two methyl ester functions (two 3 proton singlets at 8 3.64 and.3.72), and one alkenyl proton (a 1 proton doublet of doublets at 8 5.98, J = 2.1, 2.1 Hz) could be identified. The C nmr spectrum displayed the appropriate number 1 3  of signals, 14, and four negative signals that appeared in an A P T experiment (8 -8.6, 52.0, 52.5, and 144.3) were attributed to the Me Sn function, the two methyl signals from 3  the methyl ester functions, and the olefinic methine carbon, respectively.  A high  resolution mass spectrometric measurement on the (M -Me) fragment confirmed the +  molecular formula of 179. A similar analysis of the spectroscopic data ( H nmr, l  and ER) and the  HRMS  alkenyltrimethylstannanes structural identities.  measurements acquired from the  remainder  1 3  C nmr, of the  178 and 180-184 provided suitable confirmation of their  With the desired cyclization precursors in hand, we could now  examine the copper(I) chloride-mediated methodology.  1.3.2 Copper(I) mediated cyclizations  178-185 with 2.5  The results derived from treatment of the cyclization precursors  equiv of coppper(I) chloride and 5 equiv of acetic acid in dry D M F at 0 °C for 15 min to yield the bicyclic dienes  186-193 are summarized in Table 4.  R0 C  CuCl (2.5 equiv) A c O H (5 equiv)  2  n SnMe  178-185  C0 Me 2  3  DMF, 0 °C, 15 min n = 1 or 3, R = Me n = 2, R = Et  C0 R 2  m  (60)  N^C0 Me 2  186-193  49 Table 4. Synthesis of the bicycles 186-193  b  c d  Entry  Substrate  n  m  Product  % Yield  1  178  1  1  186  0  2  179  1  2  187  93  3  180  1  3  188  99  4  181  2  1  189  94  5  182  2  2  190  98  6  183  2  3  191  92  7  184  3  3  192  94  8  185  3  1  193  82  C  3  b  d  Isolated yields of purified products. A complex mixture that included the cyclized product and protiodestannylated material was obtained. This example was performed by Dr. Patricia Gladstone. The reaction in this case required 1 h to go to completion. 31  Disappointingly, when the cyclization substrate 178 was treated under standard conditions (equation 61), a complex mixture of compounds (>5 components) and colored polar baseline material was identified by tic analysis after aqueous workup.  1  H nmr  spectroscopic analysis of the crude product indicated the presence of two main components, the desired compound 186 and the protiodestannylated product 194, in a ratio of-1:1. C0 Me  CuCI AcOH  2  SnMe 178  C 0 M e DMF 0 °C 2  3  C0 Me  C0 Me  2  2  C0 Me  (61)  2  ~^^C0 Me 2  186  194  Curiously, upon flash column chromatography of the crude product on silica gel, only trace amounts of the compounds that were present in the crude mixture, as indicated by the *H nmr spectrum, were obtained from the collected column fractions. Upon some investigation, it was found that the crude product mixture was very unstable and was transformed into an intractable material within minutes when concentrated. Certainly the  50 instability of 186 would not be unexpected, since the bicyclo[3.2.0]heptene skeleton present in this substance is extremely strained. The presence of a significant amount of protiodestannylated product, a result unlike that observed in the remainder of the cyclization reactions of the substrates 179185, indicated that the intramolecular conjugate addition process for 178 was more difficult and that the rate of the cyclization process of the (proposed) organocopper intermediates 195 to the a-copper adducts 196, in this case, was comparable to the intermolecular protonation of 195 by the acetic acid. This result is not unexpected, since the highly strained nature of the a-copper adduct 196 would infer that the transition state leading from 195 to 196 is high in energy and, as a result, the cyclization event would be disfavored. Consequently, the undesirable protiodestannylation event (195 to 194) might be expected to become a major pathway in this case. C0 Me  C0 Me  2  2  M = C u or Cu(SnMe )CI 196  m  3  195 Chart 2.  In view of the failures outlined above, it was decided to treat the substrate 178 under cyclization conditions without acetic acid (i.e. 2.5 equiv CuCI, D M F , 15 min, 0 °C or 2.5 equiv CuCI, D M F , 15 min, 0 °C, then I M HCl), in the hope that the cyclization would proceed without the premature intermediate 195.  protonatation of the uncyclized  copper  Unfortunately, in each case, only the presence of relatively minor  amounts of the protiodestannylated product 194 was seen in the H nmr spectrum of the :  crude material. No product that might correspond to the bicycle 186 could be detected. The increased presence of unidentified polar materials was indicated by tic analysis and components of unknown structure were also seen in the H nmr spectrum X  To farther  exacerbate the problem, rapid product decomposition remained a major impediment in identifying and characterizing the various components in the reaction mixtures. Brief attempts to derivatize the crude product after an aqueous workup failed utterly.  51 Reduction/protection of the ester function in a reaction sequence similar to that used to synthesize the t-butyldimethylsilyl protected allylic alcohol 155 (see Discussion section 1.2.2, pg. 40) or a hydrogenation of the diene unit with H /Pd/C or H /Pt failed to provide 2  2  identifiable compounds. It was at this point it was decided to abandon this particular example and to focus on testing the remaining substrates. Greater success of the cyclization protocol was observed in the stereoselective conversion of the substrate 179 to the diene 187 (equation 60 and Table 4, entry 2, pg. 49).  A n excellent yield (93%) of l-methoxycarbonyl-(£)-6-methoxycarbonyl  methylidenebicyclo[3.3.0]oct-4-ene (187) was obtained after purification of the crude product by flash column chromatography on silica gel. This product was also somewhat unstable and completely polymerized over a period of a few weeks when stored under argon in a freezer. Nevertheless, the diester 187 could be characterized and the spectral data collected were in full accord with the proposed structure. In the TR spectrum, the presence of the carbonyl functions was shown by a strong absorption at 1725 cm" and a 1  C-C double bond stretching absorption appeared at 1636 cm" . In the H nmr spectrum, 1  X  the resonances due to four methylene groups (see experimental section for assignments), two C 0 M e functions, and two alkenyl protons were clearly visible. With the aid of a 2  correlated spectroscopy (COSY) spectrum, the assignment  of the proton  resonances in the H nmr spectrum of 187 could be made and the (£)-configuration of the X  exocyclic double bond was confirmed by several H nmr nOed experiments, which are J  illustrated in Figure 7. In the observed.  1 3  C nmr spectrum of 187, the expected 13 signals were  A high resolution mass spectrometric measurement on the molecular ion  confirmed the molecular formula of  C13H16O4.  In addition, a successful elemental  analysis was obtained. Results similar to that described for the conversion of 179 into 187 were obtained from the intramolecular conjugate addition of the substrates 180-185 (equation 60 and Table 4, entries 3-8, pg. 49).  The corresponding bicyclic structures 188-193 were  produced in excellent isolated yields (82-99%). In the case of the conversion of 183 into  52  191  192  198  Figure 7. NOed experiments on 187,188,190-192, and 198 191 (Table 4, entry 6, pg. 49), the reaction required 1 h to reach completion, rather than being finished within 15 min. Regardless,  The reasons for this slight anomaly are not clear.  l-ethoxycarbonyl-(£)-7-methoxycarbonylmethylidenebicyclo[4.4.0]oct-5-  ene (191) was obtained from the stannane 183 in excellent yield (92%). The spectral data ( H nmr, J  1 3  C nmr, and ER) and H R M S molecular mass  determinations derived from the compounds 188-193 were in full accord with the assigned structures. Also, the configuration of the trisubstituted exocyclic double bond was rigorously determined for each of the compounds 188-192 through a series of *H nmr nOed experiments which are summarized in Figure 7.  The (E) stereochemical  assignment of the bicyclo[5.2.0]nonene derivative 193 was designated by analogy with the (£)-olefin in the bicyclo[4.2.0]octene derivative 189 and with the previous examples of four membered ring formation via this methodology (see Discussion section 1.2.2). l-Ethoxycarbonyl-(£)-7-methoxycarbonylmethylidenebicyclo[4.2.0]oct-5-ene (189) although more stable than its more strained lower homolog counterpart 186, was observed to polymerize over a period of approximately one month. For the purposes of characterization and long term storage of the material, the diester 189 was reduced with 6  53 equiv of D I B A L  4 4  in T H F and the resultant diol 197, which also proved to be prone to  polymerization, was allowed to react with TBSC1 and imidazole in CH2CI2 to give the disilyl ether 198 (equation 62).  *H nmr nOed experiments (Figure 7) performed on the  disilyl ether 198 provided clear evidence for the (^-stereochemical assignment of the trisubstituted exocyclic alkene function in 198 and, by analogy, in the a,|3-unsaturated ester function of the bicycle 189.  C0 Et  X  2  '  1) DIBAL, T H F  (62) 189  197X = OH 198X = OTBS  Collectively, the acquisition of the bicyclic cyclization products 186-193 illustrates the flexibility and versatility of the copper(I) chloride-mediated cyclization methodology to stereo selectively produce bicyclic systems of general structure 85 (Chart 3). As a testament to the scope and generality of the cyclization methodology, it is interesting to note that strained bicycles incorporating unsaturated four membered rings can also be synthesized.  With the lone exception involving the conversion of the  cyclization precursor 178 into the bicycle 186, the intramolecular conjugate additions of alkenyltrimethylstannane functions to a,(3-alkynic esters are not only very clean and efficient, but, experimentally, the reactions occur under mild conditions and are very facile to perform  For a discussion of the proposed mechanistic pathway of this  transformation, see Discussion section 1.5.1, pg. 64).  C0 R 2  .(<)  (1)  . m  C0 R 2  85  Chart 3.  54 1.4 Copper CD-mediated intramolecular cyclizations of aryltrimethylstannane functions to a,(3-a]kynic esters  1.4.1 Preparation of cyclization precursors The  starting  materials  required  for  use  in  this  study  were  the  trimethylstannylbenzyl alcohols 199-201 and the corresponding benzyl bromides 202-204 (Chart 4). The preparation of these substances is described below.  199 R = R = R = H 200 R = R = H, R = Me 201 R = R = R = O M e 1  2  1  3  1  2  202 R = R = R = H 203 R = R = H, R = Me 204 R = R = R = O M e  3  2  3  1  2  1  3  1  2  3  2  3  Chart 4. Following a modified literature procedure for the directed orthometalation of benzyl alcohols, each of the commerically available benzyl alcohols 205-207 were 50  treated with 2.5 equiv of B u L i and T M E D A in E t 0 (Scheme 15). The dianions 208 2  formed from this deprotonation process  33  were quenched with 1.5 equiv of Me SnCl. 3  Workup involving the addition of excess water furnished the o-trimethylstannylbenzyl alcohol derivatives 199-201 in moderate yields (54-64%). Of the alcohols 199-201, the benzyl alcohol 199 had been prepared previously and the spectral data was in full accord with that reported in the literature.  50  The spectral  data ( H nmr, C nmr, and ER) obtained from the alcohols 200 and 201 were also in total J  1 3  agreement with their assigned structures.  Using 3,4,5-trimethoxy-2-trirnethylstannyl  benzyl alcohol (201) as an example, the ER spectrum showed a broad O H absorption at 3432 cm' and the tin-methyl rocking absorption at 774 cm" . In the *H nmr spectrum, 1  1  signals due to the Me Sn function (a 9 proton singlet at 8 0.30, 3  2  /S„-H  = 54.5 Hz), three  methoxy groups (three 3 proton singlets at 8 3.81, 3.84, and 3.85), the benzylic methylene group (a 2 proton doublet at 8 4.54, / = 5.7 Hz), the aromatic proton (a 1 proton singlet at  55 8 6.78,  4  - 15.6 Hz), and the alcoholic proton resonance (a 1 proton triplet at 8 1.53,  / s n - H  / = 5.7 Hz, disappears when shaken with D 0 ) were clearly visible.  The  2  1 3  C nmr  spectrum revealed the expected 11 signals and a high resolution mass measurement on the (M -Me) fragment confirmed the molecular formula of 201. +  ,1  2Li  BuLi, T M E D A , E t 0  +  2  205 R = R = R = H 206 R = R = H, R = Me 207 R = R = R = O M e 1  3  1  2  2  Me SnCI; H 0 3  3  2  PPh -Br imidazole 3  2  CH2CI2  SnMe  202 R = R = R = H 203 R = R = H, R = Me 204 R = R = R = O M e 1  3  1  2  3  199 R ' = R " = R° = H 200 R = R = H, R = Me 201 R = R = R = O M e  2  3  1  3  1  2  2  3  Scheme 15. Treatment of each of the benzyl alcohols 199-201 with triphenylphospliine dibromide  51  and  imidazole in methylene  chloride provided the  corresponding  trimethylstannylbenzyl bromides 202-204 in moderate to good yields (65-88%) (Scheme 15).  Again, the proposed structures of the stannanes 202-204 were fully  supported by the spectral data. For instance, in the IR spectrum of 204, the presence of the Me Sn function was confirmed by the absorption at 773 cm" . The H nmr spectrum 1  X  3  of 204 showed resonances due to the trimethylstannyl moiety (a 9 proton singlet at 8 0.36,  2  / s n - H  = 54.8 Hz), three methoxy groups (three 3 proton singlets at 8 3.82, 3.84,  and 3.86), the benzylic methylene protons (a 2 proton singlet at 8 4.66), and the lone aromatic proton (a 1 proton singlet at 8 6.72,  4  / s  n  - H  =16.1 Hz). The  1 3  C nmr spectrum  also contained the expected 11 signals. A H R M S measurement on the (M -Me) fragment +  56 confirmed the molecular formula of 204. In a manner analogous to that described above, the structures of the remaining two arylstannanes 202 and 203 were confirmed. With the alcohol 199 in hand, the cyclization precursor 211 was prepared via a three-step reaction sequence (equation 63). Thus, treatment of 199 with sodium hydride in T H F  5 2  and quenching the resultant alkoxide with the previously prepared bromide 160  (see Discussion section 1.3.1, pg. 45) yielded the silyl capped intermediate 209 in excellent yield (94%). Removal of the TBS function with T B A F  in T H F provided the  3 9  alkyne 210 as a volatile oil. The alkyne 210 was immediately sequentially treated with L D A in T H F and methyl chloroformate  41  to give the ester 211 in excellent yield (90%  over 2 steps from 282). 1) NaH, THF;  160 SnMe  2) T B A F , T H F 3) LDA, THF; CIC0 Me  3 3  199  2  (63) 'SnMe  3  209 X = T B S 210 X = H 211 X = C 0 M e 2  The spectral data ( H nmr, J  1 3  C nmr, and IR) acquired from the stannane 211 was  fully consistent with the assigned structure.  In the IR spectrum, the C-C triple bond  stretching absorption at 2239 cm" , the carbonyl stretching band at 1718 cm" , and the tin1  1  methyl rocking absorption at 751 cm" were present. 1  In the H nmr spectrum, the J  resonances due to the Me Sn moiety (a 9 proton singlet at 8 0.28, 3  2  /sn-H  = 53.8 Hz), the  methyl ester function (a 3 proton singlet at 8 3.78), the propargylic methylene group (a 2 proton singlet at 8 4.23), the benzylic methylene group (a 2 proton singlet at 8 4.59), and four aromatic protons (a 3 proton multiplet at 8 7.25-7.35, and a 1 proton doublet of multiplets at 8 7 . 5 1 , / = 5 . 3 Hz,  3  /s -H n  = 48.9 Hz) were present. The  1 3  C nmr spectrum  exhibited the expected 13 signals and a high resolution mass spectrometric measurement on the (M -Me) fragment confirmed the molecular formula of 211. +  The carbocyclic cyclization precursor 215 was prepared by successive diethyl malonate alkylations with potassium hydride and the bromides 202 and 160 to provide 9  the dialkylated product 212 (Scheme 16). Removal of the TBS function of 212 with TBAF  3 9  in THF and acylation (LDA, D M P U , THF; C l C 0 M e ) of the resultant terminal 41  2  57 alkynic function of 214 provided the alkynoate 215 in good overall yield (74% over 4 steps). SnMe  ^ J ^ ^ \ ^ C 0  1) K H , T H F  CH (C0 Et) 2  2  3  2  202  E t  C0 Et  B r  SnMe  2  2  3  212 1) K H , THF;  Br  -TBS  f  160  2) T B A F , T H F 3) LDA, D M P U , THF; C I C 0 M e 2  SnMe 213 X = T B S 214X = H ,, 215 X = C 0 M e < ^  3  i  R  R  2  X  R = C0 Et 2  Scheme 16. The spectral data obtained from 215 confirmed the proposed structure. In the ER. spectrum, the absorptions attributable to the C - C triple bond at 2242 cm" and the 1  trimethylstannyl group at 770 cm" were visible. 1  In the *H nmr spectrum of 215, the  resonances ascribed to the trimethylstannyl function (a 9 proton singlet at 8 0.34,  2  /  S  N  - H  =  53.3 Hz), two methylene groups (a 2 proton singlet at 8 2.93 and a 2 proton singlet at 8 3.49), two ethyl ester functions (a 6 proton triplet at 8 1.19, / = 7.3 Hz and a 4 proton multiplet centred at 8 4.17), the methyl ester function (a 3 proton singlet at 8 3.71), and four aromatic protons (a one proton multiplet centred at 8 7.08, a 2 proton multiplet centred at 8 7.18, and a 1 proton doublet of multiplets at 8 7.39, / = 6.3 Hz, 47.4 Hz) were present. The  1 3  3  /S,I-H  =  C nmr spectrum showed the expected 17 signals and a  H R M S measurement on the (M -Me) fragment confirmed the molecular formula of 215. +  A second cyclization precursor incorporating an oxygen ether linkage was synthesized in two steps from the stannane 200 (equation 64).  Thus, treatment of the  alcohol 200 with sodium hydride in dry D M F , followed by the addition of propargyl 52  bromide, gave the stannane 216 as an oil that exhibited an extremely noxious odour. The  58 terminal alkyne 216 was treated with L D A and methyl chloroformate  to furnish the  41  a,(3-alkynic ester 217 in excellent yield (87% over 2 steps). The structural assignment of compound 217 was fully supported by the spectrometric data (IR, H nmr, !  1 3  C nmr,  and HRMS). 1) NaH, DMF; (64) ^SnMe  2) LDA, D M P U ; CIC0 Me  200  3  216 X = H 217 X = C 0 M e  2  2  Finally, alkylation of diethyl malonate with each of the benzyl bromides 203 or 9  204, followed by alkylation of the derived products 218 and 219 with propargyl bromide, yielded the stannanes 220 and 222 in yields of 85% and 94%, respectively (Scheme 17). SnMe  3  1) K H , T H F CH (C0 Et) 2  2  2  2) 203 or 204 218 R = R 1  3  = H, R = Me 2  219 R = R = R 1  203 R = R = H, R = Me 204 R = R = R = O M e 1  3  1  2  2  2  220 R = R = H, R = Me, X = H 3  2  =OMe  2) LDA, D M P U , THF; C I C 0 M e  3  2  SnMe 1  3  R  1  R  2  3  221 R = R = H, R = Me, X = C 0 M e 1  3  2  2  222 R = R = R 1  223 R Scheme 17.  2  R = R 2  3  = OMe, X = H  3  = OMe, X = C 0 M e 2  R°  E = C0 Et 2  59 Reaction of the terminal alkyne functions of 220 and 222 with L D A and D M P U in T H F and treatment of the resultant Uthium acetyUdes with methyl chloroformate provided 41  the cyclization precursors 221 and 223 in 63% and 80% yields, respectively. The spectral data ( H nmr, X  1 3  C nmr, and IR) and H R M S mass determinations  obtained from the compounds 221 and 223 were in full accord with their assigned structures. For instance, in the H nmr spectrum of 223, two singlets at 8 3.71 and 3.84, J  and two overlapping resonances appearing as a singlet at 8 3.78, attributable to the three methoxy groups and the methyl ester function, were clearly visible.  The resonances  belonging to the trimethylstannyl groups were present in the H nmr spectra of both 221 X  and 223 (as a 9 proton singlet at 8 -0.30).  The  1 3  C nmr spectrum of 221 and 223  displayed the expected 17 and 20 signals, respectively. Lastly, the IR spectrum of each of these substances showed a carbonyl absorption at -1720 cm" and tin-methyl rocking 1  absorption at -770 cm" . 1  With the synthesis of the precursors incorporating aryltrimethylstannane and alkynoate functions completed, investigations into the internal conjugate addition reaction of arylcopper(I) species, derived from aryltrimethylstannanes, to a,(3-alkynic ester functions could be carried out.  1.4.2  Copper(I)-mediated  cyclizations of  aryltrimethylstannane  functions  to  a,P-alkynic esters The experimental results arising from the treatment of the cyclization precursors 211, 217, 215, 221, and 223 with 2.5 equiv of copper(I) chloride and 5 equiv of acetic acid in dry D M F at 0 °C for 15 minutes (equation 65) to provide the bicycles 224-228 are summarized in Table 5. CuCI (2.5 equiv) R A c O H (5.0 equiv)  1  (65)  C0 Me2  DMF, 0 °C, 15 min  224-228  C  ° 2  M  e  60 Table 5. Synthesis of the bicycles 224-228 Entry  Substrate  R  R  X  Product  % Yield  1  211  H  H  H  -0-  224  92  2  217  H  Me  H  -0-  225  97  3  215  H  H  H  -C(C0 Et) -  226  98  4  221  H  Me  H  -C(C0 Et) -  227  92  5  223  OMe  OMe  OMe  -C(C0 Et) -  228  97  1  R  2  3  2  2  2  2  2  2  3  Isolated yield of purified products  Gratifyingly, the ethers 211 and 217 were efficiently transformed into the bicycles 224 and 225 (Table 5, entries 1 and 2) upon subjection to the standard cyclization protocol (equation 65), followed by purification of the crude product by flash column chromatography on silica gel (92% and 97%, respectively). The spectral data (*H nmr, C nmr, and IR) derived from 225 were in full accord 1 3  with the assigned structure.  For example, the IR spectrum of (Z)-4-(methoxy  carbonylmethylidene)-6-methylisochromane (225) showed the methyl ester function by the strong C=0 absorption located at 1704 cm" . 1  In the H nmr spectrum of 225, the X  signals due to the methyl group (a 3 proton singlet at 8 2.34), the methyl ester function (a 3 proton singlet at 8 3.73), the benzylic methylene group (a 2 proton singlet at 8 4.64), the allylic methylene group (a 2 proton doublet at 8 5.09, / = 2.0 Hz), the lone olefinic proton (a 1 proton triplet at 8 6.35, / = 2.0 Hz), two mutually coupled aromatic ortho protons (two 1 proton doublets at 8 6.98 and 7.15 each having J = 7.6 Hz), and the isolated aromatic proton (a 1 proton singlet at 8 7.52) could be identified. The spectrum of 225 revealed the expected 13 resonances.  1 3  C nmr  In an A P T experiment, six  negative signals (8 21.3, 51.4, 110.0, 124.3, 125.1, and 131.0) were attributed to the aromatic methyl group, the methyl carbon of the ester function, and four sp methine 2  carbons, respectively.  A high resolution mass spectrometric measurement on the  molecular ion confirmed the molecular formula of C13H14O3.  In addition, H nmr nOed l  experiments confirmed the (Z)-configuration of the alkenic function in 225 (Figure 8). Likewise, the spectral data (IR, H nmr, and C nmr) confirmed the proposed structure of X  1 3  61 the bicycle 224 and *H nmr nOed experiments determined the (Z)-orientation of the exocyclic double bond (Figure 8).  8 6.36  8 7.52  224  8 6.35 225  Figure 8. NOed experiments on 224 and 225  When the copper(I) chloride/acetic acid cyclization protocol (equation 65, pg. 59) was applied to the substrates 215, 221, and 223 and the crude products were purified by flash column chromatography on silica gel, the carbobicycles 226-228 were produced cleanly and efficiently (yields >90 %, Table 5, entries 3-5, pg. 60). The spectral data acquired from the bicycles 226-228 were fully consistent with their assigned structures.  For instance, the IR spectrum of the trimethoxy substituted  bicycle 228 showed the three carbonyl functions as one broad absorption at 1734 cm" . 1  Notable in the H nmr spectrum were the resonances ascribed to the benzylic methylene X  group (a 2 proton singlet at 8 3.35), three methoxy groups (three 3 proton singlets at 8 3.22, 3.61, and 3.66), one aromatic proton (a 1 proton singlet at 8 6.19), and one alkenyl proton (a 1 proton broad triplet at 8 7.39, / = 1.8 Hz) mutually coupled to the allylic methylene protons (a 2 proton doublet at 8 4.19,/ = 1.8 Hz). The presence of four CH  3  singlets that each integrated to three protons proved to be problematic in the  assignment of the proton nmr spectrum However, with the assistance of Heteronuclear Mutiple Bond Correlation (HMBC) and Heteronuclear Multiple Quantum Coherence (HMQC) spectra, the complete assignment of the proton and carbon nmr spectra could be made (see Experimental, pg. 201 and 202). With the assignment of the proton nmr spectrum in hand, a series of *H nmr nOed experiments determined that the exocyclic double bond in 228 possessed an (^-configuration. The complete results of the *H nmr nOed experiments derived from 228 are summarized in Figure 9. Fortunately, analyses of the simpler spectral data (*H nmr,  1 3  C nmr, and IR) recorded for the compounds 226  62 and 227 provided suitable confirmation of their structures.  In addition, the (E)-  configuration of the trisubstituted double bonds in 226 and 227 were rigorously determined with H nmr nOed experiments (see Experimental, pg. 198 and 199). l  86.19  8 7.39  228 Figure 9. NOed experiments on 228 The mechanism of the conjugate addition likely follows a pattern similar to that proposed for the addition of alkenylstannane functions to a,P-alkynic esters (see Introduction section 3.4.1, pg. 19 and Discussion section 1.5.1, pg. 64). As has been noted for the analogous additions of alkenyltrimethylstannane functions to a,(3-alkynic esters, the internal cyclization process is faster than the intermolecular quench by the acetic acid.  For example, the protonation of the arylcopper(I) intermediate 229 to  produce the protiodestannylated product 230 is slower than the conjugate addition to form the adduct 231 (Scheme 18). It should be emphasized that the bicycles 224-228 (Table 5, pg. 60) were produced in excellent yields and no trace of the configurational isomers were detected by tic analyses of the reaction mixtures or by  nmr analyses of the crude products. The  high efficiency of the conversion of 223 into 228 (Table 5, entry 5) implies that the overall reaction is somewhat insensitive to the steric hinderance supplied by the two ortho substituents that surround the trimethylstannane function in compound 223.  A  determination of whether or not substrates in which the MeO groups of 223 are replaced by alkyl groups would also be efficiently transformed in the corresponding bicyclic products will require additional experimentation.  63  224  231  Scheme 18.  In summary, the intramolecular conjugate addition of arylcopper species, formed from the reversible copper-tin transmetalation of aryltrimethylstannane functions with copper(I) chloride, to a,(3-alkynic esters are highly efficient and the results show clearly that the cyclization reaction represents a viable synthetic process.  64 1.5 Limitations, extensions, and mechanistic considerations  1.5.1 Effect of varying solvents and additives  1.5.1.1 Development of the use of an in situ proton source  Throughout this section (1.5.1), the reader is referred to the proposed reaction pathway of the copper(I) mediated conjugate additions found in Scheme 19 (see next page). Using the stannane 232a as an example, the reaction is believed to be initiated by the oxidative addition of CuCl to the organostannane 232a to provide the copper(III) intermediate 232b (Introduction section 3.4.1, pg. 19). The intermediate 232b can then undergo two different reaction pathways. By the reductive loss of Me SnCl from the 3  intermediate 232b, the alkenylcopper(I) species 232c is formed.  Alternatively, the  intramolecular cyclization of the intermediate 232b and subsequent reductive elimination of CuCl yields the a-stannyl ester 232f. The alkenylcopper(I) function in 232c can cyclize onto the a,P-alkynic ester to give the copper(I) adduct 232e. The work described in this section focused on the search for an appropriate proton source (HX) that would react with the intermediates 232d and/or 232e in situ to yield the diene 232g (equations 66 and 67). Cu + CuX  + HX  (66)  E = C0 R 2  232g  232e Cu(SnMe )CI 3  + HX 232d  (67) 232g  + CuX  65  + CuCl SnMe  Cu(SnMe )CI  - Me SnCI 3  3  3  + Me SnCI  -CuCl  3  232c  232b  232a  Cu(SnMe )CI 3  Cu  - Me SnCI 3  CuCl or RC0 Cu  + Me SnCI  V  ^  E  3  2  232d + CuCI  232e  + CuCI CuCl  RC0 H 2  (- CuCl) SnMe  E = C0 R  1  w ^  2  R = C F or CH 3  3  3  E  RC0 H 2  232d 232g  232f  + RC0 SnMe (- Me SnCI) + CuCl = = = = = = = R C 0 C u + Me SnCI (- R C 0 S n M e ) 2  3  3  2  3  2  3  Scheme 19. The transformation of 129 into 144 (and 145) was found to be proceed in the presence of 2 equiv of water (equation 68) without much change in the isolated yields. This result indicated that the intermediates 232d and 232e (Scheme 19) are not sufficiently basic to react with water to any great extent.  From this result, it was  surmised that a more acidic proton source could be employed in the reaction mixture.  66  CuCI C 0 E t (2.5 equiv)  C0 Et  C0 Et  2  2  J—SnMe  •  2  Me Sn 3  (68)  DMF, 0 °C, 15 min H 144  129  3  H 145  without H 0 64% with H 0 (2 equiv) 58%  18% 26%  2  2  Satisfyingly, in the conversion of precursor 143 into the monocycle 158, the addition of trifluoroacetic acid (5.0 equiv) to the reaction mixture improved the yield obtained to 74% from 52% (Table 6, entries 1 and 2).  A mixture of unidentified  destannylated material was also isolated (-15%) after purification of the crude product by flash column chromatography on silica gel. This result revealed a vital aspect of the reaction: the intramolecular cyclization of the intermediates 232b and/or 232c into the adducts 232d and/or 232e, respectively, is faster than the intermolecular quench of 232b and/or 232c by the trifluoro acetic acid (Scheme 19 and equation 69). For an exception to  CF C0 H 3  Cu(SnMe )CI  2  or  3  232h  232c  232b  this generality, the reader is referred to Discussion section 1.3.2, pg. 49. The presence of the unidentified side products may be due to homocoupling or protiodestannylation of 8  43  the starting material or to some other unknown reactions.  C0 Me 2  C0 Et 2  X0 Me 2  Me^Sn  (70) Et0 C 2  143  158  67  Table 6. Synthesis of the diene 158 Entry  Reaction Conditions  % Yield  1  2.5 equiv CuCl, 0 °C, D M F , 15 min  52  2  2.5 equiv CuCl, 5.0 equiv C F C 0 H , 0 °C, D M F , 15 min  74  3  2.5 equiv CuCl, 5.0 equiv C H C 0 H , 0 °C, D M F , 15 min  85  3  3  2  2  3  Isolated yield of purified product.  The appropriate choice of the proton source appeared to depend upon a delicate balance between the ability of the acid to selectively protonate the intermediates 232d and 232e in the presence of the intermediates 232b and 232c. Also, protiodestannylation of the alkenyltrimethylstannyl function in the starting material 232a had to be avoided (Scheme 19, pg. 65). To our delight, the use of acetic acid served these purposes adequately (Table 6, entry 3). Upon changing the reaction conditions to include the addition of 5.0 equiv of acetic acid, the yield of 158 was excellent (85%) with the concomitant production of only minor amounts of unidentified destannylated material (-5%).  Gratifyingly, these reaction conditions were found to be successful across a  number of examples (see Discussion sections 1.2.2, 1.3.2, and 1.4.2).  1.5.1.2 Use of catalytic amounts of CuCl in the conjugate addition reaction As an examination of the proposed reaction pathway using acetic acid revealed the plausible generation of CuOAc (Scheme 19 and equation 66, where H X = HOAc), it was of interest to ascertain the efficacy of copper(I) acetate in the reaction.  In one  control experiment, treatment of the stannane 136 with 2.5 equiv of copper(I) acetate in dry D M F provided a good yield (78%) of the cyclized product 156 (Table 7, entry 3). Therefore, copper(I) acetate is a suitable agent to mediate the conjugate addition reaction.  68  136  156  Table 7. Synthesis of the diene 156 Entry  Reaction Conditions  % Yield  3  c  1  2.5 equiv CuCI, 0 °C, D M F , 1 h  2  2.5 equiv CuCI, 5.0 equiv C H C 0 H , 0 °C, D M F , 15 min  87  3  2.5 equiv CuOAc, 5.0 equiv C H C 0 H , 0 °C, D M F , 15 min  78  4  2.5 equiv CuCI, 5.0 equiv C H C 0 H , 0 °C, DMI, 15 min  83  5  0.1 equiv CuCI, 5.0 equiv C H C 0 H , 0 °C, D M F , 1 h  6  0.5 equiv CuCI, 2.0 equiv C H C 0 H , 0 °C, D M F , 45 min  7  0.1 equiv CuCI, 2.0 equiv C H C 0 H , 0 °C, D M F , 4 h 15 min  8  2.5 equiv C u C l , 5.0 equiv C H C 0 H , 0 °C, D M F , 15 min  0  e  9  2.5 equiv Cu(OAc) , 5.0 equiv C H C 0 H , 0 °C, D M F , 15 min  0  e  3  2  3  3  e,f  89  d  2  3  d  2  3  2  0  2  3  2  2  2  3  b  2  3  2  76  Unless otherwise stated, [CuCI] ~ 0.25 M . Isolated yield of purified products. A -1:1 mixture of cyclized material 156 and starting material 136 was obtained (see Discussion section 1.2.2). The substrate was added via a syringe pump over the first 15 min. Only starting material was identified in the *H nmr spectrum of the crude product. [CuCI] - 0.01 M . 3  b  0  d e  f  Given the latter result, it was conceivable that copper(I) chloride might be used catalytically in the presence of acetic acid. However, it was found that no reaction took place upon the treatment of the stannane 136 with 0.1 equiv of copper(I) choride and 5 equiv of acetic acid in dry D M F (Table 7, entry 5).  The lack of any reaction was  attributed to the low concentration of the copper(I) chloride ([CuCI] -0.01 M ) employed in this experiment.  Thus, under these conditions, the equilibrium of the copper-tin  transmetalation reaction lies heavily toward starting material 232a (Scheme 19, pg. 65) and the overall cyclization process is inhibited. In contrast, application of the standard  69 reaction protocol where the concentration of copper(I) chloride is -0.25 M provided an excellent yield of 156 (Table 7, entry 2). Equipped with this information, reaction conditions employing catalytic amounts of CuCl (0.5 equiv) were successfully developed (Table 7, entry 6). Vital to the success of this reaction was the use of CuCl at the same concentration in the standard cyclization protocol (-0.25 M , Table 7, entry 2). To maintain the concentration of CuCl at -0.25 M while simutaneously decreasing the quantity of CuCl from 2.5 to 0.5 equiv, a proportionate 5-fold reduction in the amount of solvent (DMF) relative to the standard reaction protocol was necessary. Under these altered conditions, the slow addition of a D M F solution of the stannane 137 over a 15 min period to 0.5 equiv of CuCl and acetic acid (2 equiv) in dry D M F at 0 °C provided an excellent yield (89%) of the cyclized product 156 (Table 7, entry 6). Under these new conditions where the [CuCl] -0.25 M , the yield was virtually identical to the conditions employing 2.5 equiv of copper(I) chloride (87%, Table 7, entry 2). A successful protocol employing 0.1 equiv of copper(I) chloride was also developed (Table 7, entry 7). In this case, a 25-fold decrease in the amount of D M F used compared to the standard cyclization conditions (Table 7, entry 2) was the key difference between these two protocols. As a result, the concentration of CuCl in this experiment was also kept at -0.25 M . Thus, treatment of CuCl (0.1 equiv) in D M F with the stannane 137 provided the desired product 156 in good yield (76%), although somewhat less efficiently than that observed in the previously discussed experiment (Table 7, entry 6). A contributing factor to the reduced yield in this experiment could arise from the increase in the concentrations of acetic acid and the organostannane precursor 137 compared to those employed in the standard cyclization protocol (Table 7, entry 2). This heightens the propensity of the organo stannane starting material to participate in intermolecular protiodestannylation or oxidative homocoupling pathways. 43  8  In addition, the relatively  large volumes of acetic acid and cyclization precursor in the reaction pot may have a deleterious effect by altering the characteristics of the solvent (e.g. solubility properties). To summarize the key events of catalytic cycle using acetic acid (Scheme 19, pg. 65, R = CH ), the copper-tin transmetalation and internal conjugate addition leading 3  to the formation of the intermediates 232d and 232e are analogous to those discussed  70 previously (See Introduction section 3.4.1, pg. 19). The in situ quench of the copper(I) adduct 232e by acetic acid provides the desired diene 232g and copper(I) acetate (equation 66, pg. 64). Reaction of the intermediate 232d with acetic acid would provide copper(I) acetate and Me SnCl (equation 67). 3  A mechanism by which CuCI is  regenerated can be proposed and is illustrated at the bottom of Scheme 19. It is plausible that CuOAc and Me SnCl can react (reversibly) to form Me SnOAc and regenerated 3  3  CuCI. Copper(I) chloride is also formed during the reductive elimination process of the intermediate 232d to form the stannane 232f. The catalytic cycle is then completed by the participation of the copper(I) salt (CuCI or CuOAc) in the initial equihbrium between  232a and 232b. The transformation is assisted by driving the transmetalation equilibrium towards the intermediates 232b and 232c in the presence of elevated concentrations of CuCI. In addition, any possible decomposition of the intermediates 232d and 232e is minimized by the facile protonation of these intermediates by the acetic acid. As a side note, it is clear from previous studies ' '  3 5 53  that polar aprotic solvents,  such as D M F or D M S O , promote the transmetalation of alkenylstannanes with copper(I) salts. This has been attributed to the belief that the transmetalation is facilitated by the relatively high solublity of copper(I) salts and the high dielectric constant of these solvents. A high dielectric constant enhances charge separation and may increase the reactivity of the dissolved ions.  53  Continuing the investigation for compatible solvent  systems for use in the cyclization, it has been shown recently that trimethylsilylacetylenes undergo  copper/silicon transmetalation with CuCI in D M F or l,3-dimethyl-2-  imidazolidinone (DMI).  54  Thus, it seemed reasonable that D M I might serve as a suitable  reaction medium in our work. This hypothesis proved to be correct as the cyclization reaction employing DMI, since the use of this solvent provided a good yield (83%) of 156, after purification of the crude material on silica gel (Table 7, entry 4, pg. 68). Lastly, additional control experiments confirmed the fact that both copper(II) acetate and copper(II) chloride were unable to effect the transmetalation/cyclization reaction. It was found that treatment of 137 with 2.5 equiv of G1CI2 or Cu(OAc) in dry 2  D M F resulted in the recovery of intact starting material (Table 7, entries 8 and 9, respectively). Unfortunately, due to time constraints, further experiments to explore the  71 limitations and generality of the copper(I) catalyzed protocol and the nature of the reaction pathway were discontinued.  1.5.2 Preparation of a,(3-alkynic ketone and aldehyde precursors The preparation of the substrates for use in this study required the alkyne 180b, whose synthesis was described in Discussion section 1.3.1, pg 46 and Experimental pg. 150. Following a modified literature procedure describing the one-step formation of alkynals from alkynes, treatment of the alkyne 180b with L D A in T H F and reaction of 55  the resultant acetylide with D M F provided the alkynal 233 after workup with aqueous potassium dihydrogen phosphate (equation 72). The yield of the conversion after flash column chromatography of the crude product on silica gel was moderate (66%). 1) L D A , THF, -78 °C  COgMe ^  ^  2) D M F  H  SnMe  3  2  ^  '  c  C0 Me  v.  SnMe  180b  3  233  The spectral data acquired from the aldehyde 233 was fully consistent with the assigned structure. For example, in the IR spectrum, the alkyne function was indicated by the C-C triple bond stretch at 2201 cm" , the carbonyl function by the absorption 1  located at 1733 cm" , and the Me Sn function by the absorption at 772 cm" . Significant 1  1  3  resonances in the H nmr spectrum could be ascribed to the Me Sn group (a 9 proton X  3  singlet at 8 0.12, /s -H = 54.3 Hz), the methyl ester moiety (a 3 proton singlet at 8 3.63), 2  n  the olefinic proton (a 1 proton doublet of doublets at 8 5.96, / = 2.1, 2.1 Hz, Vs -H = n  37.9 Hz), and the aldehyde proton (a 1 proton singlet at 8 9.14). The  1 3  C nmr spectrum  displayed the expected 14 signals and a H R M S measurement on the (M -Me) fragment +  confirmed the molecular formula of 233. 7-( 1 -Methoxycarbonyl-2-trimethylstannylcyclopent-2-en-1 -yl)hept-3-yn-2-one (235)  was prepared in two straightforward transformations  (Scheme 20).  from the alkyne  180b  Thus, treatment of 180b with L D A followed by the addition of ethanal  yielded the propargylic alcohol 234, presumably as a mixture of diastereomers.  56  The  72 secondary alcohol was then converted to the corresponding ketone 235 via a Swern oxidation.  The overall yield of the two-step process was 70% from the alkyne 180b.  34  235 Scheme 20.  The spectral data collected support the proposed structure of the alkynone 235. For instance, the IR spectrum displayed the alkyne triple bond stretch at 2211 cm" and 1  the carbonyl functions at 1729 cm" . 1  The H nmr spectrum showed key signals X  corresponding to the Me Sn function (a 9 proton singlet at 8 0.13, 3  2  7  S n  -H  = 54.3 Hz), the  methyl ketone function (a 3 proton singlet at 8 2.28), the methyl ester moiety (a 3 proton singlet at 8 3.63), and the olefinic proton (a 1 proton doublet of doublets at 8 5.96, / = 2.1, 2.1 Hz,  3  /sn-H  = 38.0 Hz). The C nmr spectrum exhibited the expected 15 signals. 1 3  Lastly, a high resolution mass spectrometric measurement on the (M -Me) fragment +  confirmed the molecular formula of C n ^ e C ^ S n . With the a,(3-alkynic aldehyde 233 and ketone 235 in hand, the copper(I) chloride-mediated cyclization processes could then be examined.  1.5.3 Cyclization of acetylenic ketone and aldehyde precursors It was found that treatment of the stannane 233 under standard cyclization conditions (equation 73) resulted in the clean formation of two isomeric aldehydes 236 and 237. These substances were not separable by flash column chromatography on silica  73 gel. The combined yield of the configurational isomers 236 and 237 was 89%. The ratio of these materials, as determined by integration of the aldehyde resonances in the H nmr J  spectrum of the crude product, was -1:4 ratio, respectively. COoMe  CuCl (2.5 equiv), A c O H (5 equiv), H D M F , 0 ° C , 15 min  C0 Me  C0 Me  2  2  T  O 236 (minor)  "Y  O 237 (major)  The spectral data derived from the mixture support the proposed structures of 236 and 237. In the IR spectrum of the mixture, absorptions belonging to the ester function at 1728 cm" and the a,f3-unsaturated aldehyde at 1672 cm" were visible. A high resolution 1  1  mass measurement of the mixture confirmed the molecular formula of C13H16O3. Two sets of signals in the H and 1  1 3  C nmr spectra were attributed to the presence of the  isomers 236 and 237. In the H nmr spectrum of the mixture of the two compounds, the signals ascribed X  to the major isomer 237 were the methyl ester function (a 3 proton singlet at 8 3.19), two olefinic protons (two 1 proton doublet of doublets at 8 5.44, / = 2.1, 2.1 Hz, and at 5 5.91, / = 2.0, 7.9 Hz), and the aldehyde proton (a 1 proton doublet at 8 10.12, / = 7.9 Hz). In the  1 3  C nmr spectrum of the mixture, the expected 13 resonances belonging  to the substance 237 could be identified. In an A P T experiment, four negative signals at 8 52.1, 127.5, 135.5, and 193.1 were attributed to the methoxy carbon, two methine olefin carbons, and the aldehyde function, respectively. The minor compound 236 displayed the methyl ester function (a 3 proton singlet at 8 3.23), two olefinic protons (two 1 protons doublet of doublets at 8 5.62, / = 2.5, 2.5 Hz, and 8 6.22, / = 2.1, 8.0 Hz), and the aldehyde resonance (a 1 proton doublet at 8 9.92, / = 8.0 Hz) in the H nmr spectrum of the mixture. In the l  1 3  C nmr spectrum, the  expected 13 carbon resonances arising from the presence of 236 were found. In the APT experiment, the four negative signals at 8 52.1, 124.0, 132.5, and 190.6 could be attributed to the methoxy carbon, two olefinic carbons, and the aldehyde carbon, respectively.  74 The configuration of the double bonds in 236 and 237 were indicated by the relative chemical shifts of the alkenyl and aldehyde protons in the H nmr spectrum The J  aldehyde resonance attributed to the major compound 237 was located at 8 10.22 whereas the minor compound 236 resonated at 8 9.92. The downfield shift of the aldehyde signal in the major isomer 237 is the likely result of the deshielding effects of the proximate double bond. Likewise, the relative downfield resonance of the exocyclic methine proton in the minor product 236 (8 6.22) compared to the major product 237 (8 5.91) also provided strong diagnostic evidence to assign the configuration of the trisubstituted olefins.  More definitive evidence was supplied by a series of nOed experiments  (Figure 10) which conclusively assigned the (Z)-configuration to the major compound 237 and the (£)-configuration to the minor compound 236.  236 (minor)  237 (major)  Figure 10. NOed experiments on 236 and 237  This lack of stereoselectivity was also seen in the conversion of the stannane 235 into a mixture of the ketones 238 (major) and 239 (minor) in a ratio of ~4:1, as indicated by integration of the olefinic protons in the *H nmr spectrum of the crude product (equation 74).  The minor compound 239 proved to be unstable and was found to  decompose when subjected to flash column chromatography on silica gel. Consequently, it was not possible to obtain an analytically pure sample of this material. However, a moderate yield (55%) of the major compound 238 could be isolated as a colorless solid (mp 40-44 °C).  75  COoMe C  SnMe  O  3  235  H  3  CuCl (2.5 equiv), AcOH (5 equiv),  C0 Me  C0 Me  2  2  i  +  DMF, 0 °C, 15 min  TO  CH  3  *-  (74)  Y  H3C  238 (major)  O 239 (minor)  The spectral data fully support the proposed structure of the ketone 238. In the IR spectrum, the carbonyl functions were indicated by the C=0 stretching frequencies located at 1728 cm" and 1681 cm" . Notable in the H nmr spectrum were the presence 1  1  X  of the signals due to ten methylene protons, the methyl ester group (a 3 proton singlet at 8 3.63), the methyl ketone (a 3 proton singlet at 8 2.19), and two alkenyl protons (a 1 proton broad singlet at 8 6.04 and a 1 proton doublet at 8 6.34, / = 2.4 Hz). The C nmr 1 3  spectrum showed the expected 14 carbon resonances and a high resolution mass spectrometric measurement on the (M ) fragment confirmed the molecular formula of +  238. The configuration of the double bond was determined to be E as determined by a H X  nmr nOed experiment, the results of which are illustrated in Figure 11.  C0 Me 2  8 2.19  238 Figure 11. NOed experiments on 238  The formation of isomeric mixtures of aldehydes and ketones in these instances can be explained by a modified reaction pathway illustrated in Scheme 21. Following transmetallation and cyclization (see Discussion section 1.5.1, pg. 64), it may be proposed that the intermediates 240b can undergo isomerization to the corresponding copper(I) allenoates 240d and 240e. The allenoates 240d and 240e are then protonated  76 by the acetic acid from either face of the allenoate function to provide the configurational isomers 240f and 240g. In the case of the aldehydes 236 and 237, it is interesting to note that the major compound formed possesses the configuration opposite to that obtained exclusively in the cyclization of alkenyltrimethylstannanes to a,(3-alkynic esters. This suggests that under the reaction conditions, isomerization of the unsaturated aldehyde 240b (where R = H) is fast and that protonation occurs from the least hindered face of the allenoate (opposite to the five membered ring). The isomerization of a-copper(I)-a,(3unsaturated aldehydes and ketones to allenoate species is not unprecedented, since allenoates derived from the conjugate addition of organocopper reagents to both alkynones and alkynoates have been postulated in the literature.  57  C0 Me  COoMe  C0 Me  2  Cu  2  C(=0)R  H  240b  240c  COoMe  C0 Me  PT '''OCu 240d  R  2  R = H or Me  C0 Me 2  K Scheme 21.  X(=0)R 240f  C(=0)R  X>Cu 240e  xvv  C0 Me 2  R(0=)C H 240g  77  Since only two substrates were employed to probe the reaction, it is difficult without exploration of the reaction conditions and substrate structure to comment in detail on the conjugate addition of alkenyltrimethylstannane functions to a,P-alkynals and a,(3-alkynones. However, this work supplies promising preliminary results on which to base further studies.  Additional work may include examination of other systems  (formation of monocyclic products for example) or a study of altering the experimental conditions with the goal of optimizing the ratio of geometric isomers to favor production of (Z)-olefins. This may provide a future stereoselective route to (Z)-substituted bicyclic dienes and would complement the conjugate addition methodology employing a,(3alkynic esters.  1.6 Summary  In summary, a series of cyclization precursors of general structure 241 that incorporate a,P-alkynic ester and alkenyl- or aiyltiimethylstannane moieties were synthesized. When these substances were treated as shown in equation 75, the carbon centre bearing the trimethylstannane function was shown to add successfully in a conjugate (1,4) sense to the unsaturated ester function to produce 242.  In most cases,  subjection of the cyclization precursors to the protocol developed (2.5 equiv CuCl, 5 equiv AcOH, 0 °C, D M F , 15 min) provided configurationally defined monocyclic and bicyclic systems very efficiently (Chart 5).  A brief investigation demonstrated the  adaptation of the methodology to include a,(3-alkynic ketone and a,f3-alkynic aldehyde functions as potential Michael acceptors (equation 76). The use of a catalytic amount of copper(I) chloride was also successfully demonstrated (equation 77).  78  C  ° 2  SnMe  R  CuCI (2.5 equiv), AcOH(5.0 equiv), DMF, 0 °C, 15 min  C0 R 2  (75)  3  C0 Et  C0 Me  2  GOoR  2  •fi)  m  \ - C O o R n  N  " Et0 C  n = 1, 2, 3 m = 1, 2, 3 R = Me or Et 85  2  n = 1,2,3 243  158  C0 Me 2  R = H, Me, or OMe X = O or C ( C 0 E t ) 2  2  89 Chart 5. Compounds 243,158, 85, and 89.  C0 Me 2  C0 Me  CuCI AcOH • 0 °C DMF  2  *SnMe  3  (76) C(=0)R  233 R = H 235 R = Me  236,237 R = H 238,239 R = Me C0 Et 2  Me Sn 3  C0 Et 2  CuCI (10 mol %) AcOH, DMF, 0 °C  (77)  76% 136  156  79  2.  Intermolecular and intramolecular oxidative coupling of alkenyl- and  aryltrimethylstannanes mediated by copper(I) chloride 2.1 Introductory remarks  Previous  studies  8  have  described  homocoupling of alkenylstannanes.  the  copper(I)  mediated  intermolecular  This part of the thesis is mainly focused on the  intramolecular variant of the transformation. '  9 10  In particular, it was envisaged that  tricyclic systems of general structure 243 could be produced by the copper(I)-mediated oxidative coupling of two aryltrimethylstannane functions. A generalized retro synthetic disconnection is shown below (equation 78).  243  244  At this point, another potential useful application of the copper(I) mediated intramolecular homocoupling had yet to be explored fully (see retro synthetic scheme in equation 79). The synthesis of medium-sized rings (8-11 membered) has often proved to be very difficult to accomplish.  58  The reason for this has been attributed to a variety of  unfavorable entropic and enthalpic factors in the cyclization.  59  To test the limits of the  coupling methodology, a brief study into the formation of 9- and 10-membered rings of general structure 115 was undertaken (equation 79).  115  114  80 2.2 Intermolecular coupling of p-trimethylstarmyl-a.P-unsaturated ketones mediated by copperd) chloride  2.2.1 Preparation of P-trimethylstannyl-a,^-unsaturated ketones The coupling precursors required for this study were prepared via published literature procedures. Conversion of the cyclic diketones of general structure 245 (n = 1 or 2 and R = H or Me) to the p-iodoenones 246 was accomplished by treatment of the diketones 245 with triphenylphosphine, iodine, and triethylamine in acetonitrile (Table 8).  60  The P-trimethylstannyl-a,P-unsaturated ketones of general structure 247-250  were prepared by following the procedure devised by Piers, Morton, and Chong involved  the  addition  of  hthium  (trimethylstannyl)(phenylthio)cuprate  61  which  to  the  P-iodoenones 246. The spectral data derived for the compounds 246a-246d and 247-250 were in full accord with the values published in the literature. '  60 61  O  R  PPh , l 3  Li(Me Sn)(PhS)Cu, THF  R  2  3  BN 3  MeCN  o  SnMe  245  246  3  247-250  Scheme 22. Table 8. Synthesis of the iodides 246a-246d and stannanes 247-250  b  Entry  n  R  Product  % Yield  1  1  H  246a  2  1  Me  3  2  4  2  Product  % Yield  79  247  38  246b  92  248  74  H  246c  83  249  34  Me  246d  91  250  56  Isolated yield from the diketones 245. Isolated yield from the P-iodoketones 246.  3  b  81 2.2.2 Copper(I) salt mediated coupling The results of the copper(I)-mediated homocoupling experiments, in which the (3-trimethylstannyl enones 247-250 were treated with 2.5 equiv of CuCI in dry D M F for 30 minutes at room temperature, are summarized in Table 9. In each instance (entries 1-4, Table 9), the structurally unusual, crystalline bis-enones 251-254 were produced, after  aqueous workup and purification of the crude product by flash column  chromatography on silica gel, in excellent yields (81-94%). Q 0  SnMe  CuCI (2.5 equiv)  (/) T  DMF.rt 30 min  n*\JA  ^  ( 8 0 )  [I (> )  3  247-250 251-254  Table 9. Synthesis of the diketones 251-254 Entry  Substrate  n  R  Product  % Yield  1  247  1  H  251  81  2  248  1  Me  252  91  3  249  2  H  253  94  4  250  2  Me  254  91  3  Isolated yield of purified products.  The proposed structures of the homocoupled products 251-254 were confirmed by an analysis of the spectrometric ( H nmr, l  1 3  C nmr, IR, and HRMS) data. For example,  the IR spectrum of 251 (n = 1, R = H) showed the C=0 absorption at 1698 cm" . The H 1  J  nmr spectrum showed resonances attributable to the four methylene groups (two 4 proton multiplets centred at 8 2.55 and 2.88), and the two alkenyl protons (a 2 proton triplet at 8 6.43, / = 1.5 Hz). The symmetrical nature of the product was clearly shown by the simplicity of the C nmr spectrum, which displays resonances that correspond to the four 1 3  methylene carbons (8 28.2 and 35.1), four alkenyl carbons (8 132.6 and 166.9), and the two carbonyl carbons (8 208.7). The molecular formula of 3-(3-oxocyclopent-l-en-l-  82 yl)cyclopent-2-en-l-one (251) was confirmed by a H R M S measurement on the molecular ion. The structures of the remaining homocoupled products 252-254 were assigned by similar analyses of their H nmr, J  1 3  C nmr, and ER spectra and their molecular masses  were confirmed by high resolution mass spectrometric measurements.  Of particular  interest in the *H nmr spectra of the compounds 252 and 254 are the resonances due to the methyl groups which each exhibit long range coupling to a set of methylene protons and appear as triplets (8 1.67, / = 2.1 Hz and 8 1.61, / = 1.9 Hz for the diketones 252 and 254, respectively). The element of symmetry that the products 252-254 possess was highlighted in the  1 3  C nmr spectra by the appearance of 6, 6, and 7 carbon resonances,  respectively. The examples presented clearly show that P-trimethylstannyl-a,(3-unsaturated ketone functions are amenable to the copper(f) chloride-mediated homocoupling protocol.  Future work in this area may include investigations into the stereo specific  nature of the reaction, since the substrates in this study incorporated an endocyclic double bond and, as a result, stereo specificity was not an issue. The mechanism of the homocoupling reaction of alkenyltrimethylstannanes has been discussed previously (see Introduction section 2.2, pg. 8).  83 2.3  Intramolecular copperflVmediated coupling of aryltrimethylstannane functions to  aryltrimethylstannane and alkenyltrimethylstannane functions  2.3.1 Preparation of cyclization precursors The coupling substrates utilized in this study were prepared using the following protocols. Treatment of commercially available diphenyl ether (255) with 2.2 equiv of BuLi  33  and T M E D A in E t 0 for 3 h at room temperature and quenching the resultant 2  ortho-lithiated dianion 256 with 2.4 equiv of trimethylstannyl chloride provided, as a crystalline solid (mp 67-69 °C), bis(trimethylstannylphenyl) ether (104) in a good yield (74%) (Scheme 23). BuLi (2.2 equiv)  r  2Li  TMEDA  +  rt »  255  EtoO  256 Me SnCI (2.4 equiv) 3  SnMe  3  SnMe  3  ,0  104 Scheme 23.  The seven-membered ring coupling precursor 108 was synthesized from the previously prepared o-trimethylstannylbenzyl alcohol (199) and o-trimethylstannylbenzyl bromide (202) (see Discussion section 1.4.1, pg. 55). Reaction of the alkoxide of 199, formed from the treatment of the benzyl alcohol 199 with sodium hydride in dry D M F ,  5 2  with the bromide 202 provided the symmetrical ether 108 in excellent yield (98%) (equation 81).  84 1)NaH,0 C, DMF o  SnMe  SnMe  3  3  (81) 2)  Br ^ ^ " S n M e  202  199  108  33  0 °C, 30 min; rt, 14 h The proposed structures of the symmetrical ethers 104 and 108 were fully consistent with the spectral data.  Using the distannane 108 as an example, the IR  spectrum showed the tin-methyl rocking absorption at 755 cm' . The H nmr spectrum 1  1  contained resonances corresponding to the Me Sn groups (an 18 proton singlet at 8 0.26, 3  2  /sn-H  = 54.9 Hz), the methylene groups (a 4 proton singlet at 8 4.43), and eight aromatic  protons (a 6 proton multiplet at 8 7.20-7.33 and a 2 proton multiplet at 8 7.45-7.58). The 1 3  C nmr spectrum of 108 showed the expected 8 resonances. The molecular formula of  108 was confirmed by a H R M S measurement on the (M -Me) fragment. +  A series of intramolecular coupling precursors was synthesized by successive alkylations of diethyl malonate.  Dialkylation of diethyl malonate by treatment with 9  excess potassium hydride (2.5 equiv) in THF followed by the addition of 2 equiv of the benzyl bromides 203 or 204 (see Discussion section 1.4.1, pg. 55) provided the symmetrical substrates 257 and 258 in 95% and 62% yields, respectively (equation 82). Treatment of the monoalkylated malonate 212 (pg. 57) with potassium hydride in THF, 9  Et0 C  C0 Et  2  C0 Et 2  1) K H , THF, rt, 30 min  2  2) 203 or 204,  <C 0 E t  reflux  M e  3  S n  v  ^ ^  2  >  C  rf—tfK  FT  A ^ S n M e  3  "  FT  R'  R"  257 R = R = H, R = Me 258 R = R = R = O M e 1  3  1  2  2  3  (82)  85 followed by addition of the bromide 204, provided the "mixed" bisaryltrimethylstannane 259 in good yield (78%) (equation 83). Lastly, sequential alkylation of diethyl malonate 9  with the bromides 260 and 202 provided the distannane 113 (Scheme 24). 27  Et0 C  C0 Et  2  SnMe  1 ) K H , THF, rt, 30 min  3  C0 Et 2  Me Sn  2  / ^ ^ \  3  f  2) 204, reflux  C0 Et 2  SnMe  V0Me( ) 83  MeO  212  2  Et  OMe  259 1) KH, T H F , rt, 1 h  COpEt  <C 0  3  P  xSnMe  3  SnMe  3  / L ^ \ / C 0 \  I  / —  /V^Br  2  E t  1) K H , T H F rt, 1h 2) ,  I C  261  ° 2  B  260  202  reflux  reflux Et0 C 2  C0 Et 2  Me Sn  SnMe  3  3  112 Scheme 24.  The spectral data derived from the dialkylated malonate esters 257-259, and 112 were fully consistent with their assigned structures.  For example, in the spectrometric  data acquired from the diester 257, the IR spectrum showed the C=0 absorption at 1726 c m and the tin-methyl rocking absorption at 776 cm" . The H nmr spectrum 1  1  X  displayed resonances due to the Me Sn groups (an 18 proton singlet at 8 0.24, 3  2  / „-H S  =  53.1 Hz), the benzylic methylene groups (a 4 proton singlet at 8 3.38), two aromatic methyl groups (a 6 proton singlet at 8 2.25), the ethyl ester functions (a 6 proton triplet at 8 1.03, J =1.1 Hz, mutually coupled to a 4 proton quartet at 8 4.01, J =1.1 Hz), and six aromatic protons (a 4 proton multiplet centred at 8 7.00 and a 2 proton singlet at 8 7.16,  86  3  /sn-H  = 50.6 Hz). The symmetrical nature of the diester 257 was illustrated by the  appearance of 13 resonances in the  1 3  C nmr spectrum The six negative resonances seen  in an A P T experiment (S -7.4, 13.8, 20.1, 127.8, 129.0, and 137.2) could be attributed to the trimethylstannyl functions, the methyl groups, the methyl carbon of the ester moieties, and the six sp methine carbons. The molecular formula of 257 was confirmed 2  by a H R M S measurement on the (M -Me) fragment. Analyses of the spectral data ( H +  nmr,  1 3  X  C nmr, and IR) confirmed the assigned structures of the remaining distannanes  258-259 and 112 and their molecular masses were also confirmed by H R M S measurements on their respective (M -Me) fragments. +  The coupling substrates 104,108,112, and 257-259 collectively provide a diverse series of distannanes with which to examine the scope and limitations of the proposed copper(I)-mediated methodology.  2.3.2 Copper(I) chloride-mediated cyclizations The results of the copper(I) chloride-mediated ring closures of the substrates 104, 106, and 108 to form the 5-, 6-, and 7-membered cyclic ethers 105, 107, and 109 are summarized in Table 10. Treatment of a dry D M F solution of the distannane 104 with 5 equiv of CuCl, followed by stirring of the resultant mixture for 30 min at room temperature (referred to as procedure A), resulted in the clean formation of dibenzofuran (105) (98%, Table 10, entry 1).  Application of this procedure to the conversion of 106  into the tricyclic ether 107, by the formation of a six-membered ring, was also very efficient (91%, Table 10, entry 2). However, upon application of the protocol (procedure A) developed to the symmetrical ether 108, the yield of the transformation to synthesize 109 was slightly lower (75%, Table 10, entry 3). Tic analyses of the crude reaction mixtures suggested that, in addition to 109,  polar polymeric material, perhaps due to competing  intermolecular oxidative coupling processes, was being produced.  Fortunately, this  situation could be ameliorated to a large degree by the use of a modified protocol (referred to as procedure B) in which a D M F solution of the substrate was added slowly over a period of 30 min to a stirred solution-suspension of 5 equiv of copper(I) chloride  87 in dry D M F . Under these new conditions, the yield of the conversion of 108 to 109 was excellent (91%).  Each of the compounds 105, 107, and 109 have been prepared  previously and the spectral data of 107  62  and 109  63  were in full agreement with those  reported in the literature. The synthetic sample of 105 was spectrascopically identical to a commericailly available sample of dibenzofuran (105) and the melting points of the two samples were identical.  Table 10. Synthesis of the tricycles 105,107, and 109 Entry  Starting Material SnMe3  Product  % Yield  SnMe3  1  98  O—v.  3  2  SnMe3  91  O  107  SnMe  3  3  3 108 3  b  c  d  c d  Q 106  SnMe  b  105  104  Me Sn  3  75  b  91  c  109  Isolated yield of purified products. Procedure A employed - 5 equiv CuCI, D M F , rt, 30 min. Procedure B employed - 5 equiv CuCI, D M F , rt, add substrate over 30 min, stir for an additional 30 min This experimental procedure was performed by Dr. Patricia Gladstone. 31  Examples of the formation of seven-membered carbocycles via CuCl-mediated coupling of two aryltrimethylstannane moieties are summarized in Table 11. Treatment of substrate 262 with 5 equiv of CuCI in dry D M F for 30 min (procedure A) provided a satisfactory yield (78%) of the tricycle 263 (Table 11, entry 1).  However, increased  yields were obtained when procedure B was applied to the remaining examples.  For  instance, slow addition of a dry D M F solution of the distannane 257 to a solutionsuspension of 5 equiv of CuCI in dry D M F proceeded to give the tricycle 264 in excellent  88  yield (95%, Table 11, entry 2). Although, not unexpectedly, ring closure of the highly substituted hexamethoxy compound 258 to provide the sterically congested substance 266 was somewhat less facile, the yield (62%) was still quite good (Table 11, entry 4). On the other hand, the transformation of 259 into the unsymmetrical trimethoxy tricycle Table 11. Synthesis of the tricycles 113 and 263-266 Entry  Starting Material SnMe3  1  (f  Yield  Product  SnMe3  Et0 C^/C0 Et 2  2  7 8  {^^J  R R R = -C0 Et  b,d  2  262  263  SnMe3  SnMe  Et0 C -C0 Et  3  2  v  2  2  95  c  R = -C0 Et 2  257  264  /  SnMe3  SnMe  \  EtOaCv^-COaEt  3  3 OMe R = -C0 Et  MeO  259  SnMe  4 MeO  xj OMe  SnMe  5  \__J  R = -C0 Et  R  R 2  112 a  0  d  OMe  OMe  c  EtOsCv.COj.Et  MeO—\_W MeO  2  SnMe  3  R = -C0 Et  b  3  XX 258  SnMe  62  oMe  265  3  RR  c  ^ V ^ O M e  \ J ==  OMe  2  92  [f ^ \  3  M  e  W-/ 0  O  M  e  O  O  M  M  E  e  266  £ 1 0 3 0 ^ ^ 0 0 2 Et  6-b  113 Isolated yield of purified products. Procedure A employed - 5 equiv CuCl, DMF, rt, 30 min. Procedure B employed - 5 equiv CuCl, DMF, rt, add substrate over 30 min, stir for an additional 30 min. This example was performed by Dr. Patricia Gladstone. 31  94  c  3  89  265 was highly efficient (92%, Table 11, entry 3). The last example (Table 11, entry 5) illustrates a "mixed" intramolecular coupling of alkenyl- and arlytrimethylstannane functions to form a seven-membered ring. Thus, subjection of the distannane 112 to procedure B afforded the structurally novel tricycle 113 in high yield (94%). Of the seven-membered carbocyclic compounds 263-266 listed in Table 11, the compound 263 had been reported previously and the spectral data were in accordance with the reported literature values.  63  The previously unreported tricycles 264-266  (Table 11, entries 2-5) exhibited spectral data (*H nmr,  1 3  C nmr, and IR) and H R M S  measurements in full agreement with their assigned structures.  For example, the IR  spectrum of 266 showed the carbonyl absorption band at 1726 cm" \ The *H nmr spectrum of 266 showed the presence of the ethyl ester functions (a 6 proton triplet at 8 1.26, / = 7.1 Hz, and a 4 proton multiplet centred at 8 4.18), six methoxy groups (three 6 proton singlets at 8 3.64, 3.84, and 3.87), and the isolated aromatic protons (a 2 proton singlet at 8 6.56). It is interesting to note that compound 266 exhibits a *H nmr spectrum in which the benzylic methylene protons exhibit gerninal coupling (two 2 proton doublets at 8 2.73 and 3.08, / = 14.0 Hz). A similar pattern is exhibited by the *H nmr spectrum of 265. This behavior can be explained by noncoplanarity of the aromatic rings which is assisted by hindered rotation about the newly formed carbon-carbon bond.  From an  examination of molecular models, these tricycles incur severe steric interaction between the two proximal substituents (methoxy-methoxy or methoxy-hydrogen, Figure 12). As a result, free rotation about the sigma bond linking the two aryl groups is restricted. This form of atropisomerism causes the supposedly enantiotopic methylene protons (H , Hb) 64  a  to become diastereotopic and, consequently, the protons appear as two doublets in the *H nmr spectrum.  The C nmr spectrum of 266 displays only 14 signals, which is not 1 3  surprising given the symmetrical nature of the product.  In an A P T experiment, five  negative signals (8 14.2, 55.9, 60.7, 60.9, and 108.4) could be attributed to the methyl carbons of the ethyl ester functions, three pairs of methoxy groups, and the aryl methine carbons, respectively.  The molecular formula of 266 was cornroned by a H R M S  measurement on the molecular ion. A n examination of the spectrometric data (*H nmr,  90 C nmr, H R M S , and IR) acquired from the substances 264, 265, and 113 also confirmed their respective proposed structures.  266  E = C0 Et 2  265  Figure 12. Steric interactions in 265 and 266 A plausible mechanistic pathway for the intramolecular coupling reaction of aryltrimethylstannanes is shown in Scheme 25 and is analogous to that previously proposed for the copper(I)  chloride-mediated homocoupling of alkenyltrimethyl  stannanes (see Introduction section 2.2, pg. 8). Briefly, using conversion of 108 into 109 as an illustrative example, a reversible copper-tin transmetalation  108b  Scheme 25.  3  of both trimethyl-  91 stannane moieties in 108 with 2 equiv of CuCI would result in the bisarylcopper(I) species 108a and 2 equiv of Me SnCl. A disproportionation of 108a would form Cu(0) 8  3  and the copper(II) intermediate 108b, which upon a reductive elimination of a second equivalent of Cu(0) would result in the formation of the observed product 109. The use of 5 equiv of CuCI, as described in the general reaction procedure (see Experimental, pg. 229), would facilitate the coupling process by forcing the transmetalation equilibrium (right) toward the bisarylcopper(I) species 108a. The examples presented collectively in Tables 9 and 10 (pg. 87 and 88, respectively) demonstrate the efficacy of copper(I) chloride to promote the intramolecular coupling of aryltrimethylstannane functions to form 5-, 6-, and 7-membered rings. Especially impressive is the formation of the highly substituted hexamethoxy derivative 266 albeit with reduced yield (62%). A n exploration of the electronic effects from aryl substituents on the efficiency of the transformation will have to await furthur experimentation.  65  Lastly, it is also interesting to note that "mixed" intramolecular cross-  coupling of alkenyl- and aryltrimethylstannanes can be very efficient processes (Table 11, entry 5), which expands the synthetic utility of the reaction.  92 2.4  Intramolecular oxidative coupling of bisalkenyltrimethylstannanes  to form  bicyclor7.3.01dodecane and bicyclor8.3.01tridecane derivatives  2.4.1 Preparation of cyclization precursors A series of alkylating agents of general structure 267 (Chart 6) were required for use in the synthesis of the distannanes 79 and their preparation is described below. R = H, C 0 M e , or C H 0 - a l k y l n = 1 or 2 2  2  Chart 6. Treatment of the known alcohol 268  47  imidazole  48  with triphenylphosphine diiodide and  in CH2CI2 provided the iodide 269 in excellent yield (93%). The spectral  data derived from 269 were in full agreement with those previously reported. PPh -l 3  '  S  n  M  268  e  3  .SnMe  2  Imidazole  •  CHpClp  47  3  Reaction of alkynoate 270 with hthium trimethylstannyl(cyano)cuprate 66  (84)  269  38  and  methanol in THF, followed by purification of the crude material by flash column chromatography, afforded the ester 271 as a colorless oil. This material was converted to the alkyl iodide 273 with a standard deprotection-iodination sequence. Thus, treatment of the stannane 271 with T B A F  3 9  in THF followed by treatment of the resultant alcohol with  triphenylphosphine diiodide and imidazole  48  in methylene chloride provided the  alkylating agent 273 (Scheme 26). The overall yield of the three-step sequence was 65%.  93 Me0 C> 2  L ) = T  B  S  C 0 M e Me Sn(CN)CuU 2  3  TBSO-^M^SnMe  THF, MeOH  0  270  271  3  TBAF PPh -l Imidazole  Me0 C„  3  2  'SnMe  3  MeO?C>  2  CH CI 2  2  H0^^3^SnMe  273  3  272  Scheme 26.  The spectral data support the proposed structure of the iodide 273. For instance, the H nmr spectrum showed diagnostic resonances corresponding to the trimethylstannyl X  function (a 9 proton singlet at 8 0.20, /s -H = 54.6 Hz) and the methyl ester function (a 3 2  n  proton singlet at 8 3.67). The (2?)-configuration of the double bond was determined by the tin-proton coupling constant of the olefinic proton (a 1 proton triplet at 8 5.97, / = 1.2 Hz,  3  /sn-H  72.5 Hz). It is well established that the coupling constant of a vicinal  =  proton on a double bond cis to a trimethylstannyl function are of lower magnitude (-70 Hz) than those in which the Me Sn group and the hydrogen are trans to one another 3  (-120 H z ) .  67  The  1 3  C nmr spectrum displayed the expected 9 signals.  Finally, the  molecular formula of 273 was coiifirmed by a H R M S measurement on the (M -Me) +  fragment. The methyl ether 279 was prepared in five steps from the tetrahydropyranyl protected alcohol 274  41  (Scheme 27).  trimethylstannyl(cyano)cuprate  38  Treatment of the latter material with lithium  and MeOH in T H F yielded the alkenylstannane 275.  Reduction of ester 275 with D I B A L  4 4  followed by treatment of the resultant allylic  alcohol 276 with sodium hydride and methyl iodide alkenylstannane  277.  in T H F provided the  The iodide 279 was obtained by the removal of the  tetrahydropyranyl group with PPTS in methanol acquired primary alcohol to the iodide alkynoate 274.  52  4 8  46  and subsequent conversion of the  The four-step overall yield was 35% from the  94 Me0 C, 2  -COoMe Me Sn(CN)CuLi 3  3  THPO  THPO^M^SnMeg 275 1) DIBAL 2) NaH, THF; Mel  THF, MeOH  274  MeO'  1) P P T S , M e O H ~SnMe  THPO  2) P P h - l Imidazole CH CI  3  3  278 X = O H 279 X = I  2  2  r-7 ^SnMe 3  3  2 7 6 X = OH 277 X = O M e  2  Scheme 27. The spectral data was in full accord with the proposed structure of 279. The *H nmr spectrum showed key resonances corresponding to the trimethylstannyl group (a 9 proton singlet at 8 0.12,  2  /  S n  -H  = 52.5 Hz), the methyl ether moiety (a 3 proton singlet at  8 3.33), and the lone olefinic proton (a 1 proton triplet of triplets, / = 1.2, 6.0 Hz, 77.2 Hz).  3  /sn-H =  The (E)-configuration of the trisubstituted olefin was confirmed by the  magnitude of the tin-proton coupling constant. expected 9 resonances.  67  The  1 3  C nmr spectrum showed the  The molecular formula of 279 was confirmed by a H R M S  measurement on the (M -Me) fragment. +  The alkylating agents 284, 288, and 292 were prepared according to the reaction sequences outlined in Scheme 28.  Oxidation of the alcohol 280  chlorochromate in methylene chloride,  69  68  with pyridinium  provided the corresponding crude aldehyde.  The use of a modified Corey-Fuch one carbon homologation protocol '  36 37  employed  previously (see Discussion section 1.2.1, pg. 29) provided 7-te^butyldimethylsilylhept1-yne (281) in 43% overall yield.  95 1)PCC, Na0Ac,CH CI 2  TBSO  V^l ,  OH  n  2) P P h , C B r , C H C I 3) Mg, T H F  3  3  280  -H  2  4  2  2  3  TBSO'  281 Me SnCu-Me S, THF, M e O H 3  =  C0 Me  1) MeLi, T H F 2) C I C 0 M e  2  2  2  SnMe  TBSO'^MQY  TBSO  285  3  282 1) T B A F , T H F 2) P P h , l , Imidazole SnMe  Me Sn(CN)CuLi, THF, MeOH 3  SnMe  3  3  n  3  3  283 X = O H 284 X = I  Me0 C 2  286 1) DIBAL 2) NaH, T H F ; BnBr T B S O ^ > ^ V ^  2  SnMe  1) T B A F , T H F 2) P P h , l , Imidazole 3  SnMe  3  2  3  287 288 291 292  RO^ . 289 R = H 290 R = Bn  R R R R  = = = =  C0 C0 CH CH  2  2 2  M e , X = OH Me, X =I OBn, X = OH OBn, X =I  2  Scheme 28.  The spectral data was consistent with the proposed structure of 281. For example, in the IR spectrum, the alkynic function was clearly shown by C - H stretcliing absorption at 3314 cm" and the C-C triple bond stretch at 2120 cm" . The H nmr spectrum showed 1  1  X  key signals ascribed to the silyl ether moiety (a 6 proton singlet at 8 0.02 and a 9 proton singlet at 8 0.87) and the alkyne proton (a 1 proton triplet at 8 1.90, / = 2.6 Hz). The 1 3  C nmr spectrum displayed the correct number of signals, 10, and the molecular formula  was confirmed by a H R M S measurement on the (M -Me) fragment. +  96 Treatment of the terminal alkyne 281 with Me SnCu-Me2S and methanol in 41  3  T H F and purification of the crude material by flash column chromatography on silica gel served to provide the alkenylstannane 282 (Scheme 28) in good yield (73%). Subjection of 282 to a two-step deprotection-iodination sequence provided the iodide 284. Thus, removal of the TBS group with T B A F  3 9  in T H F yielded the alcohol 283. The stannane  283 was found to protiodestannylate during purfication by flash column chromatography on silica gel. However, treatment of crude 283 with triphenylphosphine diiodide and imidazole gave the iodide 284 in excellent yield (84%) from the stannane 282. 48  The spectroscopic data acquired fully support the proposed structure of the iodide 284. For instance, the *H nmr spectrum showed the trimethylstannyl function (a 9 proton singlet at 8 0.10,  2  / „-H S  = 52.8 Hz), the TBS group (a 6 proton singlet at 8 0.02 and a 9  proton singlet at 8 0.82), and two olefinic protons (two 1 proton multiplets centred at 8 5.10 and 5.62). The C nmr spectrum showed the expected 11 carbon resonances and 1 3  a H R M S mass measurement confirmed the molecular formula of 284. Preparation of the iodide 288 commenced with acylation of the terminal alkyne 281 by sequential treatment with M e L i and methylchloroformate  to provide the a,P-  38  alkynic ester 285. Reaction of the alkynoate 285 with hthium trimethylstannyl (cyano)cuprate  38  and M e O H in T H F afforded the alkenylstannane 286 in 78% yield  (Scheme 28). In a two step deprotection-iodination sequence as described above, the alkenylstannane 286 was converted to the electrophile 288 in excellent yield (97%). The proposed structure of 288 was confirmed by the spectral data (*H nmr, 1 3  C nmr, and IR). In particular, the (£)-configuration of the double bond was confirmed  by the tin-proton coupling constant of the lone olefinic proton (/sn-H 3  1 3  =  64.6 H z ) .  67  C nmr spectrum showed the presence of the expected 10 carbon resonances.  The The  molecular formula of C12H23O2S11I was confirmed by a H R M S measurement on the (M -Me) fragment. +  Lastly, reduction of the ester 286 with D I B A L allylic alcohol 289 with NaH and B n B r  52  4 4  and reaction of the resultant  provided the benzyl ether 290 (Scheme 28).  Treatment of the latter substance with T B A F in T H F ,  39  and subjection of the acquired  primary alcohol 291 to triphenylphosphine diiodide and imidazole afforded the iodide 48  292. The four-step overall yield was 68% from the stannane 286.  97 The proposed structure of 292 was fully consistent with the spectroscopic data. For instance, the H nmr spectrum of 292 displayed the trimethylstannyl group (a 9 X  proton singlet at 8 0.11), the benzyl group (a 5 proton multiplet centred at 8 7.30), the olefinic proton (a 1 proton triplet of triplets, / = 1.2, 6.0 Hz, methylene groups.  The  1 3  3  /sn-H  =  77.9 Hz), and six  C nmr spectrum showed the expected 14 carbons.  The  molecular formula of 292 was corjfimied by a H R M S measurement on the (M -Me) +  fragment. Straightforward alkylations of the malonate 261 (whose preparation was 9  described in Discussion section 2.3.1, pg. 85), by treatment of this material with L D A or K H in THF, followed by quencWng the resultant enolate anion formed with each of the iodides 269, 273, 279, 284, 288, and 292, provided the crude distannanes 293-298, respectively. Purification of the crude materials by flash column chromatography on silica gel afforded good to excellent yields of 293-298 (73-96%, Table 12).  SnMe A / ^ C O z E t  /—,  3  \ 7 N  —'  c  R  c  ^  (85)  1  SnMe  C0 Et 2  261  3  E = C0 Et  SnMe  3  2  293-298 Table 12. Synthesis of the distannanes 293-298 Entry  n  R  Product  % Yield  1  1  -H  L D A , THF, 0 °C; 269, reflux  293  78  2  1  -C0 Me  L D A , THF, 0 °C; 273, reflux  294  86  3  1  -CH OMe  K H , THF, rt; 279, reflux  295  92  4  2  -H  K H , THF, rt; 284, reflux  296  96  5  2  -C0 Me  K H , THF, rt; 288, reflux  297  82  6  2  -CH OBn  K H , THF, rt; 292, reflux  298  73  2  2  2  2  Reaction conditions  3  Isolated yield of purified products.  The structures of the dialkylated materials 293-298 were fully supported by thenrespective *H nmr, C nmr, and IR spectra. For instance, the C=0 functions in 294 were 1 3  indicated by the broad absorption at 1729 cm" . The *H nmr spectrum of 294 showed the 1  98 presence of two alkenyltrimethylstannane functions, nine methylene groups, two ethyl ester functions, the methyl ester moiety, and the lone olefinic proton (see Experimental pg. 256 for assignments). In addition, the trans configuration of the a,P-unsaturated ester function was confirmed by the magnitude of the tin-proton coupling constant of the 67  alkenyl proton ( /s -H = 73.7 Hz). The C nmr spectrum showed the expected 21 signals. 3  1 3  n  Also, the molecular formula of C28H o06Sn was confirmed by a H R M S measurement on 5  the (M -Me) fragment. +  2  The structures of the remaining distannanes 293 and 295-298  were confirmed by analyses of their spectrometric data (*H nmr,  1 3  C nmr, IR, and  HRMS). Collectively,  the  cyclization substrates  293-298  display  a  variety  of  alkenyltrimethylstannane partners with which to test the copper(I) chloride-mediated oxidative coupling process to form 9- and 10-membered rings.  2.4.2 Copper(I) mediated cyclizations  Individual solution-suspensions of CuCI (5 equiv) in dry D M F were treated with a D M F solution of each of the distannanes 293-298 (1 equiv), added over a period of 2 h, followed by stirring the reaction mixture for an additional 2 h. The results derived from these experiments are summarized in Table 13.  SnMe  3  E = C0 Et 2  293-298  R  5 equiv CuCI DMF, rt  SnMe  add stannane over 2 h; stir 2 h  3  E (86) n R E = C0 Et 299-304 2  99  Table 13. Synthesis of the bicyclic dienes 299-304 Entry  Starting Material  n  R  Product  Yield  1  293  1  H  299  93  2  294  1  -C0 Me  300  72  3  295  1  -CH OMe 2  301  91  4  296  2  H  302  5  297  2  -C0 Me  303  45  6  298  2  -CH OBn  304  c  2  2  2  3  Yield of purified products. A mixture of product 302, protiodestannylated, dichlorodestannylated, and chlorodestannylated material was obtained. A rnixture of product 304, protiodestannylated and chlorodestannylated material was obtained. 3  b  c  Under the cyclization conditions described above (equation 86), the distannanes 293-295 were transformed into the 9-membered carbocycles 299-301, respectively, in good to excellent yields (71-93%). The experimental conditions employed in this study differed somewhat from that developed previously (5 equiv CuCl, D M F , 60 °C, addition of the substrate over 15 min followed by stirring the mixture for an additional 15 min).  9  In particular, it was found  that elevated reaction temperatures (60 °C) diminished the efficiency of the conversion of 293 into 299 to 78% (cf. 93%, Table 13, entry 1) after workup and flash column chromatography on silica gel (equation 87). 5 equiv CuCl DMF, 60 °C (87) SnMe  SnMe  3  E = C0 Et 2  293  3  add over 2 h; stir 2 h 78 %  E  = C0 Et 2  299  A faster rate of addition was also detrimental to the yield of the reaction. By the addition of the cyclization substrate 294 to the CuCl over a period of 15 min, the yield of the transformation to form 300 was reduced from 72% (Table 13, entry 2) to 50%  100 (equation 88).  The reduction in the yield was due to competing intermolecular  homocoupling processes. 8  C0 Me 2  SnMe  SnMe  3  E = C0 Et 2  3  5 q i CuCI DMF, rt e  U  (88)  v  add over 15 min; stir 15 min  E = C0 Et 2  C  ° 2  M  e  50%  294  300 + dimers (-25 %)  The structures of the carbocycles 299-301 were confirmed by an analysis of the spectroscopic data. For instance, in the IR spectrum of 299, the carbonyl stretch was present at 1729 cm" and a C=C bond stretch at 1626 cm" . In the H nmr spectrum, aside 1  1  X  from the ethyl ester functions (a 6 proton triplet at 8 1.21, / = 7.1 Hz, and a 4 proton multiplet centred at 8 4.16) and eight methylene groups, the key indication that the cyclization successfully formed 299 was the appearance of the resonances corresponding to only two alkenyl protons (a 1 proton doublet at 8 4.90, / = 2.0 Hz, and a 1 proton broad singlet at 8 4.94). The C nmr spectrum contained the expected 16 signals and, in 1 3  an A P T experiment, the presence of only one negative resonance at 8 14.0 was attributed to the methyl group of the ester functions. Lastly, the molecular formula of 299 was confirmed by a high resolution mass spectrometric measurement on the molecular ion. The structures of the remaining 9-membered ring compounds 300 and 301 were assigned by analyses of their respective *H nmr,  1 3  C nmr, and IR spectra. For instance,  the key resonances in the *H nmr spectrum of 300 and 301 was the presence of only one alkenyl proton (a 1 proton singlet at 8 5.67 and a 1 proton triplet at 5.41, J = 6.4 Hz, respectively).  The  1 3  C nmr spectra of each compound contained the expected 18  resonances. The molecular formulae of 300 and 301 were confirmed by suitable H R M S measurements on their molecular ions. Lastly, the (£)-configuration of the trisubstituted double bond in 300 and 301 was determined by a series of H nmr nOed experiments (see X  Experimental, pg. 267 and 269).  101 In contrast to the cyclizations to form the 9-membered ring compounds 299-301, application of the methodology to form the 10-membered ring compounds 302-304 was notably less successful (Table 13, entries 4-6, pg. 99). For example, upon treatment of the distannane 296 with 5 equiv of copper(I) chloride in dry D M F (equation 89), a complex mixture was isolated after aqueous workup (Table 13, entry 4).  The major  products isolated from a flash chromatographic column were protiodestannylated material 305 (-30%) and an inseparable mixture (>6 compounds, -50%) consisting primarily of cyclized adduct 302 (m/z = 334), chloroprotiodestannylated materials 306 and 307 (m/z = 370), and dichlorodestannylated material 308 (m/z = 404) in an -6:2:1 ratio, respectively, as determined by G C and GC-MS analysis.  Disappointingly, a similar result was obtained in the attempted conversion of 298 into 304 (Table 13, entry 6).  After aqueous workup, an inseparable mixture of  compounds was obtained by a flash chromatography of the crude material on silica gel. The mass balance was moderate (-70%). The purified material consisted of the cyclized adduct 304 (m/z = 454), chloroprotiodestannylated compounds 309 and 310 (m/z = 490), and unidentifiable material in a ratio of -5:3:2, respectively, as determined by G C and G C - M S analysis (equation 90).  102  310  OBn  + ? On the other hand, treatment of the distannane 297 with 5 equiv of copper(I) chloride successfully produced the cyclized adduct 303 in moderate yield (45%, Table 13, entry 5, pg. 99). The reaction was not clean. Tic analyses of the crude reaction mixtures indicated that, in addition to 303, a polar unidentified mixture was present (>5 compounds). In this case, the structural assignment related to 303 as derived from the spectral data (*H nmr) was difficult.  This difficulty was due to the numerous possible  conformations of the carbocycle 303 as indicated by molecular models.  The H nmr 1  spectra was riddled with broad unresolved multiplets but, fortunately, the vinylic region of the spectrum contained one clear singlet at 8 5.59 which corresponded to the lone olefinic proton in 303. The  1 3  C nmr spectrum showed the expected 19 resonances and  three negative resonances (8 14.1, 50.9, and 115.0) in an A P T experiment could be ascribed to the methyl carbons of the ethyl ester functions, the methyl ester, and the lone sp olefinic C - H , respectively. 2  The IR spectrum showed a carbonyl absorption at  1730 cm" and a C-C double bond stretching absorption at 1620 cm" . 1  1  Lastly, the  molecular formula of 303 was confirmed by a H R M S measurement on the molecular ion. The configuration of the exocyclic double bond in 303 could not be directly confirmed by  103 suitable nOed experiments nor did recrystallization attempts provide crystals suitable for X-ray analysis. As a result, the (£)-configuration of the olefin could only be designated by analogy with the 9-membered homo log 300. r~\  E  f  E  M e  K^K^Yf^ SnMe  3  DMF.rt  C0 Me  5 3  5 equiv CuCI  2  E = C0 Et  (91)  add over 2 h; stir 2 h E = C0 Et 303  2  C0 Me  2  297  2  The presence of chlorodestannylated material 306-308 (equation 89) and 309-310 (equation 90) in the cyclization reactions is not unprecedented.  Previous work in our  laboratory had shown that, in the presence of elevated amounts of Me SnCl (5 equiv), the 3  intermolecular homocoupling reaction of 163 is retarded and increased amounts of chlorodestannylated material 312 is formed (equation 92). ^  X0 Me  C0 Me  2  SnMe  D 3  M  F  -  ,C0 Me  2  2.5 equiv CuCI  2  'H 311  0 equiv Me SnCI, 1 h 5 equiv Me SnCI, 48 h 3  3  ^ . C 0 / | |  2 0  Cl 312 10 92  2  M e  x>  +  rt  163  53  Me0 C 313 87 8 glc ratio 2  CO  It has been proposed  that the formation of chlorodestannylated material may be  rationalized by invoking a pathway involving the copper(ffl) intermediate 314a formed from the oxidative addition of CuCI with the alkenylstannane 314 (Scheme 29). The copper(III) intermediate 314a may undergo a reductive elimination of Me SnCu to 3  provide the chlorodestannylated product 314c.  Alternatively, 314a may reductively  eliminate Me SnCl to give the copper(I) intermediate 314b. 3  The intermediate 314b can  then undergo the oxidative coupling process (see Introduction section 2.2, pg. 8). However, the presence of Me SnCl would shift the equilibrium between 314a and 314b 3  toward the copper(III) species 314a (left) and, consequently, retard the coupling reaction and promote the formation of the alkenyl chloride 314c.  104  T  A/SnMes  + CuCl  T  - Me SnCI  /L^Cu(Me Sn)CI  - CuCl  314  3  3  + Me SnCI 3  314b  314a  y  + Me SnCu 3  314c Scheme 29.  This rationale is consistent with the speculation that the reaction, as expected, provide, during the initial stages of the processes, the desired cyclized products. With continued slow addition of the cyclization substrates, the copper(I) chloride is consumed while the coproduct, Me SnCl, remains in the reaction pot. 3  In cases where the  intramolecular cyclizations are not favored (Table 13, entries 4-6, pg. 99), the organocopper(III) intermediates (314a) persist in the reaction mixture for longer periods of time.  The combination of slow rates of cyclization and higher concentrations of  Me SnCl results in the formation of chlorodestannylated material in the latter stages of 3  the reaction. Future work in this area may include the addition of reagents, such as CsF,  7  whose purpose is to sequester Me SnCl and avert the formation of such side products. 3  The results of this study indicate that the intramolecular copper(I) chloridemediated coupling of alkenylstannane functions to form 9-membered rings is a feasible synthetic process. The use of alkenylstannane substrates that contain ester and alkyl ether functions shows that these functional groups are tolerated in the cyclization methodology. However, the less facile formation of 10-membered rings and competing side reactions shows a possible limitation of the copper(I)-mediated methodology.  105 2.5 Summary  In  the  work  described  in  this  section,  a  variety  of  aryl-  and  alkenyltrimethylstannane precursors were prepared by via a series of known synthetic transformations. chloride  to  These precursors were then subjected to treatment with copper(I)  effect  bond  formation  between  the  carbon  centres bearing  the  trimethylstannane functions. For instance, the intermolecular oxidative homocoupling of p-trimethylstannyl  a,P-unsaturated  ketones  247-250  was  shown  to  corresponding products 251-254 in excellent yields (equation 80, pg. 81).  give  the  In another  study, the intramolecular coupling of two aryltrimethylstannane functions produced 5-, 6-, and 7-membered tricycles in good yields (equations 93-96). methodology  is illustrated by the  successful  aryltrimethylstannane functions (equation 97).  A n extension to this  mixed coupling of alkenyl-  and  Lastly, a brief investigation relating to  the intramolecular coupling of bisa&enyltrimethylstarrnanes was undertaken. By the use a modified experimental procedure, a series of bicyclic systems 115 were synthesized by the closure of several 9-membered rings and one 10-membered ring (equation 98).  104  105  106  114  115  107  III. E X P E R I M E N T A L  1. General  1.1 Data acquisition, presentation, and techniques  Proton nuclear magnetic resonance (*H nmr) spectra were obtained on a Bruker model WH-400 (400 MHz) or AMX-500 (500.2 MHz) spectrometer  utilizing  deuteriochloroform (CDC1 ) or hexadeuteriobenzene (C D ) as the solvent. 3  6  Signal  6  positions (8) were recorded in parts per million (ppm) from tetramethylsilane (8 0) and were measured relative to the residual proton signal of chloroform (8 7.24) or benzene (8 7.15). Coupling constants (/ values) are given in Hertz and are reported to the nearest 0.1 Hz). Tin-proton coupling constants (Js -n) are given as an average of the n  119  117  S n and  S n values. The multiplicity, number of protons, coupling constants, and assignments  (where possible) are given in parentheses following the chemical shift. Abbreviations used are: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. In the H nmr :  spectra data, H-x and H-x' have been used to designate protons on the same carbon, with H-x' being the proton resonating downfield to H-x.  In some cases, the proton  assignments were supported by two-dimensional ('H^H) - homonuclear correlation spectroscopy (COSY), which was carried out using a Bruker AC-200E or WH-400 spectrometer. Carbon nuclear magnetic resonance ( C nmr) spectra were obtained on a Varian 13  model XL-300 (75.5 MHz) or on Bruker models AC-200E (50.3 MHz) or AMX-500 (125.8 MHz) spectrometers using deuteriochloroform (CDCI3) or hexadeuteriobenzene (CeD ) as the solvent. 6  Signal positions (8) were given in parts per million from  tetramethylsilane and were measure relative to the signal of deuteriochloroform (8 77.0) or hexadeuteriobenzene (8 128.0). Attached proton tests (APTs), used to differentiate methyl and methine (negative phase signals) from methylene and quaternary carbons  108 (positive phase signals), were recorded on a Varian XL-300 or Bruker AC-200E spectrometers. Where APT data is given, signals with negative phases are so indicated in brackets (-ve) following the  1 3  C nmr chemical shifts. In some cases, the proton and  carbon assignments were supported by two-dimensional ^ H ^ C ) - heteronuclear multiple quantum coherence experiments (HMQC) and heteronuclear multiple bond correlation experiments (HMBC), which were carried out using a Bruker AMX-500 spectrometer. Infrared (IR) spectra were recorded on a Perkin Elmer 1710 Fourier transform spectrophotometer with internal calibration between sodium chloride plates (liquid samples) or as potassium bromide pellets (solid samples). In each case, only selected characteristic absorption data are given for each compound. Low and high resolution mass spectra were recorded on a Kratos M S 80 or on a Kratos Concept  II H Q mass spectrometer using an electron impact source.  molecular ion (M ) masses are given unless otherwise noted.  For some of the  +  compounds containing the trimethylstannyl (Me Sn) or the 3  (£-BuMe2Si)  moiety,  the  high  resolution mass  determinations were based on the (M -Me) peak. +  The  te^butyldimethylsilyl  spectrometry  molecular  mass  A l l compounds subjected to high  resolution mass measurements were homogeneous by G L C and/or T L C analyses. Gasliquid chromatography-mass spectrometry (GLCMS) was performed on a Carlo Erba model 4160 capillary gas chromatograph (15 m x 0.25 mm fused silca column coated with DB-5) and a Kratos/RFA M S 80 mass spectrometer. A l l compounds subjected to high resolution mass measurements were homogeneous by G L C and /or T L C analyses. Elemental analyses were performed on a Carlo Erba C H N model 1106 or on a Fisons E A model 1108 elemental analyzer, by the U B C Microanalytical Laboratory. Melting points (mp) were measured on a Fisher-Johns melting point apparatus and are uncorrected. Distillation temperature (air baths), which refer to bulb-to-bulb (Kugelrorh) distillations, are uncorrected. Unless otherwise noted, all reactions were carried out under an atmosphere of dry argon using glassware that had been oven (-140 °C) dried and/or flame dried. Glass syringes, stainless steel needles, and Teflon cannulae used to handle various anhydrous solvents and reagents were oven dried and flushed with argon prior to use. Plastic syringes were flushed with argon prior to use. The small and large bore Teflon cannulae  109 has an inner diameter of 0.38 mm and a wall thickness of 0.23 mm; the large cannulae has an inner diameter of 0.97 mm and a wall thickness of 0.30 mm. Tdiin layer chromatography (TLC) was perfomed using commercial aluminum backed silica gel 60  F254  plates (E. Merck, type 5554, thickness 0.2 mm). Visualization  of the chromatograms was accomplished using ultraviolet light (254 nm) and/or iodine (iodine which had been adsorbed onto unbound silca gel) followed by heating the plate after staining with one of the following solutions: (a) vanillin in a sulfuric acid-EtOH mixture (6% vanillin w/v, 4% sulfuric acid v/v, and 10% water v/v in EtOH), (b) phosphomolybdic acid in EtOH (20% phosphomolybdic acid w/v, Aldrich), (c) anisaldehyde in a sulfuric acid-EtOH rnixture (5% anisaldehyde v/v and 5% sulfuric acid v/v in EtOH). Flash chromatography was performed using 230-400 mesh silica gel 70  (E. Merck, Silica Gel 60), followed the technique described by Still. Gas liquid chromatography (GLC) was perfomed on a Hewlett-Packard model 5890 gas chromatograph equipped with flame ionization detectors and fused silica columns  (Hewlett-Packard  HP-5),  25  m  x  0.20  mm  coated  with  5%  phenylmethylsilicone. Concentration, evaporation, removal of solvent in vacuo, or removal of solvent under reduced pressure (water aspirator) refers to solvent removal via a Buchi rotary evaporator at -15 torr. Cold temperatures were maintained by the use of the following baths: 0 °C, icewater; -20 °C, -35 °C, -48 °C, aqueous calcium chloride-dry ice (27, 39, and 47 g CaCl /100 m L H 0 , respectively); -78 °C, acetone-dry ice. 2  2  110 1.2 Solvents and reagents A l l solvents and reagents were purified, dried, and/or distilled using standard procedures. Benzene and dichloromethane were distilled from calcium hydride. Diethyl 71  ether and tetrahydrofuran were distilled from sodium benzophenone ketyl.  The four  aforementioned solvents were distilled under an atmosphere of dry argon and used immediately. Triethylamine, dhsopropylamine, and hexamethylphosphoro amide (HMPA) were distilled from calcium hydride. Magnesium was added to methanol and, after refluxing the mixture, the methanol was distilled from the resulting solution of magnesium methoxide.  N,iV-dimethylformamide (DMF) and dimethylsulfoxide (DMSO) were  sequentially dried over 3 A molecular sieves. The aforementioned reagents were stored 72  under an atmosphere of argon in bottles sealed with a Sure/Seal (Aldrich Chemical Co., Inc.). Petroleum ether refers to a hydrocarbon mixture with a boiling range of 35-60 °C. Solutions of methyllithium in diethyl ether and n-butyllithium in hexanes were obtained from Aldrich Chemical Co., Inc. and Acros and standardized using the procedure of Kofron and Baclawski.  73  Copper(I) bromide-dimethyl sulfide complex was prepared by the method described by Wuts  74  (by Rene Lemieux of Dr. Piers' research group at UBC) and was  stored in a desiccator under an atmosphere of dry argon. Copper(I) chloride (99.995% or 99%+), copper(I) cyanide, and phenylthiocopper(I) were purchased from Aldrich Chemical Co., Inc., and were used without further purification. Hexamethylditin and trimethyltin chloride were obtained from Organometallics Inc. and Aldrich Chemical Co., Inc., respectively, and were used without further purification. Lithium dhsopropylarnide (LDA) was prepared by the addition of a solution of n-butyllithium (1 equiv) in hexanes to a solution of dry diisopropylarnine (1.1 equiv) in dry tetrahydrofuran at 0 °C. The resulting colorless solution was stirred at 0 °C for 15 minutes prior to use.  Ill Potassium hydride was obtained as a 35% suspension in mineral oil and sodium hydride as a 60% dispersion in mineral oil from Aldrich Chemical Co., Inc., and were rinsed free of oil with dry diethyl ether or pentane under a stream of dry argon prior to use. A l l other reagents were commercially available and were used without further purification. Aqueous ammonium chloride-ammonia (NH4CI-NH3-H2O) (pH 8) was prepared by the addition of -50 mL of concentrated aqueous ammonia to 950 mL of a saturated aqueous ammonium chloride solution.  112  2. Intramolecular conjugate additions to form monocycles 2.1 Preparation of cyclization precursors  Preparation of 2-(trimethvlstannvl)-6,6-dibromohexa-l,5-diene (127)  125  126  127  To a cold (-78 °C), stirred solution of oxalyl chloride (1.10 mL, 12.6 mmol) in dry CH C1 (40 mL) was added dimethyl sulfoxide (2.00 mL, 23.5 mmol) dropwise via a 2  2  syringe. The solution was stirred for a period of 15 min. 4-Trimethylstannylpent-4en-l-ol (125) was added over 3 min as a solution in dry C H C 1 (5 mL). The cloudy 35  2  white suspension was stirred for an additional 15 min.  2  Triethylamine (8.00 mL,  57.0 mmol) was added dropwise via a syringe and the mixture was stirred for 20 min. The reaction mixture was warmed to room temperature and water (20 mL) was added. The organic phase was separated and the aqueous layer was extracted with CH C1 (3 x 2  2  20 mL). The organic layers were combined, washed with brine (30 mL), and dried (MgSC>4). The solvent was removed under reduced pressure to provide the aldehyde 126 as a crude oil.  To a cool (0 °C), stirred solution of carbon tetrabromide (1.96 g, 5.90 mmol) in dry CH C1 (80 mL) was added triphenylphosphine (8.55 g, 32.3 mmol) in one portion. The 2  2  mixture was stirred for 10 min. A solution of the crude oil (obtained as described above) in dry C H C 1 (5 mL) was added via a cannula. The reaction mixture turned from a 2  2  bright orange-yellow suspension into a brown suspension. The mixture was stirred for 40 min.  Pentane (200 mL) was added and the mixture was filtered through silica gel  (-20 g) and the cake was eluted with pentane (200 mL). The combined filtrate was concentrated under reduced pressure. Flash column chromatography (75 g of silica gel, petroleum ether) of the crude product and removal of trace amounts of solvent (vacuum  113 pump) from the acquired material yielded 2.08 g (90% over two steps) of the dibromoalkene 127 as a colorless clear oil.  IR (neat): 3035, 1602, 1276, 920, 770, 528 c m . 1  H nmr (400 M H z , CDC1 ) 5: 0.14 (s, 9H, -SnMe., / . = 52.0 Hz), 2.12-2.20 (m, 2H,  l  2  3  S n  H  HO, 2.35 (t, 2H, H , / = 7.6 Hz, J . = 47.5 Hz), 5.19 (s, IH, H 3  3  (s,  1 3  IH,  Hi',  3  Sn H  / „ - H = 148.0  Hz),  S  6.45  (t,  IH,  H , 5  /=  7.0  3 1 ;  / . = 69.4 Hz), 5.67 S n  H  Hz).  C nmr (50.3 M H z , CDC1 ) 5: -9.4, 33.0, 38.3, 88.9, 125.7, 137.9, 153.8. 3  H R M S calcd for C H 8  120 13  S n B r B r (M -Me): 388.8386; found: 388.8386. 79  81  +  Anal, calcd for C H B r S n : C 26.84, H 4.00; found: C 27.12, H 4.00. 9  16  2  Preparation of ethyl 6-trimethylstaniiylhept-6-en-2-ynoate (129) C0 Et 2  •HMe Sn 3  Me Sn  B r  3  Me Sn 3  127  128  129  To a stirred suspension of crushed magnesium metal (189 mg, 7.75 mmol) in dry THF (15 mL) was added a few crystals of iodine and the mixture was refluxed for 1 h. [Note: The magnesium metal must be freshly crushed and the particles small otherwise no reaction occurs.] The dibromoalkene 127 (2.08 g, 5.16 mmol) dissolved in dry T H F (5 mL) was added and the mixture was stirred at reflux for 1 h. The mixture was cooled to room temperature and pentane (20 mL) was added. The white suspension was filtered through silica gel (~5 g) and the cake was eluted with pentane (50 mL). The combined filtrate was concentrated under reduced pressure to yield the alkyne 128 as a slightly  114 yellow tinged oil. This oil proved to be volatile and was immediately used in the next reaction.  To a cold (-78 °C), stirred solution of L D A (5.44 mmol) in dry T H F (40 mL) was added a solution of the crude oil (obtained as described above) in dry T H F (3 mL). The solution was stirred at -78 °C for 25 min. Ethyl chloroformate (0.72 ml, 7.5 mmol) was added and the solution was stirred for 1 h at -78 °C and 1 h at room temperature. Saturated aqueous sodium bicarbonate (30 mL) was added and the aqueous layer was extracted with E t 0 2  (3 x 20 mL). The organic extracts were combined, washed with brine (60 mL), dried (MgSQO, and the solvent was removed under reduced pressure.  Flash column  chromatography (125 g of silica gel, 98:2 petroleum ether-Et 0) of the crude oil and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 1.29 g (79% over two steps) of the ester 129 as a clear oil.  IR (neat): 2236, 1713, 1447, 1251, 1073, 770, 467 c m . 1  *H nmr (400 M H z , CDC1 ) 8: 0.14 (s, 9H, -SnMe^ / . 2  3  S n  H  = 53.1 Hz), 1.28 (t, 3H,  - C 0 C H C H 3 , / = 7.2 Hz), 2.40 (t, 2H, H4, / = 7.5 Hz), 2.52 (t, 2H, H , / = 7.5 Hz, 2  3  /S„.H=  2  5  50.7 Hz), 4.20 (q, 2H, -C0 CH2CH , / = 7.2 Hz), 5.22 (s, I H , H , 2  3  7  3  / „-H S  =  68.7 Hz), 5.79 (s, I H , H *, / . = 146.8 Hz). 3  7  1 3  Sn  H  C nmr (50.3 M H z , CDC1 ) 8: -9.5, 14.0, 18.7, 37.9, 61.7, 73.6, 88.6, 126.0, 152.5, 3  153.7.  H R M S calcd for C n H O 1 7  1 2 0 2  S n (M -Me): 301.0251; found: 301.0257. +  Anal, calcd for C H O S n : C 45.76, H 6.40; found: C 45.82, H 6.46. 12  20  2  115 Preparation of 2-(trimethylstarjnvlV7J-dibromohepta-l,6-diene (130b)  130  130a  130b  To a cold (-78 °C), stirred solution of oxalyl chloride (1.10 mL, 12.6 mmol) in dry CH2CI2 (40 mL) was added dimethyl sulfoxide (1.70 mL, 24.0 mmol) dropwise via a syringe. The solution was stirred for a period of 15 min. 5-Trimethylstannylhex-5-en-lol (130) (1.50 g, 5.72 mmol) was added over 3 min as a solution in dry CH2CI2 (5 mL). 35  The cloudy white suspension was stirred for an additional 15 min.  Triethylarnine  (6.50 mL, 46.6 mmol) was added dropwise via a syringe and the mixture was stirred for 20 min. The reaction mixture was warmed to room temperature and water (20 mL) was added.  The organic phase was separated and the aqueous layer was extracted with  CH2CI2 (3 x 20 mL). The organic layers were combined, washed with brine (50 mL), and dried (MgSC^).  The solvent was removed under reduced pressure to provide the  aldehyde 130a as a crude oil.  To a cool (0 °C), stirred solution of carbon tetrabromide (5.85 g, 17.6 mmol) in dry CH C1 (100 mL) was added triphenylphosphine (9.36 g, 35.7 mmol) in one portion. The 2  2  mixture was stirred for 10 min. A solution of the aldehyde 130a (obtained as described above) in dry CH2CI2 (5 mL) was added via a cannula. The reaction mixture turned from a bright orange-yellow suspension into a brown suspension. The mixture was stirred for 40 min. Pentane (200 mL) was added and the mixture was filtered through a pad of silica gel (-20 g) and the cake was eluted with pentane (200 mL). The combined filtrate was concentrated under reduced pressure. Flash column chromatography (75 g of silica gel, petroleum ether) of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 2.16 g (91% over two steps) of the dibromoalkene 130b as a colorless clear oil.  IR (neat): 2361, 1837, 1718, 1621, 1437, 1189, 917, 867, 769, 575 c m . 1  116  *H nmr (400 M H z , CDC1 ) 5: 0.12 (s, 9H, -SnMfr. / . = 52.9 Hz), 1.40-1.60 (m, 2H, 2  3  S n  H  H,), 2.00-2.15 (m, 2H, H ), 2.28 (t, 2H, H , / = 6 . 5 , / . = 50.9 Hz), 5.15-5.19 (m, I H , 3  5  Hi,  3  / s „ .  H  3  = 70.6 Hz), 5.63-5.65 (m, I H , Hj',  Sn  3  / n-H S  H  = 171.9 Hz), 6.37 (t, I H , H , 6  7=7.2 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 8: -9.4 (-ve), 27.6, 32.5, 40.0, 88.9, 125.2, 138.4 (-ve), 3  154.7.  H R M S calcd for C H 9  118 15  S n B r B r (M -Me): 400.8536; found: 400.8530. 79  81  +  Anal, calcd for C i H B r S n : C 28.82, H 4.35; found: C 28.61, H 4.35. 0  18  2  Preparation of ethyl 7-trimethvlstannyloct-7-en-2-ynoate (131)  131 To a stirred suspension of freshly crushed magnesium metal (201 mg, 8.26 mmol) in dry T H F (15 mL) was added a few crystals of iodine and the mixture was refluxed for 1 h. A solution of the dibromoalkene 130b (1.68 g, 4.05 mmol) in dry T H F (5 mL) was added and the mixture was stirred at reflux for 1 h. [Note: The magnesium metal must be freshly crushed and the particles small otherwise no reaction occurs.] The mixture was cooled to room temperature and pentane (20 mL) was added. The white suspension was filtered through a pad of silica gel (-10 g) and the cake was eluted with pentane (150 mL). The combined filtrate was concentrated under reduced pressure to yield the  117 alkyne 135 as a yellow crude oil. This oil proved to be volatile and was immediately used in the next reaction.  To a cold (-78 °C), stirred solution of L D A (4.96 mmol) in dry T H F (30 mL) was added a solution of the alkyne 135 (obtained as described above) in dry T H F (2 mL). The solution was stirred at -78 °C for 30 min. Ethyl chloroformate (0.80 mL, 8.4 mmol) was added and the solution was stirred for 1 h at -78 °C and 1.5 h at room temperature. Saturated aqueous sodium bicarbonate (20 mL) was added and the aqueous layer was extracted with E t 0 (3 x 20 mL). The organic extracts were combined, washed with 2  brine (50 mL), dried (MgS0 ), and the solvent was removed under reduced pressure. 4  Flash column chromatography (125 g of silica gel, 98:2 petroleum ether-Et 0) of the 2  crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 1.04 g (79 % over two steps) of the ester 131 as a clear oil.  IR (neat): 2237, 1714, 1456, 1250, 1073, 919, 753, 526 c m . 1  X  H nmr (400 M H z , CDC1 ) 5: 0.12 (s, 9H, -SnMe^, / . 2  3  S n  H  = 52.6 Hz), 1.28 (t, 3H,  - C 0 C H C H 3 , / = 7.2 Hz), 1.60-1.70 (m, 2H, H ) , 2.28 (t, 2H, FL,, J = 7.1 Hz), 2.35 (t, 2  2  5  2H, H , / = 7.6 Hz,  3  (m, 1H, H ,  70.4 Hz), 5.65-5.70 (m, 1H, H ' , / . = 150.0 Hz).  6  3  8  1 3  / n-H= S  / „-H= S  63.9 Hz), 4.16 (q, 2H, - C O ^ I f c C t t , , / = 7.2 Hz), 5.15-5.20 3  8  Sn  H  C nmr (75.5 MHz) 5: -9.6 (-ve), 14.0 (-ve), 17.9, 27.1, 39.4, 61.6, 73.4, 88.8, 125.8,  153.7,153.9.  H R M S calcd for C H O 1 2  1 9  1 2 0 2  S n (M -Me): 315.0407; found: 315.0409. +  Anal, calcd for C i H 0 S n : C 47.46, H 6.74; found: C 47.65, H 6.90. 3  22  2  118 Preparation of l-(fe^butyldimethylsilyl)hepta-L6-diyne (133)  TBS  132  133  To a cold (-78 °C), stirred solution of hepta-l,6-diyne (132) (2.70 mL, 23.6 mmol) in dry THF (100 mL) was added M e L i (20.0 mL, 1.56 M in E t 0 , 31.2 mmol). After 10 rnin, 2  the reaction mixture was warmed to -20 °C and stirred for an additional 60 rnin. ?er?-Butyldimethylsilyl chloride (4.95 g, 32.8 mmol) was added in one portion and the solution was stirred at -20 °C for 15 min and then warmed to room temperature for 60 min. Saturated aqueous sodium bicarbonate (50 mL) was added and the phases were separated. The aqueous phase was extracted with E t 0 (3 x 50 mL) and the combined 2  organic extracts were washed once with brine (50 mL), dried (MgS0 ), and concentrated 4  under reduced  pressure.  Purification of the crude material by flash column  chromatography  (150 g of silica gel, petroleum ether), followed by bulb-to-bulb  distillation (50-60 °C/0.1 torr) of the acquired hquid, provided 4.07 g (83 %) of the alkyne 133 as a colorless oil.  IR (neat): 3313, 2175, 1251, 839, 776 cm" . 1  *H nmr (400 M H z , CDC1 ) 8: 0.06 (s, 6H, -SiMe?-\ 0.90 (s, 9H, -Si'Bu-), 1.69-1.76 (m, 3  2H, HO, 1.93 (t, IH, H , / = 2.5 Hz), 2.29 (td, 2H, H , / = 7, 2.5 Hz), 2.34 (t, 2H, H , 7  5  /=7Hz).  1 3  C nmr (125.8 M H z , CDC1 ) 8: -4.5, 16.5, 17.5, 18.9, 26.1, 27.7, 68.7, 83.4, 83.5, 106.6. 3  HRMS calcd for C H S i : 206.1491; found: 206.1495. 13  22  Anal, calcd for C i H S i : C 75.65, H 10.74; found: C 75.58, H 10.71. 3  22  3  119  TBS  133  134 Me Sn  Me Sn  3  3  C0 Et  H  2  131  135  To a cold (-78 °C), stirred solution of hexamethylditin (7.98 g, 24.4 mmol) in dry T H F (150 mL) was added a solution of M e L i (17.2 mL, 1.41 M in E t 0 , 24.3 mmol) via a 2  syringe and the solution was stirred for 30 min. The solution was cooled to -78 °C and copper bromide-dimethyl sulfide complex (4.89 g, 23.8 mmol) was added in one portion. The red-brown suspension was stirred for 30 min. l-(fer?-Butyldimethylsilyl)hepta-l,6diyne (133) (4.30 g, 20.9 mmol) was added neat via a cannula with dry T H F (3 mL) as a rinse. Dry methanol (40.0 mL, 987 mmol) was added dropwise over 2 min via a syringe. The reaction mixture was stirred at -78 °C for 3 h , -30 °C for 3 h, and at 0 °C for 1 h. The mixture was opened to the air and aqueous ammonium chloride-ammonia (pH 8) (150 mL) was added. The suspension was stirred until the aqueous phase became a deep blue color. The organic phase was separated and the aqueous layer was extracted with E t 0 (3 x 150 mL). The organic layers were combined, washed with brine (350 mL), and 2  dried (MgSQ*).  The solvent was removed under reduced pressure.  Flash column  chromatography (150 g of silica gel, petroleum ether) yielded 3.00 g of the stannane 134 as a clear oil which was contaminated with a trace amount of the starting material 133.  The stannane 134 thus obtained was dissolved in dry T H F (80 mL) and a solution of tetrabutylammonium fluoride (16.1 mL, 1.0 M in THF, 16.1 mmol) was added. solution was stirred at room temperature for 1.5 h.  The  Saturated aqueous sodium  bicarbonate (100 mL) was added and the mixture was extracted with E t 0 (3 x 100 mL). 2  The organic extracts were combined, washed with brine (200 mL), dried (MgS0 ), and 4  the solvent was removed in vacuo to yield the alkyne 135 as a crude oil. This oil proved to be volatile and was immediately used in the next reaction.  120  To a cold (-78 °C), stirred solution of L D A (15.9 mmol) in dry T H F (100 mL) was added a solution of the alkyne 135 (obtained as described above) in dry T H F (2 mL). The solution was stirred for 30 min. Ethyl chloroformate (1.60 mL, 16.7 mmol) was added and the solution was stirred at -78 °C for 1 h and at room temperature for 1.5 h. Saturated aqueous sodium bicarbonate (100 mL) was added and the mixture was extracted with E t 0 (3 x 100 mL). The combined organic extracts were washed with 2  brine (200 mL), dried (MgSCU), and the solvent was removed under reduced pressure. Purification by flash column chromatography (200 g of silica gel, 96:4 petroleum etherE t 0 ) and removal of trace amounts of solvent (vacuum pump) from the acquired 2  material yielded 1.76 g (24 % over 3 steps) of the ester 131 as a clear oil. The material exhibited spectral characteristics (*H nmr) identical with those previously mentioned for this compound.  Preparation of ethyl 8-trimethvlstannylnon-8-en-2-vnoate (137)  136b  136c C0 Et 2  M e  3  S n ^ ^  Hg  Hg' 137  To a cold (-78 °C) solution of octa-l,6-diyne (136) (2.70 mL, 23.6 mmol) in dry T H F (100 mL) was added a solution of M e L i (20.0 mL, 1.56 M in E t 0 , 31.2 mmol). After 2  10 min, the reaction mixture was warmed to -20 °C and stirred for 1 h.  tert-  121 Butyldimethylsilyl chloride (4.95 g, 32.8 mmol) was added in one portion and the solution was stirred at -20 °C for 15 min and then warmed to room temperature for 1 h. Saturated aqueous sodium bicarbonate (50 mL) was added and the phases were separated. The aqueous phase was extracted with E t 0 (3 x 50 mL) and the combined organic 2  extracts were washed once with brine (50 mL), dried (MgSC^), and concentrated. Purification of the crude material by flash column chromatography (150 g of silica gel, petroleum ether), followed by bulb-to-bulb distillation (50-60 °C/0.1 torr) of the acquired liquid, provided 4.07 g of alkyne 136a as a colorless oil which was contaminated with a small amount of starting material 136.  To a cold (-20 °C), stirred solution of hexamethylditin (10.3 g, 31.5 mmol) in dry T H F (150 mL) was added M e L i (22.2 mL, 1.42 M in E t 0 , 31.5 mmol) via a syringe and the 2  solution stirred for 30 min. The solution was cooled to -78 °C and copper bromidedimethyl sulfide complex (6.48 g, 31.5 mmol) was added in one portion. The red-brown suspension was stirred for 30 min.  l-(fcr^-Butyldimethylsilyl)octa-l,6-diyne (136a)  (obtained as described above) was added neat via a cannula with dry T H F (3 mL) as a rinse. Dry methanol (50.0 mL, 1.23 mol) was added dropwise over 2 min via a syringe. The reaction mixture was stirred at -78 °C for 3.5 h, at -48 °C for 3.5 h, and at room temperature for 20 min. The mixture was opened to the air and aqueous ammonium chloride-ammonia (pH 8) (150 mL) was added.  The suspension was stirred until the  aqueous phase became a deep blue color. The organic phase was separated and the organic layer was extracted with E t 0 (3 x 150 mL). The organic layers were combined, 2  washed with brine (400 mL), and dried (MgSCU). The solvent was removed in vacuo. Flash column chromatography (200 g of silica gel, petroleum ether) of the crude product yielded 4.55 g of the stannane 136b which was contaminated with a minor amount of the starting material 136a.  The oil thus obtained was dissolved in dry T H F (80 mL) and a solution of tetrabutylammonium fluoride (26.0 mL, 1.0 M in THF, 26.0 mmol) was added. solution was stirred for 2.5 h at room temperature.  The  Saturated aqueous sodium  bicarbonate (100 mL) was added and the mixture was extracted with E t 0 (3 x 100 mL). 2  122 The organic extracts were combined, washed with brine (200 mL), dried (MgS0 ), and 4  the solvent was removed under reduced pressure to yield 4.27 g of a crude oil. The crude product proved to be volatile and was used immediately in the next step.  To a cold (-78 °C), stirred solution of L D A (32.0 mmol) in dry T H F (100 mL) was added the crude oil as a solution in dry T H F (2 mL). The solution was stirred for 30 min. Ethyl chloroformate (3.20 mL, 33.4 mmol) was added and the solution stirred at -78 °C for 1 h and at room temperature for 1.5 h. Saturated aqueous sodium bicarbonate (100 mL) was added and the mixture was extracted with E t 0 (3 x 100 mL). The combined organic 2  extracts were washed with brine (200 mL), dried (MgS04), and the solvent was removed under reduced pressure.  Purification of the residual material by flash column  chromatography (200 g of silica gel, 96:4 petroleum ether-Et 0), followed by bulb-to2  bulb distillation (155-180 °C/0.3 torr), yielded 2.38 g (28 % over 4 steps) of the stannane 137 as a clear oil.  IR (neat): 2237, 1713, 1250, 1077, 916, 753 c m . 1  J  H nmr (400 M H z , CDC1 ) 8: 0.11 (s, 9H, -SnMe^. / „ . 2  3  s  - C 0 C H C H 3 , / = 7.2 Hz), 1.40-1.60 (m, 4H), 2  H  = 52.9 Hz), 1.27 (t, 3H,  2.10-2.40 (m, 4H), 4.19 (q, 2H,  2  -C0 CH2CH , / = 7.2 Hz), 5.10-5.15 (m, 1H, H , / . = 70.8 Hz), 5.60-5.65 (m, 1H, 3  2  3  9  S n  H  H ' , / . = 151.4 Hz). 3  9  1 3  S n  H  C nmr (75.5 M H z , CDC1 ) 8: -9.6 (-ve), 14.0 (-ve), 18.4, 26.8, 28.4, 40.0, 61.7, 73.3, 3  89.0, 124.9, 153.7, 155.0.  H R M S calcd for C i H i O 3  2  1 2 0 2  S n (M -Me): 329.0564; found: 329.0563. +  Anal, calcd for C i H 0 S n : C 49.02, H 7.05; found: C 49.02, H 7.09. 4  2 4  2  123 Preparation of methyl 4-(tetrahydro-2i/-pyranyloxy)-but-2-ynoate M  138  (139)  .C0 Me 2  139  To a cold (-78 °C), stirred solution of commercially available ether 138 (10.0 mL, 71.4 mmol) in dry T H F (40 mL) was added a solution of n-butyllithium (55.0 mL, 1.55 M in hexanes, 85.0 mmol). The solution was stirred at -78 °C for 30 min. Methyl chloroformate (6.60 mL, 85.0 mmol) was added and the solution was stirred for 2 h at -78 °C and 2 h at room temperature. Saturated aqueous sodium bicarbonate (200 mL) was added and the aqueous layer was extracted with E t 0 (3 x 100 mL). The organic 2  extracts were combined, washed with brine (200 mL), and dried (MgS0 ). The solvent 4  was removed under reduced pressure and bulb-to-bulb distillation (120-140 °C/0.1 torr) of the crude material yielded 14.0 g (99%) of the ester 139 as a clear oil.  IR (neat): 2241, 1718, 1436, 1256, 1203, 1123, 1029, 943, 903, 752 c m . 1  *H nmr (400 M H z , CDC1 ) 8: 1.50-1.90 (m, 6H), 2.50-2.60 (m, IH), 3.70-3.90 (m, 4H, 3  includes 3H - C 0 M e singlet at 3.76), 4.36 (s, 2H), 4.78 (m, IH). 2  1 3  C nmr (75.5 M H z , CDC1 ) 8: 18.5, 25.0, 29.8, 52.5, 53.3, 61.6, 77.0, 83.7, 96.9, 153.3. 3  H R M S calcd for C i H O : 197.0813; found: 197.0806. 0  1 4  4  Anal, calcd for C i H O : C 60.59, H 7.12; found: C 60.58, H 7.24. 0  1 4  4  124  C0 Me 2  Br 139  140  To a cool (0 °C) solution of triphenylphosphine (8.97 g, 34.1 mmol) in dry C H C 1 2  2  (200 mL) was added bromine (-2.0 mL) dropwise until a yellow color persisted. A few crystals of triphenylphosphine were added until the solution was colorless. The reaction mixture was stirred for 20 min and a white precipitate appeared.  The mixture was  warmed to room temperature and the ester 139 (5.70 g, 30.0 mmol) was added neat via a cannula with C H C 1 (5 mL) as a rinse. The mixture was stirred for 1 h and the white 2  2  precipitate disappeared.  Pentane (200 mL) was added and the mixture was filtered  through a cake of silica gel (-30 g) and the silica gel was eluted with E t 0 (300 mL). 2  The combined filtrate was concentrated in vacuo. Flash column chromatography (300 g of silica gel, 9:1 petroleum ether-Et 0) of the crude product and removal of trace 2  amounts of solvent (vacuum pump) from the acquired material yielded 4.48 g of the bromide 140 (87 %) as a colorless oil. Updated characterization data is given below.  IR (neat): 2358, 2245, 1718, 1436, 1269, 1083, 945, 751, 625 c m . 1  :  H nmr (400 M H z , CDC1 ) 8: 3.77 (s, 3H, -CftMe), 3.93 (s, 2H, B r - C H r ) . 3  1 3  C nmr (75.5 M H z , CDC1 ) 8: 11.6, 52.8 (-ve), 76.6, 81.6, 152.9. 3  H R M S calcd for C H 0 5  5  8 1 2  B r : 177.9453; found: 177.9449.  Anal, calcd for C H 0 B r : C 33.93, H 2.84; found: C 34.17, H 2.91. 5  5  2  75  125 Preparation of methyl 5-ethoxvcarbonyl-6-trimethvlstarmylhept-6-en-2-ynoate (143)  141  140  143  To a cold (-78 °C), stirred solution of L D A (12.4 mmol) in dry THF (110 mL) was added H M P A (2.20 mL, 12.4 mmol). A solution of ethyl (Z)-3-trimethylstannylbut-2-enoate  (141) (2.87 g, 10.4 mmol) in dry THF (5 mL) was added to the reaction mixture. The 41  mixture was stirred at -78 °C for 30 min and at 0 °C for 30 min. The orange suspension was cooled to -78 °C and methyl 4-bromobut-2-ynoate (140) (2.22 g, 12.5 mmol) dissolved in dry T H F (5 mL) was added to the reaction mixture. After 15 min, the reaction mixture turned dark brown and saturated aqueous sodium bicarbonate (110 mL) was added. The mixture was warmed to room temperature and the black suspension was extracted with E t 0 (3 x 150 mL). The organic extracts were combined, washed with 2  brine (2 x 300 mL), dried (MgSCU), and the solvent was removed under reduced pressure. Flash column chromatography (200 g of silica gel, 9:1 petroleum ether-Et 0) of the crude 2  oil and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 2.24 g (58%) of the ester 143 as a clear oil.  IR (neat): 2241, 1718, 1259, 1176, 1079, 773, 529 c m . 1  J  H nmr (400 M H z , CDC1 ) 5: 0.16 (s, 9H, -SnMe , / . = 53.9 Hz), 1.25 (t, 3H, 2  3  3  S n  H  -CO2CH2CH3, / = 7.1 Hz), 2.51 (dd, 1H, H , , / = 7.5, 17.2 Hz), 2.80 (dd, 1H, H 4 ' , / = 7.5,  17.2 Hz), 3.43 (t, 1H, H , / = 7.5 Hz, / „ . = 58.2 Hz), 3.72 (s, 3H, -CO2CH3), 4.10-4.20 3  5  s  H  (m, 2H, -CO2CH2CH3), 5.37-5.42 (m, 1H, H , / . = 63.6 Hz), 5.80-5.85 (m, 1H, H ' , 3  7  3  S n  H  7  / . = 133.6 Hz). Sn  1 3  H  C nmr (75.5 M H z , CDC1 ) 5: -8.5 (-ve), 13.9 (-ve), 22.1, 52.3 (-ve), 53.8 (-ve), 61.0, 3  74.0, 86.1, 129.1, 150.7, 153.6, 172.2.  126 H R M S calcd for C i H 0 3  1 9  Sn (M -Me): 359.0306; found: 359.0311. +  4  Anal, calcd for C H 0 S n : C 45.08, H 5.94; found: C 44.99, H 6.03. 1 4  2 2  4  2.2 Copper(I) mediated cyclizations  General  Procedure  1:  CuCl-mediated intramolecular  conjugate  addition of  alkenyltrimethylstannanes to alkynic esters  To a cool (0 °C), stirred solution-suspension of CuCl (-2.5 equiv) in dry D M F (2 mL/mmol CuCl) was added glacial acetic acid (5.0 equiv). The mixture was stirred for 5 min and changed from a yellow to a gray-blue suspension.  A solution of the ester  (1 equiv) in dry D M F (5 mL/mmol of ester) was added dropwise via a cannula. After 15 min, the mixture became bright green. The mixture was opened to the air, was treated with aqueous ammonium chloride-ammonia (pH 8) (-10 mL/mmol of ester), and was stirred until the aqueous phase became deep blue. The mixture was diluted with water (-10 mL/mmol of ester) and then was extracted with E t 0 (3 x -10 rnL/rnmol of ester). 2  The combined organic phases were washed with brine (3 x -20 mL/mmol of ester), dried (MgS0 ), and concentrated under reduced pressure. The crude product was purified by 4  flash column chromatography.  127 Preparation of (iT)-l-ethoxycarbonylmethylidene-2-m  (144)  C0 Et 2  144  129  Following general procedure 1, the cyclobutane derivative 144 was prepared by the addition of the ester 129 (102 mg, 0.322 mmol), as a solution in dry D M F (1.6 mL), to a cool (0 °C), stirred solution-suspension of CuCI (77 mg, 0.78 mmol) and glacial acetic acid (90 uL, 1.6 mmol) in dry D M F (1.5 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 94:6 petroleum ether-Et 0) and removal of 2  trace amounts of solvent (vacuum pump) from the acquired material provided 42 mg (85 %) of the cyclization product 144 as a colorless oil.  IR (neat): 1713, 1654, 1368, 1266, 1186, 1054, 857 c m . 1  X  H nmr (400 M H z , CDC1 ) 5: 1.26 (t, 3H, - C 0 C H C H 3 , / = 7.1 Hz), 2.65-2.80 (m, 2H, 3  2  2  H-3), 3.02 (td, 2H, H-4, / = 8.0, 2.5 Hz), 4.15 (q, 2H, -C0 CH2CH , / = 7.1 Hz), 4.94 (br 2  3  s, 1H, H-5b), 5.35-5.40 (m, 1H, H-5a), 5.84-5.90 (m, 1H, H-6).  1 3  C N M R (75.5 M H z , CDC1 ) 5: 14.3 (-ve), 28.6, 29.9, 59.8, 108.3 (-ve), 108.6, 147.9, 3  161.2, 166.9.  H R M S calcd for C H 0 : 152.0837; found: 152.0842. 9  1 2  2  Anal, calcd for C H i 0 : C 71.03, H 7.95; found: C 70.99, H 7.89. 9  2  2  128  Table 14. *H nmr (400 M H z , CDC1 ) data for the ester 144: 3  C O S Y (200 MHz) and NOED experiments C0 Et 2  H  H  b  144 Assignment H-x  H nmr (400 MHz)  COSY  NOED  8 (multiplicity, 7 (Hz))  Correlations  Correlations  J  H-3  2.65-2.80 (m)  H-4  H-4  3.02 (td, 7=2.5, 8.0)  H-3, H-6  H-5a  5.35-5.40 (m)  H-5b  H-5b, H-6  H-5b  4.94 (br s)  H-5a  H-3, H-5a  H-6  5.84-5.90 (m)  H-4  H-5a  4.15 (q, 7=7.1)  -C0 CH CH3  1.26 (t, 7=7.1)  -C0 CH2CH  -C0 CH2CH 2  -C0 CH CH3 2  2  3  2  2  2  3  Preparation of (/f)-l-hvdroxvmethvlmethyhdene-2-methylidenecyclopentane (154)  Following general procedure 1, the cyclopentane derivative 153 was prepared by the addition of the ester 131 (333 mg, 1.01 mmol), as a solution in dry D M F (5 mL), to a cool (0 °C), stirred solution-suspension of CuCl (262 mg, 2.65 mmol) and glacial acetic acid (289 ]XL, 5.05 mmol) in dry D M F (5 mL). Following the workup as described in the  129 general procedure, the crude oil containing the ester 153 was used in the next step without purification because this material is prone to polymerization when concentrated.  To a cold (-78 °C), stirred solution of the ester 153 (obtained as described above) in dry THF (10 mL) was added a solution of D I B A L (4.00 mL, 1.0 M in hexanes, 4 equiv) and the mixture was stirred for 45 rnin. The solution was warmed to room temperature and stirring was continued for 45 min. Saturated aqueous ammonium chloride (2 mL) was added to the solution and the mixture was stirred for 30 min. MgS04 (-100 mg) was added and the white suspension was stirred for an additional 30 rnin. The mixture was diluted with E t 0 (20 mL) and then was filtered through Florisil (-5 g) and the cake was 2  eluted with E t 0 (150 mL). The combined filtrate was concentrated under reduced 2  pressure. Flash column chromatography (20 g of silica gel, 13:7 petroleum ether-Et 0) 2  of the crude oil and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 116 mg (92 % over two steps) of the allylic alcohol 154 as a clear oil. This compound proved to be unstable when stored under argon for extended periods of time in a freezer.  IR (neat): 3305, 1627, 1430, 1045, 995, 878 cm" . 1  *H nmr (400 M H z , CDC1 ) 8: 1.34 (br s, I H , -OH, exchanges with D 0 ) , 1.60-1.73 (m, 3  2H, -CH -CH2-CH .), 2  2  2.35-2.45 (m, 4H, -CH^-CH -CH2-), 4.22 (d, 2H, -O-CEb-,  2  2  / = 6.9 Hz), 4.86 (br s, IH), 5.30 (br s, IH), 5.95-6.05 (m, IH, =CH-CH -0-). 2  1 3  C nmr (75.5 M H z , CDC1 ) 8: 24.0, 30.0, 34.0, 61.1, 103.2, 118.2 (-ve), 142.9, 149.0. 3  H R M S calcd for C H i 0 : 124.0888; found: 124.0889. 8  2  130 Preparation  of (E)- l-Cfe^butyldimethylsiloxym  pentane (155)  OTBS  154  155  To a stirred solution of the diene 154 (116 mg, 0.933 mmol) in dry C H C 1 (4 mL) at 2  2  room temperature was added te^butyldimethylsilyl chloride (305 mg, 2.02 mmol) in one portion, followed immediately by imidazole (289 mg, 4.14 mmol). The white suspension was stirred for 1 h. The solvent was removed under reduced pressure. Flash column chromatography (20 g of silica gel, 400:3 petroleum ether-Et 0) of the crude product and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 202 mg (91 %) of the silyl ether 155 as a colorless clear oil. IR (neat): 1628, 1463, 1375, 1255, 1181, 837, 777 c m . 1  X  H nmr (400 M H z , CDC1 ) 8: 0.06 (s, 6H, -SiMe,-), 0.89 (s, 9H, -Si'Bu-), 1.60-1.75 (m, 3  2H, H-4), 2.30-2.42 (m, 4H, H-3 and H-5), 4.25 (d, 2H, H-8, / = 6.2 Hz), 4.82 (br s, 1H, H-6b), 5.27 (br s, 1H, H-6a), 5.85-5.95 (m, 1H, H-7).  1 3  C nmr (75.5 M H z , CDC1 ) 8: -5.1 (-ve), 18.4, 24.0, 26.0 (-ve), 30.0, 34.0, 61.8, 102.5, 3  119.5(-ve), 140.5, 149.1.  H R M S calcd for C i H O S i : 238.1753; found: 238.1751. 4  26  Anal, calcd for C i H O S i : C 70.52, H 10.99; found: C 70.31, H 11.03. 4  26  131  Table 15. *H nmr (400 M H z , CDC1 ) data for the silyl ether 155: N O E D experiments 3  .OTBS  3  ]6  H  b  155 Assignment  *H nmr (400 MHz)  NOED  H-x  8 (multiplicity, J (Hz))  Correlations  H-6a  4.82 (br s)  H-6b, H-7  H-6b  5.27 (br s)  H-6a, H-7 (-ve), H-3  H-7  5.85-5.95 (m)  H-6a, H-6b (-ve), H-8  Preparation of (F)-l-ethoxycarbonylmethylidene-2-methylidenecyclohexane (156)  C0 Et 2  C0 Et  5,  2  Me Sn 3  137  156  Following general procedure 1, the cyclohexane derivative 156 was prepared by the addition of the ester 137 (100 mg, 0.290 mmol), as a solution in dry D M F (1.5 mL), to a cool (0 °C), stirred solution-suspension of CuCI (75 mg, 0.76 mmol) and glacial acetic acid (83 juL, 1.5 mmol) in dry D M F (1.4 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 97:3 petroleum ether-Et 0) and removal of 2  trace amounts of solvent (vacuum pump) from the acquired material provided 45 mg (87 %) of the cyclization product 156 as a colorless oil.  132 IR (neat): 1714, 1636, 1444, 1370, 1295, 1184, 1158, 1039, 901 c m . 1  X  H nmr (400 M H z , CDC1 ) 8: 1.26 (t, 3H, -CO2CH2CH3, / = 7.1 Hz), 1.60-1.75 (m, 4H, 3  H-4 and H-5), 2.30 (br s, 2H, H-3), 2.90 (br s, 2H, H-6), 4.14 (q, 2H, -COzCHoCHs, / = 7.1 Hz), 4.75-4.80 (m, I H , H-7b), 5.00-5.05 (m, IH, H-7a), 5.80-5.85 (m, I H , H-8).  13  C nmr (75.5 M H z , CDC1 ) 8: 14.3 (-ve), 25.9, 26.5, 29.7, 35.3, 59.7, 110.7, 112.9 (-ve), 3  149.6, 161.0, 166.9.  H R M S calcd for C H i 0 : 180.1151; found: 180.1154. u  6  2  Anal, calcd for C n H 0 : C 73.30, H 8.95; found: C 73.00, H 9.05. 1 6  2  Table 16. *H nmr (400 M H z , CDC1 ) data for the ester 156: N O E D experiments 3  156 Assignment  *H nmr (400 MHz)  NOED  H-x  8 (multiplicity, / (Hz))  Correlations  H-7a  5.00-5.05 (m)  H-7b, H-8  H-7b  4.75-4.80 (m)  H-3, H-7a, H-8 (-ve)  H-8  5.80-5.85 (m)  H-7a  133 Preparation of Ethyl (in-3-methoxycarTxmylm^ carboxylate (158)  C0 Me 2  Following general procedure 1, the cyclobutane derivative 158 was prepared by the addition of the diester 143 (146 mg, 0.392 mmol), as a solution in dry D M F (2 mL), to a cool (0 °C), stirred solution-suspension of CuCI (102 mg, 1.03 mmol) and glacial acetic acid (120 ^iL, 2.10 mmol) in dry D M F (2 mL). Purification of the crude product by flash column chromatography (12 g of silica gel, 9:1 petroleum ether-Et 0) and removal of 2  trace amounts of solvent (vacuum pump) from the acquired material yielded 70 mg (85 %) of the cyclization product 158 as a colorless oil.  IR(neat): 1734, 1665, 1542, 1436, 1321, 1269, 1171, 1020 c m . 1  J  H nmr (400 MHz, CDC1 ) 5: 1.26 (t, 3H, -CO2CH2CH3, / = 7.1 Hz), 3.22 (dd, 1H, H-4, 3  / = 2.5, 18.1 Hz), 3.38 (dd, 1H, H-4*, / = 2.8, 18.1 Hz), 3.70 (s, 3H, - C 0 M e ) , 3.75-3.85 2  (m, 1H, H-l), 4.10-4.25 (m, 2H, -CO2CH2CH3), 5.25 (br s, 1H, H-5b), 5.50 (d, 1H, H-5a, / = 2.5 Hz), 5.92 (dd, 1H, H-6, / = 2.5, 2.5 Hz).  1 3  C nmr (75.5 MHz, CDC1 ) 5: 14.0 (-ve), 33.2, 44.4 (-ve), 51.0 (-ve), 60.8, 109.3 (-ve), 3  110.5, 145.1, 157.2, 166.6, 171.2.  H R M S calcd for C n H 0 : 210.0892; found: 210.0896. 1 4  4  Anal, calcd for C H 0 : C 62.85, H 6.71; found: C 62.79, H 6.81. u  1 4  4  134 Table 17. H nmr (400 M H z , CDC1 ) data for the diester 158: N O E D experiments l  3  C0 Me 2  3 E t 0  C ^ ^ - H /  2  H  a  b  158 Assignment  *H nmr (400 MHz)  NOED  H-x  5 (multiplicity, 7 (Hz))  Correlations  H-5a  5.50 (d, 7=2.5)  H-5b, H-6  H-5b  5.25 (br s)  H-5a  H-6  5.92 (dd, 7=2.5,2.5)  H-5a  135  3. Intramolecular conjugate additions to form bicyclic compounds 3.1 Preparation of cyclization precursors  General Procedure 2:  Protection of terminal alkynes with fer^-butyldimethylsilyl  chloride  To a cold (-78 °C), stirred solution of the appropriate terminal alkyne (1 equiv) in dry THF (~5 mL/mmol of alkyne) was added a solution of M e L i (1.2-1.4 equiv) in E t 0 and 2  the solution was stirred for 10 min. The mixture was warmed to -20 °C and was stirred for 1 h. ?er?-Butyldimethylsilyl chloride (1.3-1.5 equiv) was added in one solid portion and the mixture was stirred for 1 h at -20 °C and 1 h at room temperature.  Saturated  aqueous sodium bicarbonate (~1 mL/mL of THF) was added and the mixture was extracted with E t 0 (3 x ~1 mL/mL of THF). 2  The combined organic extracts were  washed with brine (~3 mL/mL of THF), dried (MgSC>4), and the solvent was removed under reduced pressure. Purification of the crude product was accomplished with flash column chromatography on silica gel.  Preparation of l-(fe^butyldimethylsilyl)-3-(tetrahvdro-2^-pvran-2-vloxv)propyne (169)  166  169  Following general procedure 2,  the commercially available alkyne 166 (5.00 g,  35.7 mmol) in dry T H F (200 mL) was converted into the title compound 169 with M e L i (27 mL, 1.6 M in E t 0 , 43 mmol) and 2  te^butyldimethylsilyl  chloride (7.00 g,  46.5 mmol). Purification of the crude product by flash column chromatography (250 g of silica gel, 19:1 petroleum ether-Et 0) and removal of trace amounts of solvent (vacuum 2  pump) from the acquired material yielded 6.90 g (72 %) of the alkyne 169 as a colorless oil.  136  TR (neat): 2175, 1472, 1251, 1122, 1030, 826 c m . 1  *H nmr (400 M H z , CDC1 ) 8: 0.09 (s, 6H, -SiMe?-), 0.91 (s, 9H, -Si'Bu-), 1.50-1.64 (m, 3  4H), 1.65-1.75 (m, 2H), 3.46-3.52 (m, IH), 3.79-3.85 (m, IH), 4.25 (s, 2H, -O-CH2-), 4.82 (t, IH, 7=3.3 Hz).  1 3  C nmr (50.3 M H z , CDCI3) 5: -4.8, 16.2, 18.5, 25.3, 25.9, 30.1, 54.4, 61.6, 88.7, 96.2,  102.2.  DCI-HRMS calcd for C i H 0 S i (M +H): 255.1780; found: 255.1779. +  4  2 7  2  Anal, calcd for C i H 0 S i : C 66.04, H 10.30; found: C 66.14, H 10.20. 4  Preparation  of  2 6  2  l-(fe^butvldimethylsilyl)-3-(tetr^  07Q1  THPO.  THPO  H  TBS  167 Following general procedure 2,  170 the alkyne 167  46  (3.62 g, 23.5 mmol) in dry T H F  (125 mL) was converted into the title compound 170 with M e L i (17.6 mL, 1.6 M in E t 0 , 2  28.2 mmol) and ^rf-butyldimethylsilyl chloride (5.10 g, 33.8 mmol). Purification of the crude product by flash column chromatography (150 g of silica gel, 37:3 petroleum etherE t 0 ) and removal of trace amounts of solvent (vacuum pump) from the acquired 2  material yielded 3.58 g (57 %) of the ether 170 as a colorless oil.  IR (neat): 2177, 1471, 1251, 1124, 1035, 838 c m . 4  137 R nmr (400 M H z , CDC1 ) 5: 0.09 (s, 6H, -SiMe,-), 0.91 (s, 9H, -Si'Bu-), 1.48-1.58 (m,  l  3  4H), 1.65-1.72 (m, 1H), 1.78-1.85 (m, 1H), 2.51 (t, 2H, -CH2-CH -), 3.49-3.56 (m, 2H), 2  3.77-3.90 (m, 2H), 4.64 (t, 1H, / = 3.3 Hz).  1 3  C nmr (50.3 M H z , CDC1 ) 5: -4.6, 16.4, 19.1, 21.3, 25.4, 26.0, 30.4, 61.8, 65.6, 83.5, 3  98.5, 104.5.  H R M S calcd for C H 0 S i (M - Bu): 211.1154; found: 211.1147. +  n  1 9  £  2  Anal, calcd for C i H 0 S i : C 67.11, H 10.51; found: C 67.31, H 10.53. 5  Preparation  of  2 8  2  l-(fe^butyldimethvlsilvl)-3-(tetTahydro-2^-pyran-2-yloxy)pent- 1-yne  am 168 Following general procedure 2,  171 the alkyne 168  (2.25 g, 13.4 mmol) in dry T H F  (125 mL) was converted into the title compound 171 with M e L i (13.4 mL, 1.4 M in E t 0 , 2  18.8 mmol) and te^butyldimethylsilyl chloride (3.15 g, 20.8 mmol). Purification of the crude product by flash column chromatography (100 g of silica gel, 37:3 petroleum etherE t 0 ) and removal of trace amounts of solvent (vacuum pump) from the acquired 2  material yielded 2.16 g (57 %) of the alkyne 171 as a colorless oil.  IR (neat): 2174, 1466,1253, 1129,1037, 826 cm' . 1  :  H nmr (400 M H z , CDC1 ) 5: 0.09 (s, 6H, -SiMe?-), 0.91 (s, 9H, -Si'Bu-), 1.48-1.90 (m, 3  8H), 2.33 (t, 2H, / = 7.0 Hz), 3.42-3.49 (m, 2H), 3.78-3.87 (m, 2H), 4.57 (t, 1H, / = 2.7 Hz).  138 1 3  C nmr (75.5 M H z , CDC1 ) 5: -4.6 (-ve), 16.4, 16.6, 19.3, 25.4, 25.9 (-ve), 28.8, 30.5, 3  61.8, 65.6, 82.6, 98.5 (-ve), 107.2.  H R M S calcd for C H 9 0 S i (M -H): 281.1937; found: 281.1929. +  16  2  2  Anal, calcd for Ci6H o0 Si: C 68.03, H 10.70; found: C 67.76, H 10.81. 3  2  General Procedure 3: Conversion of THP ethers into alkyl bromides  To a cool (0 °C), stirred solution of triphenylphosphine (-1.3 equiv) in dry C H C 1 2  2  (10 mL/mmol of THP ether) was added bromine (-1.3 equiv) dropwise until a yellow color persisted.  A few crystals of triphenylphosphine were added until the color  disappeared. The solution was stirred for a period of 20 min. The appropriate THP ether (1 equiv) was added neat and the solution was stirred at 0 °C for 20 min and at room temperature for 1 h. Pentane was added (-1 mL/mL of CH C1 ) and the white suspension 2  2  was filtered through a cake of silica gel (-10 g/g of triphenylphosphine) and the silica gel was eluted with E t 0 (-2 mL/mL of CH C1 ). After concentration of the combined 2  2  2  filtrate under reduced pressure, the crude product was purified by flash column chromatography on silica gel.  Preparation of 3-bromo-l-(fe^-butyldimethylsilyl)propyne (160)  169  160  Following general procedure 3, the alkyne 169 was converted into the bromide 160 with the following amounts of solvent and reagents: alkyne 169 (6.90 g, 25.7 mmol), bromine (-1.7 mL), triphenylphosphine (8.77 g, 33.3 mmol), and C H C 1 (250 mL). The crude 2  2  product was purified by flash column chromatography (200 g of silica gel, petroleum  139 ether) which, after removal of trace amounts of solvent (vacuum pump) from the acquired material, yielded 6.16 g (97 %) of the bromide 160 as a colorless oil.  ER (neat): 2179, 1472, 1253, 1039, 840 c m . 1  X  H nmr (400 M H z , CDC1 ) 8: 0.09 (s, 6H, -SiMeo-), 0.90 (s, 9H, -Si'Bu-), 3.90 (s, 2H, 3  Br-CEL.-).  1 3  C nmr (50.3 M H z , CDC1 ) 8: -4.8, 14.7, 16.5, 26.0, 90.8, 113.3. 3  H R M S calcd for C H i S i B r : 234.0263; found: 234.0265. 81  9  7  Anal, calcd for C H i S i B r : C 46.35, H 7.35; found: C 46.67, H 7.38. 9  7  Preparation of 4-bromo-l-(feA'f-butyldimethylsilyl)but-l-yne (161) THPCL  Brv  170  / \  161  Following general procedure 3, the alkyne 170 was converted into the bromide 161 with the following amounts of solvent and reagents: alkyne 170 (5.22 g, 19.5 mmol), bromine (-1.2 mL), triphenylphospliine (6.27 g, 24.0 mmol), and C H C 1 (200 mL). The crude 2  2  material was purified by flash column chromatography (100 g of silica gel, 200:3 petroleum ether-Et 0) which, after removal of trace amounts of solvent (vacuum pump) 2  from the acquired material, yielded 4.60 g (96 %) of the bromide 161 as a colorless oil.  ER (neat): 2177, 1472, 1251, 839 c m . 1  R nmr (400 M H z , CDC1 ) 8: 0.09 (s, 6H, -SiMeo-), 0.90 (s, 9H, -Si'Bu-), 2.76 (t, 2H,  l  3  -CH2-CH -Br, / = 7.4 Hz), 3.41 (t, 2H, -CH -CH2-Br, / = 7.4 Hz). 2  2  140 " C nmr (50.3 M H z , CDC1 ) 5: -4.7, 16.4, 24.3, 26.0, 29.3, 85.1, 106.6. 3  H R M S calcd for C H i S i B r : 248.0419; found: 248.0423. 81  10  9  Anal, calcd for CioH SiBr: C 48.58, H 7.75; found: C 48.87, H 7.48. 19  Preparation of 5-bromo-l-(fe^butyldimethylsilyl)pent-l-vne (162) ./TBS  ^ T B S  171  162  Following general procedure 3, the alkyne 171 was converted into the bromide 162 with the following amounts of solvent and reagents:  alkyne 171 (924 mg, 3.27 mmol),  bromine (-0.20 mL), triphenylphosphine (1.02 g, 3.90 mmol), and CH C1 (35 mL). The 2  2  crude product was purified by flash column chromatography (60 g of silica gel, 200:3 petroleum ether-Et 0) which, after removal of trace amounts of solvent (vacuum pump) 2  from the acquired material, yielded 797 mg (93 %) of the bromide 162 as a colorless oil.  IR (neat): 2174, 1431, 1250, 827 c m . 1  *H nmr (400 M H z , CDC1 ) 8: 0.09 (s, 6H, -SiMe?-), 0.90 (s, 9H, -Si'Bu-), 2.00-2.10 (m, 3  2H, -CH -CH2-CH -), 2.41 (t, 2H, Br-CH -CH -CH2-, / = 6.8 Hz), 3.50 (t, 2H, Br-CFb-, 2  2  2  2  /=6.6Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 5: -4.5 (-ve), 16.4, 18.5, 26.0 (-ve), 31.4, 32.0, 83.8, 105.4. 3  H R M S calcd for C n H i S i B r : 262.0575; found: 262.0580. 81  2  Anal, calcd for C H S i B r : C 50.57, H 8.10; found: C 50.87, H 8.17. u  2 1  141  C0 Me 2  HO.  172  173 C0 Me 2  159 To a cool (0 °C), stirred solution of the ester 172  (4.22 g, 18.7 mmol) in dry M e O H  4/  (50 mL) was added PPTS (463 mg, 1.87 mmol). The mixture was warmed to reflux for 21 h and then the solvent was removed in vacuo. Flash column chromatography (100 g of silica gel, 1:1 petroleum ether-Et 0) of the crude product and removal of trace 2  amounts of solvent (vacuum pump) from the acquired material yielded 2.29 g of the alcohol 173 as a colorless oil.  To a cool (0 °C), stirred solution of iodine (5.26 g, 20.9 mmol) in dry C H C 1 (125 mL) 2  2  was added triphenylphosphine (5.43 g, 16.1 mmol) in one solid portion. The mixture was stirred for 30 min and then imidazole (1.65 g, 24.2 mmol) was added. A solution of the alcohol 173 (obtained as described above) in dry C H C 1 (5 mL) was added via a cannula 2  2  and the reaction mixture was stirred for 30 min at 0 °C. Pentane (125 mL) was added to the mixture. The white suspension was filtered through silica gel (-30 g) and the cake was eluted with E t 0 (-400 mL). The combined filtrate was concentrated under reduced 2  pressure. Flash column chromatography (100 g of silica gel, 9:1 petroleum ether-Et 0) 2  of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 3.23 g (79 %) of the ester 159 as a colorless oil. This material exhibited spectral data (*H nmr) identical with those previously reported.  47  142 Preparation of methyl 2-trimethylstarmylcyclopent-l-enecarboxylate (163)  ,C0 Me  ,  2  v  ^C0 Me 2  OTf  SnMe  174  3  163  To a cold (-48 °C), stirred solution of hexamethylditin (23.9 g, 73.1 mmol) in dry T H F (500 mL) was added M e L i (46.0 mL, 1.60 M in E t 0 , 73.6 mmol) via a syringe and the 2  solution was stirred for 30 min. Copper(I) cyanide (2.99 g, 75.2 mmol) was added to the solution in one solid portion and stirring was continued for 30 min. A solution of the enol triflate 174  28b  (15.4 g, 56.1 mmol) in dry THF (5 mL) was added via a cannula to the  mixture and stirring was continued for 1 h at -48 °C and for 1 h at 0 °C. The mixture was opened to the air and aqueous ammonium chloride-ammonia (pH 8) (250 mL) was added. The suspension was stirred until the aqueous phase became a deep blue color.  The  organic phase was separated and the aqueous phase was extracted with E t 0 (3 x 2  150 mL). (MgSCU).  The organic layers were combined, washed with brine (500 mL), and dried The solvent was removed under reduced pressure.  Rash column  chromatography (400 g of silica gel, 39:1 petroleum ether-Et 0) of the crude product and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material provided 14.9 g (92 %) of the stannane 163  28b  as a colorless clear oil.  Preparation of ethyl 2-trimethvlstannvlcvclohex-l-enecarboxvlate (164)  To a cold (-48 °C), stirred solution of hexamethylditin (5.33 g, 16.2 mmol) in dry T H F (80 mL) was added M e L i (12.0 mL, 1.40 M in E t 0 , 16.8 mmol) via a syringe and the 2  solution was stirred for 30 min. Copper(I) cyanide (1.76 g, 19.6 mmol) was added to the solution in one solid portion and stirring was continued for 30 min. A solution of the enol triflate 175  28b  (3.32 g, 11.0 mmol) in dry T H F (10 mL) was added via a cannula to  the mixture and stirring was continued for 1 h at -48 °C and for 1 h at 0 °C. The mixture  143 was opened to the air and aqueous arnmonium chloride-ammonia (pH 8) (150 mL) was added. The suspension was stirred until the aqueous phase became a deep blue color. The organic phase was separated and the aqueous phase was extracted with E t 0 (3 x 2  200 mL). The organic layers were combined, washed with brine (500 mL), and dried (MgSC>4).  The solvent was removed under reduced pressure.  Rash column  chromatography (200 g of silica gel, 9:1 petroleum ether-Et 0) of the crude product and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material provided 3.24 g (93 %) of the stannane 164  28b  as a colorless clear oil.  Preparation of methyl 2-trimethvlstannvlcvclohept-l-enecarboxylate (165)  176  165  To a cold (-48 °C), stirred solution of hexamethylditin (7.56 g, 23.1 mmol) in dry T H F (100 mL) was added M e L i (14.8 mL, 1.53 M in E t 0 , 22.6 mmol) via a syringe and the 2  solution was stirred for 30 min. Copper(I) cyanide (2.10 g, 23.5 mmol) was added to the solution in one solid portion and stirring was continued for 30 min. A solution of the enol triflate 176  10  (5.27 g, 17.4 mmol) in dry T H F (12 mL) was added via a cannula to  the mixture and stirring was continued for 1 h at -48 °C and for 1 h at 0 °C. The mixture was opened to the air and aqueous ammonium chloride-ammonia (pH 8) (30 mL) was added. The suspension was stirred until the aqueous phase became a deep blue color. The organic phase was separated and the organic phase was washed with water (2 x 40 mL) and dried (MgSC^). The solvent was removed under reduced pressure. Flash column chromatography (60 g of silica gel, 19:1 petroleum ether-Et 0) of the crude 2  product and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 4.19 g (76 %) of the stannane 165 as a colorless clear oil. 10  144 Preparation  of methyl l-(3-fg^butyldimethylsilylprop-2-yn-l-yl)-2-trim  cyclopent-2-ene-1 -carboxylate (178a)  163  160  178a  To a cold (-48 °C), stirred solution of L D A (8.06 mmol) in dry T H F (60 mL) was added H M P A (1.4 mL, 8.1 mmol) and stirring was continued for 10 min. A solution of the ester 163 (1.94 g, 6.72 mmol) in dry T H F (2 mL) was added via a cannula and the mixture was stirred for 40 rnin. The solution was cooled to -78 °C and the bromide 160 (2.55 g, 11.0 mmol) was added as a solution in dry THF (2 mL). The mixture was stirred at -48 °C for 40 min and then was warmed to room temperature. Saturated aqueous sodium bicarbonate (50 mL) was added and the mixture was extracted with E t 0 (3 x 2  50 mL).  The combined organic extracts were washed with brine (3 x 60 mL), dried  (MgS0 ), and the solvent was removed under reduced pressure. 4  Flash column  chromatography (100 g of silica gel, 200:3 petroleum ether-Et 0) of the crude product 2  and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 2.30 g (78 %) of the stannane 178a as a colorless oil.  TR (neat): 2176, 1727, 1250, 775 c m . 1  X  H nmr (400 M H z , CDC1 ) 5: 0.03 (s, 6H, - S i M ^ - ) , 0.12 (s, 9H, -SnMe,, / „ . 2  3  s  H  =  54.4 Hz), 0.88 (s, 9H, -Si'Bu-), 1.98-2.05 (m, IH), 2.40-2.52 (m, 4H), 2.71 (d, I H , / = 6.7 Hz), 3.64 (s, 3H, - C O ^ , 6.00 (dd, IH, olefinic proton, / = 2.1, 2.1 Hz, V S n . H = 36.6 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 8: -8.5, -4.6, 16.4, 26.0, 29.3, 32.4, 34.3, 52.0, 65.2, 84.4, 3  104.3, 113.2, 144.8, 175.7.  H R M S calcd for C H O S i 18  31  2  120  S n (M -Me): 428.1138; found: 428.1145. +  145 Anal, calcd for CigH^OzSiSn: C 51.72, H 7.77; found: C 51.94, H 7.84.  Preparation  of  methyl  l-(prop-2-yn-l-yl)-2-tiimethylstannylcyclopent-2-ene-l-  carboxylate (178b)  178a  178b  To a stirred solution of the stannane 178a (848 mg, 1.92 mmol) in dry T H F (20 mL) at room temperature was added a solution of tetrabutylammonium fluoride (2.5 mL, 1 M in THF, 2.5 mmol) and the solution was stirred for 1 h.  Saturated aqueous sodium  bicarbonate (20 mL) was added and the mixture was extracted with E t 0 (3 x 20 mL). 2  The combined organic extracts were washed with brine (50 mL), dried (MgS0 ), and the 4  solvent was removed in vacuo to give a crude oil. Flash column chromatography (50 g of silica gel, 98:2 petroleum ether-Et 0) of the crude product and removal of trace amounts 2  of solvent (vacuum pump) from the acquired material yielded 609 mg (97 %) of the ester 178b as a colorless clear oil.  IR (neat): 1729, 1435, 1200, 772 cm  X  H nmr (400 M H z , CDC1 ) 8: 0.13 (s, 9H, -SnMe^ 3  2  / „-H S  = 54.6 Hz), 1.90 (t, 1H, H , 3  / = 2.6 Hz), 1.96-2.02 (m, 1H), 2.35-2.53 (m, 4H), 2.67 (dd, 1H, / = 2.6, 6.6 Hz), 3.67 (s, 3H, -COzMe), 6.02 (dd, 1H, olefinic proton, / = 2.1, 2.1 Hz, / _ = 36.6 Hz). 3  Sft  1 3  H  C nmr (75.5 M H z , CDC1 ) 8: -8.8, 27.7, 32.6, 34.1, 52.0, 64.7, 69.8, 81.2, 144.8, 175.5, 3  219.4.  H R M S calcd for C H O 1 2  1 7  1 2 0 2  S n (M -Me): 313.0251; found: 313.0248. +  Anal, calcd for C i H O S n : C 47.75, H 6.16; found: C 47.83, H 6.04. 3  20  2  146 Preparation  of methyl  4-(l-methoxvcarbonvl-2-trimethvlstannvlcyclopent-2-en-l-vl)  but-2-vnoate (178) C0 Me  C0 Me  2  2  To a cold (-78 °C), stirred solution of L D A (2.38 mmol) in dry THF (12 mL) was added a solution of the alkyne 178b (602 mg, 1.84 mmol) in dry T H F (2 mL) via a cannula. The reaction mixture was stirred for 1 h at -78 °C.  Methyl chloroformate (220 | i L ,  2.75 mmol) was added via a syringe and stirring was continued for 1 h at -78 °C and 1 h at room temperature. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with E t 0 (3 x 20 mL). The combined organic extracts were 2  washed with brine (30 mL), dried (MgS0 ), and the solvent was removed under reduced 4  pressure. Flash column chromatography (50 g of silica gel, 9:1 petroleum ether-Et 0) of 2  the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 510 mg (73 %) of the ester 178 as a colorless clear oil.  IR (neat): 2238, 1718 (br), 1580, 1435, 1251, 773 c m . 1  *H nmr (400 M H z , CDC1 ) 5: 0.14 (s, 9H, -SnMes, / . = 54.6 Hz), 1.93-2.01 (m, 1H), 2  3  S n  H  2.41-2.56 (m, 4H), 2.81 (d, 1H, / = 7.1 Hz), 3.67 (s, 3H, - C 0 M e ) , 3.71 (s, 3H, -C0 Me), 2  6.06 (dd, 1H, olefinic proton, / = 2.1, 2.1 Hz,  1 3  3  /  S n  -H  2  = 35.8 Hz).  C nmr (75.5 M H z , CDC1 ) 5: -8.9 (-ve), 27.8, 32.9, 34.2, 52.2 (-ve), 52.4 (-ve), 64.2, 3  73.9, 86.3, 145.3 (-ve), 146.2, 153.8, 175.1.  H R M S calcd for C i H O 4  1 9  1 2 0 4  S n (M -Me): 371.0306; found: 371.0314. +  Anal, calcd for C i H 0 S n : C 46.79, H 5.76; found: C 47.09, H 5.87. 5  22  4  147 Preparation of methyl l-(but-3-vn-l-vl)-2-trimethvlstarmvlcyclopent-2-ene-l-carboxvlate  (179b)  179a  179b  To a cold (-48 °C), stirred solution of L D A (4.14 mmol) in dry T H F (32 mL) was added H M P A (740 |UL, 4.49 mmol) and stirring was continued for 10 min. A solution of the ester 163 (998 mg, 3.45 mmol) in dry T H F (2 mL) was added via a cannula and the mixture was stirred for 40 min. The solution was cooled to -78 °C and the bromide 161 (1.03 g, 4.16 mmol) was added as a solution in dry T H F (2 mL) via a cannula. The reaction mixture was stirred at -78 °C for 1 h and at room temperature for 1 h. Saturated aqueous sodium bicarbonate (30 mL) was added and the mixture was extracted with E t 0 2  (3 x 20 mL). The combined organic extracts were extracted with brine (3 x 30 mL), dried (MgSCU), and the solvent was removed under reduced pressure.  Flash column  chromatography (50 g of silica gel, 98:2 petroleum ether-Et 0) of the crude product 2  yielded the deconjugated-alkylated product 179a as a colorless clear oil which was contaminated with the stannane 163.  To a stirred solution of the stannane 179a (obtained as described above) in dry THF (12 mL) at room temperature was added a solution of tetrabutylammonium fluoride (7.0 mL, 1 M in THF, 7.0 mmol). The solution was stirred for 1 h  Saturated aqueous  sodium bicarbonate (30 mL) was added and the mixture was extracted with E t 0 (3 x 2  20 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSCU), and the solvent was removed in vacuo to give a crude oil. Flash column chromatography (50 g silica gel, 98:2 petroleum ether-Et 0) of the crude product and removal of trace 2  148 amounts of solvent (vacuum pump) from the acquired material yielded 541 mg (46 %) of the alkyne 179b as a colorless clear oil.  IR (neat): 3308, 2120, 1733, 1580, 1435, 1167, 770 c m . 1  X  H nmr (400 M H z , CDC1 ) 5: 0.14 (s, 9H, -SnMes,/ -H= 54.3 Hz), 1.64-1.80 (m, 2H), 2  3  Sn  1.91 (t, IH, H 4 , / = 2.6 Hz), 2.00-2.20 (m, 3H), 2.36-2.55 (m, 3H), 3.64 (s, 3H, -C0 Me), 2  5.91 (dd, IH, olefinic proton, / = 2.1, 2.1 Hz, / . = 35.4 Hz). 3  Sn  1 3  H  C nmr (50.3 MHz, CDC1 ) 5: -8.6, 14.5, 31.6, 34.2, 37.1, 51.9, 65.4, 68.4, 84.0, 144.0, 3  148.1, 176.2.  H R M S calcd for C i H O 3  1 9  1 2 0 2  S n (M -Me): 327.0407; found 327.0404. +  Anal, calcd for C i H 0 S n : C 49.31, H 6.50; found: C 49.55, H 6.65. 4  Preparation  22  2  of methyl  5-n-methoxycarbonyl-2-trimethvlstannvlcyclopent-2-en-l-vl)  pent-2-ynoate (179)  179b  179  To a cold (-78 °C), stirred solution of L D A (1.55 mmol) in dry T H F (11 mL) was added a solution of the alkyne 179b (405 mg, 1.19 mmol) in dry T H F (1 mL) via a cannula. The reaction mixture was stirred for 1 h at -78 °C.  Methyl chloroformate (140 uL,  1.81 mmol) was added via a syringe and stirring was continued for 1 h at -78 °C and 1 h at room temperature. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with E t 0 (3 x 20 mL). The combined organic extracts were 2  washed with brine (30 mL), dried (MgSCU), and the solvent was removed under reduced  149 pressure. Flash column chromatography (50 g of silica gel, 9:1 petroleum ether-Et 0) of 2  the crude product, followed by bulb-to-bulb distillation (160-185 °C/0.3 torr) of the acquired material, yielded 338 mg (71 %) of the diester 179 as a colorless clear oil.  IR (neat) 2239, 1718 (br), 1435, 1256, 770 cm" . 1  *H nmr (400 M H z , CDC1 ) 5: 0.13 (s, 9H, -SnMeg, 3  2  / „-H S  = 54.3 Hz), 1.68-1.78 (m, 2H),  2.15-2.30 (m, 3H), 2.36-2.45 (m, 2H), 2.47-2.56 (m, 1H), 3.64 (s, 3H, - C 0 M e ) , 3.72 (s, 2  3H, - C 0 M e ) , 5.98 (dd, 1H, olefinic proton, / = 2.1, 2.1 Hz, / „ - = 36.1 Hz). 3  2  1 3  s  H  C nmr (75.5 M H z , CDC1 ) 8: -8.6 (-ve), 14.8, 31.7, 34.1, 35.8, 52.0 (-ve), 52.5 (-ve), 3  64.9, 72.9, 89.0, 144.3 (-ve), 147.7, 154.1, 175.9.  H R M S calcd for C i H O 5  2 1  1 2 0 4  S n (M -Me): 385.0462; found: 385.0461. +  Anal, calcd for C i H 0 S n : C 48.16; H 6.06. found C 48.34; H 6.16. 6  Preparation  of  24  4  methyl l-(5-fe^butyldimethylsilvlpent-4-yn-l-vl)-2-trimethvlstannyl  cyclopent-2-ene- 1-carboxylate (180a) ^ ^ C 0  2  C0 Me 2  M e TBS  SnMe 163  *SnMe  3  162  TBS 3  180a  To a cold (-48 °C), stirred solution of L D A (7.68 mmol) in dry T H F (60 mL) was added H M P A (1.33 mL, 7.68 mmol) and stirring was continued for 10 min. The ester 163 (1.85 g, 6.40 mmol) was added as a solution in dry T H F (4 mL) via a cannula and the mixture was stirred for 40 min. The solution was cooled to -78 °C and a solution of the bromide 162 (2.09 g, 8.00 mmol) in dry T H F (2 mL) was added via a cannula.  The  reaction mixture was stirred at -48 °C for 40 min and then the mixture was warmed to room temperature. Saturated aqueous sodium bicarbonate (50 mL) was added and the  150 rnixture was extracted with E t 0 (3 x 50 mL).  The combined organic extracts were  2  washed with brine (3 x 60 mL), dried (MgSCU), and the solvent was removed under reduced pressure. Flash column chromatography (100 g of silica gel, 98:2 petroleum ether-Et 0) of the crude product and removal of trace amounts of solvent (vacuum pump) 2  from the acquired material, yielded 2.50 g (83 %) of the stannane 180a as a colorless clear oil.  IR (neat): 2174, 1733, 1251, 775 c m . 1  R  l  nmr (400 M H z , CDC1 ) 6: 0.05 (s, 6H, -SiMe^), 0.12 (s, 9H, -SnMe , 3  3  Vsn-H = 54.2 Hz), 0.91 (s, 9H, -Si'Bu-), 1.29-1.53 (rn, 3H), 1.69-1.76 (m, IH), 1.97 (td, IH, / = 4.2, 12.6 Hz), 2.20 (t, 2H, / = 6.8 Hz), 2.35-2.51 (m, 3H), 3.63 (s, 3H, -C0 Me), 2  5.94 (dd, I H , olefinic proton, / = 2.1, 2.1 Hz, / . = 37.7 Hz). 3  Sn  1 3  H  C nmr (75.5 M H z , CDC1 ) 5: -8.5 (-ve), -4.5 (-ve), 16.4, 20.1, 24.4, 26.0 (-ve), 32.0, 3  33.9, 37.8, 51.6 (-ve), 65.2, 82.6, 107.3, 143.1 (-ve), 148.6,176.5.  H R M S calcd for C H O S i 20  35  120  2  S n (M -Me): 455.1428; found: 455.1431. +  Anal, calcd for C i H 0 S i S n : C 53.75, H 6.18; found: C 54.03, H 8.04. 2  Preparation  of  38  2  methyl  l-(pent-4-yn-l-yl)-2-trunethylstannylcyclopent-2-ene-l-  carboxylate (180b)  180a  180b  To a stirred solution of the stannane 180a (1.23 g, 2.62 mmol) in dry T H F (26 mL) at room temperature was added a solution of tetrabutylammonium fluoride (3.4 mL, 1 M in THF, 3.4 mmol) and the solution was stirred for 1 h.  Saturated aqueous sodium  151 bicarbonate (25 mL) was added and the mixture was extracted with E t 0 (3 x 25 mL). 2  The combined organic extracts were washed with brine (50 mL), dried (MgS0 ), and the 4  solvent was removed in vacuo to give a crude oil. Flash column chromatography (100 g of silica gel, 98:2 petroleum ether-Et 0) of the crude product and removal of trace 2  amounts of solvent (vacuum pump) from the acquired material yielded 900 mg (97 %) of the alkyne 180b as a colorless clear oil.  IR (neat): 3310, 1733, 1166, 771 c m . 1  J  H nmr (400 M H z , CDC1 ) 8: 0.13 (s, 9H, -SnMe . / . = 54.2 Hz), 1.30-1.54 (m, 4H), 2  3  3  S n  H  1.70-1.78 (m, IH), 1.91-2.00 (m, 2H), 2.15 (tdd, I H , / = 7.0, 1.0, 1.5 Hz), 2.35-2.53 (m, 3H), 3.64 (s, 3H), 5.95 (dd, IH, olefinic proton, J = 2.1, 2.1 Hz, / . = 38.0 Hz). 3  Sn  1 3  H  C nmr (75.5 M H z , CDC1 ) 5: -8.6, 18.7, 24.0, 31.8, 34.1, 37.5, 51.7, 65.1, 68.6, 83.9, 3  143.2, 148.5, 176.6.  H R M S calcd for C i H O 4  2 1  1 2 0 2  S n (M -Me): 341.0564; found: 341.0564. +  Anal, calcd for C i H 0 S n : C 50.74, H 6.81; found: C 50.94, H 6.94. 5  Preparation  24  2  of methyl 6-(l-methoxvcarlx)nyl-2-trimethylstannylcyclopent-2-en-l-yl)  hex-2-ynoate (180)  180b  180  To a cold (-78 °C), stirred solution of L D A (2.43 mmol) in dry T H F (18 mL) was added a solution of the alkyne 180b (663 mg, 1.87 mmol) in dry T H F (1 mL) via a cannula and the reaction mixture was stirred for 1 h at -78 °C. Methyl chloroformate (200 |JL, 2.62 mmol) was added via a syringe and stirring was continued for 1 h at -78 °C and 1 h  152 at room temperature. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with E t 0 (3 x 20 mL). The combined organic extracts were 2  washed with brine (30 mL), dried (MgS0 ), and the solvent was removed under reduced 4  pressure. Flash column chromatography (20 g of silica gel, 9:1 petroleum ether-Et 0) of 2  the crude product, followed by bulb-to-bulb distillation (170-190 °C/0.3 torr) of the acquired liquid, yielded 627 mg (81 %) of the diester 180 as a colorless clear oil.  IR (neat): 2238, 1718 (br), 1257, 772 cm" . 1  *H nmr (400 M H z , CDC1 ) 8: 0.12 (s, 9H, -SnMe,. / „ . = 54.2 Hz), 1.40-1.54 (m, 3H), 2  3  s  H  1.70-1.76 (m, 1H), 1.92-1.98 (m, 1H), 2.28-2.31 (m, 2H), 2.35-2.53 (m, 3H), 3.64 (s, 3H, - C 0 M e ) , 3.73 (s, 3H, - C O M e ) . 5.90 (dd, 1H, olefinic proton, / = 2.0, 2.0 Hz, / . = 3  2  S j l  H  37.4 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 8: -8.6 (-ve), 18.9, 23.2, 31.8, 34.1, 37.5, 51.7 (-ve), 3  52.4 (-ve), 65.1,73.1, 88.8, 143.4 (-ve), 148.3, 153.9, 176.4.  H R M S calcd for C H O 1 6  2 3  1 2 0 4  S n (M -Me): 399.0618; found: 399.0619. +  Anal, calcd for C H 0 S n : 49.43, H 6.34; found: C 49.79, H 6.38. 1 7  Preparation  of  2 6  4  methyl  4-(l-ethoxvcarbonvl-2-trimethylstannylcyclohex-2-en-l-yl)  but-2-vnoate (181)  164  140  To a cold (-78 °C), stirred solution of L D A (1.79 mmol) in dry T H F (7 mL) was added D M P U (230 | i L , 1.90 mmol) and stirring was continued for 5 min. A solution of the ester 164 (434 mg, 1.37 mmol) in dry T H F (1 mL) was added via a cannula to the  153 reaction mixture. The rnixture was stirred at -78 °C for 30 min and at 0 °C for 50 min. The orange suspension was cooled to -78 °C and methyl 4-bromobut-2-ynoate  (140)  (340 mg, 1.90 mmol), dissolved in dry T H F (1 mL), was added via a cannula to the reaction mixture. After 10 rnin, the reaction mixture turned dark brown and saturated aqueous sodium bicarbonate (30 mL) was added at -78 °C. warmed to room temperature. 25 mL).  The mixture was then  The black suspension was extracted with E t 0 (3 x 2  The organic extracts were combined, washed with brine (2 x 25 mL), dried  (MgS0 ), and the solvent was removed under reduced pressure. 4  Flash column  chromatography (40 g of silica gel, 95:5 petroleum ether-Et 0) of the crude product and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 290 mg (51 %) of the ester 181 as a clear oil.  IR (neat): 2237, 1718 (br), 1603, 1435, 1256, 1074, 769 c m . 1  H nmr (400 M H z , CDC1 ) 8: 0.11 (s, 9H, -SnMe , / „ .  l  2  3  3  s  H  = 52.8 Hz), 1.25 (t, 3H,  - C 0 C H C H 3 , / = 7.2 Hz), 1.60-1.78 (m, 2H), 1.80-1.90 (m, IH), 2.00-2.15 (m, 3H), 2  2  2.55 (d, IH, H-4, / = 17.2 Hz), 2.81 (d, I H , H-4', / = 17.2 Hz), 3.72 (s, 3H, -CO,Me). 4.07-4.20 (m, 2H, -C0 CH2CH ), 6.03 (dd, I H , olefinic proton, / = 3.7, 3.7 Hz, / . = 3  2  3  S n  H  71.2 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 8: -7.7 (-ve), 13.9 (-ve), 18.4, 26.7, 29.1, 30.8, 50.4, 52.3 3  (-ve), 61.1, 74.7, 85.8, 141.1 (-ve), 142.1, 153.6, 174.6.  H R M S calcd for C i H O 6  2 3  1 2 0 4  S n (M -Me): 399.0618; found: 399.0618. +  Anal, calcd for C i H 0 S n : C 49.43, H 6.34; found: C 49.68, H 6.28. 7  26  4  154 Preparation of ethyl l-(but-3-yn-l-vl)-2-trimethvlstamvlcyclohex-2-ene-l-carboxylate  (182b)  182a  182b  To a cold (-48 °C), stirred solution of L D A (8.60 mmol) in dry T H F (60 mL) was added H M P A (1.50 mL, 8.6 mmol) and stirring was continued for 10 min. A solution of the ester 164 (2.05 g, 6.46 mmol) in dry T H F (2 mL) was added via a cannula and the mixture was stirred for 40 min. The solution was cooled to -78 °C and the bromide 161 (2.19 g, 8.87 mmol) was added as a solution in dry T H F (2 mL) via a cannula.  The  reaction mixture was stirred at -78 °C for 3 h and then warmed to room temperature. Saturated aqueous sodium bicarbonate (50 mL) was added and the mixture was extracted with E t 0 (3 x 50 mL). 2  The combined organic extracts were washed with brine (3 x  60 mL), dried (MgSC^), and the solvent was removed under reduced pressure. Flash column chromatography (100 g of silica gel, 98:2 petroleum ether-Et 0) of the crude 2  product resulted in the isolation of 248 mg of the stannane 164 and 1.56 g of a colorless clear oil containing a mixture of the alkylated product 182a and the starting material 164.  To a stirred solution of the stannane 182a (obtained as described above) in dry T H F (30 mL) at room temperature was added a solution of tetrabutylammonium fluoride (6.5 mL, 1 M in THF, 6.5 mmol) and stirring was continued for 1 h. Saturated aqueous sodium bicarbonate (50 mL) was added and the mixture was extracted with E t 0 (3 x 2  50 mL).  The combined organic extracts were washed with brine (50 mL), dried  (MgSCU), and the solvent was removed in vacuo to give a crude oil. Flash column chromatography (100 g of silica gel, 98:2 petroleum ether-Et 0) of the crude product and 2  155 removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 635 mg of the ester 164 and 623 mg (46 % over 2 steps based on the total amount (883 mg) of recovered starting material 164) of the alkyne 182b as a colorless clear oil.  IR (neat): 3310, 2120, 1719, 1180, 769 cm' . 1  J  H nmr (400 M H z , CDC1 ) 5: 0.11 (s, 9H, -SnMe , / . 2  3  3  S n  H  = 52.3 Hz), 1.25 (t, 3H,  - C 0 C H C H 3 , / = 7.1 Hz), 1.50-1.64 (m, 3H), 1.70-1.81 (m, 1H), 1.92 (t, 1H, H4, 2  2  / = 2.4 Hz), 2.00-2.15 (m, 6H), 4.00-4.20 (m, 2H, - C 0 C t k C H ) , 5.97 (dd, 1H, olefinic 2  proton, / = 3.6, 3.6 Hz,  1 3  3  /  S n  -H  3  = 75.0 Hz).  C nmr (75.5 M H z , CDC1 ) 5: -7.1, 14.0, 14.2, 19.0, 27.2, 29.9, 38.3, 50.5, 60.8, 68.4, 3  84.0, 140.2, 144.8, 176.0.  H R M S calcd for C H O 1 5  2 3  1 2 0 2  S n (M -Me): 355.0720; found: 355.0725. +  Anal, calcd for C H 0 S n : C 52.07, H 7.10; found: C 52.30, H 7.19. 1 6  Preparation  of  2 6  2  methyl  5-(l-ethoxycarbonyl-2-trimethylstannylcyclohex-2-en-l-yl)  pent-2-ynoate (182)  182b  182  To a cold (-78 °C), stirred solution of L D A (1.72 mmol) in dry T H F (12 mL) was added a solution of the alkyne 182b (486 mg, 1.32 mmol) in dry T H F (1 mL) via a cannula and stirring was contiuned for 1 h. Methyl chloroformate (153 )nL, 1.98 mmol) was added via a syringe and the mixture was stirred for 1 h at -78 °C and 1 h at room temperature. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted  156 with E t 0 (3 x 20 mL). The combined organic extracts were washed with brine (30 mL), 2  dried (MgS0 ), and the solvent was removed under reduced pressure. 4  Flash column  chromatography (20 g of silica gel, 9:1 petroleum ether-Et 0) of the crude product, 2  followed by bulb-to-bulb distillation (160-190 °C/0.3 torr) of the acquired oil, yielded 431 mg (77 %) of the diester 182 as a colorless clear oil.  IR (neat): 2239, 1719 (br), 1435, 1256, 769 c m . 1  *H nmr (400 M H z , CDC1 ) 5: 0.11 (s, 9H, -SnMe , / . 2  3  3  S n  H  = 52.4 Hz), 1.24 (t, 3H,  - C 0 C H C H 3 , J= 7.1 Hz), 1.50-1.65 (m, 3H), 1.73-1.81 (m, IH), 1.95-2.14 (m, 4H), 2  2  2.27 (t, 2H, / = 8.1 Hz), 3.73 (s, 3H, -CO?Me). 4.05-4.19 (m, 2H, -C0 CH2CH ), 5.90 2  3  (dd, I H , olefinic proton, / = 3.6, 3.6 Hz, / . = 70.1 Hz). 3  S n  1 3  H  C nmr (75.5 M H z , CDC1 ) 5: -7.2 (-ve), 14.1 (-ve), 14.3, 18.9, 27.1, 30.0, 36.9, 50.3, 3  52.6 (-ve), 60.9, 72.9, 89.2, 140.6 (-ve), 144.3, 154.1, 175.8.  H R M S calcd for C i 7 H O 25  120 4  S n (M -Me): 413.0775, found: 413.0783. +  Anal, calcd for C i H 0 S n : C 50.62, H 6.61; found: C 50.77, H 6.61. 8  Preparation  of  28  4  methyl  6-(l-ethoxycarbonyl-2-trimethylstannylcyclohex-2-en-l-yl)  hex-2-ynoate (183)  164  159  183  To a cold (-78 °C), stirred solution of L D A (5.50 mmol) in dry T H F (30 mL) was added D M P U (660 ^iL, 5.50 mmol) and stirring was continued for 10 min. The mixture was warmed to -40 °C and a solution of the ester 164 (1.33 g, 4.20 mmol) in dry T H F (3 mL) was added via a cannula. The reaction mixture was then stirred for 40 min.  Methyl  157 6-iodohex-2-ynoate (159)  (1.43 g, 5.70 mmol) was added as a solution in dry T H F (3  mL) via a cannula. The reaction mixture was stirred at -40 °C for 40 min and then was allowed to warm to room temperature. Saturated aqueous sodium bicarbonate (25 mL) was added and the mixture was extracted with E t 0 (3 x 30 mL). 2  The combined organic  extracts were washed with brine (3 x 50 mL), dried (MgSC^), and the solvent was removed under reduced pressure. Flash column chromatography (100 g of silica gel, 9:1 petroleum ether-Et 0) of the crude product, followed by bulb-to-bulb distillation (1502  200 °C/0.3 torr) of the acquired oil, yielded 1.07 g (58 %) of the stannane 183 as a colorless clear oil.  IR (neat): 2238, 1713 (br), 1435, 1256, 769 cm" . 1  *H nmr (400 M H z , CDC1 ) 8: 0.10 (s, 9H, -SnMe^, J . 2  3  Sn H  = 52.3 Hz), 1.25 (t, 3H,  - C 0 C H C H 3 , / = 7.1 Hz), 1.40-1.64 (m, 7H), 1.86-1.94 (m, 1H), 2.00-2.12 (m, 2H), 2  2  2.28 (t, 2H, J= 6.7 Hz), 3.73 (s, 3H, - C C W e ) . 4.00-4.21 (m, 2H, - C 0 C H 2 C H ) , 5.94 2  3  (dd, 1H, olefinic proton, / = 3.7, 3.7 Hz, / . = 75.7 Hz). 3  S n  1 3  H  C nmr (75.5 M H z , CDC1 ) 8: -7.1 (-ve), 14.2 (-ve), 19.0 (2C), 22.8, 27.2, 30.2, 39.0, 3  50.6, 52.5 (-ve), 60.7, 73.1, 89.0, 139.7 (-ve), 145.4, 154.1, 176.2.  H R M S calcd for C i H O 4 8  2 7  1 2 0  S n (M -Me): 427.0931; found: 427.0939. +  Anal, calcd for C H o 0 S n : C 51.73, H 6.85; found: C 51.86, H 6.78. 19  3  4  158 Preparation  of methyl l-(5-fe^butyldimethylsilyfo  a  cyclohept-2-ene- 1-carboxylate (184a) C0 Me 2  C0 Me 2  ..TBS  SnMe  B  TBS  \ ^ \ ^ ^  r  3  165  ^ ^ S n M e  162  3  184a  To a cold (-78 °C), stirred solution of L D A (0.504 mmol) in dry THF (3 mL) was added D M P U (61 ^iL, 2.2 mmol) and stirring was continued for 10 min. The ester 165 (123 mg, 0.388 mmol) was added as a solution in dry T H F (2 mL) via a cannula and the mixture was stirred at -48 °C for 40 min. The bromide 162 (1.03 g, 4.16 mmol) was added as a solution in dry T H F (2 mL) via a cannula. The reaction mixture was stirred at -48 °C for 40 min and then the mixture was warmed to room temperature.  Saturated aqueous  sodium bicarbonate (5 mL) was added and the mixture was extracted with E t 0 (3 x 2  5 mL).  The combined organic extracts were washed with brine (3 x 10 mL), dried  (MgSO,*), and the solvent was removed under reduced pressure.  Flash column  chromatography (50 g of silica gel, 197:3 petroleum ether-Et 0) of the crude product and 2  removal of trace amounts of solvent (vacuum pump) from the acquired oils resulted in the isolation of 23 mg of the stannane 165 and 68 mg (35 %, 43 % based on the recovered starting material 165) of the alkylated product 184a as a colorless clear oil.  IR (neat): 2173, 1723, 1596, 1251, 775 cm' . 1  *H nmr (400 M H z , CDC1 ) 8: 0.05 (s, 15H, includes 6H - S i M e ^ and 9H -SnMfru 3  2  / . = 51.6 Hz), 0.72 (s, 9H, -Si'Bu-), 1.36-1.48 (m, 3H), 1.60-1.67 (m, 1H), 1.70-1.81 S n  H  (m, 3H), 1.82-1.87 (m, 2H), 1.91-1.99 (m, 1H), 2.17-2.23 (m, 4H), 3.65 (s, 3H, -CCvMe). 5.99 (dd, 1H, olefinic proton, J = 5.2, 7.2 Hz, / „ . = 84.9 Hz). 3  s  1 3  H  C nmr (75.5 M H z , CDC1 ) 8: -6.5, -4.2, 16.5, 20.4, 24.6, 26.1 (2C), 26.7, 29.8, 34.3, 3  36.4, 51.9, 56.8, 82.7, 107.6,141.7, 150.5,178.3.  H R M S calcd for C H 4 0 S i S n (M -Me): 483.1741; found: 483.1745. +  22  2  2  159  Anal, calcd for C H 4 0 S i S n : C 55.54, H 8.51; found: C 55.64, H 8.49. 23  Preparation  2  of  2  methyl  l-(pent-4-vn-l-vl)-2-trirnethvlstannvlcvcloliept-2-ene-l-  carboxylate (184b)  184a  184b  To a stirred solution of the stannane 184a (139 mg, 0.278 mmol) in dry T H F (3 mL) at room temperature was added a solution of tetrabutylammonium fluoride (0.42 mL, 1 M in THF, 0.42 mmol) and the solution was stirred for 1 h.  Saturated aqueous sodium  bicarbonate (5 mL) was added and the mixture was extracted with E t 0 ( 3 x 5 mL). The 2  combined organic extracts were washed with brine (10 mL), dried (MgS0 ), and the 4  solvent was removed in vacuo to give a crude oil. Flash column chromatography (12 g silica gel, 98:2 petroleum ether-Et 0) of the crude product and removal of trace amounts 2  of solvent (vacuum pump) from the acquired material yielded 93 mg (87 %) of the alkyne 184b as a colorless clear oil.  IR (neat): 3309,1719, 1596,1214,768 c m . 1  J  H nmr (400 M H z , CDC1 ) 5: 0.06 (s, 9H, -SnMe , / . = 51.6 Hz), 1.40-1.51 (m, 3H), 2  3  3  S n  H  1.60-1.80 (m, 4H), 1.87 (t, 2H, / = 5.9 Hz), 1.91-2.00 (m, 2H), 2.13-2.27 (m, 4H), 3.65 (s, 3H, -CO?Me), 6.00 (dd, IH, olefinic proton, / = 5.2, 7.2 Hz, / . = 84.9 Hz). 3  S n  1 3  H  C nmr (75.5 M H z , CDC1 ) 5: -6.6, 18.9, 24.2, 24.4, 26.5, 29.5, 33.9, 36.6, 51.8, 56.8, 3  68.5, 84.0, 141.7,150.3, 178.0.  H R M S calc for C i H O 6  2 5  1 2 0 2  S n (M -Me): 369.0877; found: 369.0872. +  160 Anal, calcd for C i H 0 S n : C 53.30, H 7.37; found: C 53.32, H 7.51. 7  28  2  Preparation of methyl 6-(l-methoxycarbonyl-2-trirnethvlstannvlcvclohept-2-en-l-vl)hex-2-vnoate (184)  184b  184  To a cold (-78 °C), stirred solution of L D A (0.808 mmol) in dry T H F (5 mL) was added a solution of the alkyne 184b (238 mg, 0.622 mmol) in dry T H F (1 mL) via a cannula and the reaction mixture was stirred for 1 h at -78 °C.  Methyl chloroformate (72 (iL,  0.93 mmol) was added via a syringe and stirring was continued for 1 h at -78 °C and 1 h at room temperature. Saturated aqueous sodium bicarbonate (10 mL) was added and the mixture was extracted with E t 0 (3 x 10 mL). The combined organic extracts were 2  washed with brine (20 mL), dried (MgSCU), and the solvent was removed under reduced pressure. Flash column chromatography (20 g of silica gel, 9:1 petroleum ether-Et 0) of 2  the crude product, followed by bulb-to-bulb distillation (170-190 °C/0.3 torr) of the acquired material, yielded 249 mg (91 %) of the diester 184 as a colorless clear oil.  IR (neat): 2238,1718 (br), 1435, 1257, 753 c m . 1  X  H nmr (400 M H z , CDC1 ) 5: 0.13 (s, 9H, / . = 51.6 Hz), 1.41-1.56 (m, 3H), 1.60-1.80 2  3  S n  H  (m, 4H), 1.85-1.89 (m, 2H), 1.91-1.99 (m, 1H), 2.17-2.23 (m, 2H), 2.30 (t, 2H, / = 7.0 Hz), 3.65 (s, 3H, -C0 Me), 3.73 (s, 3H, -C0 Me), 6.00 (dd, 1H, olefinic proton, 2  2  / = 5.4, 7.0 Hz, / . = 85.2 Hz) 3  S n  1 3  H  C nmr (75.5 MHz, CDC1 ) 8: -6.5 (-ve), 19.3, 23.5, 24.5, 26.6, 29.6, 34.0, 36.4, 52.1 3  (-ve), 52.6 (-ve), 56.9, 73.2, 89.3, 142.1 (-ve), 150.0, 154.2, 178.0.  H R M S calcd for C H O 1 8  2 7  1 2 0 4  S n (M -Me): 427.0931; found: 427.0941. +  161  Anal calcd. for  C19H30O4S11:  C 51.73, H 6.85; found: C 51.99, H 6.88.  3.2 Copper(I) mediated conjugate additions Preparation of 1 -methoxycarbonvl-(£^-6-methoxvcarbonylmetliylidenebicvclo\3.3.Oloct4-ene (187)  179  187  Following general procedure 1 (see pg. 126), the bicyclic diester 187 was prepared by the addition of the diester 179 (92 mg, 0.23 mmol), as a solution in dry D M F (1.2 mL), to a cool (0 °C), stirred solution-suspension of CuCl (60 mg, 0.61 mmol) and glacial acetic acid (65 |LiL, 1.1 mmol) in dry D M F (1.1 mL). Purification of the crude product by flash column chromatography (12 g of silica gel, 4:1 petroleum ether-Et 0) and removal of 2  trace amounts of solvent (vacuum pump) from the acquired material yielded 50 mg (93 %) of the bicyclic compound 187 as a colorless clear oil. This compound proved to be unstable when stored under argon for extended periods of time in a freezer.  IR (neat): 1725 (br), 1636, 1434, 1353, 1161 cm" . 1  *H nmr (400 M H z , C D ) 8 1.11-1.19 (m, I H , H-8), 1.45-1.53 (m, I H , H-2), 2.22 (ddd, 6  6  IH, H-3, / = 3.8, 8.6, 17.1 Hz), 2.33 (br dd, I H , H-8', / = 8.0, 12.3 Hz), 2.42 (br dd, I H , H-2', / = 6.5, 12.5 Hz), 2.78-2.87 (m, I H , H-3'), 3.20 (s, 3H, - C 0 M e ) , 3.30-3.46 (m, 4H, 2  includes 3H - C 0 M e singlet at 3.42, H-7), 3.51 (dddd, I H , H-7', / = 1.0, 1.9, 8.0, 2  19.4 Hz), 5.64 (dd, IH, H-4, 7= 3.8, 2.3 Hz), 6.20 (br s, IH, H-9).  162 1 3  C nmr (75.5 M H z , C D ) 8: 35.2, 37.0, 37.9, 38.6, 50.7, 51.5, 64.4, 110.9, 128.1, 152.0, 6  6  153.7, 167.0, 175.0.  HRMS calcd for C i H 0 : 236.1049; found: 236.1047. 3  1 6  4  Anal, calcd for C i H 0 : C 66.09, H 6.83; found: C 66.14, H 6.97. 3  Table 18.  X  1 6  4  H nmr (400 MHz, CDC1 ) data for the diester 187: C O S Y (200 MHz) and 3  NOED experiments  _ COpMe 2 I f  9^C0 Me 2  187 H nmr (400 MHz)  COSY  NOED  8 (multiplicity, / (Hz))  Correlation  Correlation  Assignment H-x  J  H-2  1.45-1.53 (m)  H-2', H-3, H-3'  H-2'  2.42 ( b r d d , / = 6.5, 12.5)  H-2, H-3'  H-3  2.22 (ddd, 7=3.8, 8.6, 17.1)  H-2, H-3', H-4  H-3*  2.78-2.87 (m)  H-2, H-2', H-3, H-4  H-4  5.64 (dd, 1H,7=3.8, 2.3)  H-3, H-3'  H-7  Part of 3.30-3.46 (m)  H-7', H-8, H-8', H-9  H-7'  3.51 (dddd, 7 = 1.0,1.9, 8.0,19.4)  H-7, H-8, H-8', H-9  H-8  1.11-1.19 (m)  H-7, H-7', H-8'  H-8'  2.33 (brdd, 7=8.0, 12.3)  H-7, H-7', H-8  H-9  6.20 (br s)  H-7, H-7'  -C0 Me  3.20 (s)  -C0 Me  Part of 3.30-3.46 (m)  2  2  H-3, H-3', H-9  H-4  163 Preparation of l-methoxycarbonvl-(£^-5-methoxvcarrx)nylm 6-ene ( 1 8 8 )  180  188  Following general procedure 1 (see pg. 126), the bicyclic diester 1 8 8 was prepared by the addition of the diester 1 8 0 (122 mg, 0.296 mmol), as a solution in dry D M F (1.5 mL), to a cool (0 °C), stirred solution-suspension of CuCl (75 mg, 0.74 mmol) and glacial acetic acid (85 ^iL, 1.5 mmol) in dry D M F (1.5 mL). Purification of the crude oil by flash column chromatography (12 g of silica gel, 4:1 petroleum ether-Et 0) and removal of 2  trace amounts of solvent (vacuum pump) from the acquired material yielded 73 mg (99 %) of the diester 1 8 8 as a colorless clear oil.  IR(neat): 1713 (br), 1626, 1435, 1158 cm' . 1  *H nmr (400 M H z , CDC1 ) 5: 1.38-1.54 (m, 2H), 1.75-1.92 (m, 2H), 2.00-2.09 (m, IH), 3  2.31-2.45 (m, 4H), 3.62-3.70 (m, 7H, includes two 3H - C 0 M e singlets at 3.63 and 3.68), 2  5.95 (d, IH, / = 2.3 Hz), 5.99 (br s, IH).  X  H nmr (400 M H z , C D ) 5: 1.12 (td, IH, / = 4.3, 12.7 Hz), 1.49-1.64 (m, 3H), 1.94-2.01 6  6  (ddd, I H , / = 3.0, 8.8, 16.5 Hz), 2.01-2.12 (m, I H , H-8), 2.17-2.27 (m, I H , H-8'), 2.31 (dd, IH, / = 8, 12.5 Hz), 2.41 (dm, IH, / = 13.5 Hz), 3.25 (s, 3H, -CQ Me), 3.41 (s, 3H, 2  -C0 Me), 4.09 (dm, I H , / = 13.5 Hz), 5.70 (dd, I H , H-7, / = 2.4, 2.4 Hz), 6.22 (d, I H , 2  H-10, 7=2.2 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) S: 23.1, 28.5, 30.5, 36.4, 38.6, 50.8 (-ve), 52.0 (-ve), 58.2, 3  112.8 (-ve), 130.4 (-ve), 144.1, 151.5, 167.1, 176.3.  164 H R M S calcd for C i H 0 : 250.1205; found: 250.1213. 4  1 8  4  Anal calcd for C H 0 : C 67.18, H 7.25; found: C 67.32, H 7.24. 1 4  1 8  4  Table 19. H nmr (400 M H z , C D ) data for the diester 188: NOED experiments J  6  6  9  C0 Me 2  u  C0 Me 2  188 Assignment  H nmr (400 MHz)  NOED  8 (multiplicity, 7 (Hz))  Correlation  X  H-x H-7  5.70 (dd, 7=2.4, 2.4)  H-8, H-8', H-10  H-10  6.22 (d, 7=2.2)  H-7  Preparation of l-ethoxycarfxjnyl-(/ir)-7-methoxycarbonylmethylidenebicyclor4.2.01oct-5ene (189)  C0 Et 2  SnMe  C0 Me 2  e^COoMe  3  181  189  Following general procedure 1 (see pg. 126), the diene 189 was prepared by the addition of the diester 181 (90 mg, 0.22 mmol), as a solution in dry D M F (1 mL), to a cool (0 °C), stirred solution-suspension of CuCl (57 mg, 0.58 mmol) and glacial acetic acid (60 }XL, 1.1 mmol) in dry D M F (1 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 4:1 petroleum ether-Et 0) and removal of trace 2  165 amounts of solvent (vacuum pump) from the acquired material yielded 52 mg (94 %) of the bicyclic compound 189 as a colorless oil.  IR(neat): 1723 (br), 1673, 1436, 1338, 1282, 1203, 1152, 1026 c m . 1  *H nmr (400 M H z , CDC1 ) 8: 1.2-1.4 (m, 4H, includes 3H - C 0 C H C H 3 triplet at 1.23 3  2  2  w i t h / = 7 Hz), 1.50-1.65 (m, 2H), 1.65-1.85 (m, 1H), 2.1-2.35 (m, 2H), 2.39 (dt, 1H, J = 3.4, 12.3 Hz), 2.95 (dd, 1H, H-8, / = 2.6, 16.5 Hz), 3.38 (dd, 1H, H-8', / = 1.9, 16.5 Hz), 3.68 (s, 3H, - C 0 M e ) , 4.10-4.20 (m, 2H, -C0 CH2CH ), 5.80 (s, 1H, olefinic proton), 2  2  3  5.90-6.00 (m, 1H, olefinic proton).  1 3  C nmr (75.5 M H z , CDC1 ) 8: 14.1 (-ve), 19.5, 24.6, 29.6, 44.1, 51.0 (-ve), 51.3, 66.8, 3  106.5 (-ve), 123.2 (-ve), 140.8, 159.8, 167.3, 174.5.  H R M S calcd for C i H 0 : 250.1205; found: 250.1197. 4  1 8  4  Anal, calcd for C i H 0 : C 67.18, H 7.25; found: C 67.02, H 7.11. 4  1 8  4  Preparation of 1 -(fe^butvldimethvlsiloxvmethvl)-(^-7-(fe^butvldimethvlsiloxvmethyl methylidene)bicyclo[4.2.01oct-5-ene (198) OH  T B S O . 11  C0 Et 2  1 4  \^C0 Me  OH  2  189  197  ^  10 9  0  ^OTBS  198  To a cold (-78 °C), stirred solution of the diester 189 (161 mg, 0.642 mmol) in dry T H F (6.5 mL) was added a solution of D I B A L (3.90 mL, 1.0 M in hexanes, 6 equiv) and stirring was continued for 45 min. The solution was warmed to room temperature and stirred for 45 min. Saturated aqueous ammonium chloride (2 mL) was added and the solution was stirred for 30 min. M g S 0 (-100 mg) was added and the white suspension 4  was stirred for an additional 30 min. The mixture was diluted with E t 0 (10 mL). The 2  166 mixture was then filtered through Florisil (-10 g) and the cake was eluted with E t 0 2  (50 mL) and M e O H (25 mL). The combined filtrate was concentrated under reduced pressure. Flash column chromatography (12 g of silica gel, 98:2 Et 0-MeOH) of the 2  crude product yielded the diol 197 as a clear oil. This material proved to be unstable in previous experiments and the purified material was immediately used in the next step.  The oil thus obtained was dissolved in dry C H C 1 2  2  (5 mL).  With stirring, tert-  butyldimethylsilyl chloride (265 mg, 1.76 mmol) was added in one portion, followed by imidazole (259 mg, 3.80 mmol) in one portion. The white suspension was stirred for 1 h. The solvent was removed under reduced pressure. Flash column chromatography (12 g of silica gel, 98:2 petroleum ether-Et 0) of the crude product and removal of trace amounts 2  of solvent (vacuum pump) from the acquired material yielded 194 mg (74 % over 2 steps) of the disilyl ether 198 as a colorless clear oil.  IR (neat): 1472, 1375, 1255, 1084, 837, 775 c m . 1  X  H nmr (400 M H z , CDC1 ) 8: 0.02 (s, 6H, -SiMe?-), 0.05 (s, 6H, -SiMe?-), 0.87 (s, 9H, 3  -SfBu-), 0.88 (s, 9H, -Si'Bu-), 1.11 (td, 1H, / = 4.4, 12.4 Hz), 1.55-1.70 (m, 2H), 1.97 (dt, 1H, / = 3.4, 12.4 Hz), 2.05-2.15 (m, 2H), 2.20 (d, 1H, H-8, / = 13 Hz), 2.65 (d, 1H, H-8', / = 13 Hz), 3.50 (dd, 1H, H - l l , / = 0.9, 10 Hz), 3.65 (dd, 1H, H - l l ' , / = 1.8, 10 Hz), 4.11 (d, 2H, H-10, / = 6.5 Hz), 5.45-5.55 (m, 1H, H-9). 5.57 (br t, 1H, H-5, / = 3.8 Hz).  1 3  C N M R (75.5 M H z , CDC1 ) 8: -5.39, -5.34, -5.06, -5.02, 18.5 (2C), 24.3, 26.0 (7C) 3  (-ve), 27.6, 38.8, 46.8, 60.9, 65.7, 116.7 (-ve), 116.9 (-ve), 142.5, 143.2.  H R M S calcd for C H 4 0 S i : 408.2880; found: 408.2877. 2 3  4  2  2  Anal, calcd for C ^ I ^ O ^ : C 67.58, H 10.85: found: C 67.42, H 10.80.  167 Table 20. *H nmr (400 M H z , CDC1 ) data for the diester 198: N O E D experiments 3  TBSO  Assignment H-x  R nmr (400 MHz)  NOED  5 (multiplicity, / (Hz))  Correlations  l  H-8  2.20 ( d , / = 13)  H-8*, H-10  H-8'  2.65 ( d , / = 13)  H-8, H-10, H-11,H-11'  H-10  4.11 (d, 7=6.5)  H-8', H-9  H-ll  3.50 (dd, 7=0.9, 10)  H-8, H - l l '  H-ll'  3.65 (dd, 7 = 1.8, 10)  H-ll  Preparation of 1 -ethoxycarbonvl-(F)-7-methoxvcarbonvlmethylidenebicyclo \4.3.01non-5ene (190) 2 C0 Et 2  Following general procedure 1 (see pg. 126), the bicyclic diester 190 was prepared by the addition of the diester 182 (84 mg, 0.20 mmol), as a solution in dry D M F (1 mL), to a cool (0 °C), stirred solution-suspension of CuCl (51 mg, 0.52 mmol) and glacial acetic acid (56 | i L , 0.98 mmol) in dry D M F (1 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 4:1 petroleum efher-Et 0) and removal of trace 2  amounts of solvent (vacuum pump) from the acquired material yielded 51 mg (98 %) of  168 the diene 190 as a white solid (mp 55-57 °C).  IR (KBr): 1718 (br), 1631, 1435, 1159, 733 c m . 1  :  H nmr (400 M H z , CDC1 ) 8: 1.14-1.23 (m, 4H, H-2 and 3H -CO2CH2CH3 triplet at 1.18 3  w i t h / = 7.2 Hz), 1.41-1.54 (m, 2H, H-3 and H-9), 1.70-1.80 (m, I H , H-3'), 2.10-2.30 (m, 2H, H-4 and H-4'), 2.35 (dd, IH, H-9', / = 8.1, 12.8 Hz), 2.48 (dt, I H , H-2', / = 3.3, 12.8 Hz), 2.58-2.69 (m, I H , H-8), 3.08 (ddd, I H , H-8*, / = 1.5, 8.5, 19.4 Hz), 3.68 (s, 3H, - C 0 M e ) , 4.03-4.15 (m, 2H, -C0 CH2CH ), 6.08 (br s, I H , H-10), 6.32 (dd, I H , H-5, 2  2  3  / = 3.9, 3.9 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 5: 14.1 (-ve), 19.4, 25.3, 30.2, 32.2, 36.6, 50.9 (-ve), 52.9, 3  60.8, 106.9 (-ve), 125.5, 141.6, 160.5, 167.7, 175.4.  H R M S calcd for C H o 0 : 264.1362; found: 264.1362. 15  2  4  Anal, calcd for C i H o 0 : C 68.16, H 7.63; found: C 67.86, H 7.68. 5  2  4  169 Table 21. *H nmr (400 M H z , CDC1 ) data for the diester 190: 3  C O S Y and N O E D experiments  2 C0 Et 2  190 Assignment  *H nmr (400 MHz)  COSY  NOED  H-x  5 (multiplicity, 7 (Hz))  Correlations  Correlations  H-2  Part of 1.14-1.23 (m)  H-2', H-3, H-3'  H-2'  2.48 (dt, 7=3.3, 12.8)  H-2, H-3'  H-3  Part of 1.41-1.54 (m, 2H)  H-2, H-2', H-3', H-4, H-4'  H-3'  1.70-1.80 (m)  H-2, H-2', H-3, H-4, H-4'  H-4  Part of 2.10-2.30 (m, 2H)  H-3, H-3*, H-5  H-4'  Part of 2.10-2.30 (m, 2H)  H-3, H-5  H-5  6.32 (dd, 7=3.9, 3.9)  H-4, H-4'  H-8  2.58-2.69 (m)  H-8', H-9, H-9'  H-8'  3.08 (ddd, 7 = 1.5, 8.1, 19.4)  H-8, H-9, H-9*  H-9  Part of 1.41-1.54 (m, 2H)  H-8, H-8'  H-9'  2.35 (dd, 7=8.1, 12.8)  H-8, H-8*  H-10  6.08 (br s)  -CO,Me  3.68 (s)  -C0 CH2CH 2  -C0 CH CH3 2  2  3  H-4, H-4', H-10  H-5  4.03-4.15 (m)  -C0 CH CH3  Part of 1.14-1.23 (m, 7= 7.2)  -C0 CH2CH  2  2  2  3  170  Preparation  of  l-ethoxycarbonyl-(ir)-7-methoxycarbony  non-5-ene (191) 2  C0 Et 2  183  191  Following general procedure 1 (see pg. 126), the bicyclic diester 191 was prepared by the addition of the diester 183 (124 mg, 0.281 mmol), as a solution in dry D M F (1.4 mL), to a cool (0 °C), stirred solution-suspension of CuCI (73 mg, 0.74 mmol) and glacial acetic acid (81 |JL, 1.4 mmol) in dry D M F (1.4 mL). In this case, the reaction required 1 h to go to completion. Purification of the crude product by flash column chromatography (12 g of silica gel, 17:3 petroleum ether-Et 0) and removal of trace amounts of solvent 2  (vacuum pump) from the acquired material yielded 72 mg (92 %) of the bicyclic compound 191 as a colorless clear oil.  IR (neat): 1718 (br), 1619, 1450, 1159 c m . 1  *H nmr (400 M H z , CDC1 ) 8: 1.17 (t, 3H, - C 0 C H C H 3 , / = 7.3 Hz), 1.33-1.44 (m, 3H), 3  2  2  1.58-1.64 (m, 1H), 1.69-1.74 (m, 1H), 1.91-2.00 (m, 1H), 2.08-2.11 (m, 3H), 2.14-2.18 (dd, 1H, / = 4.5, 10.2 Hz), 2.24-2.28 (m, 1H), 3.64 (s, 3H, - C 0 M e ) , 3.79 (dm, 1H, 2  / = 16.4 Hz), 4.01-4.15 (m, 2H, -C0 CH2CH ), 5.80 (d, 1H, H - l l , / = 2.5 Hz), 5.91 (dd, 2  3  1H, H - 5 , / = 3.8, 3.8 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 8: 14.2 (-ve), 19.0, 22.3, 26.2, 29.3, 35.4, 37.2, 49.2, 50.8 3  (-ve), 60.7, 113.3 (-ve), 127.5 (-ve), 140.1, 160.8, 167.5, 175.7.  H R M S calcd for C i H 0 : 278.1518; found: 278.1522. 6  2 2  4  171 Anal, calcd for  C  1 6  H220 : 4  C 69.04, H 7.97; found: C 69.17, H 7.97.  Table 22. K nmr (400 M H z , CDC1 ) data for the diester 191: selected C O S Y and l  3  NOED experiments 2  4  \  C0 Et 2  ^k  J s J7  5 1 1  C0 Me 2  191  Assignment  H nmr (400 MHz)  COSY  NOED  8 (multiplicity, / (Hz))  Correlations  Correlations  X  H-x H-5  5.91 (dd, 7=3.8,3.8)  Part of mat 2.08-2.11  H - l l , Part of mat 2.08-2.11  H-ll  5.80 (d, 7=2.5)  1.91-2.00 (m, H-8)  H-5  Preparation  of  1 -methoxycarbonyHZT)- 8 -methoxycarbony lmethylidenebic yclo 5.4.01 r  undec-6-ene (192)  184  192  Following general procedure 1 (see pg. 126), the bicyclic diester 192 was prepared by the addition of the diester 184 (68 mg, 0.15 mmol), as a solution in dry D M F (0.75 mL), to a cool (0 °C), stirred solution-suspension of CuCl (42 mg, 0.30 mmol) and glacial acetic acid (44 \XL, 0.77 mmol) in dry D M F (0.75 mL). Purification of the crude product by flash column chromatography (10 g of silica gel, 4:1 petroleum ether-Et 0) and removal 2  172 of trace amounts of solvent (vacuum pump) from the acquired material yielded 40 mg (94 %) of the diester 192 as a colorless, viscous oil.  IR(neat): 1718 (br), 1610, 1434, 1158 cm' . 1  *H nmr (400 M H z , CDC1 ) 5: 1.35-1.75 (m, 7H), 1.84-1.93 (m, 2H), 2.01 (dm, 1H, / = 3  13.1 Hz), 2.05-2.14 (m, 1H, H-5), 2.18-2.34 (m, 2H, H-5' and one of H-9), 3.45 (dm, 1H, / = 15.2 Hz), 3.65 (s, 3H, -C0 Me), 3.66 (s, 3H, -CCvMe), 5.82 (br s, 1H, H-12), 6.05 2  (dd, 1H, H-6, 7=5.4, 7.2 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 5: 21.8, 25.1, 25.2, 26.9, 28.4, 37.2, 38.7, 50.8 (-ve), 51.8 3  (-ve), 54.0, 114.5 (-ve), 132.7 (-ve), 144.4, 163.0, 167.4, 175.7.  H R M S calcd for C16H22O4: 278.1518; found: 278.1521. Anal calcd for C H 2 0 : C 69.04, H 7.97; found: C 68.86, H 7.87. 2  16  4  Table 23. *H nmr (400 M H z , CDC1 ) data for the diester 192: selected C O S Y and 3  NOED experiments 3  2 C0 Me 2  1  12N  C0 Me 2  192 Assignment H-x  H nmr (400 MHz)  COSY  NOED  8 (multiplicity, / (Hz))  Correlations  Correlations  J  H-6  6.05 (dd, 7=5.4,7.2)  2.05-2.14 (m, H-5), upfield part of 2.182.34 (m, H-5')  H-12, 2.05-2.14 (m, H-5), upfield part of 2.18-2.34 (m, H-5')  H-12  5.82 (brs)  downfield part of 2.18-2.34 (m)  H-6  173  4. Copper(I) mediated intramolecular conjugate additions of aromatic stannanes to a,p-alkynic ester functions 4.1 Preparation of precursors  General Procedure 4: Preparation of 2-trimethvlstannylbenzyl alcohol derivatives To a cold (-78 °C), stirred solution of n-BuLi (2.5 equiv) in dry E t 0 (-10 mL/mmol of 2  alcohol) was added T M E D A (2.5 equiv) via a syringe and stirring was continued for 5 min.  The appropriately substituted benzyl alcohol (1 equiv) was added neat via a  syringe and the solution was warmed to room temperature. After 3 h, the solution turned a dark red color.  The solution was cooled to -78 °C and trimethyltin chloride  (-1.5 equiv) was added in one solid portion. The reaction mixture was warmed to room temperature and stirred for 2 h whereupon the solution became turbid. Water was added (-10 mL/mmol of alcohol) and the mixture was extracted with E t 0 (3 x -10 mL/mmol 2  of alcohol). The combined organic extracts were washed with brine (-20 mL/mmol of alcohol), dried (MgSG^), and the solvent was removed in vacuo. Purification of the crude material was accomplished by flash column chromatography on silica gel.  Preparation of 2-trimethvlstannvlbenzyl alcohol (199)  205  199  Following general procedure 4, the stannane 199 was prepared with the following amounts of solvent and reagents: n-BuLi (30.1 mL, 1.6 M in hexanes, 48 mmol), T M E D A (7.39 mL, 50.0 mmol), E t 0 (200 mL), benzyl alcohol (205) 2  20.0 mmol),  and  trimethyltin  chloride  (6.00  g,  30.2  mmol).  (2.11 mL,  Flash column  chromatography (200 g of silica gel, 4:1 petroleum ether-Et 0) of the crude product and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material yielded  174 3.50 g (64 %) of the alcohol 199 as a colorless oil. This oil exhibited spectral properties (*H nmr) identical with those previously reported.  50  Preparation of 4-methyl-2-trimethvlstannvlbenzyl alcohol (200) 6  206  200  Following general procedure 4, the stannane 200 was prepared with the following amounts of solvent and reagents: n-BuLi (45.0 mL, 1.6 M in hexanes, 74 mmol), T M E D A (11.0 mL, 72.9 mmol), E t 0 (250 mL), 4-methylbenzyl alcohol (206) (3.60 g, 2  29.5 mmol),  and  trimethyltin chloride  (9.11  g,  45.7  mmol).  Flash column  chromatography (250 g of silica gel, 7:3 petroleum ether-Et 0) of the crude product and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 5.08 g (60 %) of the alcohol 200 as a colorless solid (mp 48-49 °C).  IR (KBr): 3379, 2357, 1471, 1012, 818, 764 cm" . 1  *H nmr (400 MHz, CDC1 ) 5: 0.30 (s, 9H, -SnMes, / .  = 54.5 Hz), 1.65 (br s, IH,  2  3  S n  H  -OH, exchanges with D 0 ) , 2.34 (s, 3H, -Me), 4.62 (d, 2H, -CFb-OH, / = 5.6 Hz), 7.11 2  (d, IH, 7 = 7 Hz), 7.20 (d, IH, / = 7 Hz), 7.33 (s, IH, H - 3 , / . = 50.4 Hz). 3  S n  1 3  H  C nmr (75.5 M H z , CDC1 ) 5: -8.0 (-ve), 21.1 (-ve), 67.0, 127.2 (-ve), 129.1 (-ve), 136.6, 3  137.3 (-ve), 141.3, 144.1.  H R M S calcd for C H i O 1 0  5  1 2 0  S n (M -Me): 271.0145; found: 271.0138. +  Anal, calcd for C H O S n : C 46.37, H 6.37; found: C 46.59; H 6.55. n  1 8  175 Preparation of 3,4,5-trimethoxy-2-trimethylstarmylbenzy alcohol (201)  Following general procedure 4, the stannane 201 was prepared with the following amounts of solvent and reagents: n-BuLi (8.0 mL, 1.6 mol/L, 12.8 mmol), T M E D A (1.85 mL, 12.5 mmol), E t 0 (250 mL), 3,4,5-trimethoxybenzyl alcohol (207) (0.81 mL, 2  5.0 mmol), and trimethyltin chloride (1.55 g, 7.82 mmol). Flash column chromatography (250 g of silica gel, 7:3 petroleum ether-Et 0) of the crude product and removal of trace 2  amounts of solvent (vacuum pump) from the acquired material yielded 986 mg (54 %) of the alcohol 201 as a colorless viscous oil.  IR (neat): 3432, 1583, 1478, 1316, 1015, 774, 525 c m . 1  H nmr (400 M H z , CDC1 ) 8: 0.30 (s, 9H, -SnMes, / „ . = 54.5 Hz), 1.53 (br t, 1H,  l  2  3  s  H  -OH, exchanges with D 0 , / = 5.7 Hz), 3.81 (s, 3H, -OMe), 3.84 (s, 3H, -OMe), 3.85 (s, 2  3H, -OMe), 4.54 (d, 2H, -CFb-OH, / = 5.7 Hz), 6.78 (s, 1H, aromatic proton, / . = 4  S n  H  15.6 Hz).  1 3  C nmr (50.3 M H z , CDC1 ) 5: -6.3 (-ve), 55.9 (-ve), 60.5 (-ve), 60.8 (-ve), 66.4, 107.8, 3  125.2 (-ve), 140.1, 143.2, 154.2, 157.9.  H R M S calcd for C H O 1 2  1 9  1 2 0 4  S n (M -Me): 347.0306; found: 347.0313. +  Anal, calcd for C H 0 S n : C 43.25, H 6.14; found: C 43.64, H 5.93. 1 3  2 2  4  176 General Procedure 5: Conversion of benzyl alcohol derivatives into benzyl bromides  To a cool (0 °C), stirred solution of triphenylphosphine (-1.3 equiv) in dry CH2CI2 (10 mL/mmol of alcohol) was added bromine (-1.3 equiv) dropwise until a yellow color persisted. A few crystals of triphenylphosphine were added until the color disappeared. The solution was stirred for a period of 20 min. Imidazole was added (-1.4 equiv) to the mixture in one solid portion and stirring was continued for 20 minutes. The appropriate alcohol (1 equiv) was added as a solution in CH2CI2 and the solution was stirred at 0 °C for 20 rnin and at room temperature for 1 h. Pentane (-1 mL/mL of CH C1 ) was added 2  2  and the white suspension was filtered through a cake of silica gel (-10 g/g of triphenylphosphine) and the silica gel was eluted with E t 0 (-2 mL/mL of CH C1 ). After 2  2  2  concentration of the combined filtrate under reduced pressure, the crude product was purified by flash column chromatography on silica gel.  Preparation of 2-rrimethvlstannylbenzyl bromide (202)  202  199  Following general procedure 5, the benzyl bromide 202 was prepared with the following amounts of solvent and reagents: triphenylphosphine (3.41 g, 13.0 mmol), bromine (-0.7 mL), imidazole (963 mg, 14.1 mmol), C H C 1 2  2  (100 mL), and 2-trimethyl  stannylbenzyl alcohol (199) (2.66 g, 9.85 mmol). The crude product was purified by flash column chromatography (75 g of silica gel, 193:7 petroleum ether-Et 0) and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 2.88 g (88 %) of the bromide 202 as a colorless clear oil.  IR (neat): 1471, 1220, 764, 609, 529 c m . 1  177 :  H nmr (400 M H z , CDC1 ) 5: 0.39 (s, 9H, -SnMe., / _ 2  3  Sn  H  = 53.8 Hz), 4.51 (s, 2H,  -CHa-Br, / = 5.7 Hz), 7.24 (dt, IH, / = 1.2, 7.4 Hz), 7.30 (dt, I H , / = 1.5, 7.5 Hz), 7.387.54 (m, 2H).  1 3  C nmr (50.3 M H z , CDC1 ) 5: -7.8, 36.9, 127.8, 129.0, 129.9, 136.8, 143.5, 144.5. 3  H R M S calcd for C H i 9  7 9 2  Br  1 2 0  S n (M -Me): 318.9144; found: 318.9144. +  Anal, calcd for C H B r S n : C 35.98, H 4.53; found: C 36.28, H 4.49. 10  15  Preparation of 4-methvl-2-trimethvlstarjnvlbenzvl bromide (203)  200  76  203  Following general procedure 5, the benzyl bromide 203 was prepared with the following amounts of solvent and reagents: triphenylphosphine (5.06 g, 19.3 mmol), bromine (~1 mL),  imidazole  (1.4  g,  21  mmol),  CH C1 2  2  (70  2-trimethylstannylbenzyl alcohol (200) (2.20 g, 7.72 mmol).  mL),  and  4-methyl-  The crude product was  purified by flash column chromatography (75 g of silica gel, 193:7 petroleum ether-Et 0) 2  and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 2.19 g (87 %) of the bromide 203 as a colorless clear oil.  IR (neat): 1594, 1443, 1480, 1210 cm . 1  *H nmr (400 M H z , CDC1 ) 5: 0.32 (s, 9H, -SnMe.. / . = 50.0 Hz), 2.31 (s, 3H, -Me), 2  3  S n  H  4.50 (s, 2H, - C H r B r ) , 7.05-7.10 (m, IH), 7.20-7.45 (m, 2H).  1 3  C nmr (50.3 M H z , CDC1 ) 8: -7.9, 21.2, 37.0, 128.9, 129.7 (2C), 137.5, 141.5, 143.2. 3  178 H R M S calcd for C i H 0  7 9 1 4  Br  1 2 0  S n (M -Me): 322.9301; found: 322.9301. +  Anal, calcd for CnHi BrSn: C 37.98, H 4.93; found: C 38.13, H 4.89. 7  Preparation of 3,4,5-lTimethoxy-2-trirnethvlstannvlbenzvl bromide (204)  Following general procedure 5, the benzyl bromide 204 was prepared with the following amounts of solvents and reagents: triphenylphosphine (928 mg, 3.54 mmol), bromine (-0.2 mL), imidazole (252 mg, 3.70 mmol), CH C1 (28 mL), and the stannane 201 2  2  (986 mg, 2.74 mmol). The crude product was purified by flash column chromatography (30 g of silica gel, 22:3 petroleum ether-Et 0) and removal of trace amounts of solvent 2  (vacuum pump) from the acquired material yielded 754 mg (65 %) of the bromide 204 as  [Note:  a colorless clear oil.  Perform all procedures in the fumehood as this oil is  extremely volatile.]  IR (neat): 1581, 1481, 1323, 1099, 773 c m . 1  :  H nmr (400 M H z , CDC1 ) 5: 0.36 (s, 9H, -SnMes, / . = 54.8 Hz), 3.82 (s, 3H, -OMe), 2  3  S n  H  3.84 (s, 3H, -OMe), 3.86 (s, 3H, -OMe), 4.46 (s, 2H, -CHz-Br), 6.72 (s, 1H, aromatic proton, / s n - H  1 3  =  16.1 Hz).  C nmr (50.3 M H z , CDC1 ) 5: -6.2 (-ve), 37.1, 56.0 (-ve), 60.5 (-ve), 60.8 (-ve), 109.9 3  (-ve), 128.0, 139.7, 140.8, 154.2, 157.6.  H R M S calcd for C i H 2  7 9 1 8  Br  1 2 0  S n (M -Me): 408.9461; found: 408.9467. +  179 Preparation of 1 -(fe^butyldimethylsilyl)-4-oxa-5-(2-trm  1 -yne  (209) TBS SnMe  Br>  3  199  *SnMe  160  TBS 3  209  To a cool (0 °C), stirred suspension of sodium hydride (30 mg, 1.3 mmol, washed with pentane) in dry D M F (6 mL) was added 2-trimethylstannylbenzyl alcohol (199) (252 mg, 0.933 mmol) as a solution in dry D M F (2 mL) via a cannula. The reaction mixture was stirred for 30 min. The bromide 160 (519 mg, 2.23 mmol) was added as a neat liquid via a syringe and the mixture was stirred at 0 °C for 30 min and at room temperature for 18 h. Saturated aqueous sodium bicarbonate (10 mL) was added and the mixture was extracted with E t 0 (3 x 15 mL). The combined organic extracts were washed with brine 2  (3 x 30 mL), dried (MgSQ*), and the solvent was removed under reduced pressure. Hash column chromatography (15 g of silica gel, 94:6 petroleum ether-Et 0) of the crude 2  product and removal of trace amounts of solvent from the acquired material yielded 369 mg (94 %) of the ether 209 as a colorless clear oil.  IR (neat): 2174, 1471, 1251, 1088, 826, 776 c m . 1  X  H nmr (400 M H z , CDC1 ) 8: 0.11 (s, 6H, -SiMe -), 0.28 (s, 9H, -SnMe^ 3  9  2  /  S ] 1  -H  =  53.5 Hz), 0.94 (s, 9H, -Si'Bu-), 4.14 (s, 2H, - C H r ) , 4.59 (s, 2H, - C H r ) , 7.20-7.30 (m, 3H), 7.50 (dm, 1H, aromatic proton a to -SnMe , / = 6.1 Hz, / „ - = 50.4 Hz). 3  3  1 3  s  H  C nmr (75.5 M H z , CDC1 ) 8: -8.0, -4.6, 16.5, 26.1, 57.8, 73.1, 90.2, 101.8, 127.3, 3  128.21, 128.25, 136.6,141.8, 143.9.  H R M S calcd for C H O S i 18  29  120  S n (M -Me): 409.1010; found: 409.1005. +  Anal, calcd for C H O S i S n : C 53.92, H 7.62; found: C 54.22, H 7.45. 19  32  180 Preparation of methyl 5-oxa-6-(2-trimethylstannylphenyl)hex-l-yno  (211)  To a stirred solution of the stannane 209 (353 mg, 0.800 mmol) in dry T H F (10 mL) at room temperature was added a solution of tetrabutylammonium fluoride (1.25 mL, 1 M in T H F , 1.25 mmol) and stirring was continued for 1 h.  Saturated aqueous sodium  bicarbonate was added (15 mL) and the mixture was extracted with E t 0 (3 x 15 mL). 2  The combined organic extracts were washed with brine (30 mL), dried (MgSCU), and the solvent was removed under reduced pressure.  Rash column chromatography (20 g of  silica gel, 99:1 petroleum ether-Et 0) of the crude product yielded 243 mg (99 %) of the 2  compound 210 a clear oil. [Note: This oil exhibited an extremely noxious odour and was immediately used in the next step.]  To a cold (-78 °C), stirred solution of L D A (1.02 mmol) in dry T H F (5 mL) was added D M P U (123 }XL, 1.02 mmol) and stirring was continued for 5 min. A solution of the stannane 210 (obtained as described above) in dry T H F (2 mL) was added via a cannula and the reaction mixture was stirred for 1 h at -78 °C. Methyl chloroformate (91 |uL, 1.2 mmol) was added via a syringe and stirring was continued for 1 h at -78 °C and for 1 h at room temperature. Saturated aqueous sodium bicarbonate (10 mL) was added and the mixture was extracted with E t 0 (3 x 10 mL). The combined organic extracts were 2  washed with brine (20 mL), dried (MgSCU), and the solvent was removed in vacuo. Flash column chromatography (30 g of silica gel, 95:5 petroleum ether-Et 0) and 2  removal of trace amounts of solvent from the acquired liquid (vacuum pump) yielded 268 mg (90 % over 2 steps) of the alkynic ester 211 as a colorless clear oil.  IR(neat): 2239, 1718, 1435, 1251, 1094, 751 c m . 1  181  X  H nmr (400 MHz, CDC1 ) 5: 0.28 (s, 9H, -SnMea, / .  = 53.8 Hz), 3.78 (s, 3H,  2  3  S n  H  - C 0 M e ) , 4.23 (s, 2H, - C H r ) , -59 (s, 2H, -CH2-), 7.25-7.32 (m, 3H), 7.51 (dm, I H , 4  2  aromatic proton a to -SnMe , / = 5.3 Hz, / s - H = 48.9 Hz). 3  3  13  n  C nmr (125.8 MHz, CDC1 ) 5: -8.1 (-ve), 52.7 (-ve), 56.5, 73.8, 78.2, 83.2, 127.5 (-ve), 3  128.3 (-ve), 128.5 (-ve), 136.6 (-ve), 142.2, 143.0, 153.4.  H R M S calcd for C H O 1 4  1 7  1 2 0 3  S n (M -Me): 353.0200; found: 353.0194. +  Anal, calcd for C H o 0 S n : C 49.09, H 5.49; found: C 49.14, H 5.45. 15  2  3  Preparation of diethyl 2-(2-trimethylstannvlbenzyl)malonate (212) SnMe  202  3  212  To a stirred suspension of potassium hydride (543 mg, 13.5 mmol, washed with pentane) in dry T H F (130 mL) at room temperature was added diethyl malonate (2.3 mL, 15 mmol) via a syringe.  Evolution of hydrogen gas was observed and the reaction  mixture was stirred for 1 h. A solution of the bromide 199 (1.47 g, 4.39 mmol) in dry THF (10 mL) was added and the mixture was warmed to reflux for 1.5 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The mixture was then extracted with E t 0 (3 x 50 mL). 2  The combined organic extracts were washed with  brine (50 mL), dried (MgS0 ), and the solvent was removed under reduced pressure. 4  Flash column chromatography (100 g of silica gel, 9:1 petroleum ether-Et 0) of the crude 2  product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 1.74 g (96 %) of the stannane 212 as a colorless clear oil.  IR (neat): 1731, 1200, 1036, 770 cm" . 1  182  *H nmr (400 M H z , CDC1 ) 8: 0.34 (s, 9H, -SnMej, / „ . 2  3  s  H  = 53.2 Hz), 1.11 (t, 6H,  - C 0 C H C H 3 , / = 7.2 Hz), 3.25 (d, 2H, -CEb-CH-, / = 7.8 Hz), 3.60 (t, 1H, - C H - C H - , 2  2  2  / = 7.8 Hz), 4.10-4.20 (m, 4H, -CO2CH2CH3), 7.12-7.25 (m, 3H), 7.40 (m, 1H, aromatic proton a to -SnMe , 3  1 3  3  /  S f t  -H  = 49.8 Hz).  C nmr (125.8 MHz, CDC1 ) 8: -8.3 (-ve), 13.8 (-ve), 37.1, 53.6 (-ve), 61.2, 126.1 (-ve), 3  128.1 (-ve), 128.4 (-ve), 136.4 (-ve), 142.3, 144.4, 168.5.  H R M S calcd for C i 6 H O 23  120 4  S n (M -Me): 399.0618; found: 399.0624. +  Anal, calcd for C i H 0 S n : C 49.43, H 6.34; found: C 49.78, H 6.38. 7  2 6  4  Preparation of 1 -(fe^butyldimethylsilyl)-4,4-bis(ethoxvcarbonvl)-5-(2-trimethylstarmy phenyl)pent-l-yne (213)  212  160  213  To a stirred suspension of potassium hydride (100 mg, 2.50 mmol, washed with pentane) in dry T H F (12 mL) at room temperature was added a solution of the diester 212 (721 mg, 1.75 mmol) in dry THF (1 mL). The reaction mixture was stirred for 1 h. The bromide 160 (775 mg, 3.33 mmol) was added neat via a syringe and the mixture was warmed to reflux for 1.5 h. The reaction mixture was cooled to room temperature and water (20 mL) was added.  The mixture was extracted with E t 0 (3 x 20 mL). The 2  combined organic extracts were washed with brine (30 mL), dried (MgS0 ), and the 4  solvent was removed under reduced pressure.  Rash column chromatography (40 g of  silica gel, 96:4 petroleum ether-Et 0) of the crude product and removal of trace amounts 2  183 of solvent (vacuum pump) from the acquired material yielded 986 mg (98 %) of the stannane 213 as a colorless clear oil.  IR (neat): 2179, 1752, 1584, 1201, 1030, 775 c m . 1  *H nmr (400 M H z , CDC1 ) 8: 0.06 (s, 6H, -SiMe,-), 0.34 (s, 9H, -SnM&>. / „ . 2  3  s  H  =  55.4 Hz), 0.90 (s, 9H, -Si'Bu-), 1.11 (t, 6H, - C 0 C H C H 3 , / = 7.1 Hz), 2.95 (s, 2H, 2  2  - C H r ) , 3.49 (s, 2H, - C H r ) , 4.00-4.12 (m, 4H, -C0 CH2CH ), 7.13-7.26 (m, 3H), 7.34 (d, 2  3  1H, aromatic proton a to -SnMe , / = 7.0 Hz, / s - H = 48.5 Hz). 3  3  1 3  n  C nmr (125.8 M H z , CDC1 ) 8: -7.2 (-ve), -4.6 (-ve), 13.8 (-ve), 16.4, 25.3, 26.0 (-ve), 3  40.3, 58.5, 61.4, 86.5, 102.3, 126.2 (-ve), 128.0 (-ve), 128.4 (-ve), 136.6 (-ve), 142.9, 144.9, 169.8.  H R M S calcd for C 5 H O S i 2  39  4  120  S n (M -Me): 551.1639; found: 551.1640. +  Anal, calcd for C H 4 0 S i S n : C 55.23, H 7.49; found: C 55.58, H 7.40. 26  2  4  Preparation of 4,4-bis(ethoxvcarbonvl)-5-(2-trimethvlstannvlphenvl)pent-l-yne (214) SnMe  V^  SnMe  3  3  TBS  1  R = -C0 Et  R = -C0 Et  213  214  2  2  To a stirred solution of the stannane 213 (511 mg, 0.923 mmol) in dry T H F (10 mL) at room temperature was added a solution of tetrabutylammonium fluoride (1.40 mL, 1 M in THF, 1.40 mmol) and stirring was continued for 1 h.  Saturated aqueous sodium  bicarbonate was added (15 mL) and the mixture was extracted with E t 0 (3 x 15 mL). 2  The combined organic extracts were washed with brine (30 mL), dried (MgS0 ), and the 4  184 solvent was removed under reduced pressure. Flash column chromatography (20 g of silica gel, 95:5 petroleum ether-Et 0) of the crude product and removal of trace amounts 2  of solvent (vacuum pump) from the acquired material yielded 398 mg (98 %) of the alkyne 214 as a clear oil.  IR (neat): 3290, 1736, 1440, 1192, 774 c m . 1  X  H nmr (400 M H z , CDC1 ) 5: 0.34 (s, 9H, -SnMej, 3  2  / „-H S  = 53.4 Hz), 1.17 (t, 6H,  - C 0 C H C H 3 , / = 7.2 Hz), 2.00 (t, 1H, H - l , / = 2.7 Hz), 2.84 (d, 2H, H-3, J = 2.7 Hz), 2  2  3.51 (s, 2H, H-5), 4.00-4.21 (m, 4H, -C0 CH2CH ), 7.10-7.21 (m, 3H), 7.38 (dm, 1H, 2  aromatic proton a to -SnMe , / = 6.6 Hz, 3  1 3  3  / nS  3  H  = 48.0 Hz).  C nmr (75.5 M H z , CDC1 ) S: -7.2, 13.9, 23.3, 40.2, 57.9, 61.7, 71.7, 79.4, 126.3, 127.8, 3  128.2, 136.8, 142.6, 145.0, 170.1.  H R M S calcd for C H O 4 1 9  2 5  1 2 0  S n (M -Me): 437.0775; found: 437.0778. +  Anal, calcd for C H O S n : C 53.25, H 6.26; found: C 53.11, H 6.13. 20  28  4  Preparation of methyl 5,5-bis(ethoxvcarbonyl)-6-(2-lrimethvlstannvlphenvl)hex-2-vnoate  £215}  R = -C0 Et 2  214  R = -C0 Et 2  215  To a cold (-78 °C), stirred solution of L D A (1.15 mmol) in dry T H F (6 mL) was added D M P U (139 ixL, 1.15 mmol) and stirring was continued for 5 min. A solution of the acetylene 214 (398 mg, 0.843 mmol) in dry THF (2 mL) was added via a cannula and the  185 reaction mixture was stirred for 1 h at -78 °C.  Methyl chloroformate (103 piL,  1.33 mmol) was added via a syringe. The mixture was stirred for 1 h at -78 °C and 1 h at room temperature. Saturated aqueous sodium bicarbonate (10 mL) was added and the mixture was extracted with E t 0 (3 x 10 mL). The combined organic extracts were 2  washed with brine (20 mL), dried (MgSCU), and the solvent was removed under reduced pressure. Flash column chromatography (30 g of silica gel, 85:15 petroleum ether-Et 0) 2  of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 357 mg (80 %) of the alkynic triester 215 as a colorless clear oil.  IR (neat): 2242, 1719 (br), 1438, 1259, 1079, 770 c m . 1  *H nmr (400 M H z , CDC1 ) 5: 0.34 (s, 9H, -SnMe , / . 2  3  3  S n  H  = 53.3 Hz), 1.19 (t, 6H,  - C 0 C H C H 3 , / = 7.3 Hz), 2.93 (s, 2H, - C H r ) , 3.49 (s, 2H, -CH2-), 3.71 (s, 3H, 2  2  - C 0 M e ) , 4.10-4.25 (m, 4H, -CO2CH2CH3), 7.05-7.11 (m, IH), 7.15-7.21 (m, 2H), 7.39 2  (dm,  13  I H , aromatic proton a to -SnMe , / = 6.3 Hz, 3  3  /  S I I  -H  = 47.4 Hz).  C nmr (75.5 MHz, CDC1 ) 8: -7.4 (-ve), 13.8 (-ve), 23.5, 40.6, 52.5 (-ve), 57.6, 62.0, 3  75.3,  84.2, 126.4 (-ve), 127.7 (-ve), 128.3 (-ve), 136.8 (-ve), 141.9, 144.9, 153.5, 169.5.  H R M S calcd for C i H O 2  2 7  1 2 0 6  S n (M -Me): 495.0830; found: 495.0831. +  Anal, calcd for C H O S n : C 51.90, H 5.94; found: C 52.11, H 5.84. 22  30  6  186 Preparation of methyl 5-oxa-6-(4-methyl-2-trime^  SnMe  200  216  3  (217)  SnMe  COoMe 3  217  To a cool (0 °C), stirred suspension of sodium hydride (46 mg, 1.9 mmol, washed with pentane) in dry D M F (8 mL) was added 2-trimethylstannylbenzyl alcohol (200) (467 mg, 1.63 mmol) as a solution in dry D M F (2 mL) via a cannula. The reaction mixture was stirred for 30 min. A solution of propargyl bromide (484 mg, 80 wt % in toluene, 3.26 mmol) was added via a syringe and the mixture was stirred at 0 °C for 30 min and at room temperature for 18 h. Saturated aqueous sodium bicarbonate (10 mL) was added and the mixture was extracted with E t 0 (3 x 15 mL). The combined organic extracts 2  were washed with brine (3 x 30 mL), dried (MgSQ*), and the solvent was removed under reduced pressure.  Flash column chromatography (25 g of silica gel, 200:3 petroleum  ether-Et 0) of the crude oil yielded 529 mg of the alkyne 216 as a colorless clear oil. 2  [Note: This oil exhibited an extremely noxious odour and was immediately used in the next step.]  To a cold (-78 °C), stirred solution of L D A (2.27 mmol) in dry T H F (16 mL) was added D M P U (258 | i L , 2.13 mmol) and stirring was continued for 5 rnin. A solution of the stannane 216 (obtained as described above) in dry T H F (2 mL) was added via a cannula and the reaction rnixture was stirred for 1 h at -78 °C. Methyl chloroformate (211 piL, 2.72 mmol) was added via a syringe and stirring was continued for 1 h at -78 °C and 1 h at room temperature. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with E t 0 (3 x 20 mL). The combined organic extracts were 2  washed with brine (30 mL), dried (MgSC^), and the solvent was removed in vacuo. Flash column chromatography (30 g of silica gel, 92:8 petroleum ether-Et 0) and 2  removal of trace amounts of solvent from the acquired liquid (vacuum pump) yielded 542 mg (87 % over 2 steps) of the alkynic ester 217 as a colorless clear oil.  187 IR (neat): 2238, 1719, 1435, 1251, 1060, 751 c m . 1  J  H nmr (400 M H z , CDC1 ) 8: 0.27 (s, 9H, -SnMej, / . = 53.6 Hz), 2.31 (s, 3H, -Me), 2  3  S n  H  3.78 (s, 3H, -COzMe), 4.20 (s, 2H, - C H r ) , 4.56 (s, 2H, -CIL.-), 7.09 (dd, 1H, / = 1.2, 7.6 Hz), 7.15-7.21 (m, 1H), 7.31 (br s, 1H, aromatic proton a to -SnMe , 3  3  /  S J 1  -H  =  23.9 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 5: -8.0 (-ve), 21.2 (-ve), 52.7 (-ve), 56.3, 73.6, 78.1, 83.4, 3  128.7 (-ve), 129.0 (-ve), 137.1, 137.5 (-ve), 140.0, 142.1, 152.8.  H R M S calcd for C H O 1 5  1 9  1 2 0 3  S n (M -Me): 367.0356; found: 367.0352. +  Anal, calcd for C i H 0 S n : C 50.43, H 5.82; found: C 50.61, H 5.75. 6  22  3  Preparation of diethyl 2-(4-methvl-2-trimethvlstannvlbenzyl)malonate (218)  SnMe  203  3  218  To a stirred suspension of potassium hydride (144 mg, 3.60 mmol, washed with pentane) in dry T H F (35 mL) at room temperature was added diethyl malonate (575 juL, 3.80 mmol) via a syringe. Evolution of hydrogen gas was observed and the reaction mixture was stirred for 1 h. The bromide 203 (391 mg, 1.13 mmol) was added neat via a syringe and the mixture was warmed to reflux for 1.5 h. The reaction mixture was cooled to room temperature and water (15 mL) was added. The mixture was then extracted with E t 0 (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried 2  (MgSC>4), and the solvent was removed under reduced pressure. The resulting crude product was purified by flash column chromatography (30 g of silica gel, 91:9 petroleum  188 ether-Et 0) and removal of trace amounts of solvent (vacuum pump) from the acquired 2  material yielded 415 mg (86 %) of the diester 218 as a colorless oil.  IR (neat): 1735, 1152, 858, 771 c m . 1  R nmr (400 M H z , CDC1 ) 8: 0.32 (s, 9H, -SnMe.. / „ .  X  2  3  s  H  = 53.0 Hz), 1.20 (t, 6H,  -CO2CH2CH3, / = 7.1 Hz), 2.27 (s, 3H, -Me), 3.21 (d, 2H, -CH2-CH-, / = 7.8 Hz), 3.57 (t, 1H, -CH2-CH-, / = 7.8 Hz), 4.11-4.21 (m, 4H, -CO2CH2CH3), 7.01-7.10 (m, 2H), 7.21 (br s, 1H, aromatic proton a to -SnMe , / s - H = 50.0 Hz). 3  3  1 3  n  C nmr (75.5 MHz, CDC1 ) 8: -8.1 (-ve), 14.0 (-ve), 21.0 (-ve), 36.7, 53.9 (-ve), 61.5, 3  128.1 (-ve), 129.3 (-ve), 135.5, 137.3 (-ve), 141.4, 142.2, 168.9.  H R M S calcd for C H25O 17  120 4  Sn (M -Me): 413.0775; found: 413.0781. +  Anal, calcd for C i H 8 0 S n : C 50.62, H 6.61; found: C 50.51, H 6.65. 8  2  4  Preparation of 4,4-bis(ethoxycarbonyl)-5-(4-methyl-2-trimethylstannylphenyl)pent-1 -vne (220)  To a stirred suspension of potassium hydride (34 mg, 0.85 mmol, washed with pentane) in dry T H F (8 mL) at room temperature was added a solution of the stannane 218 (343 mg, 0.80 mmol) in dry THF (1 mL) via a cannula. The reaction mixture was stirred for 1 h. A solution of propargyl bromide (309 mg, 80 wt % in toluene, 2.08 mmol) was added via a syringe and the reaction mixture was warmed to reflux for 1.5 h.  The  189 mixture was cooled to room temperature and water (10 mL) was added. The mixture was then extracted with E t 0 ( 3 x 5 mL). The combined organic extracts were washed with 2  brine (10 mL), dried (MgS0 ), and the solvent was removed under reduced pressure. 4  The resulting crude product was purified by flash column chromatography (20 g of silica gel, 50:3 petroleum ether-Et 0) and removal of trace amounts of solvent (vacuum pump) 2  from the acquired material yielded 373 mg (99 %) of the diester 220 as a colorless oil.  IR (neat): 3285, 1734, 1480, 1190, 772 c m . 1  J  H nmr (400 M H z , CDC1 ) S: 0.34 (s, 9H, -SnMes, / - = 56.1 Hz), 1.19 (t, 6H, 2  3  S n  H  - C 0 C H C H 3 , / = 7.1 Hz), 1.99 (t, IH, H - l , / = 2.6 Hz), 2.27 (s, 3H, -Me), 2.82 (d, 2H, 2  2  H-3, / = 2.6 Hz), 3.48 (s, 2H, H-5), 4.09-4.23 (m, 4H, -COzCH^CH,), 6.99-7.94 (m, 2H), 7.19 (br s, I H , aromatic proton a to -SnMe , 3  1 3  3  / „-H S  = 49.3 Hz).  C nmr (128.5 M H z , CDC1 ) 5: -7.2, 13.9, 20.6, 23.3, 39.6, 58.0, 61.7, 71.6, 79.6, 127.6, 3  129.0, 135.5, 137.4, 139.4, 144.7, 170.1.  H R M S calcd for C H O 2 0  2 7  1 2 0 4  S n (M -Me): 451.0931; found: 451.0928. +  Anal, calcd for C i H O S n : C 54.22, H 6.50; found: C 54.50, H 6.49. 2  30  4  Preparation of methyl 5,5-bis(ethoxycarfx)nvl)-6-(2-tijmethylstannvlphenvl)hex-2-vnoate (221}  SnMe  SnMe  3  3  C0 Me 2  R = -C0 Et 2  220  R = -C0 Et 2  221  To a cold (-78 °C), stirred solution of L D A (0.85 mmol) in dry T H F (6 mL) was added  190 D M P U (102 \JLL, 0.85 mmol) and stirring was continued for 5 min. A solution of the acetylene 220 (304 mg, 0.653 mmol) in dry THF (2 mL) was added via a cannula and the reaction mixture was stirred for 1 h at -78 °C. Methyl chloroformate (76 |LiL, 0.98 mmol) was added via a syringe. The mixture was stirred for 1 h at -78 °C and 1 h at room temperature. Saturated aqueous sodium bicarbonate (5 mL) was added and the mixture was extracted with E t 0 ( 3 x 5 mL). The combined organic extracts were washed with 2  brine (20 mL), dried (MgSC^), and the solvent was removed under reduced pressure. Flash column chromatography (30 g of silica gel, 85:15 petroleum ether-Et 0) of the 2  crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 79 mg of the stannane 220 and 217 mg (63 %, 86 % based on recovered starting material) of the cyclization precursor 221 as a colorless clear oil.  TR (neat): 2241, 1719 (br), 1436, 1258, 1079, 772 c m . 1  *H nmr (400 M H z , CDC1 ) 8: 0.33 (s, 9H, -SnMej, / . 2  3  -C0 CH CH3, / = 2  S n  H  = 53.2 Hz), 1.20 (t, 6H,  7.1 Hz), 2.26 (s, 3H, -Me), 2.90 (s, 2H, -CH2-), 3.45 (s, 2H, - C & r ) ,  2  3.70 (s, 3H, -COzMe), 4.12-4.23 (m, 4H, - C 0 C H 2 C H ) , 6.92-7.04 (m, 2H), 7.17 (br s, 2  3  1H, aromatic proton a to - S n M e , / s n - H = 49.9 Hz). 3  3  1 3  C nmr (75.5 M H z , CDC1 ) 8: -7.4 (-ve), 13.9 (-ve), 20.9 (-ve), 23.4, 40.2, 52.5 (-ve), 3  57.7, 62.0, 75.2, 84.4, 127.5 (-ve), 129.1 (-ve), 135.8, 137.5 (-ve), 138.7, 144.7, 153.6, 169.7.  H R M S calcd for C H O 2 2  2 9  1 2 0 6  S n (M -Me): 509.0986; found: 509.0979. +  Anal, calcd for C H 0 S n : C 52.80, H 6.16; found: C 52.69, H 6.14. 2 3  3 2  6  191 Preparation of 4,4-bis(ethoxycarbonyl)-5-(3,4,5-trimethoxv-2-trimethylstam phenyDpent-l-yne (222)  OMe  R = -C0 Et 2  222 To a stirred suspension of potassium hydride (213 mg, 5.35 mmol, washed with pentane) in dry T H F (15 mL) at room temperature was added diethyl malonate (945 | i L , 6.23 mmol). The reaction mixture was stirred for 1 h  A solution of the bromide 204  (754 mg, 1.78 mmol) in dry T H F (2 mL) was added via a cannula and the mixture was warmed to reflux for 1.5 h  The reaction mixture was cooled to room temperature and  water (15 mL) was added. The mixture was then extracted with E t 0 (3 x 10 mL). The 2  combined organic extracts were washed with brine (20 mL), dried (MgS04), and the solvent was removed under reduced pressure. The resulting crude product was purified by flash column chromatography (30 g of silica gel, 7:3 petroleum ether-Et 0) yielded 2  839 mg of a mixture of diethyl malonate and the diester 219 as a colorless oil.  To a stirred suspension of potassium hydride (200 mg, 5.00 mmol, washed with pentane) in dry T H F (17 mL) at room temperature was added a solution of diethyl malonate and the stannane 219 (obtained as described above) in dry T H F (2 mL) via a cannula. The reaction mixture was stirred for 1 h A solution of propargyl bromide (668 mg, 80 wt % in toluene, 4.49 mmol) was added via a syringe and the rnixture was warmed to reflux for 1.5 h. The reaction mixture was cooled to room temperature and water (17 mL) was added. The mixture was then extracted with E t 0 (3 x 10 mL). The combined organic 2  192 extracts were washed with brine (20 mL), dried (MgSC^), and the solvent was removed under reduced pressure.  The resulting crude product was purified by flash column  chromatography (30 g of silica gel, 7:3 petroleum ether-Et 0) and removal of trace 2  amounts of solvent (vacuum pump) from the purified material yielded 903 mg (94 % over 2 steps) of the alkyne 222 as a colorless oil.  IR (neat): 3280, 1734 (br), 1585, 1102, 774 c m . 1  X  H nmr (400 M H z , CDC1 ) 8: 0.31 (s, 9H, -SnMej, / „ . 2  3  s  H  = 54.3 Hz), 1.17 (t, 6H,  - C 0 C H C H 3 , / = 7.2 Hz), 2.02 (t, 1H, H - l , / = 2.6 Hz), 2.77 (d, 2H, H-3, J = 2.6 Hz), 2  2  3.40 (s, 2H, H-5), 3.78 (s, 6H, includes 2 3H -OMe singlets), 3.83 (s, 3H, -OMe), 4.064.19 (m, 4H, -C0 CH2CH ), 6.59 (s, 1H, aromatic proton, 2  1 3  3  4  /  S n  -H  = 17.4 Hz).  C nmr (75.5 M H z , CDC1 ) 5: -5.4, 13.9, 23.1, 38.6, 55.8, 58.5, 60.4, 60.9, 61.6, 71.9, 3  79.5, 108.6, 129.2, 138.3, 139.5, 153.8, 157.2, 170.0.  H R M S calcd for C H O 2 2  3 1  1 2 0 7  S n (M -Me): 527.1092; found: 527.1081. +  Anal, calcd for C H 0 S n : C 51.04, H 6.33; found: C 51.04, H 6.19. 23  34  7  Preparation of methyl 5,5-bis(ethoxycarbonvl)-6-(3,4,5-trimethoxv-2-trimethylstarm phenyl)hex-2-ynoate (223) SnMe  SnMe  3  3  MeOs C0 Me 2  MeO' OMe  R = -C0 Et  222  2  OMe  R = -C0 Et 2  223  To a cold (-78 °C), stirred solution of L D A ( 3 . 3 6 mmol) in dry T H F (15 mL) was added D M P U ( 4 0 6 J J L , 3 . 3 6 mmol) and stirring was continued for 5 min. A solution of the  193 acetylene 222 (903 mg, 1.67 mmol) in dry T H F (2 mL) was added via a cannula and the reaction mixture was stirred for 1 h at -78 °C.  Methyl chloroformate (390 \iL,  5.00 mmol) was added to the reaction mixture via a syringe. The mixture was stirred for 1 h at -78 °C and 1 h at room temperature.  Saturated aqueous sodium bicarbonate  (15 mL) was added and the mixture was extracted with E t 0 (3 x 10 mL). The combined 2  organic extracts were washed with brine (20 mL), dried (MgS0 ), and the solvent was 4  removed under reduced pressure. Flash column chromatography (50 g of silica gel, 7:3 petroleum ether-Et 0) of the crude product and removal of trace amounts of solvent 2  (vacuum pump) from the acquired material yielded 805 mg (80 %) of the alkynic triester 223 as a colorless clear oil.  IR (neat): 2241, 1719 (br), 1585, 1558, 1261, 1099, 775 c m . 1  X  H nmr (400 M H z , CDC1 ) 5: 0.30 (s, 9H, -SnMe.. 3  2  / „-H S  = 54.3 Hz), 1.20 (t, 6H,  - C 0 C H C H 3 , / = 7.1 Hz), 2.88 (s, 2H, - C H r ) , 3.39 (s, 2H, -CEL.-), 3.71 (s, 3H, -OMe), 2  2  3.78 (s, 6H, includes 2 3H -OMe singlets), 3.84 (s, 3H, -OMe), 4.10-4.24 (m, 4H, -COiCEzCKj),  1 3  6.54 (s, 1H, aromatic proton, / „ . = 17.3 Hz). 4  s  H  C nmr (50.3 M H z , CDC1 ) 5: -6.2 (-ve), 13.9 (-ve), 23.5, 39.2, 52.6 (-ve), 55.8 (-ve), 3  58.2, 60.4 (-ve), 60.9 (-ve), 62.0, 75.5, 84.3, 109.0 (-ve), 129.3, 137.8, 139.7, 153.6, 154.0, 157.3, 169.6.  H R M S calcd for C H O 2 4  3 3  1 2 0 9  S n (M -Me): 585.1147; found: 585.1151. +  Anal, calcd for C H 0 S n : C 50.11, H 6.06; found: C 50.35, H 5.99. 2 5  3 6  9  194 4.2 Copper(I) mediated conjugate additions  Preparation of (Z)-4-(methoxvcarbonvlmethvlidene)isochromane (224)  211  224  Following general procedure 1 (pg. 126), the ester 224 was prepared by the addition of the stannane 211 (85 mg, 0.23 mmol), as a solution in dry D M F (1 mL), to a cool (0 °C), stirred solution-suspension of CuCl (57 mg, 0.58 mmol) and glacial acetic acid (61 \xL, 1.1 mmol) in dry D M F (1.1 mL). Purification by flash column chromatography (10 g of silica gel, 9:1 petroleum ether-Et 0) of the crude product and removal of trace amounts 2  of solvent (vacuum pump) from the acquired material provided 40 mg (92 %) of the isochromane derivative 224 as a white solid (mp 62-63 ° C ) .  IR(KBr): 1708, 1622, 1174, 1110 c m . 1  J  H nmr (400 MHz, CDC1 ) 5: 3.73 (s, 3H, - C O o M e ) , 4.67 (s, 2H, H - l ) , 5.11 (d, 2H, H-3, 3  / = 2.1 Hz), 6.36 (t, I H , H-9, / = 2.1 Hz), 7.09 (d, I H , / = 7.4 Hz), 7.25-7.35 (rn, 2H), 7.70 (d, IH, H-5, 7=7.7 Hz).  1 3  C nmr (75.5 MHz, CDC1 ) 8: 51.3 (-ve), 68.0 (2C), 110.3 (-ve), 123.9 (-ve), 125.1 (-ve), 3  127.6 (-ve), 129.9, 130.0 (-ve), 137.2, 149.6, 166.7.  H R M S calcd for C H 0 : 204.0786; found: 204.0782. 1 2  1 2  3  Anal, calcd for C H 0 : C 70.59, H 5.92; found: C 70.49, H 5.85. 1 2  1 2  3  195  Table 24. H rrrnr (400 MHz, X  CDCI3)  data for the ester 224: N O E D experiments  224 Assignment H-x  H nmr (400 MHz)  NOED  8 (multiplicity, 7 (Hz))  Correlations  J  H-5  7.70 (d, 7=7.7)  H-9, Part of mat 7.25-7.35  H-9  6.36 (t, 7=2.1)  H-5  Preparation of (Z)-4-(methoxvcarbonyjtoethylidene)-6-methylisocljromane (225)  Following general procedure 1 (see pg. 126), the ester 225 was prepared by the addition of the stannane 206 (78 mg, 0.20 mmol), as a solution in dry D M F (1 mL), to a cool (0 °C), stirred solution-suspension of CuCl (54 mg, 0.55 mmol) and glacial acetic acid (58 u L , 1.1 mmol) in dry D M F (1 mL). Purification by flash column chromatography (10 g of silica gel, 3:2 petroleum efher-Et 0) of the crude product and removal of trace 2  amounts of solvent (vacuum pump) from the acquired material provided 43 mg (97 %) of the isochromane derivative 225 as a white solid (mp 94-94.5 °C).  IR (KBr): 1704, 1604, 1170, 1105 c m . 1  J  H nmr (400 M H z , CDCI3) 8: 2.34 (s, 3H, -Me), 3.73 (s, 3H, -CO^Me). 4.64 (s, 2H, H - l ) ,  196 5.09 (d, 2H, H-3,7= 2.0 Hz), 6.35 (t, IH, H-9, 7 = 2.0 Hz), 6.98 (d, I H , H-8, 7= 7.6 Hz), 7.15 (d, IH, H-7, 7 = 7.6 Hz), 7.52 (s, IH, H-5).  1 3  C nmr (75.5 M H z , CDC1 ) 5: 21.3 (-ve), 51.4 (-ve), 67.9, 68.0, 110.0 (-ve), 124.3 (-ve), 3  125.1 (-ve), 129.7, 131.0 (-ve), 134.4, 137.1, 149.9, 166.8.  H R M S calcd for  C13H14O3:  218.0943; found: 218.0939.  Anal, calcd for C i H i 0 : C 71.54, H 6.47; found: C 71.74, H 6.58. 3  4  3  Table 25. *H nmr (400 M H z , CDC1 ) data for the ester 225: NOED experiments 3  225 Assignment  *H nmr (400 MHz)  NOED  H-x  8 (multiplicity, 7 (Hz))  Correlations  H-5  7.52 (s)  H-9, H-10  H-9  6.35 (t, 7=2.0)  H-5  H-10  2.34 (s)  H.5, H-7  197 Preparation of 2,2-bis(ethoxvcarbonyl)-(ir)-4-methoxycarbony  1,2,3,4-tetra  hydronapthalene (226)  R = -C0 Et  C0 Me  2  2  215  226  Following general procedure 1 (see pg. 126), the triester 226 was prepared by the addition of the stannane 215 (84 mg, 0.17 mmol), as a solution in dry D M F (0.9 mL), to a cool (0 °C), stirred solution-suspension of CuCl (44 mg, 0.45 mmol) and glacial acetic acid (47 |U,L, 0.82 mmol) in dry D M F (0.8 mL). Purification of the crude product by flash column chromatography (10 g of silica gel, 7:3 petroleum ether-Et 0) and removal of 2  trace amounts of solvent (vacuum pump) from the acquired material yielded 57 mg (98 %) of the triester 226 as a colorless viscous oil.  IR (neat): 1734 (br), 1620, 1435, 1230, 1046 c m . 1  *H nmr (400 M H z , CDC1 ) 8: 1.13 (t, 6H, -C0 CH CH3, / = 7.1 Hz), 3.30 (s, 2H, H - l ) , 3  2  2  3.69 (d, 2H, H-3, / = 1.8 Hz), 3.74 (s, 3H, -C0 Me), 4.10 (q, 4H, -C0 CH2CH , / = 2  2  3  7.1 Hz), 6.38 (br t, I H , H-9, / = 1.8 Hz), 7.15-7.30 (m, 3H), 7.60 (d, I H , H-5, / = 7.8 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 8: 13.8 (-ve), 33.6, 35.3, 51.1 (-ve), 53.9, 61.6, 113.8 (-ve), 3  124.4 (-ve), 127.1 (-ve), 129.3 (-ve), 130.1 (-ve), 133.0, 135.6, 150.4, 166.8, 170.4.  H R M S calcd for C H 0 : 346.1416; found: 346.1420. 1 9  2 2  6  Anal, calcd for C i H 0 : C 65.88, H 6.40; found: C 66.08, H 6.31. 9  2 2  6  198  Table 26. H nmr (400 M H z , CDC1 ) data for the triester 226: N O E D experiments X  3  C0 Me 2  226 Assignment  *H nmr (400 MHz)  NOED  H-x  8 (multiplicity, / (Hz))  Correlations  H-5  7.60 (d,/=7.8)  H-9, Part of mat 7.15-7.30  H-9  6.38 ( b r t , / = 1.8)  H-5  Preparation  of  2,2-bis(ethoxvcarbonvl)-(£)-4-methoxvcarbonvlmethvlidene-6-methyl-  1,2,3,4-tetrahydronapthalene (227)  Following general procedure 1 (see pg. 126), the triester 227 was prepared by the addition of the stannane 221 (52 mg, 0.10 mmol), as a solution in dry D M F (0.5 mL), to a cool (0 °C), stirred solution-suspension of CuCI (24 mg, 0.24 mmol) and glacial acetic acid (28 |LiL, 0.50 mmol) in dry D M F (0.5 mL).  Purification by flash column  chromatography (10 g of silica gel, 7:3 petroleum ether-Et20) of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 34 mg (92 %) of the triester 227 as a white solid (mp 91-92 °C).  IR (KBr): 1733 (br), 1606, 1435, 1263, 1047 cm" . 1  199 H nmr (400 M H z , CDC1 ) 8: 1.14 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 2.30 (s, 3H, -Me),  l  3  3.25 (s, 2H, H - l ) , 3.67 (d, 2H, H-3, / = 1.9 Hz), 3.73 (s, 3H, -C0 Me), 4.10 (q, 4H, 2  -CO2CH2CH3, / = 7.1 Hz), 6.37 (br t, 1H, H-9, / = 1.9 Hz), 7.04 (d, 1H, H-8, / = 7.7 Hz),  7.10 (dd, 1H, H-7, / = 1.0, 7.7 Hz), 7.40 (br s, 1H, H-5).  13  C nmr (125.8 M H z , CDC1 ) 5: 13.9 (-ve), 21.1 (-ve), 33.6, 35.2, 51.1 (-ve), 54.0, 61.5, 3  113.6 (-ve), 124.9 (-ve), 129.2 (-ve), 131.1 (-ve), 132.7, 132.8, 136.6, 150.6, 166.9, 170.5.  H R M S calcd for C20H24O6: 360.1573; found: 360.1564.  Anal, calcd for  C20H24O6:  C 66.65, H 6.71; found: C 66.57, H 6.80.  Table 27. *H nmr (400 M H z , CDC1 ) data for the triester 227: N O E D experiments 3  7  (|  2pC0 Et 2  0  C0 Me 2  227 Assignment  *H nmr (400 MHz)  NOED  H-x  8 (multiplicity, / (Hz))  Correlations  H-l  3.25 (s)  H-8  H-5  7.40 (br s)  H-9, H-10  H-9  6.37(brt,/= 1.9)  H-5  H-10  2.30 (s)  H-5, H-7  200 Preparation  of  2,2-bis(ethoxvcarbonyl)-(£V^  trimethoxy-1,2,3,4-tetrahydronapthalene (228) 9  SnMe  10  11  CO2CH2CH3 3  CO2CH2CH3 C0 Me i 2  OMe  6  OMe 15  R = -C0 Et  13  2  223  14  228  Following general procedure 1 (see pg. 126), the triester 228 was prepared by the addition of the stannane 223 (96 mg, 0.16 mmol), as a solution in dry D M F (0.8 mL), to a cool (0 °C), stirred solution-suspension of CuCl (43 mg, 0.44 mmol) and glacial acetic acid (46 }XL, 0.80 mmol) in dry D M F (0.8 mL).  Purification by flash column  chromatography (10 g of silica gel, 1:1 petroleum ether-Et 0) of the crude product and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material provided 68 mg (97 %) of the triester 228 as a colorless, viscous oil.  IR (neat): 1734 (br), 1591, 1489, 1250, 915, 733 c m . 1  *H nmr (500.2 M H z , C D ) 8: 0.83 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 3.22 (s, 3H, H-17), 6  6  3.35 (s, 2H, H - l ) , 3.45 (s, 3H, -C0 Me). 3.61 (s, 3H, H-15), 3.66 (s, 3H, H-16), 3.88 (q, 7  4H, -C0 CH2CH , / = 7.1 Hz), 4.19 (d, 2H, H-3, / = 1.8 Hz), 6.19 (s, I H , H-8), 7.39 2  3  (brt, IH, H - 1 2 , / = 1.8 Hz).  1 3  C nmr (125.8 MHz, C D ) 8: 13.9, 34.9, 36.8, 50.6, 54.4, 55.3, 60.4, 60.6, 61.5, 108.2, 6  6  117.8, 121.3, 133.1, 142.6, 147.3,153.6, 154.8,167.7, 170.7.  H R M S calcd for  Anal, calcd for  C22H28O9:  C22H28O9:  436.1733; found: 436.1729.  C 60.54, H 6.47; found: C 60.22, H 6.67.  201  Table 28. *H nmr (400 M H z , C D ) data for the triester 228: N O E D experiments 6  6  9 10 11 C0 CH CH  ^  2  2  3  2pC0 CH CH 2  2  3  3  15  12 C0 Me  v  2  13  228  14  Assignment  *H nmr (400 MHz)  NOED  H-x  8 (multiplicity, / (Hz))  Correlations  H-l  3.35 (s)  H-8  H-3  4.19 ( d , / = 1.8)  H-14  H-8  6.19 (s)  H - l , H-17  H-10, -CO2CH2CH3  3.88 (q, 7=7.1)  H-11,-C0 CH CH3  0.83 (t, 7=7.1)  H-12  7.39(brt,/= 1.8)  H-15  3.45 (s)  H-3  H-15  3.61 (s)  H-12  H-16  3.66 (s)  H-17  3.22 (s)  2  H-14.  2  -COMe  H-8  202 Table 29.  1 3  C nmr (128.5 M H z , C D ) data for the triester 228: H M B C and H M Q C 6  6  experiments 10  9  11  CO2CH2CH3  2[^C0 CH CH 2  2  3  3  C0 Me 13  2  14  228 Assignment  1 3  C nmr (125.8 MHz)  C-x  5  HMQC  HMBC  Correlations  Correlations  H-l  C-l  36.8  C-2  54.4  C-3  34.9  C-4  147.3  H-3  C-4a  133.1  H-l  C-5  153.6  H-15  C-6  142.6  H-9, H-16  C-7  154.8  H-9, H-17  C-8  108.2  C-8a  121.3  H - l , H-3, H-8, H-12  C-9  170.7  H-3,H-10  C-10  61.5  H-10  H-ll  C-ll  13.9  H-ll  H-10  C-12  117.8  H-12  H-3  C-13  167.7  C-14  50.6  H-14  C-15  60.3  H-15  C-16  60.6  H-16  C-17  55.3  H-17  H-l H-3  H-8  H - l , H-12  H-l  H-14  203 5. Extensions and limitations  5.1 Effect of solvent and additives  Conjugate addition in the absence of a proton source  129  144  145  To a cool (0 °C), stirred solution of the stannane B3 (142 mg, 0.43 mmol) in dry D M F (4.3 mL) was added copper(I) chloride (111 mg, 1.12 mmol) in one solid portion. The resulting red suspension was stirred for 15 min. Aqueous ammonium cMoride-ammonia (pH 8) (4 mL) was added and stirred until the mixture was a deep blue. The mixture was extracted with E t 0 (3 x 10 mL) and the combined organic extracts were washed with 2  brine (3 x 20 mL), dried (MgSCU), and the solvent was removed under reduced pressure. Purification of the crude product by flash column chromatography (12 g of silica gel, 24:1 petroleum ether-Et 0) and removal of trace amounts of solvent (vacuum pump) 2  from the acquired material yielded 42 mg (64 %) of the diene 144 and 26 mg (18 %) of the stannane 146, both as colorless oils. The diene 144 exhibited spectral characteristics ( H nmr) identical with those previously mentioned (pg. 127). In a separate experiment, X  when the reaction time was increased to a period of 1 h, the diene 144 and the stannane 145 were obtained in 60 % and 6 % yields, respectively. Characterization data for the stananne 145 is given below.  IR (neat): 1699, 1600, 1207, 772 cm" . 1  *H nmr (200 M H z , CDC1 ) 8: 3  0.25 (s, 9H, -SnMes,  2  /  S n  -H  = 56.2 Hz), 1.26 (t, 3H,  - C 0 C H C H 3 , / = 7.1 Hz), 2.56-2.70 (m, 2H, H-4), 2.88-3.02 (m, 2H, H-3), 4.14 (q, 2H, 2  2  -C0 CH2CH , / = 7.1 Hz), 4.88 (br s, IH, H-5b), 5.18 (br t, I H , H-5a, / = 2.7 Hz). 2  3  204  FIRMS calcd for C H 0 S n (M -Me): 301.0251; found: 301.0253. +  n  1 7  2  Table 30. *H nmr (200 MHz, CDC1 ) data for the ester 145: NOED experiments 3  C0 Et 2  j j — SnMe  M  H  3  b  145  Assignment  *H nmr (200 MHz)  NOED  H-x  8 (multiplicity, / (Hz))  Correlations  0.25 (s)  H-5a  H-5a  5.18 (brt, 7=2.7)  H-5b, -SnMe  H-5b  4.88 (brs)  H-3, H-5a  -SnMe  3  3  Conjugate addition utilizing an aqueous H C l work up  C0 Et 2  . . .  To a cool (0 °C), stirred solution of the stannane 129 (142 mg, 0.43 mmol) in dry D M F (4.3 mL) was added copper(I) chloride (111 mg, 1.12 mmol) in one solid portion. The resulting red suspension was stirred for 15 min. To the mixture was added aqueous 1 M H C l (2 mL, 2 mmol) and stirring was continued for 5 min.  Aqueous ammonium  chloride-ammonia (pH 8) (4 mL) was added and stirred until the mixture was a deep blue. The mixture was extracted with E t 0 (3 x 10 mL) and the combined organic extracts 2  205 were washed with brine (3 x 20 mL), dried (MgS0 ), and the solvent was removed under 4  reduced pressure.  Purification of the crude product by flash column chromatography  (12 g of silica gel, 24:1 petroleum ether-Et 0) and removal of trace amounts of solvent 2  (vacuum pump) from the acquired material yielded 39 mg (77 %) of the diene 144 as a colorless oil. The diene 144 exhibited spectral characteristics (*H nmr) identical with those previously mentioned (pg. 127).  Conjugate addition in the presence of CF^CO?!! C0 Me 2  143  158  Following general procedure 1 (see pg. 126), the cyclobutane derivative 158 was prepared by the addition of the ester 143 (161 mg, 0.433 mmol), as a solution in dry D M F (2 mL), to a cool (0 °C), stirred solution-suspension of CuCI (115 mg, 1.16 mmol) and trifluoro acetic acid (166 \iL, 2.17 mmol) in dry D M F (2 mL). Purification of the crude product by flash column chromatography (12 g of silica gel, 9:1 petroleum ether-Et 0) 2  and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 67 mg (74 %) of the cyclization product 158 as a colorless oil. The product obtained exhibited spectral characteristics ( H nmr) identical with those previously J  mentioned (pg. 133). In addition, 18 mg of an uncharacterized mixture of unidentified destannylated material was obtained.  206 Conjugate addition utilizing copper(D acetate as the copperd) source  136  156  Following general procedure 1 (see pg. 126), the cyclohexane derivative 156 was prepared by the addition of the ester 136 (105 mg, 0.306 mmol), as a solution in dry D M F (1.7 mL), to a cool (0 °C), stirred solution-suspension of CuOAc (95 mg, 0.77 mmol) and glacial acetic acid (91 | i L , 1.53 mmol) in dry D M F (1.7 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 96:4 petroleum ether-Et 0) 2  and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 43 mg (78 %) of the cyclization product 156 as a colorless oil. The diene 156 exhibited spectral characteristics  nmr) identical with those previously mentioned  (pg. 131).  Conjugate addition in the presence of 0.5 equiv CuCl COoEt C0 Et 2  Me Sn 3  136  156  To a cool (0 °C), stirred solution-suspension of CuCl (12.2 mg, 0.12 mmol) in dry D M F (240 |uL) was added glacial acetic acid (27 uL, 0.47 mmol) and stirring was continued for 5 minutes. To the grey-blue suspension was added, via a syringe pump over 15 rnin, the stannane 136 (81 mg, 0.24 mmol) as a solution in dry D M F (240 uL). The mixture was stirred for 30 min, during which time the following color and texture changes were noted: a green suspension to a yellow suspension to an opaque, cloudy green suspension. Workup as described in general procedure 1 (see pg. 126) and purification of the crude material by flash column chromatography (10 g of silica gel, 97:3 petroleum ether-Et 0) 2  207 yielded 38 mg (89 %) of the cyclohexane derivative 156.  The diene 156 exhibited  spectral characteristics ( H nmr) identical with those previously mentioned (pg. 131). X  Conjugate addition in the presence of 0.1 equiv CuCI  136  156  To cool (0 °C), test tube (1 mL volume) equipped with a rubber septa and a micro stirbar was added CuCI (1.5 mg, 0.015 mmol), dry D M F (18 |LiL), and glacial acetic acid (17 juL, 0.30 mmol) and the mixture was stirred for 5 minutes. To the clear solution was added, via a syringe pump over 15 min, a solution of the stannane 136 (50 mg, 0.15 mmol) in dry D M F (20 |iL) and with dry D M F (20 \iL) as a rinse. The mixture was stirred for 4 h, during which time the following color and texture changes were noted: a colorless solution to a cloudy white suspension to a cloudy green/black suspension to a very pasty white slurry.  With no work-up, the mixture was subjected directly to flash column  chromatography (10 g of silica gel, 97:3 petroleum ether-Et 0). Removal of trace 2  amounts of solvent (vacuum pump) from the acquired material yielded 20 mg (76 %) of the cyclohexane derivative 156. material was recovered.  In addition, 2 mg of uncharacterized destannylated  The diene 156 exhibited spectral characteristics ( H nmr)  identical with those previously mentioned (pg. 131).  J  208 Conjugate addition utilizing D M I as the solvent  136  156  Following general procedure 1 (see pg. 126), the cyclohexane derivative 156 was prepared by the addition of the ester 136 (115 mg, 0.334 mmol), as a solution in dry D M I (1.7 mL), to a cool (0 °C), stirred solution-suspension of CuCI (87 mg, 0.88 mmol) and glacial acetic acid (100 uL, 1.67 mmol) in dry D M I (1.7 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 96:4 petroleum ether-Et 0) 2  and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 50 mg (83 %) of the cyclization product 156 as a colorless oil. The diene 156 exhibited spectral characteristics (*H nmr) identical with those previously mentioned (pg. 131).  5.2 Preparation of a,3-alkvnic aldehyde and ketone substrates  Preparation of 6-( 1 -methoxvcarbonyl-2-trimethvlstannylcyclopent-2-en-1 -yl)hex-2-ynal  (233)  180b  233  To a cold (-78 °C), stirred solution of L D A (0.45 mmol) in dry T H F (2 mL) was added a solution of the stannane 180b (107 mg, 0.300 mmol) (pg. 150) in dry T H F (1 mL) and the solution was warmed to -48 °C. The reaction mixture was stirred for 1 h. To the mixture was added D M F (46 | i L , 0.60 mmol) via a syringe and the solution was warmed to room temperature. The mixture was stirred for 30 min. The reaction mixture was transferred via a cannula to a vigorously stirred aqueous solution of 10 % K H P 0 2  4  (10 mL) and  209 stirring was continued for 1 h. The rnixture was extracted with E t 0 (3 x 10 mL). The 2  combined organic extracts were washed with brine (20 mL), dried (MgSCU), and the solvent was removed under reduced pressure. Flash column chromatography (10 g of silica gel, 4:1 petroleum ether-Et 0) of the crude product and removal of trace amounts 2  of solvent (vacuum pump) from the acquired material yielded 76 mg (66 %) of the aldehyde 233 as a colorless clear oil.  IR (neat): 2201, 1733, 1670, 1434, 1166, 772 c m . 1  X  H nmr (400 M H z , CDC1 ) 8: 0.12 (s, 9H, -SnMe , / _ = 54.3 Hz), 1.40-1.60 (m, 3H), 2  3  3  Sn  H  1.68-1.77 (m, IH), 1.93-2.00 (m, IH), 2.36-2.55 (m, 5H), 3.63 (s, 3H, - C 0 M e ) , 5.96 (dd, 2  IH, olefinic proton, / = 2.1, 2.1 Hz,  1 3  3  / „-H S  = 37.9 Hz), 9.14 (s, I H , -C(=0)H).  C nmr (125.8 M H z , CDC1 ) 8: -8.6 (-ve), 19.5, 23.3, 32.0, 34.2, 37.7, 51.8 (-ve), 65.2, 3  81.9, 98.3, 143.6 (-ve), 148.4, 176.6, 176.9 (-ve).  H R M S calcd for C i H i O 5  2  1 2 0 3  S n (M -Me): 369.0513; found: 369.0505. +  Anal, calcd for C i H 0 S n : C 50.17, H 6.32; found: C 50.40, H 6.47. 6  Preparation of  24  3  7-(l-methoxycarbonyl-2-trmiethvlstannvlcyclopent-2-en-l-yl)hept-3-vn-  2-one (234)  180b  234  210 C0 Me 2  235 To a cold (-78 °C), stirred solution of L D A (2.48 mmol) in dry T H F (15 mL) was added D M P U (300 JLXL, 2.48 mmol) and stirring was continued for 5 min. A solution of the alkyne 180b (585 mg, 1.65 mmol) (pg. 150) in dry T H F (2 mL) was added via a cannula and the reaction mixture was stirred for 1 h at -78 °C. Ethanal (270 | i L , 4.83 mmol) was added neat via a syringe. The mixture was stirred for 1 h at -78 °C and 1 h at room temperature. Saturated aqueous sodium bicarbonate (10 mL) was added and the mixture was extracted with E t 0 (3 x 10 mL). The combined organic extracts were washed with 2  brine (20 mL), dried (MgSd,), and the solvent was removed under reduced pressure. Flash column chromatography (20 g of silica gel, 3:2 petroleum ether-Et 0) of the crude 2  product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 486 mg (74 %) of the alcohol 234 as a colorless clear oil.  To a cold (-78 °C), stirred solution of oxalyl chloride (0.92 mL, 2 M in CH C1 , 2  2  1.84 mmol) in dry CH C1 (10 mL) was added dimethyl sulfoxide (260 JLIL, 3.66 mmol) 2  2  dropwise via a syringe. The solution was stirred for 15 min. The alcohol (234) (obtained as described above) was added over 3 min as a solution in dry C H C 1 (2 mL). 2  The  2  cloudy white suspension was stirred for an additional 15 min. Triethylamrne (1.00 mL, 7.17 mmol) was added dropwise via a syringe and the mixture was stirred for 20 min. The reaction mixture was warmed to room temperature and water (10 mL) was added. The organic phase was separated and the aqueous layer was extracted with C H C 1 (3 x 2  2  20 mL). The organic layers were combined, washed with brine (30 mL), dried (MgSC^), and the solvent was removed under reduced pressure. Flash column chromatography (40 g of silica gel, 3:2 petroleum ether-Et 0) of the crude product and removal of trace 2  amounts of solvent (vacuum pump) from the acquired material yielded 460 mg (70 % over 2 steps) of the alkynic ketone 235 as a colorless clear oil.  211 IR (neat): 2211,1729,1678, 1433,1228,768 c m . 1  X  H nmr (400 M H z , CDC1 ) 8: 0.13 (s, 9H, -SnMe , / . = 54.3 Hz), 1.38-1.56 (m, 3H), 2  3  3  S n  H  1.68-1.77 (m, IH), 1.92-2.00 (m, IH), 2.26-2.52 (m, 8H, includes 3H -CH3 singlet at 2.28), 3.63 (s, 3H, -CC^Me). 5.96 (dd, I H , olefinic proton, / = 2.1, 2.1 Hz, / „ . = 3  s  H  38.0 Hz).  1 3  C nmr (125.8 M H z , CDC1 ) 8: -8.6 (-ve), 19.3, 23.5, 31.9, 32.7 (-ve), 34.2, 37.7, 51.7 3  (-ve), 65.2, 81.6, 93.1, 143.6 (-ve), 148.3, 176.6, 184.7.  H R M S calcd for C i H O 3 6  2 3  1 2 0  S n (M -Me): 383.0669; found: 383.0673. +  Anal, calcd for C i H 0 S n : C 51.42, H 6.60; found: C 51.48, H 6.70. 7  26  3  5.3 Copper(I) mediated cyclizations  Preparation  of  l-methoxvcarbonvl-(£)-5-foimylmetliylidenebicvclor4.3.01non-6-ene  (236) and l-methoxycarbonvl-(Z)-5-formylmetlivlidenebicvclor4.3.01non-6-ene (237)  233  236 (minor)  237 (major)  Following general procedure 1 (see pg. 126), the aldehydes 236 and 237 was prepared by the addition of the stannane 233 (60 mg, 0.16 mmol), as a solution in dry D M F (0.8 mL), to a cool (0 °C), stirred solution-suspension of CuCl (44 mg, 0.45 mmol) and glacial acetic acid (45 ]XL, 0.79 mmol) in dry D M F (0.8 mL). Purification of the crude product by flash column chromatography (10 g of silica gel, 3:2 petroleum ether-Et 0) and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material provided  212 30 mg (89 %) of a mixture of the isomeric aldehydes 236 and 237 as a colorless clear oil. The ratio of these products, as determined by integration of the *H nmr aldehyde signals, was-1:4, respectively.  IR (neat): 1728, 1672, 1434, 1241, 1152 c m . 1  Signals attributable to the major isomer 237:  X  H nmr (400 M H z , C D ) 8: 3.19 (s, 3H, -C0 Me), 5.44 (dd, 1H, H-7, / = 2.1, 2.1 Hz), 6  6  2  5.91 (dd, 1H, H-10, / = 2.0, 7.9 Hz), 10.12 (d, 1H, H - l l , / = 7.9 Hz).  1 3  C nmr (125.8 M H z , CDC1 ) 8: 24.8, 31.4, 36.1, 37.3, 37.6, 52.1 (-ve), 59.2, 127.5 (-ve), 3  135.3 (-ve), 139.6, 159.7, 175.8, 193.1 (-ve).  Signals attributable to the minor isomer 236:  J  H nmr (400 M H z , C D ) 8: 2.83 (dm, 1H, H-4, / = 15.4 Hz), 3.23 (s, 3H, - C 0 M e ) , 5.62 6  6  2  (dd, 1H, H-7, / = 2.5, 2.5 Hz), 6.22 (dd, 1H, H-10, / = 2.1, 8.0 Hz), 9.92 (d, 1H, H - l l , / = 8.0 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 8: 23.1, 27.7, 30.8, 36.2, 38.6, 52.1 (-ve), 58.2, 124.0 (-ve), 3  132.5 (-ve), 143.6, 156.9, 176.0, 190.6 (-ve).  H R M S calcd for C H 0 : 220.1099; found: 220.1100. 1 3  1 6  3  Anal, calcd for C H 0 : C 70.89, H 7.32; found: C 70.96, H 7.20. 1 3  1 6  3  213 Table 31. H nmr (400 M H z , CDC1 ) data for the aldehdye 237: N O E D experiments X  3  C0 Me  9  2  O 237 Assignment  *H nmr (400 MHz)  NOED  H-x  8 (multiplicity, / (Hz))  Correlations  H-7  5.44 (dd,/= 2.1, 2.1)  H-10  5.91 (dd,7=2.0,7.9)  H-ll  10.12 (d, 7=7.9)  H-ll  H-7, H-10  Table 32. H nmr (400 M H z , CDC1 ) data for the aldehyde 236: N O E D experiments X  3  Assignment H-x  H nmr (400 MHz)  NOED  8 (multiplicity, 7 (Hz))  Correlations  X  H-7  5.62 (dd, 7=2.5,2.5)  H-10  H-10  6.22 (dd, 7= 2.1, 8.0)  H-7  H-ll  9.92 (d,7=8.0)  One of H-4  214 (238)  Preparation of l-methoxycarbonyHiT)-5-acety  235  238 (major)  239 (minor)  Following general procedure 1 (see pg. 126), the ester 238 was prepared by the addition of the stannane 235 (83 mg, 0.21 mmol), as a solution in dry D M F (1 mL), to a cool (0 °C), stirred solution-suspension of CuCI (54 mg, 0.55 mmol) and glacial acetic acid (60 \xL, 1.1 mmol) in dry D M F (1 mL). Purification by flash column chromatography (12 g of silica gel, 13:7 petroleum ether-Et 0) of the crude product and removal of trace 2  amounts of solvent (vacuum pump) from the acquired material provided 27 mg (55 %) of the ketone 238 as a colorless solid (mp 40-44 °C) and 7.6 mg of a mixture of the two geometric isomers 238 and 239. The minor isomer 239 proved to be extremely unstable and the mixture containing both compounds decomposed readily. The major isomer 238 decomposed to a small degree over long C nmr acquisition times in CDCI3; however a 1 3  clean H nmr spectrum was obtained. Integration of the olefinic protons, in the *H nmr 1  spectrum of the crude product after workup, provided a ratio of -4:1 of the methyl ketones 238 and 239, respectively. Characterization data for the ketone 238 is given below.  IR(KBr): 1728, 1681, 1433, 1357, 1165 c m . 1  H nmr (400 M H z , CDC1 ) 8: 1.37-1.51 (m, 2H), 1.70-1.76 (m, 1H), 1.82-1.92 (m, 1H),  l  3  2.00-2.10 (m, 1H), 2.19 (s, 3H, -C(=0)CH3), 2.33-2.47 (m, 4H), 3.57-3.65 (m, 4H, includes 3H - C O M e singlet at 3.63), 6.04 (br s, 1H, H-7), 6.34 (d, 1H, H-10, / = 2.4 Hz).  1 3  C nmr (125.8 M H z , CDC1 ) 8: 23.0, 28.8, 30.5, 32.1 (-ve), 36.3, 38.7, 52.1 (-ve), 58.2, 3  120.6 (-ve), 130.7 (-ve), 144.4, 152.6, 176.4, 199.0.  215 H R M S calcd for C i H 0 : 234.1256; found: 234.1251. 4  1 8  3  Anal, calcd for C i H 0 : C 71.77, H 7.74; found: C 71.49, H 7.95. 4  1 8  3  Table 33. *H nmr (400 M H z , CDC1 ) data for the ketone 238: 3  9  8'  NOED experiments  C0 Me 2  ^  238 Assignment  *H nmr (400 MHz)  NOED  H-x  8 (multiplicity, / (Hz))  Correlations  H-7  6.04 (br s)  Part of mat 2.33-2.47  H-10  6.34 (d, 7=2.4)  H-7, -C(=0)CH  -C(=0)CH  3  2.19 (s)  3  216  6. Intermolecular coupling of P-trimeth.ylstannyl-(X,P-unsaturated ketones mediated by copper(I) chloride 6.1 Intermolecular copper(I) mediated couplings  General Procedure 6:  Copper(D chloride mediated intermolecular coupling of  (3-lrimethvlstannvl-a,3-unsaturated ketones  To a stirred solution-suspension of CuCl (2.5 equiv) in dry D M F (~4 ml/mmol of substrate)  at  room  temperature  was  added  a  solution  of  the  appropriate  a&enyltrimethylstannane (1 equiv) in dry D M F (~4 ml/mmol of substrate), and the resulting mixture was stirred for 30 min.  Saturated aqueous ammonium chloride  (~1 mL/mL of DMF) and water (~1 mL/mL of DMF) were added and the mixture was opened to the atmosphere. The mixture was stirred until the aqueous layer turned bright blue and then was extracted with E t 0 or CH C1 (3 x ~1 mL/mL of DMF). 2  2  2  The  combined organic extracts were washed with water (~2 mL/mL of D M F ) and brine (3 x ~2 mL/mL of D M F ) , dried (MgSCU), and concentrated under reduced pressure.  The  crude product was purified by flash column chromatography on silica gel.  Preparation of 3-(3-oxocyclopent-l-en-l-vDcyclopent-2-en-l-one (251)  O  Following general procedure 6, the diketone (251) was synthesized from 3-trimethyl stannylcyclopent-2-en-l-one (247) (101 mg, 0.414 mmol), copper(I) chloride (104 mg, 61  1.05 mmol), and dry D M F (4.4 mL). In this case, the crude product was isolated by the extraction of the reaction mixture with CH C1 . 2  2  Flash column chromatography of the  217 crude product (12 g of silica gel, ethyl acetate) and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 27 mg (81 %) of the coupled product 251 as a colorless crystalline solid (mp 211-214 °C).  IR (neat): 1698, 1675, 1561, 1243, 1184, 865, 848 c m . 1  J  H nmr (400 M H z , CDC1 ) 8: 2.52-2.57 (m, 4H), 2.85-2.90 (m, 4H), 6.43 (t, 2H, H-2, 3  / = 1.5 Hz).  1 3  C nmr (50.3 M H z , CDC1 ) 8: 28.2, 35.1,132.6, 166.9, 208.7. 3  H R M S calcd for C i o H 0 : 162.0681; found: 162.0677. 10  2  Anal, calcd for C i o H i 0 : C 74.06, H 6.21; found: C 74.13, H 6.10. 0  2  Preparation of 3-(3-oxocyclohex-l-en-l-yl)cyclohex-2-en-l-one (253)  O  253  249 Following  general  procedure  6,  the  diene  253  was  prepared  from  3-trimethylstannylcyclohex-2-en-1 -one (249) (121 mg, 0.469 mmol), copper(I) chloride 61  (120 mg, 1.21 mmol), and dry D M F (4.6 mL). In this case, the crude product was obtained by the extraction of the reaction mixture with E t 0 . Purification of the crude 2  product by flash column chromatography (7 g of silica gel, E t 0 ) and removal of trace 2  amounts of solvent (vacuum pump) from the acquired material yielded 40 mg (91 %) of the diene 253 as a colorless crystalline solid (mp 107-108 °C).  218  LR (neat): 1662, 1575, 1263, 1186, 1144, 901 c m . 1  J  H nmr (400 M H z , CDC1 ) 5: 2.00-2.15 (m, 4H, H-5), 2.42 (t, 4H, / = 6.7 Hz), 2.50 (t, 3  4H, 7=6.0 Hz), 6.27 (s, 2H).  1 3  C nmr (50.3 M H z , CDC1 ) 8: 22.2, 25.8, 37.4, 128.0, 156.5, 199.7. 3  H R M S calcd for C i H 0 : 190.0994; found: 190.0993. 2  1 4  2  Anal, calcd for C i H 0 : C 75.76, H 7.42; found: C 75.54, H 7.42. 2  Preparation  of  1 4  2  2-methyl-3-( 2-methyl-3-oxocvclopent-l-en-l-vl)cyclopent-2-en-l-one ,  (2521  248  252  Following general procedure 6, the diketone 252 was synthesized from 2-methyl-3trimethylstannylcyclopent-2-en-l-one (248)  61  (110 mg, 0.43 mmol), copper(I) chloride  (110 mg, 1.11 mmol), and dry D M F (4.2 mL). In this case, the crude product was obtained by the extraction of the reaction mixture with CH C1 . Purification of the crude 2  2  product by flash column chromatography (20 g of silica gel, ethyl acetate) and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 38 mg (94 %) of the coupled product 252 as a colorless crystalline solid (mp 94-94.5 °C).  IR (neat): 1690, 1626, 1292, 995, 947, 781 c m . 1  219 *H nmr (400 M H z , CDC1 ) 8: 1.67 (t, 6H, H-6, / = 2.1 Hz), 2.48-2.53 (m, 4H), 2.65-2.72 3  (m, 4H).  1 3  C nmr (75.5 M H z , CDC1 ) S: 9.9 (-ve), 28.5, 33.8, 138.7, 163.5, 208.6. 3  H R M S calcd for C i H 0 : 190.0994; found: 190.0993. 2  1 4  2  Anal, calcd for C i H 0 : C 75.76, H 7.42; found: C 75.72, H 7.68. 2  Preparation  of  1 4  2  2-methyl-3-(2-methyl-3-oxocyclohex- 1-en- l-yDcyclohex-2-en- 1-one  £2541  O  250  254  Following general procedure 6, the compound 254 was prepared from 2-methyl-3trimethylstannylcyclohex-2-en-1 -one (250)  61  (114 mg, 0.421 mmol), copper(I) chloride  (111 mg, 1.12 mmol), and dry D M F (4.2 mL). In this case, the crude material was isolated by the extraction of the reaction mixture with CH C1 . 2  2  Flash column  chromatography (21 g of silica gel, 1:1 petroleum ether-Et 0) of the crude product and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 41 mg (91 %) of the diketone 254 as a colorless crystalline solid (mp 121-122 °C).  IR(neat): 1657, 1606, 1299, 1195, 1113, 1035,900 c m . 1  X  H nmr (400 M H z , CDC1 ) 5: 1.61 (br t, 6H, H-7, / = 1.9 Hz), 1.95-2.11 (m, 4H), 2.203  2.32 (m, 2H), 2.38-2.52 (m, 6H).  1 3  C nmr (75.5 M H z , CDC1 ) 5: 11.9, 22.9, 28.9, 37.7,129.8, 155.4, 198.9. 3  H R M S calcd for C i H 0 : 218.1307; found: 218.1309. 4  1 8  2  Anal, calcd for C i H i 0 : C 77.03, H 8.31; found: C 77.11, H 8.46. 4  8  2  221  7. Intramolecular coupling  of aryltrimethylstannanes mediated by copper(I)  chloride 7.1 Preparation of coupling precursors  Preparation of bis(trimethvlstannylphenyl) ether ( 1 0 4 ) SnMe  SnMe  3  3  ,0  Y^ 255  104  To a cold (-78 °C), stirred solution of n-BuLi (2.75 mL, 1.6 M in hexanes, 4.40 mmol) in dry E t 0 (20 mL) was added T M E D A (664 ixL, 4.40 mmol) followed by diphenyl ether 2  ( 2 5 5 ) (320 fxL, 2.01 mmol) neat via a syringe. The reaction rnixture was warmed to room temperature and stirred for 3 h.  The dark red solution was cooled to -78 °C and  trimethyltin chloride (958 mg, 4.81 mmol) was added as a solid in one portion. The mixture was warmed to room temperature and stirred for 1.5 h.  Saturated aqueous  sodium bicarbonate (10 mL) was added and the mixture was extracted with E t 0 (3 x 2  10 mL).  The organic extracts were combined, washed with brine (20 mL), dried  (MgSCU), and the solvent was removed under reduced pressure.  Flash column  chromatography of the crude product (30 g of silica gel, pentane) yielded 669 mg of the distannane 1 0 4 and further flash column chromatography (20 g of silica gel, pentane) on the impure material yielded 68 mg, giving a total yield of 737 mg (74 %) of the stannane 1 0 4 as a crystalline solid (mp 67-69 °C).  IR (KBr): 1578, 1205, 755 cm" . 1  *H nmr (400 M H z , CDC1 ) 8: 0.26 (s, 18H, -SnMe . / „ . = 54.9 Hz), 6.62-6.68 (m, 2H), 2  3  3  s  H  7.05-7.10 (m, 2H), 7.20-7.24 (m, 2H), 7.46 (dd, 2H, / = 1.6, 7.1 Hz).  222 1 3  C nmr (75.5 M H z , CDC1 ) 5: -8.6 (-ve), 118.1 (-ve), 123.6 (-ve), 130.5 (-ve), 132.8, 3  137.0 (-ve), 163.3.  H R M S calcd for C i H 2 3 O S n (M -Me): 482.9793; found: 482.9802. 120  7  +  2  Anal, calcd for C i H O S n : C 43.61, H 5.29; found: C 43.93, H 5.30. 8  26  2  Preparation of bis(2-trimethvlstannvbenzyl) ether (108) SnMe  N  SnMe  3  3  199  202  108  To a cold (0 °C), stirred suspension of sodium hydride (79 mg, 3.3 mmol, washed with pentane) in dry D M F (12 mL) was added a solution of the alcohol 199 (211 mg, 0.779 mmol) in dry D M F (5 mL) via a cannula. After 30 min, a solution of the bromide 202 (443 mg, 1.33 mmol) in dry D M F (4 mL) was added via a cannula and the reaction mixture was stirred for 30 min at 0 °C and at room temperature for 14 h. E t 0 (40 mL) 2  was added and the mixture was washed with water (2 x 20 mL). The organic extract was dried (MgSQ*) and the solvent was removed under reduced pressure.  Flash column  chromatography (30 g silica gel, 99:1 petroleum ether-Et 0 with gradual elution to 95:5 2  petroleum ether-Et 0) of the crude product and removal of trace amounts of solvent 2  (vacuum pump) from the acquired material yielded 401 mg (99 %) of the distannane 108 as a colorless oil.  IR (neat): 1069, 1047, 751 c m . 1  *H nmr (400 M H z , CDC1 ) 8: 0.22 (s, 18H, -SnMe^. / . 2  3  -CHz-O-), 7.20-7.33 (m, 6H), 7.45-7.58 (m, 2H).  S n  H  = 53.5 Hz), 4.43 (s, 4H,  223 1 3  C nmr (75.5 M H z , CDC1 ) 5: -8.1 (-ve), 72.8, 127.2 (-ve), 128.2 (-ve), 128.3 (-ve), 3  136.6 (-ve), 142.1, 144.1.  H R M S calcd for Ci H27O Sn (M -Me): 511.0106; found: 511.0088. 120  9  +  2  Anal, calcd for C oH3oOSn : C 45.86, H 5.77; found: C 46.02, H 5.88. 2  2  Preparation of diethyl 2,2-bis(4-methyl-2-tiimethvlstannylbenzyl)malonate (257)  203  257  To a stirred suspension of potassium hydride (73 mg, 1.8 mmol, washed with pentane) in dry T H F (10 mL) at room temperature was added diethyl malonate (108 ixL, 0.715 mmol) via a syringe and the reaction mixture was stirred for 30 min. A solution of the bromide 203 (514 mg, 1.48 mmol) in dry T H F (1 mL) was added via a cannula and the mixture was warmed to reflux for 1 h. The reaction mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with E t 0 (3 x 10 mL) and the 2  combined organic extracts were washed with brine (20 mL), dried (MgSCM), and the solvent was removed under reduced pressure. Flash column chromatography (25 g of silica gel, 47:3 petroleum ether-Et 0) of the crude product and removal of trace amounts 2  of solvent (vacuum pump) from the acquired material yielded 486 mg (98 %) of the distannane 257 as a colorless solid (mp 101-103 °C).  IR (KBr): 1726, 1251, 776 c m . 1  R nmr (400 M H z , CDC1 ) 5: 0.24 (s, 18H, -SnMfe,  l  3  2  /  S n  -H  = 53.1 Hz), 1.03 (t, 6H,  - C 0 C H C H 3 , / = 7.1 Hz), 2.25 (s, 6H, -Me), 3.38 (s, 4H, -CIL.-), 4.01 (q, 4H, 2  2  224 -CO2CH2CH3, / = 7.1 Hz), 6.97-7.03 (m, 4H), 7.16 (s, 2H, aromatic protons a to -SnMe , 3  3  /sn-H  1 3  = 50.6Hz).  C nmr (75.5 M H z , CDC1 ) 5: -7.4 (-ve), 13.8 (-ve), 20.1 (-ve), 42.0, 59.8, 61.3, 3  127.8 (-ve), 129.0 (-ve), 135.3, 137.2 (-ve), 140.2, 144.6, 171.4.  H R M S calcd for C 8H4iO 2  120 4  Sn Sn (M -Me): 679.1043; found: 679.1050. 118  +  Anal, calcd for C 9H440 Sn : C 50.19, H 6.39; found: C 50.50, H 6.57. 2  4  2  Preparation of diethyl 2,2-bis(3,4,5-trjmethoxy-2-trjmethylstannylbenzyl)malonate (258)  204  258  To a stirred suspension of potassium hydride (56 mg, 1.4 mmol, washed with pentane) in dry T H F (10 mL) at room temperature was added diethyl malonate (94 jaL, 0.62 mmol) and stirring was continued for 30 min.  A solution of the bromide 204 (574 mg,  1.32 mmol) in dry THF (1 mL) was added via a cannula and the mixture was warmed to reflux for 1.5 h.  The reaction mixture was cooled to room temperature and water  (10 mL) was added. The mixture was extracted with E t 0 (3 x 10 mL) and the combined 2  organic extracts were washed with brine (20 mL), dried (MgS0 ), and the solvent was 4  removed under reduced pressure. Flash column chromatography (25 g of silica gel, 7:3 petroleum ether-Et 0) of the crude product and removal of trace amounts of solvent 2  (vacuum pump) from the acquired material yielded 437 mg (84 %) of the distannane 258 as a colorless solid (mp 111-112 °C).  LR (KBr): 1727, 1102, 770 cm" . 1  225  *H nmr (400 M H z , CDC1 ) 8: 0.25 (s, 18H, -SnMe.. 3  V .  Sn H  = 54.2 Hz), 0.99 (t, 6H,  - C 0 C H C H 3 , / = 7.1 Hz), 3.11 (s, 4H, - C H r ) , 3.76 (s, 6H, -OMe), 3.77 (s, 6H, -OMe), 2  2  3.83 (s, 6H, -OMe), 3.92 (q, 4H, -CCfeCHzCHa, / = 7.1 Hz), 6.60 (s, 2H, aromatic pro tons, /sn-H  1 3  17.5 Hz).  =  C nmr (75.5 M H z , CDC1 ) 8: -5.3 (-ve), 13.7 (-ve), 41.8, 55.8 (-ve), 60.4 (-ve), 3  60.8 (-ve), 60.9, 61.3, 109.2 (-ve), 128.7, 139.25, 139.36, 153.7, 157.0, 171.2.  H R M S calcd for C3 H4 Oio Sn (M -Me): 833.1370; found: 833.1393. 120  2  9  +  2  Anal, calcd for C 3 H O i S n : C 46.84, H 6.19; found: C 47.15, H 6.26. 3  Preparation  of  52  0  diethyl  2  2-(3,4,5-trimethoxv-2-trimethylstam  stannylbenzyDmalonate (259)  212  204  259  To a stirred suspension of potassium hydride (42 mg, 1.05 mmol, washed with pentane) in dry T H F (8 mL) at room temperature was added a solution of the stannane 212 (344 mg, 0.832 mmol) in dry T H F (1 mL). After 1 h, a solution of the bromide 204 (364 mg, 0.861 mmol) in dry THF (1 mL) was added via a cannula. The reaction mixture was warmed to reflux for 1.5 h and then was cooled to room temperature. Water (10 mL) was added and the mixture was extracted with E t 0 (3 x 10 mL). The combined organic 2  extracts were washed with brine (20 mL), dried (MgS04), and the solvent was removed under reduced pressure. Flash column chromatography (30 g of silica gel, 9:1 petroleum ether-Et 0) of the crude product and removal of trace amounts of solvent (vacuum pump) 2  226 from the acquired material yielded 489 mg (78 %) of the distannane 259 as a white solid (mp 66-71 °C).  IR (KBr): 1727, 1102, 771 c m . 1  :  H nmr (400 M H z , CDC1 ) 8: 0.20 (s, 9H, -SnMej, / .  = 53.0 Hz), 0.25 (s, 9H,  2  3  S n  H  -SnMej, / „ - H = 54.0 Hz), 1.01 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 3.34 (s, 2H, - C H r ) , 2  S  3.42 (s, 2H, - C H r ) , 3.74 (s, 3H, -OMe), 3.78 (s, 3H, -OMe), 3.84 (s, 3H, -OMe), 3.99 (q, 4H, -CO2CH2CH3, / = 7.1 Hz), 6.54 (s, 1H, / „ - H = 17.6 Hz), 7.11-7.24 (m, 3H), 7.344  S  7.34 (m, 1H).  1 3  C nmr (50.3 M H z , CDC1 ) 8: -7.5 (-ve), -5.4 (-ve), 13.6 (-ve), 41.5, 42.2, 49.2, 3  55.6 (-ve), 60.3 (-ve), 60.7 (-ve), 61.0, 108.9 (-ve), 125.9 (-ve), 127.9 (-ve), 128.0 (-ve), 128.9,136.7 (-ve), 138.9, 139.4,143.4, 144.6,153.7,157.0, 171.1.  H R M S calcd for C z g H ^ O ? ^ (M -Me): 743.1053; found: 743.1061. 1 2  +  Anal, calcd for C oH4 0 Sn2: C 47.66, H 6.13; found: C 47.87, H 6.20. 3  6  7  Preparation of diethyl 2-r(2-trimethylstannylcyclopent-l-en-l-yl)methyllmalonate (261) SnMe  260  3  261  To a stirred suspension of potassium hydride (0.546 g, 13.6 mmol) in dry THF (50 mL) at room temperature was added diethyl malonate (3.00 mL, 17.8 mmol) neat via a syringe. After 1 h, a solution of the bromide 260 ' (1.44 g, 4.39 mmol) in dry T H F (5 mL) was 27 76  added to the mixture via a cannula. The reaction mixture was warmed to reflux for 1 h and then was cooled to room temperature. Water (50 mL) was added and the mixture was extracted with Et20 (3 x 50 mL).  The combined organic extracts were washed with  227 brine (100 mL), dried (MgS0 ), and the solvent was removed under reduced pressure. 4  Flash column chromatography (100 g of silica gel, 93:7 petroleum ether-Et 0) of the 2  crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 1.47 g (82 %) of the diester 2 6 1 as a colorless clear oil.  TR (neat): 1736,1615,1239, 1039,771 c m . 1  :  H nmr (400 M H z , CDC1 ) 8: 3  2  3  S n  H  = 53.8 Hz), 1.19 (t, 6H,  7=7.1 Hz), 1.70-1.80 (m, 2H, -CH -CH2-CH -), 2.20-2.30 (br t, 2H,  -C0 CH CH3, 2  0.11 (s, 9H, -SnMe . / . 2  2  2  -CH2-CH -CH - 7= 7.4 Hz), 2.30-2.35 (m, 2H, -CH -CH -CH2-), 2.72 (d, 2H, - C H i - C H - , 2  2  2  2  / = 7.8 Hz), 3.43 (t, I H , - C H - C H - , 7= 7.8 Hz), 4.10-4.19 (m, 4H, -C0 CH2CH ). 2  1 3  2  3  C nmr (125.8 M H z , CDC1 ) 8: -9.5 (-ve), 14.0 (-ve), 24.3, 32.3, 35.6, 39.3, 51.2 (-ve), 3  61.1, 139.8, 148.6, 169.0.  H R M S calcd for C i 5 H O 25  120 4  S n : 389.0775; found: 389.0770.  Anal, calcd for C H 0 S n : C 47.68, H 7.00; found: C 47.60, H 7.03. 1 6  Preparation  of  2 8  4  diethyl 2-r(2-tiTmethvlstarmvlcyclopenten-l-yl)m  stannylbenzvDmalonate ( 1 1 3 )  To a stirred suspension of potassium hydride (56 mg, 1.4 mmol, washed with pentane) in dry THF (13 mL) at room temperature was added a solution of the stannane 2 6 0 (534 mg, 1.32 mmol) in dry T H F (1 mL) via a cannula. After 1 h, a solution of the bromide 2 0 2 (703 mg, 2.10 mmol) in dry T H F (1 mL) was added via a cannula. The reaction mixture  228 was warmed to reflux for 1.5 h and then was cooled to room temperature. Water (20 mL) was added and the mixture was extracted with E t 0 (3 x 15 mL). 2  The organic extracts  were combined, washed with brine (40 mL), dried (MgSCU), and the solvent was removed under reduced pressure. Flash column chromatography (50 g of silica gel, 24:1 petroleum ether-Et 0) of the crude product afforded, after removal of trace amounts of 2  solvent (vacuum pump) from the acquired material, 822 mg (94 %) of the distannane 112 as a white solid (mp 67-69 °C).  IR (KBr): 1744, 1722, 1248, 773 cm . -1  *H nmr (400 MHz,  CDC1 ) 8: 0.08 (s, 9H, -SnMes, / . = 53.6 Hz), 0.30 (s, 9H, 2  3  S n  H  -SnMes, / . = 53.2 Hz), 1.09 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 1.74-1.81 (m, 2H, 2  S n  H  -CH2-CH2-CH2-),  CH2-,  2.24 (br t, 2H, - C H r C H - C H - , / = 7.3 Hz), 2.31 (br t, 2H, - C H - C H 2  2  2  2  / = 7.0 Hz), 2.98 (s, 2H, - C H r ) , 3.32 (s, 2H, - C H r ) , 4.00-4.07 (m, 4H,  -C0 CH2CH ), 7.11-7.18 (m, 3H), 7.29-7.45 (m, 1H). 2  13  3  C nmr (50.3 MHz, CDC1 ) 8: -9.2 (-ve), -7.3 (-ve), 13.9 (-ve), 24.7, 36.3, 39.0, 39.2, 3  42.8, 58.5, 61.1, 126.0 (-ve), 128.0 (-ve), 128.1 (-ve), 136.4 (-ve), 141.8, 143.4, 143.7, 148.3, 171.4.  H R M S calcd for C H O 25  Anal, calcd for  39  120 4  S n 2 (M -Me): 643.0892; found: 643.0895.  C26H42O4S112:  +  C 47.60, H 6.45; found: C 47.89, H 6.36.  229 1.2 Intramolecular couplings mediated by copper(f) chloride  General Procedure  7: Copper(I) chloride mediated  intramolecular coupling of  aryltrimethylstannanes  To a stirred, solution-suspension of copper(I) chloride (~5 equiv) in dry D M F (-15 mL/mmol of substrate) at room temperature was added, via a syringe pump over 30 min, a solution of the appropriate distannane (1 equiv) in dry D M F (-15 mL/mmol of substrate).  The mixture was stirred for an additional 30 min.  Aqueous ammonium  chloride-ammonia (pH 8) was added (-2 mL/mL of DMF) and the mixture was stirred open to the atmosphere until it was a deep blue. The mixture was extracted with E t 0 2  (3 x -2 mL/mL of DMF) and the combined organic extracts were washed with brine (3 x -2 mL/mL of DMF), dried (MgS0 ), and the solvent was removed under reduced 4  pressure. The resulting crude material was purified by flash column chromatography.  Preparation of dibenzofuran (105)  104  105  To a stirred solution of the distannane 104 (113 mg, 0.228 mmol) in dry D M F (4.5 mL) at room temperature was added, in one portion, solid CuCl (120 mg, 1.22 mmol). The resulting mixture was stirred for a period of 30 min. Aqueous ammonium chlorideammonia (pH 8) (5 mL) was added and stirring was continued, open to the atmosphere, until the mixture was a deep blue. 10 mL).  The mixture was then extracted with E t 0 (3 x 2  The combined organic extracts were washed with brine (3 x 10 mL), dried  (MgS0 ), and the solvent was removed under reduced pressure. 4  Flash column  chromatography (10 g of silica gel, 99:1 petroleum ether-Et 0) of the crude product and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 37 mg (98 %) of dibenzofuran (105) as a white solid (mp 81-83 °C). This material  230 exhibited spectral characteristics (*H nmr) identical with those of an authentic sample and a melting point simliar to that previously reported (mp 83-85 °C).  77  Preparation of dibenzorc.eloxepine (109)  108  109  Following general procedure 7, the ether 108 was prepared by the addition of the distannane 108 (92 mg, 0.18 mmol) in dry D M F (2.5 mL) to a stirred solution-suspension of CuCI (97 mg, 0.98 mmol) in dry D M F (1.5 mL). Purification of the crude material by flash column chromatography (7 g of silica gel, 9:1 petroleum ether-Et 0) and removal of 2  trace amounts of solvent (vacuum pump) from the acquired material provided 32 mg (91 %) of the cyclic ether 109 as a colorless oil. 63  ER (KBr): 1077,752 c m . 1  *H nmr (400 M H z , CDC1 ) 5: 4.35 (s, 4H), 7.55 (d, 2H, / = 7.4 Hz), 7.49 (td, 2H, / = 1.8, 3  7.5 Hz), 7.40-7.43 (m, 4H).  1 3  C nmr (75.5 M H z , CDC1 ) 5: 67.5, 127.4, 128.2, 128.9, 129.7, 135.1, 141.2. 3  H R M S calcd for C H 0 : 196.0888; found: 196.0882. 1 4  1 2  231 Preparation  of  2,2'-(2,2-bis(efhoxvcarbonvr)propane-13-divl)-5,5'-dimethvlbiphenyl  £2641  257  264  Following general procedure 7, the diester 264 was prepared by the addition of the distannane 257 (86 mg, 0.12 mmol) in dry D M F (1.9 mL) to a stirred solution-suspension of CuCI (62 mg, 0.63 mmol) in dry D M F (1.9 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 17:3 petroleum ether-Et 0) and removal 2  of trace amounts of solvent (vacuum pump) from the acquired material provided 43 mg (95 %) of the diester 264 as a colorless solid (mp 88-89 °C).  IR (KBr): 1729, 1266, 1197 c m . 1  X  H nmr (400 M H z , CDC1 ) 8: 1.26 (t, 6H, / = 7.1 Hz), 2.37 (s, 6H, -Me), 2.82 (br s, 2H), 3  3.14 (br s, 2H), 4.20 (br s, 4H), 7.06 (m, 2H), 7.16 (d, 2H, / = 7.6 Hz), 7.19 (s, 2H).  1 3  C nmr (75.5 M H z , CDC1 ) 8: 14.1 (-ve), 21.2 (-ve), 36.4, 61.4, 64.6, 128.0 (-ve), 3  128.8 (-ve), 129.9 (-ve), 132.4, 137.0, 140.5, 170.9.  H R M S calcd for C 3 H 2 0 : 366.1831; found: 366.1831. 2  6  4  Anal, calcd for C H 6 0 : C 75.38, H 7.15; found: C 75.41, H 7.24. 23  2  4  232 Preparation of 2',6-(2,2-bis(ethoxycarbonyl)propane-13-diyl)-23,4-trunethoxybiphenyl {2651  Following general procedure 7, the diester 265 was prepared by the addition of the distannane 259 (97 mg, 0.13 mmol) in dry D M F (2 mL) to a stirred solution-suspension of CuCl (63 mg, 0.64 mmol) in dry D M F (2 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 7:3 petroleum ether-Et 0) and removal of 2  trace amounts of solvent (vacuum pump) from the acquired material provided 50 mg (92 %) of the diester 265 as a colorless solid (mp 94-96 °C).  IR (KBr): 1729, 1599 cm" . 1  1  H nmr (400 M H z , CDC1 ) 8: 1.26 (t, 3H, -CO2CH0CH3, / = 7.1 Hz), 1.28 (t, 3H, / = 3  7.1 Hz), 2.72 (d, I H , / = 13.7 Hz), 2.85 (d, I H , / = 13.7 Hz), 3.09 (d, I H , J= 13.7 Hz), 3.18 (d, I H , J= 13.7 Hz), 3.57 (s, 3H, -OMe), 3.86 (s, 3H, -OMe), 3.89 (s, 3H, -OMe), 4.15-4.27 (m, 4H, -COzCILJIHa), 6.61 (s, IH), 7.19-7.31 (m, 3H), 7.49 (dd, I H , / = 1.0, 7.5 Hz).  1 3  C nmr (75.5 MHz, CDC1 ) 8: 14.1 (-ve), 14.2 (-ve), 36.7, 37.0, 55.9 (-ve), 60.8 (-ve), 3  61.0 (-ve), 61.5, 61.6, 64.4, 108.2 (-ve), 125.8, 126.7 (-ve), 127.0 (-ve), 129.8, 130.1 (-ve), 131.5 (-ve), 135.5, 135.9, 141.6, 150.8, 152.3, 170.3, 170.7.  H R M S calcd for C 4 H 0 : 428.1835; found: 428.1831. 2  2 8  7  Anal, calcd for C H 0 : C 67.28, H 6.59; found: C 67.03, H 6.86. 2 4  2 8  7  233 Preparation of 6,6'-(2,2-bis(ethoxycarbonyi)propane-1,3-diyl)-2,2',3,3',4,4'-hexamethoxy biphenyl (266)  Following general procedure 7, the diester 266 was prepared by the addition of the distannane 258 (43 mg, 0.18 mmol) in dry D M F (0.8 mL) to a stirred solution-suspension of CuCl (25 mg, 0.25 mmol) in dry D M F (0.8 mL). Purification of the crude product by flash column chromatography (12 g of silica gel, 13:7 petroleum ether-Et 0) and removal 2  of trace amounts of solvent (vacuum pump) from the acquired material provided 16.4 mg (62 %) of the diester 266 as a colorless solid (mp 141-142 °C).  IR (KBr): 1726, 1599, 1111 cm" . 1  *H nmr (400 M H z , CDC1 ) 5: 1.26 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 2.73 (d, 2H, / = 3  14.0 Hz), 3.08 (d, 2H, / = 14.0 Hz), 3.64 (s, 6H, -OMe), 3.84 (s, 6H, -OMe), 3.87 (s, 6H, -OMe), 4.11-4.26 (m, 4H, -CO2CH2CH3), 6.56 (s, 2H).  13  C nmr (75.5 M H z , CDC1 ) 5: 14.2 (-ve), 36.9, 55.9 (-ve), 60.7 (-ve), 60.9 (-ve), 61.5, 3  63.9, 108.4 (-ve), 122.2, 131.3, 141.2, 151.4, 152.4, 170.5.  H R M S calcd for C H O : 27  Anal, calcd for  34  w  C^HMOIO:  518.2152; found: 518.2150.  C 62.54, H 6.61; found: C 62.20, H 6.59.  234 Preparation of 2,3-benzo-5,5-bis('ethoxycarbonvl')bicvclor5.3.01dec-U7Veiie (113)  112  113  Following general procedure 7, the diester 113 was prepared by the addition of the distannane 112 (86 mg, 0.13 mmol) in dry D M F (2 mL) to a stirred solution-suspension of CuCI (68 mg, 0.69 mmol) in dry D M F (2 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 9:1 petroleum ether-Et 0) and removal of 2  trace amounts of solvent (vacuum pump) from the acquired material provided 40 mg (94 %) of the diester 112 as a colorless solid (mp 72-73 °C).  IR(KBr): 1736, 1641, 1251,762 c m . 4  *H nmr (400 M H z , CDC1 ) 5: 1.14 (t, 6H, - C 0 C H C H 3 , / = 7.1 Hz), 1.89-1.98 (m, 2H), 3  2  2  2.60 (br t, 2H, / = 7.6 Hz), 2.70 (s, 2H), 2.77-2.82 (m, 2H), 3.24 (s, 2H), 4.00-4.11 (m, 4H, -C0 CH2CH ), 7.01-7.11 (m, 1H), 7.18-7.20 (m, 3H). 2  1 3  3  C nmr (75.5 M H z , CDC1 ) 8: 14.0 (-ve), 22.1, 35.8, 36.8, 39.5, 40.0, 60.7, 61.3, 3  125.9 (-ve), 126.3 (-ve), 126.8 (-ve), 131.2 (-ve), 134.7, 135.3, 137.1, 137.9, 171.2.  H M R S calcd for C o H 0 : 328.1675; found: 328.1664. 2  24  4  Anal, calcd for C H O : C 73.15, H 7.37; found: C 73.07, H 7.46. 2 0  2 4  4  235  8. Intramolecular oxidative coupling of bisalkenyltrimethylstannanes to form bicyclor7.3.01dodecane and bicvclo 8.3.01tridecane derivatives r  8.1 Preparation of precursors  Preparation of 6-iodo-2-trimethylstannylhex-l-ene  (269)  268  269  To a cool (0 °C), stirred suspension of iodine (3.02 g, 11.8 mmol) in dry CH2CI2 (100 mL) was added triphenylphosphine (3.05 g, 11.6 mmol) in one solid portion. The mixture was stirred for 20 min and a yellow precipitate appeared.  Imidazole (1.37 g,  20.1 mmol) was added in one solid portion and the mixture was stirred for an additional 20 min. A solution of the alcohol 268 (2.62 g, 10.0 mmol) in dry C H C 1 (5 mL) was 47  2  2  added via a cannula and the reaction mixture was stirred for 1 h. Pentane (125 mL) was added and the mixture was filtered through a cake of silica gel (-30 g) and the silica gel was eluted with 9:1 petroleum ether-Et 0 (500 mL). 2  The combined filtrate was  concentrated under reduced pressure. The crude product was purified by flash column chromatography (100 g of silica gel, 99:1 petroleum ether-Et 0) which, after removal of 2  trace amounts of solvent (vacuum pump) from the acquired material, yielded 3.46 g (93 %) of the iodide 269 as a colorless clear oil.  This material exhibited spectral  characteristics (*H nmr) identical to those previously reported.  78  236 Preparation of methyl  (£l-7-fe^butyldmiethylsiloxy-3-tj±nethylstam  (2711  271  270  To a cold (-48 °C), stirred solution of hexamethylditin (10.6 g, 32.4 mmol) in dry T H F (200 mL) was added M e L i (21.0 mL, 1.55 M in E t 0 , 32.5 mmol) via a syringe and the 2  solution was stirred for 30 min. Copper(I) cyanide (2.99 g, 33.3 mmol) was added to the solution in one solid portion and stirring was continued for 30 min. The mixture was cooled to -78 °C and dry methanol (1.31 mL, 32.4 mmol) was added via a syringe. The reaction rnixture was stirred for 5 rnin. A solution of the ester 270 (6.06 g, 25.0 mmol) 66  in dry T H F (5 mL) was added via a cannula to the mixture and stirring was continued for 4 h. The rnixture was warmed to room temperature, opened to the air, and aqueous ammonium chloride-ammonia (pH 8) (150 mL) was added. The suspension was stirred until the aqueous phase became a deep blue color. The organic phase was separated and the aqueous phase was extracted with E t 0 (3 x 150 mL). The organic layers were 2  combined, washed with brine (350 mL), and dried (MgSQ*). The solvent was removed under reduced pressure.  Flash column chromatography (250 g of silica gel, 24:1  petroleum ether-Et 0 with gradual change to 93:7 petroleum ether-Et 0) of the crude 2  2  product and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 8.57 g (78 %) of the stannane 271 as a colorless clear oil.  IR (neat): 1718,1596,1163, 835,775 c m . 1  U nmr (400 M H z , CDC1 ) 8: 0.02 (s, 6H, -SiMe-?-;, 0.18 (s, 9H, -SnMe . V -H =  l  3  3  Sn  53.4 Hz), 0.87 (s, 9H, -Si'Bu-), 1.40-1.58 (m, 4H, -CH^-CHr), 2.89 (td, 2H, allylic -CHz-, / = 7.7, 1.2 Hz, / . = 61.9 Hz), 3.60 (t, 2H, -O-CHz-, / = 6.6 Hz), 3.67 (s, 3H, 3  S n  H  -C0 Me), 5.95 (t, IH, olefinic proton, / = 1.2 Hz, / . = 73.6 Hz). 3  2  S n  H  237 1 3  C nmr (50.3 M H z , CDC1 ) 5: -9.1, -6.3, 18.3, 25.95, 26.02, 32.8, 34.4, 50.8, 62.9, 3  127.0, 164.6, 173.7.  H R M S calcd for C i H 3 3 O S i S n (M -Me): 421.1221; found: 421.1230. 120  6  +  3  Anal, calcd for Cn^eOsSiSn: C 46.91, H 8.34; found: C 47.17, H 8.38.  Preparation of methyl (^-7-hydroxy-3-tiimethylstarmylhept-2-enoate (272)  Me0 C  Me0 C  2  2  271 272 To a cool (0 °C), stirred solution of the stannane 271 (5.93 g, 13.7 mmol) in dry T H F (130 mL) was added a solution of tetrabutylammonium fluoride (20.4 mL, 1 M in THF, 20.4 mmol) and the solution was stirred for 2 h. Saturated aqueous sodium bicarbonate (100 mL) was added and the mixture was extracted with E t 0 (3 x 100 mL). The 2  combined organic extracts were washed with brine (200 mL), dried (MgS0 ), and the 4  solvent was removed in vacuo to give a crude oil. Flash column chromatography (150 g of silica gel, 1:1 petroleum ether-Et 0) of the crude product and removal of trace 2  amounts of solvent (vacuum pump) from the acquired material yielded 4.16 g (95 %) of the stannane 272 as a colorless clear oil. IR (neat): 1719, 1594, 1161, 770 c m . 1  *H nmr (400 M H z , CDC1 ) 5: 0.18 (s, 9H, -SnMe , / - = 53.4 Hz), 1.45-1.76 (m, 5H, 2  3  3  S n  H  -OH and - C H ^ C H r ) , 2.87 (t, 2H, allylic - C H r / = 7.8 Hz, / . = 61.4 Hz), 3.64-3.68 3  S n  H  (m, 5H, includes 3H -CQ9Me singlet at 3.66 and HO-CH?-), 5.96 (s, 1H, olefinic proton, 3  / . = 72.5Hz). S n  H  C nmr (50.3 M H z , CDC1 ) 8: -9.3, 25.4, 32.4,33.9, 50.8, 61.9, 127.0, 164.6, 173.9. 3  238 H R M S calcd for C i o H 0 1 9  ° S n (M -Me): 307.0356; found: 307.0363.  1 2  +  3  Anal, calcd for C n H 0 S n : C 41.16, H 6.91; found: C 41.43, H 6.98. 22  3  SnMe  Me0 C  3  Me0 C  2  2  272  273  To a cool (0 °C), stirred suspension of iodine (3.15 g, 12.4 mmol) in dry CH2CI2 (100 mL) was added triphenylphosphine (3.30 g, 12.6 mmol) in one solid portion. The mixture was stirred for 20 min and a yellow precipitate appeared.  Imidazole (1.37 g,  20.1 mmol) was added in one solid portion and the mixture was stirred for an additional 20 min. A solution of the alcohol 272 (3.03 g, 9.44 mmol) in dry C H C 1 (5 mL) was 2  2  added via a cannula and the reaction mixture was stirred for 1 h. Pentane (150 mL) was added and the mixture was filtered through a cake of silica gel (-30 g) and the silica gel was eluted with E t 0 (250 mL). 2  The combined filtrate was concentrated under reduced  pressure. The crude product was purified by flash column chromatography (100 g of silica gel, 19:1 petroleum ether-Et 0) which, after removal of trace amounts of solvent 2  (vacuum pump) from the acquired material, yielded 3.56 g (88 %) of the iodide 273 as a colorless clear oil. IR (neat): 1717, 1595, 1173, 773 c m . 1  J  H nmr (400 MHz, CDC1 ) 8: 0.20 (s, 9H, -SnMe.. / _ = 54.6 Hz), 1.47-1.55 (m, 2H, 3  3  Sn  H  -CH2-CH2-), 1.80-1.88 (m, 2H, -CH2-CH2-), 2.89 (td, 2H, allylic proton, / = 7.3, 1.2 Hz, 3  / - = 70.7 Hz), 3.19 (t, 2H, I-CH2-, / = 6.6 Hz), 3.67 (s, 3H, -CCyMe), 5.97 (t, 1H, S n  H  olefinic proton, / = 1.2 Hz,  3  /  S n  -H  = 72.5 Hz).  C nmr (75.5 MHz, CDC1 ) 8: -9.0, 6.8, 30.4, 33.1, 33.4, 50.9, 127.5, 164.5, 172.7. 3  239  H R M S calcd for C i o H 0 18  120 2  S n I (M -Me): 416.9374; found: 416.9371. +  Anal, calcd for C11H21O2S11I: C 30.66, H 4.91; found: C 30.82, H 4.96.  Preparation of methyl (7n-7-(tetrahydro-2#-pwan-2-vloxvV3-tr]m enoate (275)  274  275  To a cold (-48 °C), stirred solution of hexamethylditin (10.6 g, 32.4 mmol) in dry T H F (200 mL) was added M e L i (20.2 mL, 1.55 M in E t 0 , 32.3 mmol) via a syringe and the 2  solution was stirred for 30 min. Copper(I) cyanide (2.95 g, 33.0 mmol) was added to the solution in one solid portion and stirring was continued for 30 min. The mixture was cooled to -78 °C and dry methanol (1.30 mL, 32.2 mmol) was added via a syringe. The reaction rnixture was stirred for 5 min. A solution of the ester 274 (6.00 g, 25.0 mmol) 41  in dry T H F (5 mL) was added via a cannula and stirring was continued for 4 h. The mixture was warmed to room temperature, opened to the air, and aqueous ammonium chloride-ammonia (pH 8) (150 mL) was added.  The suspension was stirred until the  aqueous phase became a deep blue color. The organic phase was separated and the aqueous phase was extracted with E t 0 (3 x 150 mL). 2  The organic layers were  combined, washed with brine (350 mL), and dried (MgSC^). The solvent was removed under reduced pressure.  Flash column chromatography (250 g of silica gel, 17:3  petroleum ether-Et 0) of the crude product and removal of trace amounts of solvent 2  (vacuum pump) from the acquired material provided 7.11 g (70 %) of the stannane 275 as a colorless clear oil.  ER (neat): 1719, 1595, 1166, 770 cm" . 1  240 X  H nmr (400 M H z , CDC1 ) 8: 0.18 (s, 9H, -SnMe.. / . = 53.4 Hz), 1.40-1.85 (m, 10H), 2  3  S n  H  2.91 (br t, 2H, allylic -CH2-, / = 7.7 Hz, / . = 61.2 Hz), 3.34-3.40 (m, IH), 3.44-3.50 3  S n  H  (m, IH), 3.66 (s, 3H, -COjMe), 3.69-3.75 (m, IH), 3.80-3.83 (m, IH), 4.56 (t, IH, / = 3.7 Hz), 5.96 (t, IH, olefinic proton, / = 1.3 Hz, / „ . = 73.4 Hz). 3  s  1 3  H  C nmr (50.3 M H z , CDC1 ) 8: -9.1 (-ve), 19.5, 25.5, 26.3, 29.6, 30.7, 34.7, 50.8 (-ve), 3  62.1, 67.1, 98.7 (-ve), 127.1 (-ve), 164.6, 173.4.  H R M S calcd for C H27O 15  120 4  Sn (M -Me): 391.0931; found: 391.0932. +  Anal, calcd for Ci6H o0 Sn: C 47.44, H 7.46; found: C 47.69, H 7.55. 3  4  Preparation of (£V7-(tetrahydro-2i /-pvran-2-vloxy)-l-methoxy-3-trunethylstannylheptl  2-ene (277)  275  276  277 To a cold (-78 °C), stirred solution of the ester 275 (6.19 g, 15.3 mmol) in dry T H F (150 mL) was added a solution of D I B A L (38.5 mL, 1.0 M in hexanes, 38.5 mmol, 2.5 equiv) and the mixture was stirred for 1 h.  The solution was warmed to room  temperature and stirring was continued for 1 h. Saturated aqueous potassium sodium tartrate (Rochelle salt) (125 mL) was added and, after the mixture had been stirred for 1 h, it was extracted with E t 0 (3 x 100 mL). The combined organic extracts were 2  washed with brine (100 mL), dried (MgS0 ), and the solvent was removed under reduced 4  pressure.  Flash column chromatography (200 g of silica gel, 1:1 petroleum ether-Et 0) 2  241 of the crude material yielded 5.25 g (92 %) of the alcohol 276 as a clear oil. This oil was used directly in the next step.  To a cool (0 °C), stirred suspension of sodium hydride (466 mg, 19.4 mmol) in dry T H F (140 mL) was added a solution of the alcohol 276 (obtained as described above) in dry T H F (5 mL). The mixture was stirred for 1 h. Methyl iodide (2.6 mL, 42 mmol) was added to the suspension neat via a syringe and stirring was continued for 1 hr at 0 °C and for 24 h at room temperature. Water (100 mL) was added and the mixture was extracted with E t 0 (3 x 100 mL). The combined organic extracts were washed with brine (200 2  mL), dried (MgSQ*), and the solvent was removed in vacuo.  Hash column  chromatography (200 g of silica gel, 17:3 petroleum ether-Et 0) of the crude product and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 5.21 g (96 %, 88 % over 2 steps) of the stannane 277 as a clear oil.  IR (neat): 1454, 1121, 1035, 768 c m . 1  J  H nmr (400 M H z , CDC1 ) 8: 0.11 (s, 9H, -SnMe,. / „ . = 52.5 Hz), 1.38-1.84 (m, 10H), 2  3  s  H  2.31 (t, 2H, / = 7.6 Hz, / . = 62.4 Hz), 3.32 (s, 3H, -OMe), 3.34-3.39 (m, 1H), 3.453  S n  H  3.49 (m, 1H), 3.68-3.74 (m, 1H), 3.81-3.87 (m, 1H), 4.00 (d, 2H, M e - O - C H r , / = 5.9 Hz), 4.54-4.57 (m, 1H), 5.68 (t, 1H, olefinic proton, / = 5.9 Hz, / . = 78.2 Hz). 3  S n  1 3  H  C nmr (50.3 M H z , CDC1 ) 8: -9.3 (-ve), 19.5, 25.5, 26.8, 29.4, 30.7, 32.9, 58.1 (-ve), 3  62.1, 67.1, 68.7, 98.7 (-ve), 136.2 (-ve), 148.7.  H R M S calcd for Ci H29O 5  120 3  Sn (M -Me): 377.1139; found: 377.1132. +  Anal, calcd for C H 0 S n : C 49.14, H 8.25; found: C 49.44, H 8.46. 1 6  3 2  3  242  Me  277  278  3  279  To a stirred solution of the stannane 277 (4.84 g, 12.5 mmol) in dry methanol (125 mL) at room temperature was added PPTS (471 mg, 1.87 mmol) in one solid portion.  The  mixture was warmed to reflux for 2 h. The solution was cooled to room temperature and the solvent was removed under reduced pressure. Purification of the crude product by flash column chromatography (100 g of silica gel, 1:1 petroleum ether-Et 0 with gradual 2  change to Et 0) yielded 1.68 g (35 %) of the starting material 277 and 2.25 g (59 %, 2  90 % based on recovered starting material) of the alcohol 278 as a clear oil.  To a cool (0 °C), stirred suspension of iodine (2.51 g, 9.89 mmol) in dry C H C 1 (75 mL) 2  2  was added triphenylphosphine (2.67 g, 10.2 mmol) in one solid portion. The mixture was stirred for 20 min and a yellow precipitate appeared.  Imidazole (731 mg, 10.7 mmol)  was added in one solid portion and the mixture was stirred for an additional 20 min. A solution of the alcohol 278 (obtained as described above) in dry C H C 1 (5 mL) was 2  2  added via a cannula and the reaction mixture was stirred for 1 h. Pentane (150 mL) was added and the mixture was filtered through a cake of silica gel (-30 g) and the silica gel was eluted with E t 0 (250 mL). The combined filtrate was concentrated under reduced 2  pressure. The crude product was purified by flash column chromatography (60 g of silica gel, 24:1 petroleum ether-Et 0) which, after removal of trace amounts of solvent 2  (vacuum pump) from the acquired material, yielded 2.92 g (56 % over two steps) of the iodide 279 as a colorless clear oil.  IR (neat): 1456, 1211, 1115, 763 cm' . 1  J  H nmr (400 M H z , CDC1 ) 8: 0.12 (s, 9H, -SnMe , / „ . = 52.5 Hz), 1.39-1.46 (m, 2H, 2  3  3  s  H  -CH2-CH -), 1.75-1.82 (m, 2H, - C H r O L . - ) , 2.30 (br t, 2H, allylic - C H r , / = 7.2 Hz, 2  3  / „-H S  = 61.1 Hz), 3.17 (t, 2H, I - C H r , / = 6.9 Hz), 3.33 (s, 3H, -OMe), 3.99 (d, 2H,  -O-CH2-, / = 6.0 Hz), 5.71 (tt, 1H, olefinic proton, / = 1.2, 6.0 Hz, / . = 77.2 Hz). 3  S n  H  243  1 3  C nmr (75.5 M H z , CDC1 ) 8: -9.3 (-ve), 6.7, 30.7, 31.9, 32.9, 58.1 (-ve), 68.5, 3  136.4 (-ve), 148.1.  H R M S calcd for C H o 0 S n I (M -Me): 402.9581; found: 402.9587. 120  10  +  2  Anal, calcd for C n H ^ O S n l : C 31.69, H 5.56; found: C 31.86, H 5.65.  Preparation of 7-fe^butyldimethylsiloxyhept-l-yne (281)  O  280b  281  To a stirred solution of the alcohol 280 (11.8 g, 47.8 mmol) in dry C H C 1 (475 mL) at 68  2  2  room temperature was added sodium acetate (2.88 g, 35.1 mmol) and P C C (20.8 g, 96.5 mmol), each as solids. The reaction mixture was stirred for 2 h. The mixture was diluted with E t 0 (500 mL) and then was filtered through Florisil (-50 g). The cake of 2  Florisil was eluted with E t 0 (1 L) and the combined filtrate was concentrated under 2  reduced pressure.  Flash column chromatography (200 g of silica gel, 7:3 petroleum  ether-Et 0) of the crude material yielded 8.62 g (78 %) of the aldehyde 280a as an oil. 2  This material was used immediately in the next reaction.  To a cool (0 °C), stirred solution of carbon tetrabromide (18.7 g, 56.4 mmol) in dry CH C1 (500 mL) was added triphenylphosphine (29.5 g, 112 mmol) in one portion. The 2  2  mixture was stirred for 10 min. A solution of the aldehyde 280a (8.62 g, 37.4 mmol) in dry C H C 1 (20 mL) was added via a cannula. The mixture was stirred for 40 min. 2  2  Pentane (500 mL) was added and the mixture was filtered through silica gel (-20 g) and  244 the cake was eluted with pentane (200 mL). The combined filtrate was concentrated under reduced pressure.  Flash column chromatography (300 g of silica gel, 200:1  petroleum efher-Et 0) of the crude product and removal of trace amounts of solvent 2  (vacuum pump) from the acquired material yielded 9.63 g (67 %) of the dibromoalkene 280b as a colorless clear oil. This oil was used directly in the next reaction.  To a stirred suspension of magnesium metal (3.00 g, 123 mmol) in dry T H F (100 mL) at room temperature was added a solution of the alkene 280b (9.63 g, 24.9 mmol) in dry T H F (5 mL) via a cannula.  The resulting mixture was sonicated for 18 h.  Pentane  (100 mL) was added and the mixture was filtered through a pad of silica gel (-50 g). The cake of silica gel was eluted with E t 0 (400 mL) and the combined filtrate was 2  concentrated under reduced pressure.  Bulb-to-bulb distillation (140-160 °C/15 torr) of  the crude product yielded 4.69 g (83 %, 43 % over 3 steps) of the alkyne 281 as a colorless clear oil.  IR (neat): 3314, 1256, 1161, 838, 776 c m . 1  U nmr (400 M H z , CDC1 ) 5: 0.02 (s, 6H, -SiMe?-;, 0.87 (s, 9H, -Si'Bu-), 1.37-1.57 (m,  l  3  6H), 1.90 (t, I H , acetylenic proton, / = 2.6 Hz), 2.17 (td, 2H, propargylic -CFb-, / = 7.0, 2.6 Hz), 3.59 (t, 2H, -O-CH2-, / = 6.3 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 8: -5.3,18.4, 25.0,25.9 (2C), 28.3, 32.3, 62.9, 68.2, 84.4. 3  H R M S calcd for C H O S i (M -Me): 211.1518; found: 211.1517. +  1 2  2 3  Anal, calcd for C H O S i : C 68.96, H 11.57; found: C 69.01, H 11.51. 13  26  245 Preparation of 7-fe^butyldimethylsifo  (282)  TBSO  281  282  To a cold (-48 °C), stirred solution of hexamethylditin (6.80 g, 20.5 mmol) in dry T H F (80 mL) was added a solution of M e L i (13.1 mL, 1.6 M in E t 0 , 21.0 mmol) via a 2  syringe and the solution was stirred for 30 min. The solution was cooled to -78 °C and copper bromide-dimethyl sulfide complex (4.70 g, 22.8 mmol) was added in one portion. The red-brown suspension was stirred for 30 rnin. A solution of the alkyne 281 (2.26 g, 10.0 mmol) in dry THF (20 mL) was added via a cannula to the mixture followed by dry methanol (24.0 mL, 59.2 mmol) dropwise over 2 min via a syringe. The reaction rnixture was stirred at -78 °C for 3 h , at -48 °C for 3 h, and at 0 °C for 1 h. The rnixture was opened to the air and aqueous ammonium chloride-ammonia (pH 8) (100 mL) was added. The suspension was stirred until the aqueous phase became a deep blue color.  The  organic phase was separated and the aqueous layer was extracted with E t 0 (3 x 2  150 mL). The organic layers were combined, washed with brine (200 mL), and dried (MgS04).  The solvent was removed under reduced pressure.  Flash column  chromatography (100 g of silica gel, 200:1 petroleum ether-Et 0) yielded 2.86 g (73 %) 2  of the stannane 282 as a clear oil.  IR (neat): 1472, 1255, 1105, 835, 774 c m . 4  *H nmr (400 M H z , CDC1 ) 5: 0.02 (s, 6H, -SiMe.-). 0.10 (s, 9H, -SnMe , 3  3  2  / „-H = S  52.8 Hz), 0.82 (s, 9H, -Si'Bu-), 1.25-1.41 (m, 4H), 1.46-1.53 (m, 2H), 2.25 (t, 2H, H-3, / = 7.4 Hz, / . = 52.2 Hz), 3.58 (t, 2H, H-7, / = 6.7 Hz), 5.09-5.11 (m, I H , H - l , / . 3  3  S n  H  S n  H  = 71.8 Hz), 5.61-5.63 (m, I H , H - l ' , / . = 154.6 Hz). 3  S n  1 3  H  C nmr (50.3 M H z , CDC1 ) 5: -9.5 (-ve), -5.3 (-ve), 18.4, 25.4, 26.0 (-ve), 29.6, 32.7, 3  40.8, 63.2, 124.3,135.8.  246 H R M S calcd for C i H O S i 5  33  120  S n (M -Me): 377.1323; found: 377.1326. +  Anal, calcd for C i H O S i S n : C 49.12, H 9.24; found: C 49.35, H 9.22. 6  36  Preparation of 7-iodo-2-trirnethvlstannvlhept-l-ene (284) ,SnMe  TBSO  SnMec  3  282  283  To a cool (0 °C), stirred solution of the stannane 282 (1.09 g, 2.80 mmol) in dry T H F (25 mL) was added a solution of tetrabutylammonium fluoride (4.2 mL, 1 M in THF, 4.2 mmol) and the solution was stirred for 1 h. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with E t 0 (3 x 15 mL). The combined 2  organic extracts were washed with brine (20 mL), dried (MgS0 ), and the solvent was 4  removed in vacuo to provide a crude oil that was used directly for the next reaction.  To a cool (0 °C), stirred suspension of iodine (1.15 g, 4.48 mmol) in dry CH2CI2 (25 mL) was added triphenylphosphine (1.15 g, 4.38 mmol) in one solid portion. The mixture was stirred for 20 min and a yellow precipitate appeared.  Imidazole (0.373 g, 5.47 mmol)  was added in one solid portion and the mixture was stirred for an additional 20 min. A solution of the alcohol 283 (obtained as described above) in dry CH2CI2 (2 mL) was added via a cannula and the reaction mixture was stirred for 1 h. Pentane (50 mL) was added and the mixture was filtered through a cake of silica gel (-15 g) and the silica gel was eluted with E t 0 (150 mL). 2  The combined filtrate was concentrated under reduced  pressure. The crude product was purified by flash column chromatography (60 g of silica gel, petroleum ether) which, after removal of trace amounts of solvent (vacuum pump)  247 from the acquired material, yielded 910 mg (84 % over 2 steps) of the iodide 284 as a colorless clear oil.  IR (neat): 1434, 1209, 916, 769 cm" . 1  H nmr (400 M H z , CDC1 ) 5: 0.11 (s, 9H, -SnMe^,  V .  1.77-1.85 (m, 2H), 2.24-2.24 (m, 2H, H-3, / „ -  = 51.7 Hz), 3.16 (t, 2H, H-7, / =  J  3  3  s  7.0 Hz), 5.12-5.13 (m, I H , H - l , / „ . 3  s  H  Sn H  = 52.8 Hz), 1.35-1.39 (m, 4H),  = 52.2 Hz), 5.61-5.63 (m, I H , H-l*, / . 3  H  S n  H  =  152.7 Hz).  1 3  C nmr (75.5 M H z , CDC1 ) 8: -9.4, 7.0, 28.4, 30.0, 33.4, 40.5, 124.6, 155.5. 3  H R M S calcd for C H 9  120 18  S n I (M -Me): 372.9475; found: 372.9473. +  Anal, calcd for CioH iSnI: C 31.05, H 5.47; found: C 31.09, H 5.53. 2  Preparation of methyl 8-fe^-butyldimethvlsiloxvoct-2-ynoate (285)  281  285  To a cold (-78 °C), stirred solution of the alkyne 281 (2.87 g, 12.7 mmol) in dry T H F (50 mL) was added a solution of methyllithium (11.2 mL, 1.6 M in hexanes, 17.9 mmol). The solution was stirred for 10 rnin at -78 °C and for 1 h at -20 °C.  Methyl  chloroformate (1.50 mL, 19.4 mmol) was added neat via a syringe and the mixture was stirred for 1 h at -20 °C and at room temperature for 1 h  Saturated aqueous sodium  bicarbonate (50 mL) was added and the mixture was extracted with E t 0 (3 x 50 mL). 2  The combined organic extracts were washed with brine (100 mL), dried (MgS0 ), and 4  the solvent was removed in vacuo. Purification of the crude product by flash column chromatography (100 g of silica gel, 19:1 petroleum ether-Et 0) and removal of trace 2  248  amounts of solvent (vacuum pump) from the acquired material yielded 3.34 g (93 %) of the ester 285 as a colorless oil.  IR (neat): 2 2 3 9 ,  *H nmr  (400  (t,  6 H ) , 2.32  1724,  MHz,  1435,  1267,  C D C 1 ) 8: 0.02 3  propargylic  2H,  1099, 839, 774  (s,  6H,  cm . 1  -SiMe?-).  0.87  (s,  Hz), 3.59 (t,  2H,  -CHo.-, / =  7.1  ) 8:  (-ve),  9H,  -Si'Bu-),  -O-CH2-,  1.40-1.60  / = 6.2  Hz),  (m, 3.73  (s, 3 H , -COVMe).  1 3  C nmr  52.4  (75.5  (-ve),  MHz, CDC1  62.8, 72.9, 89.6,  3  -5.4  18.3,  269.1573;  Anal, calcd for C H 0 S i : C  9.92;  +  1 5  Preparation  of  3  2 8  3  methyl  25.1,  25.9  (-ve),  27.3,  32.1,  154.1.  H R M S calcd for C H 2 5 0 S i (M -Me): 1 4  18.6,  63.33,  H  found:  found: C  269.1574.  63.66,  H  9.93.  (j^-8-fe^butyldimethylsiloxy-3-trimethvlstariQvloct-2-enoate  (286)  285  286  To a cold (-48 °C), stirred solution of hexamethylditin (5.31 g, 16.2 mmol) in dry T H F (200 mL) was added M e L i (10.1 mL, 1.6 M in E t 0 , 16.2 mmol) via a syringe and the 2  solution was stirred for 3 0 min. Copper(I) cyanide (1.49 g, 16.2 mmol) was added to the solution in one solid portion and stirring was continued for 30 min. The mixture was cooled to -78 °C and dry methanol (0.60 mL, 16.2 mmol) was added via a syringe. The reaction rnixture was stirred for 5 min. A solution of the ester 285 (3.55 g, 12.5 mmol) in dry T H F (5 mL) was added via a cannula to the mixture and stirring was continued for 4h  The mixture was warmed to room temperature, opened to the air, and aqueous  249 ammonium chloride-ammonia (pH 8) (150 mL) was added. The suspension was stirred until the aqueous phase became a deep blue color. The organic phase was separated and the aqueous phase was extracted with E t 0 (3 x 150 mL). The organic layers were 2  combined, washed with brine (350 mL), dried (MgSO^), and the solvent was removed under reduced pressure.  Flash column chromatography (250 g of silica gel, 40:1  petroleum ether-Et 0 with gradual change to 20:1 petroleum ether-Et 0) of the crude 2  2  product and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 8.57 g (78 %) of the stannane 286 as a colorless clear oil.  IR (neat): 1719, 1596, 1164, 837, 775 c m . 1  H nmr (400 M H z , CDC1 ) 8: 0.02 (s, 6H, -SiMer), 0.17 (s, 9H, -SnMe^, / „ .  l  2  3  s  H  =  53.2 Hz), 0.87 (s, 9H, -Si'Bu-), 1.32-1.53 (m, 6H), 2.87 (tm, 2H, allylic -CHz-, / = 7.0 Hz, / . = 64.6 Hz), 3.58 (t, 2H, - O - C H r , / = 6.5 Hz), 3.60 (s, 3H, -CO-Me), 5.94 3  S n  H  (t, 1H, olefinic proton, / = 1.2 Hz,  1 3  3  /s -H n  =  73.7 Hz).  C nmr (75.5 M H z , CDC1 ) 8: -9.3 (-ve), -5.3 (-ve), 18.3, 25.8, 26.0 (-ve), 29.5, 32.7, 3  34.7, 50.8 (-ve), 63.1, 126.9 (-ve), 164.6, 173.8.  H R M S calcd for C H O S i 17  35  3  120  S n (M -Me): 435.1377; found: 435.1371. +  Anal, calcd for C H 0 S i S n : C 48.12, H 8.53; found: C 47.88, H 8.58. 18  38  3  250 Preparation of methyl (jEl-8-iodo-3-trimethylstannyloct-2-enoate (288) SnMe  286  3  287 SnMe  3  Me0 C 2  288  To a stirred solution of the stannane 286 (1.38 g, 3.07 mmol) in dry T H F (30 mL) at room temperature was added a solution of tetrabutylarnmonium fluoride (4.6 mL, 1 M in THF, 4.6 mmol) and the solution was stirred for 1 h.  Saturated aqueous sodium  bicarbonate (20 mL) was added and the mixture was extracted with E t 0 (3 x 15 mL). 2  The combined organic extracts were washed with brine (30 mL), dried (MgS0 ), and the 4  solvent was removed in vacuo to give a crude oil. Flash column chromatography (12 g silica gel, 98:2 petroleum ether-Et 0) of the crude product yielded the alcohol 287 as a 2  colorless clear oil that was used directly in the next reaction.  To a cool (0 °C), stirred suspension of iodine (1.15 g, 4.55 mmol) in dry C H C 1 (30 mL) 2  2  was added triphenylphosphine (1.19 g, 4.55 mmol) in one solid portion. The mixture was stirred for 20 min and a yellow precipitate appeared.  Imidazole (494 mg, 7.25 mmol)  was added in one solid portion and the mixture was stirred for an additional 20 min. A solution of the alcohol 287 (obtained as described above) in dry C H C 1 (5 mL) was 2  2  added via a cannula and the reaction mixture was stirred for 1 h. Pentane (150 mL) was added and the mixture was filtered through a cake of silica gel (-30 g) and the silica gel was eluted with E t 0 (250 mL). The combined filtrate was concentrated under reduced 2  pressure.  The crude product was purified by flash column chromatography (100 g of  silica gel, 19:1 petroleum ether-Et 0) which, after removal of trace amounts of solvent 2  (vacuum pump) from the acquired material, yielded 1.32 g (97 % over 2 steps) of the iodide 288 as a colorless clear oil.  IR(neat): 1718, 1595, 1172, 771 c m . 1  251  J  H nmr (400 M H z , CDC1 ) 5: 0.17 (s, 9H, -SnMeg, / . = 54.4 Hz), 1.38-1.44 (m, 4H), 2  3  S n  H  1.79-1.87 (m, 2H), 2.87 (td, 2H, allylic - C H r , / = 6.8, 1.3 Hz, / . = 64.6 Hz), 3.17 (t, 3  S n  H  2H, I-CH2-, / = 6.7 Hz), 3.68 (s, 3H, -COjMe), 5.96 (t, 1H, olefinic proton, / = 1.3 Hz, 3  /sn.H  1 3  = 73.1Hz).  C nmr (75.5 M H z , CDC1 ) 8: -9.1 (-ve), 6.9, 28.3, 30.3, 33.1, 34.3, 50.8 (-ve), 3  127.2 (-ve), 164.5, 173.2.  H R M S calcd for C i i H O 20  120 2  S n I (M -Me): 428.9524; found: 428.9525. +  Anal, calcd for CizH^OjSnl: C 32.40, H 5.21; found: C 32.29, H 4.99.  Preparation of (E)- l-tenzvloxv-8-fe^butvldimethvlsiloxv-3-trimethylstannyloct-2-ene (290)  To a cold (-78 °C), stirred solution of the ester 286 (1.77 g, 3.94 mmol) in dry T H F (40 mL) was added a solution of D I B A L (11.8 mL, 1.0 M in hexanes, 11.8 mmol, 3.0 equiv) and the mixture was stirred for 1 h.  The solution was warmed to room  temperature and stirring was continued for 1 h. Saturated aqueous potassium sodium tartrate (Rochelle salt) (50 mL) was added. After the mixture had been stirred for 1 h, it was extracted with E t 0 (3 x 50 mL). The combined organic extracts were washed with 2  brine (100 mL), dried (MgSC>4), and the solvent was removed under reduced pressure to provide the alcohol 289 as a crude oil that was used directly in the next reaction.  252  To a cool (0 °C), stirred suspension of sodium hydride (142 mg, 5.91 mmol) in dry T H F (40 mL) was added a solution of the alcohol 289 (obtained as described above) in dry THF (5 mL) via a cannula. The reaction mixture was stirred for 1 h. Benzyl bromide (1.50 mL, 12.6 mmol) was added via a syringe and stirring was continued for 1 hr at 0 °C and for 24 h at room temperature. Water (50 mL) was added and the mixture was extracted with EtzO (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried (MgS0 ), and the solvent was removed in vacuo. Flash column 4  chromatography (200 g of silica gel, 9:1 petroleum ether-Et 0) of the crude oil and 2  removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 1.51 g (75 % over 2 steps) of the stannane 290 as a clear oil.  IR (neat): 1497, 1255, 1099, 836, 775 cm" . 1  *H nmr (400 M H z , CDC1 ) 8: 0.02 (s, 6H, -SiMe^-), 0.10 (s, 9H, -SnMe , 3  3  2  / „-H S  =  52.5 Hz), 0.87 (s, 9H, -Si'Bu-), 1.28-1.38 (m, 4H), 1.44-1.53 (m, 2H), 2.25 (br t, 2H, H-4, /=  7.0 Hz,  3  /  S N  - H = 62.0 Hz), 3.56  (t, 2H, H-8, / =  6.5 Hz), 4.10  (d, 2H, H - l , / =  5.9  Hz),  4.50 (s, 2H, benzylic -CH?,-), 5.92-5.78 (m, I H , H - 2 , / „ . = 77.5 Hz), 7.24-7.35 (m, 5H, 3  s  H  aromatic protons).  1 3  C nmr (75.5 M H z , CDC1 ) 8: -9.2 (-ve), -5.3 (-ve), 18.4, 25.6, 26.0 (-ve), 30.0, 32.7, 3  33.2, 63.1, 66.3, 72.1, 127.6, 127.8 (-ve), 128.3 (-ve), 136.0 (-ve), 138.3 (-ve), 149.1.  H R M S calcd for C H 4 i O S i S n (M -Me): 497.1898; found: 497.1884. 120  23  +  2  Anal, calcd for C H 4 0 S i S n : C 56.37, H 8.67; found: C 56.59, H 8.60. 24  4  2  253  SnMe  290  3  291 SnMe  3  BnCvJ^  292 To a stirred solution of the stannane 290 (1.51 g, 2.94 mmol) in dry T H F (30 mL) at room temperature was added a solution of tetrabutylammonium fluoride (4.5 mL, 1 M in THF, 4.5 mmol) and the solution was stirred for 1 h.  Saturated aqueous sodium  bicarbonate (30 mL) was added and the mixture was extracted with E t 0 (3 x 15 mL). 2  The combined organic extracts were washed with brine (30 mL), dried (MgSC^), and the solvent was removed in vacuo to provide the alcohol 291 as a crude oil that was used directly for the next reaction.  To a cool (0 °C), stirred suspension of iodine (1.15 g, 4.55 mmol) in dry CH2CI2 (50 mL) was added triphenylphosphine (1.28 g, 4.87 mmol) in one solid portion. The mixture was stirred for 20 min and a yellow precipitate appeared.  Imidazole (420 mg, 6.17 mmol)  was added in one solid portion and the mixture was stirred for 20 min. A solution of the alcohol 291 (obtained as described above) in dry CH2CI2 (5 mL) was added via a cannula and the reaction mixture was stirred for 1 h.  Pentane (100 mL) was added and the  mixture was filtered through a cake of silica gel (-30 g) and the silica gel was eluted with E t 0 (250 mL). The combined filtrate was concentrated under reduced pressure. The 2  crude product was purified by flash column chromatography (75 g of silica gel, 24:1 petroleum ether-Et 0) which, after removal of trace amounts of solvent (vacuum pump) 2  from the acquired material, yielded 1.34 g (90 % over 2 steps) of the iodide 292 as a colorless clear oil.  IR (neat): 1454, 1358, 1204, 1092, 767 cm" . 1  254 *H nmr (400 M H z , CDC1 ) 5: 0.11 (s, 9H, -SnMej, / . = 52.5 Hz), 1.30-1.38 (m, 4H), 2  3  S n  H  1.74-1.81 (m, 2H), 2.25 (br t, 2H, H-4, / = 6.0 Hz, / . = 61.6 Hz), 3.14 (t, 2H, H-8, / = 3  S n  H  7.0 Hz), 4.08 (d, 2H, H - l , / = 6.0 Hz), 4.51 (s, 2H, benzylic -CKb-), 5.77 (tt, I H , H-2, / = 1.2, 6.0 Hz,  1 3  3  /sn-H  = 77.9 Hz), 7.26-7.34 (m, 5H, aromatic protons).  C nmr (75.5 M H z , CDC1 ) 8: -9.2 (-ve), 6.9, 29.0, 30.2, 32.9, 33.2, 66.2, 72.4, 127.5 3  (-ve), 127.8 (-ve), 128.3 (-ve), 136.3 (-ve), 138.2, 148.7.  H R M S calcd for C i H O 7  120  26  S n I (M -Me): 493.0050; found: 493.0049. +  Anal, calcd for C H O S n I : C 42.64, H 5.77; found: C 42.83, H 5.83. 18  29  Preparation of diethyl 2-r(2-trimethylstamylcyclopent-l-en-l-vl)methvll-2-(5-tTimethvl stannylhex-5-en-l-yl)malonate (293) SnMe  3  SnMe  3  To a cold (-78 °C), stirred solution of L D A (1.80 mmol) in dry T H F (18 mL) was added a solution of the stannane 261 (763 mg, 1.89 mmol) in dry T H F (1 mL) via a cannula. The mixture was stirred for 1 h at -78 °C and at 0 °C for 15 min. A solution of the iodide 269 (876 mg, 2.35 mmol) in dry T H F (1 mL) was added via a cannula and the mixture was warmed to reflux for 21 h  The reaction mixture was cooled to room temperature and  saturated aqueous sodium bicarbonate (15 mL) was added.  The mixture was extracted  with E t 0 (3 x 20 mL). The combined organic extracts were washed with brine (50 mL), 2  255 dried (MgSCU), and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (100 g of silica gel, 95:5 petroleum etherE t 0 ) which, after removal of trace amounts of solvent (vacuum pump) from the acquired 2  material, yielded 888 mg (72 %) of the distannane 293 as a colorless clear oil.  IR (neat): 1734, 1607, 1240, 770, 471 cm" . 1  J  H nmr (400 MHz,  CDC1 ) 5: 3  0.09 (s, 9H, -SnMe,, J . 2  Sn  H  = 52.8 Hz), 0.15 (s, 9H,  -SnMea, Vsn-H = 53.2 Hz), 1.15-1.27 (m, 8H, includes 6H -CO2CH2CH3 triplet at 1.22 w i t h / = 7.1 Hz), 1.30-1.40 (m, 2H), 1.73-1.85 (m, 4H), 2.15-2.35 (m, 6H), 2.86 (br s, 2H, H-a), 4.10-4.20 (m, 4H, -CO2CH2CH3), 5.07-5.10 (m, I H , H-6, / 3  S n  5.58-5.60 (rn, I H , H-6',  13  3  / n-H S  H  = 70.4 Hz),  = H7.6 Hz).  C nmr (75.5 MHz, CDC1 ) 8: -9.5 (-ve), -9.2 (-ve), 14.0 (-ve), 24.1, 24.7, 29.8, 33.7, 3  35.8, 37.5, 38.8, 40.4, 57.1, 61.0, 124.5,141.3, 148.2,155.4, 171.8.  H R M S calcd for C24H43O  118 4  Sn Sn (M -Me): 633.1199; found: 633.1204. 120  +  Anal, calcd for C ^ r L ^ A S n ^ C 46.34, H 7.15; found: C 46.63, H 7.39.  256 Preparation  of  methyl (iT)-8,8-bis(ethoxvcarlxmvl)-3-trimem^  stannvlcyclopent-l-en-l-yl)non-2-enoate (294)  SnMe  3  R = -C0 Et  SnMe  2  294 To a cold (-78 °C), stirred solution of L D A (2.52 mmol) in dry T H F (25 mL) was added a solution of the stannane 261 (1.07 g, 2.66 mmol) in dry T H F (5 mL). The mixture was stirred for 1 h at -78 °C and at 0 °C for 15 rnin. A solution of the iodide 273 (1.41 g, 3.30 mmol) in dry T H F (5 mL) was added via a cannula and the mixture was warmed to reflux for 21 h. The reaction rnixture was cooled to room temperature and saturated aqueous sodium bicarbonate (30 mL) was added.  The mixture was extracted with E t 0 2  (3 x 20 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSCU), and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (100 g of silica gel, 37:3 petroleum ether-Et 0) 2  which, after removal of trace amounts of solvent (vacuum pump) from the acquired material, yielded 1.54 g (86 %) of the distannane 294 as colorless viscous oil.  IR (neat): 1729, 1597, 1163, 771 c m . 1  J  H nmr (400 M H z , CDC1 ) 8: 0.15 (s, 9H, -SnMe , / . 2  3  3  S n  H  = 53.4 Hz), 0.16 (s, 9H,  -SnMea, / _ = 53.3 Hz), 1.20-1.40 (m, 10H, includes 6H - C 0 C H C H 3 triplet at 1.22 2  S n  H  2  2  with / = 7.1 Hz), 1.73-1.80 (m, 4H), 2.19 (br t, 2H, / = 7.2 Hz), 2.32 (br t, 2H, / = 7.2 Hz), 2.74-2.94 (m, 4H, H-4 and H-9), 3.66 (s, 3H, -COM&), 4.10-4.20 (m, 4H, -C0 CH2CH ), 5.93 (s, IH, H - 2 , / „ . = 73.4 Hz). 3  2  3  s  H  257 1 3  C nmr (75.5 M H z , CDC1 ) 5: -9.3 (-ve), -9.2 (-ve), 14.0 (-ve), 24.63, 24.67, 30.0, 33.9, 3  34.4, 35.8, 37.7, 38.8, 50.7,57.1, 60.9,127.1 (-ve), 141.3, 148.2, 164.4, 171.7, 173.0.  H R M S calcd for C26H45O Sn (M -Me): 693.1260; found: 693.1258. 120  6  +  2  Anal, calcd for C 7H480 Sn : C 45.93, H 6.85; found: C 45.89, H 6.76. 2  Preparation  of  6  2  diethyl  2-r(F)-7-methoxv-5-trimethvlstannvlhept-5-en-l-vll-2-r(2-  trimethylstannylcyclopent-1 -en-1 -vDmethyllmalonate (295)  SnMe  3  R = -C0 Et  SnMe  3  2  295 To a stirred suspension of potassium hydride (143 mg, 3.58 mmol) in dry T H F (25 mL) at room temperature was added a solution of the stannane 261 (1.24 g, 3.08 mmol) in dry T H F (5 mL) via a cannula. The mixture was stirred for 1 h. A solution of the iodide 279 (876 mg, 2.35 mmol) in dry T H F (5 mL) was added via a cannula and the mixture was warmed to reflux for 2 h. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate (30 mL) was added.  The mixture was extracted  with E t 0 (3 x 20 mL). The combined organic extracts were washed with brine (50 mL), 2  dried (MgSC^), and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (80 g of silica gel, 92:8 petroleum etherE t 0 with gradual change to 4:1 petroleum ether-Et 0) which, after removal of trace 2  2  amounts of solvent (vacuum pump) from the acquired material, yielded 888 mg (72 %) of the distannane 295 as a colorless clear oil.  258  IR (neat): 1733, 1607, 1237, 769 c m . 1  H nmr (400 M H z , CDC1 ) 5: 0.09 (s, 9H, -SnMe ,  l  3  3  2  / „-H S  = 52.6 Hz), 0.16 (s, 9H,  -SnMea, / „ . = 53.3 Hz), 1.18-1.33 (m, 10H, includes 6H - C 0 C H C H 3 triplet at 1.22 2  s  H  2  2  with J = 7.1 Hz), 1.73-1.80 (m, 4H), 2.15-2.19 (m, 2H), 2.25 (br t, 2H, / = 7.3 Hz), 2.302.35 (m, 2H), 2.86 (br s, 2H, H-a), 3.32 (s, 3H, -OMe), 3.97 (d, 2H, H-7, / = 6.0 Hz), 4.12-4.18 (m, 4H, -CO^HoCHs), 5.66 (tm, IH, H-6, / = 6.0 Hz, / . = 78.0 Hz). 3  S n  1 3  H  C nmr (75.5 M H z , CDC1 ) 8: -9.3 (-ve), -9.2 (-ve), 14.0 (-ve), 24.6, 24.7, 30.6, 33.1, 3  33.8, 35.8, 37.6,38.8, 57.1,58.1 (-ve), 61.0, 68.6, 136.0 (-ve), 141.1, 148.2, 148.7, 171.8.  H R M S calcd for C H47O 26  120 5  Sn (M -Me): 679.1467; found: 679.1462. +  2  Anal, calcd for C H o 0 S n : C 46.98, H 7.28; found: C 46.68, H 7.23. 27  5  5  2  Preparation of diethyl 2-r(2-trimethylstannylcyclopent-l-en-l-yl)m stannylhept-6-en- l-yl)malonate (296)  To a stirred suspension of potassium hydride (114 mg, 2.86 mmol) in dry T H F (25 mL) at room temperature was added a solution of the diester 261 (1.16 g, 2.89 mmol) in dry T H F (5 mL) via a cannula. After 1 h, a solution of the iodide 284 (910 mg, 2.35 mmol) in dry  259 T H F (2 mL) was added to the mixture via a cannula. The reaction mixture was warmed to reflux for 18 h and then cooled to room temperature. Water (20 mL) was added and the mixture was extracted with E t 0 (3 x 20 mL). The combined organic extracts were 2  washed with brine (60 mL), dried (MgSCu), and the solvent was removed under reduced pressure. Flash column chromatography (80 g of silica gel, 24:1 petroleum ether-Et 0) 2  of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 1.50 g (96 %) of the distannane 296 as a colorless, extremely viscous oil.  IR (neat): 1733, 1607, 1234, 769 c m . 1  J  H nmr (400 M H z , CDC1 ) 5: 0.08 (s, 9H, -SnM&t. / . 2  3  S n  H  = 53.6 Hz), 0.15 (s, 9H,  -SnMes, / „ . = 54.6 Hz), 1.16-1.36 (m, 12H, includes 6H - C 0 C H C H 3 triplet at 1.22 2  s  H  2  2  with / = 7.2 Hz), 1.70-1.80 (m, 4H), 2.16-2.34 (m, 6H), 2.86 (br s, 2H, H-a), 4.10-4.20 (m, 4H, -C0 CH2CH ), 5.08-5.10 (m, 1H, H - 7 , / . = 70.5 Hz), 5.58-5.60 (m, 1H, H-7', 3  2  3  /S„-H=  1 3  154.0  3  S n  H  Hz).  C nmr (75.5 M H z , CDC1 ) 8: -9.6 (-ve), -9.2 (-ve), 14.0 (-ve), 24.4, 24.6, 29.3, 29.4, 3  33.7, 35.8, 37.5, 38.8, 40.7, 57.1, 60.9, 124.3, 141.2,148.2, 155.6,171.8.  H R M S calcd for C H 4 5 O 25  120 4  S n (M -Me): 649.1362; found: 649.1352. +  2  Anal, calcd for C H 4 8 0 S n : C 47.17, H 7.31; found: C 47.23, H 7.18. 26  4  2  260 Preparation of methyl (£V9,9-bis(ethoxycarIxmvl)-3-trimeth^^ stannvlcyclopent-l-en-l-yBdec-2-enoate (297)  SnMe  3  C0 Me 2  R = -C0 Et 2  297 To a stirred suspension of potassium hydride (88 mg, 2.2 mmol) in dry T H F (25 mL) at room temperature was added a solution of the diester 261 (992 mg, 2.46 mmol) in dry THF (2 mL) via a syringe. After 1 h, a solution of the iodide 288 (876 mg, 1.97 mmol) in dry T H F (2 mL) was added to the mixture via a cannula.  The reaction mixture was  warmed to reflux for 1.5 h and then was cooled to room temperature. Water (30 mL) was added and the mixture was extracted with E t 0 (3 x 30 mL). The combined organic 2  extracts were washed with brine (100 mL), dried (MgSC^), and the solvent was removed under reduced pressure.  Flash column chromatography (75 g of silica gel, 37:3  petroleum ether-Et 0) of the crude product and removal of trace amounts of solvent 2  (vacuum pump) from the acquired material yielded 1.17 g (82 %) of the distannane 297 as a colorless, extremely viscous oil.  IR (neat): 1729 (br), 1596, 1434, 1171, 770 c m . 1  *H nmr (400 M H z , C D C k ) 8: 0.15 (s, 9H, -SnMes, / . 2  S n  H  = 52.3 Hz), 0.16 (s, 9H,  -SnMea, / . = 52.1 Hz), 1.16-1.39 (m, 12H, includes 6H - C 0 C H C H 3 triplet at 1.24 2  S n  H  2  2  w i t h / = 7.1 Hz), 1.73-1.80 (m, 4H), 2.18 (br t, 2H, / = 7.3 Hz), 2.31 (br t, 2H, / = 7.1 Hz), 2.82-2.88 (m, 4H, H-4 and H-10), 3.66 (s, 3H, -CC^Me), 4.10-4.20 (m, 4H, -C0 CH2CH ), 5.94 (t, 1H, H-2, / = 2.1 Hz, / . = 73.7 Hz). 3  2  3  S n  H  261 1 3  C nmr (75.5 M H z , CDC1 ) 5: -9.2 (-ve), -9.1 (-ve), 14.0 (-ve), 24.56, 24.60, 29.5, 30.0, 3  33.7, 34.6, 35.8, 37.5, 38.8, 50.7 (-ve), 57.1, 60.9, 126.9 (-ve), 141.2, 148.2, 164.5, 171.8, 173.5.  H R M S calcd for C 7H47O 2  118 6  Sn Sn (M -Me): 705.1411; found: 705.1418. 120  +  Anal, calcd for C 8H5o0 Sn : C 46.70, H 7.00; found: C 47.02, H 7.03. 2  Preparation  of  6  diethyl  2  2-r(^-8-benzyloxy-6-trimethylstannyloct-6-en-l-yll-2-r(2-  trimethvlstannylcyclopent-1 -en-1 -vDmethyllmalonate (298)  To a stirred suspension of potassium hydride (93 mg, 2.3 mmol) in dry T H F (25 mL) at room temperature was added a solution of the diester 261 (992 mg, 2.46 mmol) in dry T H F (2 mL) via a syringe. After 1 h, a solution of the iodide 292 (1.00 g, 1.97 mmol) in dry T H F (2 mL) was added to the mixture via a cannula.  The reaction mixture was  warmed to reflux for 2 h and then was cooled to room temperature. Water (30 mL) was added and the mixture was extracted with Et 0 (3 x 30 mL). The combined organic 2  extracts were washed with brine (100 mL), dried (MgSC^), and the solvent was removed under reduced pressure.  Flash column chromatography (75 g of silica gel, 17:3  petroleum ether-Et 0) of the crude product and removal of trace amounts of solvent 2  (vacuum pump) from the acquired material yielded 1.11 g (73 %) of the distannane 298 as a colorless, extremely viscous oil.  262  IR (neat): 1729, 1607, 1234, 769 cm" . 1  J  H nmr (400 M H z , CDC1 ) 8: 0.09 (s, 9H, -SnMe., / . 2  3  S n  H  = 52.6 Hz), 0.16 (s, 9H,  -SnMea, / „ . = 53.0 Hz), 1.17-1.30 (m, 12H, includes 6H -CO2CH2CH3 triplet at 1.22 2  s  H  with / = 7.1 Hz), 1.73-1.81 (m, 4H), 2.10-2.35 (m, 6H), 2.85 (br s, 2H, H-a), 4.05-4.20 (m, 6H, includes H-8 and -CO2CH2CH3), 4.50 (s, 2H, benzylic -CH2-), 5.73 (t, 1H, H-7, J = 6.0 Hz,  1 3  3  / „-H s  = 74.0 Hz), 7.24-7.35 (m, 5H, aromatic protons).  C nmr (75.5 MHz, CDC1 ) 8: -9.3 (-ve), -9.2 (-ve), 14.0 (-ve), 24.60, 24.64, 29.8, 30.0, 3  33.2, 33.8, 35.8, 37.6, 38.8, 57.1, 60.9, 66.3, 72.4, 127.5 (-ve), 127.8 (-ve), 128.3 (-ve), 136.1 (-ve), 138.3, 141.3, 148.2, 148.9, 171.8.  H R M S calcd for C 3 3 H O 5 S n S n (M -Me): 767.1931; found: 767.1929. 118  120  +  53  Anal, calcd for Cg^eC^Snz: C 52.21, H 7.22; found: C 52.07, H 7.27.  263 8.2 Intramolecular oxidative couplings mediated by copperd) chloride  General  Procedure 8:  CuCl-mediated intramolecular  oxidative  coupling of  bisalkenyltrimethylstannanes  To a stirred solution-suspension of CuCI (~5 equiv) in dry D M F (10 mL/mmol of substrate) at room temperature was added a solution of the bisalkenyltrimethylstannane (1 equiv) in dry D M F (20 mL/mmol of substrate) via a syringe pump over 2 h. After the addition of the stannane was complete, the reaction mixture was stirred for 2 h. The mixture was opened to the atmosphere, aqueous ammonium chloride-ammonia (pH 8) (~5 mL/mmol of substrate) was added, and the mixture was stirred until the aqueous phase became deep blue. The mixture was diluted with water (~5 mL/mmol of substrate) and extracted with E t 0 (3 x -10 mL/mmol of substrate). The combined organic phases 2  were washed with brine (3 x -20 mL/mmol of substrate), dried (MgS0 ), and 4  concentrated under reduced pressure. The crude product was purified by flash column chromatography.  264 Preparation  of  7J-bisrethoxvcarbonvl)-2-methylidenebicyclor7.3.01-dodec-l(9)-ene  (299)  293  299  Following general procedure 8, the diene 299 was prepared by the addition of the distannane 293 (91 mg, 0.14 mmol), as a solution in dry D M F (2.8 mL), to a stirred solution-suspension of CuCI (71 mg, 0.72 mmol) in dry D M F (1.4 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 19:1 petroleum ether-Et^O) and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 42 mg (93 %) of the diene 299 as a colorless oil. IR (neat): 1729, 1467, 1446, 1203 cm" . 1  *H nmr (400 M H z , CDC1 ) 8: 1.21 (t, 6H, - C 0 C H C H 3 , / = 7.1 Hz), 1.33-1.39 (m, 2H, 3  2  2  H-5), 1.60-1.74 (m, 4H, H-4 and H - l l ) , 1.88 (br t, 2H, H-6, / = 6.2 Hz), 2.18 (br t, 2H, H-10, / = 7.4 Hz), 2.30 (br t, 2H, H-3, / = 7.3 Hz), 2.42 (br t, 2H, H-12, / = 7.2 Hz), 2.92 (br s, 2H, H-8), 4.08-4.20 (m, 4H, -CC^CIfcCHa), 4.90 (d, 1H, H-13, / = 2.0 Hz), 4.94 (unresolved m, 1H, H-13').  1 3  C nmr (50.3 M H z , CDC1 ) 8: 14.0 (-ve), 20.3, 22.1, 28.6, 29.6, 31.0, 32.3, 37.6, 38.8, 3  57.2,61.0, 114.8, 132.0, 142.6, 147.3, 171.9.  H R M S calcd for C i H 0 : 320.1988; found: 320.1988. 9  2 8  4  Anal, calcd for C H 0 : C 71.22, H 8.81; found: C 70.98, H<9.07. 1 9  2 8  4  265  Table 34. *H nmr (200 M H z , CDC1 ) data for the diester 299: C O S Y experiment 3  R = -C0 Et 2  299 Assignment  H nmr (400 MHz)  COSY  8 (multiplicity, / (Hz))  Correlations  X  H-x H-3  2.30 ( b r t , / = 7.3)  H-4,H-13  H-4  high-field portion of 1.60-1.74 (m)  H-3, H-5  H-5  1.33-1.39 (m)  H-4, H-6  H-6  1.88 ( b r t , / = 6.2)  H-5  H-8  2.92 (br s)  H-10  2.18 (brt, 7=7.4)  H-ll  H-ll  low-field portion of 1.60-1.74 (m)  H-10, H-12  H-12  2.42 (brt, 7=7.2)  H-ll  H-13  4.90 (d, 7=2.0)  H-3  H-13'  4.94 (unresolved m)  -C0 CH2CH 2  3  -C0 CH CH3 2  2  4.08-4.20 (m)  -C0 CH CH3  1.21 (t,7=7.1)  -C0 CH2CH  2  2  2  3  266 Preparation  of  7J-bis(ethoxvcarbonvl)-2-r(^-methoxvcarbonylmethylidene1  bicvclor7.3.01dodec-l(9Vene(300) 11  10  R  C0 Me 2  SnMe  3  R = -C0 Et  SnMe  3  R = -C0 Et  2  C0 Me 2  2  294  300  Following general procedure 8, the triester 300 was prepared by the addition of the distannane 294 (154 mg, 0.218 mmol), as a solution in dry D M F (4.5 mL), to a stirred solution-suspension of CuCl (111 mg, 1.12 mmol) in dry D M F (2.5 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 9:1 petroleum etherE t 0 ) and removal of trace amounts of solvent (vacuum pump) from the acquired 2  material yielded 60 mg (72 %) of the triester 300 as a colorless oil.  IR(neat): 1730, 1627, 1590, 1432, 1163 c m . 1  *H nmr (400 M H z , CDC1 ) 5: 1.17-1.29 (m, 8H, includes 6H -CO2CH2CH3 triplet at 1.19 3  w i t h / = 7.1 Hz and H-5), 1.70-1.90 (m, 6H, H-4, H-6, H - l l ) , 2.19 (br t, 2H, H-10, / = 7.3 Hz), 2.44 (unresolved m, 2H, H-12), 2.67 (unresolved m, 2H, H-3), 2.87 (br s, 2H, H-8), 3.67 (s, 3H, -CCbMe,, 3.95-4.20 (m, 4H, -C0 CH2CH ), 5.67 (s, IH, H-13). 2  1 3  3  C nmr (125.8 M H z , CDC1 ) 5: 14.0 (-ve), 19.9, 22.4, 26.5, 27.6, 28.4, 30.7, 37.8, 38.7, 3  50.9 (-ve), 56.2, 61.2, 117.8, 134.0, 143.9, 160.6, 166.5, 171.6.  H R M S calcd for C i H O : 378.2043; found: 378.2043. 2  3 0  6  Anal, calcd for C i H O : C 66.65, H 7.99; found: C 66.47, H 7.96. 2  3 0  6  267 Table 35. *H nmr (400 M H z , CDC1 ) data for the diester 300: N O E D and C O S Y 3  experiments  COoMe  R = -C0 Et 2  300  Assignment  *H nmr (400 MHz)  COSY  NOED  H-x  8 (multiplicity, J (Hz))  Correlation  Correlation  H-3  2.67 (unresolved m)  H-4  H-4 and H-6  low-field portion of 1.701.90 (m)  H-3, H-5  H-5  low-field portion of 1.171.29 (m)  H-4, H-6  H-8  2.87 (brs)  H-10  2.19 (brt, 7=7.3)  H - l l , H-12  H-8, H - l l , H-12 (-ve), -CO2CH2CH3  H-ll  high-field portion of 1.701.90 (m)  H-10, H-12  H-12  2.44 (unresolved m)  H-10, H - l l  H-13  5.67 (s)  H - l l , H-13 H-12  3.95-4.20 (m)  -C0 CH CH3  -CO2CH9CH3  high-field portion of 1.171.29 (m)  -C0 CH2CH  -C0 Me  3.67 (s)  -C0 CH2CH 2  2  3  2  2  2  3  268 Preparation of 7J-bis(ethoxycarbonyl)-2-F(ffi dodec-l(9)-ene(301)  OMe 301  295  Following general procedure 8, the diester 301 was prepared by the addition of the distannane 295 (115 mg, 0.166 mmol), as a solution in dry D M F (3.4 mL), to a stirred solution-suspension of CuCI (82 mg, 0.83 mmol) in dry D M F (1.7 mL). Purification of the crude product by flash column chromatography (12 g of silica gel, 4:1 petroleum ether-Et 0) and removal of trace amounts of solvent (vacuum pump) from the acquired 2  material yielded 55 mg (91 %) of the diester 301 as a colorless oil. IR(neat): 1729, 1466, 1367, 1197 c m . 1  *H nmr (400 MHz, CDC1 ) 5: 1.21 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 1.26-1.33 (m, 2H, 3  H-5), 1.55-1.62 (m, 2H, H-4), 1.67-1.75 (m, 2H, H - l l ) , 1.83 (br t, 2H, H-6, J = 6.7 Hz), 2.14 (br t, 2H, H-10, / = 7.5 Hz), 2.28 (br t, 2H, H-3, / = 6.5 Hz), 2.39 (unresolved m, 2H, H-12), 2.85 (br s, 2H, H-8), 3.32 (s, 3H, -OMe), 3.95 (d, 2H, H-14, / = 6.4 Hz), 4.084.19 (m, 4H, -CO2CH2CH3), 5.41 (t, 1H, H-13, / = 6.4 Hz).  1 3  C nmr (75.3 MHz, CDC1 ) 5: 14.0 (-ve), 19.1, 22.2, 26.7 (2C), 27.2, 30.3, 37.7, 38.0, 3  56.0,58.0 (-ve), 61.0, 69.1, 125.6,130.7, 140.2, 144.6,171.7.  H R M S calcd for C2iH 0 : 364.2250; found: 364.2253. 32  5  Anal, calcd for C2iH 0 : C 69.20, H 8.85; found: C 68.98, H 8.87. 32  5  269  Table 36. H nmr (400 M H z , CDC1 ) data for the diester 301: N O E D and C O S Y J  3  experiments H  10,  11  R 6  OMe  Assignment  H nmr (400 MHz)  COSY  NOED  5 (multiplicity, 7 (Hz))  Correlation  Correlation  J  H-x H-3  2.28 (brt, 7=6.5)  H-4  H-4  1.55-1.62 (m)  H-3, H-5  H-5  1.26-1.33 (m)  H-4, H-6  H-6  1.83 (brt, 7=6.7)  H-5  H-8  2.85 (brs)  H-10  2.14 (brt, 7 =7.5)  H-ll,H-12  H-ll  1.67-1.75 (m)  H-10,H-12  H-12  2.39 (unresolved m)  H-10, H - l l  H-ll,H-13  H-13  5.41 (t,7=6.4)  H-14  H-12,H-14  H-14  3.95 (d,7=6.4)  H-13  H-3, H-13, -OMe  4.08-4.19 (m)  -C0 CH CH3  -C0 CH CH3  1.21 (t,7=7.1)  -C0 CH2CH  -OMe  3.32 (s)  -C0 CH2CH 2  2  2  3  2  2  2  3  270 Preparation  of  8,8-bis(ethoxycarbonyl)-2- [(F)-methoxvcarbonvlmethylidenel  bicvclor8.3.0ltridec-1 (lOVene (303)  SnMe  3  R = -C0 Et  COoMe  2  R = -C0 Et  C0 Me 2  2  297  303  Following general procedure 8, the triester 303 was prepared by the addition of the distannane 297 (96 mg, 0.13 mmol), as a solution in dry D M F (2.6 mL), to a stirred solution-suspension of CuCl (68 mg, 0.69 mmol) in dry D M F (1.3 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 17:3 petroleum ether-Et 0) and removal of trace amounts of solvent (vacuum pump) from the acquired 2  material yielded 24 mg (45 %) of the triester 303 as a colorless oil. This material solidified upon prolonged standing in a freezer to give a waxy white solid (mp 88-90 °C).  IR(neat): 1730 (br), 1620, 1435, 1276, 1166 c m . 1  *H nmr (400 M H z , CDC1 ) 8: 1.00-1.90 (br m, 16H, includes 6H -CO2CH2CH3 br t at 3  1.22 with / = 6.8 Hz), 1.90-2.80 (br m, 6H), 3.00-3.50 (br s, 2H), 3.68 (s, 3H, -C0 Me), 2  4.11-4.20 (m, 4H, -COjCHjCHs), 5.59 (br s, IH, H-14).  1 3  C nmr (75.3 M H z , CDC1 ) 5: 14.1 (-ve), 19.5, 21.5, 22.3, 27.7, 28.4, 29.8 (2C), 36.3, 3  36.4, 50.9 (-ve), 55.6, 61.3, 111.4, 115.0(-ve), 135.5, 143.2, 161.8, 167.1.  H R M S calcd for C H 0 : 392.2199; found: 392.2199. 2 2  3 2  6  Anal, calcd for C H 0 : C 67.32, H 8.22; found: C 67.36, H 8.11. 2 2  3 2  6  271  References and Footnotes 1.  (a) Stille, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25,508. (b) Mitchell, T. N . Synthesis 1992, 803. (c) Farina, V . ; Krishnamurthy, V . ; Scott, W. Org. React. 1997, 50, 1.  2.  Labadie, J. W.; Stille, J. K. / . Am. Chem. Soc. 1983,105, 6129.  3.  (a) Farina, V . ; Kapadia, S.; Krishnan, B.; Wang, C ; Liebeskind, L . S. / . Org. Chem. 1994, 59, 5905. (b) Liebseskind, L . S.; Fengl, R. W. / . Org. Chem. 1990, 55, 5359. (c) Farina, V . Pure Appl. Chem. 1996, 68, 73. (n) (d) Han, X . ; Stoltz, B. M . ; Corey, E. J. / . A m Chem. Soc. 1999,121, 7600.  4.  (a) Piers, E . ; Friesen, R. W.; Keay, B. A . / . Chem. Soc. Commun. 1985, 809. (b) Piers, E . ; Friesen, R. W.; Keay, B. A . Tetrahedron 1991, 47, 4555. (c) for a recent review on the intramolecular Stille reaction, see Duncton, A . J.; Pattenden, G. / . Chem. Soc, Perkin Trans. 1,1999, 1235. and references cited therein.  5.  (a) Piers, E . ; Wong, T. / . Org. Chem. 1993, 58, 3609. (b) Wong, T. Ph.D. Thesis, University of British Columbia, Vancouver, B.C., 1993.  6.  Huang, A . X . ; Zhaoming X . ; Corey, E. J. / . Amer. Chem. Soc. 1999,121, 9999.  7.  Allred, G. D.; Liebeskind, L . S. /. Am. Chem. Soc. 1996,118, 2748.  8.  (a) Piers, E . ; Gladstone, P. L.; Yee, J. G. K.; McEachern, E. J. Tetrahedron 1998, 54,10609. (b) Piers, E . ; McEachern, E. J.; Romero, M . A . ; Gladstone, P. L . Can. J. Chem. 1997, 75, 694. (c) Piers, E.; McEachern, E. J.; Romero, M . A . Tetrahedron Lett. 1996, 37, 1173.  9.  Piers, E . ; Romero, M . A . / . Am. Chem. Soc. 1996,118, 1215.  10. Kaller, A . M . Ph. D. Thesis, University of British Columbia, Vancouver, B.C., 1997. 11. Ghosal, S.; Luke, G. P.; Kyler, K. S. / . Org. Chem. 1987, 52, 4296. 12. Crisp, G. T.; Glink, P. T. Tetrahedron Lett. 1992, 33, 4649.  272 13. Zhang, H . 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React.  1995,47,315. 20. For other examples see (a) Behling, J.; Babiak, K.; Ng.; Campbell, A.; Moretti, R.; Koerner, M . ; Lipshutz, B. / . Am. Chem. Soc. 1988,110, 2641. (b) Behling, J.; Babiak, K.; Ng.; Campbell, A.; Moretti, R.; Koerner, M . ; Lipshutz, B. Tetrahedron Lett. 1989, 30,27. (need) (c) Cooke, M . P.; Gopal, D. /. Org. Chem. 1987, 52, 1381. (d) Cooke, M . P. / . Org. Chem. 1984,49, 1144. (e) Cooke, M . P.; Huang, J. J. Synlett. 1997, 535. (f) Curran, D. P.; Wolin, R. L . Synlett 1991, 317. (g) Kocovsky, P.; Srogl, J. / . Org. Chem. 1992, 57, 4565. (h) Tanaka, H ; Kameyana, S. S.; Sumida, S.; Torii, S. Tetrahedron Lett. 1992, 33, 7029. (i) Wender, P. A.; Eck, S. L . Tetrahedron Lett. 1977,14, 1245. 21. Wender, P. A.; White, A. W. / . Am, Chem. Soc. 1988,110, 2218. 22. Cooke, M . P.;Widener. R. K . J. Org. Chem. 1987, 52, 1381. 23. Cooke, M . P. / . Org. Chem. 1993, 58, 6833. 24. Bronk, B. S.; Lippard, S. J.; Danheiser, R. L . Organometallics 1993,12, 3340. 25. Lee, S. 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