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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 GEE KEN YEE B. Sc., University of Calgary, 1995 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA July, 2000 © James G. K. Yee,<3(?CO U B C Special Collections - Thesis Authorisation Form 21/07/00 12:56 I n presenting 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 of the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that 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 reference and study. I f u r t h e r agree that permission f o r extensive copying of 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 granted by the head of my department or by h i s o r her representatives. I t i s understood that copying o r p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be allowed without my w r i t t e n permission. The U n i v e r s i t y of B r i t i s h Columbia Vancouver, Canada Department of http://www.library.ubc.ca/spcoll/thesauth.html 11 A B S T R A C T 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 M e 3 S n COpMe R Me C 0 2 M e R = H, Me, o r O M e X = O or C ( C 0 2 E t ) 2 Q 8 9 ,R S n M e 3 100 "SnMe 3 233 R = H 235 R = Me S n M e 3 S n M e 3 . 0 . C (=0 )R 236,237 R = H 238,239 R = Me S n M e 3 S n M e 3 108 S n M e 3 S n M e 3 E = C 0 2 E t 112 E = C 0 2 E t 113 n = 1 or 2 R E = C 0 2 E t 115 iv T A B L E O F C O N T E N T S ABSTRACT i i TABLE OF CONTENTS iv LIST OF TABLES viii LIST OF FIGURES xi LIST OF GENERAL PROCEDURES xii LIST OF ABBREVIATIONS xi i i ACKNOWLEDGEMENTS xvi I. 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 alkenyl-trimethylstannane functions to a,(3-alkynic esters to form monocycles 16 3.2 Intramolecular conjugate addition of alkenyl-trimethylstannane functions to a,f3-alkynic esters to form bicycles 17 3.3 Intramolecular conjugate addition of aryl-trimethylstannane 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-trimethyl-stannyl a, ^ unsaturated ketones mediated by copper(I) chloride 23 3.6 Oxidative intramolecular couplings of bisaryltrimethyl-stannanes mediated by copper(I) chloride 24 3.7 Intramolecular oxidative coupling of bisalkenyltrimethyl-stannanes to produce 9- and 10-membered rings 26 II. RESULTS AND DISCUSSION 27 1. Intramolecular conjugate additions of alkenyltrimethyl-stannanes to Michael acceptors mediated by copper(I) salts 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 aryltrimethyl-stannane 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 64 1.5.1.2 Use of catalytic amounts of CuCl in the conjugate addition reaction 67 1.5.2 Preparation of a,(3-alkynic ketone and aldehyde precursors 71 1.5.3 Cyclization of oc,|3-alkynic ketone and aldehyde precursors 72 1.6 Summary 77 2. Intermolecular and intramolecular oxidative coupling of alkenyl- and aryltrimethylstannanes mediated by copper(I) chloride 79 2.1 Introductory remarks 79 2.2 Intermolecular coupling of P-trimethylstannyl-a,(3-unsaturated ketones mediated by copper(I) chloride.... 80 2.2.1 Preparation of P-trimethylstannyl-a,(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 bisalkenyltrimethyl-stannanes 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 105 III. EXPERIMENTAL 107 1. General 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 216 6.1 Intermolecular copper(I)-mediated couplings 216 7. Intramolecular coupling of aryltrimethylstannanes to aryltrimethylstannane and alkenyltrimethylstannanes 221 7.1 Preparation of coupling precursors 221 7.2 Intramolecular couplings mediated by copper(I) chloride... 235 8. Intramolecular oxidative coupling of bisalkenyltrimefhyl-stannanes 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 I V . 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, CDC13) data for the ester 144: COSY (200 MHz) and NOED experiments 128 ix Table 15. lH nmr (400 MHz, CDC13) data for the silyl ether 155: NOED experiments 131 Table 16. *H nmr (400 MHz, CDC13) data for the ester 156: NOED experiments 132 Table 17. *H nmr (400 MHz, CDC13) data for the diester 158: NOED experiments 134 Table 18. X H nmr (400 MHz, CDC13) data for the diester 187: COSY (200 MHz) and NOED experiments 162 Table 19. *H nmr (400 MHz, C 6 D 6 ) data for the diester 188: NOED experiments 164 Table 20. *H nmr (400 MHz, CDC13) Data for the diester 198: NOED experiments 167 Table 21. X H nmr (400 MHz, CDC13) data for the diester 190: C O S Y and NOED experiments 169 Table 22. *H nmr (400 MHz, CDC13) data for the diester 191: COSY and NOED experiments 171 Table 23. *H nmr (400 MHz, CDC13) data for the diester 192: COSY and NOED experiments 172 Table 24. *H nmr (400 MHz, CDC13) data for the ester 224: NOED experiments 195 Table 25. *H nmr (400 MHz, CDC13) data for the ester 225: NOED experiments 196 Table 26. J H nmr (400 MHz, CDC13) data for the triester 226: NOED experiments 198 Table 27. *H nmr (400 MHz, CDC13) data for the triester 227: NOED experiments 199 Table 28. lH nmr (400 MHz, C 6 D 6 ) data for the triester 228: NOED experiments 201 Table 29. 1 3 C nmr (128.5 MHz, C 6 D 6 ) data for the triester 228: H M B C and H M Q C experiments 202 Table 30. *H nmr (200 MHz, CDC13) data for the ester 145: NOED experiments 204 Table 31. *H nmr (400 MHz, CDC13) data for the aldehdye 237: NOED experiments 213 Table 32. J H nmr (400 MHz, CDC13) data for the aldehyde 236: NOED experiments 213 Table 33. r H nmr (400 MHz, CDC13) data for the ketone 238: NOED experiments 215 Table 34. *H nmr (200 MHz, CDC13) data for the diester 299: COSY experiment 265 Table 35. *H nmr (400 MHz, CDC13) data for the diester 300: NOED and COSY experiments 267 Table 36. 'Hnmr (400 MHz, CDC13) data for the diester 301: NOED and COSY experiments. 269 LIST O F F I G U R E S 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. NOED experiments on 238 75 Figure 12. Steric interactions in 265 and 266 90 xu LIST OF GENERAL PROCEDURES General Procedure 1: General Procedure 2: General Procedure 3: General Procedure 4: General Procedure 5: General Procedure 6: General Procedure 7: General Procedure 8: CuCl-mediated intramolecular conjugate addition of alkenyltrimethylstannanes to alkynic esters 126 Protection of terminal alkynes with te^butyldimethylsilylcMoride 135 Conversion of THP ethers into alkyl bromides.. 138 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 xii i LIST O F A B B R E V I A T I O N S 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 - ( 1H- 1H) - homonuclear correlation spectroscopy C-x - carbon number x d - doublet 8 - chemical shift in parts per million from tetramethylsilane A - heat D I B A L - dnsobutylaluminum hydride D M F - A/,iV-dimethylformamide DMI - l,3-dimethyl-2-imidazolidinone D M P U - 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) H M P A - hexamethylpho sphoramide H-x - hydrogen number x Hz Hertz IR infrared J coupling constant in hertz RJsa-n - n bond coupling for tin and proton nuclei in Hertz L D A - lithium diisopropylamide m multiplet m meta M molar Me methyl mg milUgram(s) M H z - 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 T B A F - tetrabutylarnmonium fluoride TBS - te^butyldimethylsilyl tert - tertiary THF - tetrahydrofuran tic - thin layer chromatography T M E D A - N, N, N', JV'-tetramethy leneethy lenediamine -ve - negative Z - zusammen (configuration) • - coordination or complex xvi A C K N O W L E D G E M E N T S 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. An 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 (R1) when a ligand (R) that 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 . l a Pd(0) RSnR'g R"-X R-R" + X S n R ' 3 (1) SiMe, OTf Pd(Ph 3) 4 /LiCI 1 2 90% SiMe, (2) 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 4) to form a coordinatively unsaturated species (Pdl^). In the presence of the appropriate electrophile Pdl_ 4 +2_Lfl R-R" reductive elimination R"-X oxidative addition cis-trans isomerization R S n R ' 3 transmetalation X S n R ' 3 Figure 1. Catalytic cycle of the Stille coupling reaction 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'3) to form the bis(organo)palladium(II) species (R-Pd(L2)-R") 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^). In addition, in highly polar solvents such as N-dimethylformamide (DMF) and JV-methylpyrrolidone (NMP), a reversible tin-copper transmetalation occurs which produces an organocopper(I) derivative (vide infra). The organocopper(I) species (RCu) transmetalates with the palladium(II) species (R"-Pd(L2.)-X) to form the bis(organo)palladium complex L L R - P d - X " R - P d - X RSnR'3 L L il A 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 reaction4 for the synthesis of substituted bis(alkylidene)cyclopentanes utilizing copper(I) salts as a co-catalyst, Piers and Wong 5 made a valuable discovery: the cyclization was found to 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(Ph3P)4 (5 mol %), L i C l (2 equiv), 105 °C, 1.5 h, DMF) to 81% when copper(I) chloride was employed alone (equation 3). 5 b This method was recently exploited by Corey in the total synthesis of aegiceradienol6 (9). In this case, the internal Stille coupling of the alkenylstannane-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. C 0 2 E t TBSO CuCI (2.5 eq) 5 min, 60 °C DMF 81 % (Me 3 Sn) 2 Pd(Ph 3 ) 4 LiCl C 0 2 E t (3) SnMe, THF reflux CuCI 1 DMF, 60 °C HO' 9 T B S O 55 % over 3 steps Scheme 1. 6 Since the initial report by Piers, several instances of copper(I) salt mediated couplings have appeared in the literature. An important advance was reported by Allred and Liebeskind,7 who showed that copper(I) thiophene-2-carboxylate (CuTC) effectively carries out intermolecular cross couplings of alkenyl- and aryl iodides with alkenyl- and aryltributylstannanes in NMP. An example of this process is shown below in equation 4. 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. Liebeskind and coworkers,33 by employing 1 1 9 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 3 SnCl to the reaction mixture.7 These two observations, as well as similar evidence provided by other research groups,3 led to the conclusion that the copper(I) 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 3 SnCl and, as a result, the beneficial effect of the added copper(I) salt would be lessened or annulled. (4) 11 + CuCI + 13 14 7 CuCl ^= + Bu 3 SnCI (6) 15 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 C 0 2 M e C 0 2 M e C 0 2 M e CuCl DMF 60 °C S n M e 3 1 0 min (7) 17 15% 4 2 % C 0 2 M e 1 4 % 19 This key observation was investigated further by Piers and coworkers,8 with the 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.81* A reasonable mechanistic pathway 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). / ^ / S n R j + 2 CuCI 29 32 + Cu c A X u 1 2 R 3SnCI + 2 . C u " V 31 + Cu c 30 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). C 0 2 M e SnMe 3 32 SnMe 3 CuCI (5 equiv) DMF, 60 °C 8 2 % C 0 2 M e CD 33 I (13) 10 CuCI (5 equiv) DMF, 60 °C E t 0 2 Q s SnMe 3 3 4 SnMe 3 87% Et0 2 C (14) 3 5 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 3 CuCI (5 equiv) DMF, 60 °C SnMe 3 3 6 n = 1 3 7 n = 2 3 8 n = 3 OAc (15) 3 9 n = 1, 67 % 4 0 n = 2, 82 % 4 1 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) nitrate-mediated 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).1 1 The exact mechanistic details of this process are unclear. Ph-4 2 -SnBu; -SnBu, 4 4 Cu(N0 3) 2-3H 20 THF, rt, 30 min 50% Cu(N0 3) 2-3H 20 THF, rt, 10 min 67% Ph- -Ph 4 3 4 5 (16) (17) Since this initial report, Crisp and Glink reported the dimerization of certain alkenylstannanes facilitated by copper(II) nitrate (equation 18) in T H F . 1 2 Zhang and coworkers reported the single example of a copper(II)-mediated coupling of an a-tributylstannyl a,|3-unsaturated ester (equation 19) 1 3 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%). ,C0 2 Et Cu(N0 3 ) 2 -3H 2 0 C0 2 Et THF, rt, 1 h AcHN Bu 3Sn NHAc 46 5 2 % EtQ 2C (18) NHAc 47 SnBu 3 48 C 0 2 M e PhS COoMe SnBu 3 50 Cu(N0 3) 2-3H 20 THF, rt, 10 min 58% Cu(N0 3 ) 2 -3H 2 0 THF, rt 5 8 % Me0 2C, 49 SPh C 0 2 M e C 0 2 M e (19) (20) Me0 2 C SPh 51 Palladium salts have recently been reported by Liebeskind and Riesinger to mediate the coupling process.1 5'1 6 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(PPh3)2 and copper(I) iodide in the presence of air. II n - J rs i 1 o 3 R SnBu 3 PdCI 2(PPh 3) 2 Cul, NMP, air O 52 (21) 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 3 P h o y / o P h ( 2 2 ) 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, in a conjugate sense, to a,p-unsaturated carbonyl systems is well known, 1 8 reports on the intramolecular conjugate addition of unstabilized carbanions19 to Michael acceptors is a rarity in the published literature. 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). 2 1 In this case, the order of addition of the alkenyl (sp2) centre and the primary (sp3) centre of the bis(cuprate) to the unsaturated enone is not known. This type of reaction was applied to form a variety of spiro compounds in moderate to excellent yields (39-94%). 0 PhSCu L i 2 56 THF, -20 °C 5 6 % (23) 57 In studies by Cooke and Widener,2 2 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). I l ^ . L J ^ ' ' " " ^COR k ^ ^ x ^ / C O R R = -C(PPh 3)C0 2Et 1. BuLi, THF -78 °C 2. H 2 0 87% // (24) 58 59 In another report by Cooke, 2 3 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 BuLi 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. n-BuLi, Me3SiCI == CO^Bu THF, -78 °C 4 8 % 60 61 ^SiMe 3 = < t (25) C Q 2 B u In a study by Danheiser and coworkers,24 the conjugate addition of primary 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). C 0 2 M e Zn dust ,C0 2 Me 62 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. 2 5 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 Piers and coworkers have used organocopper(I) intermediates to effect intramolecular conjugate additions of alkenyl functions to a,(3-unsaturated ketones (enones).26 A series of ds-fused bicyclo[4.3.0]nonenones 67 can be prepared efficiently 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 2 = Et, /-Pr, or CH=CH 2), the use of copper(I) cyanide was found to give results superior to those derived from the use of copper(I) chloride. For example, when R 1 = H and R 2 = /-Pr, the application of the reaction 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). (27) 64a n = 1, R = H 64b n = 1, R = Me 64c n = 0, R = H 65a 86 % 65b 75 % 65c 45 % O CuCl , DMF, rt or O R ^ ^ - S n M e 3 C u C N , DMSO, 60 °C R Me (28) Me 66 67 15 Table 1. Synthesis of the bicycles 67 Entry R 1 R 2 Copper Source3 % Yield b 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 15c 6 H j-Pr CuCN 73 7 H CH=CH 2 CuCI 6C 8 H CH=CH 2 CuCN 60 9 Me H CuCI 85 10 Me Me CuCI 90 3 Reaction conditions: CuCI (2.5 equiv), DMF, rt, or CuCN (2.5 equiv), DMSO, 60 °C. b Unless otherwise stated, isolated yield of the purified product. c 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 DMSO 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 C u C N D M S O 60 °C m *SnMe 3 68 n = 1,2 m = 1,2 R 1 = H, Me R 2 = H, Me (29) 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. M e 3 S n C ° 2 R CuCl (2.5 equiv) DMF, 0 °C C 0 2 R C 0 2 R 70 n = 1, R = Me 71 n = 2, R = Et 72 n = 3, R = Me S n M e 3 CuCl (2.5 equiv) . ^ C U 2 M e D M F ) 0 o C C 0 2 R 7 3 n = 1, 9 5 % 74 n = 2, 94 % 75 n = 3, 74 % y ^ C 0 2 M e (30) (31) 76 n = 1 77 n = 2 OH 78 n = 1, 73 % 79 n = 2, 75 % 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. Me3Sn> C 0 2 R CuCI n = 1,2,3 80 C 0 2 R 81 C 0 2 R . C 0 2 R 1 C 0 2 R 1 M e 3 S n CuCI R 0 2 C 83 (32) (33) 3.2 Intramolecular conjugate 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,(3-alkynic 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 R 0 2 C C 0 2 R K) CuCl n C 0 2 R m (34) S n M e 3 n = 1,2, or 3 m = 1, 2, or 3 C 0 2 R 84 85 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, it was determined that it was possible for aryltrialkylstannanes to undergo a reversible transmetalation with copper(I) salts (Introduction section 2.1, pg. 6). 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 2 R)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 2 R ) 2 C 0 2 R 86 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 R = H, alkyl, or OMe 89 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). 2 8 b 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 3 SnCl, the expected copper(I) intermediate 92. This hypothesis 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) intermediate29 91 was supplied by the 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 manner30 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 2 C> 2.5 equiv CuCI f ^ S n M e 3 DMF, 0 °C COoMe 72 COoMe C 0 2 M e 75 7 min: 2 60 min: 74% C 0 2 M e S n M e 3 (37) C 0 2 M e 90 1 (glc ratio) 0 % (isolated yield) II " ^ ^ S n M e a 72 E = C 0 2 M e Cu(SnMe 3)CI - Me 3 SnCI + Me 3 SnCI II ^ " C u 92 Cu(SnMe 3)CI "E - Me 3 SnCI + Me 3 SnCI 93 + CuCI E . + CuCI 94 CuCI S n M e 3 •E (- CuCI) workup 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 C 0 2 M e Me 3 SnCI + + X Y C 0 2 M e 94 C 0 2 M e 95 + Me 3 SnCI + CuY i I i t to participate in transmetalation/ cyclization rxn CuCl + + X Y C 0 2 M e 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 (XY, e.g. acetic acid) that may perform the two-fold 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). C 0 2 R C 0 2 R CuCI (38) 96 O 97 23 C 0 2 R C 0 2 R CuCl H (39) S n M e 3 O H 9 8 O 9 9 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) chloride-mediated 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 R = H or Me n = 1 o r2 CuCl n (40) 100 o 101 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 M CuCI (2.5 equiv) b n M 6 3 DMF, rt, 1.5 h 68% (41) 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. To test the proposed methodology, a series of bisaryltrimethylstannanes 104, 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 SnMe 3 -CL CuCI 104 (42) 25 CuCl S n M e 3 CuCl S n M e 3 S n M e 3 (43) (44) 108 109 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) S n M e 3 R H H R R = H, Alkyl, o r O M e Lastly, an example involving a "mixed" aryltrimethylstannane and alkenyltrimethylstannane coupling would be attempted. It was envisaged that the distannane 112 would be transformed into the tricycle 113 upon treatment with copper(I) chloride (equation 46). E E CuCl E = C 0 2 E t S n M e 3 112 S n M e 3 (46) 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,9 it 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). R (47) E = C 0 2 E t R = H , C 0 2 M e , R 114 115 or C H 2 0 - A l k y l n = 1 or 2 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 deconjugation-alkylation 3 2 strategy involving cyclic P-trimethylstannyl a,(3-unsaturated esters would be 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 n S n M e 3 116 R R 0 2 C S n M e 3 116a T B S R = ester, ketone, C 0 2 R •TBS + Br-S n M e 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 of substituted 0-trimethylstannylbenzyl alcohols 123 and, by a suitable functional group interconversion, the o-trimethylstannylbenzyl bromides 121 can be accessed by use of directed ortho-metalation33 (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. S n M e 3 S n M e 3 C 0 2 M e 1 1 9 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 oxidation3 4 of 4-trimethylstannylpent-4-en-l-ol35 (125) to the corresponding aldehyde 126 with oxalyl chloride, DMSO, 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 one-carbon homologation protocol developed by Corey and Fuchs. 3 6 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. Swern oxidation O M e 3 S n OH M e 3 S n H 125 126 1) LDA, THF 2) C I C 0 2 E t X 0 2 E t 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 lH nmr spectrum indicated the presence 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, 3 / s n - H = 148.0 Hz, and a one 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, 3 / S n - H = 69.4 Hz). The 1 3 C nmr spectrum contained the expected 7 signals. 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,38 employing Uthium diisopropylamide (LDA) and ethyl chloroformate, served 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, 1 3 C nmr, and IR) data. The *H nmr spectrum indicated the presence of a Me 3 Sn function as a 9 proton singlet located at 8 0.14 with 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, 3 7 S n - H = 50.7 Hz), and the ethyl ester 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"1 and the carbonyl function was shown by the absorption at 1713 cm"1. In addition, the molecular 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-ol35 (130) in an overall yield of 72% (equation 48). The structure of 129 was confirmed by analyses of the lK nmr, 1 3 C nmr, and IR spectra. 31 Notable in the *H nmr spectrum were the signals due to the Me 3 Sn function (a 9 proton 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. 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 THF at -20 °C, followed by quenching the resultant hthium acetylide with ^-butyldimethylsilyl chloride (TBSC1). 1) Swern oxidation M e 3 S n C 0 2 E t (48) 1) MeLi, THF 2) TBSCI 133 T B S | M e 3 S n C u - M e 2 S , • T H F , MeOH M e 3 S n T B A F M e 3 S n 1) LDA, THF „ 2) C I C 0 2 E t 131 Scheme 8. 32 The acquired TBS-capped acetylene 133 1 0 was converted to the alkenyltrimethylstannane 134 by the treatment of 133 with the organocopper reagent Me3SnCu-Me2S35 in THF in 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 fluoride39 (TBAF) in THF. The resultant mixture of 132 and 135 could be separated by chromatography on silica gel. To complete the synthetic sequence, acylation38 of the terminal alkyne function of 135 by sequential 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 (137) was supported by spectroscopic data. For example, the *H nmr spectrum of 137 showed resonances corresponding to the Me 3 Sn function, four methylene groups, two alkenyl 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) Me3SnCu-Me2S, MeOH M e 3 S n 3) T B A F 136 4) LDA; C I C 0 2 E t 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 BuLi and methyl chloroformate38 in THF at -78 °C provided the a,(3-alkynic ester 139 in an excellent yield (99%). Following a modified literature procedure,40 the tetrahydropyranyl ether function in 139 was converted directly 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%). THPCX • j 1) BuLi, THF, -78 °C 2 ) C I C 0 2 M e THPCX 138 - C 0 2 M e 139 P P h 3 , Br 2 , 1, C H 2 C I 2 C 0 2 M e 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"1, the bromide function by the C-Br stretching absorption located at 625 cm"1, and the carbonyl group was shown by the absorption at 1718 cm"1. In the *H nmr spectrum, signals for the methylene group (a 2 proton singlet at 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 Treatment32 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 Scheme 10. E t 0 2 C . M e 3 S n C H 3 141 LDA, H M P A THF, -78 °C v u 2 t t • Me 3 Sn-M e 3 S n 143 C 0 2 M e 140 C 0 2 E t . C 0 2 M e The proposed structure of methyl 5-ethoxycarbonyl-6-trimethylstarrriylhept-6-en-2-ynoate (143) formed from the deconjugation-alkylation reaction was confirmed by the spectroscopic (lH nmr, 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"1, the carbonyl functions by the strong absorption band located at 1718 cm"1, and the Me 3 Sn moiety by the absorption at 773 cm"1. Notable in the X H nmr spectrum were the resonances ascribed to the Me 3 Sn function (a 9 proton singlet at 8 0.11, 2 / s n - H = 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). The 1 3 C nmr spectrum contained the 12 resonances expected for 143. 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 (129) was subjected to a reaction protocol developed previously for the copper(I)-mediated cyclization of alkenyltrimethylstannane functions to a,f3-alkynic esters28 (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 chloride-ammonia, 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. M e 3 S n CuCl C 0 2 E t (2.5 equiv) DMF, 0 ° C , 15 min C 0 2 E t C 0 2 E t X— S n M e 3 (50) 129 Table 2. Synthesis of the dienes 144 and 145 H 144 H 145 Entry Reaction Conditions3 % Yield b 144 % Yield b 145 1 CuCl (2.5 equiv), DMF, 0 °C, 15 min 64 18 2 CuCl (2.5 equiv), DMF, 0 °C, 1 h 60 6 3 CuCl (2.5 equiv), DMF, 0 °C, 15 min, then 1 M HC1 77 0 4 CuCl (2.5 equiv), AcOH (5 equiv), DMF, 0 °C, 15 min 85 0 N H 4 C I - N H 3 (pH 8) was used in the workup in each case. Isolated yield of purified products. 13 The proposed structure of the diene 144 was confirmed by the spectral ( XH nmr, C nmr, and IR) data. In the IR spectrum of 144, the carbonyl function was indicated by the absorption located at 1713 cm"1. In the *H nmr spectrum, resonances due to two 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 APT experiment, two negative signals at 8 14.3 and 108.3 could be attributed to the trimethylstannyl group and the lone sp2 methine carbon, respectively. The molecular formula of 144 was confirmed with a HRMS measurement on the molecular ion. 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"1 and the presence of the trimethylstannyl function was indicated by the tin-methyl rocking absorption located at 772 cm"1. The X H nmr spectrum exhibited signals due to the presence of the Me 3 Sn moiety (a 9 proton singlet at 8 0.25, 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 144 8 4.88 145 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 3 Sn group, determined the (Z)-configuration of the exocyclic tetrasubstituted double bond. The corresponding reverse nOed effects were also observed (Figure 3). Lastly, a HRMS 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,28b successfully 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)-2,3-bis(trimethylstannyl)-2-alkenoates 146, 147, and 149 can be selectively removed by hydrochloric acid-mediated and copper(I) chloride-catalyzed protiodestannylations (equations 51 and 52, respectively).43 R 1 C 0 2 R R 1 S n M e 3 H r i H n R 1 H W W W (51) M e 3 S n S n M e 3 M e 3 S n C 0 2 R D M F M e 3 S n C 0 2 R 146 147 148 R * p 0 2 R CuCI, H 2 0 Rv" C 0 2 R / \ ) = \ (52) M e 3 S n S n M e 3 DMF M e s S { ( H 149 150 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). C 0 2 E t C 0 2 E t , C 0 2 E t Jr-S nMe 3 129a 145 Cu 151 HCI C 0 2 E t 144 CuCl + or Me 3 SnCI 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 C 0 2 B ™ F complex mixture (53) 131 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 hydride4 4 (DIBAL) in THF yielded the 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 3 9 in the presence of imidazole formed the ether 155 in excellent overall yield (84%) from the stannane 131 (Scheme 12). Me 3 Sn 155 Scheme 12. 131 C 0 2 E t O T B S J B S C ^ imidazole CHpClp CuCl (2.5 equiv) AcOH (5 equiv) DMF, 0 °C, 15 min DIBAL, T H F -78 °C-> 0°C 154 152 153 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"1. In the X H nmr spectrum, resonances due to four methylene 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 260Si was confirmed by a high resolution mass spectrometric 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 4 5 was also observed as illustrated below. 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, DMF, 0 °C, 15 min) resulted in CuCl (2.5 equiv), C0 2 Et 0 _Et A c 0 H ( 5 e c l u i v ) ' ^ J * DMF, 0 °C, 15 min r ^ ^ T — M e 3 S n (54) 137 156 C0 2 Et 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"1 and the carbonyl absorption at 1714 cm"1. Notable in the X H nmr spectrum were the signals for three alkenyl protons (three 1 proton multiplets 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 ( J H nmr and ER). The ER spectrum showed the presence of the trimethylstannyl function by the absorption at 774 cm"1 and the alkenyl functions by the 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 HRMS 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. C 0 2 M e M e 3 S n . ™ r- ™ M C u C I (2-5 equiv), j I 2 2 A c 0 H (5 equiv), A DMF, 0 °C, 15 min (56) E t 0 2 C 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"1 and the C=C double bond stretch at 1665 cm"1 could be seen clearly. The : H nmr spectrum showed 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. C 0 2 M e I * . 8 5.92 E t 0 2 C 8 5.50 158 Figure 6. NOed experiments on 158 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 AcOH, DMF, 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 previously28 can be found in Discussion 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 R 0 2 C n K ) S n M e 3 C 0 2 M e 140 160 n = 1 161 n = 2 162 n = 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 166-16846 was, in each case, achieved by reaction of the substrate with M e L i in THF, followed by quenching the resultant Uthium acetylide with TBSC1. 1 0 Reaction of each of the resultant products 169-171 with 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 166-168, 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*S ^ r " 2 ^ T B S T H P O o ^ ^ THF | T H P Q . ^ C H 2 C ' 2 T B r ^ ^ ^ ' n 2)TBSCI r y n r ) n 166n = 1 169n = 1 160 n = 1 167 n =2 170 n = 2 161 n = 2 168 n = 3 171 n = 3 162 n =3 Scheme 13. The iodide 159 was prepared from the known alkynoate 17247 by a standard removal of the THP group with pyridinium /?-toluenesufonate (PPTS) in methanol,46 followed by treatment of the resultant alcohol with triphenylphosphine diiodide and imidazole.4 8 The overall yield of 159 was 79%. The iodide 159 exhibited spectral characteristics identical with those reported previously.47 - C 0 2 M e 1 ) p p T S i M e 0 H THPO. 2) PPh 3 - l 2 , Imid COoMe (57) 172 1 7 3 X = OH 159 X = I Reaction of each of the enol triflates 174,28b 175,Z8b and 1761U with Uthium • 2  <10 (trimethylstannyl)(cyano)cuprate38 in THF provided the known cyclic 46 alkenyltrimethylstannanes 163-165 in isolated yields of 92%, 93%, and 76%, 4 9 respectively (equation 58). The spectroscopic data derived from the esters 163-16428b and 16510 were in full accord with those previously reported. OTf 174 n = 1, R = Me 175 n = 2, R = Et 176 n = 3, R = Me Li[(Me 3Sn)(CN)Cu] THF C 0 2 R „«oc S n M e 3 163 n = 1, R = Me 164 n = 2, R = Et 165 n = 3, R = Me (58) 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-alkylation32 of the 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 C 0 2 R R 0 2 C ,«) 1) LDA, H M P A or D M P U , THF S n M e 3 2) 160,161, or 162 163-165 n = 1 or 3, R = Me n = 2, R = Et T B S TBAF S n M e 3 178-180 182, 184 11) LDA, THF C 0 2 M e 2 ) C I C 0 2 M e 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 2 C 1) LDA, DMPU, THF 'SnMe, 2) 140 or 159 164 Table 3. Synthesis of the cyclization precursors 178-184 SnMe 3 181,183 C 0 2 M e (59) Entry Substrate n m Product Procedure3 % Yield b 1 163 1 1 178 A 55 2 163 1 2 179 A 33 c 3 163 1 3 180 A 65 4 164 2 1 181 B 51 5 164 2 2 182 A 35 c 6 164 2 3 183 B 58 7 165 3 3 184 A 22 a Procedure A - following the reaction sequence illustrated in Scheme 14. Procedure B - following the reaction sequence illustrated in equation 59. b Isolated (overall) yields of purified products from the substrates 163-165. 0 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"1, the carbonyl functions by the strong C=0 stretching absorption band centred at 1718 cm"1, and the Me 3 Sn function by the tin-methyl rocking absorption at 770 cm"1. In the : H nmr spectrum, resonances due to the Me 3 Sn moiety (a 9 proton singlet at 8 0.13, 2 - / s n - 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 1 3 C nmr spectrum displayed the appropriate number of signals, 14, and four negative signals that appeared in an APT experiment (8 -8.6, 52.0, 52.5, and 144.3) were attributed to the Me 3 Sn function, the two methyl signals from 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 (lH nmr, 1 3 C nmr, and ER) and the HRMS measurements acquired from the remainder of the alkenyltrimethylstannanes 178 and 180-184 provided suitable confirmation of their structural identities. With the desired cyclization precursors in hand, we could now examine the copper(I) chloride-mediated methodology. 1.3.2 Copper(I) mediated cyclizations The results derived from treatment of the cyclization precursors 178-185 with 2.5 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. R 0 2 C CuCl (2.5 equiv) AcOH (5 equiv) C 0 2 R n S n M e 3 C 0 2 M e DMF, 0 °C, 15 min n = 1 or 3, R = Me n = 2, R = Et N ^ C 0 2 M e m (60) 178-185 186-193 49 Table 4. Synthesis of the bicycles 186-193 Entry Substrate n m Product % Yield 3 1 178 1 1 186 0 b 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 d 7 184 3 3 192 94 8C 185 3 1 193 82 Isolated yields of purified products. b A complex mixture that included the cyclized product and protiodestannylated material was obtained. c This example was performed by Dr. Patricia Gladstone.31 d The reaction in this case required 1 h to go to completion. 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. C 0 2 M e C 0 2 M e (61) C 0 2 M e CuCI AcOH S n M e 3 178 C 0 2 M e DMF 0 °C C 0 2 M e ~ ^ ^ C 0 2 M e 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 179-185, 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. C 0 2 M e C 0 2 M e M = Cu or Cu(SnMe 3)CI m 195 196 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 protonatation of the uncyclized copper intermediate 195. 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 X H nmr spectrum 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 2 /Pd/C or H 2/Pt failed to provide 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"1 and a C-C double bond stretching absorption appeared at 1636 cm"1. In the X H nmr spectrum, the resonances due to four methylene groups (see experimental section for assignments), two C 0 2 M e functions, and two alkenyl protons were clearly visible. With the aid of a correlated spectroscopy (COSY) spectrum, the assignment of the proton resonances in the X H nmr spectrum of 187 could be made and the (£)-configuration of the exocyclic double bond was confirmed by several J H nmr nOed experiments, which are illustrated in Figure 7. In the 1 3 C nmr spectrum of 187, the expected 13 signals were observed. 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. The reasons for this slight anomaly are not clear. Regardless, l-ethoxycarbonyl-(£)-7-methoxycarbonylmethylidenebicyclo[4.4.0]oct-5-ene (191) was obtained from the stannane 183 in excellent yield (92%). The spectral data ( J H nmr, 1 3 C nmr, and ER) and HRMS 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 THF 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 2 Et X ' 1) DIBAL, THF (62) 189 1 9 7 X = OH 1 9 8 X = O T B S 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 2 R ( 1 ) . m C0 2 R 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 1 = R 2 = R 3 = H 202 R 1 = R 2 = R 3 = H 200 R 1 = R 3 = H, R 2 = Me 203 R 1 = R 3 = H, R 2 = Me 201 R 1 = R 2 = R 3 = OMe 204 R 1 = R 2 = R 3 = OMe Chart 4. Following a modified literature procedure for the directed orthometalation of benzyl alcohols,5 0 each of the commerically available benzyl alcohols 205-207 were treated with 2.5 equiv of BuLi and T M E D A in E t 2 0 (Scheme 15). The dianions 208 formed from this deprotonation process33 were quenched with 1.5 equiv of Me 3 SnCl. 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 ( J H nmr, 1 3 C nmr, and ER) obtained from the alcohols 200 and 201 were also in total agreement with their assigned structures. Using 3,4,5-trimethoxy-2-trirnethylstannyl benzyl alcohol (201) as an example, the ER spectrum showed a broad OH absorption at 3432 cm' 1 and the tin-methyl rocking absorption at 774 cm"1. In the *H nmr spectrum, signals due to the Me 3 Sn function (a 9 proton singlet at 8 0.30, 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 / s n - H - 15.6 Hz), and the alcoholic proton resonance (a 1 proton triplet at 8 1.53, / = 5.7 Hz, disappears when shaken with D 2 0) were clearly visible. The 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 BuLi, TMEDA, E t 2 0 205 R = R = R = H 206 R 1 = R 3 = H, R 2 = Me 207 R 1 = R 2 = R 3 = OMe 202 R = R = R = H 203 R 1 = R 3 = H, R 2 = Me 204 R 1 = R 2 = R 3 = OMe P P h 3 - B r 2 imidazole CH2CI2 2 L i + Me 3 SnCI; H 2 0 S n M e 3 199 R ' =R" = R° = H 200 R 1 = R 3 = H, R 2 = Me 201 R 1 = R 2 = R 3 = OMe Scheme 15. Treatment of each of the benzyl alcohols 199-201 with triphenylphospliine dibromide51 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 3 Sn function was confirmed by the absorption at 773 cm"1. The X H nmr spectrum 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 HRMS 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 3 9 in THF provided the alkyne 210 as a volatile oil. The alkyne 210 was immediately sequentially treated with L D A in THF and methyl chloroformate41 to give the ester 211 in excellent yield (90% over 2 steps from 282). 1) NaH, THF; 160 199 S n M e 3 2) TBAF, THF 3 3) LDA, THF; C I C 0 2 M e (63) ' S n M e 3 209 X = T B S 210 X = H 211 X = C 0 2 M e The spectral data ( J H nmr, 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"1, the carbonyl stretching band at 1718 cm"1, and the tin-methyl rocking absorption at 751 cm"1 were present. In the J H nmr spectrum, the resonances due to the Me 3 Sn moiety (a 9 proton singlet at 8 0.28, 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 87 .51 , /=5 .3 Hz, 3 / s n - H = 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 alkylations9 with potassium hydride and the bromides 202 and 160 to provide the dialkylated product 212 (Scheme 16). Removal of the TBS function of 212 with T B A F 3 9 in THF and acylation41 (LDA, D M P U , THF; ClC0 2 Me) of the resultant terminal 57 alkynic function of 214 provided the alkynoate 215 in good overall yield (74% over 4 steps). S n M e 3 1) K H , THF ^ J ^ ^ \ ^ C 0 2 E t C H 2 ( C 0 2 E t ) 2 B r C 0 2 E t S n M e 3 202 212 1) KH, THF; f Br 160 2) TBAF, THF 3) LDA, D M P U , THF; C I C 0 2 M e S n M e 3 213 X = TBS 2 1 4 X = H ,, i R R 215 X = C 0 2 M e < ^ R = C 0 2 E t X -TBS 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"1 and the trimethylstannyl group at 770 cm"1 were visible. 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, 3 / S , I - H = 47.4 Hz) were present. The 1 3 C nmr spectrum showed the expected 17 signals and a HRMS 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 hydride5 2 in dry DMF, followed by the addition of propargyl 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 chloroformate41 to furnish the 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) 200 2) LDA, DMPU; C I C 0 2 M e ^SnMe 3 216 X = H 217 X = C 0 2 M e Finally, alkylation9 of diethyl malonate with each of the benzyl bromides 203 or 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). S n M e 3 C H 2 ( C 0 2 E t ) 2 1) KH, THF 2) 203 or 204 218 R 1 = R 3 = H, R 2 = Me 219 R 1 = R 2 = R 3 = O M e 203 R 1 = R 3 = H, R 2 = Me 204 R 1 = R 2 = R 3 = OMe 220 R 1 = R 3 = H, R 2 = Me, X = H R 1 221 R 1 = R 3 = H, R 2 = Me, X = C 0 2 M e 222 R 1 = R 2 = R 3 = OMe, X = H R 2 2) LDA, DMPU, THF; C I C 0 2 M e S n M e 3 223 R Scheme 17. R 2 = R 3 = OMe, X = C 0 2 M e R° E = C 0 2 E t 59 Reaction of the terminal alkyne functions of 220 and 222 with L D A and D M P U in THF and treatment of the resultant Uthium acetyUdes with methyl chloroformate41 provided the cyclization precursors 221 and 223 in 63% and 80% yields, respectively. The spectral data (XH nmr, 1 3 C nmr, and IR) and HRMS mass determinations obtained from the compounds 221 and 223 were in full accord with their assigned structures. For instance, in the J H nmr spectrum of 223, two singlets at 8 3.71 and 3.84, 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 X H nmr spectra of both 221 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"1 and tin-methyl rocking 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 1 AcOH (5.0 equiv) C 0 2 M e -DMF, 0 °C, 15 min (65) 224-228 C ° 2 M e 60 Table 5. Synthesis of the bicycles 224-228 Entry Substrate R 1 R 2 R 3 X Product % Yield 3 1 211 H H H -0- 224 92 2 217 H Me H -0- 225 97 3 215 H H H -C(C0 2 Et) 2 - 226 98 4 221 H Me H -C(C0 2 Et) 2 - 227 92 5 223 OMe OMe OMe -C(C0 2 Et) 2 - 228 97 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, 1 3 C nmr, and IR) derived from 225 were in full accord 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 X H nmr spectrum of 225, the 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 1 3 C nmr spectrum of 225 revealed the expected 13 resonances. In an APT 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 sp2 methine carbons, respectively. A high resolution mass spectrometric measurement on the molecular ion confirmed the molecular formula of C13H14O3. In addition, lH nmr nOed experiments confirmed the (Z)-configuration of the alkenic function in 225 (Figure 8). Likewise, the spectral data (IR, X H nmr, and 1 3 C nmr) confirmed the proposed structure of 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 8 6.35 224 225 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 X H nmr spectrum were the resonances ascribed to the benzylic methylene 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 C H 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 lH nmr nOed experiments (see Experimental, pg. 198 and 199). 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 3 SnCl from the 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 + C u X (66) + HX E = C 0 2 R 232e 232g Cu(SnMe 3 )CI + HX (67) + CuX 232d 232g 65 S n M e 3 + CuCl - C u C l 232a CuCl or R C 0 2 C u E = C 0 2 R 1 R = C F 3 or C H 3 Scheme 19. Cu(SnMe 3)CI - Me 3 SnCI + Me 3 SnCI 232b 232c Cu(SnMe 3)CI - Me 3 SnCI + Me 3 SnCI Cu V ^ E 232d + CuCI + CuCI 232e CuCl S n M e 3 w ^ E (- CuCl) R C 0 2 H 232d R C 0 2 H 232f 232g + R C 0 2 S n M e 3 (- Me 3 SnCI) + CuCl = = = = = = = R C 0 2 C u + Me 3 SnCI (- R C 0 2 S n M e 3 ) 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 M e 3 S n 129 CuCI C 0 2 E t (2.5 equiv) • DMF, 0 °C, 15 min without H 2 0 C 0 2 E t C 0 2 E t J — S n M e 3 (68) H 144 64% H 145 18% 26% with H 2 0 (2 equiv) 58% 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 Cu(SnMe 3)CI or C F 3 C 0 2 H 232c 232h 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 homocoupling8 or protiodestannylation43 of the starting material or to some other unknown reactions. C 0 2 E t X 0 2 M e Me^Sn C 0 2 M e 143 E t 0 2 C (70) 158 67 Table 6. Synthesis of the diene 158 Entry Reaction Conditions % Yield 3 1 2.5 equiv CuCl, 0 °C, DMF, 15 min 52 2 2.5 equiv CuCl, 5.0 equiv C F 3 C 0 2 H , 0 °C, DMF, 15 min 74 3 2.5 equiv CuCl, 5.0 equiv C H 3 C 0 2 H , 0 °C, DMF, 15 min 85 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 Conditions3 % Yield b 1 2.5 equiv CuCI, 0 °C, DMF, 1 h c 2 2.5 equiv CuCI, 5.0 equiv C H 3 C 0 2 H , 0 °C, DMF, 15 min 87 3 2.5 equiv CuOAc, 5.0 equiv C H 3 C 0 2 H , 0 °C, DMF, 15 min 78 4 2.5 equiv CuCI, 5.0 equiv C H 3 C 0 2 H , 0 °C, DMI, 15 min 83 5 0.1 equiv CuCI, 5.0 equiv C H 3 C 0 2 H , 0 °C, DMF, 1 h 0e,f 6 0.5 equiv CuCI, 2.0 equiv C H 3 C 0 2 H , 0 °C, DMF, 45 min d 89 7 0.1 equiv CuCI, 2.0 equiv C H 3 C 0 2 H , 0 °C, DMF, 4 h 15 min d 76 8 2.5 equiv CuCl 2 , 5.0 equiv C H 3 C 0 2 H , 0 °C, DMF, 15 min 0e 9 2.5 equiv Cu(OAc) 2, 5.0 equiv C H 3 C 0 2 H , 0 °C, DMF, 15 min 0 e 3 Unless otherwise stated, [CuCI] ~ 0.25 M . b Isolated yield of purified products. 0 A -1:1 mixture of cyclized material 156 and starting material 136 was obtained (see Discussion section 1.2.2). d The substrate was added via a syringe pump over the first 15 min. e Only starting material was identified in the *H nmr spectrum of the crude product. f [CuCI] - 0.01 M . 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 protiodestannylation43 or oxidative homocoupling pathways.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 3 ) , the copper-tin transmetalation and internal conjugate addition leading 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 3 SnCl (equation 67). 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 3 SnCl can react (reversibly) to form Me 3 SnOAc and regenerated 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 studies3'5'53 that polar aprotic solvents, such as D M F or DMSO, 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. 5 3 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). 5 4 Thus, it seemed reasonable that DMI 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) 2 in dry 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,55 treatment of the alkyne 180b with L D A in THF and reaction of 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%). COgMe ^ 1) LDA , THF, C 0 2 M e -78 °C ^ c H 2) DMF ^ v. S n M e 3 ' S n M e 3 180b 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"1, the carbonyl function by the absorption located at 1733 cm"1, and the Me 3 Sn function by the absorption at 772 cm"1. Significant resonances in the X H nmr spectrum could be ascribed to the Me 3 Sn group (a 9 proton singlet at 8 0.12, 2/sn-H = 54.3 Hz), the methyl ester moiety (a 3 proton singlet at 8 3.63), the olefinic proton (a 1 proton doublet of doublets at 8 5.96, / = 2.1, 2.1 Hz, Vsn-H = 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 HRMS 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 from the alkyne 180b (Scheme 20). Thus, treatment of 180b with L D A followed by the addition of ethanal56 yielded the propargylic alcohol 234, presumably as a mixture of diastereomers. The 72 secondary alcohol was then converted to the corresponding ketone 235 via a Swern oxidation.34 The overall yield of the two-step process was 70% from the alkyne 180b. 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"1 and the carbonyl functions at 1729 cm"1. The X H nmr spectrum showed key signals corresponding to the Me 3 Sn function (a 9 proton singlet at 8 0.13, 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 / s n - H = 38.0 Hz). The 1 3 C nmr spectrum exhibited the expected 15 signals. Lastly, a high resolution mass spectrometric measurement on the (M +-Me) fragment confirmed the molecular formula of Cn^eC^Sn. 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 J H nmr spectrum of the crude product, was -1:4 ratio, respectively. COoMe C 0 2 M e C 0 2 M e CuCl (2.5 equiv), AcOH (5 equiv), H D M F , 0 ° C , 15 min T "Y O O 236 (minor) 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"1 and the a,f3-unsaturated aldehyde at 1672 cm"1 were visible. A high resolution mass measurement of the mixture confirmed the molecular formula of C13H16O3. Two sets of signals in the 1 H and 1 3 C nmr spectra were attributed to the presence of the isomers 236 and 237. In the X H nmr spectrum of the mixture of the two compounds, the signals ascribed 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 APT 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 lH nmr spectrum of the mixture. In the 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 J H nmr spectrum The 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. 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). 236 (minor) 237 (major) 75 COoMe CuCl (2.5 equiv), AcOH C0 2 Me C 0 2 M e i *-C H 3 (5 equiv), + (74) SnMe 3 O DMF, 0 °C, 15 min T C H 3 H3C Y 235 O 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"1 and 1681 cm"1. Notable in the X H nmr spectrum were the presence 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 1 3 C nmr 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 X H nmr nOed experiment, the results of which are illustrated in Figure 11. 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 C0 2 Me 8 2.19 238 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,(3-unsaturated 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 COoMe R = H or Me C 0 2 M e Cu C(=0)R C 0 2 M e 240b H C(=0)R 240c COoMe PT '''OCu 240d C0 2 Me C 0 2 M e Rxvv X>Cu 240e C 0 2 M e K X(=0)R R(0=)C H 240f 240g Scheme 21. 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,(3-alkynic 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, DMF, 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 SnMe 3 C ° 2 R CuCI (2.5 equiv), AcOH(5.0 equiv), DMF, 0 °C, 15 min C 0 2 R (75) C0 2 Et C0 2 Me GOoR n N " E t 0 2 C n = 1,2,3 243 •fi) m \ - C O o R 158 n = 1, 2, 3 m = 1, 2, 3 R = Me or Et 85 C 0 2 M e Chart 5. Compounds 243,158, 85, and 89. R = H, Me, or OMe X = O or C(C0 2 Et) 2 89 Me 3Sn C0 2 Me *SnMe 3 233 R = H 235 R = Me C0 2 Et CuCI AcOH • 0 °C DMF C 0 2 M e (76) C(=0)R 236,237 R = H 238,239 R = Me CuCI (10 mol %) AcOH, DMF, 0 °C 76% C0 2 Et (77) 136 156 79 2. Intermolecular and intramolecular oxidative coupling of alkenyl- and aryltrimethylstannanes mediated by copper(I) chloride 2.1 Introductory remarks Previous studies8 have described the copper(I) mediated intermolecular homocoupling of alkenylstannanes. 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). 2 4 3 2 4 4 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.5 9 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). 1 1 5 1 1 4 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). 6 0 The P-trimethylstannyl-a,P-unsaturated ketones of general structure 247-250 were prepared by following the procedure devised by Piers, Morton, and Chong 6 1 which involved the addition of hthium (trimethylstannyl)(phenylthio)cuprate 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 3, l2-B 3 N o MeCN R Li(Me3Sn)(PhS)Cu, THF 2 4 6 2 4 5 Scheme 22. Table 8. Synthesis of the iodides 246a-246d and stannanes 247-250 SnMe 3 2 4 7 - 2 5 0 Entry n R Product % Yield 3 Product % Yield b 1 1 H 246a 79 247 38 2 1 Me 246b 92 248 74 3 2 H 246c 83 249 34 4 2 Me 246d 91 250 56 Isolated yield from the diketones 245. b Isolated yield from the P-iodoketones 246. 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 CuCI (2.5 equiv) ( / ) T DMF.r t n * \ J A ^ ( 8 0 ) 30 min [I (> ) S n M e 3 247-250 251-254 Table 9. Synthesis of the diketones 251-254 Entry Substrate n R Product % Yield 3 1 247 1 H 251 81 2 248 1 Me 252 91 3 249 2 H 253 94 4 250 2 Me 254 91 Isolated yield of purified products. The proposed structures of the homocoupled products 251-254 were confirmed by an analysis of the spectrometric (lH nmr, 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"1. The J H 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 1 3 C nmr spectrum, which displays resonances that correspond to the four 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 HRMS measurement on the molecular ion. The structures of the remaining homocoupled products 252-254 were assigned by similar analyses of their J H nmr, 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 B u L i 3 3 and T M E D A in E t 2 0 for 3 h at room temperature and quenching the resultant 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). 255 BuLi (2.2 equiv) r T M E D A rt » EtoO 256 2 L i + Me 3 SnCI (2.4 equiv) S n M e 3 S n M e 3 , 0 1 0 4 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 ) N a H , 0 o C , DMF S n M e 3 S n M e 3 2) Br 199 ^ ^ " S n M e 3 202 3 0 °C, 30 min; rt, 14 h (81) 108 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' 1. The 1 H nmr spectrum contained resonances corresponding to the Me 3 Sn groups (an 18 proton singlet at 8 0.26, 2 / s n - 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 HRMS measurement on the (M +-Me) fragment. A series of intramolecular coupling precursors was synthesized by successive alkylations of diethyl malonate. Dialkylation9 of diethyl malonate by treatment with 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 hydride9 in THF, < E t 0 2 C C 0 2 E t C 0 2 E t 1) KH, THF, rt, 30 min M e 3 S n v ^ ^ > C A ^ S n M e 3 C 0 2 E t 2) 203 or 204, rf—tfK " (82) reflux FT FT R ' R" 257 R 1 = R 3 = H, R 2 = Me 258 R 1 = R 2 = R 3 = OMe 85 followed by addition of the bromide 204, provided the "mixed" bisaryltrimethylstannane 259 in good yield (78%) (equation 83). Lastly, sequential alkylation9 of diethyl malonate with the bromides 260 2 7 and 202 provided the distannane 113 (Scheme 24). E t 0 2 C C 0 2 E t 1 ) K H , THF, M e 3 S n / ^ ^ \ S n M e 3 C 0 2 E t rt, 30 min S n M e 3 C 0 2 E t 2) 204, reflux f V0Me( 8 3) 212 1) KH, THF, < COpEt rt, 1 h S n M e 3 / L ^ \ / C 0 2 E t C 0 2 E t P x S n M e 3 \ / I I — C ° 2 B / V ^ B r 261 MeO OMe 259 1) KH, T H F rt, 1h 2) , 260 reflux 202 reflux E t 0 2 C C 0 2 E t Me 3 Sn S n M e 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 1 and the tin-methyl rocking absorption at 776 cm"1. The X H nmr spectrum displayed resonances due to the Me 3 Sn groups (an 18 proton singlet at 8 0.24, 2 / S „ - H = 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 / s n - 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 APT 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 sp2 methine carbons. The molecular formula of 257 was confirmed by a HRMS measurement on the (M +-Me) fragment. Analyses of the spectral data ( XH nmr, 1 3 C nmr, and IR) confirmed the assigned structures of the remaining distannanes 258-259 and 112 and their molecular masses were also confirmed by HRMS 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 DMF. 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 6 2 and 109 6 3 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 Product % Yield 3 1 S n M e 3 SnMe3 104 105 98 b 2 Me 3 Sn O—v. SnMe3 O Q 106 107 9 1 c d 3 SnMe 3 SnMe 3 108 109 75 b 91 c 3 Isolated yield of purified products. b Procedure A employed - 5 equiv CuCI, DMF, rt, 30 min. c Procedure B employed - 5 equiv CuCI, DMF, rt, add substrate over 30 min, stir for an additional 30 min d 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 solution-suspension 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 Product Yield3 1 SnMe3 SnMe3 (f R R {^^J R = - C 0 2 E t 262 E t 0 2 C ^ / C 0 2 E t 263 7 8 b , d 2 SnMe3 SnMe 3 R = - C 0 2 E t 257 E t 0 2 C v - C 0 2 E t / 264 \ 95c 3 SnMe3 SnMe 3 OMe R = - C 0 2 E t OMe 259 E t O a C v ^ - C O a E t \==J ^ V ^ O M e MeO o M e 265 92c 4 SnMe 3 SnMe 3 xj R R X X MeO OMe OMe OMe R = - C 0 2 E t 258 E t O s C v . C O j . E t M e O — \ _ W W - / O M E MeO M e 0 O M e O M e 266 62c 5 S n M e 3 SnMe 3 \__J R R [f ^ \ R = - C 0 2 E t 112 £ 1 0 3 0 ^ ^ 0 0 2 Et 6-b 113 94c a Isolated yield of purified products. b Procedure A employed - 5 equiv CuCl, DMF, rt, 30 min. 0 Procedure B employed - 5 equiv CuCl, DMF, rt, add substrate over 30 min, stir for an additional 30 min. d This example was performed by Dr. Patricia Gladstone.31 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 HRMS 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 atropisomerism64 causes the supposedly enantiotopic methylene protons (H a , Hb) to become diastereotopic and, consequently, the protons appear as two doublets in the *H nmr spectrum. The 1 3 C nmr spectrum of 266 displays only 14 signals, which is not surprising given the symmetrical nature of the product. In an APT 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 HRMS measurement on the molecular ion. An examination of the spectrometric data (*H nmr, 90 C nmr, HRMS, and IR) acquired from the substances 264, 265, and 113 also confirmed their respective proposed structures. 266 E = C0 2 Et 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 transmetalation3 of both trimethyl-108b Scheme 25. 91 stannane moieties in 108 with 2 equiv of CuCI would result in the bisarylcopper(I) species 108a and 2 equiv of Me 3SnCl. A disproportionation8 of 108a would form Cu(0) 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%). An 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 2 M e , or CH 2 0-a lky l n = 1 or 2 Chart 6. Treatment of the known alcohol 26847 with triphenylphosphine diiodide and imidazole4 8 in CH2CI2 provided the iodide 269 in excellent yield (93%). The spectral data derived from 269 were in full agreement with those previously reported.47 268 P P h 3 - l 2 ' S n M e 3 Imidazole • CHpClp 269 . S n M e 3 (84) Reaction of alkynoate 27066 with hthium trimethylstannyl(cyano)cuprate38 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 imidazole48 in methylene chloride provided the alkylating agent 273 (Scheme 26). The overall yield of the three-step sequence was 65%. 93 Me0 2 C> L ) = C 0 2 M e Me 3 Sn(CN)CuU T B S 0 THF, MeOH T B S O - ^ M ^ S n M e 3 270 M e 0 2 C „ 273 P P h 3 - l 2 Imidazole ' S n M e 3 C H 2 C I 2 271 T B A F MeO?C> H 0 ^ ^ 3 ^ S n M e 3 272 Scheme 26. The spectral data support the proposed structure of the iodide 273. For instance, the X H nmr spectrum showed diagnostic resonances corresponding to the trimethylstannyl function (a 9 proton singlet at 8 0.20, 2 /s n-H = 54.6 Hz) and the methyl ester function (a 3 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 3 Sn group and the hydrogen are trans to one another (-120 Hz) . 6 7 The 1 3 C nmr spectrum displayed the expected 9 signals. Finally, the molecular formula of 273 was coiifirmed by a HRMS measurement on the (M +-Me) fragment. The methyl ether 279 was prepared in five steps from the tetrahydropyranyl protected alcohol 274 4 1 (Scheme 27). Treatment of the latter material with lithium trimethylstannyl(cyano)cuprate38 and MeOH in THF 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 5 2 in THF provided the alkenylstannane 277. The iodide 279 was obtained by the removal of the tetrahydropyranyl group with PPTS in methanol46 and subsequent conversion of the acquired primary alcohol to the iodide 4 8 The four-step overall yield was 35% from the alkynoate 274. 94 T H P O 3 274 -COoMe Me 3 Sn(CN)CuLi M e 0 2 C , M e O ' ~SnMe 3 278 X = OH 279 X = I THF, MeOH T H P O ^ M ^ S n M e g 275 1) DIBAL 2) NaH, THF; Mel 1) P P T S , MeOH 2) P P h 3 - l 2 Imidazole C H 2 C I 2 T H P O r - 7 3 ^ S n M e 3 2 7 6 X = OH 277 X = OMe 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, 3 /sn-H = 77.2 Hz). The (E)-configuration of the trisubstituted olefin was confirmed by the magnitude of the tin-proton coupling constant.67 The 1 3 C nmr spectrum showed the expected 9 resonances. The molecular formula of 279 was confirmed by a HRMS 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 28068 with pyridinium chlorochromate in methylene chloride,6 9 provided the corresponding crude aldehyde. The use of a modified Corey-Fuch one carbon homologation protocol 3 6 ' 3 7 employed previously (see Discussion section 1.2.1, pg. 29) provided 7-te^butyldimethylsilylhept-1-yne (281) in 43% overall yield. 95 1 ) P C C , N a 0 A c , C H 2 C I 2 T B S O V^ln, OH -3 2) P P h 3 , C B r 4 , C H 2 C I 2 TBSO' -H 280 T B S O 3) Mg, THF = C 0 2 M e 3 281 285 Me 3 Sn(CN)CuLi , THF, MeOH M e 0 2 C S n M e 3 286 1) DIBAL 2) NaH, THF; BnBr T B S O ^ > ^ V ^ R O ^ . S n M e 3 289 R = H 290 R = Bn 1) MeLi, THF 2) C I C 0 2 M e Me 3 SnCu-Me 2 S, THF, MeOH 1) T B A F , THF 2) P P h 3 , l2, Imidazole T B S O ' ^ M Q Y 282 S n M e 3 1) T B A F , THF 2) P P h 3 , l 2 , Imidazole S n M e 3 n 3 283 X = O H 284 X = I S n M e 3 287 R = C 0 2 M e , X = OH 288 R = C 0 2 M e , X = I 291 R = C H 2 O B n , X = OH 292 R = C H 2 O B n , X = I 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"1 and the C-C triple bond stretch at 2120 cm"1. The X H nmr spectrum showed 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 HRMS measurement on the (M +-Me) fragment. 96 Treatment of the terminal alkyne 281 with Me3SnCu-Me2S41 and methanol in THF 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 THF 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 imidazole4 8 gave the iodide 284 in excellent yield (84%) from the stannane 282. 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 / S „ - H = 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 1 3 C nmr spectrum showed the expected 11 carbon resonances and a HRMS 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 methylchloroformate38 to provide the a,P-alkynic ester 285. Reaction of the alkynoate 285 with hthium trimethylstannyl (cyano)cuprate38 and MeOH in THF 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 (3/sn-H = 64.6 Hz) . 6 7 The 1 3 C nmr spectrum showed the presence of the expected 10 carbon resonances. The molecular formula of C12H23O2S11I was confirmed by a HRMS measurement on the (M +-Me) fragment. Lastly, reduction of the ester 286 with D I B A L 4 4 and reaction of the resultant allylic alcohol 289 with NaH and BnBr 5 2 provided the benzyl ether 290 (Scheme 28). Treatment of the latter substance with T B A F in T H F , 3 9 and subjection of the acquired primary alcohol 291 to triphenylphosphine diiodide and imidazole4 8 afforded the iodide 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 X H nmr spectrum of 292 displayed the trimethylstannyl group (a 9 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, 3 / s n - H = 77.9 Hz), and six methylene groups. The 1 3 C nmr spectrum showed the expected 14 carbons. The molecular formula of 292 was corjfimied by a HRMS measurement on the (M +-Me) fragment. Straightforward alkylations9 of the malonate 261 (whose preparation was 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 3 / — , c c R A / ^ C O z E t ^ \ 7 1 N — ' C0 2 Et (85) 261 SnMe 3 E = C0 2 Et 293-298 SnMe 3 Table 12. Synthesis of the distannanes 293-298 Entry n R Reaction conditions Product % Yield 3 1 1 - H L D A , THF, 0 °C; 269, reflux 293 78 2 1 - C 0 2 M e L D A , THF, 0 °C; 273, reflux 294 86 3 1 -CH 2 OMe K H , THF, rt; 279, reflux 295 92 4 2 - H K H , THF, rt; 284, reflux 296 96 5 2 - C 0 2 M e K H , THF, rt; 288, reflux 297 82 6 2 -CH 2 OBn K H , THF, rt; 292, reflux 298 73 Isolated yield of purified products. The structures of the dialkylated materials 293-298 were fully supported by then-respective *H nmr, 1 3 C nmr, and IR spectra. For instance, the C=0 functions in 294 were indicated by the broad absorption at 1729 cm"1. The *H nmr spectrum of 294 showed the 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 constant67 of the alkenyl proton ( 3/s n-H = 73.7 Hz). The 1 3 C nmr spectrum showed the expected 21 signals. Also, the molecular formula of C28H5o06Sn2 was confirmed by a HRMS measurement on the (M +-Me) fragment. 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 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. HRMS). S n M e 3 S n M e 3 R add stannane over 2 h; stir 2 h 5 equiv CuCI DMF, rt E n (86) R E = C 0 2 E t 293-298 E = C 0 2 E t 299-304 99 Table 13. Synthesis of the bicyclic dienes 299-304 Entry Starting Material n R Product Yield 3 1 293 1 H 299 93 2 294 1 -C0 2 Me 300 72 3 295 1 -CH 2 OMe 301 91 4 296 2 H 302 5 297 2 - C 0 2 M e 303 45 6 298 2 -CH 2 OBn 304 c 3 Yield of purified products. b A mixture of product 302, protiodestannylated, dichlorodestannylated, and chlorodestannylated material was obtained. c A rnixture of product 304, protiodestannylated and chlorodestannylated material was obtained. 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, DMF, 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 S n M e 3 E = C 0 2 E t 293 S n M e 3 add over 2 h; stir 2 h (87) 78 % E = C 0 2 E t 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 homocoupling8 processes. C 0 2 M e 5 e q U i v CuCI DMF, rt S n M e 3 E = C 0 2 E t 294 S n M e 3 add over 15 min; stir 15 min (88) E = C 0 2 E t C ° 2 M e 5 0 % 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"1 and a C=C bond stretch at 1626 cm"1. In the X H nmr spectrum, aside 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 1 3 C nmr spectrum contained the expected 16 signals and, in an APT 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 HRMS measurements on their molecular ions. Lastly, the (£)-configuration of the trisubstituted double bond in 300 and 301 was determined by a series of X H nmr nOed experiments (see 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 GC 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 GC and GC-MS 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 1 H nmr 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 APT experiment could be ascribed to the methyl carbons of the ethyl ester functions, the methyl ester, and the lone sp2 olefinic C-H, respectively. The IR spectrum showed a carbonyl absorption at 1730 cm"1 and a C-C double bond stretching absorption at 1620 cm"1. Lastly, the molecular formula of 303 was confirmed by a HRMS 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 E f M e 3 5 equiv CuCI K^K^Yf^ DMF.rt S n M e 3 5 E = C 0 2 E t 297 C 0 2 M e add over 2 h; stir 2 h (91) E = C 0 2 E t C 0 2 M e 303 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 3 SnCl (5 equiv), the intermolecular homocoupling reaction of 163 is retarded and increased amounts of chlorodestannylated material 312 is formed (equation 92). 5 3 ^ . C 0 2 M e , C 0 2 M e / | | x > M e 0 2 C 313 ^ X 0 2 M e 2.5 equiv CuCI S n M e 3 D M F - rt C 0 2 M e + ' H Cl 163 311 0 equiv Me 3 SnCI, 1 h 2 5 equiv Me 3 SnCI, 48 h 0 312 10 92 87 8 glc ratio 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 3 SnCu to provide the chlorodestannylated product 314c. Alternatively, 314a may reductively eliminate Me 3 SnCl to give the copper(I) intermediate 314b. The intermediate 314b can then undergo the oxidative coupling process (see Introduction section 2.2, pg. 8). However, the presence of Me 3 SnCl would shift the equilibrium between 314a and 314b toward the copper(III) species 314a (left) and, consequently, retard the coupling reaction and promote the formation of the alkenyl chloride 314c. 104 A / S n M e s + CuCl T - CuCl 314 / L ^ C u ( M e 3 S n ) C I T - Me 3 SnCI + Me 3 SnCI 314a 314b Scheme 29. y + M e 3 S n C u 314c 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 3 SnCl, remains in the reaction pot. 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 3 SnCl results in the formation of chlorodestannylated material in the latter stages of the reaction. Future work in this area may include the addition of reagents, such as CsF, 7 whose purpose is to sequester Me 3 SnCl and avert the formation of such side products. The results of this study indicate that the intramolecular copper(I) chloride-mediated 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. These precursors were then subjected to treatment with copper(I) chloride to 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 give the corresponding products 251-254 in excellent yields (equation 80, pg. 81). In another study, the intramolecular coupling of two aryltrimethylstannane functions produced 5-, 6-, and 7-membered tricycles in good yields (equations 93-96). An extension to this methodology is illustrated by the successful mixed coupling of alkenyl- and aryltrimethylstannane functions (equation 97). 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 (CDC13) or hexadeuteriobenzene (C 6 D 6 ) as the solvent. Signal 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 (Jsn-n) are given as an average of the 1 1 7 S n and 1 1 9 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 ( 1 3 C nmr) spectra were obtained on a Varian 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 (CeD6) as the solvent. 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 MS 80 or on a Kratos Concept II HQ mass spectrometer using an electron impact source. The molecular ion (M + ) masses are given unless otherwise noted. For some of the compounds containing the trimethylstannyl (Me3Sn) or the te^butyldimethylsilyl (£-BuMe2Si) moiety, the high resolution mass spectrometry molecular mass determinations were based on the (M +-Me) peak. A l l compounds subjected to high resolution mass measurements were homogeneous by G L C and/or T L C analyses. Gas-liquid 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 MS 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 chromatography70 was performed using 230-400 mesh silica gel (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, ice-water; -20 °C, -35 °C, -48 °C, aqueous calcium chloride-dry ice (27, 39, and 47 g CaCl 2/100 mL H 2 0 , respectively); -78 °C, acetone-dry ice. 110 1.2 Solvents and reagents A l l solvents and reagents were purified, dried, and/or distilled using standard procedures.71 Benzene and dichloromethane were distilled from calcium hydride. Diethyl 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.72 The aforementioned reagents were stored 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. 7 3 Copper(I) bromide-dimethyl sulfide complex was prepared by the method described by Wuts 7 4 (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. I l l 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 2 C1 2 (40 mL) was added dimethyl sulfoxide (2.00 mL, 23.5 mmol) dropwise via a syringe. The solution was stirred for a period of 15 min. 4-Trimethylstannylpent-4-en-l-ol (125)35 was added over 3 min as a solution in dry CH 2 C1 2 (5 mL). The cloudy white suspension was stirred for an additional 15 min. 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 2 C1 2 (3 x 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 2 C1 2 (80 mL) was added triphenylphosphine (8.55 g, 32.3 mmol) in one portion. The mixture was stirred for 10 min. A solution of the crude oil (obtained as described above) in dry CH 2 C1 2 (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 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 cm 1 . lH nmr (400 MHz, CDC13) 5: 0.14 (s, 9H, -SnMe., 2 / S n . H = 52.0 Hz), 2.12-2.20 (m, 2H, HO, 2.35 (t, 2H, H 3 , / = 7.6 Hz, 3JSn.H= 47.5 Hz), 5.19 (s, IH, H 1 ; 3 / S n . H = 69.4 Hz), 5.67 (s, IH, H i ' , 3 / S „ - H = 148.0 Hz), 6.45 (t, IH, H 5 , / = 7.0 Hz). 1 3 C nmr (50.3 MHz, CDC13) 5: -9.4, 33.0, 38.3, 88.9, 125.7, 137.9, 153.8. HRMS calcd for C 8 H 1 3 1 2 0 S n 7 9 B r 8 1 B r (M +-Me): 388.8386; found: 388.8386. Anal, calcd for C 9 H 1 6 Br 2 Sn: C 26.84, H 4.00; found: C 27.12, H 4.00. Preparation of ethyl 6-trimethylstaniiylhept-6-en-2-ynoate (129) •HMe 3Sn Me3Sn B r Me3Sn C0 2 Et 129 127 128 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 THF (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 THF (40 mL) was added a solution of the crude oil (obtained as described above) in dry THF (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 2 0 (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-Et20) of the crude oil and 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 cm 1 . *H nmr (400 MHz, CDC13) 8: 0.14 (s, 9H, -SnMe^ 2 / S n . H = 53.1 Hz), 1.28 (t, 3H, -C0 2 CH 2 CH3, / = 7.2 Hz), 2.40 (t, 2H, H4, / = 7.5 Hz), 2.52 (t, 2H, H 5 , / = 7.5 Hz, 3 / S „ . H = 50.7 Hz), 4.20 (q, 2H, -C0 2CH2CH 3, / = 7.2 Hz), 5.22 (s, IH, H 7 , 3 / S „ - H = 68.7 Hz), 5.79 (s, IH, H 7*, 3 / S n . H = 146.8 Hz). 1 3 C nmr (50.3 MHz, CDC13) 8: -9.5, 14.0, 18.7, 37.9, 61.7, 73.6, 88.6, 126.0, 152.5, 153.7. HRMS calcd for C n H 1 7 O 2 1 2 0 S n (M +-Me): 301.0251; found: 301.0257. Anal, calcd for C 1 2 H 2 0 O 2 S n : C 45.76, H 6.40; found: C 45.82, H 6.46. 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-l-ol (130)35 (1.50 g, 5.72 mmol) was added over 3 min as a solution in dry CH2CI2 (5 mL). 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 2 C1 2 (100 mL) was added triphenylphosphine (9.36 g, 35.7 mmol) in one portion. The 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 cm 1 . 116 *H nmr (400 MHz, CDC13) 5: 0.12 (s, 9H, -SnMfr. 2 / S n . H = 52.9 Hz), 1.40-1.60 (m, 2H, H,), 2.00-2.15 (m, 2H, H 5 ) , 2.28 (t, 2H, H 3 , / = 6.5, 3 / S n . H = 50.9 Hz), 5.15-5.19 (m, IH, H i , 3 / s „ . H = 70.6 Hz), 5.63-5.65 (m, IH, Hj', 3 / S n - H = 171.9 Hz), 6.37 (t, IH, H 6 , 7=7.2 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -9.4 (-ve), 27.6, 32.5, 40.0, 88.9, 125.2, 138.4 (-ve), 154.7. HRMS calcd for C 9 H 1 5 1 1 8 S n 7 9 B r 8 1 B r (M +-Me): 400.8536; found: 400.8530. Anal, calcd for C i 0 H 1 8 Br 2 Sn : C 28.82, H 4.35; found: C 28.61, H 4.35. 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 THF (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 THF (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 THF (30 mL) was added a solution of the alkyne 135 (obtained as described above) in dry THF (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 2 0 (3 x 20 mL). The organic extracts were combined, washed with brine (50 mL), dried (MgS0 4 ), and the solvent was removed under reduced pressure. Flash column chromatography (125 g of silica gel, 98:2 petroleum ether-Et20) of the 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 cm 1 . X H nmr (400 MHz, CDC13) 5: 0.12 (s, 9H, -SnMe^, 2 / S n . H = 52.6 Hz), 1.28 (t, 3H, -C0 2 CH 2 CH3, / = 7.2 Hz), 1.60-1.70 (m, 2H, H 5 ) , 2.28 (t, 2H, FL,, J = 7.1 Hz), 2.35 (t, 2H, H 6 , / = 7.6 Hz, 3 / S „ - H = 63.9 Hz), 4.16 (q, 2H, -CO^IfcCtt , , / = 7.2 Hz), 5.15-5.20 (m, 1H, H 8 , 3 / S n - H = 70.4 Hz), 5.65-5.70 (m, 1H, H 8 ' , 3 / S n . H = 150.0 Hz). 1 3 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. HRMS calcd for C 1 2 H 1 9 O 2 1 2 0 S n (M +-Me): 315.0407; found: 315.0409. Anal, calcd for C i 3 H 2 2 0 2 S n : C 47.46, H 6.74; found: C 47.65, H 6.90. 118 Preparation of l-(fe^butyldimethylsilyl)hepta-L6-diyne (133) T B S 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 MeLi (20.0 mL, 1.56 M in E t 2 0 , 31.2 mmol). After 10 rnin, 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 2 0 (3 x 50 mL) and the combined organic extracts were washed once with brine (50 mL), dried (MgS0 4 ) , and concentrated 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 MHz, CDC13) 8: 0.06 (s, 6H, -SiMe?-\ 0.90 (s, 9H, -Si'Bu-), 1.69-1.76 (m, 2H, HO, 1.93 (t, IH, H 7 , / = 2.5 Hz), 2.29 (td, 2H, H 5 , / = 7, 2.5 Hz), 2.34 (t, 2H, H 3 , 1 3 C nmr (125.8 MHz, CDC13) 8: -4.5, 16.5, 17.5, 18.9, 26.1, 27.7, 68.7, 83.4, 83.5, 106.6. HRMS calcd for C 1 3 H 2 2 S i : 206.1491; found: 206.1495. Anal, calcd for C i 3 H 2 2 S i : C 75.65, H 10.74; found: C 75.58, H 10.71. / = 7 H z ) . 119 TBS 133 134 Me3Sn Me3Sn H C0 2 Et 135 131 To a cold (-78 °C), stirred solution of hexamethylditin (7.98 g, 24.4 mmol) in dry THF (150 mL) was added a solution of MeLi (17.2 mL, 1.41 M in E t 2 0 , 24.3 mmol) via a 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,6-diyne (133) (4.30 g, 20.9 mmol) was added neat via a cannula with dry THF (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 2 0 (3 x 150 mL). The organic layers were combined, washed with brine (350 mL), and 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 THF (80 mL) and a solution of tetrabutylammonium fluoride (16.1 mL, 1.0 M in THF, 16.1 mmol) was added. The solution was stirred at room temperature for 1.5 h. Saturated aqueous sodium bicarbonate (100 mL) was added and the mixture was extracted with E t 2 0 (3 x 100 mL). The organic extracts were combined, washed with brine (200 mL), dried (MgS0 4 ) , and 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 THF (100 mL) was added a solution of the alkyne 135 (obtained as described above) in dry THF (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 2 0 (3 x 100 mL). The combined organic extracts were washed with 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 ether-Et 2 0) and removal of trace amounts of solvent (vacuum pump) from the acquired 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 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 THF (100 mL) was added a solution of M e L i (20.0 mL, 1.56 M in E t 2 0 , 31.2 mmol). After 10 min, the reaction mixture was warmed to -20 °C and stirred for 1 h. tert-136c C 0 2 E t 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 2 0 (3 x 50 mL) and the combined organic 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 THF (150 mL) was added MeLi (22.2 mL, 1.42 M in E t 2 0 , 31.5 mmol) via a syringe and the solution stirred for 30 min. The solution was cooled to -78 °C and copper bromide-dimethyl 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 THF (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 2 0 (3 x 150 mL). The organic layers were combined, 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 THF (80 mL) and a solution of tetrabutylammonium fluoride (26.0 mL, 1.0 M in THF, 26.0 mmol) was added. The solution was stirred for 2.5 h at room temperature. Saturated aqueous sodium bicarbonate (100 mL) was added and the mixture was extracted with E t 2 0 (3 x 100 mL). 122 The organic extracts were combined, washed with brine (200 mL), dried (MgS0 4 ) , and 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 THF (100 mL) was added the crude oil as a solution in dry THF (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 2 0 (3 x 100 mL). The combined organic 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-Et20), followed by bulb-to-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 cm 1 . J H nmr (400 MHz, CDC13) 8: 0.11 (s, 9H, -SnMe^. 2 / s „ . H = 52.9 Hz), 1.27 (t, 3H, -C0 2 CH 2 CH3, / = 7.2 Hz), 1.40-1.60 (m, 4H), 2.10-2.40 (m, 4H), 4.19 (q, 2H, -C0 2CH2CH 3, / = 7.2 Hz), 5.10-5.15 (m, 1H, H 9 , 3 / S n . H = 70.8 Hz), 5.60-5.65 (m, 1H, H 9 ' , 3 / S n . H = 151.4 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -9.6 (-ve), 14.0 (-ve), 18.4, 26.8, 28.4, 40.0, 61.7, 73.3, 89.0, 124.9, 153.7, 155.0. HRMS calcd for C i 3 H 2 i O 2 1 2 0 S n (M +-Me): 329.0564; found: 329.0563. Anal, calcd for C i 4 H 2 4 0 2 S n : C 49.02, H 7.05; found: C 49.02, H 7.09. 123 Preparation of methyl 4-(tetrahydro-2i/-pyranyloxy)-but-2-ynoate (139) M . C 0 2 M e 138 139 To a cold (-78 °C), stirred solution of commercially available ether 138 (10.0 mL, 71.4 mmol) in dry THF (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 2 0 (3 x 100 mL). The organic extracts were combined, washed with brine (200 mL), and dried (MgS0 4 ). The solvent 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 cm 1 . *H nmr (400 MHz, CDC13) 8: 1.50-1.90 (m, 6H), 2.50-2.60 (m, IH), 3.70-3.90 (m, 4H, includes 3H - C 0 2 M e singlet at 3.76), 4.36 (s, 2H), 4.78 (m, IH). 1 3 C nmr (75.5 MHz, CDC13) 8: 18.5, 25.0, 29.8, 52.5, 53.3, 61.6, 77.0, 83.7, 96.9, 153.3. HRMS calcd for C i 0 H 1 4 O 4 : 197.0813; found: 197.0806. Anal, calcd for C i 0 H 1 4 O 4 : C 60.59, H 7.12; found: C 60.58, H 7.24. 124 Br C02Me 139 140 To a cool (0 °C) solution of triphenylphosphine (8.97 g, 34.1 mmol) in dry CH 2 C1 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 CH 2 C1 2 (5 mL) as a rinse. The mixture was stirred for 1 h and the white 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 2 0 (300 mL). The combined filtrate was concentrated in vacuo. Flash column chromatography (300 g of silica gel, 9:1 petroleum ether-Et20) of the crude product and removal of trace 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. 7 5 IR (neat): 2358, 2245, 1718, 1436, 1269, 1083, 945, 751, 625 cm 1 . : H nmr (400 MHz, CDC13) 8: 3.77 (s, 3H, -CftMe), 3.93 (s, 2H, Br-CHr) . 1 3 C nmr (75.5 MHz, CDC13) 8: 11.6, 52.8 (-ve), 76.6, 81.6, 152.9. HRMS calcd for C 5 H 5 0 2 8 1 B r : 177.9453; found: 177.9449. Anal, calcd for C 5 H 5 0 2 B r : C 33.93, H 2.84; found: C 34.17, H 2.91. 125 Preparation of methyl 5-ethoxvcarbonyl-6-trimethvlstarmylhept-6-en-2-ynoate (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)41 (2.87 g, 10.4 mmol) in dry THF (5 mL) was added to the reaction mixture. The 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 THF (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 2 0 (3 x 150 mL). The organic extracts were combined, washed with 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-Et20) of the crude 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 cm 1 . J H nmr (400 MHz, CDC13) 5: 0.16 (s, 9H, -SnMe 3, 2 / S n . H = 53.9 Hz), 1.25 (t, 3H, -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 5 , / = 7.5 Hz, 3 / s „ . H = 58.2 Hz), 3.72 (s, 3H, -CO2CH3), 4.10-4.20 (m, 2H, -CO2CH2CH3), 5.37-5.42 (m, 1H, H 7 , 3 / S n . H = 63.6 Hz), 5.80-5.85 (m, 1H, H 7 ' , 3 / S n . H = 133.6 Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: -8.5 (-ve), 13.9 (-ve), 22.1, 52.3 (-ve), 53.8 (-ve), 61.0, 74.0, 86.1, 129.1, 150.7, 153.6, 172.2. 141 140 143 126 HRMS calcd for C i 3 H 1 9 0 4 Sn (M +-Me): 359.0306; found: 359.0311. Anal, calcd for C 1 4 H 2 2 0 4 S n : C 45.08, H 5.94; found: C 44.99, H 6.03. 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 2 0 (3 x -10 rnL/rnmol of ester). The combined organic phases were washed with brine (3 x -20 mL/mmol of ester), dried (MgS0 4 ) , and concentrated under reduced pressure. The crude product was purified by flash column chromatography. 127 Preparation of (iT)-l-ethoxycarbonylmethylidene-2-m (144) 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-Et20) and removal of 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 cm 1 . X H nmr (400 MHz, CDC13) 5: 1.26 (t, 3H, -C0 2 CH 2 CH3, / = 7.1 Hz), 2.65-2.80 (m, 2H, H-3), 3.02 (td, 2H, H-4, / = 8.0, 2.5 Hz), 4.15 (q, 2H, -C0 2CH2CH 3, / = 7.1 Hz), 4.94 (br 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 MHz, CDC13) 5: 14.3 (-ve), 28.6, 29.9, 59.8, 108.3 (-ve), 108.6, 147.9, 161.2, 166.9. HRMS calcd for C 9 H 1 2 0 2 : 152.0837; found: 152.0842. Anal, calcd for C 9 H i 2 0 2 : C 71.03, H 7.95; found: C 70.99, H 7.89. C0 2 Et 129 144 128 Table 14. *H nmr (400 MHz, CDC13) data for the ester 144: COSY (200 MHz) and NOED experiments C 0 2 E t H H b 144 Assignment H-x J H nmr (400 MHz) 8 (multiplicity, 7 (Hz)) COSY Correlations NOED Correlations 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 -C0 2CH2CH 3 4.15 (q, 7=7.1) -C0 2 CH 2 CH3 -C0 2 CH 2 CH3 1.26 (t, 7=7.1) -C0 2CH2CH 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 2 0 (20 mL) and then was filtered through Florisil (-5 g) and the cake was eluted with E t 2 0 (150 mL). The combined filtrate was concentrated under reduced pressure. Flash column chromatography (20 g of silica gel, 13:7 petroleum ether-Et20) 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 MHz, CDC13) 8: 1.34 (br s, IH, -OH, exchanges with D 2 0) , 1.60-1.73 (m, 2H, -CH 2-CH2-CH 2.), 2.35-2.45 (m, 4H, -CH^-CH2-CH2-), 4.22 (d, 2H, -O-CEb-, / = 6.9 Hz), 4.86 (br s, IH), 5.30 (br s, IH), 5.95-6.05 (m, IH, =CH-CH 2-0-). 1 3 C nmr (75.5 MHz, CDC13) 8: 24.0, 30.0, 34.0, 61.1, 103.2, 118.2 (-ve), 142.9, 149.0. HRMS calcd for C 8 H i 2 0 : 124.0888; found: 124.0889. 130 Preparation of (E)- l-Cfe^butyldimethylsiloxym pentane (155) To a stirred solution of the diene 154 (116 mg, 0.933 mmol) in dry CH 2 C1 2 (4 mL) at 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-Et20) of the crude product and 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 cm 1 . X H nmr (400 MHz, CDC13) 8: 0.06 (s, 6H, -SiMe,-), 0.89 (s, 9H, -Si'Bu-), 1.60-1.75 (m, 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 MHz, CDC13) 8: -5.1 (-ve), 18.4, 24.0, 26.0 (-ve), 30.0, 34.0, 61.8, 102.5, 119.5(-ve), 140.5, 149.1. HRMS calcd for C i 4 H 2 6 O S i : 238.1753; found: 238.1751. Anal, calcd for C i 4 H 2 6 O S i : C 70.52, H 10.99; found: C 70.31, H 11.03. OTBS 154 155 131 Table 15. *H nmr (400 MHz, CDC13) data for the silyl ether 155: NOED experiments . O T B S 3 ] 6 H b 155 Assignment H-x *H nmr (400 MHz) 8 (multiplicity, J (Hz)) NOED 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 2 Et 5, M e 3 S n C0 2 Et 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-Et20) and removal of 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 cm 1 . X H nmr (400 MHz, CDC13) 8: 1.26 (t, 3H, -CO2CH2CH3, / = 7.1 Hz), 1.60-1.75 (m, 4H, 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, IH, H-7b), 5.00-5.05 (m, IH, H-7a), 5.80-5.85 (m, IH, H-8). 1 3 C nmr (75.5 MHz, CDC13) 8: 14.3 (-ve), 25.9, 26.5, 29.7, 35.3, 59.7, 110.7, 112.9 (-ve), 149.6, 161.0, 166.9. HRMS calcd for C u H i 6 0 2 : 180.1151; found: 180.1154. Anal, calcd for C n H 1 6 0 2 : C 73.30, H 8.95; found: C 73.00, H 9.05. Table 16. *H nmr (400 MHz, CDC13) data for the ester 156: NOED experiments 156 Assignment H-x *H nmr (400 MHz) 8 (multiplicity, / (Hz)) NOED 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) C 0 2 M e 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-Et20) and removal of 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 cm 1 . J H nmr (400 MHz, CDC13) 5: 1.26 (t, 3H, -CO2CH2CH3, / = 7.1 Hz), 3.22 (dd, 1H, H-4, / = 2.5, 18.1 Hz), 3.38 (dd, 1H, H-4*, / = 2.8, 18.1 Hz), 3.70 (s, 3H, -C0 2 Me), 3.75-3.85 (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, CDC13) 5: 14.0 (-ve), 33.2, 44.4 (-ve), 51.0 (-ve), 60.8, 109.3 (-ve), 110.5, 145.1, 157.2, 166.6, 171.2. HRMS calcd for C n H 1 4 0 4 : 210.0892; found: 210.0896. Anal, calcd for C u H 1 4 0 4 : C 62.85, H 6.71; found: C 62.79, H 6.81. 134 Table 17. lH nmr (400 MHz, CDC13) data for the diester 158: NOED experiments C 0 2 M e 3 E t 0 2 C / ^ ^ - H a H 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 MeLi (1.2-1.4 equiv) in E t 2 0 and 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 2 0 (3 x ~1 mL/mL of THF). 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) Following general procedure 2, the commercially available alkyne 166 (5.00 g, 35.7 mmol) in dry THF (200 mL) was converted into the title compound 169 with M e L i (27 mL, 1.6 M in E t 2 0 , 43 mmol) and 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-Et20) and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 6.90 g (72 %) of the alkyne 169 as a colorless oil. 166 169 136 TR (neat): 2175, 1472, 1251, 1122, 1030, 826 cm 1 . *H nmr (400 MHz, CDC13) 8: 0.09 (s, 6H, -SiMe?-), 0.91 (s, 9H, -Si'Bu-), 1.50-1.64 (m, 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 MHz, 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 4 H 2 7 0 2 S i (M++H): 255.1780; found: 255.1779. Anal, calcd for C i 4 H 2 6 0 2 S i : C 66.04, H 10.30; found: C 66.14, H 10.20. Preparation of l-(fe^butvldimethylsilyl)-3-(tetr^ 07Q1 THPO. THPO H TBS 167 170 Following general procedure 2, the alkyne 16746 (3.62 g, 23.5 mmol) in dry THF (125 mL) was converted into the title compound 170 with M e L i (17.6 mL, 1.6 M in E t 2 0 , 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 ether-Et 2 0) and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 3.58 g (57 %) of the ether 170 as a colorless oil. IR (neat): 2177, 1471, 1251, 1124, 1035, 838 cm 4 . 137 lR nmr (400 MHz, CDC13) 5: 0.09 (s, 6H, -SiMe,-), 0.91 (s, 9H, -Si'Bu-), 1.48-1.58 (m, 4H), 1.65-1.72 (m, 1H), 1.78-1.85 (m, 1H), 2.51 (t, 2H, -CH2-CH2-), 3.49-3.56 (m, 2H), 3.77-3.90 (m, 2H), 4.64 (t, 1H, / = 3.3 Hz). 1 3 C nmr (50.3 MHz, CDC13) 5: -4.6, 16.4, 19.1, 21.3, 25.4, 26.0, 30.4, 61.8, 65.6, 83.5, 98.5, 104.5. HRMS calcd for C n H 1 9 0 2 S i (M +- £Bu): 211.1154; found: 211.1147. Anal, calcd for C i 5 H 2 8 0 2 S i : C 67.11, H 10.51; found: C 67.31, H 10.53. Preparation of l-(fe^butyldimethvlsilvl)-3-(tetTahydro-2^-pyran-2-yloxy)pent- 1-yne Following general procedure 2, the alkyne 168 (2.25 g, 13.4 mmol) in dry THF (125 mL) was converted into the title compound 171 with M e L i (13.4 mL, 1.4 M in E t 2 0 , 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 ether-Et 2 0) and removal of trace amounts of solvent (vacuum pump) from the acquired 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 MHz, CDC13) 5: 0.09 (s, 6H, -SiMe?-), 0.91 (s, 9H, -Si'Bu-), 1.48-1.90 (m, 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). am 168 171 138 1 3 C nmr (75.5 MHz, CDC13) 5: -4.6 (-ve), 16.4, 16.6, 19.3, 25.4, 25.9 (-ve), 28.8, 30.5, 61.8, 65.6, 82.6, 98.5 (-ve), 107.2. HRMS calcd for C 1 6 H 2 9 0 2 S i (M + -H): 281.1937; found: 281.1929. Anal, calcd for Ci6H 3o0 2Si: C 68.03, H 10.70; found: C 67.76, H 10.81. General Procedure 3: Conversion of THP ethers into alkyl bromides To a cool (0 °C), stirred solution of triphenylphosphine (-1.3 equiv) in dry CH 2 C1 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 2C1 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 2 0 (-2 mL/mL of CH 2C1 2). After concentration of the combined 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) 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 CH 2 C1 2 (250 mL). The crude product was purified by flash column chromatography (200 g of silica gel, petroleum 169 160 139 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 cm 1 . X H nmr (400 MHz, CDC13) 8: 0.09 (s, 6H, -SiMeo-), 0.90 (s, 9H, -Si'Bu-), 3.90 (s, 2H, Br-CEL.-). 1 3 C nmr (50.3 MHz, CDC13) 8: -4.8, 14.7, 16.5, 26.0, 90.8, 113.3. HRMS calcd for C 9 H i 7 S i 8 1 B r : 234.0263; found: 234.0265. Anal, calcd for C 9 Hi 7 SiBr : C 46.35, H 7.35; found: C 46.67, H 7.38. Preparation of 4-bromo-l-(feA'f-butyldimethylsilyl)but-l-yne (161) THPCL Brv / \ 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 CH 2 C1 2 (200 mL). The crude material was purified by flash column chromatography (100 g of silica gel, 200:3 petroleum ether-Et20) which, after removal of trace amounts of solvent (vacuum pump) from the acquired material, yielded 4.60 g (96 %) of the bromide 161 as a colorless oil. ER (neat): 2177, 1472, 1251, 839 cm 1 . lR nmr (400 MHz, CDC13) 8: 0.09 (s, 6H, -SiMeo-), 0.90 (s, 9H, -Si'Bu-), 2.76 (t, 2H, -CH2-CH2-Br, / = 7.4 Hz), 3.41 (t, 2H, -CH2-CH2-Br, / = 7.4 Hz). 170 161 140 " C nmr (50.3 MHz, CDC13) 5: -4.7, 16.4, 24.3, 26.0, 29.3, 85.1, 106.6. HRMS calcd for C 1 0 H i 9 S i 8 1 B r : 248.0419; found: 248.0423. Anal, calcd for CioH 1 9SiBr: C 48.58, H 7.75; found: C 48.87, H 7.48. Preparation of 5-bromo-l-(fe^butyldimethylsilyl)pent-l-vne (162) ^ T B S . / 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 2 C1 2 (35 mL). The crude product was purified by flash column chromatography (60 g of silica gel, 200:3 petroleum ether-Et20) which, after removal of trace amounts of solvent (vacuum pump) from the acquired material, yielded 797 mg (93 %) of the bromide 162 as a colorless oil. IR (neat): 2174, 1431, 1250, 827 cm 1 . *H nmr (400 MHz, CDC13) 8: 0.09 (s, 6H, -SiMe?-), 0.90 (s, 9H, -Si'Bu-), 2.00-2.10 (m, 2H, -CH 2-CH2-CH 2-), 2.41 (t, 2H, Br-CH 2-CH 2-CH2-, / = 6.8 Hz), 3.50 (t, 2H, Br-CFb-, /=6 .6Hz) . 1 3 C nmr (75.5 MHz, CDC13) 5: -4.5 (-ve), 16.4, 18.5, 26.0 (-ve), 31.4, 32.0, 83.8, 105.4. HRMS calcd for CnH 2 iS i 8 1 Br : 262.0575; found: 262.0580. Anal, calcd for C u H 2 1 S i B r : C 50.57, H 8.10; found: C 50.87, H 8.17. 141 HO. C 0 2 M e 172 173 C 0 2 M e 159 To a cool (0 °C), stirred solution of the ester 1724/ (4.22 g, 18.7 mmol) in dry MeOH (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-Et20) of the crude product and removal of trace 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 CH 2 C1 2 (125 mL) 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 CH 2 C1 2 (5 mL) was added via a cannula 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 2 0 (-400 mL). The combined filtrate was concentrated under reduced pressure. Flash column chromatography (100 g of silica gel, 9:1 petroleum ether-Et20) 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 2 Me , ^ C 0 2 M e vOTf SnMe 3 174 163 To a cold (-48 °C), stirred solution of hexamethylditin (23.9 g, 73.1 mmol) in dry THF (500 mL) was added M e L i (46.0 mL, 1.60 M in E t 2 0 , 73.6 mmol) via a syringe and the 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 17428b (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 2 0 (3 x 150 mL). The organic layers were combined, washed with brine (500 mL), and dried (MgSCU). The solvent was removed under reduced pressure. Rash column chromatography (400 g of silica gel, 39:1 petroleum ether-Et20) of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 14.9 g (92 %) of the stannane 1632 8 b 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 THF (80 mL) was added M e L i (12.0 mL, 1.40 M in E t 2 0 , 16.8 mmol) via a syringe and the 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 1752 8 b (3.32 g, 11.0 mmol) in dry THF (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 2 0 (3 x 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-Et20) of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 3.24 g (93 %) of the stannane 1642 8 b as a colorless clear oil. Preparation of methyl 2-trimethvlstannvlcvclohept-l-enecarboxylate (165) To a cold (-48 °C), stirred solution of hexamethylditin (7.56 g, 23.1 mmol) in dry THF (100 mL) was added M e L i (14.8 mL, 1.53 M in E t 2 0 , 22.6 mmol) via a syringe and the 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 17610 (5.27 g, 17.4 mmol) in dry THF (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-Et20) of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 4.19 g (76 %) of the stannane 16510 as a colorless clear oil. 176 165 144 Preparation of methyl l-(3-fg^butyldimethylsilylprop-2-yn-l-yl)-2-trim cyclopent-2-ene-1 -carboxylate (178a) To a cold (-48 °C), stirred solution of L D A (8.06 mmol) in dry THF (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 THF (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 2 0 (3 x 50 mL). The combined organic extracts were washed with brine (3 x 60 mL), dried (MgS0 4 ), and the solvent was removed under reduced pressure. Flash column chromatography (100 g of silica gel, 200:3 petroleum ether-Et20) of the crude product 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 cm 1 . X H nmr (400 MHz, CDC13) 5: 0.03 (s, 6H, -S iM^- ) , 0.12 (s, 9H, -SnMe,, 2 / 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, IH, / = 6.7 Hz), 3.64 (s, 3H, - C O ^ , 6.00 (dd, IH, olefinic proton, / = 2.1, 2.1 Hz, V S n . H = 1 3 C nmr (75.5 MHz, CDC13) 8: -8.5, -4.6, 16.4, 26.0, 29.3, 32.4, 34.3, 52.0, 65.2, 84.4, 104.3, 113.2, 144.8, 175.7. HRMS calcd for C 1 8 H 3 1 O 2 S i 1 2 0 S n (M +-Me): 428.1138; found: 428.1145. 163 160 178a 36.6 Hz). 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) To a stirred solution of the stannane 178a (848 mg, 1.92 mmol) in dry THF (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 2 0 (3 x 20 mL). The combined organic extracts were washed with brine (50 mL), dried (MgS0 4 ) , and the solvent was removed in vacuo to give a crude oil. Flash column chromatography (50 g of silica gel, 98:2 petroleum ether-Et20) of the crude product and removal of trace amounts 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 MHz, CDC13) 8: 0.13 (s, 9H, -SnMe^ 2 / S „ - H = 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, 3 / S f t _ H = 36.6 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -8.8, 27.7, 32.6, 34.1, 52.0, 64.7, 69.8, 81.2, 144.8, 175.5, 219.4. HRMS calcd for C 1 2 H 1 7 O 2 1 2 0 S n (M +-Me): 313.0251; found: 313.0248. Anal, calcd for C i 3 H 2 0 O 2 S n : C 47.75, H 6.16; found: C 47.83, H 6.04. 178a 178b 146 Preparation of methyl 4-(l-methoxvcarbonvl-2-trimethvlstannvlcyclopent-2-en-l-vl) but-2-vnoate (178) C 0 2 M e C 0 2 M e 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 THF (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 2 0 (3 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried (MgS0 4 ), and the solvent was removed under reduced pressure. Flash column chromatography (50 g of silica gel, 9:1 petroleum ether-Et20) of 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 cm 1 . *H nmr (400 MHz, CDC13) 5: 0.14 (s, 9H, -SnMes, 2 / S n . H = 54.6 Hz), 1.93-2.01 (m, 1H), 2.41-2.56 (m, 4H), 2.81 (d, 1H, / = 7.1 Hz), 3.67 (s, 3H, -C0 2 Me), 3.71 (s, 3H, -C0 2 Me), 6.06 (dd, 1H, olefinic proton, / = 2.1, 2.1 Hz, 3 / S n - H = 35.8 Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: -8.9 (-ve), 27.8, 32.9, 34.2, 52.2 (-ve), 52.4 (-ve), 64.2, 73.9, 86.3, 145.3 (-ve), 146.2, 153.8, 175.1. HRMS calcd for C i 4 H 1 9 O 4 1 2 0 S n (M +-Me): 371.0306; found: 371.0314. Anal, calcd for C i 5 H 2 2 0 4 S n : C 46.79, H 5.76; found: C 47.09, H 5.87. 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 THF (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 THF (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 THF (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 2 0 (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-Et20) of the crude product 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 2 0 (3 x 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-Et20) of the crude product and removal of trace 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 cm 1 . X H nmr (400 MHz, CDC13) 5: 0.14 (s, 9H, -SnMes, 2/Sn-H= 54.3 Hz), 1.64-1.80 (m, 2H), 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 2 Me), 5.91 (dd, IH, olefinic proton, / = 2.1, 2.1 Hz, 3 / S n . H = 35.4 Hz). 1 3 C nmr (50.3 MHz, CDC13) 5: -8.6, 14.5, 31.6, 34.2, 37.1, 51.9, 65.4, 68.4, 84.0, 144.0, 148.1, 176.2. HRMS calcd for C i 3 H 1 9 O 2 1 2 0 S n (M +-Me): 327.0407; found 327.0404. Anal, calcd for C i 4 H 2 2 0 2 S n : C 49.31, H 6.50; found: C 49.55, H 6.65. Preparation 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 THF (11 mL) was added a solution of the alkyne 179b (405 mg, 1.19 mmol) in dry THF (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 2 0 (3 x 20 mL). The combined organic extracts were 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-Et20) of 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 MHz, CDC13) 5: 0.13 (s, 9H, -SnMeg, 2 / S „ - H = 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, -C0 2 Me), 3.72 (s, 3H, -C0 2 Me), 5.98 (dd, 1H, olefinic proton, / = 2.1, 2.1 Hz, 3 / s „ - H = 36.1 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -8.6 (-ve), 14.8, 31.7, 34.1, 35.8, 52.0 (-ve), 52.5 (-ve), 64.9, 72.9, 89.0, 144.3 (-ve), 147.7, 154.1, 175.9. HRMS calcd for C i 5 H 2 1 O 4 1 2 0 S n (M +-Me): 385.0462; found: 385.0461. Anal, calcd for C i 6 H 2 4 0 4 S n : C 48.16; H 6.06. found C 48.34; H 6.16. Preparation of methyl l-(5-fe^butyldimethylsilvlpent-4-yn-l-vl)-2-trimethvlstannyl cyclopent-2-ene- 1-carboxylate (180a) C 0 2 M e ^ ^ C 0 2 M e S n M e 3 T B S TBS *SnMe 3 163 162 180a To a cold (-48 °C), stirred solution of L D A (7.68 mmol) in dry THF (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 THF (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 THF (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 2 0 (3 x 50 mL). The combined organic extracts were 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-Et20) of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material, yielded 2.50 g (83 %) of the stannane 180a as a colorless clear oil. IR (neat): 2174, 1733, 1251, 775 cm 1 . lR nmr (400 MHz, CDC13) 6: 0.05 (s, 6H, -SiMe^), 0.12 (s, 9H, -SnMe 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 2 Me), 5.94 (dd, IH, olefinic proton, / = 2.1, 2.1 Hz, 3 / S n . H = 37.7 Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: -8.5 (-ve), -4.5 (-ve), 16.4, 20.1, 24.4, 26.0 (-ve), 32.0, 33.9, 37.8, 51.6 (-ve), 65.2, 82.6, 107.3, 143.1 (-ve), 148.6,176.5. HRMS calcd for C 2 0 H 3 5 O 2 S i 1 2 0 S n (M +-Me): 455.1428; found: 455.1431. Anal, calcd for C 2 i H 3 8 0 2 S i S n : C 53.75, H 6.18; found: C 54.03, H 8.04. Preparation of methyl l-(pent-4-yn-l-yl)-2-trunethylstannylcyclopent-2-ene-l-carboxylate (180b) To a stirred solution of the stannane 180a (1.23 g, 2.62 mmol) in dry THF (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 180a 180b 151 bicarbonate (25 mL) was added and the mixture was extracted with E t 2 0 (3 x 25 mL). The combined organic extracts were washed with brine (50 mL), dried (MgS0 4 ) , and the solvent was removed in vacuo to give a crude oil. Flash column chromatography (100 g of silica gel, 98:2 petroleum ether-Et20) of the crude product and removal of trace 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 cm 1 . J H nmr (400 MHz, CDC13) 8: 0.13 (s, 9H, -SnMe 3. 2 / S n . H = 54.2 Hz), 1.30-1.54 (m, 4H), 1.70-1.78 (m, IH), 1.91-2.00 (m, 2H), 2.15 (tdd, IH, / = 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, 3 / S n . H = 38.0 Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: -8.6, 18.7, 24.0, 31.8, 34.1, 37.5, 51.7, 65.1, 68.6, 83.9, 143.2, 148.5, 176.6. HRMS calcd for C i 4 H 2 1 O 2 1 2 0 S n (M +-Me): 341.0564; found: 341.0564. Anal, calcd for C i 5 H 2 4 0 2 S n : C 50.74, H 6.81; found: C 50.94, H 6.94. Preparation of methyl 6-(l-methoxvcarlx)nyl-2-trimethylstannylcyclopent-2-en-l-yl) hex-2-ynoate (180) To a cold (-78 °C), stirred solution of L D A (2.43 mmol) in dry THF (18 mL) was added a solution of the alkyne 180b (663 mg, 1.87 mmol) in dry THF (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 180b 180 152 at room temperature. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with E t 2 0 (3 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried (MgS0 4), and the solvent was removed under reduced pressure. Flash column chromatography (20 g of silica gel, 9:1 petroleum ether-Et20) of 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 MHz, CDC13) 8: 0.12 (s, 9H, -SnMe,. 2 / s „ . H = 54.2 Hz), 1.40-1.54 (m, 3H), 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, -C0 2 Me), 3.73 (s, 3H, -COMe) . 5.90 (dd, 1H, olefinic proton, / = 2.0, 2.0 Hz, 3 / S j l . H = 37.4 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -8.6 (-ve), 18.9, 23.2, 31.8, 34.1, 37.5, 51.7 (-ve), 52.4 (-ve), 65.1,73.1, 88.8, 143.4 (-ve), 148.3, 153.9, 176.4. HRMS calcd for C 1 6 H 2 3 O 4 1 2 0 S n (M +-Me): 399.0618; found: 399.0619. Anal, calcd for C 1 7 H 2 6 0 4 S n : 49.43, H 6.34; found: C 49.79, H 6.38. Preparation of 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 THF (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 THF (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 THF (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. The mixture was then warmed to room temperature. The black suspension was extracted with E t 2 0 (3 x 25 mL). The organic extracts were combined, washed with brine (2 x 25 mL), dried (MgS0 4 ), and the solvent was removed under reduced pressure. Flash column chromatography (40 g of silica gel, 95:5 petroleum ether-Et20) of the crude product and 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 cm 1 . lH nmr (400 MHz, CDC13) 8: 0.11 (s, 9H, -SnMe 3, 2 / s „ . H = 52.8 Hz), 1.25 (t, 3H, -C0 2 CH 2 CH3, / = 7.2 Hz), 1.60-1.78 (m, 2H), 1.80-1.90 (m, IH), 2.00-2.15 (m, 3H), 2.55 (d, IH, H-4, / = 17.2 Hz), 2.81 (d, IH, H-4', / = 17.2 Hz), 3.72 (s, 3H, -CO,Me). 4.07-4.20 (m, 2H, -C02CH2CH3), 6.03 (dd, IH, olefinic proton, / = 3.7, 3.7 Hz, 3 / S n . H = 71.2 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -7.7 (-ve), 13.9 (-ve), 18.4, 26.7, 29.1, 30.8, 50.4, 52.3 (-ve), 61.1, 74.7, 85.8, 141.1 (-ve), 142.1, 153.6, 174.6. HRMS calcd for C i 6 H 2 3 O 4 1 2 0 S n (M +-Me): 399.0618; found: 399.0618. Anal, calcd for C i 7 H 2 6 0 4 S n : C 49.43, H 6.34; found: C 49.68, H 6.28. 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 THF (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 THF (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 THF (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 2 0 (3 x 50 mL). 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-Et20) of the crude 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 THF (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 2 0 (3 x 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-Et20) of the crude product and 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 MHz, CDC13) 5: 0.11 (s, 9H, -SnMe 3, 2 / S n . H = 52.3 Hz), 1.25 (t, 3H, -C0 2 CH 2 CH3, / = 7.1 Hz), 1.50-1.64 (m, 3H), 1.70-1.81 (m, 1H), 1.92 (t, 1H, H4, / = 2.4 Hz), 2.00-2.15 (m, 6H), 4.00-4.20 (m, 2H, - C 0 2 C t k C H 3 ) , 5.97 (dd, 1H, olefinic proton, / = 3.6, 3.6 Hz, 3 / S n - H = 75.0 Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: -7.1, 14.0, 14.2, 19.0, 27.2, 29.9, 38.3, 50.5, 60.8, 68.4, 84.0, 140.2, 144.8, 176.0. HRMS calcd for C 1 5 H 2 3 O 2 1 2 0 S n (M +-Me): 355.0720; found: 355.0725. Anal, calcd for C 1 6 H 2 6 0 2 S n : C 52.07, H 7.10; found: C 52.30, H 7.19. Preparation of 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 THF (12 mL) was added a solution of the alkyne 182b (486 mg, 1.32 mmol) in dry THF (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 2 0 (3 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried (MgS0 4 ), and the solvent was removed under reduced pressure. Flash column chromatography (20 g of silica gel, 9:1 petroleum ether-Et20) of the crude product, 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 cm 1 . *H nmr (400 MHz, CDC13) 5: 0.11 (s, 9H, -SnMe 3, 2 / S n . H = 52.4 Hz), 1.24 (t, 3H, -C0 2 CH 2 CH3, J= 7.1 Hz), 1.50-1.65 (m, 3H), 1.73-1.81 (m, IH), 1.95-2.14 (m, 4H), 2.27 (t, 2H, / = 8.1 Hz), 3.73 (s, 3H, -CO?Me). 4.05-4.19 (m, 2H, -C02CH2CH3), 5.90 (dd, IH, olefinic proton, / = 3.6, 3.6 Hz, 3 / S n . H = 70.1 Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: -7.2 (-ve), 14.1 (-ve), 14.3, 18.9, 27.1, 30.0, 36.9, 50.3, 52.6 (-ve), 60.9, 72.9, 89.2, 140.6 (-ve), 144.3, 154.1, 175.8. HRMS calcd for C i7H 2 5 O 4 1 2 0 Sn (M +-Me): 413.0775, found: 413.0783. Anal, calcd for C i 8 H 2 8 0 4 S n : C 50.62, H 6.61; found: C 50.77, H 6.61. Preparation of 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 THF (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 THF (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 THF (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 2 0 (3 x 30 mL). 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-Et20) of the crude product, followed by bulb-to-bulb distillation (150-200 °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 MHz, CDC13) 8: 0.10 (s, 9H, -SnMe^, 2JSn.H = 52.3 Hz), 1.25 (t, 3H, -C0 2 CH 2 CH3, / = 7.1 Hz), 1.40-1.64 (m, 7H), 1.86-1.94 (m, 1H), 2.00-2.12 (m, 2H), 2.28 (t, 2H, J= 6.7 Hz), 3.73 (s, 3H, -CCWe) . 4.00-4.21 (m, 2H, - C 0 2 C H 2 C H 3 ) , 5.94 (dd, 1H, olefinic proton, / = 3.7, 3.7 Hz, 3 / S n . H = 75.7 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -7.1 (-ve), 14.2 (-ve), 19.0 (2C), 22.8, 27.2, 30.2, 39.0, 50.6, 52.5 (-ve), 60.7, 73.1, 89.0, 139.7 (-ve), 145.4, 154.1, 176.2. HRMS calcd for C i 8 H 2 7 O 4 1 2 0 S n (M +-Me): 427.0931; found: 427.0939. Anal, calcd for C 1 9 H 3 o0 4 Sn: C 51.73, H 6.85; found: C 51.86, H 6.78. 158 Preparation of methyl l-(5-fe^butyldimethylsilyfo cyclohept-2-ene- 1-carboxylate (184a) C 0 2 M e aC 0 2 M e . . T B S TBS S n M e 3 B r \ ^ \ ^ ^ ^ ^ S n M e 3 165 162 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 THF (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 THF (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 2 0 (3 x 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-Et20) of the crude product and 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 MHz, CDC13) 8: 0.05 (s, 15H, includes 6H -SiMe^ and 9H -SnMfru 2 / S n . H = 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 (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, 3 / s „ . H = 84.9 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -6.5, -4.2, 16.5, 20.4, 24.6, 26.1 (2C), 26.7, 29.8, 34.3, 36.4, 51.9, 56.8, 82.7, 107.6,141.7, 150.5,178.3. HRMS calcd for C 2 2 H 4 2 0 2 S i S n (M +-Me): 483.1741; found: 483.1745. 159 Anal, calcd for C 2 3 H4 2 0 2 SiSn : C 55.54, H 8.51; found: C 55.64, H 8.49. Preparation of methyl l-(pent-4-vn-l-vl)-2-trirnethvlstannvlcvcloliept-2-ene-l-carboxylate (184b) To a stirred solution of the stannane 184a (139 mg, 0.278 mmol) in dry THF (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 2 0 ( 3 x 5 mL). The combined organic extracts were washed with brine (10 mL), dried (MgS0 4 ) , and the solvent was removed in vacuo to give a crude oil. Flash column chromatography (12 g silica gel, 98:2 petroleum ether-Et20) of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 93 mg (87 %) of the alkyne 184b as a colorless clear oil. J H nmr (400 MHz, CDC13) 5: 0.06 (s, 9H, -SnMe 3, 2 / S n . H = 51.6 Hz), 1.40-1.51 (m, 3H), 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, 3 / S n . H = 84.9 Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: -6.6, 18.9, 24.2, 24.4, 26.5, 29.5, 33.9, 36.6, 51.8, 56.8, 68.5, 84.0, 141.7,150.3, 178.0. HRMS calc for C i 6 H 2 5 O 2 1 2 0 S n (M +-Me): 369.0877; found: 369.0872. 184a 184b IR (neat): 3309,1719, 1596,1214,768 cm 1 . 160 Anal, calcd for C i 7 H 2 8 0 2 S n : C 53.30, H 7.37; found: C 53.32, H 7.51. Preparation of methyl 6-(l-methoxycarbonyl-2-trirnethvlstannvlcvclohept-2-en-l-vl)-hex-2-vnoate (184) To a cold (-78 °C), stirred solution of L D A (0.808 mmol) in dry THF (5 mL) was added a solution of the alkyne 184b (238 mg, 0.622 mmol) in dry THF (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 2 0 (3 x 10 mL). The combined organic extracts were 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-Et20) of 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 cm 1 . X H nmr (400 MHz, CDC13) 5: 0.13 (s, 9H, 2 / S n . H = 51.6 Hz), 1.41-1.56 (m, 3H), 1.60-1.80 (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 2 Me), 3.73 (s, 3H, -C0 2 Me), 6.00 (dd, 1H, olefinic proton, / = 5.4, 7.0 Hz, 3 / S n . H = 85.2 Hz) 1 3 C nmr (75.5 MHz, CDC13) 8: -6.5 (-ve), 19.3, 23.5, 24.5, 26.6, 29.6, 34.0, 36.4, 52.1 (-ve), 52.6 (-ve), 56.9, 73.2, 89.3, 142.1 (-ve), 150.0, 154.2, 178.0. HRMS calcd for C 1 8 H 2 7 O 4 1 2 0 S n (M +-Me): 427.0931; found: 427.0941. 184b 184 161 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.Oloct-4-ene (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-Et20) and removal of 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 MHz, C 6 D 6 ) 8 1.11-1.19 (m, IH, H-8), 1.45-1.53 (m, IH, H-2), 2.22 (ddd, IH, H-3, / = 3.8, 8.6, 17.1 Hz), 2.33 (br dd, IH, H-8', / = 8.0, 12.3 Hz), 2.42 (br dd, IH, H-2', / = 6.5, 12.5 Hz), 2.78-2.87 (m, IH, H-3'), 3.20 (s, 3H, -C0 2 Me), 3.30-3.46 (m, 4H, includes 3H - C 0 2 M e singlet at 3.42, H-7), 3.51 (dddd, IH, H-7', / = 1.0, 1.9, 8.0, 19.4 Hz), 5.64 (dd, IH, H-4, 7= 3.8, 2.3 Hz), 6.20 (br s, IH, H-9). 179 187 162 1 3 C nmr (75.5 MHz, C 6 D 6 ) 8: 35.2, 37.0, 37.9, 38.6, 50.7, 51.5, 64.4, 110.9, 128.1, 152.0, 153.7, 167.0, 175.0. HRMS calcd for C i 3 H 1 6 0 4 : 236.1049; found: 236.1047. Anal, calcd for C i 3 H 1 6 0 4 : C 66.09, H 6.83; found: C 66.14, H 6.97. Table 18. X H nmr (400 MHz, CDC13) data for the diester 187: C O S Y (200 MHz) and NOED experiments _ COpMe 2 I f 9 ^ C 0 2 M e 187 Assignment H-x J H nmr (400 MHz) 8 (multiplicity, / (Hz)) COSY Correlation NOED Correlation H-2 1.45-1.53 (m) H-2', H-3, H-3' H-2' 2.42 (brdd, /= 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-3, H-3', H-9 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' H-4 - C 0 2 M e 3.20 (s) - C 0 2 M e Part of 3.30-3.46 (m) 163 Preparation of l-methoxycarbonvl-(£^-5-methoxvcarrx)nylm 6-ene ( 1 8 8 ) 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-Et20) and removal of 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 MHz, CDC13) 5: 1.38-1.54 (m, 2H), 1.75-1.92 (m, 2H), 2.00-2.09 (m, IH), 2.31-2.45 (m, 4H), 3.62-3.70 (m, 7H, includes two 3H - C 0 2 M e singlets at 3.63 and 3.68), 5.95 (d, IH, / = 2.3 Hz), 5.99 (br s, IH). X H nmr (400 MHz, C 6 D 6 ) 5: 1.12 (td, IH, / = 4.3, 12.7 Hz), 1.49-1.64 (m, 3H), 1.94-2.01 (ddd, IH, / = 3.0, 8.8, 16.5 Hz), 2.01-2.12 (m, IH, H-8), 2.17-2.27 (m, IH, H-8'), 2.31 (dd, IH, / = 8, 12.5 Hz), 2.41 (dm, IH, / = 13.5 Hz), 3.25 (s, 3H, -CQ 2 Me), 3.41 (s, 3H, -C0 2 Me), 4.09 (dm, IH, / = 13.5 Hz), 5.70 (dd, IH, H-7, / = 2.4, 2.4 Hz), 6.22 (d, IH, H-10, 7=2.2 Hz). 1 3 C nmr (75.5 MHz, CDC13) S: 23.1, 28.5, 30.5, 36.4, 38.6, 50.8 (-ve), 52.0 (-ve), 58.2, 112.8 (-ve), 130.4 (-ve), 144.1, 151.5, 167.1, 176.3. 1 8 0 1 8 8 164 HRMS calcd for C i 4 H 1 8 0 4 : 250.1205; found: 250.1213. Anal calcd for C 1 4 H 1 8 0 4 : C 67.18, H 7.25; found: C 67.32, H 7.24. Table 19. J H nmr (400 MHz, C 6 D 6 ) data for the diester 188: NOED experiments 9 C0 2 Me u C0 2 Me 188 Assignment H-x X H nmr (400 MHz) 8 (multiplicity, 7 (Hz)) NOED Correlation 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-5-ene (189) C0 2 Et SnMe 3 C0 2 Me e ^ C O o M e 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-Et20) and removal of trace 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 cm 1 . *H nmr (400 MHz, CDC13) 8: 1.2-1.4 (m, 4H, includes 3H -C0 2 CH 2 CH3 triplet at 1.23 wi th /= 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, -C0 2 Me), 4.10-4.20 (m, 2H, -C02CH2CH3), 5.80 (s, 1H, olefinic proton), 5.90-6.00 (m, 1H, olefinic proton). 1 3 C nmr (75.5 MHz, CDC13) 8: 14.1 (-ve), 19.5, 24.6, 29.6, 44.1, 51.0 (-ve), 51.3, 66.8, 106.5 (-ve), 123.2 (-ve), 140.8, 159.8, 167.3, 174.5. HRMS calcd for C i 4 H 1 8 0 4 : 250.1205; found: 250.1197. Anal, calcd for C i 4 H 1 8 0 4 : C 67.18, H 7.25; found: C 67.02, H 7.11. Preparation of 1 -(fe^butvldimethvlsiloxvmethvl)-(^-7-(fe^butvldimethvlsiloxvmethyl methylidene)bicyclo[4.2.01oct-5-ene (198) O H T B S O . C0 2 Et \ ^ C 0 2 M e 1 4 ^ 11 10 OH 0 9 ^ O T B S 189 197 198 To a cold (-78 °C), stirred solution of the diester 189 (161 mg, 0.642 mmol) in dry THF (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 4 (-100 mg) was added and the white suspension was stirred for an additional 30 min. The mixture was diluted with E t 2 0 (10 mL). The 166 mixture was then filtered through Florisil (-10 g) and the cake was eluted with E t 2 0 (50 mL) and MeOH (25 mL). The combined filtrate was concentrated under reduced pressure. Flash column chromatography (12 g of silica gel, 98:2 Et 2 0-MeOH) of the 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 CH 2 C1 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-Et20) of the crude product and removal of trace amounts 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 cm 1 . X H nmr (400 MHz, CDC13) 8: 0.02 (s, 6H, -SiMe?-), 0.05 (s, 6H, -SiMe?-), 0.87 (s, 9H, -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 MHz, CDC13) 8: -5.39, -5.34, -5.06, -5.02, 18.5 (2C), 24.3, 26.0 (7C) (-ve), 27.6, 38.8, 46.8, 60.9, 65.7, 116.7 (-ve), 116.9 (-ve), 142.5, 143.2. HRMS calcd for C 2 3 H 4 4 0 2 S i 2 : 408.2880; found: 408.2877. 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 MHz, CDC13) data for the diester 198: NOED experiments T B S O Assignment H-x lR nmr (400 MHz) 5 (multiplicity, / (Hz)) NOED Correlations 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 - l l 3.50 (dd, 7=0.9, 10) H-8, H - l l ' H - l l ' 3.65 (dd, 7 = 1.8, 10) H - l l Preparation of 1 -ethoxycarbonvl-(F)-7-methoxvcarbonvlmethylidenebicyclo \4.3.01non-5-ene (190) 2 C 0 2 E t 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-Et20) and removal of trace 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 cm 1 . : H nmr (400 MHz, CDC13) 8: 1.14-1.23 (m, 4H, H-2 and 3H -CO2CH2CH3 triplet at 1.18 wi th /= 7.2 Hz), 1.41-1.54 (m, 2H, H-3 and H-9), 1.70-1.80 (m, IH, 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, IH, H-2', / = 3.3, 12.8 Hz), 2.58-2.69 (m, IH, H-8), 3.08 (ddd, IH, H-8*, / = 1.5, 8.5, 19.4 Hz), 3.68 (s, 3H, -C0 2 Me), 4.03-4.15 (m, 2H, -C02CH2CH3), 6.08 (br s, IH, H-10), 6.32 (dd, IH, H-5, / = 3.9, 3.9 Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: 14.1 (-ve), 19.4, 25.3, 30.2, 32.2, 36.6, 50.9 (-ve), 52.9, 60.8, 106.9 (-ve), 125.5, 141.6, 160.5, 167.7, 175.4. HRMS calcd for C 1 5 H 2 o 0 4 : 264.1362; found: 264.1362. Anal, calcd for C i 5 H 2 o 0 4 : C 68.16, H 7.63; found: C 67.86, H 7.68. 169 Table 21. *H nmr (400 MHz, CDC13) data for the diester 190: COSY and NOED experiments 2 C0 2 Et 190 Assignment H-x *H nmr (400 MHz) 5 (multiplicity, 7 (Hz)) COSY Correlations NOED 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-4, H-4', H-10 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) H-5 -CO,Me 3.68 (s) -C0 2CH2CH 3 4.03-4.15 (m) -C0 2 CH 2 CH3 -C0 2 CH 2 CH3 Part of 1.14-1.23 (m, 7= 7.2) -C0 2CH2CH 3 170 Preparation of l-ethoxycarbonyl-(ir)-7-methoxycarbony non-5-ene (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-Et20) and removal of trace amounts of solvent (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 cm 1 . *H nmr (400 MHz, CDC13) 8: 1.17 (t, 3H, -C0 2 CH 2 CH3, / = 7.3 Hz), 1.33-1.44 (m, 3H), 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, -C0 2 Me), 3.79 (dm, 1H, / = 16.4 Hz), 4.01-4.15 (m, 2H, -C02CH2CH3), 5.80 (d, 1H, H - l l , / = 2.5 Hz), 5.91 (dd, 1H, H - 5 , / = 3.8, 3.8 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: 14.2 (-ve), 19.0, 22.3, 26.2, 29.3, 35.4, 37.2, 49.2, 50.8 (-ve), 60.7, 113.3 (-ve), 127.5 (-ve), 140.1, 160.8, 167.5, 175.7. HRMS calcd for C i 6 H 2 2 0 4 : 278.1518; found: 278.1522. 2 C0 2 Et 183 191 171 Anal, calcd for C 1 6 H 2 2 0 4 : C 69.04, H 7.97; found: C 69.17, H 7.97. Table 22. lK nmr (400 MHz, CDC13) data for the diester 191: selected COSY and NOED experiments 2 4 \ ^ 5 C 0 2 E t k J s J 7 1 1 C 0 2 M e 191 Assignment H-x X H nmr (400 MHz) 8 (multiplicity, / (Hz)) COSY Correlations NOED Correlations 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 - l l 5.80 (d, 7=2.5) 1.91-2.00 (m, H-8) H-5 Preparation of 1 -methoxycarbonyHZT)- 8 -methoxycarbony lmethylidenebic yclo r5.4.01 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 20) and removal 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 MHz, CDC13) 5: 1.35-1.75 (m, 7H), 1.84-1.93 (m, 2H), 2.01 (dm, 1H, / = 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 2 Me), 3.66 (s, 3H, -CCvMe), 5.82 (br s, 1H, H-12), 6.05 (dd, 1H, H-6, 7=5.4, 7.2 Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: 21.8, 25.1, 25.2, 26.9, 28.4, 37.2, 38.7, 50.8 (-ve), 51.8 (-ve), 54.0, 114.5 (-ve), 132.7 (-ve), 144.4, 163.0, 167.4, 175.7. HRMS calcd for C16H22O4: 278.1518; found: 278.1521. Anal calcd for C 1 6 H 2 2 0 4 : C 69.04, H 7.97; found: C 68.86, H 7.87. Table 23. *H nmr (400 MHz, CDC13) data for the diester 192: selected COSY and NOED experiments 3 2 C 0 2 M e 1 12N C 0 2 M e 192 Assignment H-x J H nmr (400 MHz) 8 (multiplicity, / (Hz)) COSY Correlations NOED Correlations H-6 6.05 (dd, 7=5.4,7.2) 2.05-2.14 (m, H-5), upfield part of 2.18-2.34 (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 2 0 (-10 mL/mmol of 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 2 0 (3 x -10 mL/mmol 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) 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 2 0 (200 mL), benzyl alcohol (205) (2.11 mL, 20.0 mmol), and trimethyltin chloride (6.00 g, 30.2 mmol). Flash column chromatography (200 g of silica gel, 4:1 petroleum ether-Et20) of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 205 199 174 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) 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 2 0 (250 mL), 4-methylbenzyl alcohol (206) (3.60 g, 29.5 mmol), and trimethyltin chloride (9.11 g, 45.7 mmol). Flash column chromatography (250 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 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, CDC13) 5: 0.30 (s, 9H, -SnMes, 2 / S n . H = 54.5 Hz), 1.65 (br s, IH, -OH, exchanges with D 2 0) , 2.34 (s, 3H, -Me), 4.62 (d, 2H, -CFb-OH, / = 5.6 Hz), 7.11 (d, IH, 7 = 7 Hz), 7.20 (d, IH, / = 7 Hz), 7.33 (s, IH, H - 3 , 3 / S n . H = 50.4 Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: -8.0 (-ve), 21.1 (-ve), 67.0, 127.2 (-ve), 129.1 (-ve), 136.6, 137.3 (-ve), 141.3, 144.1. HRMS calcd for C 1 0 H i 5 O 1 2 0 S n (M +-Me): 271.0145; found: 271.0138. Anal, calcd for C n H 1 8 O S n : C 46.37, H 6.37; found: C 46.59; H 6.55. 6 206 200 175 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 2 0 (250 mL), 3,4,5-trimethoxybenzyl alcohol (207) (0.81 mL, 5.0 mmol), and trimethyltin chloride (1.55 g, 7.82 mmol). Flash column chromatography (250 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 yielded 986 mg (54 %) of the alcohol 201 as a colorless viscous oil. IR (neat): 3432, 1583, 1478, 1316, 1015, 774, 525 cm 1 . lH nmr (400 MHz, CDC13) 8: 0.30 (s, 9H, -SnMes, 2 / s „ . H = 54.5 Hz), 1.53 (br t, 1H, -OH, exchanges with D 2 0 , / = 5.7 Hz), 3.81 (s, 3H, -OMe), 3.84 (s, 3H, -OMe), 3.85 (s, 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 MHz, CDC13) 5: -6.3 (-ve), 55.9 (-ve), 60.5 (-ve), 60.8 (-ve), 66.4, 107.8, 125.2 (-ve), 140.1, 143.2, 154.2, 157.9. HRMS calcd for C 1 2 H 1 9 O 4 1 2 0 S n (M +-Me): 347.0306; found: 347.0313. Anal, calcd for C 1 3 H 2 2 0 4 S n : C 43.25, H 6.14; found: C 43.64, H 5.93. 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 2C1 2) was added 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 2 0 (-2 mL/mL of CH 2C1 2). After 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) 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), CH 2 C1 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-Et20) and 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. 199 202 IR (neat): 1471, 1220, 764, 609, 529 cm 1 . 177 : H nmr (400 MHz, CDC13) 5: 0.39 (s, 9H, -SnMe., 2 / S n _ 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, IH, / = 1.5, 7.5 Hz), 7.38-7.54 (m, 2H). 1 3 C nmr (50.3 MHz, CDC13) 5: -7.8, 36.9, 127.8, 129.0, 129.9, 136.8, 143.5, 144.5. HRMS calcd for C 9 H i 2 7 9 B r 1 2 0 S n (M +-Me): 318.9144; found: 318.9144. Anal, calcd for C 1 0 H 1 5 BrSn : C 35.98, H 4.53; found: C 36.28, H 4.49. Preparation of 4-methvl-2-trimethvlstarjnvlbenzvl bromide (203)7 6 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 2 C1 2 (70 mL), and 4-methyl-2-trimethylstannylbenzyl alcohol (200) (2.20 g, 7.72 mmol). The crude product was purified by flash column chromatography (75 g of silica gel, 193:7 petroleum ether-Et20) 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 cm1. *H nmr (400 MHz, CDC13) 5: 0.32 (s, 9H, -SnMe.. 2 / S n . H = 50.0 Hz), 2.31 (s, 3H, -Me), 4.50 (s, 2H, -CHrBr) , 7.05-7.10 (m, IH), 7.20-7.45 (m, 2H). 1 3 C nmr (50.3 MHz, CDC13) 8: -7.9, 21.2, 37.0, 128.9, 129.7 (2C), 137.5, 141.5, 143.2. 200 203 178 HRMS calcd for C i 0 H 1 4 7 9 B r 1 2 0 S n (M +-Me): 322.9301; found: 322.9301. Anal, calcd for CnHi 7 BrSn: C 37.98, H 4.93; found: C 38.13, H 4.89. 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 2 C1 2 (28 mL), and the stannane 201 (986 mg, 2.74 mmol). The crude product was purified by flash column chromatography (30 g of silica gel, 22:3 petroleum ether-Et20) and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 754 mg (65 %) of the bromide 204 as a colorless clear oil. [Note: Perform all procedures in the fumehood as this oil is extremely volatile.] IR (neat): 1581, 1481, 1323, 1099, 773 cm 1 . : H nmr (400 MHz, CDC13) 5: 0.36 (s, 9H, -SnMes, 2 / S n . H = 54.8 Hz), 3.82 (s, 3H, -OMe), 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 = 16.1 Hz). 1 3 C nmr (50.3 MHz, CDC13) 5: -6.2 (-ve), 37.1, 56.0 (-ve), 60.5 (-ve), 60.8 (-ve), 109.9 (-ve), 128.0, 139.7, 140.8, 154.2, 157.6. HRMS calcd for C i 2 H 1 8 7 9 B r 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) Br> S n M e 3 T B S T B S *SnMe 3 199 160 209 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 2 0 (3 x 15 mL). The combined organic extracts were washed with brine (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-Et20) of the crude 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 cm 1 . X H nmr (400 MHz, CDC13) 8: 0.11 (s, 6H, -SiMe 9-), 0.28 (s, 9H, -SnMe^ 2 / S ] 1 - H = 53.5 Hz), 0.94 (s, 9H, -Si'Bu-), 4.14 (s, 2H, -CHr) , 4.59 (s, 2H, -CHr ) , 7.20-7.30 (m, 3H), 7.50 (dm, 1H, aromatic proton a to -SnMe 3, / = 6.1 Hz, 3 / s „ - H = 50.4 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -8.0, -4.6, 16.5, 26.1, 57.8, 73.1, 90.2, 101.8, 127.3, 128.21, 128.25, 136.6,141.8, 143.9. HRMS calcd for C 1 8 H 2 9 O S i 1 2 0 S n (M +-Me): 409.1010; found: 409.1005. Anal, calcd for C 1 9 H 3 2 OSiSn: C 53.92, H 7.62; found: C 54.22, H 7.45. 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 THF (10 mL) at room temperature was added a solution of tetrabutylammonium fluoride (1.25 mL, 1 M in THF, 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 2 0 (3 x 15 mL). 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-Et20) of the crude product yielded 243 mg (99 %) of the 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 THF (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 THF (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 2 0 (3 x 10 mL). The combined organic extracts were 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-Et20) and 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 cm 1 . 181 X H nmr (400 MHz, CDC13) 5: 0.28 (s, 9H, -SnMea, 2 / S n . H = 53.8 Hz), 3.78 (s, 3H, -C0 2 Me), 4.23 (s, 2H, -CHr) , 4-59 (s, 2H, -CH2-), 7.25-7.32 (m, 3H), 7.51 (dm, IH, aromatic proton a to -SnMe 3, / = 5.3 Hz, 3 / s n -H = 48.9 Hz). 1 3 C nmr (125.8 MHz, CDC13) 5: -8.1 (-ve), 52.7 (-ve), 56.5, 73.8, 78.2, 83.2, 127.5 (-ve), 128.3 (-ve), 128.5 (-ve), 136.6 (-ve), 142.2, 143.0, 153.4. HRMS calcd for C 1 4 H 1 7 O 3 1 2 0 S n (M +-Me): 353.0200; found: 353.0194. Anal, calcd for C 1 5 H 2 o0 3 Sn: C 49.09, H 5.49; found: C 49.14, H 5.45. Preparation of diethyl 2-(2-trimethylstannvlbenzyl)malonate (212) S n M e 3 To a stirred suspension of potassium hydride (543 mg, 13.5 mmol, washed with pentane) in dry THF (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 2 0 (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried (MgS0 4 ) , and the solvent was removed under reduced pressure. Flash column chromatography (100 g of silica gel, 9:1 petroleum ether-Et20) of the crude 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. 202 212 IR (neat): 1731, 1200, 1036, 770 cm"1. 182 *H nmr (400 MHz, CDC13) 8: 0.34 (s, 9H, -SnMej, 2 / s „ . H = 53.2 Hz), 1.11 (t, 6H, -C0 2 CH 2 CH3, / = 7.2 Hz), 3.25 (d, 2H, -CEb-CH-, / = 7.8 Hz), 3.60 (t, 1H, -CH 2 -CH- , / = 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, 3 / S f t - H = 49.8 Hz). 1 3 C nmr (125.8 MHz, CDC13) 8: -8.3 (-ve), 13.8 (-ve), 37.1, 53.6 (-ve), 61.2, 126.1 (-ve), 128.1 (-ve), 128.4 (-ve), 136.4 (-ve), 142.3, 144.4, 168.5. HRMS calcd for C i6H 2 3 O 4 1 2 0 Sn (M +-Me): 399.0618; found: 399.0624. Anal, calcd for C i 7 H 2 6 0 4 S n : C 49.43, H 6.34; found: C 49.78, H 6.38. 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 THF (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 2 0 (3 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried (MgS0 4 ) , and the solvent was removed under reduced pressure. Rash column chromatography (40 g of silica gel, 96:4 petroleum ether-Et20) of the crude product and removal of trace amounts 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 cm 1 . *H nmr (400 MHz, CDC13) 8: 0.06 (s, 6H, -SiMe,-), 0.34 (s, 9H, -SnM&>. 2 / s „ . H = 55.4 Hz), 0.90 (s, 9H, -Si'Bu-), 1.11 (t, 6H, -C0 2 CH 2 CH3, / = 7.1 Hz), 2.95 (s, 2H, - C H r ) , 3.49 (s, 2H, -CHr) , 4.00-4.12 (m, 4H, -C02CH2CH3), 7.13-7.26 (m, 3H), 7.34 (d, 1H, aromatic proton a to -SnMe 3, / = 7.0 Hz, 3 / s n -H = 48.5 Hz). 1 3 C nmr (125.8 MHz, CDC13) 8: -7.2 (-ve), -4.6 (-ve), 13.8 (-ve), 16.4, 25.3, 26.0 (-ve), 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. HRMS calcd for C 2 5 H 3 9 O 4 S i 1 2 0 S n (M +-Me): 551.1639; found: 551.1640. Anal, calcd for C 2 6 H4 2 0 4 SiSn : C 55.23, H 7.49; found: C 55.58, H 7.40. Preparation of 4,4-bis(ethoxvcarbonvl)-5-(2-trimethvlstannvlphenvl)pent-l-yne (214) SnMe 3 SnMe 3 TBS V ^ 1 R = -C0 2 Et R = -C0 2 Et 213 214 To a stirred solution of the stannane 213 (511 mg, 0.923 mmol) in dry THF (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 2 0 (3 x 15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgS0 4 ) , and the 184 solvent was removed under reduced pressure. Flash column chromatography (20 g of silica gel, 95:5 petroleum ether-Et20) of the crude product and removal of trace amounts 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 cm 1 . X H nmr (400 MHz, CDC13) 5: 0.34 (s, 9H, -SnMej, 2 / S „ - H = 53.4 Hz), 1.17 (t, 6H, -C0 2 CH 2 CH3, / = 7.2 Hz), 2.00 (t, 1H, H - l , / = 2.7 Hz), 2.84 (d, 2H, H-3, J = 2.7 Hz), 3.51 (s, 2H, H-5), 4.00-4.21 (m, 4H, -C02CH2CH3), 7.10-7.21 (m, 3H), 7.38 (dm, 1H, aromatic proton a to -SnMe 3, / = 6.6 Hz, 3 / S n - H = 48.0 Hz). 1 3 C nmr (75.5 MHz, CDC13) S: -7.2, 13.9, 23.3, 40.2, 57.9, 61.7, 71.7, 79.4, 126.3, 127.8, 128.2, 136.8, 142.6, 145.0, 170.1. HRMS calcd for C 1 9 H 2 5 O 4 1 2 0 S n (M +-Me): 437.0775; found: 437.0778. Anal, calcd for C 2 0 H 2 8 O 4 S n : C 53.25, H 6.26; found: C 53.11, H 6.13. Preparation of methyl 5,5-bis(ethoxvcarbonyl)-6-(2-lrimethvlstannvlphenvl)hex-2-vnoate £215} R = -C0 2 Et R = -C0 2 Et 214 215 To a cold (-78 °C), stirred solution of L D A (1.15 mmol) in dry THF (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 2 0 (3 x 10 mL). The combined organic extracts were 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-Et20) 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 cm 1 . *H nmr (400 MHz, CDC13) 5: 0.34 (s, 9H, -SnMe 3, 2 / S n . H = 53.3 Hz), 1.19 (t, 6H, -C0 2 CH 2 CH3, / = 7.3 Hz), 2.93 (s, 2H, -CHr) , 3.49 (s, 2H, -CH2-), 3.71 (s, 3H, -C0 2 Me), 4.10-4.25 (m, 4H, -CO2CH2CH3), 7.05-7.11 (m, IH), 7.15-7.21 (m, 2H), 7.39 (dm, IH, aromatic proton a to -SnMe 3, / = 6.3 Hz, 3 / S I I - H = 47.4 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -7.4 (-ve), 13.8 (-ve), 23.5, 40.6, 52.5 (-ve), 57.6, 62.0, 75.3, 84.2, 126.4 (-ve), 127.7 (-ve), 128.3 (-ve), 136.8 (-ve), 141.9, 144.9, 153.5, 169.5. HRMS calcd for C 2 i H 2 7 O 6 1 2 0 S n (M +-Me): 495.0830; found: 495.0831. Anal, calcd for C 2 2 H 3 0 O 6 S n : C 51.90, H 5.94; found: C 52.11, H 5.84. 186 Preparation of methyl 5-oxa-6-(4-methyl-2-trime^ (217) SnMe 3 COoMe SnMe 3 200 216 217 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 2 0 (3 x 15 mL). The combined organic extracts 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-Et20) of the crude oil yielded 529 mg of the alkyne 216 as a colorless 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 (2.27 mmol) in dry THF (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 THF (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 2 0 (3 x 20 mL). The combined organic extracts were 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-Et20) and 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 cm 1 . J H nmr (400 MHz, CDC13) 8: 0.27 (s, 9H, -SnMej, 2 / S n . H = 53.6 Hz), 2.31 (s, 3H, -Me), 3.78 (s, 3H, -COzMe), 4.20 (s, 2H, -CHr) , 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 MHz, CDC13) 5: -8.0 (-ve), 21.2 (-ve), 52.7 (-ve), 56.3, 73.6, 78.1, 83.4, 128.7 (-ve), 129.0 (-ve), 137.1, 137.5 (-ve), 140.0, 142.1, 152.8. HRMS calcd for C 1 5 H 1 9 O 3 1 2 0 S n (M +-Me): 367.0356; found: 367.0352. Anal, calcd for C i 6 H 2 2 0 3 S n : C 50.43, H 5.82; found: C 50.61, H 5.75. Preparation of diethyl 2-(4-methvl-2-trimethvlstannvlbenzyl)malonate (218) To a stirred suspension of potassium hydride (144 mg, 3.60 mmol, washed with pentane) in dry THF (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 2 0 (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried (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 SnMe 3 203 218 188 ether-Et20) and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 415 mg (86 %) of the diester 218 as a colorless oil. IR (neat): 1735, 1152, 858, 771 cm 1 . XR nmr (400 MHz, CDC13) 8: 0.32 (s, 9H, -SnMe.. 2 / 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 3, 3 / s n -H = 50.0 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -8.1 (-ve), 14.0 (-ve), 21.0 (-ve), 36.7, 53.9 (-ve), 61.5, 128.1 (-ve), 129.3 (-ve), 135.5, 137.3 (-ve), 141.4, 142.2, 168.9. HRMS calcd for C 1 7 H25O 4 1 2 0 Sn (M +-Me): 413.0775; found: 413.0781. Anal, calcd for Ci 8 H 2 80 4 Sn: C 50.62, H 6.61; found: C 50.51, H 6.65. 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 THF (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 2 0 ( 3 x 5 mL). The combined organic extracts were washed with brine (10 mL), dried (MgS0 4 ), and the solvent was removed under reduced pressure. The resulting crude product was purified by flash column chromatography (20 g of silica gel, 50:3 petroleum ether-Et20) and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 373 mg (99 %) of the diester 220 as a colorless oil. IR (neat): 3285, 1734, 1480, 1190, 772 cm 1 . J H nmr (400 MHz, CDC13) S: 0.34 (s, 9H, -SnMes, 2 / S n - H = 56.1 Hz), 1.19 (t, 6H, -C0 2 CH 2 CH3, / = 7.1 Hz), 1.99 (t, IH, H - l , / = 2.6 Hz), 2.27 (s, 3H, -Me), 2.82 (d, 2H, 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, IH, aromatic proton a to -SnMe 3, 3 / S „ - H = 49.3 Hz). 1 3 C nmr (128.5 MHz, CDC13) 5: -7.2, 13.9, 20.6, 23.3, 39.6, 58.0, 61.7, 71.6, 79.6, 127.6, 129.0, 135.5, 137.4, 139.4, 144.7, 170.1. HRMS calcd for C 2 0 H 2 7 O 4 1 2 0 S n (M +-Me): 451.0931; found: 451.0928. Anal, calcd for C 2 i H 3 0 O 4 S n : C 54.22, H 6.50; found: C 54.50, H 6.49. Preparation of methyl 5,5-bis(ethoxycarfx)nvl)-6-(2-tijmethylstannvlphenvl)hex-2-vnoate (221} SnMe 3 SnMe 3 C 0 2 M e R = -C0 2 Et R = -C0 2 Et 220 221 To a cold (-78 °C), stirred solution of L D A (0.85 mmol) in dry THF (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 2 0 ( 3 x 5 mL). The combined organic extracts were washed with 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-Et20) of the 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 cm 1 . *H nmr (400 MHz, CDC13) 8: 0.33 (s, 9H, -SnMej, 2 / S n . H = 53.2 Hz), 1.20 (t, 6H, -C0 2 CH 2 CH3, / = 7.1 Hz), 2.26 (s, 3H, -Me), 2.90 (s, 2H, -CH2-), 3.45 (s, 2H, - C&r), 3.70 (s, 3H, -COzMe), 4.12-4.23 (m, 4H, - C 0 2 C H 2 C H 3 ) , 6.92-7.04 (m, 2H), 7.17 (br s, 1H, aromatic proton a to - S n M e 3 , 3 / s n - H = 49.9 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -7.4 (-ve), 13.9 (-ve), 20.9 (-ve), 23.4, 40.2, 52.5 (-ve), 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. HRMS calcd for C 2 2 H 2 9 O 6 1 2 0 S n (M +-Me): 509.0986; found: 509.0979. Anal, calcd for C 2 3 H 3 2 0 6 S n : C 52.80, H 6.16; found: C 52.69, H 6.14. 191 Preparation of 4,4-bis(ethoxycarbonyl)-5-(3,4,5-trimethoxv-2-trimethylstam phenyDpent-l-yne (222) OMe R = - C 0 2 E t 222 To a stirred suspension of potassium hydride (213 mg, 5.35 mmol, washed with pentane) in dry THF (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 THF (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 2 0 (3 x 10 mL). The 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-Et20) yielded 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 THF (17 mL) at room temperature was added a solution of diethyl malonate and the stannane 219 (obtained as described above) in dry THF (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 2 0 (3 x 10 mL). The combined organic 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-Et20) and removal of trace 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 cm 1 . X H nmr (400 MHz, CDC13) 8: 0.31 (s, 9H, -SnMej, 2 / s „ . H = 54.3 Hz), 1.17 (t, 6H, -C0 2 CH 2 CH3, / = 7.2 Hz), 2.02 (t, 1H, H - l , / = 2.6 Hz), 2.77 (d, 2H, H-3, J = 2.6 Hz), 3.40 (s, 2H, H-5), 3.78 (s, 6H, includes 2 3H -OMe singlets), 3.83 (s, 3H, -OMe), 4.06-4.19 (m, 4H, -C02CH2CH3), 6.59 (s, 1H, aromatic proton, 4 / S n - H = 17.4 Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: -5.4, 13.9, 23.1, 38.6, 55.8, 58.5, 60.4, 60.9, 61.6, 71.9, 79.5, 108.6, 129.2, 138.3, 139.5, 153.8, 157.2, 170.0. HRMS calcd for C 2 2 H 3 1 O 7 1 2 0 S n (M +-Me): 527.1092; found: 527.1081. Anal, calcd for C 2 3 H 3 4 0 7 S n : C 51.04, H 6.33; found: C 51.04, H 6.19. Preparation of methyl 5,5-bis(ethoxycarbonvl)-6-(3,4,5-trimethoxv-2-trimethylstarm phenyl)hex-2-ynoate (223) S n M e 3 S n M e 3 MeOs MeO' C 0 2 M e OMe R = -C0 2 Et OMe R = -C0 2 Et 222 223 To a cold (-78 °C), stirred solution of L D A ( 3 . 3 6 mmol) in dry THF (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 THF (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 2 0 (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgS0 4 ) , and the solvent was removed under reduced pressure. Flash column chromatography (50 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 yielded 805 mg (80 %) of the alkynic triester 223 as a colorless clear oil. IR (neat): 2241, 1719 (br), 1585, 1558, 1261, 1099, 775 cm 1 . X H nmr (400 MHz, CDC13) 5: 0.30 (s, 9H, -SnMe.. 2 / S „ - H = 54.3 Hz), 1.20 (t, 6H, -C0 2 CH 2 CH3, / = 7.1 Hz), 2.88 (s, 2H, -CHr) , 3.39 (s, 2H, -CEL.-), 3.71 (s, 3H, -OMe), 3.78 (s, 6H, includes 2 3H -OMe singlets), 3.84 (s, 3H, -OMe), 4.10-4.24 (m, 4H, -COiCEzCKj), 6.54 (s, 1H, aromatic proton, 4 / s „ . H = 17.3 Hz). 1 3 C nmr (50.3 MHz, CDC13) 5: -6.2 (-ve), 13.9 (-ve), 23.5, 39.2, 52.6 (-ve), 55.8 (-ve), 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. HRMS calcd for C 2 4 H 3 3 O 9 1 2 0 S n (M +-Me): 585.1147; found: 585.1151. Anal, calcd for C 2 5 H 3 6 0 9 S n : C 50.11, H 6.06; found: C 50.35, H 5.99. 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-Et20) of the crude product and removal of trace amounts 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 cm 1 . J H nmr (400 MHz, CDC13) 5: 3.73 (s, 3H, - C O o M e ) , 4.67 (s, 2H, H- l ) , 5.11 (d, 2H, H-3, / = 2.1 Hz), 6.36 (t, IH, H-9, / = 2.1 Hz), 7.09 (d, IH, / = 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, CDC13) 8: 51.3 (-ve), 68.0 (2C), 110.3 (-ve), 123.9 (-ve), 125.1 (-ve), 127.6 (-ve), 129.9, 130.0 (-ve), 137.2, 149.6, 166.7. HRMS calcd for C 1 2 H 1 2 0 3 : 204.0786; found: 204.0782. Anal, calcd for C 1 2 H 1 2 0 3 : C 70.59, H 5.92; found: C 70.49, H 5.85. 195 Table 24. X H rrrnr (400 MHz, CDCI3) data for the ester 224: NOED experiments 224 Assignment H-x J H nmr (400 MHz) 8 (multiplicity, 7 (Hz)) NOED Correlations 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-Et20) of the crude product and removal of trace 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 cm 1 . J H nmr (400 MHz, 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, IH, 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 MHz, CDC13) 5: 21.3 (-ve), 51.4 (-ve), 67.9, 68.0, 110.0 (-ve), 124.3 (-ve), 125.1 (-ve), 129.7, 131.0 (-ve), 134.4, 137.1, 149.9, 166.8. HRMS calcd for C13H14O3: 218.0943; found: 218.0939. Anal, calcd for C i 3 H i 4 0 3 : C 71.54, H 6.47; found: C 71.74, H 6.58. Table 25. *H nmr (400 MHz, CDC13) data for the ester 225: NOED experiments 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) 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-Et20) and removal of 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 cm 1 . *H nmr (400 MHz, CDC13) 8: 1.13 (t, 6H, -C0 2CH 2CH3, / = 7.1 Hz), 3.30 (s, 2H, H- l ) , 3.69 (d, 2H, H-3, / = 1.8 Hz), 3.74 (s, 3H, -C0 2 Me), 4.10 (q, 4H, -C0 2CH2CH 3, / = 7.1 Hz), 6.38 (br t, IH, H-9, / = 1.8 Hz), 7.15-7.30 (m, 3H), 7.60 (d, IH, H-5, / = 7.8 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: 13.8 (-ve), 33.6, 35.3, 51.1 (-ve), 53.9, 61.6, 113.8 (-ve), 124.4 (-ve), 127.1 (-ve), 129.3 (-ve), 130.1 (-ve), 133.0, 135.6, 150.4, 166.8, 170.4. HRMS calcd for C 1 9 H 2 2 0 6 : 346.1416; found: 346.1420. Anal, calcd for C i 9 H 2 2 0 6 : C 65.88, H 6.40; found: C 66.08, H 6.31. R = -C0 2 Et C 0 2 M e 215 226 198 Table 26. X H nmr (400 MHz, CDC13) data for the triester 226: NOED experiments C 0 2 M e 226 Assignment H-x *H nmr (400 MHz) 8 (multiplicity, / (Hz)) NOED Correlations H-5 7.60 (d,/=7.8) H-9, Part of mat 7.15-7.30 H-9 6.38 (br 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 lH nmr (400 MHz, CDC13) 8: 1.14 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 2.30 (s, 3H, -Me), 3.25 (s, 2H, H- l ) , 3.67 (d, 2H, H-3, / = 1.9 Hz), 3.73 (s, 3H, -C0 2 Me), 4.10 (q, 4H, -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). 1 3 C nmr (125.8 MHz, CDC13) 5: 13.9 (-ve), 21.1 (-ve), 33.6, 35.2, 51.1 (-ve), 54.0, 61.5, 113.6 (-ve), 124.9 (-ve), 129.2 (-ve), 131.1 (-ve), 132.7, 132.8, 136.6, 150.6, 166.9, 170.5. HRMS 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 MHz, CDC13) data for the triester 227: NOED experiments 7(| 2 p C 0 2 E t 0 C0 2 Me 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) S n M e 3 C 0 2 M e i 6 9 10 11 CO2CH2CH3 CO2CH2CH3 OMe 15 13 14 OMe R = - C 0 2 E t 223 228 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-Et20) of the crude product and 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 cm 1 . *H nmr (500.2 MHz, C 6 D 6 ) 8: 0.83 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 3.22 (s, 3H, H-17), 3.35 (s, 2H, H- l ) , 3.45 (s, 3H, -C0 7 Me). 3.61 (s, 3H, H-15), 3.66 (s, 3H, H-16), 3.88 (q, 4H, -C0 2CH2CH 3, / = 7.1 Hz), 4.19 (d, 2H, H-3, / = 1.8 Hz), 6.19 (s, IH, H-8), 7.39 (brt, IH, H-12 , /= 1.8 Hz). 1 3 C nmr (125.8 MHz, C 6 D 6 ) 8: 13.9, 34.9, 36.8, 50.6, 54.4, 55.3, 60.4, 60.6, 61.5, 108.2, 117.8, 121.3, 133.1, 142.6, 147.3,153.6, 154.8,167.7, 170.7. HRMS calcd for C22H28O9: 436.1733; found: 436.1729. Anal, calcd for C22H28O9: C 60.54, H 6.47; found: C 60.22, H 6.67. 201 Table 28. *H nmr (400 MHz, C 6 D 6 ) data for the triester 228: NOED experiments 9 10 11 ^ C 0 2 C H 2 C H 3 2 p C 0 2 C H 2 C H 3 3 12 15 v C 0 2 M e 13 14 228 Assignment H-x *H nmr (400 MHz) 8 (multiplicity, / (Hz)) NOED 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 - 1 1 , - C 0 2 C H 2 C H 3 0.83 (t, 7=7.1) H-12 7.39(brt, /= 1.8) H-15 H-14. -COMe 3.45 (s) H-3 H-15 3.61 (s) H-12 H-16 3.66 (s) H-17 3.22 (s) H-8 202 Table 29. 1 3 C nmr (128.5 MHz, C 6 D 6 ) data for the triester 228: H M B C and H M Q C experiments 9 10 11 C O 2 C H 2 C H 3 2 [ ^ C 0 2 C H 2 C H 3 3 C 0 2 M e 13 1 4 228 Assignment C-x 1 3 C nmr (125.8 MHz) 5 H M Q C Correlations H M B C Correlations C - l 36.8 H - l C-2 54.4 H - l C-3 34.9 H-3 H - l , H-12 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 H-8 H - l 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 - l l C - l l 13.9 H - l l H-10 C-12 117.8 H-12 H-3 C-13 167.7 H-14 C-14 50.6 H-14 C-15 60.3 H-15 C-16 60.6 H-16 C-17 55.3 H-17 203 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 2 0 (3 x 10 mL) and the combined organic extracts were washed with 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-Et20) and removal of trace amounts of solvent (vacuum pump) 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 ( XH nmr) identical with those previously mentioned (pg. 127). In a separate experiment, 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 MHz, CDC13) 8: 0.25 (s, 9H, -SnMes, 2 / S n - H = 56.2 Hz), 1.26 (t, 3H, -C0 2 CH 2 CH3, / = 7.1 Hz), 2.56-2.70 (m, 2H, H-4), 2.88-3.02 (m, 2H, H-3), 4.14 (q, 2H, -C0 2CH2CH 3 , / = 7.1 Hz), 4.88 (br s, IH, H-5b), 5.18 (br t, IH, H-5a, / = 2.7 Hz). 204 FIRMS calcd for C n H 1 7 0 2 S n (M +-Me): 301.0251; found: 301.0253. Table 30. *H nmr (200 MHz, CDC13) data for the ester 145: NOED experiments C0 2 Et M j j — SnMe 3 H b 145 Assignment *H nmr (200 MHz) NOED H-x 8 (multiplicity, / (Hz)) Correlations -SnMe 3 0.25 (s) H-5a H-5a 5.18 (brt, 7=2.7) H-5b, -SnMe 3 H-5b 4.88 (brs) H-3, H-5a Conjugate addition utilizing an aqueous H C l work up C0 2 Et . . . 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 2 0 (3 x 10 mL) and the combined organic extracts 205 were washed with brine (3 x 20 mL), dried (MgS0 4 ), 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-Et20) and removal of trace amounts of solvent (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?!! 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-Et20) 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 ( J H nmr) identical with those previously mentioned (pg. 133). In addition, 18 mg of an uncharacterized mixture of unidentified destannylated material was obtained. C 0 2 M e 143 158 206 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-Et20) 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 M e 3 S n C 0 2 E t C O o E t 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-Et20) 207 yielded 38 mg (89 %) of the cyclohexane derivative 156. The diene 156 exhibited spectral characteristics ( XH nmr) identical with those previously mentioned (pg. 131). 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-Et20). Removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 20 mg (76 %) of the cyclohexane derivative 156. In addition, 2 mg of uncharacterized destannylated material was recovered. The diene 156 exhibited spectral characteristics ( J H nmr) identical with those previously mentioned (pg. 131). 208 Conjugate addition utilizing DMI 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 DMI (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 DMI (1.7 mL). Purification of the crude product by flash column chromatography (7 g of silica gel, 96:4 petroleum ether-Et20) 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 THF (2 mL) was added a solution of the stannane 180b (107 mg, 0.300 mmol) (pg. 150) in dry THF (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 2 P 0 4 (10 mL) and 209 stirring was continued for 1 h. The rnixture was extracted with E t 2 0 (3 x 10 mL). The 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-Et20) of the crude product and removal of trace amounts 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 cm 1 . X H nmr (400 MHz, CDC13) 8: 0.12 (s, 9H, -SnMe 3, 2 / S n _ H = 54.3 Hz), 1.40-1.60 (m, 3H), 1.68-1.77 (m, IH), 1.93-2.00 (m, IH), 2.36-2.55 (m, 5H), 3.63 (s, 3H, -C0 2 Me), 5.96 (dd, IH, olefinic proton, / = 2.1, 2.1 Hz, 3 / S „ - H = 37.9 Hz), 9.14 (s, IH, -C(=0)H). 1 3 C nmr (125.8 MHz, CDC13) 8: -8.6 (-ve), 19.5, 23.3, 32.0, 34.2, 37.7, 51.8 (-ve), 65.2, 81.9, 98.3, 143.6 (-ve), 148.4, 176.6, 176.9 (-ve). HRMS calcd for C i 5 H 2 i O 3 1 2 0 S n (M +-Me): 369.0513; found: 369.0505. Anal, calcd for C i 6 H 2 4 0 3 S n : C 50.17, H 6.32; found: C 50.40, H 6.47. Preparation of 7-(l-methoxycarbonyl-2-trmiethvlstannvlcyclopent-2-en-l-yl)hept-3-vn-2-one (234) 180b 234 210 C 0 2 M e 235 To a cold (-78 °C), stirred solution of L D A (2.48 mmol) in dry THF (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 THF (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 2 0 (3 x 10 mL). The combined organic extracts were washed with 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-Et20) of the crude 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 2 C1 2 , 1.84 mmol) in dry CH 2 C1 2 (10 mL) was added dimethyl sulfoxide (260 JLIL, 3.66 mmol) 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 CH 2 C1 2 (2 mL). The 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 CH 2 C1 2 (3 x 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-Et20) of the crude product and removal of trace 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 cm 1 . X H nmr (400 MHz, CDC13) 8: 0.13 (s, 9H, -SnMe 3, 2 / S n . H = 54.3 Hz), 1.38-1.56 (m, 3H), 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, IH, olefinic proton, / = 2.1, 2.1 Hz, 3 / s „ . H = 38.0 Hz). 1 3 C nmr (125.8 MHz, CDC13) 8: -8.6 (-ve), 19.3, 23.5, 31.9, 32.7 (-ve), 34.2, 37.7, 51.7 (-ve), 65.2, 81.6, 93.1, 143.6 (-ve), 148.3, 176.6, 184.7. HRMS calcd for C i 6 H 2 3 O 3 1 2 0 S n (M +-Me): 383.0669; found: 383.0673. Anal, calcd for C i 7 H 2 6 0 3 S n : C 51.42, H 6.60; found: C 51.48, H 6.70. 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) 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-Et20) and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 233 236 (minor) 237 (major) 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 cm 1 . Signals attributable to the major isomer 237: X H nmr (400 MHz, C 6 D 6 ) 8: 3.19 (s, 3H, -C0 2 Me), 5.44 (dd, 1H, H-7, / = 2.1, 2.1 Hz), 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 MHz, CDC13) 8: 24.8, 31.4, 36.1, 37.3, 37.6, 52.1 (-ve), 59.2, 127.5 (-ve), 135.3 (-ve), 139.6, 159.7, 175.8, 193.1 (-ve). Signals attributable to the minor isomer 236: J H nmr (400 MHz, C 6 D 6 ) 8: 2.83 (dm, 1H, H-4, / = 15.4 Hz), 3.23 (s, 3H, -C0 2 Me), 5.62 (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 MHz, CDC13) 8: 23.1, 27.7, 30.8, 36.2, 38.6, 52.1 (-ve), 58.2, 124.0 (-ve), 132.5 (-ve), 143.6, 156.9, 176.0, 190.6 (-ve). HRMS calcd for C 1 3 H 1 6 0 3 : 220.1099; found: 220.1100. Anal, calcd for C 1 3 H 1 6 0 3 : C 70.89, H 7.32; found: C 70.96, H 7.20. 213 Table 31. X H nmr (400 MHz, CDC13) data for the aldehdye 237: NOED experiments 9 C 0 2 M e O 237 Assignment *H nmr (400 MHz) NOED H-x 8 (multiplicity, / (Hz)) Correlations H-7 5.44 (dd,/= 2.1, 2.1) H - l l H-10 5.91 (dd,7=2.0,7.9) H - l l 10.12 (d, 7=7.9) H-7, H-10 Table 32. X H nmr (400 MHz, CDC13) data for the aldehyde 236: NOED experiments Assignment X H nmr (400 MHz) NOED H-x 8 (multiplicity, 7 (Hz)) Correlations 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 - l l 9.92 (d,7=8.0) One of H-4 214 Preparation of l-methoxycarbonyHiT)-5-acety (238) 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-Et20) of the crude product and removal of trace 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 1 3 C nmr acquisition times in CDCI3; however a clean 1 H nmr spectrum was obtained. Integration of the olefinic protons, in the *H nmr 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 cm 1 . lH nmr (400 MHz, CDC13) 8: 1.37-1.51 (m, 2H), 1.70-1.76 (m, 1H), 1.82-1.92 (m, 1H), 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 MHz, CDC13) 8: 23.0, 28.8, 30.5, 32.1 (-ve), 36.3, 38.7, 52.1 (-ve), 58.2, 120.6 (-ve), 130.7 (-ve), 144.4, 152.6, 176.4, 199.0. 215 HRMS calcd for C i 4 H 1 8 0 3 : 234.1256; found: 234.1251. Anal, calcd for C i 4 H 1 8 0 3 : C 71.77, H 7.74; found: C 71.49, H 7.95. Table 33. *H nmr (400 MHz, CDC13) data for the ketone 238: NOED experiments 9 C 0 2 M e 8 ' ^ 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 3 -C(=0)CH 3 2.19 (s) 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 2 0 or CH 2 C1 2 (3 x ~1 mL/mL of DMF). The combined organic extracts were washed with water (~2 mL/mL of DMF) and brine (3 x ~2 mL/mL of DMF), 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) 6 1 (101 mg, 0.414 mmol), copper(I) chloride (104 mg, 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 2 C1 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 cm 1 . J H nmr (400 MHz, CDC13) 8: 2.52-2.57 (m, 4H), 2.85-2.90 (m, 4H), 6.43 (t, 2H, H-2, / = 1.5 Hz). 1 3 C nmr (50.3 MHz, CDC13) 8: 28.2, 35.1,132.6, 166.9, 208.7. HRMS calcd for C i o H 1 0 0 2 : 162.0681; found: 162.0677. Anal, calcd for C ioHi 0 0 2 : C 74.06, H 6.21; found: C 74.13, H 6.10. Preparation of 3-(3-oxocyclohex-l-en-l-yl)cyclohex-2-en-l-one (253) O Following general procedure 6, the diene 253 was prepared from 3-trimethylstannylcyclohex-2-en-1 -one (249)61 (121 mg, 0.469 mmol), copper(I) chloride (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 2 0 . Purification of the crude product by flash column chromatography (7 g of silica gel, Et 2 0) and removal of trace 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). 249 253 218 LR (neat): 1662, 1575, 1263, 1186, 1144, 901 cm 1 . J H nmr (400 MHz, CDC13) 5: 2.00-2.15 (m, 4H, H-5), 2.42 (t, 4H, / = 6.7 Hz), 2.50 (t, 4H, 7=6.0 Hz), 6.27 (s, 2H). 1 3 C nmr (50.3 MHz, CDC13) 8: 22.2, 25.8, 37.4, 128.0, 156.5, 199.7. HRMS calcd for C i 2 H 1 4 0 2 : 190.0994; found: 190.0993. Anal, calcd for C i 2 H 1 4 0 2 : C 75.76, H 7.42; found: C 75.54, H 7.42. Preparation of 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-3-trimethylstannylcyclopent-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 2 C1 2 . Purification of the crude 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 cm 1 . 219 *H nmr (400 MHz, CDC13) 8: 1.67 (t, 6H, H-6, / = 2.1 Hz), 2.48-2.53 (m, 4H), 2.65-2.72 (m, 4H). 1 3 C nmr (75.5 MHz, CDC13) S: 9.9 (-ve), 28.5, 33.8, 138.7, 163.5, 208.6. HRMS calcd for C i 2 H 1 4 0 2 : 190.0994; found: 190.0993. Anal, calcd for C i 2 H 1 4 0 2 : C 75.76, H 7.42; found: C 75.72, H 7.68. Preparation of 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-3-trimethylstannylcyclohex-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 2 C1 2 . Flash column chromatography (21 g of silica gel, 1:1 petroleum ether-Et20) of the crude product and 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 cm 1 . X H nmr (400 MHz, CDC13) 5: 1.61 (br t, 6H, H-7, / = 1.9 Hz), 1.95-2.11 (m, 4H), 2.20-2.32 (m, 2H), 2.38-2.52 (m, 6H). 1 3 C nmr (75.5 MHz, CDC13) 5: 11.9, 22.9, 28.9, 37.7,129.8, 155.4, 198.9. HRMS calcd for C i 4 H 1 8 0 2 : 218.1307; found: 218.1309. Anal, calcd for C i 4 H i 8 0 2 : C 77.03, H 8.31; found: C 77.11, H 8.46. 221 7. Intramolecular coupling of aryltrimethylstannanes mediated by copper(I) chloride 7.1 Preparation of coupling precursors Preparation of bis(trimethvlstannylphenyl) ether ( 104 ) S n M e 3 S n M e 3 , 0 Y^ 2 5 5 1 0 4 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 2 0 (20 mL) was added T M E D A (664 ixL, 4.40 mmol) followed by diphenyl ether ( 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 2 0 (3 x 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 MHz, CDC13) 8: 0.26 (s, 18H, -SnMe 3. 2 / s „ . H = 54.9 Hz), 6.62-6.68 (m, 2H), 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 MHz, CDC13) 5: -8.6 (-ve), 118.1 (-ve), 123.6 (-ve), 130.5 (-ve), 132.8, 137.0 (-ve), 163.3. HRMS calcd for Ci 7 H23O 1 2 0 Sn 2 (M +-Me): 482.9793; found: 482.9802. Anal, calcd for C i 8 H 2 6 O S n 2 : C 43.61, H 5.29; found: C 43.93, H 5.30. Preparation of bis(2-trimethvlstannvbenzyl) ether (108) S n M e 3 N S n M e 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 2 0 (40 mL) 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-Et20 with gradual elution to 95:5 petroleum ether-Et20) of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 401 mg (99 %) of the distannane 108 as a colorless oil. IR (neat): 1069, 1047, 751 cm 1 . *H nmr (400 MHz, CDC13) 8: 0.22 (s, 18H, -SnMe^. 2 / S n . H = 53.5 Hz), 4.43 (s, 4H, -CHz-O-), 7.20-7.33 (m, 6H), 7.45-7.58 (m, 2H). 223 1 3 C nmr (75.5 MHz, CDC13) 5: -8.1 (-ve), 72.8, 127.2 (-ve), 128.2 (-ve), 128.3 (-ve), 136.6 (-ve), 142.1, 144.1. HRMS calcd for Ci 9 H27O 1 2 0 Sn 2 (M +-Me): 511.0106; found: 511.0088. Anal, calcd for C2oH3oOSn2: C 45.86, H 5.77; found: C 46.02, H 5.88. Preparation of diethyl 2,2-bis(4-methyl-2-tiimethvlstannylbenzyl)malonate (257) To a stirred suspension of potassium hydride (73 mg, 1.8 mmol, washed with pentane) in dry THF (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 THF (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 2 0 (3 x 10 mL) and the 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-Et20) of the crude product and removal of trace amounts 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 cm 1 . 203 257 lR nmr (400 MHz, CDC13) 5: 0.24 (s, 18H, -SnMfe, 2 / S n - H = 53.1 Hz), 1.03 (t, 6H, -C0 2 CH 2 CH3, / = 7.1 Hz), 2.25 (s, 6H, -Me), 3.38 (s, 4H, -CIL.-), 4.01 (q, 4H, 224 -CO2CH2CH3, / = 7.1 Hz), 6.97-7.03 (m, 4H), 7.16 (s, 2H, aromatic protons a to -SnMe 3, 3 / s n - H = 50.6Hz). 1 3 C nmr (75.5 MHz, CDC13) 5: -7.4 (-ve), 13.8 (-ve), 20.1 (-ve), 42.0, 59.8, 61.3, 127.8 (-ve), 129.0 (-ve), 135.3, 137.2 (-ve), 140.2, 144.6, 171.4. HRMS calcd for C 2 8H4iO 4 1 2 0 Sn 1 1 8 Sn (M +-Me): 679.1043; found: 679.1050. Anal, calcd for C29H4404Sn2: C 50.19, H 6.39; found: C 50.50, H 6.57. 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 THF (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 2 0 (3 x 10 mL) and the combined organic extracts were washed with brine (20 mL), dried (MgS0 4 ) , and the solvent was removed under reduced pressure. Flash column chromatography (25 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 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 MHz, CDC13) 8: 0.25 (s, 18H, -SnMe.. VSn.H = 54.2 Hz), 0.99 (t, 6H, -C0 2 CH 2 CH3, / = 7.1 Hz), 3.11 (s, 4H, -CHr) , 3.76 (s, 6H, -OMe), 3.77 (s, 6H, -OMe), 3.83 (s, 6H, -OMe), 3.92 (q, 4H, -CCfeCHzCHa, / = 7.1 Hz), 6.60 (s, 2H, aromatic pro tons, /sn-H = 17.5 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -5.3 (-ve), 13.7 (-ve), 41.8, 55.8 (-ve), 60.4 (-ve), 60.8 (-ve), 60.9, 61.3, 109.2 (-ve), 128.7, 139.25, 139.36, 153.7, 157.0, 171.2. HRMS calcd for C3 2 H4 9 Oio 1 2 0 Sn 2 (M +-Me): 833.1370; found: 833.1393. Anal, calcd for C 3 3H 5 2 Oi 0 Sn 2 : C 46.84, H 6.19; found: C 47.15, H 6.26. Preparation of diethyl 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 THF (8 mL) at room temperature was added a solution of the stannane 212 (344 mg, 0.832 mmol) in dry THF (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 2 0 (3 x 10 mL). The combined organic 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-Et20) of the crude product and removal of trace amounts of solvent (vacuum pump) 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 cm 1 . : H nmr (400 MHz, CDC13) 8: 0.20 (s, 9H, -SnMej, 2 / S n . H = 53.0 Hz), 0.25 (s, 9H, -SnMej, 2 / S „ - H = 54.0 Hz), 1.01 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 3.34 (s, 2H, -CHr) , 3.42 (s, 2H, -CHr ) , 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, 4 / S „ - H = 17.6 Hz), 7.11-7.24 (m, 3H), 7.34-7.34 (m, 1H). 1 3 C nmr (50.3 MHz, CDC13) 8: -7.5 (-ve), -5.4 (-ve), 13.6 (-ve), 41.5, 42.2, 49.2, 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. HRMS calcd for C z g H ^ O ? 1 2 ^ (M +-Me): 743.1053; found: 743.1061. Anal, calcd for C3oH4607Sn2: C 47.66, H 6.13; found: C 47.87, H 6.20. Preparation of diethyl 2-r(2-trimethylstannylcyclopent-l-en-l-yl)methyllmalonate (261) S n M e 3 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 26027'76 (1.44 g, 4.39 mmol) in dry THF (5 mL) was 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 260 261 227 brine (100 mL), dried (MgS0 4 ), and the solvent was removed under reduced pressure. Flash column chromatography (100 g of silica gel, 93:7 petroleum ether-Et20) of the 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 cm 1 . : H nmr (400 MHz, CDC13) 8: 0.11 (s, 9H, -SnMe 3. 2 / S n . H = 53.8 Hz), 1.19 (t, 6H, - C 0 2 C H 2 C H 3 , 7=7.1 Hz), 1.70-1.80 (m, 2H, -CH 2-CH2-CH 2-), 2.20-2.30 (br t, 2H, -CH2-CH 2-CH 2- 7= 7.4 Hz), 2.30-2.35 (m, 2H, -CH 2-CH 2-CH2-), 2.72 (d, 2H, -CHi-CH- , / = 7.8 Hz), 3.43 (t, IH, -CH 2 -CH- , 7= 7.8 Hz), 4.10-4.19 (m, 4H, -C0 2CH2CH 3). 1 3 C nmr (125.8 MHz, CDC13) 8: -9.5 (-ve), 14.0 (-ve), 24.3, 32.3, 35.6, 39.3, 51.2 (-ve), 61.1, 139.8, 148.6, 169.0. HRMS calcd for Ci5H 2 5 O 4 1 2 0 Sn: 389.0775; found: 389.0770. Anal, calcd for C 1 6 H 2 8 0 4 S n : C 47.68, H 7.00; found: C 47.60, H 7.03. Preparation of 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 THF (1 mL) via a cannula. After 1 h, a solution of the bromide 2 0 2 (703 mg, 2.10 mmol) in dry THF (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 2 0 (3 x 15 mL). 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-Et20) of the crude product afforded, after removal of trace amounts of 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, CDC13) 8: 0.08 (s, 9H, -SnMes, 2 / S n . H = 53.6 Hz), 0.30 (s, 9H, -SnMes, 2 / S n . H = 53.2 Hz), 1.09 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 1.74-1.81 (m, 2H, -CH2-CH2-CH2-), 2.24 (br t, 2H, - C H r C H 2 - C H 2 - , / = 7.3 Hz), 2.31 (br t, 2H, - C H 2 - C H 2 -CH2-, / = 7.0 Hz), 2.98 (s, 2H, -CHr) , 3.32 (s, 2H, -CHr ) , 4.00-4.07 (m, 4H, -C0 2CH2CH 3), 7.11-7.18 (m, 3H), 7.29-7.45 (m, 1H). 1 3 C nmr (50.3 MHz, CDC13) 8: -9.2 (-ve), -7.3 (-ve), 13.9 (-ve), 24.7, 36.3, 39.0, 39.2, 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. HRMS calcd for C 2 5 H 3 9 O 4 1 2 0 Sn2 (M +-Me): 643.0892; found: 643.0895. Anal, calcd for 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 2 0 (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 4 ), and the solvent was removed under reduced 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 chloride-ammonia (pH 8) (5 mL) was added and stirring was continued, open to the atmosphere, until the mixture was a deep blue. The mixture was then extracted with E t 2 0 (3 x 10 mL). The combined organic extracts were washed with brine (3 x 10 mL), dried (MgS0 4 ) , and the solvent was removed under reduced pressure. Flash column chromatography (10 g of silica gel, 99:1 petroleum ether-Et20) of the crude product and 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). 7 7 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-Et20) and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 32 mg (91 %) of the cyclic ether 10963 as a colorless oil. ER (KBr): 1077,752 cm 1 . *H nmr (400 MHz, CDC13) 5: 4.35 (s, 4H), 7.55 (d, 2H, / = 7.4 Hz), 7.49 (td, 2H, / = 1.8, 7.5 Hz), 7.40-7.43 (m, 4H). 1 3 C nmr (75.5 MHz, CDC13) 5: 67.5, 127.4, 128.2, 128.9, 129.7, 135.1, 141.2. HRMS calcd for C 1 4 H 1 2 0 : 196.0888; found: 196.0882. 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-Et20) and removal 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 cm 1 . X H nmr (400 MHz, CDC13) 8: 1.26 (t, 6H, / = 7.1 Hz), 2.37 (s, 6H, -Me), 2.82 (br s, 2H), 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 MHz, CDC13) 8: 14.1 (-ve), 21.2 (-ve), 36.4, 61.4, 64.6, 128.0 (-ve), 128.8 (-ve), 129.9 (-ve), 132.4, 137.0, 140.5, 170.9. HRMS calcd for C 2 3 H 2 6 0 4 : 366.1831; found: 366.1831. Anal, calcd for C 2 3 H 2 60 4 : C 75.38, H 7.15; found: C 75.41, H 7.24. 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-Et20) and removal of 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 MHz, CDC13) 8: 1.26 (t, 3H, -CO2CH0CH3, / = 7.1 Hz), 1.28 (t, 3H, / = 7.1 Hz), 2.72 (d, IH, / = 13.7 Hz), 2.85 (d, IH, / = 13.7 Hz), 3.09 (d, IH, J= 13.7 Hz), 3.18 (d, IH, 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, IH, / = 1.0, 7.5 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: 14.1 (-ve), 14.2 (-ve), 36.7, 37.0, 55.9 (-ve), 60.8 (-ve), 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. HRMS calcd for C 2 4 H 2 8 0 7 : 428.1835; found: 428.1831. Anal, calcd for C 2 4 H 2 8 0 7 : C 67.28, H 6.59; found: C 67.03, H 6.86. 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-Et20) and removal 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 MHz, CDC13) 5: 1.26 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 2.73 (d, 2H, / = 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). 1 3 C nmr (75.5 MHz, CDC13) 5: 14.2 (-ve), 36.9, 55.9 (-ve), 60.7 (-ve), 60.9 (-ve), 61.5, 63.9, 108.4 (-ve), 122.2, 131.3, 141.2, 151.4, 152.4, 170.5. HRMS calcd for C27H34Ow: 518.2152; found: 518.2150. Anal, calcd for C ^ H M O I O : 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) 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-Et20) and removal of 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 cm 4 . *H nmr (400 MHz, CDC13) 5: 1.14 (t, 6H, -C0 2 CH 2 CH3, / = 7.1 Hz), 1.89-1.98 (m, 2H), 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, -C02CH2CH3), 7.01-7.11 (m, 1H), 7.18-7.20 (m, 3H). 1 3 C nmr (75.5 MHz, CDC13) 8: 14.0 (-ve), 22.1, 35.8, 36.8, 39.5, 40.0, 60.7, 61.3, 125.9 (-ve), 126.3 (-ve), 126.8 (-ve), 131.2 (-ve), 134.7, 135.3, 137.1, 137.9, 171.2. HMRS calcd for C 2 o H 2 4 0 4 : 328.1675; found: 328.1664. Anal, calcd for C 2 0 H 2 4 O 4 : C 73.15, H 7.37; found: C 73.07, H 7.46. 112 113 235 8. Intramolecular oxidative coupling of bisalkenyltrimethylstannanes to form bicyclor7.3.01dodecane and bicvclor8.3.01tridecane derivatives 8.1 Preparation of precursors Preparation of 6-iodo-2-trimethylstannylhex-l-ene (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 26847 (2.62 g, 10.0 mmol) in dry CH 2 C1 2 (5 mL) was 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-Et20 (500 mL). 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-Et20) which, after removal of 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.78 268 269 236 Preparation of methyl (£l-7-fe^butyldmiethylsiloxy-3-tj±nethylstam To a cold (-48 °C), stirred solution of hexamethylditin (10.6 g, 32.4 mmol) in dry THF (200 mL) was added M e L i (21.0 mL, 1.55 M in E t 2 0 , 32.5 mmol) via a syringe and the 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 6 (6.06 g, 25.0 mmol) in dry THF (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 2 0 (3 x 150 mL). The organic layers were 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-Et20 with gradual change to 93:7 petroleum ether-Et20) of the crude 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 cm 1 . lU nmr (400 MHz, CDC13) 8: 0.02 (s, 6H, -SiMe-?-;, 0.18 (s, 9H, -SnMe 3. VS n-H = 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, 3 / S n . H = 61.9 Hz), 3.60 (t, 2H, -O-CHz-, / = 6.6 Hz), 3.67 (s, 3H, -C0 2 Me), 5.95 (t, IH, olefinic proton, / = 1.2 Hz, 3 / S n . H = 73.6 Hz). (2711 270 271 237 1 3 C nmr (50.3 MHz, CDC13) 5: -9.1, -6.3, 18.3, 25.95, 26.02, 32.8, 34.4, 50.8, 62.9, 127.0, 164.6, 173.7. HRMS calcd for Ci 6 H33O 3 Si 1 2 0 Sn (M +-Me): 421.1221; found: 421.1230. 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) To a cool (0 °C), stirred solution of the stannane 271 (5.93 g, 13.7 mmol) in dry THF (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 2 0 (3 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried (MgS0 4 ) , and the solvent was removed in vacuo to give a crude oil. Flash column chromatography (150 g of silica gel, 1:1 petroleum ether-Et20) of the crude product and removal of trace 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 cm 1 . *H nmr (400 MHz, CDC13) 5: 0.18 (s, 9H, -SnMe 3, 2 / S n - H = 53.4 Hz), 1.45-1.76 (m, 5H, -OH and - C H ^ C H r ) , 2.87 (t, 2H, allylic - C H r / = 7.8 Hz, 3 / S n . H = 61.4 Hz), 3.64-3.68 (m, 5H, includes 3H -CQ9Me singlet at 3.66 and HO-CH?-), 5.96 (s, 1H, olefinic proton, 3 / S n . H = 72.5Hz). M e 0 2 C M e 0 2 C 271 272 C nmr (50.3 MHz, CDC13) 8: -9.3, 25.4, 32.4,33.9, 50.8, 61.9, 127.0, 164.6, 173.9. 238 HRMS calcd for C i o H 1 9 0 3 1 2 ° S n (M +-Me): 307.0356; found: 307.0363. Anal, calcd for C n H 2 2 0 3 S n : C 41.16, H 6.91; found: C 41.43, H 6.98. SnMe 3 M e 0 2 C M e 0 2 C 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 CH 2 C1 2 (5 mL) was 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 2 0 (250 mL). 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-Et20) which, after removal of trace amounts of solvent (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 cm 1 . J H nmr (400 MHz, CDC13) 8: 0.20 (s, 9H, -SnMe.. 3 / S n _ H = 54.6 Hz), 1.47-1.55 (m, 2H, -CH2-CH2-), 1.80-1.88 (m, 2H, -CH2-CH2-), 2.89 (td, 2H, allylic proton, / = 7.3, 1.2 Hz, 3 / S n - H = 70.7 Hz), 3.19 (t, 2H, I-CH2-, / = 6.6 Hz), 3.67 (s, 3H, -CCyMe), 5.97 (t, 1H, olefinic proton, / = 1.2 Hz, 3 / S n - H = 72.5 Hz). C nmr (75.5 MHz, CDC13) 8: -9.0, 6.8, 30.4, 33.1, 33.4, 50.9, 127.5, 164.5, 172.7. 239 HRMS calcd for CioH 1 8 0 2 1 2 0 SnI (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) To a cold (-48 °C), stirred solution of hexamethylditin (10.6 g, 32.4 mmol) in dry THF (200 mL) was added M e L i (20.2 mL, 1.55 M in E t 2 0 , 32.3 mmol) via a syringe and the 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 4 1 (6.00 g, 25.0 mmol) in dry THF (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 2 0 (3 x 150 mL). 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-Et20) of the crude product and removal of trace amounts of solvent (vacuum pump) from the acquired material provided 7.11 g (70 %) of the stannane 275 as a colorless clear oil. 274 275 ER (neat): 1719, 1595, 1166, 770 cm"1. 240 X H nmr (400 MHz, CDC13) 8: 0.18 (s, 9H, -SnMe.. 2 / S n . H = 53.4 Hz), 1.40-1.85 (m, 10H), 2.91 (br t, 2H, allylic -CH2-, / = 7.7 Hz, 3 / S n . H = 61.2 Hz), 3.34-3.40 (m, IH), 3.44-3.50 (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, 3 / s „ . H = 73.4 Hz). 1 3 C nmr (50.3 MHz, CDC13) 8: -9.1 (-ve), 19.5, 25.5, 26.3, 29.6, 30.7, 34.7, 50.8 (-ve), 62.1, 67.1, 98.7 (-ve), 127.1 (-ve), 164.6, 173.4. HRMS calcd for C 1 5 H27O 4 1 2 0 Sn (M +-Me): 391.0931; found: 391.0932. Anal, calcd for Ci6H 3o0 4Sn: C 47.44, H 7.46; found: C 47.69, H 7.55. Preparation of (£V7-(tetrahydro-2il/-pvran-2-vloxy)-l-methoxy-3-trunethylstannylhept-2-ene (277) To a cold (-78 °C), stirred solution of the ester 275 (6.19 g, 15.3 mmol) in dry THF (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 2 0 (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgS0 4 ), and the solvent was removed under reduced pressure. Flash column chromatography (200 g of silica gel, 1:1 petroleum ether-Et20) 275 276 277 241 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 THF (140 mL) was added a solution of the alcohol 276 (obtained as described above) in dry THF (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 2 0 (3 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried (MgSQ*), and the solvent was removed in vacuo. Hash column chromatography (200 g of silica gel, 17:3 petroleum ether-Et20) of the crude product and 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 cm 1 . J H nmr (400 MHz, CDC13) 8: 0.11 (s, 9H, -SnMe,. 2 / s „ . H = 52.5 Hz), 1.38-1.84 (m, 10H), 2.31 (t, 2H, / = 7.6 Hz, 3 / S n . H = 62.4 Hz), 3.32 (s, 3H, -OMe), 3.34-3.39 (m, 1H), 3.45-3.49 (m, 1H), 3.68-3.74 (m, 1H), 3.81-3.87 (m, 1H), 4.00 (d, 2H, Me-O-CHr , / = 5.9 Hz), 4.54-4.57 (m, 1H), 5.68 (t, 1H, olefinic proton, / = 5.9 Hz, 3 / S n . H = 78.2 Hz). 1 3 C nmr (50.3 MHz, CDC13) 8: -9.3 (-ve), 19.5, 25.5, 26.8, 29.4, 30.7, 32.9, 58.1 (-ve), 62.1, 67.1, 68.7, 98.7 (-ve), 136.2 (-ve), 148.7. HRMS calcd for Ci 5 H29O 3 1 2 0 Sn (M +-Me): 377.1139; found: 377.1132. Anal, calcd for C 1 6 H 3 2 0 3 S n : C 49.14, H 8.25; found: C 49.44, H 8.46. 242 M e 3 277 278 279 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-Et20 with gradual change to Et 2 0) yielded 1.68 g (35 %) of the starting material 277 and 2.25 g (59 %, 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 CH 2 C1 2 (75 mL) 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 CH 2 C1 2 (5 mL) was 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 2 0 (250 mL). The combined filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (60 g of silica gel, 24:1 petroleum ether-Et20) which, after removal of trace amounts of solvent (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 MHz, CDC13) 8: 0.12 (s, 9H, -SnMe 3, 2 / s „ . H = 52.5 Hz), 1.39-1.46 (m, 2H, -CH2-CH2-), 1.75-1.82 (m, 2H, - C H r O L . - ) , 2.30 (br t, 2H, allylic - C H r , / = 7.2 Hz, 3 / S „ - H = 61.1 Hz), 3.17 (t, 2H, I -CHr, / = 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, 3 / S n . H = 77.2 Hz). 243 1 3 C nmr (75.5 MHz, CDC13) 8: -9.3 (-ve), 6.7, 30.7, 31.9, 32.9, 58.1 (-ve), 68.5, 136.4 (-ve), 148.1. HRMS calcd for C 1 0 H 2 o0 1 2 0 SnI (M +-Me): 402.9581; found: 402.9587. Anal, calcd for CnH^OSnl : 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 6 8 (11.8 g, 47.8 mmol) in dry CH 2 C1 2 (475 mL) at room temperature was added sodium acetate (2.88 g, 35.1 mmol) and PCC (20.8 g, 96.5 mmol), each as solids. The reaction mixture was stirred for 2 h. The mixture was diluted with E t 2 0 (500 mL) and then was filtered through Florisil (-50 g). The cake of Florisil was eluted with E t 2 0 (1 L) and the combined filtrate was concentrated under reduced pressure. Flash column chromatography (200 g of silica gel, 7:3 petroleum ether-Et20) of the crude material yielded 8.62 g (78 %) of the aldehyde 280a as an oil. 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 2 C1 2 (500 mL) was added triphenylphosphine (29.5 g, 112 mmol) in one portion. The mixture was stirred for 10 min. A solution of the aldehyde 280a (8.62 g, 37.4 mmol) in dry CH 2 C1 2 (20 mL) was added via a cannula. The mixture was stirred for 40 min. 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-Et20) of the crude product and removal of trace amounts of solvent (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 THF (100 mL) at room temperature was added a solution of the alkene 280b (9.63 g, 24.9 mmol) in dry THF (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 2 0 (400 mL) and the combined filtrate was 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 cm 1 . lU nmr (400 MHz, CDC13) 5: 0.02 (s, 6H, -SiMe?-;, 0.87 (s, 9H, -Si'Bu-), 1.37-1.57 (m, 6H), 1.90 (t, IH, 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 MHz, CDC13) 8: -5.3,18.4, 25.0,25.9 (2C), 28.3, 32.3, 62.9, 68.2, 84.4. HRMS calcd for C 1 2 H 2 3 O S i (M +-Me): 211.1518; found: 211.1517. Anal, calcd for C 1 3 H 2 6 O S i : C 68.96, H 11.57; found: C 69.01, H 11.51. 245 Preparation of 7-fe^butyldimethylsifo (282) T B S O 281 282 To a cold (-48 °C), stirred solution of hexamethylditin (6.80 g, 20.5 mmol) in dry THF (80 mL) was added a solution of MeLi (13.1 mL, 1.6 M in E t 2 0 , 21.0 mmol) via a 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 2 0 (3 x 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-Et20) yielded 2.86 g (73 %) of the stannane 282 as a clear oil. IR (neat): 1472, 1255, 1105, 835, 774 cm 4 . *H nmr (400 MHz, CDC13) 5: 0.02 (s, 6H, -SiMe.-). 0.10 (s, 9H, -SnMe 3, 2 / S „ - H = 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, 3 / S n . H = 52.2 Hz), 3.58 (t, 2H, H-7, / = 6.7 Hz), 5.09-5.11 (m, IH, H - l , 3 / S n . H = 71.8 Hz), 5.61-5.63 (m, IH, H - l ' , 3 / S n . H = 154.6 Hz). 1 3 C nmr (50.3 MHz, CDC13) 5: -9.5 (-ve), -5.3 (-ve), 18.4, 25.4, 26.0 (-ve), 29.6, 32.7, 40.8, 63.2, 124.3,135.8. 246 HRMS calcd for C i 5 H 3 3 O S i 1 2 0 S n (M +-Me): 377.1323; found: 377.1326. Anal, calcd for Ci 6 H 3 6 OSiSn: C 49.12, H 9.24; found: C 49.35, H 9.22. Preparation of 7-iodo-2-trirnethvlstannvlhept-l-ene (284) , S n M e 3 T B S O SnMec 282 283 To a cool (0 °C), stirred solution of the stannane 282 (1.09 g, 2.80 mmol) in dry THF (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 2 0 (3 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried (MgS0 4 ) , and the solvent was 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 2 0 (150 mL). 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. J H nmr (400 MHz, CDC13) 5: 0.11 (s, 9H, -SnMe^, VSn.H = 52.8 Hz), 1.35-1.39 (m, 4H), 1.77-1.85 (m, 2H), 2.24-2.24 (m, 2H, H-3, 3 / s „ - H = 51.7 Hz), 3.16 (t, 2H, H-7, / = 7.0 Hz), 5.12-5.13 (m, IH, H - l , 3 / s „ . H = 52.2 Hz), 5.61-5.63 (m, IH, H-l*, 3 / S n . H = 152.7 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -9.4, 7.0, 28.4, 30.0, 33.4, 40.5, 124.6, 155.5. HRMS calcd for C 9 H 1 8 1 2 0 S n I (M +-Me): 372.9475; found: 372.9473. Anal, calcd for CioH 2iSnI: C 31.05, H 5.47; found: C 31.09, H 5.53. 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 THF (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 2 0 (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried (MgS0 4 ) , and the solvent was removed in vacuo. Purification of the crude product by flash column chromatography (100 g of silica gel, 19:1 petroleum ether-Et20) and removal of trace 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): 2239, 1724, 1435, 1267, 1099, 839, 774 cm 1 . *H nmr (400 MHz, C D C 1 3 ) 8: 0.02 (s, 6 H , -SiMe?-). 0.87 (s, 9 H , -Si'Bu-), 1.40-1.60 (m, 6 H ) , 2.32 (t, 2 H , propargylic -CHo.- , / = 7.1 Hz), 3.59 (t, 2 H , -O-CH2-, / = 6.2 Hz), 3.73 (s, 3 H , -COVMe). 1 3 C nmr (75.5 MHz, C D C 1 3 ) 8: -5.4 (-ve), 18.3, 18.6, 25.1, 25.9 (-ve), 27.3, 32.1, 52.4 (-ve), 62.8, 72.9, 89.6, 154.1. HRMS calcd for C 1 4 H 2 5 0 3 S i (M +-Me): 269.1573; found: 269.1574. Anal, calcd for C 1 5 H 2 8 0 3 S i : C 63.33, H 9.92; found: C 63.66, H 9.93. Preparation of methyl (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 THF (200 mL) was added MeLi (10.1 mL, 1.6 M in E t 2 0 , 16.2 mmol) via a syringe and the solution was stirred for 30 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 THF (5 mL) was added via a cannula to the mixture and stirring was continued for 4 h 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 2 0 (3 x 150 mL). The organic layers were 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-Et20 with gradual change to 20:1 petroleum ether-Et20) of the crude 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 cm 1 . lH nmr (400 MHz, CDC13) 8: 0.02 (s, 6H, -SiMer), 0.17 (s, 9H, -SnMe^, 2 / 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, 3 / S n . H = 64.6 Hz), 3.58 (t, 2H, -O-CHr , / = 6.5 Hz), 3.60 (s, 3H, -CO-Me), 5.94 (t, 1H, olefinic proton, / = 1.2 Hz, 3 / s n - H = 73.7 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -9.3 (-ve), -5.3 (-ve), 18.3, 25.8, 26.0 (-ve), 29.5, 32.7, 34.7, 50.8 (-ve), 63.1, 126.9 (-ve), 164.6, 173.8. HRMS calcd for C 1 7 H 3 5 O 3 S i 1 2 0 S n (M +-Me): 435.1377; found: 435.1371. Anal, calcd for C 1 8 H 3 8 0 3 S i S n : C 48.12, H 8.53; found: C 47.88, H 8.58. 250 Preparation of methyl (jEl-8-iodo-3-trimethylstannyloct-2-enoate (288) S n M e 3 286 287 S n M e 3 Me02C 288 To a stirred solution of the stannane 286 (1.38 g, 3.07 mmol) in dry THF (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 2 0 (3 x 15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgS0 4 ) , and the solvent was removed in vacuo to give a crude oil. Flash column chromatography (12 g silica gel, 98:2 petroleum ether-Et20) of the crude product yielded the alcohol 287 as a 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 CH 2 C1 2 (30 mL) 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 CH 2 C1 2 (5 mL) was 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 2 0 (250 mL). 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-Et20) which, after removal of trace amounts of solvent (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 cm 1 . 251 J H nmr (400 MHz, CDC13) 5: 0.17 (s, 9H, -SnMeg, 2 / S n . H = 54.4 Hz), 1.38-1.44 (m, 4H), 1.79-1.87 (m, 2H), 2.87 (td, 2H, allylic - C H r , / = 6.8, 1.3 Hz, 3 / S n . H = 64.6 Hz), 3.17 (t, 2H, I-CH2-, / = 6.7 Hz), 3.68 (s, 3H, -COjMe), 5.96 (t, 1H, olefinic proton, / = 1.3 Hz, 3 / s n . H = 73.1Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -9.1 (-ve), 6.9, 28.3, 30.3, 33.1, 34.3, 50.8 (-ve), 127.2 (-ve), 164.5, 173.2. HRMS calcd for C i i H 2 0 O 2 1 2 0 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 THF (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 2 0 (3 x 50 mL). The combined organic extracts were washed with 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 THF (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 4 ), and the solvent was removed in vacuo. Flash column chromatography (200 g of silica gel, 9:1 petroleum ether-Et20) of the crude oil and 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 MHz, CDC13) 8: 0.02 (s, 6H, -SiMe^-), 0.10 (s, 9H, -SnMe 3, 2 / S „ - H = 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, IH, H - 2 , 3 / s „ . H = 77.5 Hz), 7.24-7.35 (m, 5H, aromatic protons). 1 3 C nmr (75.5 MHz, CDC13) 8: -9.2 (-ve), -5.3 (-ve), 18.4, 25.6, 26.0 (-ve), 30.0, 32.7, 33.2, 63.1, 66.3, 72.1, 127.6, 127.8 (-ve), 128.3 (-ve), 136.0 (-ve), 138.3 (-ve), 149.1. HRMS calcd for C 2 3 H4iO 2 Si 1 2 0 Sn (M +-Me): 497.1898; found: 497.1884. Anal, calcd for C 2 4 H 4 4 0 2 S i S n : C 56.37, H 8.67; found: C 56.59, H 8.60. 253 S n M e 3 290 291 S n M e 3 B n C v J ^ 292 To a stirred solution of the stannane 290 (1.51 g, 2.94 mmol) in dry THF (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 2 0 (3 x 15 mL). 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 2 0 (250 mL). The combined filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (75 g of silica gel, 24:1 petroleum ether-Et20) which, after removal of trace amounts of solvent (vacuum pump) 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 MHz, CDC13) 5: 0.11 (s, 9H, -SnMej, 2 / S n . H = 52.5 Hz), 1.30-1.38 (m, 4H), 1.74-1.81 (m, 2H), 2.25 (br t, 2H, H-4, / = 6.0 Hz, 3 / S n . H = 61.6 Hz), 3.14 (t, 2H, H-8, / = 7.0 Hz), 4.08 (d, 2H, H - l , / = 6.0 Hz), 4.51 (s, 2H, benzylic -CKb-), 5.77 (tt, IH, H-2, / = 1.2, 6.0 Hz, 3 / s n - H = 77.9 Hz), 7.26-7.34 (m, 5H, aromatic protons). 1 3 C nmr (75.5 MHz, CDC13) 8: -9.2 (-ve), 6.9, 29.0, 30.2, 32.9, 33.2, 66.2, 72.4, 127.5 (-ve), 127.8 (-ve), 128.3 (-ve), 136.3 (-ve), 138.2, 148.7. HRMS calcd for C i 7 H 2 6 O 1 2 0 S n I (M +-Me): 493.0050; found: 493.0049. Anal, calcd for C 1 8 H 2 9 OSnI: C 42.64, H 5.77; found: C 42.83, H 5.83. Preparation of diethyl 2-r(2-trimethylstamylcyclopent-l-en-l-vl)methvll-2-(5-tTimethvl stannylhex-5-en-l-yl)malonate (293) S n M e 3 S n M e 3 To a cold (-78 °C), stirred solution of L D A (1.80 mmol) in dry THF (18 mL) was added a solution of the stannane 261 (763 mg, 1.89 mmol) in dry THF (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 THF (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 2 0 (3 x 20 mL). The combined organic extracts were washed with brine (50 mL), 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 ether-Et 2 0) which, after removal of trace amounts of solvent (vacuum pump) from the acquired 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, CDC13) 5: 0.09 (s, 9H, -SnMe,, 2JSn.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 wi th /= 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, IH, H-6, 3 / S n - H = 70.4 Hz), 5.58-5.60 (rn, IH, H-6', 3 / S n - H = H7.6 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -9.5 (-ve), -9.2 (-ve), 14.0 (-ve), 24.1, 24.7, 29.8, 33.7, 35.8, 37.5, 38.8, 40.4, 57.1, 61.0, 124.5,141.3, 148.2,155.4, 171.8. HRMS calcd for C24H43O 4 1 1 8 Sn 1 2 0 Sn (M +-Me): 633.1199; found: 633.1204. 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) S n M e 3 SnMe R = -C0 2 E t 294 To a cold (-78 °C), stirred solution of L D A (2.52 mmol) in dry THF (25 mL) was added a solution of the stannane 261 (1.07 g, 2.66 mmol) in dry THF (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 THF (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 2 0 (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-Et20) 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 cm 1 . J H nmr (400 MHz, CDC13) 8: 0.15 (s, 9H, -SnMe 3, 2 / S n . H = 53.4 Hz), 0.16 (s, 9H, -SnMea, 2 / S n _ H = 53.3 Hz), 1.20-1.40 (m, 10H, includes 6H -C0 2 CH 2 CH3 triplet at 1.22 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, -C02CH2CH3), 5.93 (s, IH, H - 2 , 3 / s „ . H = 73.4 Hz). 257 1 3 C nmr (75.5 MHz, CDC13) 5: -9.3 (-ve), -9.2 (-ve), 14.0 (-ve), 24.63, 24.67, 30.0, 33.9, 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. HRMS calcd for C26H45O 6 1 2 0Sn 2 (M +-Me): 693.1260; found: 693.1258. Anal, calcd for C 27H480 6Sn 2: C 45.93, H 6.85; found: C 45.89, H 6.76. Preparation of diethyl 2-r(F)-7-methoxv-5-trimethvlstannvlhept-5-en-l-vll-2-r(2-trimethylstannylcyclopent-1 -en-1 -vDmethyllmalonate (295) S n M e 3 S n M e 3 R = -C0 2 E t 295 To a stirred suspension of potassium hydride (143 mg, 3.58 mmol) in dry THF (25 mL) at room temperature was added a solution of the stannane 261 (1.24 g, 3.08 mmol) in dry THF (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 THF (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 2 0 (3 x 20 mL). The combined organic extracts were washed with brine (50 mL), 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 ether-E t 2 0 with gradual change to 4:1 petroleum ether-Et20) which, after removal of trace 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 cm 1 . lH nmr (400 MHz, CDC13) 5: 0.09 (s, 9H, -SnMe 3, 2 / S „ - H = 52.6 Hz), 0.16 (s, 9H, -SnMea, 2 / s „ . H = 53.3 Hz), 1.18-1.33 (m, 10H, includes 6H -C0 2 CH 2 CH3 triplet at 1.22 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), 2.30-2.35 (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, 3 / S n . H = 78.0 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -9.3 (-ve), -9.2 (-ve), 14.0 (-ve), 24.6, 24.7, 30.6, 33.1, 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. HRMS calcd for C 2 6 H47O 5 1 2 0 Sn 2 (M +-Me): 679.1467; found: 679.1462. Anal, calcd for C 2 7 H 5 o0 5 Sn 2 : C 46.98, H 7.28; found: C 46.68, H 7.23. 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 THF (25 mL) at room temperature was added a solution of the diester 261 (1.16 g, 2.89 mmol) in dry THF (5 mL) via a cannula. After 1 h, a solution of the iodide 284 (910 mg, 2.35 mmol) in dry 259 THF (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 2 0 (3 x 20 mL). The combined organic extracts were 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-Et20) 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 cm 1 . J H nmr (400 MHz, CDC13) 5: 0.08 (s, 9H, -SnM&t. 2 / S n . H = 53.6 Hz), 0.15 (s, 9H, -SnMes, 2 / s „ . H = 54.6 Hz), 1.16-1.36 (m, 12H, includes 6H -C0 2 CH 2 CH3 triplet at 1.22 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, -C02CH2CH3), 5.08-5.10 (m, 1H, H - 7 , 3 / S n . H = 70.5 Hz), 5.58-5.60 (m, 1H, H-7', 3 /S„-H = 154.0 Hz). 1 3 C nmr (75.5 MHz, CDC13) 8: -9.6 (-ve), -9.2 (-ve), 14.0 (-ve), 24.4, 24.6, 29.3, 29.4, 33.7, 35.8, 37.5, 38.8, 40.7, 57.1, 60.9, 124.3, 141.2,148.2, 155.6,171.8. HRMS calcd for C 2 5 H 4 5 O 4 1 2 0 S n 2 (M +-Me): 649.1362; found: 649.1352. Anal, calcd for C 2 6 H480 4 Sn 2 : C 47.17, H 7.31; found: C 47.23, H 7.18. 260 Preparation of methyl (£V9,9-bis(ethoxycarIxmvl)-3-trimeth^^ stannvlcyclopent-l-en-l-yBdec-2-enoate (297) S n M e 3 C 0 2 M e R = - C 0 2 E t 297 To a stirred suspension of potassium hydride (88 mg, 2.2 mmol) in dry THF (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 THF (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 2 0 (3 x 30 mL). The combined organic 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-Et20) of the crude product and removal of trace amounts of solvent (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 cm 1 . *H nmr (400 MHz, CDCk) 8: 0.15 (s, 9H, -SnMes, 2 / S n . H = 52.3 Hz), 0.16 (s, 9H, -SnMea, 2 / S n . H = 52.1 Hz), 1.16-1.39 (m, 12H, includes 6H -C0 2 CH 2 CH3 triplet at 1.24 wi th /= 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, -C02CH2CH3), 5.94 (t, 1H, H-2, / = 2.1 Hz, 3 / S n . H = 73.7 Hz). 261 1 3 C nmr (75.5 MHz, CDC13) 5: -9.2 (-ve), -9.1 (-ve), 14.0 (-ve), 24.56, 24.60, 29.5, 30.0, 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. HRMS calcd for C 2 7H47O 6 1 1 8 Sn 1 2 0 Sn (M +-Me): 705.1411; found: 705.1418. Anal, calcd for C28H5o06Sn2: C 46.70, H 7.00; found: C 47.02, H 7.03. Preparation of diethyl 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 THF (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 292 (1.00 g, 1.97 mmol) in dry THF (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 20 (3 x 30 mL). The combined organic 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-Et20) of the crude product and removal of trace amounts of solvent (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 MHz, CDC13) 8: 0.09 (s, 9H, -SnMe., 2 / S n . H = 52.6 Hz), 0.16 (s, 9H, -SnMea, 2 / s „ . H = 53.0 Hz), 1.17-1.30 (m, 12H, includes 6H -CO2CH2CH3 triplet at 1.22 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, 3 / s „ - H = 74.0 Hz), 7.24-7.35 (m, 5H, aromatic protons). 1 3 C nmr (75.5 MHz, CDC13) 8: -9.3 (-ve), -9.2 (-ve), 14.0 (-ve), 24.60, 24.64, 29.8, 30.0, 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. HRMS calcd for C33H 5 3 O5 1 1 8 Sn 1 2 0 Sn (M +-Me): 767.1931; found: 767.1929. 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 2 0 (3 x -10 mL/mmol of substrate). The combined organic phases were washed with brine (3 x -20 mL/mmol of substrate), dried (MgS0 4 ) , and 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 MHz, CDC13) 8: 1.21 (t, 6H, -C0 2 CH 2 CH3, / = 7.1 Hz), 1.33-1.39 (m, 2H, 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 MHz, CDC13) 8: 14.0 (-ve), 20.3, 22.1, 28.6, 29.6, 31.0, 32.3, 37.6, 38.8, 57.2,61.0, 114.8, 132.0, 142.6, 147.3, 171.9. HRMS calcd for C i 9 H 2 8 0 4 : 320.1988; found: 320.1988. Anal, calcd for C 1 9 H 2 8 0 4 : C 71.22, H 8.81; found: C 70.98, H<9.07. 265 Table 34. *H nmr (200 MHz, CDC13) data for the diester 299: COSY experiment R = -C02Et 299 Assignment X H nmr (400 MHz) COSY H-x 8 (multiplicity, / (Hz)) Correlations H-3 2.30 (br 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 (br t , /= 6.2) H-5 H-8 2.92 (br s) H-10 2.18 (brt, 7=7.4) H- l l H - l l low-field portion of 1.60-1.74 (m) H-10, H-12 H-12 2.42 (brt, 7=7.2) H - l l H-13 4.90 (d, 7=2.0) H-3 H-13' 4.94 (unresolved m) -C0 2CH2CH 3 4.08-4.20 (m) -C0 2 CH 2 CH3 -C0 2 CH 2 CH3 1.21 (t,7=7.1) -C0 2CH2CH 3 266 Preparation of 7J-bis(ethoxvcarbonvl)-2-r(^-methoxvcarbonylmethylidene1 bicvclor7.3.01dodec-l(9Vene(300) 10 11 C 0 2 M e R SnMe 3 R = -C0 2 Et SnMe 3 R = -C0 2 Et C 0 2 M e 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 ether-Et 2 0) and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 60 mg (72 %) of the triester 300 as a colorless oil. IR(neat): 1730, 1627, 1590, 1432, 1163 cm 1 . *H nmr (400 MHz, CDC13) 5: 1.17-1.29 (m, 8H, includes 6H -CO2CH2CH3 triplet at 1.19 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, -C02CH2CH3), 5.67 (s, IH, H-13). 1 3 C nmr (125.8 MHz, CDC13) 5: 14.0 (-ve), 19.9, 22.4, 26.5, 27.6, 28.4, 30.7, 37.8, 38.7, 50.9 (-ve), 56.2, 61.2, 117.8, 134.0, 143.9, 160.6, 166.5, 171.6. HRMS calcd for C 2 i H 3 0 O 6 : 378.2043; found: 378.2043. Anal, calcd for C 2 i H 3 0 O 6 : C 66.65, H 7.99; found: C 66.47, H 7.96. 267 Table 35. *H nmr (400 MHz, CDC13) data for the diester 300: NOED and COSY experiments C O o M e R = - C 0 2 E t 300 Assignment H-x *H nmr (400 MHz) 8 (multiplicity, J (Hz)) COSY Correlation NOED Correlation H-3 2.67 (unresolved m) H-4 H-4 and H-6 low-field portion of 1.70-1.90 (m) H-3, H-5 H-5 low-field portion of 1.17-1.29 (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 - l l high-field portion of 1.70-1.90 (m) H-10, H-12 H-12 2.44 (unresolved m) H-10, H - l l H - l l , H-13 H-13 5.67 (s) H-12 -C0 2CH2CH 3 3.95-4.20 (m) -C0 2 CH 2 CH3 -CO2CH9CH3 high-field portion of 1.17-1.29 (m) -C0 2CH2CH 3 - C 0 2 M e 3.67 (s) 268 Preparation of 7J-bis(ethoxycarbonyl)-2-F(ffi dodec-l(9)-ene(301) 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-Et20) and removal of trace amounts of solvent (vacuum pump) from the acquired material yielded 55 mg (91 %) of the diester 301 as a colorless oil. IR(neat): 1729, 1466, 1367, 1197 cm 1 . *H nmr (400 MHz, CDC13) 5: 1.21 (t, 6H, -CO2CH2CH3, / = 7.1 Hz), 1.26-1.33 (m, 2H, 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), 4.08-4.19 (m, 4H, -CO2CH2CH3), 5.41 (t, 1H, H-13, / = 6.4 Hz). 1 3 C nmr (75.3 MHz, CDC13) 5: 14.0 (-ve), 19.1, 22.2, 26.7 (2C), 27.2, 30.3, 37.7, 38.0, 56.0,58.0 (-ve), 61.0, 69.1, 125.6,130.7, 140.2, 144.6,171.7. HRMS calcd for C2iH 3 2 0 5 : 364.2250; found: 364.2253. Anal, calcd for C2iH 3 2 0 5 : C 69.20, H 8.85; found: C 68.98, H 8.87. OMe 295 301 269 11 Table 36. J H nmr (400 MHz, CDC13) data for the diester 301: NOED and COSY experiments 1 0 , H R 6 OMe Assignment H-x J H nmr (400 MHz) 5 (multiplicity, 7 (Hz)) COSY Correlation NOED Correlation 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 - l l , H - 1 2 H - l l 1.67-1.75 (m) H-10,H-12 H-12 2.39 (unresolved m) H-10, H - l l H - l l , H - 1 3 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 -C0 2CH2CH 3 4.08-4.19 (m) -C0 2 CH 2 CH3 -C0 2 CH 2 CH3 1.21 (t,7=7.1) -C0 2CH2CH 3 -OMe 3.32 (s) 270 Preparation of 8,8-bis(ethoxycarbonyl)-2- [(F)-methoxvcarbonvlmethylidenel bicvclor8.3.0ltridec-1 (lOVene (303) SnMe 3 COoMe C0 2 M e R = -C0 2 Et R = -C0 2 Et 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-Et20) and removal of trace amounts of solvent (vacuum pump) from the acquired 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 cm 1 . *H nmr (400 MHz, CDC13) 8: 1.00-1.90 (br m, 16H, includes 6H -CO2CH2CH3 br t at 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 2 Me), 4.11-4.20 (m, 4H, -COjCHjCHs), 5.59 (br s, IH, H-14). 1 3 C nmr (75.3 MHz, CDC13) 5: 14.1 (-ve), 19.5, 21.5, 22.3, 27.7, 28.4, 29.8 (2C), 36.3, 36.4, 50.9 (-ve), 55.6, 61.3, 111.4, 115.0(-ve), 135.5, 143.2, 161.8, 167.1. HRMS calcd for C 2 2 H 3 2 0 6 : 392.2199; found: 392.2199. Anal, calcd for C 2 2 H 3 2 0 6 : C 67.32, H 8.22; found: C 67.36, H 8.11. 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 . X . ; Guibe, F.; Balavoine, G. / . Org. Chem. 1990, 55, 1857. 14. Beddos, R. L. ; Cheeseright, T.; Wang, J.; Quayle, P. Tetrahedron Lett. 1995, 36, 283. 15. Liebeskind, L. S.; Riesinger, S. W. Tetrahedron Lett. 1991, 32, 5681. 16. For other examples of paUadium(II) mediated couplings see also (a) Kanemoto, S. Matsubara, S.; Oshima, K. ; Utimoto, K. ; Nozaki, H . Chem. Lett. 1987, 5. (b) Borzilleri, R. M . ; Weinreb, S. W. / . Am. Chem. Soc. 1994,116, 9789. (c) Kang, S. -K. ; Namkoong, E. - Y . ; Yamaguchi, T. Synth. Comm. 1997, 27, 641. (d) Alcaraz, L . ; Taylor, R. J. K. Synlett 1997, 791. (e) Borzilleri, R. M . ; Weinreb, S. W.; Parvez, M . / . Am. Chem. Soc. 1995,117, 10905. 17. Tius, M . A. ; Kawakami, J. K. Tetrahedron 1995, 51, 3997. 18. (a) Lipshutz, B. H. ; Sengupta, S. Org. React. 1992,41, 135. (b) Perlmettuer, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon Press: Oxford, 1992. 19. Little, R. D.; Masjudizadeh, M . R.; Wallquist, O.; Mclaughlin, J. I. Org. 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. W.; Fuchs, P. L. Tetrahedron Lett. 1993, 34, 5209. 273 . 26. (a) Piers, E. ; McEachern, E. J.; Burns, P. A. / . Org. Chem. 1995, 60, 2322. (b) Piers, E. ; McEachern, E. J.; Burns, P. A. Tetrahedron. 2000, in press, (b) Piers, E. ; McEachern, E. J. Synlett 1996, 1087. 27. Piers, E. ; Skupinska, K. A . ; Wallace, D. J. Synlett. 1999, 1867. 28. (a) Piers, E.; Boehringer, E. M . ; Yee, J. G. K. / . Org. Chem. 1998, 63, 8642. (b) Boehringer, E. M . , M . Sc. Thesis, University of British Columbia, Vancouver, B.C., 1996. 29. (a) For a discussion on the existence of copper(III) intermediates in copper-mediated conjugate additions see 22(a). (b) Cotton. F. A. ; Wilkinson, W. Adavanced Inorganic Chemistry, 5thEd.; Wiley: New York, 1988; pp. 755-775. 30. The cis addition of organocopper(I) species across triple bonds of alkynoates is well established. For some representative examples see (a) Corey, E. J.; Katzenellenbogen, J. A. / . Am. Chem. Soc. 1969, 91, 1851. (b) Cooper, J.; Knight, D. W.; Gallagher, P. T. / . Chem. Soc. Chem. Commun. 1987, 1220. (c) Walba, D. M . ; Stoudt. G. S. / . Org. Chem. 1983,48, 5404. (d) Roush, W. R.; Peseckis, S. M . / . Amer. Chem. Soc. 1981,103, 6196. (e) Marino, J. P.; Browne, L. J. /. Org. Chem. 1976,41, 3629. 31. Gladstone, P. L . , Post-doctoral Report, University of British Columbia, Vancouver, B.C., 1998. 32. Piers, E. ; Tse, H. L. A . Can. J. Chem. 1993, 71, 983. 33. Snieckus, V . Chem Rev. 1990, 6, 879. 34. Omura, K. ; Swern, D. Tetrahedron 1978, 34, 1651. 35. (a) Piers, E.; Chong, J. M . / . Chem. Soc, Chem. Commun. 1983,934. (b) Piers, E. ; Chong, J. M . Can. J. Chem. 1988,66,1425. 36. Corey, E. J.; Fuchs, P. L . Tetrahedron Lett. 1972,23, 3769. 37. Hijfte, L . V . ; Kolb, M . ; Witz, P. Tetrahedron Lett. 1989,30, 3655. 38. Piers, E. ; Wong, T.; Ellis, K. A . Can. J. Chem. 1992, 70, 2058. 39. Corey, E. J.; Venkatesarlu, A. / . Amer. Chem. Soc, 1972, 94, 6190. 40. Sonnet, P. E. Synth. Comm. 1976, 6, 21. 274 41. Piers, E. ; Chong, J. M . ; Morton, H . E. Tetrahedron 1989, 45, 363. 42. Friebolin, H . Basic One- and Two-Dimensional NMR Spectroscopy, V C H Publishers: New York, USA, 1993, pp. 275-286. 43. Piers, E. ; McEachern, E. J.; Romero, M . A. / . Org. Chem. 1997, 62, 6034. 44. Winterfeldt, E. Synthesis 1975, 617. 45. Silverstein, R. M . ; Bassler, G. C ; Morrill, T. C. Spectrometric Identification of Organic Compounds, John Wiley and Sons: New York, USA, 1981, p. 281. 46. These compounds were prepared by standard treatment of the respective alcohols with dihydropyran and PPTS. See Miyashita, N . ; Yoshikoshi, A. ; Grieco, P. J. Org. Chem, 1977, 42, 3372. 47. Chong, J. M . Ph. D. Thesis, University of British Columbia, Vancouver, B.C., 1983. 48. Millar, J. G.; Underhill, E. W. / . Org. Chem. 1986, 51, 4726. 49. The experimental preparation of 165 was supplied by Dr. Patricia Gladstone, a post-doctoral fellow of the Piers research group. 50. Meyer, N . ; Seebach, D. Chem Ber. 1980,113, 1304. 51. (a) Wiley, G. A.;Hershkowitz, R. L . ; Rien, B. M . ; Chung, B. C. / . Amer. Chem. Soc. 1964,86, 964. (b) Scaefer, J. P.; Higgins, J. / . Org. Chem. 1967, 32, 1607. 52. Jung, M . E. ; Kaas, S. M . Tetrahedron Lett. 1989,30, 641. 53. McEachern, E. J. Ph.D. Thesis, University of British Columbia, Vancouver, B.C., 1997. 54. Ito, H. ; Arimoto, K.; Sensui, H . ; Hosomi, A. Tetrahedron Lett. 1997, 38, 3997. 55. Journet, M . ; Cai, D.; DiMichele, L . M . ; Larsen, R. D. Tetrahedron Lett. 1998, 39, 6427. 56. (a) Yamamoto, K. ; Miyaura, N . ; Itoh, M . ; Suzuki, A. Synthesis 1997, 679. (b) Midland, M . M . ; Tramontano, A . ; Cable, J. R. / . Org. Chem. 1980, 45, 28. 275 57. (a) Linderrnan, R. J.; Lonikar, M . S. / . Org. Chem. 1988, 53, 6013. (b) Reming, I.; Perry, D. A. Tetrahedron 1981, 37, 4027. (c) Marino, J. P.; Linderman, R. J. J. Org. Chem. 1983,48, 4621. (d) Marino, J. P.; Linderman, R. J. / . Org. Chem. 1981, 46, 3696. (e) Sundberg, R. J.; Pearce, B. C. / . Org. Chem. 1982, 47, 725. 58. (a) For a review on the synthesis of medium sized rings see Petasis, N . A . ; Patane, M . A. Tetrahedron 1992, 48, 5757. For some recent examples see (b) Crimmins, M . T.; Huang, S.; Guise-Zawacki, L. E. Tetrahedron Lett. 1996, 37, 6519. (c) Molander, G. A. ; Machrouhi, F. / . Org. Chem. 1999, 64, 4119. (d) Crimmins, M . T.; Choy, A . L . / . Am. Chem. Soc. 1999,121, 5653. (e) Shengming, M . ; Negishi, E. / . Am, Chem. Soc. 1995,117, 6345. (f) Rigby, J. H . ; Ateeq, H . S.; Krueger, A. C. Tetrahedron Lett. 1992, 33, 5873. (g) Matsuda, F.; Sakai, T.; Okada, O.; Miyashita, M . Tetrahedron Lett. 1998, 39, 863. (h) Molander, G. A . ; Alonso-Alija, C. / . Org. Chem. 1998, 63, 4366. 59. (a) Casadei, M . A . ; Galli, G.; Mandolini, L. / . Am. Chem. Soc. 1984,106, 1051. (b) muminati, G.; Mandolini, L. Acc. Chem. Res. 1981,14, 95. and references cited therein. 60. (a) Piers, E. ; Grierson, J. R.; Lau, C. K. ; Nagakura, I. Can. J. Chem. 1982, 60, 210. (b) Piers, E. ; Nagakura, I. Synth. Comm. 1975, 5, 193. 61. Piers, E. ; Morton, H . E.; Chong, J. M . Can. J. Chem. 1987, 65, 78. 62. Devlen, J. P. Can. J. Chem. 1975, 53, 343. 63. Hennings, D. D.; Iwama, T.; Rawal, V . H. Org. Lett. 1999,1, 1205. 64. Eliel, E. L . ; Wilen, S. H . ; Mander, L. N . Stereochemistry of Organic Compounds, John Wiley and Sons, Inc.: New York, 1994; pp. 1142-1148. and references cited therein. 65. The intermolecular homocoupling of aryltrimethylstannane functions are inhibited by the presence of methoxy substituents. See ref. 31. 66. This compound was prepared via acylation of the TBS ether of hex-6-yn-l-ol with MeLi and methyl chloroformate. The preparation of this compound by Keith Sun is gratefully acknowledged. 67. Leusink, A. J.; Budding, H. A. ; Marsman, J. W. / . Organometal. Chem. 1967, 9, 285. 276 68. Mcdougal, P. G.; Rico, J. G.; Young-Im, O.; Condon, B. D. / . Org. Chem. 1986, 51, 3388. 69. Corey, E. J.; Sluggs, J. W. Tetrahedron Lett. 1975,16,2647. 70. Still, W. C ; Kahn, M . ; Mitra, A. / . Org. Chem. 1978, 43, 2923. 71. Perrin, D. D.; Armarego, W. L . ; Perrin, D. R. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: Oxford, 1988. 72. Burfield, D. R.; Smithers, R. H. / . Org. Chem. 1978, 43, 3966. 73. Kofron, W. G.; Baclawski, L. H. / . Org. Chem. 1976,41, 1879. 74. Wuts, P. G. M . Synth. Commun. 1981,11, 139. 75. Henbest, H. B.; Jones, E. R. H . ; Walls, I. M . S. / . Chem. Soc. 1950, 3646. 76. The preparation of this compound by Miss Krystyna Skupinska is gratefully acknowledged. 77. Cass, R. C ; Fletcher, S. E.; Mortimer, C. T.; Springall, H . D.; White, T. R. / . Chem. Soc. 1958, 1406. 78. Friesen, R. W. Ph.D. Thesis, University of British Columbia, Vancouver, B.C., 1988. 

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