Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Synthesis and conformational studies of 10, 10-dimethyltridecanolide Hu, Thomas Qiuxiong 1988

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1988_A6_7 H82.pdf [ 4.07MB ]
Metadata
JSON: 831-1.0060354.json
JSON-LD: 831-1.0060354-ld.json
RDF/XML (Pretty): 831-1.0060354-rdf.xml
RDF/JSON: 831-1.0060354-rdf.json
Turtle: 831-1.0060354-turtle.txt
N-Triples: 831-1.0060354-rdf-ntriples.txt
Original Record: 831-1.0060354-source.json
Full Text
831-1.0060354-fulltext.txt
Citation
831-1.0060354.ris

Full Text

SYNTHESIS A N D C O N F O R M A T I O N A L STUDIES O F 10,10-DIMETHYLTRIDECANOLIDE  By Thomas Qiuxiong Hu B . S c , South C h i n a Institute of T e c h n o l o g y , 1985  A T H E S I S S U B M I T T E D IN P A R T I A L F U L F I L L M E N T O F THE REQUIREMENTS FOR THE DEGREE OF MASTER O F SCIENCE in T H E F A C U L T Y O F G R A D U A T E STUDIES Department of C h e m i s t r y  W e accept this thesis a s conforming to the required standard  T H E UNIVERSITY O F BRITISH C O L U M B I A August  1988  T h o m a s Qiuxiong H u , 1988  In  presenting  degree freely  at  this  the  available  copying  of  department publication  of  in  partial  fulfilment  University  of  British  Columbia,  for  this or  thesis  reference and  thesis by  this  for  his thesis  scholarly  or for  her  of  QAB^^T^Y  The University of British Vancouver, Canada  Date  DE-6  (2/88)  C>cl  Columbia  ' f f i  I  I further  purposes  gain  the  shall  requirements  agree  that  agree  may  representatives.  financial  permission.  Department  study.  of  be  It not  is  that  the  permission  granted  allowed  an  advanced  Library shall  by  understood be  for  for  the that  without  make  it  extensive  head  of  my  copying  or  my  written  i i  ABSTRACT  The synthesis of 10,10-dimethyltridecanolide (42) was achieved via a fifteen-step sequence in 9% overall yield. The  hydrolysis  of macrolides  conformational behavior of macrolide 42-  412., 3_5_, and ester 109 was used to probe the The results of this study were rationalized through  molecular mechanics (MM2) calculations of conformations for macrolide 42MM2 studies confirmed initial conformational analyses that macrolide 42 should exist predominantly in the [3434] conformation 42a. existence of a [3344] conformation  More importantly, they also revealed the  421-  Hydrolysis studies showed that macrolides 42 and 3J> hydrolyzed more slowly than ester 109 due to the steric effect of the intermediates.  They also suggested that the minor  conformation 421 very likely controlled the hydrolysis process of macrolide 42.  21  101  ii i Table of Contents  Page Abstract  ii  List of Figures  iv  List of Abbreviations  -v  Acknowledgements  vi  Introduction  1  1.1  Lactonization of Long-Chain Hydroxy Acids  1.2  Remote Asymmetric Induction Via Conformational Control  1 0  1.3  Conformational Behavior of 14-Membered Lactones  1 3  1.4  Restricting the Low-Energy Conformations of 14-Membered Lactones by Geminal Disubstitution  Results and Discussion  5  1 9 20  2.1  Synthesis of 10,10-Dimethyltridecanolide  2.2  Hydrolysis of 10,10-Dimethyltridecanolide,Tridecanolide and n-Octyl Pentanoate...3 8  2.3  Molecular Mechanics Calculations of Conformations for  2.4  20  10,10-Dimethyltridecanolide  42  Conclusion  54  Experimental  55  3.0  General  55  3.1  Preparation of 10,10-Dimethyltridecanolide  58  3.2  Preparation of n-Octyl Pentanoate  73  3.3  Preparation of Tridecanolide  74  3.4  Hydrolysis of 10,10-Dimethyltridecanolide.Tridecanolide and n-Octyl Pentanoate...75  References  76  Appendix 1 (MM2 calculations), Appendix 2 (NMR and IR spectra)  80  iv  List of  Figure  Figures  Title  Page  1  Structures of macrolide antibiotics isolated in the 1950's  2  2  Conformation models for cyclotetradecane a n d erythronolide B  4  3  Magnitude of hydrogen interactions in the [3434] conformation of cyclotetradecane  14  4  T o p a n d side views of the [3434] conformation of cyclotetradecane  15  5  Retrosynthetic analysis of macrolide 12  21  6  Plot of the rates of the hydrolysis of 4 2 , 2 5 . and 1 0 9 at room temperature  40  7  C o m p u t e r plots of the [3434] conformations for macrolide 42  45  8  T h e polar m a p conventions  4 6  9  T h e [3434] conformation of cyclotetradecane a n d the polar m a p of its torsional a n g l e s  1 0  Superposition of the polar m a p s of the ideal [3434] conformation (broken line) a n d the [3434] conformations of macrolide 4J>  1 1  48  T h e [3344] a n d [3335] conformations of cyclotetradecane a n d their polar m a p s  12  47  50  C o m p u t e r plots a n d polar m a p s of the [3344] a n d [3335] conformations of macrolide 4J>  51  V  List of  Abbreviations  AcO  acetoxy]  AC2O  acetic anhydride  CD  circular  DCC  1,3-dicyclohexylcarbodiimide  DMAP  4-dimethylaminopyridine  dichroism  ether  diethyl  ether  glc  gas-liquid chromatography  h  hour(s)  HMPA  hexamethylphosphoramide  IR  infrared  min  minute(s)  MCPBA  meta-chloroperoxybenzoic acid  MS  m a s s spectrometry  NMR  nuclear magnetic r e s o n a n c e  PPTs  pyridinium  p_-toluenesulphonate  TEA  triethylamine  THF  tetrahydrofuran  THP  tetrahydropyran  tic  thin layer c h r o m a t o g r a p h y  TBDMS  tert-butyldimethylsilyl  TMS  trimethylsilyl  vi  ACKNOWLEDGEMENTS  I w i s h to e x p r e s s m y s i n c e r e gratitude to my s u p e r v i s o r , D r . Larry W e i l e r , for his guidance and advice during the course of this work. I a m indebted to Dr. E d w a r d N e e l a n d for h i s v a l u a b l e d i s c u s s i o n s a n d constructive suggestions concerning the progress of this research and the preparation of this thesis. T h a n k s are also d u e to Karin Albert, Sigrid Albert, P a u l C h e u n g , R o s s L o n e r g a n , Margot P u r d o n , A n n i e W o n g , G r a c e W u , J a c k s o n W u and G e r a l d Y e u n g w h o s e friendships have made the past two y e a r s a time to remember. In addition, financial a s s i s t a n c e in the form of graduate fellowships from the University of British C o l u m b i a a n d the efficient cooperation of the staff of the N M R a n d m a s s spectrometry service are gratefully a c k n o w l e d g e d . Finally a n d most importantly, I would like to thank my parents for their e n c o u r a g e m e n t , patience a n d support throughout the c o u r s e of my education. mere words.  M y gratitude to them is b e y o n d  This thesis is dedicated to my parents.  1  CHAPTER ONE Introduction  Perhaps one of the most significant breakthroughs in the development of natural product chemistry was the isolation of pikromycin  (1) by  Brockmann and Henkel in  first macrolide antibiotic isolated from a bacterial source.  1950.  1  It was the  Soon afterwards, several other  microbially produced antibiotics were discovered which were thought to be structurally related to pikromycin. gross (Figure  By the end of 1957, chemical degradation studies led to the revelation of the  structures of methymycin  1).  2-5  (2J, erythromycin A (3J and B (4) and carbomycin A (5J  Each of these antibiotics shared a common feature - a lactone incorporated in a  medium or large-ring system.  This was the genesis of macrolide chemistry.  O  II  1  The term "macrolide" originally referred to the above antibiotics but, as time passed, it has gradually been used in a broader sense to define all organic compounds with a large lactone ring (12 or more atoms).  2  Figure 1.  Structures of macrolide antibiotics isolated in the 1950's, R, R-j and R 2 represent different carbohydrates.  Over the next 20 years, the field of macrolide chemistry was firmly established with the isolation of more than 100 large ring lactone natural products possessing diverse biological activities.^  Approximately one-half of these natural products are classified as "polyoxo"  3 macrolides, which normally contain 12, 14 or 16-membered lactone rings with numerous ring substituents including one to three glycoside units. An interesting structural feature of the macrolide antibiotics, which may be related to their biological activities, is the relative conformational rigidity of the molecules in solution. These molecules often exist in one identical conformation whether in solution or in the solid state.  7  Presumably, the high degree of substitution on the macrolide plays an important role in  this rigidity in that the accommodation of many steric and electronic factors leads to a single minimum energy conformation for any particular macrolide. The conformations of complex 14-membered macrolide antibiotics have aroused considerable interest among chemists and a number of models have been proposed to explain the conformations of various macrolides.  One of the most studied conformations is that of  erythronolide B, the aglycone of erythromycin B. In 1963, Dale introduced a minimum energy diamond-lattice conformation 6_ (bold line) for cyclotetradecane.  8  A model for the preferred conformer of erythronolide B (7_) was  advanced by Celmer in 1965.  9  Although Celmer's model was in close agreement with the H 1  NMR data, it did not agree with X-ray crystallographic data. Celmer's conformation was also very strained because of transannular hydrogen interactions and a 1,3-diaxial methyl interaction.  A second diamond-lattice conformation 8_ was proposed for erythronolide B (9_)  from NMR and CD spectra data. This eventually led to the Perun model IQ..  10  The Perun model  was favourably compared to the solid state conformation of erythromycin A  1 0  and is now  widely used as a basis for assigning stereochemistries of substituents in 14-membered macrolide antibiotics.  CH,  1Q Figure 2. Conformation models for cyclotetradecane and erythronolide B.  Although a considerable number of conformational studies of macrolide antibiotics have been carried out over the past 30 years, the total synthesis of macrolide antibiotics has been slow to develop. There were two major problems associated with the synthesis of macrolide antibiotics: one was the construction of a medium or large-size lactone and the other involved the introduction of numerous chiral centres into the molecule.  Efficient lactone ring  construction procedures are now available due to the development of new synthetic methodology and advanced experimental techniques. However, selective introduction of chiral centres on a large ring remains challenging and still demands creativity and imagination for its satisfactory completion.  5  1.1  Lactonization of Long-Chain Hydroxy Acids  The first problem associated with the synthesis  of a macrolide antibiotic is the  construction of the lactone functionality. Although many methods to generate lactones have been developed over the past 30 y e a r s , " 1 1  most common.  1 9  lactonization of long-chain hydroxy acids is by far the  This stems from the ready availability of the acyclic precursors and from the  belief that the biosynthesis of a macrolide antibiotic very likely proceeds through a final lactonization stage to form the aglycone. However, the employment of the lactonization procedure, while conceptually simple, is not always an easy task to accomplish. Ring closure of a long-chain precursor is disfavoured due to an entropy loss as the two distant chain ends approach each other. As a result, intermolecular rather than intramolecular cyclization often occurs.  Nevertheless, efforts to develop highly  effective lactonization procedures have proven to be successful over the years. The first lactonization of long-chain hydroxy acids i i was carried out by Stoll and Rouve in 1 9 3 4 .  20  In their studies, the use of dilute solutions (e.g. 2.0 - 8.0 x 10~  4  M) and  catalysts such as p-toluenesulfonic acid were found to be essential.  The synthesis of lactones has been conducted in this manner with yields ranging from approximately 1 % for nonanolide (12.) to 8 7 % for hexadecanolide (13_).  20  However, this  method suffers from the awkward high dilution conditions needed to effect lactonizations and from the resulting poor yields of the lactones.  o  12 The desire to perform cyclizations under milder conditions and with higher yields led to a strategy which activated the carboxylic acid before the lactonization. It was anticipated that the intramolecular attack of the free hydroxyl functionality on the newly activated carboxylic acid would occur under relatively mild conditions.  The reaction of hydroxy acids with  phosgene-triethylamine or with trifluoroacetic anhydride has successfully produced lactones through the formation of a mixed anhydride 14.  :=o 14 For example, treatment of the hydroxy acid 15. with trifluoroacetic anhydride followed in moderate yield.21  by cleavage of the methoxyl ethers gave zearalenone  1) ( C F C O ) 0 2  3  O  MeO  15  2) B B r  3  O  H(  li  7 A different strategy for the c y c l i z a t i o n of hydroxy a c i d s h a s a l s o b e e n reported by K u r i h a r a et a l . , wherein the hydroxyl function w a s activated and the carboxylate anion acted a s the n u c l e o p h i l e . diethyl  In this w a y , the reaction of the hydroxy a c i d s with triphenylphosphine and  2 2  azodicarboxylate  ( 1 7 ) at  room  temperature  effected  ring  closures  via  an  a l k o x y p h o s p h o n i u m carboxylate IS..  +  Ph P=0 3  18  T h i s p r o c e d u r e h a s b e e n e m p l o y e d by White a n d c o - w o r k e r s in their s y n t h e s i s of vermiculine  (19).  23  C y c l i z a t i o n of the hydroxy a c i d 2Q. with t r i p h e n y l p h o s p h i n e a n d diethyl  azodicarboxylate produced vermiculine  (19J in 1 5 % yield.  inversion of the stereochemistry of the original a l c o h o l .  20.  This p r o c e s s a l s o resulted in an  2 3  12  T h e a d v a n t a g e of activating the c a r b o x y l i c a c i d or h y d r o x y l function esterification step w a s o b v i o u s .  prior to  the  A n e v e n more expedient procedure i n v o l v e d simultaneously  8  activating both the hydroxyl and carboxylic acid groups. Corey and N i c o l a o u  24  envisioned a  "double activation" through a carboxylic derivative that was able to transfer a proton from the hydroxyl to the carboxylic oxygen. One such derivative was the 2-pyridinethiol ester 21 prepared from the reaction of a hydroxy acid and di(2-pyridyl)disulfide (22) in the presence of triphenylphosphine. ^ The proton transfer from the hydroxyl to carbonyl oxygen in 21 was 2  greatly facilitated by the basic nitrogen of the pyridine ring. The zwitterionic intermediate 22. thus generated underwent a facile cyclization to eventually yield the desired lactone 24.  G:  Ph P 3  OH  22  22  21  'H  r  o N H s x  24 Corey and co-workers have successfully applied this methodology in the synthesis of several complex macrolides.  24  In their synthesis of zearalenone (1_6J, the key lactonization  step was accomplished by heating the hydroxy acid 23. with di(2-pyridyl)disulfide and triphenylphosphine in benzene. Subsequent hydrolysis of the ketal and tetrahydropyranyl ether protecting groups produced zearalenone (16.) in 7 5 % yield overall.  24  a N.^ S ^ 1) Ph P, ^ 3  2) H 0  THPO  +  3  21  16  9 Recently, a modification of C o r e y ' s double activation method w a s reported by G e r l a c h and Thalmann  2 6  w h o found that the p r e s e n c e of silver ions ( A g C I 0  4  or A g B F ) c o m p l e x e d with 24  pyridinethiol esters a s shown in 2j6_ which then were able to undergo a rapid cyclization at room temperature.  A problem a s s o c i a t e d with C o r e y ' s double activation method is that the reaction products must be s e p a r a t e d from thiopyridone, triphenylphosphine o x i d e , dipyridyl sulfide, a n d in the c a s e of Ag-activation, from e x c e s s silver thiolate.  T o circumvent this p r o b l e m , another simple  a n d highly effective cyclization method h a s b e e n d e v e l o p e d by Schmidt and D i e t s c h e . m e t h o d , 1-phenyl-2-tetrazoline-5-thione  a n d tert-butylisocyanide  w e r e u s e d for the  2 7  In this double  activation of the hydroxy a c i d s to p r o d u c e 16, 17, 18, and 2 0 - m e m b e r e d lactones in over 9 0 % yield. T h e purification of lactones s o produced w a s uncomplicated. Previously, our laboratory has u s e d a modified form of C o r e y ' s double activation method for the construction of 1 4 - m e m b e r e d lactones of interest.  Although the lactonization reactions  p r o c e e d e d smoothly with moderate to g o o d yields, the difficulties in purifying the final products remained. the  In this project, S c h m i d t a n d Dietsche's method w a s applied to the cyclization step in  s y n t h e s i s of  lactone.  10,10-dimethyltridecanolide,  a strategically  dimethylated  14-membered  10 1.2  R e m o t e A s y m m e t r i c Induction V i a Conformational Control  T h e s e c o n d p r o b l e m e n c o u n t e r e d in the s y n t h e s i s of m a c r o l i d e antibiotics w a s the e s t a b l i s h m e n t of the relative stereochemistry of n u m e r o u s a s y m m e t r i c c e n t r e s o n a n a c y c l i c precursor.  This is a problem that continues to challenge synthetic c h e m i s t s .  There  are  a variety  of  stereochemical relationships  synthetic  using  methods  a v a i l a b l e to  e s t a b l i s h v i c i n a l or  r e a c t i o n s that p r o c e e d with high  internal  or  1,2-  relative  a s y m m e t r i c induction, a n d to set up 1,3 a n d a few 1,4-relationships using reactions b a s e d on well understood 5 and 6 - m e m b e r e d ring conformations. H o w e v e r , the  e s t a b l i s h m e n t of c o r r e c t s t e r e o c h e m i c a l r e l a t i o n s h i p s b e t w e e n  widely  s e p a r a t e d or remote a s y m m e t r i c centres usually requires s o m e form of absolute s t e r e o c h e m i c a l control.  E a c h set of remote asymmetric centres c a n only be prepared from a n enantiomerically  pure starting material or by a reaction p r o c e e d i n g with high enantioselectivity. Traditionally, the large n u m b e r of a s y m m e t r i c centres are introduced into the a c y c l i c p r e c u r s o r s of the m a c r o l i d e s using enantiomerically pure starting materials, but this strategy is very difficult to a c c o m p l i s h . A  new  strategy  for  the  establishment  of  remote  stereochemical relationships  m a c r o l i d e s y n t h e s i s h a s b e e n d e v e l o p e d by Still a n d c o - w o r k e r s * * 2  2 9  who exploited  in the  conformations of medium or large-membered lactones a s a source of stereocontrol in generating new a s y m m e t r i c c e n t r e s .  In their s y n t h e s i s of 3 - d e o x y r o s a r a n o l i d e ( 2 7 ) .  m e m b e r e d l a c t o n e 2JL w a s first constructed.  2 9  the simple 16-  T h e other six a s y m m e t r i c centres in the target  m o l e c u l e 2Z were then established with excellent diastereoselectivity using the two asymmetric centres at C i  4  a n d C - j , and the conformational preference of the 1 6 - m e m b e r e d lactone. 5  22  2& Although  the  conformation  ultimately  responsible  for  the  success  of  this  stereoselectivity w a s not d e t e r m i n e d , this s y n t h e s i s clearly illustrated the c o n c e p t of remote a s y m m e t r i c induction v i a conformational c o n t r o l : large-membered  lactone  c a u s e d the  molecule  the pre-existing a s y m m e t r i c centre(s) in a to  adopt  a  particular  conformation  or  conformations which then directed the s t e r e o c h e m i c a l outcome of the reaction (e.g. by allowing the attack of a reagent to o c c u r from only one face of the molecule). Interestingly, Still h a s a l s o e x t e n d e d this conformational stereocontrol strategy to the preparation of s t e r e o c h e m i c a l ^ c o m p l e x acyclic c o m p o u n d s . This strategy entails the synthesis of a m e d i u m or l a r g e - m e m b e r e d l a c t o n e , e l a b o r a t i o n of the d e s i r e d s t e r e o c h e m i s t r y via conformational control a n d c l e a v a g e of the lactone ring. tris(tetrahydrofuranoid)  compound  2J.,  30  F o r e x a m p l e , in the s y n t h e s i s of the  a 1 6 - m e m b e r e d lactone  20.  w a s first c o n s t r u c t e d .  Treatment of the lactone 20. with m e t a - c h l o r o p e r o x y b e n z o i c a c i d g a v e the triepoxide 21, greater  than  9 0 % diastereoselectivity.  S a p o n i f i c a t i o n of 21  f o l l o w e d by a c i d c a t a l y z e d  polycyclization led directly to the d e s i r e d product £ £ .  2Q  21  in  21  Unfortunately, the conformation of the reacting lactone w a s not determined.  H o w e v e r , it  is c l e a r that the u s e of conformational control in the introduction of a s y m m e t r i c c e n t r e s will eventually provide e a s y a c c e s s to a large number of c o m p l e x macrolide antibiotics a n d s o m e a c y c l i c natural products which otherwise may h a v e b e e n difficult to s y n t h e s i z e . O b v i o u s l y , in order to a c c e l e r a t e a n d extend the application of this n e w strategy, an understanding of the conformational behavior of large lactone rings a n d the factors controlling their c o n f o r m a t i o n a l p r e f e r e n c e s i s important. :  T h i s k n o w l e d g e c a n a i d in predicting  and  controlling the s t e r e o c h e m i c a l outcome of a reaction involving in the lactone ring. As  a contribution  to the d e v e l o p m e n t of this c o n f o r m a t i o n a l control strategy,  our  laboratory h a s b e e n involved in the studies of the conformational b e h a v i o r of 1 4 - m e m b e r e d lactones a n d the f u n d a m e n t a l principles g o v e r n i n g the stereochemistry of reactions of these compounds.  T h e 1 4 - m e m b e r e d lactones were c h o s e n a s our primary targets b e c a u s e many  macrolide antibiotics contain s u c h a lactone skeleton and also 1 4 - m e m b e r e d rings are the next ring size after c y c l o h e x a n e which c a n adopt a strain-free c o n f o r m a t i o n .  31  1.3  Conformational Behavior of 14-Membered Lactones The simplest 14-membered ring is the hydrocarbon cyclotetradecane whose  conformation has been described in detail by D a l e .  8,31  From an inspection of space-filling  models, Dale recognized a tendency for saturated large rings to adopt compact conformations consisting of two parallel methylene chains linked by bridges of minimum length. These rectangularly shaped conformations could be generated from the three-dimensional framework of a diamond-lattice 22 where the ideal tetrahedral carbon geometry and the favorable torsional angles of 60° or 180° were obtained.  8  Dale predicted a strain-free (i.e. free of bond angle  strain, torsional angle strain and severe transannular hydrogen interactions), lowest-energy conformation 22. for cyclotetradecane and named it as the [3434] conformation.  32  The  numbers within the square brackets represent the number of carbon-carbon bonds between atoms having two adjoining gauche angles of equal sign each followed by an anti a n g l e .  3 2 , 3 3  Dale's prediction was later confirmed by X-ray analysis of cyclotetradecane in the solid state.  34  At first glance, Dale's [3434] conformation of cyclotetradecane shares many similarities with the well-known chair conformation of cyclohexane.  However, a close  comparison of both strain-free conformations reveals an important difference between them. The 14-membered strain-free conformation is less symmetric and as such contains four diastereotopic methylene environments. The four unique methylenes are numbered in Figure 3  14  which  also  illustrates  the  relative  magnitude  of  transannular  interactions  that  internal  hydrogen atoms experience in this conformation.  o  Least Severe  Mos Severe  Figure 3.  Magnitude of hydrogen interactions in the [3434] conformation of cyclotetradecane.  T h e different m a g n i t u d e of the h y d r o g e n interactions h a s a profound effect on the preferences for substitution of a ring carbon atom a s well as substitution of the hydrogen atoms. S i n c e replacement of an s p  3  carbon atom in the ring with an oxygen or with an s p  2  carbon atom  will reduce the transannular hydrogen repulsions, the preference for s u c h a substitution should therefore  follow the o r d e r  substitution  patterns  >C  4  >C  2  >C . 3  e x i s t : a s i n g l e substitution  For hydrogen or  r e p l a c e m e n t , two  a geminal disubstitution.  substituent attached to any of the c a r b o n atoms c a n only o c c u p y exterior positions. the transannular interactions would be prohibitively l a r g e .  3 3 , 3 4  different A  single  Otherwise  This will lead to a mixture of  four conformers which differ from one another only in the choice of the substituent position. T h e two g e m i n a l substituents, however, will be restricted to a corner position C 3 since it is only at this position that the substituents e x p e r i e n c e little transannular interactions.  Dale  defined the corner atom as having two adjoining g a u c h e angles of equal sign e a c h followed by an anti angle ( e . g . 1 8 0 ° , - 6 0 ° , - 6 0 ° , 1 8 0 ° ) .  3 2  A c o r n e r position r e p r e s e n t s the s o l e position  1 5  a v a i l a b l e for g e m i n a l disubstitution in that substituents on this position e x p e r i e n c e the least amount of steric interaction from the  ring.  3 3  '  3 4  A top v i e w d i a g r a m of the [3434] strain-free conformation 24. immediately r e v e a l s the corner positions a s c a r b o n atoms 3, 6, 10 a n d 13.  10  13  21 Figure 4. T o p a n d side views of the [3434] conformation of cyclotetradecane.  T h e ring s y s t e m which is of primary interest in this project, the 1 4 - m e m b e r e d l a c t o n e , c a n now be c o n s i d e r e d . T h e introduction of an ester linkage into the cyclotetradecane ring should not distort the [3434] conformation of the ring itself, s i n c e no n e w angular strain is introduced. Dale's strain-free [3434] conformation for c y c l o t e t r a d e c a n e c a n also be r e a s o n a b l y e x p e c t e d to be the lowest-energy c o n f o r m a t i o n for most of the 1 4 - m e m b e r e d l a c t o n e s , e x c e p t for substituted o n e s with d e m a n d i n g steric a n d g e o m e t r i c r e q u i r e m e n t s .  highly  O n e s u c h exception is  erythronolide B ( l f i j w h e r e the P e r u n m o d e l must be adopted in order to explain experimental results. F o r r e a s o n s of brevity, only 1 4 - m e m b e r e d l a c t o n e s w h i c h w e e x p e c t to adopt [3434] c o n f o r m a t i o n  will b e d i s c u s s e d in detail  and publications  c o n f o r m a t i o n s other than [3434] are g i v e n for i n t e r e s t .  concerning those  the with  It s h o u l d be e m p h a s i z e d that  3 5 , 3 6  most simple 1 4 - m e m b e r e d lactones s e e m to adopt the [3434] conformation a s demonstrated by our laboratory through d e t a i l e d c o n f o r m a t i o n a l  a n a l y s e s using X - r a y c r y s t a l l o g r a p h y , N M R  s p e c t r o s c o p y a n d molecular m e c h a n i c s ( M M 2 ) c a l c u l a t i o n s . " 3 7  3 9  16  Even membered  if o u r lactone  a n a l y s i s is r e s t r i c t e d tridecanolide  (35)  to  the  [3434] c o n f o r m a t i o n ,  the  simplest  14-  c a n still be e x p e c t e d to exist in s e v e n different  conformers. H o w e v e r , the preference of a planar s-trans geometry for esters immediately eliminates four of the p o s s i b l e c o n f o r m e r s .  It h a s b e e n reported by D e s l o n g c h a m p s  4 0  that the planar s-  trans geometry in ester 3_fL is approximately 3.0 k c a l / m o l e more stable than the planar s - c i s i s o m e r 2Z.  In fact, there is not a single e x a m p l e of an acyclic s-cis e s t e r .  4 1  O  A s - cis  21 T h e 1 4 - m e m b e r e d ring is large e n o u g h to a c c o m m o d a t e a p l a n a r s-trans linkage a s c o n f i r m e d by dipole m o m e n t m e a s u r e m e n t s 1.86 D e b y e s ,  4 2  4  2  ,  4  3  Tridecanolide (25.) h a s a dipole moment of  similar to those of acyclic esters which range from 1.6 to 2.0 D e b y e s .  4 3  O n the  other h a n d , 8-valerolactone (3Ji) where the lactone group is held rigidly in the s-cis linkage has a dipole moment of 4.22 D e b y e s .  s - cis  For tridecanolide only three [3434] conformations 35a, 25b. a n d 25c c a n a c c o m m o d a t e a planar s-trans lactone.  T h e relative steric energies of these conformations have b e e n found to  b e 0.2 k c a l / m o l e , 0.0 k c a l / m o l e a n d 0.1 k c a l / m o l e , respectively, by M M 2 c a l c u l a t i o n s .  4 4  In  contrast, the relative steric e n e r g i e s of the four conformers with s - c i s lactone linkages have been  found  to  be  7.2  k c a l / m o l e , 7.8  kcal/mole,  7.9  kcal/mole  and  8.2  kcal/mole.  4  4  A c c o r d i n g l y , conformations p o s s e s s i n g s-trans lactones s h o u l d predominate a n d tridecanolide (25) s h o u l d exist a s a mixture of conformers 3 5 a . 3 5 b a n d 35c. in nearly equal a m o u n t s .  252  35£  a£b  Obviously, in order to exploit the conformations of 1 4 - m e m b e r e d lactones a s a s o u r c e of stereocontrol, minimum.  the  number  of  low-energy  reacting  conformations  must  be  r e d u c e d to  a  This c a n be a c h i e v e d by introducing rigidity to the lactone rings through appropriate  substitutions  and/or  functionalizations.  B a s e d on the simple conformational a n a l y s e s of 1 4 - m e m b e r e d lactones d i s c u s s e d a b o v e , our laboratory h a s b e e n able to plan the s y n t h e s i s of c o n f o r m a t i o n a l ^ rigid  14-membered  l a c t o n e s a n d take a d v a n t a g e of their e x p e c t e d [3434] conformations to s u c c e s s f u l l y control diastereoselective reactions. F o r e x a m p l e , e n route to the s y n t h e s i s of z e r a n o l ( 3 9 h  the  required  9R*, 13S*  s t e r e o c h e m i s t r y w a s e s t a b l i s h e d v i a a [3434] c o n f o r m a t i o n a l ^ controlled d i a s t e r e o s e l e c t i v e reduction r e a c t i o n .  T h e p r e f e r e n c e of a p l a n a r s-trans lactone linkage a n d the  preferred  o c c u p a t i o n of a carbonyl at a non-corner position resulted in a single [3434] conformation 4 0 a for macrolide 4Q..  W h e n this macrolide w a s treated with L-Selectride, reduction o c c u r r e d from  the  exocyclic  more  open  diastereoselectivity.  face,  leading  to  the  desired  product  4 J _ with  excellent  19  1.4  Restricting the L o w - E n e r g y Conformations of 1 4 - M e m b e r e d L a c t o n e s bv G e m i n a l Disubstitution  It is c l e a r that 1 4 - m e m b e r e d l a c t o n e s are potentially templates for the introduction of a s y m m e t r i c c e n t r e s .  useful as  three-dimensional  In our laboratory, v a r i o u s 1 4 - m e m b e r e d  lactones have b e e n s y n t h e s i z e d and investigated for conformationally controlled reactions over the past few y e a r s .  During the c o u r s e of these studies, o n e c o m m o n problem a r o s e : often, the 14-  m e m b e r e d lactone under investigation p o s s e s s e d more than o n e stable low-energy conformation which c o m p l i c a t e d the a n a l y s i s a n d r e d u c e d the utility of the results o b t a i n e d .  It w a s felt that a  synthesis a n d study of a lactone with one stable conformation would provide valuable insight into the c o n f o r m a t i o n a l a n d c h e m i c a l b e h a v i o r of 1 4 - m e m b e r e d l a c t o n e s . 10,10-dimethyltridecanolide  T h e total s y n t h e s i s of  (42) w a s c o n d u c t e d with this goal in mind.  O n e of the many efficient w a y s to introduce rigidity into the lactone rings, a n d therefore r e d u c e the n u m b e r of c o n f o r m a t i o n s a v a i l a b l e , is by g e m i n a l disubstitution.  The geminal  substituents  in w h i c h  s h o u l d f o r c e a 1 4 - m e m b e r e d l a c t o n e to adopt a c o n f o r m a t i o n  the  quaternary c a r b o n atom o c c u p i e s a corner position. 10,10-Dimethyltridecanolide rigid [3434] c o n f o r m a t i o n  42a  (4.2) could b e e x p e c t e d to exist predominantly in a single  in w h i c h the g e m i n a l dimethyl g r o u p o c c u p i e s the  position and the lactone function has a planar s-trans geometry.  corner  Conformational a n d reactivity  s t u d i e s of this c o m p o u n d s h o u l d l e a d to a better u n d e r s t a n d i n g of the c o n f o r m a t i o n a l a n d c h e m i c a l behavior of 1 4 - m e m b e r e d lactones.  20 CHAPTER Results and  TWO  Discussion  T h i s c h a p t e r c o n s i s t s of four s e c t i o n s : (1) the s y n t h e s i s of the target m o l e c u l e 10,10dimethyltridecanolide (3)  MM2  (42);  (2) hydrolysis studies of two m a c r o l i d e s 42, 25., a n d an ester 1 0 9 :  c a l c u l a t i o n s of c o n f o r m a t i o n s  for m a c r o l i d e 42. a n d  (4) c o n c l u s i o n s from t h e s e  investigations a n d future c o n s i d e r a t i o n s .  2.1  S y n t h e s i s of  The following  10.10-Dimethyltridecanolide  synthetic  route  considerations.  to  (42^  10,10-dimethyltridecanolide  A geminal dimethyl  group  (42)  w a s d e v i s e d using  w a s to be i n t r o d u c e d  prior  to  the the  construction of the lactone ring so that it could serve to reduce the n u m b e r of conformations a v a i l a b l e to the r e m a i n d e r of the ring.  T h e lactone ring, o n the other h a n d , w a s to be  constructed v i a the lactonization of a long chain hydroxy a c i d precursor.  T h u s , the penultimate  target for the synthesis b e c a m e the co-hydroxy a c i d 42 with a geminal dimethyl group 6 to the hydroxyl function  (Figure 5).  S i n c e the g e m i n a l dimethyl group w a s an isolated o n e , direct alkylation w a s not feasible. N e v e r t h e l e s s , it c o u l d be g e n e r a t e d from a keto transformations.  functionality  v i a a s e r i e s of  chemical  T h e carboxylic a c i d functionality in 42 c o u l d be p r e p a r e d from the oxidation  of a pre-existing hydroxyl g r o u p .  H e n c e , the synthetic problem w a s further r e d u c e d to the  preparation of the 7-hydroxy ketone 44-  Further d i s c o n n e c t i o n of the synthetic  intermediate  44. w a s m a d e in v i e w of the fact that the most logical p r e c u r s o r of a -y-hydroxy derivative w a s y-butyrolactone  (45)  ketone  c o u p l e d with the c o r r e s p o n d i n g G r i g n a r d reagent 45. T h e  G r i g n a r d reagent 45 c o u l d be p r e p a r e d from the commercially available 1,9-nonanediol T h i s c o m p l e t e d our retrosynthetic s y n t h e s i s of macrolide  42.  a n a l y s i s a n d it s u g g e s t e d a n efficient  a p p r o a c h to  (47). the  21  Figure 5.  Retrosynthetic analysis of macrolide 42.-  Based on the synthetic scheme outlined above, our synthesis was initiated with the monobromination  of 1,9-nonanediol  (47).  This reaction was achieved by continuously  extracting a mixture of the diol and aqueous hydrobromic acid with heptane. The yield obtained after column chromatographic purification was 84%. The infrared (IR) spectrum of the bromo alcohol 48. showed a hydroxyl stretching absorption at 3337 cm" . The H NMR spectrum of 1  1  42. exhibited two sets of triplets at 5 3.42 and 5 3.66 which were attributed to the a-methylene protons of the bromo and hydroxyl groups respectively. HBr 42  41  22  Protection of the hydroxyl group of the bromo alcohol 45 w a s carried out by treatment of this material with dihydropyran in the p r e s e n c e of pyridinium p-toluenesulphonate  (PPTs).  T h e reaction p r o c e e d e d smoothly to give the tetrahydropyranyl ether 42 in 9 1 % yield. A b s e n c e of a hydroxyl absorption in the IR spectrum of 42. indicated a s u c c e s s f u l reaction. A triplet at 8 4.60 in the H N M R spectrum of 42 confirmed the p r e s e n c e of the acetal methine proton. 1  OTHP  T h e next step in the s y n t h e s i s w a s to convert c o m p o u n d 42  into a nucleophile a n d  prepare a 7-hydroxy ketone derivative v i a a nucleophilic addition to 7 - b u t y r o l a c t o n e . W h e n the bromide 42 w a s treated with m a g n e s i u m a n d the resulting G r i g n a r d reagent a d d e d slowly to 7-butyrolactone, the d e s i r e d 7-hydroxy ketone c o u l d not b e d e t e c t e d .  Instead,  we isolated the diol 52 which w a s the product of the addition of two equivalents of G r i g n a r d reagent to the lactone. It appeared that the s e c o n d Grignard addition to the ring o p e n e d c o m p o u n d w a s faster than addition to the 7-butyrolactone.  OTHP  In another attempt to prepare the d e s i r e d 7-hydroxy w e r e investigated.  ketone, organolithium  reagents  T h e simple alkyl bromide 51 reacted with lithium to give the organolithium  reagent 52. which s u c c e s s f u l l y o p e n e d 7-butyrolactone to give the 7-hydroxy ketone 52 in 5 6 %  23  yield. Surprisingly, when the tetrahydropyranyloxy bromide 49_ and the benzyloxy bromide £4. were subjected to this procedure, no reaction was observed and the starting bromides were recovered.  *>  y  u  2 )  ,  Q  At this point, we were forced to search for alternate conditions for this reaction. Our attention turned to the use of sulfone chemistry. It had been reported by Covicchioli et a l .  4 5  that a.oc-dilithio derivatives of alkyl phenyl  sulfones react with small and medium-size lactones to give the corresponding hydroxy ketones. The a.rx-dilithio derivatives of alkyl phenyl sulfones were prepared by treatment of the sulfones 5JL with two equivalents of a-butyllithium. The attack of lactones by these gemdimetallic compounds afforded intermediate enolates 5£. which upon workup gave the single addition products 5_Z. The formation of diols by a second organometallic addition was therefore avoided. OLi 2n-BuLi  p^y^oii] R  55  0  <. ^ Y ^ S  a q u e o u s N H  C I  R  56  52  O  H  24  T o apply C o v i c c h i o l i ' s method in our s y n t h e s i s , the bromide 42 must first b e converted into its corresponding phenyl sulfone. S e v e r a l methods are available for s u c h a c o n v e r s i o n . Direct alkylation of alkali m e t a l s a l t s of b e n z e n e s u l p h i n i c a c i d s is a widely procedure. ** 4  used  T h e reaction is usually performed in refluxing alcohol or in dimethylformamide at  room temperature, but it p r o c e e d s slowly and often gives only moderate yields of sulfones. A n improved synthesis of sulfones h a s b e e n reported by V e e n s t r a a n d Z w a n e n b u r g u s e d tetrabutylammonium  p-toluenesulphonate  4 7  who  (55) a s the nucleophile in reactions with alkyl  halides to give the c o r r e s p o n d i n g sulfones 52 in g o o d yields. C o m p o u n d 55 w a s p r e p a r e d by extraction of a c o n c e n t r a t e d a q u e o u s solution of tetrabutylammonium bromide (52) a n d sodium p-toluenesulphinate  (51) with methylene chloride.  ( n-C^ J ^ B r  R  ~~  +  N a S O z - Q - CH  R — SO2—^-CH  X  3  (  3  +  ^ N SC* +  CH  3  (n-C^^tfX  52  R e c e n t l y , a versatile p r o c e d u r e for the preparation of p h e n y l s u l f o n e s h a s a l s o b e e n p u b l i s h e d by M a n e s c a l c h i et a l .  4 8  T h i s m e t h o d involved the alkylation of b e n z e n e s u l p h i n a t e  anion supported on Amberlyst A - 2 6 , a macroreticular quaternary a m m o n i u m g r o u p .  a n i o n e x c h a n g e resin c o n t a i n i n g  a  T h e A m b e r l y s t A - 2 6 supported b e n z e n e s u l p h i n a t e anion 52 w a s  p r e p a r e d by the e x c h a n g e reaction of s o d i u m b e n z e n e s u l p h i n a t e (63) with the resin in chloride form £4..  T h e alkylation reaction w a s a c h i e v e d by stirring 52. with alkyl halides in refluxing  benzene.  T h e phenyl sulfones 55 thus p r o d u c e d were isolated simply by filtering the resin and  r e m o v i n g the s o l v e n t u n d e r r e d u c e d p r e s s u r e .  T h e y i e l d s with primary alkyl h a l i d e s w e r e  reproducibly a b o v e 9 0 % a n d the unpurified products s h o w e d very low levels of by-products by spectral a n a l y s i s .  4 8  25  64  62  S02—R  62  +  CH N (CH ) X" +  2  3  3  65 = polymer  Although e a c h of these three methods d i s c u s s e d a b o v e could be applied to our synthesis, we  favoured  Manescalchi's procedure  straightforward workup.  in v i e w  of  its s u p e r i o r  yields  and  relatively  U s i n g this p r o c e d u r e , the p h e n y l sulfone ££. w a s p r e p a r e d from the  b r o m i d e 12. in 9 4 % yield. T h e H N M R spectrum of 6J1 exhibited a multiplet at 8 7.52-7.92 1  for five a r o m a t i c p r o t o n s  a n d a triplet at 8 3 . 0 8 for the a - m e t h y l e n e  protons  of t h e  benzenesulfonyl group. In addition, the m a s s spectrum of £ £ s h o w e d the expected parent peak at m/e 3 6 8 .  •OTHP  +  \" CH N (CH >3 * ~0 62 +  2  12  SO  3  "  66  Having o b t a i n e d the phenyl sulfone in high y i e l d , w e s e t out to perform the alkylation reaction a g a i n . T h e sulfone ££. w a s first treated with two equivalents of n-butyllithium to give the a.a-dilithio s p e c i e s which w a s then stablized with a small amount of H M P A a n d allowed to react with Y-butyrolactone. hydroxy ketone £ Z in 81%  T h e reaction p r o c e e d e d smoothly a n d rapidly to afford the yyield.  26  ^  ^  ^  ^  ^  2 n-BuLi, HMPA  OTHP  ft  The IR spectrum of £7. showed absorptions at 3440 cm"  1  and at 1720 cm" , indicating 1  the presence of a hydroxyl and a carbonyl group respectively. In addition, the diastereotopic methylene protons, a to the carbonyl group, gave rise to two sets of triplets at 8 2.64-2.78 and 8 2.98-3.10 in the H NMR 1  spectrum of 6_Z,  Reductive desulfonation of £ 7 to the hydroxy ketone  was smoothly accomplished in  7 9 % yield by means of aluminum amalgam in refluxing aqueous tetrahydrofuran. The H 49  NMR  1  spectrum of £2. supported the desulfonated structure of this product.  OTHP  Al-Hg THF-H2O  OTHP  The desulfonated product 6JL exhibited two spots by tic after purification. The less polar fraction was identified as the hemiketal 6JL which was in equilibrium with the y-hydroxy ketone £8_. This equilibrium was not observed in compound £Z, possibly due to the steric effect of the benzenesulfonyl group. •OTHP  OTHP  O 68  The presence of £9_ was not expected to interfere with our synthetic scheme since differences in reactivity between the primary and tertiary alcohols or the carbonyl functionality could be used to shift the equilibrium to the desired acyclic form 6_8_- However, reaction of ££, might proceed slowly due to the existence of the less reactive hemiketal ££. This was indeed found to be the case in subsequent steps.  27 With the c a r b o n framework of the 1 4 - m e m b e r e d lactone constructed, continuation of the s y n t h e s i s next required the introduction of the g e m i n a l dimethyl g r o u p .  T h e replacement of a  k e t o n e by two methyl g r o u p s is an attractive strategy a n d a n u m b e r of m e t h o d s for s u c h a transformation h a v e b e e n reported. O n e of the most popular methods u s e s a three-step s e q u e n c e .  5 0 , 5 1  A Wittig olefination  of a ketone p r o d u c e s an alkene which is then transformed into a c y c l o p r o p a n e v i a a S i m m o n s S m i t h reaction. dimethyl g r o u p .  T h e c y c l o p r o p a n e ring thus obtained c a n be hydrogenated to give a g e m i n a l Money and c o - w o r k e r s  (+)-longiborneol (ZOJ. T h e ketone Z I  5 0  have reported this p r o c e d u r e in the s y n t h e s i s of  w a s first treated with  methylenetriphenylphosphorane  to give the alkene 7-2. which w a s then subjected to the cyclopropanation reaction.  Subsequent  hydrogenation of the c y c l o p r o p a n e ring in Z 3 . a n d reduction of the a c e t o x y l g r o u p furnished (+)-longiborneol  (70).  20.  H o w e v e r , certain p r o b l e m s a c c o m p a n y the u s e of this p r o c e d u r e :  (1) Wittig reactions  are very sensitive to the steric environment around the carbonyl group undergoing r e a c t i o n .  5 2  (2) T h e b a s i c c h a r a c t e r of the ylide reagent is often i n c o m p a t i b l e with e a s i l y e n o l i z a b l e ketones.  5 3  (3) C y c l o p r o p a n a t i o n reactions frequently give low yields d u e to the interference of  other functional g r o u p s with the cyclopropanating r e a g e n t s .  5 4  28 In 1 9 8 0 , Reetz et al. ^ reported a different approach to the preparation of a geminal 5  dimethyl group from a carbonyl function. trichloride  This method involved the use of methyltitanium  ( 7 4 ) which was prepared quantitatively  by treatment  of methyllithium or  methylmagnesium chloride with titanium tetrachloride.  MeLi (MeMgCl)  +  Ti04  — CH TiCl 3  3  24 Methyltitanium  trichloride ( 7 4 ) is a non-basic reagent and reacts chemo- and  stereoselectively with carbonyl compounds.  Thus, the reaction of the titanium reagent with a  ketone produces a tertiary alcohol 25. which can be readily converted into the tertiary chloride 26- The addition of another equivalent of 24 produces the geminal dimethyl compound 22-  9 R^^R'  CH TiCl 3  V-P HC^ \~P R^^R' R^^R  CH TiCl  H  3 f  25 One year later, Reetz et a l .  3  w R^^R'  3  1  26  22  reported that dimethyltitaniumdichloride (22), from the  5 6  reaction of titanium tetrachloride with two equivalents  of methyllithium,  exhaustively  methylated ketones to form geminal dimethyl compounds 22.  TiCL,  +  2 MeLi  M^TiCfe 71  \y  o R  A> . R  +  Me2Tia  2  21  -  R^R  1  22  Interestingly, another titanium reagent 29_ has also been reported capable of directly dimethylating a ketone.  This reagent was first synthesized by Tebbe et al. in  become known as Tebbe's reagent.  1978  5 7  and has  It was prepared by treatment of titanocene dichloride (8J2)  with two e q u i v a l e n t s of trimethylaluminum  (81).  T h e reagent w a s s o o n m a d e c o m m e r c i a l l y  available due to its versatile applications in organic s y n t h e s i s .  a  A1(CH )  2 A1(CH )  +  3 2  3 3  a  22  £1  O n e of the most useful properties of T e b b e ' s reagent is its superiority in methylenating carbonyl compounds.  It c a n m e t h y l e n a t e  carboxylic acid d e r i v a t i v e s .  a l d e h y d e s , k e t o n e s , a n d the c a r b o n y l g r o u p s  of  It d o e s not appear to enolize ketones a s Wittig reagents s o m e t i m e s  5 8  d o . T h u s , the optically active ketone £2 c a n be converted to the corresponding methylene product 8 3 in 9 3 % yield without racemization  5  8  O  S2  S2  In 1 9 8 3 , G r u b b s et a\?°  reported that the conversion of a ketone to a g e m i n a l dimethyl  group c o u l d , in s o m e c a s e s , be a c h i e v e d by using two equivalents of T e b b e ' s reagent.  These  authors cited a single e x a m p l e - this being the dimethylation of c y c l o h e x a n o n e 8JL- In this reaction, a small amount of methylenated product &5_ w a s also isolated  5  8  O (95%)  +  (5%)  In light of t h e s e results, it s e e m e d worthwhile to investigate the u s e of the titanium reagents in our s y n t h e s i s .  W e first c h o s e to explore the possibility of direct dimethylation of  30 our m o l e c u l e using T e b b e ' s reagent.  T h u s , the hydroxyl group in c o m p o u n d £ £ w a s first  benzylated to give the keto c o m p o u n d £ £ in 7 5 % yield.  •OTHP  NaH PhCH Br  OTHP  2  £6  W h e n the keto c o m p o u n d £ £ w a s treated with 2.4 equivalents of T e b b e ' s reagent using Grubbs' p r o c e d u r e ,  5 8  only the methylenated product £ 7 w a s isolated. Attempts to effect the  dimethylation reaction were then carried out with varying equivalents of T e b b e ' s reagents using different reaction conditions.  Unfortunately, in no c a s e w a s any dimethylated product detected.  However, the methylenation reaction did p r o c e e d rapidly in yields of greater than 80%.  OTHP  22  OTHP  PhCH 0' 2  22  £6  Although T e b b e ' s reagent proved to b e a powerful methylenating reagent in our studies, its high c o s t detracted from its u s e in a large s c a l e s y n t h e s i s . reagent d e s c r i b e d by R e e t z a n d c o - w o r k e r s .  O u r attention next turned to the  5 6  Titanium tetrachloride w a s treated with two equivalents of methyllithium a c c o r d i n g to Reetz's p r o c e d u r e .  5 6  T h e resulting titanium reagent w a s then allowed to react with one-half  equivalent of c y c l o d o d e c a n o n e (££) which w a s u s e d a s a model. T h e reaction proceeded smoothly to give 1 - m e t h y l c y c l o d o d e c a n o l (££) instead of the d e s i r e d 1,1-dimethylcyclododecane (90). Efforts to effect the direct dimethylation reaction under a variety of conditions again proved to b e fruitless.  H o w e v e r , the dimethylated product 9J1 w a s obtained by c o n v e r s i o n of the tertiary  alcohol £9. into the chloride 9J_ and subsequent treatment of £1 with the titanium reagent a g a i n .  31  £2  21  2Q  T h e strong a c i d i c conditions required for the c o n v e r s i o n of 8j9_ to 2 1 a n d its low yield p r e s u m a b l y d u e to the competing dehydration reaction a l s o m a d e this route impractical in our synthesis. This method w a s , therefore, a b a n d o n e d . T h e failure of direct dimethylation with titanium reagents led us to return to the more c l a s s i c a l procedures of converting a ketone group into a geminal dimethyl group. w a s a Wittig olefination reaction.  T h e first step  T h u s , the y-hydroxy ketone £ £ a n d its cyclic form 6JL were  a l l o w e d to react with three equivalents of methylenetriphenylphosphorane.  A s e x p e c t e d , the  reaction p r o c e e d e d slowly d u e to the p r e s e n c e of the unreactive hemiketal 612..  However, a  prolonged reaction time of 80 h g a v e the alkene 2 2 in 8 0 % yield. T h e a b s e n c e of the carbonyl a b s o r p t i o n a n d a p p e a r a n c e of a n olefinic a b s o r p t i o n at 1 6 4 4 c m " c o m p o u n d 2 2 . indicated a s u c c e s s f u l Wittig reaction.  1  in the IR s p e c t r u m of  T h e absorption at 8 4 . 7 5 in its H N M R 1  s p e c t r u m w a s a s c r i b e d to the terminal vinyl protons.  •OTHP  Ph P=CH 3  2  32  At this s t a g e , it w a s n e c e s s a r y to protect the hydroxyl group in c o m p o u n d 2£.  A n acetate  protecting group w a s c h o s e n , since it would survive the subsequent oxidation reaction.  Treatment  of the alcohol 22. with acetic anhydride a n d pyridine in the p r e s e n c e of a catalytic amount of 4dimethylaminopyridine ( D M A P ) g a v e the d e s i r e d ester 22 in 9 4 % yield.  AC2O, C5H5N •OTHP  » DMAP  II  22  22  T h e IR spectrum of 22 s p e c t r u m of 22.  _  A c O ^ ^ ^ ^ ^ ^ ^ ^  s h o w e d a carbonyl stretching b a n d at 1743 c m " . T h e H N M R 1  1  exhibited a s h a r p singlet at 8 2.08 attributed to the methyl protons of the  acetate a n d a triplet at 8 4.08 ascribable to the methylene protons a to the acetoxyl group.  In  addition, the m a s s spectrum of 22 s h o w e d a molecular ion peak at m/e 354. T h e next step in the synthesis w a s to convert the alkene into a cyclopropyl ring.  O n e of  the first effective s y n t h e s e s of a c y c l o p r o p a n e unit from an alkene w a s performed in 1958 by S i m m o n s and S m i t h copper couple.  5 9  who treated an olefin with methylene iodide in the p r e s e n c e of zinc-  T h e s e authors p r o p o s e d that methylene iodide reacted with z i n c - c o p p e r to form  a n intermediate  i o d o m e t h y l z i n c iodide (24),  the c a r b o n atom of which w a s electrophilic a n d  thus attacked the double b o n d to give cyclopropane 26. through the transition state 9 5 .  c f  +  C H  /\  '  .  [r tY«  \ i  1968,  Furukawa  ]  1  c  v , „ C H ,  .  A  24 In  -2M  / \ 25  and  co-workers  +  5 9  j  7 x 1  1  26 6 0  published  a  paper  concerning  the  cyclopropanation of a l k e n e s using diethylzinc a n d methylene iodide. T h e s e authors s h o w e d that c y c l o p r o p a n e s c o u l d be o b t a i n e d more easily with this n e w cyclopropanating reagent.  Since  33  t h e n , the F u r u k a w a modification of the S i m m o n s - S m i t h c y c l o p r o p a n a t i o n p r o c e d u r e h a s b e e n u s e d in organic synthesis with considerable s u c c e s s .  6 1  W h e n the olefin 23. w a s heated with diethylzinc-methylene iodide in toluene at 6 0 °C , the c o r r e s p o n d i n g c y c l o p r o p a n e c o m p o u n d 2 Z w a s p r o d u c e d , but in low yield (about 2 5 - 3 0 % ) . C a p i l l a r y glc a n a l y s i s of the c r u d e reaction mixture indicated the p r e s e n c e of more polar byproducts. they  Although these by-products were not isolated and c h a r a c t e r i z e d , it s e e m e d likely that  were  formed  by  r e a c t i o n of the  tetrahydropyranyl  ether  in c o m p o u n d 2 3 . with the  cyclopropanating reagents.  OTHP  C l e a r l y , the low yield of this reaction warranted alternative plans for the preparation of compound 2Z-  S p e c i f i c a l l y , it w a s felt that the alcohol 2 3 . obtained by the c l e a v a g e of the  tetrahydropyranyl ether in 2 2 might be a better substrate for the cyclopropanation reaction. Treatment of 23. with pyridium p-toluenesulfonate  afforded the hydroxy a l k e n e 23. in  9 0 % yield.  W h e n the hydroxy olefin 23. w a s subjected to the modified S i m m o n s - S m i t h reaction, the c o r r e s p o n d i n g c y c l o p r o p y l c o m p o u n d 22. w a s p r o d u c e d in 4 1 % yield. T h i s yield w a s higher than the o n e obtained earlier, but still left m u c h to be d e s i r e d .  Et Zn, CH2I2 2  ^  /  V  V  V  ^  ^  S  A  O  H  ^  A c O - ^ ^ V ^ ^ ^ ^ ^ O H  34 At this point, w e were e n c o u r a g e d by the improved yield a n d d e c i d e d to investigate the reaction  by further  butyldimethylsilyl  modifying  (TBDMS)  the substrate  by p r o t e c t i n g  t h e a l c o h o l 2JL a s a t e r t -  ether.  Silyl ether derivatives of a l c o h o l s h a v e a number of useful properties. trimethylsilyl  ethers  m a k e s them  s u i t a b l e for s e p a r a t i o n a n d structure  T h e volatility of e l u c i d a t i o n by a  combination of g a s chromatography and m a s s s p e c t r o m e t r y .  62  to mild conditions limits their u s e a s protecting g r o u p s .  H o w e v e r , t h e stability of T B D M S  6 3  O n the other h a n d , their lability  ethers to a w i d e r a n g e of reaction c o n d i t i o n s m a k e s t h e m particularly effective g r o u p s for the h y d r o x y l f u n c t i o n .  6 4  protecting  T h i s stability results from the fact that most of their  r e a c t i o n s p r o c e e d by n u c l e o p h i l i c attack at s i l i c o n , w h i c h i s , therefore, s e n s i t i v e to steric hindrance. R e a c t i o n of the a l c o h o l 9JL with triethylamine ( T E A ) , i e i l - b u t y l d i m e t h y l s i l y l  chloride  a n d a catalytic amount of 4-dimethylaminopyridine g a v e the silyl ether 1 0 0 in 9 5 % yield.  TBDMS-Cl TEA. DMAP  t  AcO'  1  •OTBDMS lffi  2S  The  AcO"  H N M R spectrum of c o m p o u n d 1 0 0 exhibited a six-proton singlet at 8 0.06 due to  the silyl methyl p r o t o n s , while a s e c o n d singlet a s c r i b a b l e to the tert-butyl methyl  protons  a p p e a r e d at S 0 . 9 0 . T o our satisfaction, the cyclopropanation reaction of the silyl ether a l k e n e 100 p r o c e e d e d c l e a n l y , under the conditions u s e d earlier, to give the cyclopropyl c o m p o u n d 101 in 8 8 % y i e l d . T h e IR spectrum of 101 s h o w e d a cyclopropyl-hydrogen stretching absorption at 3 0 6 5 c m " . In 1  addition, the cyclopropyl protons of 1 Q 1 g a v e rise to a doublet at 8 0.22 in the  OTBDMS  1  Et Zn 2  •OTBDMS  CH2l2  1QQ  H N M R spectrum.  101  35 Hydrogenolysis of the least hindered cyclopropyl b o n d  bJ)  of compound 101 was  accomplished by treatment of a solution of 101 in glacial acetic acid with a catalytic amount of platinum oxide under hydrogen. The geminal dimethyl silyl ether 102 thus produced (in 7 9 % yield) was hydrolyzed to the corresponding alcohol 1Q2, in 8 7 % yield by treatment of 1Q2. with pyridinium p-toluenesulfonate.  OTBDMS  103.  The IR spectrum of 103 showed a hydroxyl absorption at 3560-3204 cm" . The H 1  1  NMR spectrum exhibited a sharp singlet at 5 0.84 which was attributed to the six protons of the geminal dimethyl group in the molecule. The next two steps in the synthesis were rather straightforward. Oxidation of alcohol 66  103 gave the carboxylic acid 104 in 7 7 % yield. The IR spectrum of 104 showed the acid absorptions at 3480-3014 cm* and 1712 cm" . In addition, the H NMR spectrum of 104 1  1  1  exhibited a triplet at 8 2.36 which was ascribable to the a-methylene protons of the carboxylic acid function.  The acetate protecting group in compound 104 was hydrolyzed with potassium carbonate in methanol. The ©-hydroxy acid 105 thus produced (in 9 8 % yield) was highly pure and was carried directly to the lactonization reaction.  KM  105  With a m p l e quantities of the hydroxy a c i d 1 0 5 in h a n d , w e were ready to perform final cyclization step in our s y n t h e s i s .  the  T h e literature records an extensive list of methods for  effecting the lactonizations of hydroxy a c i d s , a n d many of t h e s e have b e e n d i s c u s s e d in the Introduction. reliable.  2 7  A m o n g the several existing methods, Schmidt and Dietsche's procedure h a s proven O u r lactonization reaction w a s therefore carried out using this p r o c e d u r e .  Treatment  of  1-phenyl-2-tetrazoline-5-thione  (106)  with o n e e q u i v a l e n t of tert-  b u t y l i s o c y a n i d e (107) in toluene at room temperature g a v e c o m p o u n d 1 0 8 a and 1 0 8 b which upon addition of 0.8 equivalent of the o - h y d r o x y a c i d 1 0 5 afforded the 1 4 - m e m b e r e d lactone 42. in 6 6 % y i e l d .  Ph  Ph—  N—N  Ph—N—N  N—N  +  +  N H — O N  H  101  106  108a  \ 108b  42 The IR spectrum of macrolide 42 showed a lactone carbonyl absorption at 1718 cm" . 1  The H NMR spectrum of 42 was readily assignable. The six methyl protons gave rise to a sharp 1  37  singlet at 8 0.84. T h e a-methylene protons of the lactone o x y g e n a n d the a - m e t h y l e n e  protons  of the c a r b o n y l group resulted in two sets of multiplets at 8 4.18 and 8 2.40 respectively.  In  addition, the m a s s spectrum exhibited a molecular ion peak at m/e 2 4 0 . T h u s , the synthesis of 10,10-dimethyltridecanolide  (42) w a s c o m p l e t e d .  38  2.2  H y d r o l y s i s of 1 0 . 1 0 - D i m e t h y l t r i d e c a n o l i d e (42). Pentanoate  T r i d e c a n o l i d e (35)  and  n-Octvl  M091  T o investigate the conformational behavior of the macrolide s y n t h e s i z e d in this project, the  hydrolysis  of  10,10-dimethyltridecanolide  p e n t a n o a t e (109) w a s p e r f o r m e d .  (42).  tridecanolide  (35)  and  n-octyl  F r o m s i m p l e conformational a n a l y s e s , m a c r o l i d e 42  e x p e c t e d to exist predominantly in conformation 4 2 a .  was  O n the other h a n d , tridecanolide  (35)  w a s known to exist a s a mixture of conformers 3 5 a . 3 5 b and 35£ in nearly e q u a l a m o u n t s .  35s  25J2  4 4  25£  E x a m i n a t i o n of the e n v i r o n m e n t s surrounding the lactone functionality in e a c h of the above conformations  r e v e a l e d that 4 2 a a n d 3 5 a directed the lactone c a r b o n y l t o w a r d s the  sterically more hindered interior of the ring. C o n s i d e r a t i o n of the steric interactions of the tetrahedral intermediates in the b a s e c a t a l y z e d hydrolysis reaction led to an initial prediction that hydrolysis of c o n f o r m e r s 4 2 a and 3 5 a w o u l d b e s l o w e r than that of c o n f o r m e r 3 5 b or 3 5 c .  S i n c e macrolide 35.  mixture of 3 5 a . 3 5 b a n d 3 5 c . it s h o u l d h y d r o l y z e faster than m a c r o l i d e 42.  exists a s a which  exists  predominantly in conformation 4 2 a . T h e intermediates involved in the hydrolysis of 422. o x y a n i o n is forced into a sterically c r o w d e d environment.  and 35a  are 110 a n d H I  where the  T h e intermediates encountered in the  39  hydrolysis of 3 5 b a n d 3 5 c (112 and 1 1 3 respectively) are less steric h i n d e r e d .  All of these  intermediates are a s s u m e d to maintain the [3434] ring conformations of the starting materials.  HO  HO  112 In addition to studying the hydrolysis of macrolides 42. and 35_, the hydrolysis of a 13c a r b o n ester w a s a l s o c o n d u c t e d .  It w a s e x p e c t e d that the ester would hydrolyze faster than  either of the m a c r o l i d e s . T h e synthesis of macrolide 42. has b e e n detailed in Section 2.1. T h e other two c o m p o u n d s u s e d for hydrolysis studies were prepared as follows: E s t e r 1 0 9 w a s p r e p a r e d by treatment of 1-octanol (114) a n d valeric a c i d (115) with dicyclohexylcarbodiimide  ( D C C ) in the p r e s e n c e of 4 - d i m e t h y l a m i n o p y r i d i n e  (DMAP).  The  esterification reaction p r o c e e d e d smoothly to give the d e s i r e d product 10j9_ in 9 4 % yield.  O  115  DMAP  114  O  102  Macrolide 25. w a s s y n t h e s i z e d using a modified B a e y e r Villiger r e a c t i o n . cyclotridecanone yield.  ( 1 1 6 ) with peroxytrifluoroacetic  6 7  Treatment of  a c i d g a v e the d e s i r e d product 2 5 in 6 7 %  40  25  116 Hydrolysis of macrolides 12. and 25.,  and ester 109 with potassium carbonate in  methanol was first carried out at room temperature. The relative rates of hydrolysis were determined by monitoring a reaction mixture which contained the hydrocarbon dodecane as an internal standard and following the disappearance of the ester and the macrolides by gas-liquid chromatography (glc). The data obtained from this reaction are plotted in Figure 6 as relative intensities of the hydrolysis compounds to the internal standard versus reaction time.  0  29  50  73  Time (min) Figure 6. Plot of the rates of the hydrolysis of 12,25. and 109 at room temperature.  41  Figure 6 s h o w s that ester 1 0 9 conditions.  h y d r o l y z e d faster than the m a c r o l i d e s u n d e r  these  T h i s result c o u l d be explained in terms of the steric hindrance of the intermediates  i n v o l v e d in the r e a c t i o n .  A t t a c k o n the m a c r o l i d e s by the hydroxyl anion w o u l d force the  o x y a n i o n into a sterically c r o w d e d environment regardless of their conformations.  O n the other  h a n d , attack o n a long-chain ester by the hydroxyl anion would be free of any steric interaction. O n e would therefore anticipate a much more rapid hydrolysis of the ester than the macrolides. H o w e v e r , the o b s e r v a t i o n that both m a c r o l i d e s h y d r o l y z e d at the surprising.  s a m e rate  was  If macrolide 42 existed in a single [3434] conformation 4 2 a a n d the hydrolysis of  t h e s e m a c r o l i d e s p r o c e e d e d through m a c r o l i d e 42  intermediates  maintaining  s h o u l d hydrolyze more slowly than macrolide 25-  the [3434]  conformations,  Hydrolysis of m a c r o l i d e s  41  and 25., and ester 1 0 9 at low temperatures (0 °C and -20 °C) also g a v e similar results to those s h o w n in Figure 6. T o interpret the hydrolysis results a n d u n d e r s t a n d the conformational p r e f e r e n c e s of m a c r o l i d e 42. from a theoretical point of v i e w , we next undertook the m o l e c u l a r m e c h a n i c s (MM2) c a l c u l a t i o n s  3 8  '  3 9  of conformations for macrolide  42.-  42  2.3  M o l e c u l a r M e c h a n i c s C a l c u l a t i o n s of C o n f o r m a t i o n s for  10.10-Dimethvrtridecanolide  im O n e of the g o a l s of this project w a s to construct and investigate a 1 4 - m e m b e r e d macrolide w h i c h should exist predominantly in o n e conformation.  T h e structural requirements w e u s e d to  predict a single conformation for macrolide 4£ were the preference for a planar s-trans lactone linkage a n d the o c c u p a t i o n of a g e m i n a l dimethyl group at the c o r n e r position in the [3434] conformation of the 1 4 - m e m b e r e d lactone. Our theoretical a p p r o a c h to studying the conformational preferences of this s y s t e m w a s to c a l c u l a t e the steric e n e r g i e s of all likely c o n f o r m a t i o n s of m a c r o l i d e 4 2 . a n d from t h e s e e n e r g i e s to d e t e r m i n e their a p p r o x i m a t e B o l t z m a n n distributions.  T h e c a l c u l a t i o n of t h e s e  conformational e n e r g i e s w a s performed using the molecular m e c h a n i c s ( M M 2 ) p r o g r a m .  3 8 , 3 9  Molecular m e c h a n i c s calculations have b e e n gaining popularity in the past few years a s researchers  try  to  interpret  conformational a n a l y s e s .  their  results  and  formulate  synthetic  plans  based  T h e M M 2 program w a s introduced by Allinger a n d c o - w o r k e r s  on 3 8 , 3 9  a s a n alternative to the complicated, sh. initio m o l e c u l a r orbital (MO) m e t h o d s of calculating molecular energies.  T h e e n e r g i e s c a l c u l a t e d by the M M 2 p r o g r a m are b a s e d o n c l a s s i c a l  m e c h a n i c s in which the equations u s e d to calculate the energies are parameterized to best fit the experimental d a t a .  M o l e c u l e s are r e p r e s e n t e d a s though constructed from balls a n d springs  with a s e r i e s of potential energy functions to e x p r e s s the "steric" energy of a molecule. T h e "steric" energy of a molecule is the s u m of five different e n e r g i e s . T h e first energy term is a s s o c i a t e d with b o n d stretching which the M M 2 program treats a s a modified H o o k e ' s law equation.  T h e remaining four terms include angle b e n d i n g , torsional strain, dipole and V a n  der W a a l s interactions. T o calculate the minimum energy conformation of a molecule, the M M 2 program e m p l o y s the s t e e p e s t - d e s c e n t m e t h o d .  A likely conformation of a m o l e c u l e is first constructed using  molecular m o d e l s and its approximate co-ordinates are determined.  T h e s e are provided as an  43  input file to the M M 2 computer program and the steric energy is c a l c u l a t e d from this given set of co-ordinates. T h e computer then m o v e s one atom to a new set of co-ordinates and recalculates the energy.  If the atom movement results in a lower energy, then the atom is further m o v e d in  the s a m e direction until the energy difference is less than or equal to a preset v a l u e .  Although  this p r o c e s s h a s b e e n d e s c r i b e d using a single a t o m , in fact, every atom within the molecule is simultaneously subjected to this movement-calculation s e q u e n c e until the energy of the s y s t e m is m i n i m i z e d . T h e resulting steric e n e r g y of a certain c o n f o r m a t i o n  is a n e n e r g y  relative to  a  hypothetical, strain-free, reference s y s t e m . T h e difference in energy between conformations of a m o l e c u l e is g i v e n by direct c o m p a r i s o n of the c a l c u l a t e d steric e n e r g i e s .  H o w e v e r , if a  c o m p a r i s o n b e t w e e n different m o l e c u l e s is required, steric e n e r g i e s s h o u l d not b e u s e d ; an alternative for this type of c o m p a r i s o n is to u s e the heats of formation, w h i c h c a n a l s o be calculated by the M M 2 p r o g r a m . T h e c o n f o r m a t i o n s of m a c r o l i d e 4 £ to be investigated a r o s e from the conformational analyses  of  simple  14-membered  lactones.  As  d e s c r i b e d p r e v i o u s l y , the  c o n f o r m a t i o n s for tridecanolide (25J are 3 5 a . 3 5 b and 3 5 c .  4 4  low-energy  T h e s e three c o n f o r m e r s were  taken a s the b a s i c framework to g e n e r a t e c o n f o r m e r s 4 2 a . 4 2 b and 4 2 c for macrolide 42. Their relative steric e n e r g i e s w e r e determined by M M 2 c a l c u l a t i o n s .  In addition, the relative  steric energy of conformer 4 2 d which had a geminal dimethyl group at the corner position but a lactone linkage at a position different from that of conformer 4 2 a w a s also c a l c u l a t e d .  44  Figure 7 s h o w s the computer plots of the side a n d top views of conformations 4 2 a . 4 2 b . 4 2 c a n d 4 2 d . a n d their relative steric e n e r g i e s .  side view  side view  Figure 7.  4 2 a (0.0 kcal/mole)  42Ja (5.8 kcal/mole)  top view  top view  side view  4£c_ (4.2 kcal/mole)  top view  side view  424  (7.8 kcal/mole)  top view  C o m p u t e r plots of the [3434] conformations for macrolide 42.  46  M M 2 calculations s h o w e d that the energy of conformer 4 2 a w a s the lowest. Accordingly, the steric interactions in this conformation should be the least. simple conformational analysis.  This w a s in agreement with our  T h e n o n - c o r n e r g e m i n a l dimethyl g r o u p s in 4 2 b and 4 2 c  introduced steric interaction in the rings a n d therefore r a i s e d their steric e n e r g i e s . 4 2 b h a d a higher energy than conformer 42c..  Conformer  T h i s w a s due to the fact that the dimethyl group  in 4 2 b w a s at a sterically more hindered position.  A s e x p e c t e d , conformer 4 2 d . containing the  s-cis lactone linkage, w a s destabilized a n d resulted in a relatively high energy state. A l t h o u g h the d i a g r a m s s h o w n in F i g u r e 7 d e m o n s t r a t e d the [3434] c h a r a c t e r of the conformations  and  their  structures,  it  was  difficult  to  recognize  c o n f o r m a t i o n s or to e a s i l y c o m p a r e one conformation with another.  the  of  the  It w a s a l s o difficult to  determine if any deviation from the ideal [3434] conformation had o c c u r r e d . difficulties could b e s o l v e d through the u s e of polar m a p s .  symmetry  Fortunately, these  6 8  A polar m a p is a circular graph which plotting the sign a n d magnitude of the internal torsional angles of a ring v s . the bonds along which they are found.  T h e concentric circles of a  polar m a p represent v a l u e s of the torsional angle in ± 60° increments a n d the straight lines w h i c h intersect the circles are the bonds (numbers 1-14) where the torsional angle is formed (Figure 8).  A c c o r d i n g l y , a 1 4 - m e m b e r e d ring p r o d u c e s 14 d a t a points on a polar m a p .  points, when c o n n e c t e d , generate a "star pattern" representing the conformation. 14  1  3  12  4  5 10 8  Figure 8. T h e polar map conventions.  8  7  These  47  T h e v a l u e of polar m a p s is that the c o m p l e t e set of torsional a n g l e s formed by the ring atoms will a l w a y s uniquely define the conformation.  T h e torsional a n g l e s may be obtained from  M M 2 c a l c u l a t i o n s , from X - r a y d a t a or from an i n s p e c t i o n of a m o l e c u l a r m o d e l .  Recent  developments in the determination of the signs of torsional angles have also e n h a n c e d the general u s e of polar m a p s .  3 5 , 6 9  T h e polar map of the [3434] conformation of cyclotetradecane is s h o w n in Figure 9. polar m a p clearly illustrates the C  rotation a x i s through b o n d s 4 a n d 1 1 .  2  The  In addition, the  patterns of the polar map c a n be u s e d to quickly indicate the p r e s e n c e a n d location of corner a t o m s within a conformation  by r e c o g n i z i n g the c o r n e r ' s c h a r a c t e r i s t i c a n t i - g a u c h e - g a u c h e -  anti s e q u e n c e of torsional a n g l e s .  3 5  T h e position of the corner atoms on the conformations and  polar m a p s are marked with an asterisk.  C2 axis of macrolide Figure 9. T h e [3434] conformation of cyclotetradecane a n d the polar m a p of its torsional angles.  With the aid of polar m a p s , conformations c a n be unambiguously identified a n d e x a m i n e d . T h i s is facilitated  if the i d e a l c o n f o r m a t i o n , for e x a m p l e , the ideal [3434] c o n f o r m a t i o n ,  simultaneously plotted o n the s a m e map with the one under examination.  is  T h e polar m a p s of the  four c o n f o r m a t i o n s d e t e r m i n e d by M M 2 c a l c u l a t i o n s (Figure 7) are g i v e n in Figure 10 which also s h o w s the ideal [3434] conformation in broken lines.  48  14  Figure 1 0 .  1  H  S u p e r p o s i t i o n of the polar m a p s of the ideal [3434] conformation (broken lines) and the [3434] conformations of macrolide 4£.  T h e polar m a p s in Figure 10 s h o w that conformer 4 2 a c l o s e l y a p p r o x i m a t e d the ideal [3434] conformation.  T h i s w a s in agreement with our prediction that a g e m i n a l dimethyl group  at the c o r n e r position w o u l d not introduce s e v e r e transannular interactions into the ring a n d w o u l d therefore not significantly distort the [3434] ring  framework.  49  O n the other h a n d , the polar m a p s of c o n f o r m e r s 4 2 b a n d 4 2 c s h o w e d a s m a l l but significant d e v i a t i o n from the i d e a l [3434] c o n f o r m a t i o n at b o n d s 10 a n d 9, r e s p e c t i v e l y . T h e s e are the b o n d s that contain the n o n - c o r n e r dimethyl substituted c a r b o n .  T h e steric  hindrance introduced by the dimethyl group h a s forced the ring to c h a n g e its conformation.  It is  interesting to note that the strain a p p e a r s to b e c o n c e n t r a t e d at a few b o n d s rather  than  distributes o v e r m a n y b o n d s a n d the m a i n portion of the ring still a d h e r e s to the [3434] framework.  S i m i l a r l y , the m a i n portion of the ring is [3434] like for c o n f o r m e r 4 2 d  with  deviation occurring at b o n d 3 which contains the s-cis lactone group. Early  in o u r project,  m a c r o l i d e 42conformations  w e w e r e only c o n c e r n e d with the  [3434] c o n f o r m a t i o n s  H o w e v e r , recent work in our laboratory r e v e a l e d s e v e r a l other for  certain  macrolides.  conformations d e s c r i b e d by D a l e .  3 5 , 3 6  for  low-energy  A m o n g t h e m w e r e two n o n - d i a m o n d  lattice  3 2  In his pioneering work on conformations of c y c l i c a l k a n e s , Dale c o n s i d e r e d only those ring c o n f o r m a t i o n s w h i c h w e r e s u p e r i m p o s a b l e on a d i a m o n d lattice.  However, calculations on  c y c l o t e t r a d e c a n e later r e v e a l e d two low-energy conformations which w e r e not d i a m o n d lattice superimposable.  T h e s e w e r e d e s i g n a t e d the [3344] (1.1  k c a l / m o l e higher than the  b a s e ) a n d [3335] (2.2 k c a l / m o l e ) c o n f o r m a t i o n s (Figure 1 1 ) .  3 2  T h e s e conformations  [3434] were  found to be lower in energy than every d i a m o n d lattice conformation with the exception of the [3434] a r r a n g e m e n t ( b a s e v a l u e of 0.0 k c a l / m o l e ) .  T h e position of the corner a t o m s of the  conformations in Figure 11 is m a r k e d with an asterisk.  50  Figure 1 1 .  T h e [3344] a n d [3335] conformations of cyclotetradecane a n d their polar m a p s .  W e w e r e p r o m p t e d to investigate these two conformations for m a c r o l i d e 42  by M M 2  c a l c u l a t i o n s a n d w e restricted our c a l c u l a t i o n s to those conformations containing a n s-trans lactone linkage a n d a g e m i n a l dimethyl group at the corner position.  S i n c e the [3344] a n d  [3335] a r r a n g e m e n t s w e r e l e s s s y m m e t r i c than the [3434], two [3344] c o n f o r m a t i o n s a n d 421,  a n d three [3335] conformations 42a.  4 2 h a n d 42i  w e r e p o s s i b l e for macrolide  42e 42.  T h e i r c a l c u l a t e d steric e n e r g i e s relative to 4 2 a . c o m p u t e r plots a n d polar m a p s are given in Figure 12.  top view  polar map  top view  4 2 e (1.2 kcal/mole)  42f  top view  polar m a p (1.3  kcal/mole)  polar map  4 2 i (3.5 k c a l / m o l e ) Figure 1 2 .  C o m p u t e r plots a n d polar m a p s of the [3344] a n d [3335] conformations for macrolide 42 (relative steric energy in k c a l / m o l e ) .  52  With the  steric e n e r g i e s of all likely c o n f o r m a t i o n s  different c o n f o r m a t i o n s distribution e q u a t i o n .  for  macrolide  42.  c a l c u l a t e d , the proportions  c o u l d now b e e s t i m a t e d  u s i n g the  of  Boltzmann  F o r two i s o m e r s A and B in equilibrium, the equilibrium constant K (the  ratio of the number of A m o l e c u l e s , N ^ , to the number of B m o l e c u l e s , N g ) is given by equation 1.  a n d E g are the e n e r g i e s of two i s o m e r s , R is the g a s constant a n d T is the absolute  temperature.  K =  NA  (EA  exp  • EB)  (D  RT  NB  U s i n g the c a l c u l a t e d relative steric e n e r g i e s of the a b o v e conformations, an estimate of their distribution c a n be o b t a i n e d .  F o r e x a m p l e , c o n s i d e r c o n f o r m e r s 4 2 a a n d 4 2 c at 2 5 ° C ,  equation 1 b e c o m e s  N42a N42C  exp  I-  C o n f o r m a t i o n 42c  ( 0.0 - 4 . 2 ) x 10 1.986 c a l / K mole  cal/mole x  = 1.2 x 10  298 K  is not significantly populated at room temperature a n d for practical  p u r p o s e s it c a n be i g n o r e d .  Similarly, conformations 4 2 b . 4 2 d . 4 2 g . 4 2 h a n d 42i n e e d not be  considered as possible conformers  for  m a c r o l i d e 42-  O u r attention c o u l d therefore  concentrated o n o n e [3434] conformation 4 2 a and two [3344] conformations 42£ and 42fB o l t z m a n n distribution of t h e s e c o n f o r m a t i o n s i s ; 4 2 a : 4 2 e : 4 2 f = 80 : 11 : 9. macrolide 42a  should exist a s a mixture of these three conformations.  42£  421  be The  Accordingly,  53  A m o n g t h e s e three conformations containing the lactone functionality.  42fi. is  identical with  42a in  the region of the molecule  T h e chemistry of 4 2 e should b e similar to that of 4 2 a and  it would be sufficient to d e s c r i b e macrolide 42 in terms of conformations 4 2 a and 421T h e lactone groups of 4 2 a and 421 are in different environments.  Conformer 4 2 a has the  lactone carbonyl group directed toward a sterically more hindered ring interior than conformer 421.  T h e tetrahedra! intermediate from hydrolysis of 421 s h o u l d b e sterically l e s s hindered  than that of 42a a n d the hydrolysis of 421 should therefore b e faster than 4 2 a . T h e results of the hydrolysis studies c o u l d now be interpreted.  A p o s s i b l e explanation  for our o b s e r v a t i o n of the similar rates of the hydrolysis of the two m a c r o l i d e s is that the [3434] ring c o n f o r m a t i o n s w e r e not m a i n t a i n e d in the hydrolysis i n t e r m e d i a t e s .  T h e steric  hindrance introduced by the hydrolysis intermediates may h a v e led to a c h a n g e of the [3434] conformation s u c h that the difference of the lactone carbonyl environment in the ground state conformations w a s not reflected in the reaction. A n o t h e r e x p l a n a t i o n for the equilibrium  mixture  h y d r o l y s i s s t u d i e s is that m a c r o l i d e 42. exists a s a n  of c o n f o r m a t i o n s 4 2 a / e a n d 4 2 f .  T h e rates of c o n f o r m a t i o n a l c h a n g e  b e t w e e n these c o n f o r m e r s are m u c h faster than that of the hydrolysis reaction a n d conformer 421 is e x p e c t e d to hydrolyze more easily than conformer 4 2 a . A c c o r d i n g to the Curtin-Hammett principle,  7 0  the ratio of the c o n f o r m a t i o n s of m a c r o l i d e 42  hydrolysis p r o c e s s .  w o u l d not be reflected in the  F r o m L e C h a t e l i e r ' s principle, the selective hydrolysis of c o n f o r m e r  w o u l d shift the equilibrium from c o n f o r m e r 4 2 a to 4 2 f .  T h e r e f o r e the minor c o n f o r m e r  421 421  w a s the o n e that controlled the hydrolysis p r o c e s s a n d not the predominant c o n f o r m e r 4 2 a . C o n s e q u e n t l y , the h y d r o l y s i s of m a c r o l i d e 42 w a s o b s e r v e d to b e faster than e x p e c t e d in c o m p a r i s o n to macrolide 25,  54  2.4  Conclusion  T h e s y n t h e s i s of 10,10-dimethyltridecanolide (42) w a s a c c o m p l i s h e d v i a a fifteen-step s e q u e n c e in 9 % overall yield.  During the synthesis, it w a s found that direct G r i g n a r d attack of  Y-butyrolactone failed to p r o d u c e the c o r r e s p o n d i n g y-hydroxy k e t o n e . s o l v e d by the u s e of sulfone chemistry.  H o w e v e r , this w a s  C o n v e r s i o n of the keto functionality into a g e m i n a l  dimethyl g r o u p in our m o l e c u l e w a s a c h i e v e d by a three-step s e q u e n c e (Wittig olefination, S i m m o n s - S m i t h reaction a n d hydrogenation). M M 2 s t u d i e s c o n f i r m e d the c o n f o r m a t i o n a l a n a l y s i s that m a c r o l i d e 1 2 s h o u l d exist predominantly  in the [3434] c o n f o r m a t i o n  4 2 a w h i c h p o s s e s s e d a p l a n a r s-trans  linkage a n d the g e m i n a l dimethyl group at a corner position. studies  a l s o r e v e a l e d the  lactone  H o w e v e r , more importantly, M M 2  e x i s t e n c e of a [3344] c o n f o r m a t i o n 1 2 1 w h i c h  evidently  was  controlling the rate of hydrolysis of macrolide 1 2 . In the b e g i n n i n g , w e restricted the conformational a n a l y s i s to the [3434] conformation. But during this project, it w a s found that the [3434] conformation w a s not sufficient to explain the hydrolysis results.  B a s e c a t a l y s e d hydrolysis of macrolides 1 2 a n d 25. a p p e a r s c o m p l e x for  detailed conformational a n a l y s i s . It c a n b e e x p e c t e d that further elaboration of the lactone ring, for e x a m p l e , introduction of additional g e m i n a l dimethyl g r o u p s , should favour the existence of only o n e conformation a n d therefore simplify conformational a n a l y s i s . O b v i o u s l y , there is m u c h work that c a n a n d s h o u l d be d o n e o n c o n s t r u c t i o n s of 14m e m b e r e d lactones with defined conformation(s) a n d on c h e m i c a l reactions of s u c h m a c r o l i d e s . Ultimately, the conformational behavior of 1 4 - m e m b e r e d l a c t o n e s c o u l d culminate in the total s y n t h e s i s of the macrolide antibiotics a n d the application of conformational control in synthetic chemistry a s a w h o l e .  55  CHAPTER THREE Experimental  General  Solvents, reagents and equipment setup. Solvents were dried as follows: diethyl ether (ether), benzene, toluene and tetrahydrofuran (THF) were distilled into a collecting reservoir by heating at reflux over sodium benzophenone ketyl radical under a dry nitrogen (N ) atmosphere. 2  Methylene chloride (CH CI ) and triethylamine (TEA) were distilled from 2  2  calcium hydride and methanol (MeOH) from magnesium methoxide.  Using an oven dried  syringe, an anhydrous solvent was removed through a stopcock fitted on the reservoir. Unless otherwise specified, all reagents were supplied by the Aldrich Chemical Company and used without further purification. Bottles of n-butyllithium (in hexanes) and diethylzinc (in toluene) were equipped with used glc gas port septa wedged between the Sure/Seal crown and the twist cap. In this way, they were stored with no significant changes in molarity for up to nine months. a-Butyllithium was standardized by titration against 2,2-diphenylacetic acid in THF at room temperature to the faintest appearance of a yellow color. Acetic anhydride and 3,4-dihydro-2H-pyran were distilled over calcium hydride.  7-  Butyrolactone, pyridine, and hexamethylphosphoramide (HMPA) were distilled under reduced pressure from calcium hydride and stored over molecular sieves (3 °A). Methylene iodide was distilled under reduced pressure and stored over tin metal. Nitrogen was supplied by Union Carbide and prior to use was passed through two columns of indicating Drierite ( C a S 0  4  impregnated with CoCI ). 2  Syringes and needles were oven-dried at 120 °C for a minimum of 3-4 hours and stored in a desiccator. Unless stated otherwise, all reactions were carried out under an atmosphere of dry nitrogen. The glassware (including the Teflon coated magnetic stirring bar) was assembled and connected to the vacuum pump and flame-dried. After the glassware had cooled, dry nitrogen was introduced to the system.  56  Cold temperatures  were  maintained  u s i n g either  a n i c e / w a t e r bath  (0 °C) o r a n  acetone/dry i c e bath (-78 ° C ) . T h e concentration or evaporation of solvents under v a c u u m refers to the u s e of a B u c h i rotary evaporator. Reaction (tic)  P e t r o l e u m ether refers to the fraction boiling b e t w e e n 3 0 - 6 0 ° C . monitoring.  A l l reactions w e r e monitored by thin layer c h r o m a t o g r a p h y  and/or gas-liquid chromatography  (glc).  A n a l y t i c a l tic w a s p e r f o r m e d o n a l u m i n u m  b a c k e d , p r e c o a t e d silica ( S i 0 ) g e l plates ( E . M e r c k , type 5 5 5 4 ) . 2  T h e plates w e r e v i s u a l i z e d  by ultraviolet f l u o r e s c e n c e or by heating the plates after s p r a y i n g t h e m with 3 M sulfuric a c i d . Analytical glc w a s performed o n a Hewlett P a c k a r d model 5 8 8 0 A g a s chromatography using a 12 m x 0.2 m m capillary C a r b o w a x c o l u m n o r a 15 m x 0.2 m m capillary D B - 2 1 0 c o l u m n . both c a s e s , flame ionization detection w a s u s e d with a helium carrier g a s .  In  All samples were  m a d e up in ether a n d injection v o l u m e s were 2 u l . Product  purification.  U n l e s s otherwise s t a t e d , all reaction products w e r e  purified  by flash c h r o m a t o g r a p h y using 2 3 0 - 4 0 0 m e s h A S T M silica g e l s u p p l i e d by E . M e r c k C o . most c a s e s , the silica g e l w a s reclaimed after c o l u m n chromatography.  In  This involved discarding  the upper 2-4 c m of silica g e l in the column a n d flushing the remaining silica g e l with methanol until c l e a n .  A h o s e c o n n e c t e d to a water aspirator w a s attached to the c o l u m n spigot a n d the  silica g e l s u c k e d to d r y n e s s (powder dry).  T h e silica g e l w a s subsequently regenerated by o v e n  heating for 6-8 hours at 120 ° C . This recycling procedure c o u l d b e r e p e a t e d 3-4 times before the silica g e l turned a yellow color whereupon it w a s d i s c a r d e d . This procedure greatly extended the general u s a g e of silica gel column chromatography. Product  characterization.  M i c h e l s o n 100 F T spectrophotometer.  Infrared (IR) s p e c t r a w e r e r e c o r d e d o n a B o m e m S a m p l e s were d i s s o l v e d in chloroform a n d the spectrum  w a s taken a n d subsequently subtracted from a spectrum of pure chloroform.  In s o m e c a s e s , a  neat s a m p l e w a s directly e m p l o y e d .  a n d abbreviations  Absorption positions are given in c m "  1  u s e d in quoting the IR b a n d s are: st=strong, m=medium, w=weak a n d br=broad.  57  Low resolution m a s s spectra were determined on a Varian M A T model C H 4 B or a KratosAEI model M S 50 spectrometer.  T h e parent p e a k a s well a s major ion fragmentations  are  reported a s p e r c e n t a g e s of the b a s e peak. Exact m a s s e s were obtained by high resolution m a s s s p e c t r o s c o p y using a K r a t o s - A E I model M S 5 0 spectrometer.  A l l instruments were operated at  7 0 ev. N u c l e a r m a g n e t i c r e s o n a n c e ( N M R ) s p e c t r a w e r e taken in deuterochloroform ( C D C I ) 3  solution with s i g n a l positions given in parts per million (ppm) from the internal s t a n d a r d of tetramethylsilane (0.00 ppm) o n the 8 s c a l e .  Proton nuclear m a g n e t i c r e s o n a n c e ( H N M R ) 1  s p e c t r a were r e c o r d e d at 3 0 0 M H z on a V a r i a n X L - 3 0 0 or at 4 0 0 M H z on a Bruker W H - 4 0 0 spectrometer  and are  reported  multiplicities).  T h e abbreviations u s e d in quoting the d a t a a r e : s=singlet, d=doublet, t=triplet,  q=quartet a n d m=multiplet.  in the  f o r m : c h e m i c a l shift  (number  of  protons,  signal  58  3.1  P r e p a r a t i o n of  10.10-Dimethvltridecanolide  9-Bromo-1-nonanol  (42)  (48)  A s u s p e n s i o n of  1,9-nonanediol  (35.1  g , 2 1 9 mmol)  prepared in an 1 L liquid-liquid continuous extractor.  in 5 0 m L of 4 8 % H B r w a s  T h e s u s p e n s i o n w a s heated to 90 °C and  w a s extracted with 4 0 0 m L of heptane at this temperature for 72 h.  T h e extract w a s c o o l e d ,  w a s h e d twice with saturated a q u e o u s sodium bicarbonate and o n c e with brine. T h e organic layer w a s dried over M g S 0  4  and concentrated under v a c u u m .  T h e crude oil w a s purified by column  chromatography using a mixture of petroleum ether : ethyl acetate (3 : 1) a s eluent to give the m o n o b r o m i n a t e d product 48_ (40.8 g , 84%) a s colorless crystals. 1  H  IR MS 178  (9),  (300 M H z , C D C I g ) 8:  NMR  (CHCI3,  cm' ): 1  3 3 3 7 (free O H , st), 1260 ( C - B r , m);  (m/e, relative intensity): 176  (9),  (58),  83  (44),  (17),  55  (100),  82 54  164  (13),  162  81  (14),  (21), (12).  3.66 ( 2 H , t), 3.42 ( 2 H , t), 1.92-1.28 ( 1 5 H , m);  206 ( (13), 70  8 1  Br: M  150 (13),  +  2  (19), 69  - H 0 , 9), 2 0 4 ( 148  (85),  (19),  68  137  (20),  67  7 9  Br: M  (32), (17),  - H 0,  9),  135  (34),  97  57  (14),  56  +  2  59  1-Bromo-9-rnetrahvdro-2H-pyran-2-ynoxy1-nonane  (49)  42  Pyridinium p-toluenesulfonate ( P P T s ) (1.50 g , 5.97 mmol) w a s a d d e d into 120 m L of dry C H C I 2  at room temperature under N .  2  9-Bromo-1 -nonanol (13.8 g , 6 1 . 9 mmol) w a s  2  d i s s o l v e d in 20 m L of dry C H C I 2  and injected. T h e mixture w a s c o o l e d to 0 °C with a n ice bath  2  a n d freshly distilled d i h y d r o p y r a n (8.17 m L , 89.6 mmol) w a s a d d e d d r o p w i s e . a d d i t i o n , the c o o l i n g bath w a s r e m o v e d a n d the temperature for 4 h.  r e a c t i o n mixture  After  w a s stirred  at  the  room  T h e mixture w a s diluted with ether, w a s h e d twice with c o l d 1N HCI and  o n c e with brine. T h e organic p h a s e w a s dried over M g S 0  4  and concentrated under v a c u u m . T h e  crude yellow oil w a s chromatographed on a silica gel column using a mixture of petroleum ether : ethyl acetate (3 : 1) to give the desired product 4 J . (17.3 g , 91%) a s a c o l o r l e s s oil. 1  H  (300 M H z , C D C I g ) 8:  NMR  4.60 ( 1 H , t), 3 . 9 4 - 3 . 3 6 ( 6 H , m), 1.92-1.26  (20H,  m); IR MS (100),  84  (38),  40  (cm" ):  (m/e, relative intensity): (10), (13),  Exact C  1  4  H  2  6  1 2 6 0 ( C - B r , m), 1 1 2 8 ( C - O , m);  1  79Br0  83 32  mass 2  (13), (27),  69 29  (22), (20),  c a l c . for C  : 305.1117;  307 (  1  4  67 28  H  Br:  (12),  57  M  +  - 1, 7), 3 0 5 (  (21),  56  (28),  7 9  55  Br:  M  (34),  +  - 1, 9), 85  43  (18),  41  (27); 8  2  8 1  6  1  Br0  Found: 305.1115.  2  : 307.1097;  F o u n d : 3 0 7 . 1 1 0 7 ; c a l c . for  60  1-Phenvlsulfonvl-9-f(tetrahvdro-2H-pvran-2-yhoxy1-nonane  (661  OTHP  A 0.1 M a q u e o u s solution of s o d i u m benzenesulfinate w a s slowly p e r c o l a t e d through a c o l u m n filled with Amberlyst A - 2 6 ( R o h m a n d H a a s ) in the chloride form until a negative test for chloride ion in the eluate w a s o b t a i n e d .  T h e resin w a s s u c c e s s i v e l y w a s h e d with water,  acetone,  at  ether  and dried  benzenesulfinate form.  under  vacuum  50  This resin (47.5 g , 158 meq.) w a s a d d e d into a solution of bromide 4 3  (40.5 g , 132 mmol) in 3 0 0 m L of dry b e n z e n e . for 48 h.  °C for 5 h to g i v e A m b e r l y s t A - 2 6 in  T h e mixture w a s vigorously stirred at reflux  T h e resin w a s filtered and w a s h e d with C H C I . 2  T h e filtrate w a s concentrated under  2  v a c u u m a n d the c r u d e oil w a s c h r o m a t o g r a p h e d on a s i l i c a g e l c o l u m n using a mixture of petroleum ether : ethyl acetate (4 : i ) a s eluent to recover bromide 4 £ (3.80 g , 8.4%) and to give sulfone 6JL (41.3 g, 94%) a s a light yellow oil. 1  H  3.92-3.04  N M R (300 (6H,  m),  M H z , CDCI3) 8 :  1.90-1.20  (20H,  7.92  ( 2 H , d), 7 . 7 0 - 7 . 5 2 ( 3 H , m), 4 . 5 8 ( 1 H , t),  m);  IR ( c m - ) :  3 0 6 2 (phenyl C - H , w), 1310 ( S = 0 ,  MS  relative  1  (m/e,  intensity):  368  st);  ( M , 2), 3 6 7 +  (M  (40),  284  (13),  283  (43),  268  (12),  267  (51),  255  (23),  (12),  143  (56),  125  (37),  124  (14),  101  (38),  100  (10),  (24),  69  (17),  56  (47),  67  (13),  57  Exact mass c a l c . for C  2  0  H  3  2  (10),  55  - 1, 7), 3 3 9 (13), 254(11), 85  251  (100),  (36).  S O : 368.2023; 4  +  Found: 368.2017.  84  (20), (19),  285 239 83  61  1-Hvdroxv-5-phenvlsulfonvl-13-rrtetrahydro-2H-pvran-2-vl\oxv1-tridecan-4-one  um PhS0  2  0  62 a-Butyllithium (6.8 m L , 11 mmol) w a s injected at 0 °C into a well-stirred solution of sulfone 6j6_ (2.0 g , 5.4 mmol) in 60 m L of dry T H F under N .  After stirring for 3 0 minutes the  2  reaction  was  c o o l e d to  -78  °C  a n d freshly  distilled  butyrolactone (0.44 m L , 5.4 mmol) were a d d e d . warm to room temperature. acetate (3 x 30 mL).  HMPA  (0.6  m L , 3 mmol)  and  y-  T h e mixture w a s stirred for 3 h a n d allowed to  It w a s then q u e n c h e d with a q u e o u s N H C I a n d extracted with ethyl 4  T h e organic layers were c o m b i n e d , w a s h e d twice with saturated a q u e o u s  cupric sulfate a n d o n c e with brine, dried over M g S 0  and evaporated under v a c u u m . T h e crude  4  product w a s c h r o m a t o g r a p h e d on a silica gel c o l u m n using a mixture of petroleum ether : ethyl acetate (1 : 1) a s eluent to give the y-hydroxy keto c o m p o u n d £ Z (1.64 g , 81%) as a yellow oil. 1  H  4.18-4.08 IR  NMR  (300  ( 1 H , m),  3.92-3.32  (cm' ):  3556-3328  1  st), 1 3 1 0 ( S = 0 MS  M H z , CDCIg) 8:  7.80  ( 6 H , m),  ( 2 H , d), 7 . 7 4 - 7 . 5 4  3.10-2.66  ( 2 H , m),  ( H - b o n d e d O H , br), 3 0 6 2  ( 3 H , m), 4 . 5 8 ( 1 H , t),  1.92-1.14  (phenyl  (21H,  C - H , w),  m);  1718  (C=0,  st);  (m/e, relative intensity):  367 ( M  - C  +  4  H  7  0  2  ,  2 3 ) , 3 5 3 (16), 3 5 2 (17),  351  (18),  350  (17),  340  (11),  339  (45),  313  (33),  309  (12),  285  (14),  283  (17),  267  (21) ,  211  (11),  144  (14),  143  (51),  142  (20),  126  (21),  211  (11),  144  (14),  143  (51),  142  (20),  126  (21),  125  (100),  (15),  95  (12),  86(50),  (22) , 7 7  (37),  71  (86),  (14),  43  54  (14), (56),  85 70 42  (49), (13), (57),  84 69 41  124  (73), (53), (83),  (45), 83 68  39  101  (85), (18), (17).  (58),  82 67  100  (30),  97  (21),  96  (18),  81  (22),  79  (12),  78  (47),  57  (63),  56  (53),  55  62  1-Hvdroxv-13-metrahvdro-2H-pyran-2-ynoxy]-tridecan-4-one  (M)  PhS02 OTHP  OTHP  O  O  sa  A l u m i n u m foil (813 m g , 0.15 mmol) w a s cut into strips approximately 5 c m x 0.5 c m and i m m e r s e d into a 2 % a q u e o u s mercuric chloride solution for 15-25 s e c o n d s .  T h e aluminum  strips were rinsed with methanol and ether, cut into p i e c e s approximately 0.5 c m  2  and a d d e d  immediately to a solution of sulfone QI (909 m g , 2.01 mmol) in 60 m L of 1 0 % a q u e o u s T H F . T h e mixture w a s stirred at reflux for 8 h, c o o l e d a n d filtered. T h e solid p h a s e w a s w a s h e d with T H F and the filtrate evaporated under v a c u u m to remove most of the solvent. extracted with ether (3 x 20 m L ) . concentrated under v a c u u m .  T h e residue w a s  T h e c o m b i n e d organic layers w e r e dried over M g S 0  4  and  Purification of the crude product by c o l u m n chromatography using  a mixture of petroleum ether : ethyl acetate (1 : 1) a s eluent g a v e c o m p o u n d 6JL (495 m g , 79%) a s a light yellow o i l . 1  (2H,  H  t), IR  NMR  1.90-1.22 (cm ): - 1  MS 95  (13),  (60),  43  (300 M H z , C D C I g ) 8: (21H,  (100),  (19),  41  m);  3441 (free O H , st), 1710 ( C = 0 , st);  ( m / e , relative 85  4 . 5 8 ( 1 H , t), 3 . 9 2 - 3 . 3 2 ( 6 H , m), 2 . 5 8 ( 2 H , t), 2.44  84  intensity):  (49),  (25).  81  (14),  296 71  (M  +  (13),  - H 0, 2  69  18), 211  (18),  67  (21),  (22),  57  101  (16), 97  (13), 5 6  (15),  (88), 55  63  4-f9-(Tetrahvdro-2H-pvran-2-vnoxynonyll-pent-4-ene-1-ol  liO^^^^^^^^^^^^^^ O  a-Butyllithium temperature  under  OTHP  (92)  HO^* -^ H ' V  S  X  , N /  ^^  1  22 (3.13 m L , 5 . 0 mmol) w a s injected into 5 0 m L of dry ether at room  N  2  .  Triphenylmethylphosphonium  bromide  ( 1 . 7 9 g , 5 . 0 mmol) w a s  cautiously a d d e d in portions a n d the resulting o r a n g e solution w a s stirred vigorously at room temperature for 4 h. T h e keto c o m p o u n d £ £ (628 m g , 2 . 0 mmol) w a s d i s s o l v e d in 15 m L of dry ether and a d d e d dropwise to the reaction v i a a n addition funnel, upon which the orange color d i s c h a r g e d a n d a white precipitate formed. a n d filtered.  T h e mixture w a s stirred at reflux for 8 0 h, c o o l e d  T h e ether filtrate w a s w a s h e d with 1 N HCI a n d brine, dried o v e r M g S 0 a n d 4  concentrated under v a c u u m . T h e crude oil w a s chromatographed o n a silica g e l column using a mixture of petroleum ether : ethyl acetate (6 : 1) a s eluent to give the a l k e n e c o m p o u n d £ 2 (499 m g , 80%) a s a light yellow o i l . 1  2.12  H  NMR  ( 2 H , t), 2 . 0 4 ( 2 H , t), 1.90-1.22 IR ( c m ' ) : 1  MS 101  ( 3 0 0 M H z , CDCI3) 8:  4 . 7 4 ( 2 H , s ) , 4 . 5 8 ( 1 H , t), 3 . 9 2 - 3 . 3 2 ( 6 H , m ) ,  (21H, m);  3536-3252 (H-bonded O H , br), 3076 (=C-H, w), 1644 ( C = C , m);  ( m / e , relative  intensity):  311 ( M - 1, 3 ) , 2 1 0 ( M +  +  -THPOH,  7), 109  (48), 97 (20), 96 (10), 95 (38), 86 (22), 85 (70), 84 (53), 83 (37), 82  81  (40), 6 9 (68), 68 (24), 6 7 (81), 5 7 (50), 5 6 (51), 5 5 (100),  41  (87), 39  (23);  4 3 (55), 42  (15), (27), (13),  64  2-[(3-Acetoxv)-propvn-11-rnetrahvdro-2H-pyran-2-ynoxv1-undec-1-ene  ££3_)  £2 F r e s h l y distilled a c e t i c a n h y d r i d e (0.99 m L , 10 mmol) mmol) w e r e injected into 125 m L pi  a n d pyridine  a n h y d r o u s ether at room t e m p e r a t u r e  catalytic amount of 4-dimethylaminopyridine ( D M A P ) w a s a d d e d .  (0.85 m L , 10 under N . 2  A  T h e a l c o h o l SZ (2.18 g , 7.0  mmol) w a s d i s s o l v e d in 2 0 m L of dry ether a n d a d d e d dropwise to the mixture v i a a n addition funnel.  T h e reaction w a s stirred at room temperature for 4 h.  ether a n d w a s h e d three times with brine. concentrated under v a c u u m .  T h e mixture w a s diluted with  T h e o r g a n i c p h a s e w a s dried o v e r M g S 0  4  and  Purification of the crude product by c o l u m n chromatography using  a mixture of petroleum ether : ethyl acetate (3 : 1) a s eluent g a v e the acylated c o m p o u n d SZ (2.41 g , 94%) a s a yellow o i l . 1  (4H,  H  m),  (300 M H z , CDCI3) 8:  NMR  2.12-1.98  IR ( c m ) : (m/e, (13),  1.90-1.22  (20H,  m);  3 0 7 6 ( = C - H , w), 1 7 4 3 ( C = 0 , st), 1646 ( C = C , m);  - 1  MS  ( 7 H , m),  4.74 ( 2 H , d), 4 . 5 8 ( 1 H , t), 4 . 0 8 ( 2 H , t), 3.92-3.34  relative 111  intensity):  (15),  121  (18),  96  (22),  95  (62),  94  (54),  80  (13),  79  (27),  (26),  53  (21),  42  (88),  Exact mass  (10),  110  354  ( M , 4), 3 5 3 +  (15),  109  (21),  (13),  93  (21),  85  69  (42),  68  (30),  41  (67);  c a l c . for C 2 i H  3  8  67  (16),  - H , 3), 2 1 0 (18),  +  107  (10),  123  101  (17),  97  (79),  84  (39),  83  (39),  82  (88),  81  (100),  57  (24),  56  (37),  55  (90),  54  0 : 354.2771; 4  108  (M  Found: 354.2769.  65  10-f(3-Acetoxyl-propvn-undec-10-ene-1-ol  (98)  T h e T H P ether 23. (4.17, 11.8 mmol) w a s d i s s o l v e d in 30 m L of dry M e O H a n d injected into 120 m L of dry M e O H at room temperature under N .  Pyridinium p-toluenesulfonate  (306  m g , 1.18 mmol) w a s a d d e d a n d the mixture w a s stirred at room temperature for 4 8 h.  The  2  solvent w a s e v a p o r a t e d under v a c u u m a n d the r e s i d u e w a s taken up in ether, w a s h e d with s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e , dried over M g S 0  4  a n d c o n c e n t r a t e d under v a c u u m .  Purification of the crude product by column chromatography using a mixture of petroleum ether : ethyl acetate (3 : 1) a s eluent g a v e the alcohol 2fi (2.85 g, 90%) a s a c o l o r l e s s oil. 1  (7H,  H  m), IR  NMR  1.86-1.22  (17H,  (cm" ):  3534-3220  1  1646 (C=C, MS 109 69  (12), (23),  (300 M H z , C D C I g ) 8: m);  ( H - b o n d e d , O H , br),  3076  (=C-H,  w),  1743  (C=0,  st),  m); (m/e, relative  108 68  4.74 ( 2 H , d), 4.08 ( 2 H , t), 3.64 ( 2 H , t), 2.12-1.98  (11),  (19),  67  97  intensity): (10),  (92),  57  96  252 ( M (13),  (10),  56  95  +  - H 0 , 7), 2 1 0 ( M 2  (51),  (14),  55  83  (18),  (32),  43  82  +  - A c O H , 4), 110  (100),  (42),  41  81  (18),  (22).  79  (10), (12),  66  2-[(3-Acetoxy^propyl1-11-tert-butyldimethvlsiloxvundec-1-ene  To 40 mL of dry C H C I 2  2  (100)  at room temperature was added successively the alcohol 9_Q.  (540 mg, 2.0 mmol) in 5 mL of dry C H C I , triethylamine (0.56 mL, 4.0 mmol), DMAP (49 2  2  mg, 0.4 mmol) and tert-butyldimethylsilyl chloride (452 mg, 3.0 mmol) under N . 2  The  mixture was vigorously stirred at room temperature for 4 h, quenched with 1N HCI and extracted with ether. The organic layer was washed with saturated aqueous bicarbonate, brine, dried over M g S 0 and concentrated under vacuum. The crude product was purified by column 4  chromatography using a mixture of petroleum ether : ethyl acetate (6 : 1) as eluent to give the protected TBDMS ether 1Q0_ (730 mg, 95%) as a yellow oil. 1  H  NMR  (300 MHz,  CDCI3) 8:  4.74 (2H, d), 4.08 (2H, t), 3.60 (2H, t), 2.12-1.98  (7H, m), 1.84-1.22 (16H, m), 0.90 (9H, s), 0.06 (6H, s); IR (cm" ): 1  MS  3076 (=C-H, w), 1743 (C=0, st), 1646 (C=C, m), 1100 (Si-O, st);  (m/e, relative intensity):  327 ( M  +  - C H , 23), 118 (10), 117 (100), 109 4  9  (13), 95 (20), 83 (12), 81 (22), 75 (37), 73 (11), 69 (20), 67 (21), 55 (22), 43 (18), 41  (14).  67  1-ff3-Acetoxy)-propvl|-1-f(9-tert-butyldimethvlsMoxyl-nonyn-cyclopropane  AcO^—~Y^^—^^OTBDMS  (101)  A c O ^ ^ ^ r ^ ^ ^ ^  101 To a well-stirred, heated (55 °C) solution of the alkene 1Q0_ (450 mg, 0.96 mmol) in 20 mL of dry toluene was injected a solution of diethyl zinc (Et Zn) in toluene (1.75 mL, 1.92 2  mmol) and freshly distilled methylene iodide (CH I ) (0.30 mL, 3.8 mmol) under N . 2  2  2  mixture was stirred at 55 °C for 22 h. A further injection of C H I 2  2  The  (0.15 mL, 1.9 mmol) and  E t Z n (0.88 mL in toluene, 0.96 mmol) followed by 11 hours of stirring was still not 2  sufficient to complete the reaction. Two further additions of C H I 2  2  (0.15 mL, 1.9 mmol) and  E t Z n (0.88 mL, 0.96 mmol) and a further stirring for 20 h completed the reaction. 2  The  mixture was cooled to room temperature and quenched with 10 mL of 1N HCI. The layers were separated and the aqueous layer extracted with ether. The combined organic phases were washed with 1N HCI, brine, dried over M g S 0  4  and concentrated under vacuum.  Purification of the  crude product by column chromatography using a mixture of petroleum ether : ethyl acetate (9 : 1) gave the cyclopropyl compound 1QJ_ (410 mg, 88%) as a yellow oil. 1  H  NMR  (300 MHz, CDCIg) 8:  4.08 (2H, t), 3.60 (2H, t), 2.06 (3H, s), 1.74-1.22  (20H, m), 0.90 (9H, s), 0.22 (4H, d), 0.06 (6H, s); IR MS  (cm ): -1  3065 (cyclopropyl C-H, w), 1743 (C=0, st), 1100 (Si-O, st);  (m/e, relative intensity):  341 ( M  +  - C H , 4  9  23), 118 (10), 117 (100), 109  (13), 95 (20), 83 (12), 81 (22), 75 (37), 73 (11), 69 (19), 67 (19), 55 (20), 43 (13), 41  (10).  68  1-Acetoxy-4.4-dimethyl-13-tert-butyldimethylsiloxytridecane  (1 0 2 )  OTBDMS  T o a solution of the cyclopropyl c o m p o u n d 101 (580 m g , 1.46 mmol) in 5 m L of glacial acetic acid was added P t 0  2  (99 mg).  a t m o s p h e r e (3.5 atm.) for 24 h.  T h e resultant s u s p e n s i o n w a s stirred under an H  S a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e w a s a d d e d to the  mixture with stirring until it b e c a m e b a s i c . ether (4 x 2 0 m L ) .  2  T h e resultant a q u e o u s slurry w a s extracted with  T h e c o m b i n e d ether extracts w e r e w a s h e d with brine, dried over  MgS0  4  a n d concentrated under v a c u u m . T h e crude product w a s chromatographed on a silica gel column using a mixture of petroleum ether : ethyl acetate (9 : 1) a s eluent to give the hydrogenation product 1Q2. (110 mg) a s a yellow oil a n d the dimethyl alcohol 1 0 3 (218 mg) a s a c o l o r l e s s oil. T h e hydrogenation reaction yield w a s 7 9 % b a s e d o n the yield of the next reaction. 1  H  NMR (300 M H z , CDCI3) 8 :  4.04 ( 2 H , t), 3.60 ( 2 H , t), 2.06 ( 3 H , s ) , 1.60-1.16  ( 2 0 H , m), 0.90 ( 9 H , s), 0.84 ( 6 H , s), 0.06 ( 6 H , s ) ; IR  (cm' ): (m/e,  MS (10), 73  255  (11),  1 7 4 3 ( C = 0 , st), 1 1 0 0 ( S i - O , st);  1  (11), 71  relative 135  (11),  69  (18), (31),  intensity): 118 57  (10),  343 117  (13), 5 5  (M  +  - C  (100),  (23), 4 3  4  H  9  111 (13).  ,  48),  (16),  97  300  (10),  (25),  83  299 (43),  (35),  283  75  (27),  69  13-Acetoxy-10.10-dimethvltridecan-1-ol  M03)  The T B D M S ether 1Q£ (220 mg, 0.55 mmol) was dissolved in 5 mL of dry MeOH and injected into 20 mL of MeOH at room temperature under N . 2  PPTs (15.6 mg, 0.06 mmol) was  added and the mixture was stirred at room temperature for 24 h. The solvent was evaporated under vacuum and the residue was taken up in ether, washed twice with saturated aqueous sodium bicarbonate and once with brine. concentrated under vacuum.  The organic phase was dried over M g S 0  4  and  Purification of the crude product by column chromatography using  a mixture of petroleum ether : ethyl acetate (3 : 1) as eluent gave alcohol 103 (136 mg, 87%) as a colorless oil. 1  H  (300 MHz, CDCIg) 8:  NMR  4.04 (2H, t), 3.64 (2H, t), 2.06 (3H, s), 1.62-1.14  (21H, m), 0.84 (6H, s); IR ( c m ) : -1  MS (18), 111 (71),  82  3560-3204 (H-bonded, OH, br), 1743 (C=0,  (m/e, relative intensity): (28), 109 (28),  81  (18), t5 (100), 43  (16), 101 (23),  268  (M  +  - H 0, 2  st);  0.2), 226  (M  +  - A c O H , 5), 211  (14), 97 (43), 96 (11), 95 (22), 85 (16), 84 (20),  71  (18), 70  (13),  (56), 42  (11), 41  (32).  69  (70),  67  (21),  61  (29), 57  (29),  83 56  70  13-Acetoxy-10.10-dimethyltridecanoic  acid  M041  O  104 A l c o h o l 1 0 3 (270 m g , 0.94 mmol) w a s d i s s o l v e d in 5 m L of acetone and c o o l e d to 0 °C with a n ice bath. J o n e s reagent w a s a d d e d dropwise v i a a small syringe under N solution stayed dark-brown (like the J o n e s reagent itself). 20 minutes.  2  until the  T h e mixture w a s stirred at 0 °C for  2 - P r o p a n o l w a s a d d e d slowly until the solution b e c a m e c l e a r with a  precipitate being f o r m e d .  T h e solid w a s filtered a n d w a s h e d with a c e t o n e .  blue  T h e filtrate w a s  concentrated under v a c u u m and the residue taken up in ether. A q u e o u s 1 5 % N a O H w a s a d d e d and the layers s e p a r a t e d . T h e a q u e o u s p h a s e w a s acidified with 1N HCI a n d extracted with E t O A c . T h e c o m b i n e d o r g a n i c p h a s e s w e r e dried o v e r M g S 0  4  and concentrated under v a c u u m .  Purification of the c r u d e product by c o l u m n c h r o m a t o g r a p h y  using a mixture of  petroleum  ether : ethyl acetate ( 3 : 1 ) a n d approximately 1% acetic a c i d a s eluent g a v e acid 104 (105 m g , 77%) a s a c o l o r l e s s o i l . 1  H  (300  NMR  ( 1 9 H , m), 0.84  181  (10),  55  (m/e, (10), (37),  4.04 ( 2 H , t), 2.36 ( 2 H , t), 2.06 ( 3 H , s ) .  1.68-1.14  3 4 8 0 - 3 0 1 4 (acid O H , br), 1 7 4 3 (ester C = 0 , st), 1712 (acid C = 0 , st);  1  (12),  3  (6H, s);  IR ( c m " ) : MS  M H z , C D C I ) S:  relative 97  43  (12), (28),  intensity): 84 41  (12), (16).  240 83  (M  (100),  +  82  - AcOH, (11),  69  3), 2 2 5 (18),  (13), 61  212  (13),  57  (34), (12),  199 56  71  10.10-Dimethvl-13-hydroxvthdecanoic  acid  M05)  A c e t a t e 1 0 4 (100 m g , 0.33 mmol) w a s d i s s o l v e d in 5 m L of dry M e O H . p o t a s s i u m carbonate (101 m g , 0.73 mmol) w a s a d d e d under N  2  Pulverized  and the mixture w a s vigorously  stirred at room temperature for 5 h. T h e solvent w a s evaporated under v a c u u m a n d the residue w a s taken up in ether, w a s h e d twice with 1N HCI a n d o n c e with brine. dried over M g S 0  T h e organic p h a s e w a s  a n d concentrated under v a c u u m to give the c l e a n co-hydroxy a c i d 1 0 5 (84  4  m g , 98%) which w a s carried directly to the next reaction. 1  0.84  H  (300  NMR  MS  (71),  3.62 ( 2 H , t), 2.36 ( 2 H , t), 1.68-1.14  ( 2 0 H , m),  3 5 6 4 - 3 0 1 4 (alcohol O H , a c i d O H , br), 1 7 1 2 (acid C = 0 , st);  1  (100),  4  (6H, s); IR ( c n r ) :  125  M H z , C D C I ) 8:  (10), 82 43  (m/e, relative 111  (12),  (10),  81  (33),  41  intensity):  101 (28),  (31).  (30), 71  99  (17),  240 ( M (10), 70  (10),  - H 0,  +  2  97 69  (22), (37),  1), 199 (12),  181  95  (10),  67  (10), (11),  85 57  (17),  (26),  163  (13),  84  (12),  83  56  (18),  55  72  10.10-Dimethyltridecanolide  (42)  1-Phenyl-2-tetrazoline-5-thione  (71  mg,  0.40  mmol)  and  tert-butylisocyanide  (0.05 m L , 0.4 mmol) were a d d e d to 3 m L of dry toluene at room temperature under N . 2  After  10 minutes of stirring the h o m o g e n e o u s solution w a s a d d e d to a solution of the hydroxy acid 10J*. (80 m g , 0.31 mmol) in 6 m L of dry toluene under N . 2  T h e mixture w a s diluted with 60 m L of  dry toluene a n d stirred at reflux for 4 h. T h e mixture w a s c o o l e d , evaporated under v a c u u m to a v o l u m e of approximately 4 m L .  This c o n c e n t r a t e d solution w a s filtered through a short silica  gel c o l u m n using b e n z e n e a s eluent to give macrolide 4 2 (49 mg, 66%) a s a light yellow solid. T h e dimer by-product (12 m g , 20%) w a s also isolated, which could b e hydrolyzed b a c k to acid 105. 1  H  N M R (400 M H z , CDCI3.) 5:  4 . 2 2 - 4 . 1 4 ( 2 H , m), 2 . 4 4 - 2 . 3 6 ( 2 H , m),  1.74-1.12  ( 1 8 H , m), 0.84 ( 6 H , s ) ; IR ( c m ) :  1718 ( C = 0 ,  - 1  MS (13),  83  (m/e, relative (100),  82  Exact mass  (22),  st);  intensity): 69  c a l c . for C  (22), 1  5  H  2  240 67  8  ( M , 11), 2 2 5 ( M  (10),  +  56  (13),  0 : 240.2090; 2  55  +  (43),  - C H , 14), 2 1 2 (47), 3  43  Found: 240.2085.  (10),  41  (20);  84  73  3.2  P r e p a r a t i o n of n-Octyl P e n t a n o a t e M 0 9 )  109 T o a well-stirred, ice c o o l e d solution of 1-octanol (390 m g , 3.0 mmol) a n d valeric acid (367  mg,  3.6  mmol)  in  30  mL  of  dry  CH CI 2  was  2  added  dicyclohexylcarbodiimide ( D C C ) (655 m g , 3.2 mmol) in 5 m L of C H C I 2  of D M A P .  T h e mixture w a s stirred at room temperature overnight.  s u c t i o n filtration.  T h e filtrate w a s diluted with C H C I 2  s a t u r a t e d s o d i u m b i c a r b o n a t e a n d brine. c o n c e n t r a t e d under v a c u u m .  2  slowly  a  solution  of  a n d a catalytic amount  2  T h e urea w a s filtered off by  a n d w a s h e d twice with 1 N H C I ,  The organic phase w a s dried over M g S 0  4  and  T h e crude oil w a s purified by c o l u m n c h r o m a t o g r a p h y using a  mixture of petroleum ether : ethyl acetate (6 : 1) a s eluent to give ester 1 0 9 (604 m g , 94%) a s a colorless oil. 1  H  (400 M H z , C D C I ) 8:  NMR  IR ( c m " ) : 1  MS  (m/e,  (40),  103  (100),  (10),  57  (97),  4 . 2 5 ( 2 H , t), 2.50 ( 2 H , t), 1.85-1.05 ( 2 2 H , m);  3  56  1 7 2 2 ( C = 0 , st), 1 1 7 3 ( C - O , m); relative 85  intensity):  (87),  (51),  55  84  (41),  (43),  214 83  44  ( M , 4), +  (38),  (13),  43  71  3  2  2  (23),  (53),  E x a c t m a s s c a l c . for C - ) H g 0 : 2 1 4 . 1 9 3 4 ;  172  42  (7),  70  158  (56),  (27),  41  (12),  69  (30),  (62),  Found: 214.1934.  157  39  61  (22), (13),  (13);  112 60  74 3.3  P r e p a r a t i o n of tridecanolide  (35)  15 Trifluoroacetic anhydride (0.68 m L , 4.8 mmol) w a s a d d e d slowly to a solution of 9 0 % hydrogen peroxide (0.14 m L , 4.0 mmol) in 4 m L of C H C I 2  stirred  at  0 °C  for  25  min  and  at  room  2  at 0 °C under N . T h e solution w a s 2  temperature  for  10  min.  The  resulting  peroxytrifluoroacetic a c i d w a s a d d e d slowly to a well-stirred mixture of c y c l o t r i d e c a n o n e (393 m g , 2.0 mmol) a n d d i s o d i u m h y d r o g e n p h o s p h a t e in 3 0 m L of C H C I 2  a d d i t i o n , the  mixture  w a s stirred  at reflux  temperature a n d p o u r e d into water.  for 2 h.  T h e mixture  2  at 0 °C.  After the  w a s c o o l e d to  room  T h e o r g a n i c layer w a s w a s h e d with saturated a q u e o u s  sodium bicarbonate, brine, dried over M g S 0  4  and concentrated under v a c u u m . T h e crude oil w a s  purified by c o l u m n c h r o m a t o g r a p h y using toluene a s eluent to g i v e m a c r o l i d e 3JL (246 m g , 63%) a s a colorless o i l . 1  H  (400 M H z , C D C I ) 5:  NMR  IR ( c m ) :  1 7 2 0 ( C = 0 , st), 1144 ( C - O , m);  - 1  MS  4.35 ( 2 H , m), 2.58 ( 2 H , m), 1.90-1.40 ( 2 0 H , m);  3  (m/e,  (15),  110  (21),  (22),  73  (16),  (28),  55  (100),  relative 98  71 54  (33), (13), (13),  intensity): 97  (30),  212 96  (M ,  (34),  +  12), 1 9 4 (14),  95  (31),  83  (42),  82  (41),  81  67  (27),  60  (10),  57  (18),  56  69  (58),  68  (32),  43  (32),  42  (21),  41  (59);  3  H  2  4  0 : 212.1777; 2  111  84  (22),  1  169 (8),  (17),  70  E x a c t m a s s c a l c . for C  176 (11),  Found: 212.1775.  75  3.4  H y d r o l y s i s of 10.10-Dimethvrtridecanolide Pentanoate  (42).  T r i d e c a n o l i d e (35)  and  n-Octvl  hOQ)  M a c r o l i d e 42. (5 m g , 0.02 mmol), macrolide 2 5 (4 m g , 0.02 mmol), ester 1 0 9 (7 m g , 0.03 mmol) a n d d o d e c a n e (3 m g , 0.02 mmol) w e r e d i s s o l v e d in 1 m L of M e O H .  Pulverized  p o t a s s i u m c a r b o n a t e (20 m g , 0.15 mmol) w a s a d d e d a n d the mixture w a s stirred at room temperature.  T h e reaction w a s monitored by g a s - l i q u i d c h r o m a t o g r a p h y (glc).  T h e relative  intensities of the hydrolysis c o m p o u n d s to the d o d e c a n e internal standard were recorded.  The  hydrolysis reaction w a s a l s o c a r r i e d out at 0 °C a n d -20 °C u n d e r the s a m e p r o c e d u r e a s described a b o v e .  REFERENCES  (1)  B r o c k m a n n , H . a n d H e n k e l , W . , Naturwissenschaften,  1 9 5 0 , 2 Z . 138.  (2)  Djerassi, C . a n d Zderic, J . A . , J. Am. Chem. Soc, 1 9 5 6 , ZS., 6390.  (3)  W i l e y , P . F . , G e r z o n , K . , S i g a l , M . V . , W e a v e r , 0., Q u a r c k , U . C . , C h a u v e t t e ,  R.R. and  M o n a h a n , R., J. Am. Chem. Soc, 1 9 5 7 , ZS, 6062. (4)  Wiley, P . F . , S i g a l , M . V . , W e a v e r , O . , M o n a h a n , R. a n d G e r z o n , K., J. Am. Chem. Soc,  1 9 5 7 , 7_9_, 6070. (5) (6)  W o o d w a r d , R . B . , Angew.  (a) K e l l e r - S c h i e r l e i n , W . , Fortschr.  T . G . , Tetrahedron, (7)  Chem., 1 9 5 7 , 55, 50. Chem.  Org. Naturstoffe,  1 9 7 3 , 3JL 313; (b) B a c k ,  1 9 7 7 , 3J1, 3041; (c) N i c o l a o u , K . C . , Tetrahedron,  1 9 7 7 , 3JL 683.  M a s a m u n e , S . , B a t e s , G . S . a n d C o r c o r a n , J . W . , Angew. Chem. Int. Ed. Engl., 1 9 7 7 . 16.  585. (8)  Dale, J . , J. Chem. Soc, 1 9 6 3 , 93.  (9)  C e l m e r , W . D . , Antimicrob.  Agents  Chemother., 1 9 6 5 , 144.  (10) E g a n , R . S . , P e r u n , T . J . , Martin, J . R . a n d Mitscher, L A . , Tetrahedron, (11) Harris, D . R . , M c G e a c h i n , S . G . a n d Mills, H . H . , Tetrahedron (12) (a) M a r s h a l l , J . A . , Synthesis,  1 9 7 3 , £9., 2 5 2 5 .  Lett., 1 9 6 5 , 679.  1 9 7 1 , 229; (b) G r o b , C . A . , Angew.  Chem. Int. Ed. Engl.,  1 9 6 7 , 5 , 1; (c) Felix, D., S c h r e i b e r , J . , Ohloff, G . a n d E s c h e h m o s e r , A . , Helv. Chim.  Acta,  1 9 7 1 , 5 4 . , 2896. (13) B e r g e l s o n , L . D . , Molotkovsky, J . G . a n d S h e m y a k i n , M . M . , Chem. and Ind., 1 9 6 0 , 5 5 8 . (14) Carnduff, J . , Eglinton, G . , M c C r a e , W . a n d R a p h a e l , R . A . , Chem. and Ind., 1 9 6 0 , 559. (15) (a) C o r e y , E . J . a n d H a m a n a k a , E . , J. Am. Chem. Soc, 1 9 6 4 , £5, 1641; (b) C o r e y , E . J . and Semmelhack, Tetrahedron  M . F . , Tetrahedron  Lett., 1 9 6 6 , 6237; (c) C o r e y , E . J . a n d Helquist, P . ,  Lett, 1 9 7 5 , 4091.  (16) D a u b e n , W . G . , B e a s l e y , G . H . , Broadhurst, M . D . , Muller, B., P e p p a r d , D . J . , P e s n e l l e , S . a n d Suter, C , J. Am. Chem. Soc, 1 9 7 5 , 31, 4973.  77  (17) C r o m b i e , L , K n e e n , G . a n d Pattenden, G . , J. Chem. Soc Chem. Commun., 1976, 6 6 . (18) C o r e y , E . J . a n d P e t r z i l k a , M . , Tetrahedron  Lett., 1975, 2 5 3 7 .  1973,28.,  3 9 0 ; (b) H u r d , B . N . a n d S h a h ,  1934,12,  1 2 8 3 ; (b) Stoll, M . a n d R o u v e ,  (19) (a) H u r d , B . N . a n d S h a h , D . H . , J. Org. Chem., D.H.,  J. Med. Chem.,  1973,11,  543.  (20) (a) Stoll, M . a n d R o u v e , A . , Helv. Chim. Acta, A., Helv. Chim. Acta,  1935,11,  1087.  (21) P e t e r s , C A . a n d H u r d , R . N . , J. Med. Chem.,  1975,11,  215.  (22) K u r i h a r a , T., N a k a j i m a , Y . a n d M i t s u n o b u , 0., Tetrahedron  Lett., 1976, 2 4 5 5 .  (23) F u k u y a m a , Y . , K i r k e m o , C L a n d White, J . D . , J. Am. Chem. Soc, (24) (a) C o r e y , E . J . a n d N i c o l a o u , K . C , J. Am. Chem. Soc,  1977,21,  1974,21,  646.  5 6 1 4 ; (b) C o r e y , E . J . ,  T r y b u l s k i , E . J . , M e l v i n , L . S . , N i c o l a o u , K . C , S e c r i s t , J . A . , Lett, R., S h e l d r a k e , P . W . , F a l c k , J.R.,  B r u n e l l e , D . J . , H a s l a h g e r , M . F . , K i m , S . a n d Y o o , S . , J. Am. Chem. Soc, 1978. 1 0 0 .  4 6 1 8 ; (c) C o r e y , E . J . , K i m , S . , Y o o , S . , N i c o l a o u , K . C , M e l v i n , L . S . , B r u n e l l e , D . J . , F a l c k , J . R . , Trybulski, E . J . , Lett, R. a n d S h e l d r a k e , P . W . , J. Am. Chem. Soc, (25) (a) M u k a i y a m a , T., Synthetic  1972,2,  Comm.,  1978,111,  4620.  2 4 3 ; (b) M u k a i y a m a , T., Angew.  Chem.  Int. Ed. Engl., 1976, H , 9 4 . (26) (a) G e r l a c h , H . a n d T h a l m a n n , A . , Helv. Chim. Acta, K u n z l e r , P . , Helv. Chim. Acta, 1978, H ,  1974,51, 2 9 3 ; (b)  2503.  (27) Schmidt, U . a n d Dietsche, M . , Angew. Chem. Int. Ed. Engl., (28) Still, W . C , J. Am. Chem. Soc,  1979,111,  W . C . a n d N o v a c k , V . J . , J. Am. Chem. Soc,  (30) Still,  W . C . a n d R o m e r o , A . G . , J. Am. Chem. Soc,  (31) D a l e , J . , Angew. Chem. Int. Ed. Engl.,  (33)  Chemica.  1981,21, 7 7 1 .  2493.  (29) Still,  (32) D a l e , J . , Acta  1966,1,  1984,111,  1148.  1986,101,  2105.  1000.  Scand., 1 9 7 3 , 2 7 , 1 1 1 5 ; 1973, 2Z,  Dunitz, J . D . , X - r a y A n a l y s i s a n d the S t r u c t u r e of O r g a n i c  University P r e s s , Ithaca.  Gerlach, H. and  1 1 3 1 ; 1973, 2Z,  1149.  Molecules. 1979, Cornell  78  (34) (a) Bjornstad, S.L., Borgen, G., Dale, J. and Gaupset, G., Acta Chemica. Scand., 1975, B29. 320; (b) Groth, P., Acta Chemica. Scand. Ser. A.,  1976,3J1, 155.  (35) Neeland, E., Ph.D. Thesis, Univ. of British Columbia, 1988. (36) Keller, T.H., Ph.D. Thesis, Univ. of British Columbia, 1988. (37) Neeland, E., Ounsworth, J.P., Sims, R.J. and Weiler, L, Tetrahedron  Lett., 1987, 2JL  35. (38) (a) Allinger, N.L., Gorden, B. and Profeta, S.Jr., Tetrahedron,  1980, 3JL, 859; (b)  Burkert, U and Allinger, N L, Molecular Mechanics. ASC Monograph 177, Washington, D.C, 1982. (39) Allinger, N.L, Gorden, B.J., Newton, M.G., Norskov-Lauristsen, L. and Profeta, S. Jr., Tetrahedron.  1982. 38. 2905.  (40) Deslongchamps, P., Stereoelectronic Effects in Organic Chemistry. 1983, Permagon Press, Willowdale. (41) Schweizer, W.B. and Dunitz, J.D., Helv. Chim. Acta, 1982, £5_, 1547.  (42) Huisgen, R. and Ott., H., Tetrahedron, 1959, £, 253. (43) Jones, G.I.L. and Owen, N.L, J. Mol. Struct, 1973, lfi, 1. (44) Ounsworth, J., Ph.D.- Thesis, Univ. of British Columbia, 1985. (45) Cavicchioli, S., Savoia, D., Trombini, C. and Umani-Ronchi, A., J. Org. Chem., 1984, 4JL 1246. (46) Suter, C.H., The Organic Chemistry of Sulfur. John Wiley & Sons, New York, 1948, 667. (47) Veenstra, G.E. and Zwanenburg, B., Synthesis, 1975, 519. (48) Manescalchi, F., Orena, M. and Savoia, D., Synthesis, 1979, 445. (49) Corey, E.J. and Chaykowsky, M., J. Am. Chem. Soc, 1965, fiL 1345. (50) Money, T. and Kuo, D.L, J. Chem. Soc, Chem. Commun., 1986, 69.  (51) Oppolzer, W. and Godel, T., J. Am. Chem. Soc,  1978,10JL 2583.  (52) (a) McMurry, J.E. and Choy, W., Tetrahedron R.K. and Silver, S.M., Tetrahedron Lett., 1973, 3497.  Lett,  1980,21, 2477; (b) Boeckman,  79  (53) (a) Maercker, A . , Org. React, (N.Y.) Lett., 1982, 23.  1965,14, 270. (b) Lombardo, L, Tetrahedron  4293.  (54) Karunaratne, V., Ph.D. Thesis, The Univ. of British Columbia, 1985. (55) Reetz, M.T., Westermann, J. and Steinbach, R., Angew. Chem. Int. Ed. Engl., 1980.1JL 900. (56) Reetz, M.T., Westermann, J. and Steinbach, R . , J. Chem.Soc, Chem. Commun., 1981, 237. (57) Tebbe, F.N., Parshall, G.W. and Reddy, G.S., J. Am. Chem. Soc, 1978,1M, 3611. (58) Brown-Wensley, K.A., Buchwald, S.L, Cannizzo, L, Clawson, L, Ho, S., Meinhardt, D., Stille, J.R., Strauss, D. and Grubbs, R.H. et al., Pure & Appl. Chem., 1983, 5JL 1733. (59) (a) Simmons, H.E. and Smith, R.D., J. Am. Chem. Soc, 1958, fifi.. 5323; (b) Simmons, H.E. and Smith, R.D., J. Am. Chem. Soc, 1959,8_L 4256. (60) Furukawa, J., Kawabata, H. and Nishimura, J., Tetrahedron, 1968, 24, 53. (61) Trost, B.M. and Hiemstra, H., J. Am. Chem. Soc, 1982. 104. 886. (62) (a) Baker, K.M., Shaw, M.A. and Williams, D.H., J. Chem. Soc, Chem. Commun., 1969, 1108; (b) White, E. and McCloskey, J.A., J. Org. Chem.,  1970,31, 4241.  (63) Klebe, J.F., "Silylation in Organic Synthesis" in " A d v a n c e s in Organic Chemistry. Methods and Results. Vol. 8". Wiley Intersciehce, New York, N.Y., 1972, 97. (64) (a) Lalonde, M. and Chan, T.H., Synthesis,  1985, 817; (b) Colvin, E., "Silicon in  Organic Synthesis". Butterworth, London, 1980, 184. (65) Newham, J., J. Chem. Rev., 1963, 6JL 123. (66) Bowden, K., Heilbon, I.M., Jones, E.R.H. and Weedon, B.C.L. J. Chem. Soc, 1946, 39. (67) Emmons, W.D. and Lucas, G.B., J. Am. Chem. Soc, 1955, TL 2287. (68) (a) Ogura, H., Furuhata, K., litaka, Y., J. Am. Chem. Soc,  1978,1QJ2, 6733; (b) Ogura,  H., Furuhata, K., Kuwano, H. and Suzuki, M., Tetrahedron, 1981, 3Z (suppl. 1), 165. (69) Weiler, L. and Ounsworth, J.P., J. Chem. Ed. 1987, £4, 568. (70) Seeman, J.I., Chem. Rev., 1983,33, 83.  80 Appendix 1  M M 2 calculations  The strain energies of different conformations for macrolide 42, were calculated using Allinger's  MM2  computer program.  38b  The force field used in molecular mechanics  calculations consists of a set of equations derived from classical mechanics, which contain adjustable parameters that are optimized to obtain the best fit of the calculated and experimental properties of the molecules.  The MM2 program is much faster than quantum  mechanical calculations and produces very reliable values.  In addition, the MM2 program  allows rapid calculations of considerably large molecules, since the equations used are sufficiently simple to be rapidly solved by modern computers. The quality of a molecular mechanics force field, and hence the reliability of its predictions, is critically dependant on the parameters used. For the calculations in this thesis, the parameters of Allinger's 1982 MM2 force field were employed. All the calculations were performed on the Amdohl computer in the Computing Centre of the University of British Columbia. The time required to generate the conformations, screen out unfavorable selections and calculate the energies were usually 5 to 10 min.  Appendix 2  NMR and IR spectra  41  82  66  85  89  90  92  95  96  4000.  3400.  2B00.  2200.  1600.  1000.  CM-i  

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0060354/manifest

Comment

Related Items