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Synthesis of [beta]-keto lactones and the synthetic consequences of the conformational preferences of… Ounsworth, James Paul 1985

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SYNTHESIS OF 0-KETO LACTONES AND THE SYNTHETIC CONSEQUENCES OF THE CONFORMATIONAL PREFERENCES OF 14-MEMBERED LACTONES By JAMES PAUL OUNSWORTH B.Sc, Carleton University, 1978 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard The University of B r i t i s h Columbia January 1985 ® James Paul Ounsworth, 1985 I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an advanced degree a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I agree t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y purposes may be g r a n t e d by t h e head o f my department o r by h i s o r h e r r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department o f CSk £ rvv l'$"ft ^ The U n i v e r s i t y o f B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date m.as^eA H] \ 185 - i i -ABSTRACT The preparation of the 3-keto lactones 19_ v i a intramolecular a l c o h o l y s i s of hydroxy Meldrum's acid d e r i v a t i v e s was examined. Good yi e l d s of the 6- and 14-membered compounds were obtained, but the method was completely unsuccessful for medium-size ri n g s . An investigation was conducted on the conformational preference of substituted 14-merabered lactones with a view to understanding the stereochemical consequences of the reactions of these compounds. The conformational preferences of simple 14-membered c y c l i c compounds were f i r s t determined. These preferences are described in terms of s t e r i c and e l e c t r o n i c i n t e r a c t i o n s , with the support of computer-calculated s t e r i c energies. A number of 14-membered lactones were prepared, beginning with the 8-keto lactone 3-oxo-13-tetradecanolide (138). Hydride reduction of (138) gave the diastereomeric alcohols 146 and 147, which were then elaborated to give a series of d e r i v a t i v e s . The stereochemistry and conformations of these compounds were determined by X-ray crystallography and/or nmr analysis. The preferred conformation was found to be Dale's [3434] diamond l a t t i c e model. The r e l a t i v e rates of reaction were determined for several reactions of the alcohols 146 and 147 and for one reaction of the corresponding acetates. The conformational e f f e c t s were found to be much smaller than those observed in 6-merabered ri n g s . Explanations of this difference are given. - i i i -The preparation of the a, 3-unsaturated lactones 163 and 164, the 3^methyl-a,^-unsaturated lactones 185 and 186, the dimethyl lactones 154 and 155 and the epoxides 197 and 198 are described. The r e s u l t i n g geometry of double bonds and the stereochemistry of substituents are explained in terms of conformational preferences. 0 0 2 n 19 0 138 'OH 0 OH 146 147 197 198 - v -T A B L E O F CONTENTS Page ABSTRACT i i TABLE OF CONTENTS v LIST OF FIGURES • v i i i LIST OF TABLES x i i LIST OF ABBREVIATIONS x i i i ACKNOWLEDGEMENTS xv INTRODUCTION • 1 I. Construction of Medium- and Large-Size Lactones 6 II. Control of Stereochemistry in Macrolide Synthesis..... 14 A. Computer Calculations of Minimum-Energy Conformations 16 B. Conformational Stereocontrol in Synthesis 18 RESULTS AND DISCUSSION 45 I. 3-Keto Lactone Synthesis 45 II. Conformations of 14-Membered Rings 56 A. Cyclotetradecane 57 B. Oxacyclotetradecane 62 C. Cyclotetradecanone and Cyclotetradecene 64 D. 14-Membered Lactones - Tridecanolide.............. 65 E. Al k y l Substitution on Cyclotetradecane 69 F. Monosubstituted 14-Membered Lactones -13-Tetradecanolide 70 - v i -Page III. Synthesis and Conformations of 14-Merabered Lactones... 74 A. Synthesis of 3-Oxo-13-Tetradecanolide 75 B. Stereoselective Reduction of 3-0xo-13-Tetradecanolide 79 C. Conformations of 3,13-Disubstituted Lactones -Dihedral Maps 89 D. Conformations of 3,13-Disubstituted Lactones -MM2 Ca l c u l a t i o n s . . . . 93 E. The Relative Rates of Reaction of c i s - and trans-3,13-Disubstituted 14-Membered Lactones. 97 F. Preparation of a, 3-Unsaturated Lactones 112 G. Conjugate Addition to the E_-ot, B-Unsaturated Lactone 163 117 H. Comparison of the NtfR Data of c i s - and trans-Disubstituted Lactones 123 I. The NMR Data and Conformations of the Disubstituted Lactones 129 J . Conjugate Addition to the _Z-ct, B-Unsaturated Lactone 164 137 K. Preparation and Hydrogenation of 8-Methyl-a,8-Unsaturated Lactones 185 and 186 145 L. Epoxidation Reactions of a, B-Unsaturated Lactones 163 and 164 158 M. Conclusion. 166 EXPERIMENTAL 167 I. General 167 I I . B-Keto Lactone Synthesis 170 I I I . Synthetic Studies of 14-Membered Lactones 203 - v i i -Pag^e REFERENCES 2 60 APPENDIX A - Derivation of Rate Equation 266 APPENDIX B - Spectral Appendix 268 - v i i i -LIST OF FIGURES Figure T i t l e Page 1 Synthesis of 8-keto lactones via s u l f i d e contraction 8 2 Synthesis of 8-keto lactones v i a a hetero-Diels-Alder reaction 10 3 8-Keto lactone synthesis v i a intramolecular a l c o h o l y s i s 13 4 Comparison of cyclohexene and cis-cyclodecene 19 5 The preference for an s-trans 1,3-diene conformation... 26 6 Possible conformations and s t e r i c energies ( i n kcal/ mole) of the enolate 60_ and of the corresponding a l k y l a t i o n products. 30 7 Relationship between s t e r e o s e l e c t i v i t y and distance from the c o n t r o l l i n g asymmetric centre in a l k y l a t i o n s . . 32 8 The lowest-energy conformations of 62_ ( s t e r i c energies in kcal/mole) 33 9 An example of complementary product stereochemistry.... 33 10 Preparation of 8-keto lactones v i a intramolecular alcoholysis 46 11 Preparation of a>-benzyloxy acids 47 12 Preparation of long-chain benzyloxy acids.. 48 13 Preparation of Meldrum's acid 49 14 Acylation of Meldrum's acid 50 15 The MM2 plot of 8-keto lactone 122 5 2 16 R e a c t i v i t y p r o f i l e for lactone formation... 55 17 S p a c e - f i l l i n g models of cyclotetradecane: (a) top view (b) side view 57 18 The lowest-energy conformations of cyclotetradecane: (a) perspective diagrams ( s t e r i c energies in kcal/mole) (b) corresponding MM2 plots 59 - ix -Figure T i t l e Page 19 Diamond models A, B, C, D and F. Steric energies i n kcal/mole are given for selected conformations 61 20 Hydrogen interactions of cyclotetradecane in the [3434] conformation 62 21 The four possible conformations of oxacyclo-tetradecane ( s t e r i c energies in kcal/mole) 63 22 Conformations of cyclotetradecanone ( s t e r i c energies in kcal/mole) 65 23 The two planar conformations of carboxylic esters 66 24 Overlap of oxygen lone pair electrons with the o* o r b i t a l in the s-trans conformation 67 25 Comparison of the dipole moments of 6-valerolactone (132) and tridecanolide (133) 67 26 The possible conformations of tridecanolide ( s t e r i c energies i n kcal/mole) 68 27 D i s u b s t i t u t i o n of an R group at a corner position introduces one less gauche i n t e r a c t i o n 70 28 The possible conformations of 13-tetradecanolide ( s t e r i c energies in kcal/mole) 71 29 Conformational preferences of substituted esters 73 30 Synthesis of B-keto lactone 138 76 31 The X-ray c r y s t a l structures of bromoacetates 148 and 149_ 80 32 C h i r a l synthesis of alcohol 146 to prove i t s stereochemistry 81 33 The possible conformations of B-keto lactone 138: (a) diamond l a t t i c e ( s t e r i c energies in kcal/mole) (b) corresponding stereo s p a c e - f i l l i n g plots 83 34 The v a r i a t i o n of the TI-contribution to geminal coupling (J ) with i> 85 35 Hydride reduction of the 0-keto lactone 138 in i t s possible conformations.. 88 - x -Figure T i t l e Page 36 Dihedral angles: Angle A-B-C-D i s positive i f D i s clockwise from A 90 37 Dihedral maps: (a) [3434] X-ray structure of 1A9 (b) [3434] cyclotetradecane model (c) [3344] X-ray structure of 149 (d) [3344] cyclotetradecane model 91 38 Dihedral maps: (a) [3335] X-ray structure of 148 (b) [3335] cyclotetradecane model 92 39 The [3434] and [3344] conformations of the c i s -dimethyllactone 154 ( s t e r i c energies i n kcal/mole) 94 40 The possible [3434] conformations of 154 ( s t e r i c energies in kcal/mole) 94 41 The [3434] and [3335] conformations of the trans-dimethyllactone 155 ( s t e r i c energies i n kcal/mole) 95 42 The possible [3434] conformations of 155 ( s t e r i c energies in kcal/mole) 96 43 The possible conformations of alcohol 146 99 44 Plots of the k i n e t i c data for acetylation of alcohols _146_ and j_47_ 101 45 Tetrahedral intermediates in acetate formation 102 46 P l o t s of the k i n e t i c data for formation of sulfonates 160 and 16J_ 105 47 Plots of the k i n e t i c data for cleavage of acetates 156 and _157 106 48 Tetrahedral intermediates i n t r a n s e s t e r i f i c a t i o n of acetates 156 and 157 107 49 Plots of the k i n e t i c data for oxidation of alcohols 146 and _147_ 109 50 Intermediate chromate esters in the oxidation of alcohols (a) 147. and (b) JL46 110 51 Lowest energy conformations of 163 ( s t e r i c energies in kcal/mole) 120 52 Hydrolysis of 155 and 154 and r e l a c t o n i z a t i o n 122 - x i -Figure T i t l e Page 53 Computer simulations and actual nmr spectra of the C-2 protons in (a) the trans-acetate 156 and (b) the cis-acetate 157 128 54 The resonance peak of the low-field C-2 proton i n 155 at low temperature 136 55 The lowest-energy conformation 164a of the _Z-olefin 164 140 56 The mechanism of cuprate conjugate a d d i t i o n . . . . 142 57 Preparation and reactions of the enol phosphates of the 16-membered B-keto lactone 187 146 58 Reaction of the Ji-enol phosphate 192 with dimethyl lithium cuprate 149 59 Comparison of r e a c t i v i t i e s of isomeric enol phosphates with dimethyllithium cuprate 153 60 Epoxidation of 163 with basic hydrogen peroxide 164 - x i i -LIST OF TABLES Table T i t l e Page 1 Synthesis of B-keto lactones v i a intramolecular dianion a l k y l a t i o n 11 2 K i n e t i c data for acetylation of alcohols 146 and 147 100 3 K i n e t i c data for formation of sulfonates 160 and 161 104 4 K i n e t i c data for cleavage of acetates 156 and 157 (0.18 M) 107 5 K i n e t i c data for oxidation of alcohols 146 and 147... 109 6 Experimentally determined r e l a t i v e rates of reaction. I l l 7 The nmr data of trans-disubstituted lactones 124 8 The nmr data of c i s - d i s u b s t i t u t e d lactones 125 9 Spectral data from nmr decoupling experiments on the trans-acetate 156 126 10 Reduction potentials of 163, 164 and cyclopentanone.. 144 11 Spin decoupling on the 400 MHz nmr spectrum of compound 197 161 12 Spin decoupling on the 400 MHz nmr spectrum of compound 198 162 - x i i i -LIST OF ABBREVIATIONS A C 2 O a c e t i c anhydride AIBN 2,2'-azobisisobutyronitrile D Debye(s) DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DMAP 4-dimethylaminopyridine DMF N,N-diraethylformamide DMSO dimethylsulfoxide ether d i e t h y l ether Eu(fod>3 Siever's reagent, tris(6,6,7,7,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium GC gas l i q u i d chromatography h hour(s) HMPA hexaraethylphosphoramide i r i n f r a red LDA li t h i u m diisopropylamide MCPBA m-chloroperbenzoic acid min minute(s) MM molecular mechanics MO molecular o r b i t a l ms mass spectrometry nmr nuclear magnetic resonance PCC pyridinium chlorochromate PDC pyridinium dichromate py pyridine THF tetrahydrofuran - xiv -t i c thin layer chromatography Ts (j2~Ts) para-toluenesulfonyl r t room temperature SCE saturated calomel electrode std standard V v o l t ( s ) Abbreviations for m u l t i p l i c i t i e s of nmr signals s s i n g l e t d doublet t t r i p l e t q quartet dd doublet of doublets dt doublet of t r i p l e t s br broad m m u l t i p l e t - XV -ACKNOWLEDGEMENTS I wish to express my gratitude to Professor Larry Weiler for his advice and guidance during the course of th i s work. I am indebted to Professor Chris Whiteley for reading through the manuscript of th i s thesis and providing valuable opinions. The numerous computer (MM2) c a l c u l a t i o n s done by Janet Teague and John Warkentin are g r a t e f u l l y acknowledged, as i s the e f f i c i e n t cooperation of the s t a f f of the nmr, mass spectroscopy and microa n a l y t i c a l services. F i n a l l y , I would l i k e to thank Debbie N i c o l l - G r i f f i t h whose constant encouragement and hel p f u l suggestions made this thesis p o s s i b l e . - 1 -INTRODUCTION The chemistry of the macrolides began in 1927 with the i s o l a t i o n (1) of pentadecanolide ( e x a l t o l i d e ) (1_) and A -hexadecenolide (ambrettolide) (2_) from the vegetable musk o i l s of angelica root and 1 2 ambrette seed respectively. Vigorous e f f o r t s to develop synthetic routes to these and related compounds ensued, prompted by the challenge of preparing the novel macrocyclic lactone structures and by t h e i r commercial importance in the fragrance industry. Several preparative techniques were developed to form these large rings, generally involving c y c l i z a t i o n of b i f u n c t i o n a l precursors under high d i l u t i o n conditions (2). The next major development in macrolide chemistry occurred in 1950 when the f i r s t macrolide a n t i b i o t i c , pikromycin (3_), was is o l a t e d from- an Actinomyces culture (3). Since then well over 100 macrolides possessing diverse b i o l o g i c a l a c t i v i t y have been iso l a t e d from natural sources ( 4 ) . - 2 -The terra "macrolide" was o r i g i n a l l y used to represent the class of a n t i b i o t i c s which are characterized by a large lactone ring contain-ing few double bonds and one or more sugar residues. However, as the number of n a t u r a l l y occurring tnacrocyclic compounds has increased, the terra macrolide has gradually found use in a broader context encompassing a l l natural products with a large lactone r i n g (13 or more atoms) as well as those with medium lactone rings (7 to 12 atoms). The macrolide natural products as a group are diverse in s t r u c t -ure and p h y s i o l o g i c a l a c t i v i t y . However, the major subgroup of these compounds exhibits a remarkable s i m i l a r i t y of structure among i t s members. The molecules of this subgroup, comprising approximately one half of the known macrolides, are those which f i t the o r i g i n a l d e f i n i t i o n of macrolide. C l a s s i f i e d as "polyoxo" macrolides, they are normally 12-, 14- or 16-membered and have an array of substituents s p e c i f i c a l l y and systematically attached to the ring structure, as well as linkages of one or more sugars. Examples of polyoxo macrolides are pikromycin (3_), narbonolide (4_), erythromycins A (5), and B (6), methymycin (7_) and carbomycin A (8) (4). The fact that the polyoxo macrolides possess a systematic arrangement of substituents means that they mainly d i f f e r from one another only in the degree of oxidation (5). An i n t e r e s t i n g feature of the three-dimensional structures of these compounds i s that the hydroxyl groups l i e above the ring framework, while most of the methyl groups are directed below the r i n g . (See 1_2_ and 13_ below.) This s t r u c t u r a l c h a r a c t e r i s t i c l i k e l y has an important bearing on the a b i l i t y of these compounds to act as a n t i b i o t i c s . - 3 -0 3 R' = desosaminyl,R 2=OH 4 R^desosaminyl, R 2=H 0 5 R = desosaminyl R 2 = cladinosyl, R 3 =OH 6 R = desosaminyl, R 2 = cladinosyl, R 3=H 7 R = desosaminyl 8 R = (isovaleryl )-mycarosyl- mycaminosyl - 4 -Another s t r u c t u r a l c h a r a c t e r i s t i c of the macrolide a n t i b i o t i c s , also probably related to t h e i r b i o l o g i c a l a c t i v i t y , i s the r e l a t i v e r i g i d i t y of conformations in s o l u t i o n . These molecules, in f a c t , often have e s s e n t i a l l y the same conformation in solution as in the c r y s t a l s tructure. Presumably the high degree of s u b s t i t u t i o n plays an important role in this r i g i d i t y : the accommodation of a l l s t e r i c and e l e c t r o n i c factors leads to a single minimum energy conformation for any p a r t i c u l a r macrolide a n t i b i o t i c . The conformational problems of the complex 14-membered macrolide a n t i b i o t i c s have aroused considerable i n t e r e s t among chemists. As a r e s u l t , a number of models have been proposed to explain the observed structures of the various macrolides. One of the most studied conforma-tions i s that of erythronolide, the aglycone of erythromycin B. Based on the minimum energy diamond-lattice conformation 9_ proposed for cyclotetradecane by Dale (6), Celmer (7) advanced the model 10 for a preferred conformer of erythronolide B in 1965. However, while the model was in reasonable agreement with the ^-nmr data, i t did not agree with the X-ray data. The model i s very strained because of the non-bonded i n t e r a c t i o n of the three hydrogen atoms directed inside the ring system and also because of a 1,3-diaxial methyl i n t e r a c t i o n . A second diamond l a t t i c e conformation (as shown in 11_ and 12) was proposed and led eventually to the Perun model (13) (8). The Perun model can be used as a basis for many of the 14-membered macrolides which are similar to erythromycin B. However, since the model does not exactly follow a diamond framework but deviates - 5 -- 6 -from i t with varying substituents, each of these macrolides may possess s l i g h t l y d i f f e r e n t conformations. (The change of conformation with changing su b s t i t u t i o n w i l l be seen to have an important consequence for the synthesis of these compounds.) While s t r u c t u r a l studies of macrolide natural products have abounded over the l a s t 30 years, only in the l a s t decade have there been major synthetic accomplishments in th i s f i e l d . Synthetic organic chemists have met the challenge of the to t a l synthesis of such groups of natural products as carbohydrates, terpenes and a l k a l o i d s . The macrolide a n t i b i o t i c s are the only remaining major family of compounds to be investigated. The t o t a l synthesis of macrolide natural products has been slow to develop because of two problems associated with i t : 1) the construc-tion of medium and large-s i z e lactones and 2) the introduction of c h i r a l centres on a long carbon chain. Solutions to both problems have been reported, but each, p a r t i c u l a r l y the l a t t e r , s t i l l presents an extensive area for further i n v e s t i g a t i o n . This thesis consists of two parts, each dealing with one of these general synthetic problems. I. Construction of Mediurt- and Large-Size Lactones The complex stereochemistry and the number and l a b i l i t y of substituents borne by the skeletons of macrolide a n t i b i o t i c s has generally precluded their synthesis v i a the simple approaches which had been successful in preparing derivatives and homologues of the musk - 7 -lactones. Hence, over the l a s t decade a v a r i e t y of synthetic methods for the preparation of medium- and large-size lactones has been develop-ed. These methods can be divided into two general s t r a t e g i e s : ( i ) the cleavage of int e r n a l bonds in p o l y c y c l i c systems and ( i i ) c y c l i z a t i o n of long-chain a c y c l i c precursors. The l a t t e r method i s the most general and includes acetylene coupling, a l l y l i c dibromide-nickel carbonyl coupling, the intramolecular Diels-Alder reaction, the Dieckmann conden-sation, the intramolecular Wittig reaction and l a c t o n i z a t i o n . Lactoni-zation i s by far the most common method employed. These synthetic methods have been reviewed elsewhere (2, 4) and w i l l not be discussed here. The a v a i l a b i l i t y of new methods for the construction of large ri n g lactones has resulted in successful t o t a l syntheses of a number of natural raacrocyclic lactones (2, 4, 9). Most c y c l i z a t i o n procedures s u f f e r , however, from a v a r i e t y of problems including low y i e l d s , poly-merization and requirements for high temperatures and high d i l u t i o n conditions (10). Consequently there i s an ongoing search for new methods which might circumvent these d i f f i c u l t i e s . For a number of years our laboratory has examined synthetic applications of g-keto ester chemistry. The existence of natural products such as pikromycin ( 3 ) , narbonolide (4_) and d i p l o d i a l i d e A (14) (11) which contain the $-keto lactone system suggested studies of the preparation of such macrocycles. In addition, 3-keto lactones might function as useful precursors to more complex macrolides. - 8 -Four methods for the preparation of 6-keto lactones have been reported to date. Ireland and Brown (12) reported a method involving an [• BH*X •] 0 'CH 17 > N C H 2 / 0 18 [•R'P = S] Figure 1. Synthesis of 6-keto lactones via sulfide contraction. intramolecular sulfide contraction (Figure 1) in which an N,N-dialkyl-thioamide _15_ could be converted direct ly into a 6-keto lactone. The intermediate thioimmonium salt 16_ could be induced to undergo the - 9 -s u l f i d e contraction by treatment with a phosphine ( R 3 P ) and an amine base. Upon hydrolysis of the enamine product 17_, the 8-keto lactone 1_8 was obtained. Thus they were able to prepare the 10-membered 8-keto lactone _19_ (n = 6) and the 12-raerabered compound 19 (n = 8), each in 35% 0 0 y i e l d , but they were not able to prepare the 7-merabered compound 19_ (n = 3). The method was successfully applied to the preparation of d i p l o d i a l i d e (14) in an eight-step sequence. Recently C a s t e l l i n o and Sims (13) reported a method of preparing substituted 6-raembered 8-keto lactones based on a Lewis acid catalyzed hetero-Diels-Alder reaction. The reaction between aldehyde _21_ and bis-1,l-diraethoxy-3-triraethylsiloxy-l,3-butadiene (20) , catalyzed by the lanthanide s h i f t reagent E u ( f o d ) 3 , provided the enol ether 22_ (Figure 2). Hydrolysis of 22, gave 8-keto lactone 23_ in an o v e r a l l y i e l d of 57-81%, depending on the substituent R. Under E u ( f o d ) 3 c a t a l y s i s , the carbonyl double bond of the aldehyde reacted in preference to a carbon-carbon double bond in the same molecule ( i . e . when R = 1 2 3 -CR =CR R in Figure 2 ) . Without c a t a l y s i s , t h i s s e l e c t i v i t y was not observed. Attempts to use a ketone in place of aldehyde 21 were unsuccessful. - 10 -Figure 2. Synthesis of B-keto lactones v i a a hetero-Diels-Alder react i o n . The synthesis of (3-keto lactones v i a the intramolecular a l k y l a -t i o n of the dianions of B-keto esters has been reported from our laboratory by Sims, T i s c h l e r and Weiler (14). A series of g-keto esters 25 was prepared by heating a solution of acetyl Meldrum's acid (24) and an (D-bromoalcohol. Subsequent dianion generation and intramolecular a l k y l a t i o n was attempted using lithium diisopropylamide (LDA) as base. The r e s u l t s are shown in Table 1. - 1 1 -24 25 19 26 Table 1 Synthesis of g-keto lactones v i a intramolecular dianion a l k y l a t i o n n % y i e l d (19) % y i e l d ( 2 6 _ ) 6 0 4 1 7 0 4 5 8 0 5 7 9 0 4 1 1 0 4 3 0 1 1 4 5 0 1 2 4 9 0 For 2 _ 5 , n >^  1 0 , the dianion underwent c y c l i z a t i o n v i a a l k y l a t i o n at the ^-carbon to give the B-keto lactones J 9 _ in modest y i e l d . How-ever, for 2_5_ with n <^  9 the only product isolated was the alkene 26_ a r i s i n g from elimination. Application of t h i s method in synthesis was demonstrated by the preparation of the musk constituent, 13-tetra-decanolide ( 2 7 ) , in 4 steps and of two termite B-hydroxy lactones 2 8 , and 2 9 , in 5 steps each. - 12 -27 28 n = 2l 29 n=23 A v a r i a t i o n of the above approach for the construction of g-keto lactones was also developed in our laboratory (15). Instead of using dianion a l k y l a t i o n as the c y c l i z a t i o n step, the lactone ring was formed by the intramolecular alcoholysis of a hydroxy acyl Meldrum's acid d e r i v a t i v e (Figure 3). The 14-membered B-keto lactone 34_ was prepared in the following manner. The acid 30_ was converted to i t s acyl Meldrum's acid d e r i v a t i v e 32_ by reaction with N,N'-carbonyldiimidazole (Im2C0), followed by addition of this reaction mixture to a solution of the anion of Meldrum's acid (31). Cleavage of the s i l y l ether and c y c l i z a t i o n gave the B-keto lactone in a y i e l d comparable to those of the c y c l i z a t i o n procedures described previously. Considering the limited success reported for the formation of medium-sized (8- to 12-merabered) B-keto lactones, we f e l t that further i n v e s t i g a t i o n into the preparation of these compounds would be worthwhile. We therefore undertook the synthesis of B-keto lactones by means of intramolecular alcoholysis of hydroxy acyl Meldrum's acid d e r i v a t i v e s . - 13 -0 33(98%) 34(35%) Figure 3. 8-Keto lactone synthesis v i a intramolecular a l c o h o l y s i s . - 14 -I I . Control of Stereochemistry in Macrolide Synthesis The control of stereochemistry remains a s i g n i f i c a n t problem in macrolide synthesis and, indeed, in organic synthesis i n general. To meet t h i s challenge, numerous approaches to stereocontrol in the synthesis of ac y c l i c systems have been developed (16). However, e f f e c t -ive as these methods may be, one problem that they do not address i s the establishment of correct r e l a t i v e stereochemistry between widely separated asymmetric centres. Most of the current syntheses of a c y c l i c and macrocyclic natural products depend on some form of absolute stereo-chemical control to set up such distant diastereomeric r e l a t i o n s h i p s . This absolute stereochemistry usually involves a re a d i l y a v a i l a b l e , enantiomerically pure s t a r t i n g material (17), chemical re s o l u t i o n of an intermediate, or in some cases, asymmetric induction by an enantiomeric-a l l y pure reagent (18). Although each of these approaches has i t s strengths, each also has inherent problems. An a l t e r n a t i v e to these absolute stereocontrol methods for the establishment of distant stereochemical r e l a t i o n s h i p s has been developed in recent years, mainly by S t i l l and coworkers (vide i n f r a ) . His approach d i f f e r s from other methods in that the s t e r e o s e l e c t i v i t y of a reaction can be directed by the existing c h i r a l i t y of another centre in the molecule, even though that centre may be quite distant from the reaction s i t e . The idea i s i n t r i g u i n g since asymmetric induction operating by a d i r e c t i n t e r a c t i o n between widely separated asymmetric centres i s generally not very e f f e c t i v e . However, i f the molecule i s c y c l i c , the pre-existing asymmetric centre can cause the molecule to - 15 -adopt a p a r t i c u l a r conformation. If t h i s conformation can then d i r e c t the stereochanical outcome of a reaction (for example, by allowing the attack of a reagent to occur only from one face of the molecule) , then the asymmetric centre can control the s t e r e o s e l e c t i v i t y of the re a c t i o n . This type of control i s of course common in cyclohexane-derived ring systems where ax i a l - e q u a t o r i a l preferences are often used for stereochemical control in synthesis. In recent years i t has been demonstrated that substituents on medium- and lar g e - r i n g molecules can also d i r e c t the stereochemical outcome of chemical reactions at centres d i s t a n t l y removed from the c o n t r o l l i n g asymmetric centre (vide i n f r a ) . Although medium- and large-ring molecules have been regarded as f l e x i b l e or "floppy", numerous studies including dynamic nmr and X-ray crystallography (19) have shown otherwise. While macrocyclic compounds may be capable of existing in a number of stable conformations, only a few of these conformations are low enough in energy to be appreciably populated at normal temperatures. The conformational preferences of substituted macrocycles r e s u l t from the minimization of transannular repulsions, angular s t r a i n and torsi o n a l s t r a i n . As noted previously for the macrocyclic a n t i b i o t i c s , a high degree of s u b s t i t u t i o n may in fact lead to a s i n g l e , r e l a t i v e l y r i g i d conformation. The concept of c o n t r o l l i n g stereochemistry in medium- and large-si z e rings v i a molecular conformation has gained acceptance recently, as demonstrated by i t s use in an increasing number of syntheses. A survey of these syntheses w i l l be presented following a b r i e f d e c r i p t i o n of - 16 -molecular mechanics, a computational method which has been used to r a t i o n a l i z e some of these r e s u l t s as well as the r e s u l t s of our own work. I I . A. Computer Calculations of Minium-Energy Conformations Molecular mechanics (MM) c a l c u l a t i o n s (20) have been gaining popularity in the last few years with synthetic organic chemists as researchers try to interpret their r e s u l t s or formulate synthetic plans based on conformational preference. In contrast with ^b i n i t i o molecular o r b i t a l (MO) and semi-empirical MO methods, the molecular mechanics method i s based on empirical p r i n c i p l e s . Molecules are represented as though constructed from b a l l s and springs with a series of potential energy functions to express the t o t a l energy of the system. The parameters of the potential energy functions are adjusted so that the f i n a l set reproduces the desired properties of molecules (e.g. molecular geometry, heat of formation, s t r a i n energy and dipole moment). The parameters themselves are i n i t i a l l y derived from a set of experimentally observed values of these properties, and are assumed to be transferable among molecules of d i f f e r e n t types. The molecular mechanics computation involves a l l possible atom-atom i n t e r a c t i o n pairs - a r e l a t i v e l y small population compared to the vast number of i n t e r o r b i t a l i n t e g r a l s that must be computed during MO c a l c u l a t i o n s . As a consequence, molecular mechanics c a l c u l a t i o n s far exceed MO methods in speed and accuracy for large molecules. However, while molecular mechanics can account for interatomic forces, i t cannot account for the behaviour of electrons. Therefore molecules which - 17 -incorporate e l e c t r o n i c factors such as the anomeric e f f e c t , hydrogen bonding or a conjugated carbanion lone pair must be treated by a d i f f e r e n t type of c a l c u l a t i o n . The most widely used molecular mechanics programs are A l l i n g e r ' s MM2 (21) and MMPI (22). MM2 covers alkanes, non-conjugated alkenes and alkynes, non-conjugated carbonyl compounds, alcohols, ethers, s u l f i d e s , mercaptans, monohalides and amines. MMPI i s designed for molecules containing a conjugated ir-electron system such as aromatics, poly o l e f i n s and a,B-unsaturated carbonyls. MM2 can be modified to handle conjugated systems by i n c l u s i o n of parameters for these systems. The c a l c u l a t i o n of the " s t e r i c " energy of a molecule includes the following i n t e r a c t i o n s : compression ( s t r e t c h i n g ) , bending, van der Waals, t o r s i o n a l and dip o l e . To calculate the minimum energy conforma-tion of a molecule, MM2 employs the steepest-descent method. The energy of a molecule i s calculated with i t s i n i t i a l coordinates. Atom 1 i s then moved s l i g h t l y and the energy Is recalculated ( t e s t increment). The remaining atoms are treated s i m i l a r l y . A l l of the atoms are then simultaneously moved i n di r e c t i o n s that would y i e l d a reduction i n energy by varying amounts (c o r r e c t i o n terms). The greater the reduction in energy for the test increment, the further the atoms are moved. After one appl i c a t i o n of these correction terms to the coordinates, the to t a l energy i s recalculated. If the energy remained constant, the molecule i s already at an energy minimum. (This may be a l o c a l minimum, not n e c e s s a r i l y the lowest energy conformation of the molecule.) If the energy decreased, the process i s repeated u n t i l the energy change is less than a preset l i m i t . - 18 -The r e s u l t i n g s t e r i c energy of a molecule i s an energy r e l a t i v e to a hypothetical reference system. The difference in energies between conformations i s given by d i r e c t comparison of the calculated s t e r i c energies. However, i f a comparison between d i f f e r e n t molecules i s required, s t e r i c energies should not be used; an a l t e r n a t i v e for this type of comparison i s to use the heats of formation, which are also calculated by MM2. In organic synthesis MM2 i s generally used to deter-mine lowest-energy conformations, so s t e r i c energies can be used for comparisons. II. B. Conformational Stereocontrol In Synthesis The underlying premise of conformational stereocontrol i s that there i s a d e f i n i t e r e l a t i o n s h i p between the reacting conformation and the stereochemical outcome of a reaction. However, while conformational biasing may be a necessary requirement for control of stereochemistry, i t i s not always a s u f f i c i e n t one. For example, six-membered rings containing a single substituent frequently exist mainly In one conforma-t i o n , but they are often open to attack from both sides of the r i n g . Thus, many reactions of single conformation compounds are not n e c e s s a r i l y s t e r e o s p e c i f i c . Functionalized macrocycles, on the other hand, t y p i c a l l y have three-dimensional structures which are s i g n i f i c a n t l y d i f f e r e n t from smaller r i n g s . In p a r t i c u l a r , double bonds in medium-size rings tend to have the i r it o r b i t a l s aligned in the plane of the ring and the substituents perpendicular to the plane, such that - 19 -serious transannular interactions are minimized. The consequences of th i s conformational arrangement may be seen by a comparison of the lowest energy structures of cyclohexene (35) and cis-cyclodecene (36) H Figure 4. Comparison of cyclohexene and cis-cyclodecene. (Figure 4). In cyclohexene, the top and bottom faces are equivalent. However, the two faces of the o l e f i n i c ir-system in cis-cyclodecene are s t e r i c a l l y d i f f e r e n t . Since one face of the n-system i s severely hindered by the r i n g , various a d d i t i o n reactions should occur predominantly, or perhaps ex c l u s i v e l y , from the less hindered face of attack from less hindered face - 20 -the o l e f i n i c linkage. This d i f f e r e n t i a t i o n of the two faces of a medium-ring o l e f i n w i l l be used to explain the s t e r e o s e l e c t i v i t y observed in the next few syntheses. Some of the f i r s t reports of stereocontrol i n macrocycles came from the study of gerraacradiene natural products, compounds that were known to exist in predictable, well-defined conformations (23). For example, in 1972 Doskotch, Keely and Hufford (24) determined the stereo-chemistry of l i p i f e r o l i d e (37) through controlled modification of a known gerraacradiene. Epoxidation of e p i t u l i p i n o l i d e (38) with one equivalent of m-chloroperbenzoic acid (MCPBA) gave exclu s i v e l y the 1,10-epoxide 39. Epoxidation of _38_ with excess MCPBA gave the bisepoxide 40_ as the sole product. Comparison of the spectral data of these compounds led to the i d e n t i f i c a t i o n of the stereochemistry of l i p i f e r o l i d e (37). The s t e r e o s e l e c t i v i t y which was observed in these reactions was at t r i b u t e d to the preferred conformation of _38_, shown as 41. Epoxida-tion of the accessible faces of the double bonds in 41_ would lead to the observed products. - 21 -41 In 1979 S t i l l (25) reported a synthesis of periplanone-B, the sex pheromone of the American cockroach, a synthesis which made excellent use of the d i f f e r e n t i a t i o n of faces of medium-size rings. The gross structure of the pheromone had previously been determined to be - 22 -4 2 42, and the stereochemistry of the 2,3-epoxide had been found to be c i s while the 6,7-alkene was trans. However, the r e l a t i v e stereochemistry of the asymmetric centres was unknown. S t i l l devised a f l e x i b l e plan which could lead to three of the four possible diastereomers. Planning such as synthesis required a knowledge of the conformations of several intermediates. The preferred conformation of each intermediate was determined by minimizing trans-annular, non-bonded i n t e r a c t i o n s , t o r s i o n a l angle energies and non-bonded repulsions of proximate atoms. It was then possible to predict, or at least r a t i o n a l i z e , the stereochemical outcome of the reactions in this synthesis. While t h i s approach often leads to a single preferred conformer of a compound, It must be used with caution since the reactive conforma-tio n may not be the lowest energy conformation. S t i l l used extensive nmr and X-ray crystallography data to confirm the proposed conforma-tions . The synthesis began with compound 4_3, prepared v i a an oxy-Cope rearrangement. The alcohol was protected and the conjugated alkene - 23 -4 4 epoxidized with t e r t - b u t y l hydroperoxide in the presence of T r i t o n B to give 44. This reaction i s the f i r s t example of conformational stereocontrol in this synthesis - only one epoxy ketone was obtained. Conversion of 44_ to the bisepoxide 45_ by epoxidation with dimethylsulfonium methylide also gave only one diastereomer (75% y i e l d ) . Generation of the exo-methylene by deprotection of the primary a l c o h o l , s e l e n y l a t i o n and selenoxide elimination, followed by removal of the s i l y l protecting group and oxidation gave 46. Spectral comparison with authentic periplanone-B showed that 46 was not the natural product. - 24 -The second diastereoraer to be synthesized is epimeric with 46 at C - l . Preparat ion of the exocyc l i c o l e f i n at C - l by Peterson—Chan o l e f i n a t i o n of 44_ to give 47_, followed by epoxidat ion from the more open face should have lead to the desired C - l epimer. It was found necessary to deprotect the a lcohol at C-10 and to use hydroxy l -d irec ted epoxida-t i o n ( t e r t - b u t y l hydroperoxide and vanadyl acetylacetonate) since the 6 , 7 - o l e f i n of 47_ was more r e a c t i v e . Under these condi t ions the bisepoxide 4_8 was obtained i n 95% y i e l d from 47. Ox idat ion , deprotec t ion and e l iminat ion v i a the selenoxide as before gave 49_. Like 46, th is mater ia l was found to d i f f e r from per ip lanone-B. - 25 -S 4 8 4) H O 4 9 2 2 Preparation of the third diastereomer of 42_ required construction of the diastereomeric 2,3-epoxide. The desired epoxide is now the more hindered one, so a different tactic was required for i t s preparation. The elimination sequence was executed f i r s t , leading to 5_0_ which had a new ring conformation. The appearance of this new conformation is apparently due to the preference of 1,3-dienes for the 8-trans arrange-ment (Figure 5). - 26 -0 Figure 5. The preference for an s-trans 1,3-diene conformation. Epoxidation of _50_ using t e r t - b u t y l hydroperoxide and potassium hydride gave a 4:1 mixture of epoxy ketones in 74% yi e l d of which the major component was the desired isomer 5l_. Treatment of _51_ with diraethylsulfonium raethylide gave a single bisepoxide, 5_2, in 69% y i e l d . F i n a l l y deprotection and oxidation gave 5_3_ which was i d e n t i c a l with periplanone-B. In this synthesis S t i l l not only established the r e l a t i v e stereo-chemistry of the pheromone, but also demonstrated the a b i l i t y to use the ring conformation to control the introduction of new asymmetric centres. Achievement of the same degree of s t e r e o s e l e c t i v i t y using a c y c l i c precursors most l i k e l y would have required a much longer synthe-s i s . The germacrane skeleton has been used to control stereochemistry in two other examples. Kuroda, Hirota and Takahashi (26) were able to s t e r e o s e l e c t i v e l y alkylate a ketone intermediate in their synthesis of a 5 3 - 28 -germacradienolide. Kinetic deprotonation of _54_ with lithium diisopropylaraide followed by a l k y l a t i o n with ethyl broraoacetate gave keto ester 5_5_ as the sole product in 74% y i e l d . The stereochemistry of the reaction was attributed to an attack of the reagent from the less hindered side of the enolate anion as shown in 56. COOEt S t i l l , jet al, (27) also used the conformational bias of the germacrane structure to control the stereochemistry of a synthetic intermediate. Reduction of the ketone 57_ with sodium borohydride gave 58, in 75% y i e l d , as the only isolated alcohol. They were able to r a t i o n a l i z e this r e s u l t (using MM2 calculations) as attack of hydride from the le s s hindered side of a low-energy conformation of 57_ (shown in 59). - 29 -S t i l l and Galynker (19) in 1981 reported a more detailed study of the conformations of medium-ring molecules (mainly 8- to 10-membered) and the consequences of conformational preferences on the stereochemical outcome of chemical reactions of these r i n g s . They examined k i n e t i c enolate a l k y l a t i o n s , dimethyllithiura cuprate additions and c a t a l y t i c hydrogenations on a v a r i e t y of monosubstituted ketones and lactones. It was found that i n many systems a single methyl substituent provided enough conformational bias to allow highly st e r e o s e l e c t i v e formation of new asymmetric centres. The results were r a t i o n a l i z e d as involving the low-energy conformations calculated by MM2. Some representative examples w i l l be described here. K i n e t i c a l k y l a t i o n of 2-methylcyclooctanone 60_, by deprotonation with l i t h i u m diisopropylamide followed by treatment with iodoraethane at -60°C, gave 6l_. The high d i a s t e r e o s e l e c t i v i t y obtained in th i s reaction - 30 -17.9 22.2 19.2 24.9 Figure 6. Possible conformations and s t e r i c energies ( i n kcal/mole) of the enolate of 60_ and of the corresponding a l k y l a t i o n products. - 31 -contrasts with the 60:40 to 80:20 mixtures obtained in related 6-raembered ring alleviations (28). MM2 calculations were carried out on several possible conformations of the enolate from 60. (In these c a l c u l a t i o n s , S t i l l and Galynker (19) introduced new parameters to model carbanions. Unfortunately these parameters cannot be v e r i f i e d by experiment.) The calculated conformations and s t e r i c energies ( i n kcal/mole) are shown in Figure 6. The r e l a t i v e l y low energies of enolates 60a and 60c were used to r a t i o n a l i z e the observed preference for the formation of the trans-product. A l k y l a t i o n of the corresponding 9- and 10-merabered ketones was not s t e r e o s e l e c t i v e , r e s u l t i n g in 1:1 mixtures of the dimethyl products. The analogous lactones, on the other hand, reacted with high s t e r e o s e l e c t i v i t y . An i n t e r e s t i n g study in the 10-merabered series showed how the s t e r e o s e l e c t i v i t y f a l l s o f f as the distance between the enolate and the c o n t r o l l i n g asymmetric centre increases (Figure 7). Cuprate additions to a,S-unsaturated carbonyls were found to be highly s t e r e o s e l e c t i v e in these systems. For example, the addition of dimethyl lithium cuprate to 62_ resulted in a single product, j>3_, in 72% y i e l d . This trans-dimethyl product may be formed by attack from the les s hindered side of either of the two lowest-energy conformations of 62_ (Figure 8). Cuprate additions to 9- and 10-raembered a,6-unsaturated ketones and lactones were also s t e r e o s e l e c t i v e . It was found as well that cuprate additions and c a t a l y t i c hydrogenations gave complementary product stereochemistry in a l l cases studied. An example i s given in - 32 -cis : trans Figure 7. Relationship between s t e r e o s e l e c t i v i t y and distance from the c o n t r o l l i n g asymmetric centre In a l k y l a t i o n s . Figure 9. This r e s u l t indicates that the substrates must react from the same basic conformation, with the reaction proceeding by attack from the less hindered face by methyl in the one case and hydrogen in the other. A l k y l a t i o n and cuprate addition reactions were also performed on 11-, 12- and 13-membered lactones. The s t e r e o s e l e c t i v i t y was found to be very high in a l l cases. However, other than suggesting that the - 33 -Figure 9 . An example of complementary product stereochemistry. - 34 -s t e r e o s e l e c t i v i t y i s under l o c a l conformational c o n t r o l , no conformational rationale of the results was provided. In 1982 S t i l l and Galynker (29) reported their f i r s t a p p l i c a t i o n of the stereocontrol described above to natural products synthesis. As part of the sequence leading to the fragment 64_ of the marine toxin palytoxin, they converted lactone 65_ into 66_ in 92% y i e l d by a stereo-s e l e c t i v e cuprate addition. The remaining asymmetry at C-36 and C-37 (palytoxin numbering system) was then established by a st e r e o s e l e c t i v e , intramolecular addition (iodolactonization) to the Z - t r i s u b s t i t u t e d 6 6 - 35 -double bond. Whereas much of the chemistry currently being developed approaches the synthesis of macrocyclic compounds v i a a c y c l i c presursors, S t i l l and Galynker used a macrocyclic precursor to control the stereochemistry of an a c y c l i c molecule. Vedejs and Gapinski (30)' have reported l o c a l conformational control in the epoxidation and osmylation of substituted 10-, 12- and 15-merabered cycloalkenes. While medium- and large-ring alkenes are known to be f l e x i b l e molecules with many low-energy conformations (31), ( i n contrast with the r i g i d i t y of other macrolides), the l o c a l ring segment containing the alkene tends to adopt only c e r t a i n geometries. Further r e s t r i c t i o n s i n conformational p o s s i b i l i t i e s arise for molecules having an a l l y l i c a l k y l substituent. In the case of (_Z)-alkenes, a l o c a l conformation i s favoured where the a l l y l i c a l k y l group can occupy a pseudoequatorial orientation as in 67. A pseudoequatorial a l l y l i c a l k y l group i s also observed in the (E)-alkene s e r i e s , and the l o c a l o l e f i n conformation can be described by a crownlike geometry as in 70. Attack of MCPBA (epoxidation) and OsO^ (osmylation) from the least hindered face i n 67_ resulted i n 68_ and 69_ as the sole products. Compounds 71_ and 7_2_ were obtained as the sole products from 70. Vedejs, Dolphin and Mastalerz (32) used this procedure for the stereocontrolled synthesis of an erythronolide fragment. The key step was the osmylation of the 9-membered-ring alkene 7_3 to give a single d i o l , 74, i n 75% y i e l d . - 37 -The syntheses of several complex macrolides have appeared in which ring conformation was used to control the stereochemistry of newly introduced asymmetric centres. Corey, et^ al_. (33) reported the t o t a l synthesis of erythronolide A, the aglycone of the a n t i b i o t i c erythromycin A, building on the chemistry that had been developed e a r l i e r for the t o t a l synthesis of erythronolide B (34). Absolute stereocontrol was used to e s t a b l i s h the r e l a t i v e stereochemistry of a complex a c y c l i c precursor, which was then lactonized. However, one reaction involving the introduction of new asymmetric centres came after the ring had been formed: 7_5 was epoxidized with MCPBA to q u a n t i t a t i v e l y give 76_. Considering the high s t e r e o s e l e c t i v i t y of t h i s r e a c t i o n , i t i s i n t e r e s t i n g to speculate whether the ring conformation could have been exploited to control the introduction of additional asymmetric centres. - 38 -- 39 -S t i l l , _et _al. (35) recently reported the t o t a l synthesis of the antileukemic baccharin B5. Most of the c h i r a l centres were established v i a absolute stereocontrol, but three centres were introduced by taking advangage of the conformational bias of the 18-raembered macrolide r i n g . Alkene 77_ was epoxidized with MCPBA i n 70% y i e l d to give 7_8_ with 15:1 stereose l e c t i o n . Following base mediated opening of the epoxide to give 79, hydroxyl-directed epoxidation with t e r t - b u t y l hydroperoxide and vanadyl acetylacetonate provided a 90% y i e l d of a single diastereomeric epoxide 80_. The stereocontrol demonstrated here i s excellent, and the number of steps required to introduce these three new asymmetric centres i s low. However, to f u l l y understand why the s t e r e o s e l e c t i v i t y i s so high, i t i s necessary (as seen throughout the preceding examples) to have some knowledge of the conformations of the molecule. Unfortunately, no explanation of th i s s t e r e o s e l e c t i v i t y was offered. Unlike the conformations of medium-size rings, the conformations of substituted large rings are not well understood. Recently, S t i l l and Novack (36) described a synthesis of the 16-raembered compound 81, a deoxy de r i v a t i v e of the aglycon 82_ of the macrolide a n t i b i o t i c acumycin (37) [also known as rosaramicin (38)]. In thi s synthesis most of the stereochemistry was introduced with conforma-t i o n a l stereocontrol; consequently the synthesis was much shorter than the macrolide syntheses which have used absolute stereocontrol to e s t a b l i s h r e l a t i v e stereochemistry. - 40 -0 C H 3 81 R = H 8 2 R=OH The f i r s t conformationally controlled reaction in the synthesis immediately followed formation of the macrocyclic r i n g . K i n e t i c deprotonation of 8_3 with potassium hexamethyldisilazane and a l k y l a t i o n with iodomethane produced a single C-8 methylated material, J$4_, i n 70% y i e l d and with 20:1 d i a s t e r e o s e l e c t i o n . (The k i n e t i c nature of t h i s and of the following a l k y l a t i o n reactions was demonstrated by base e q u i l i -bration of the alkylated product to a 1:1 diastereomeric mixture at the newly established asymmetric centre.) After hydrolysis of the t h i o k e t a l , the second side chain was introduced to give 85 with 20:1 r e g i o s e l e c t i v i t y for C-6 and 6:1 s t e r e o s e l e c t i v i t y for the ct-configura-t i o n , by using lithium hexamethyldisilazane and t e r t - b u t y l bromo-acetate. - 41 -Introduction of the C-4 methyl by a l k y l a t i o n of 85_ was accomp-li s h e d with high s t e r e o s e l e c t i v i t y , but unfortunately led to the unnatural 46-isomer j36_. This problem was resolved by protonation from the 6-face of a C-4 substituted enolate. The ketone 8_5 was deprotonated and treated with gaseous formaldehyde to give a single 4-hydroxymethyl ketone ( i n 62% y i e l d ) . The methylene ketone 87_ was generated by an elimination of the corresponding mesylate. Addition of thiophenol - 42 -COOtBu COOtBu 8 8 followed by Raney n i c k e l d e s u l f u r i z a t i o n gave the required 4a-compound 88 in 44% y i e l d with 25:1 s t e r e o s e l e c t i v i t y . Direct reduction of 88_ with sodium borohydride-cerium (III) chloride gave the 5 6-alcohol with 20:1 s t e r e o s e l e c t i v i e y . The desired 5a-alcohol 9_0_ was prepared with 5:1 s t e r e o s e l e c t i v i t y at C-5 by sodium borohydride reduction of the mixed - 43 -- 44 -anhydride 89_. Oxidation and epoxidation (MCPBA) lead to _91_ with 15:1 s t e r e o s e l e c t i v i t y . F i n a l l y , oxidation of 91_ gave 3-deoxyrosaranolide (81). In a l l , 11 k i n e t i c reactions were used in this synthesis to e s t a b l i s h the stereochemistry of 3-deoxyrosaranolide. The high degree of s t e r e o s e l e c t i v i t y of these reactions demonstrates the value of macro-c y c l i c stereocontrol as a strategy in the synthesis of complex mole-cules. Unfortunately no attempt to determine the conformations that are ultimately responsible for the success of t h i s strategy was reported. This survey of syntheses has shown that both medium- and l a r g e -r i n g compounds have conformational biases which can be exploited to control the s t e r e o s e l e c t i v i t y of reactions of these compounds. However, while the preferred conformations of medium-size rings were explained in d e t a i l , no conformations were described for the large-ring compounds. The factors c o n t r o l l i n g the conformational preferences of large- s i z e rings are not well understood. We decided to begin an inv e s t i g a t i o n of t h i s problem by examining the chemistry of simple macrolides. The aim of the project has been to develop an understanding of macrolide conformations which could be applied to the synthesis of more complex molecules. - 45 -RESULTS AND DISCUSSION I. B—Keto Lactone Synthesis Our approach to the synthesis of B-keto lactones involved the intramolecular alcoholysis of acylated Meldrum's acid d e r i v a t i v e s . The intermolecular v a r i a t i o n of t h i s reaction i s known (14,39) to provide (5-keto esters 92_ in good y i e l d by heating at reflux a solution of acetyl Meldrum's acid (24) and an alcohol in THF. Modification of t h i s procedure such that the acylated Meldrum's acid moiety and the alcohol are both contained in the same molecule would allow for intramolecular r e a c t i o n . The general strategy for the preparation of B-keto lactones i s given in Figure 10. A c t i v a t i o n of carboxylic acid 9_3_ and acylation of Meldrum's acid (31), followed by deprotection and thermolysis should provide the desired 3-keto lactones 19. The f i r s t step of the sequence was the preparation of protected hydroxy acids 93. The protecting group needed to be stable to carboxylic acid a c t i v a t i o n and to be e a s i l y removed in the presence of the l a b i l e Meldrum's acid moiety. The benzyloxy acids were therefore - 46 -19 Figure 10. Preparation of 6-keto lactones v i a intramolecular a l c o h o l y s i s . prepared as shown in Figure 11. Acid 98_ was prepared by heating at re f l u x a mixture of $-propiolactone (94) and benzyl alcohol (40). The acids 99, 100 and 101 were obtained by tre a t i n g ot-butyrolactone (95) , 6-valerolactone (96), and e-caprolactone (97) re s p e c t i v e l y with hydroxide and benzyl chloride (41). Yields are given in Figure 11. Benzyloxy acids of longer chain length were prepared by the sequence shown in Figure 12. Chloroalcohols 104 and 105 were prepared - 47 -o>CH20(CH2)nCOOH 0 II 95 n=3 96 n = 4 97 n = 5 Figure 11. Preparation of (D-benzyloxy acids. from 1,6-hexanediol (102) , and 1,8-octanediol (103) i n 67 and 60% r e s p e c t i v e l y , by heating the d i o l s with concentrated hydrochloric acid while the mixture was continuously extracted with toluene (42). Protec-t i o n of the alcohols as benzyl ethers proceeded in 90 and 97% respect-i v e l y . The chloroethers were then chain extended using the procedure of Fujisawa, ja_t _al. (43). The Grignard reagents prepared from the chlorides were coupled with 6-propiolactone in a copper(II)-catalyzed reaction (using lithium tetrachlorocuprate as catalyst) to give the K0H,$CH2CI 98 n = 2 (76%) 99 n = 3 (73%) 100 n = 4 (74%) 101 n = 5 (85%) - 48 -HCl, $ Me, A HO(CH2)n.2OH •HO(CH 2 ) n _ 2 CI 102 n = 8 103 n = IO 104 n= 8 105 n = 10 NaH, ^CH2Br THF, A I) M Q . T H F . A <^>CH20(CH2) C 0 0 H M oSCH20(CH2)n 2CI 2>rf° •—o 1 0 8 n =8 109 n =10 106 n = 8 107 n = IO Figure 12. Preparation of long-chain benzyloxy acids. carboxylic acids 108 and 109 in y i e l d s of 59 and 56% r e s p e c t i v e l y . Also i s o l a t e d from the reaction mixtures were quenched Grignard reagent and 3-chloropropanoic acid, the l a t t e r r e s u l t i n g from nucleophilic attack of chloride on 8-propiolactone. When the bromide corresponding to chloride 106 was used in the coupling reaction the only i s o l a t e d products were quenched Grignard reagent and 3-bromopropanoic ac i d . This l a t t e r r e s u l t presumably r e f l e c t s the greater n u c l e o p h i l i c i t y of bromide ion r e l a t i v e to c h l o r i d e . Meldrum's acid (31) (44) was prepared in 53% y i e l d from malonic acid and acetone, in the presence of acetic anhydride and a c a t a l y t i c amount of s u l f u r i c acid (Figure 13). - 49 -0 Q COOH 'COOH A c 2 0 0 31 Figure 13. Preparation of Meldrum1s acid. The carboxylic acids were activated by conversion to the corresponding acid chlorides. Thus, treatment of the acid 98_ with neat oxalyl chloride gave the acid chloride in good y i e ld . However, treat-ment of 99_ in the same manner resulted in cleavage of the benzyl ether -the only isolated products were benzyl chloride and y-butyrolactone. The addition of pyridine to remove the HC1 generated in the reaction solved this problem, and also catalyzed the desired reaction. Accord-ingly, carboxylic acids 100, 101, 108 and 109 were also treated with oxalyl chloride and pyridine. Use of pyridine with acid 98_, however, lead to the elimination of benzyl alcohol. The acid chlorides were not isolated, but were added immediately to a solution of the anion of Meldrum's acid, prepared by s t irr ing Meldrum's acid with pyridine in dichloromethane. Yields of the acylated derivatives following chromatography are given in Figure 14. - 50 -<£CH20(CH2)nCOOH O(COCl), ,(py) 2) py, CH2CI2 9bCH 20(CHJ n /r~° 0 1 1 0 n « 2 (76%) I I I n = 3 (84%) 1 1 2 n = 4 (80 %) 1 1 3 n = 5 (83 %) 1 1 4 n • 8 (63 %) 1 1 5 n = 10 (50 %) Figure 14. Acylation of Meldrum's a c i d . Deprotection of the alcohols by hydrogenolysis of the benzyl ethers proceeded i n 85-90% y i e l d for each compound to give the corres-ponding alcohols. The addition of a c a t a l y t i c amount of hydrochloric H 2 ,Pd/C, EtOAc y or H2 , Pd/C, EtOH, HCl H 0 ( C H ) 2 n 1 1 6 n=2 119 n = 5 1 1 7 n«3 1 2 0 n = 8 1 1 8 n«4 1 2 1 n = IO - 51 -acid g r e a t l y accelerated the rate of the reaction (45). Hydrogenolysis of compound 111 without acid c a t a l y s i s resulted in the formation of the enol ether 122 as the only isolated product (70% y i e l d ) . With acid c a t a l y s i s and a shorter reaction time the desired alcohol was obtained. The last step in the formation of the B-keto lactones 19_ was the intramolecular a l c o h o l y s i s . Thermolysis of 116 by the slow addition of a d i l u t e THF solution of t h i s compound to THF heated at reflux resulted in the 6-membered B-ketolactone 3-oxo-5-pentanolide (123) , an amorphous white s o l i d , i n 87% y i e l d . As far as we know, t h i s i s the f i r s t reported synthesis of t h i s compound (46). 0 122 0 116 123 - 52 -The lack of success previously encountered in the preparation of this compound may in part be due to i t s l a b i l i t y . (Hydrolysis occurs readily, on standing unless moisture i s r i g o r o u s l y excluded). It i s well known that the s - c i s - e s t e r conformation, that small-ring lactones are forced to adopt, i s less stable by _ca. 3 kcal/mole than the s-trans-conformation (47). (See p. 66 .) The s - c i s - e s t e r conformation i s therefore much more susceptible to hydrolysis than an open chain ester (48). The addition of a second carbonyl as i n 123 should increase the s t e r i c s t r a i n . As shown by the MM2 computer plot of t h i s compound (Figure 15), 123 i s nearly planar, a strained geometry for six-membered rings containing so many sp hybridized atoms. Figure 15. The MM2 plot of B-keto lactone 123. Thermolysis of the longest-chain member of the Meldrum's acid d e r i v a t i v e s , 121, gave the desired 14-membered B-keto lactone 3_4_ as a - 53 -white s o l i d i n 32% y i e l d , the same y i e l d as reported e a r l i e r (15). Unfortunately, attempts to form the 7-, 8-, 9- and 12-merabered B-keto lactones were e n t i r e l y unsuccessful. Upon thermolysis of 117, the enol ether 122 was obtained i n 80% y i e l d , demonstrating the k i n e t i c prefer-ence for formation of five-membered rings over seven-membered rings. Thermolysis of 118, 119 and 120 resulted primarily i n polymerization. A v a r i e t y of methods were attempted (very high d i l u t i o n , very long addition times, gas phase p y r o l y s i s , etc) with the same r e s u l t s . Chromatography yielded the dimers 124, 125 and 126 i n low y i e l d . Also i s o l a t e d from the thermolysis of 118 were 127 and 128. S i m i l a r l y , thermolysis of 120 resulted in a low y i e l d of 129, as well as dimer 126, but no desired 12-membered B-keto lactone. The preparation of B-keto lactones by the intramolecular alcoho-l y s i s of acylated Meldrum's acid derivatives i s successful for small-(6-membered) and large (14-membered) rings but not for medium-size rings (7- to 12-membered). This r e s u l t i s consistent with other reported methods of B-keto lactone formation (12,14) in that medium-size rings are d i f f i c u l t to obtain. It i s also consistent with the reported - 54 -127 128 r e a c t i v i t y p r o f i l e for lactone formation from w-bromoalkane-carboxylate ions (49), (Figure 16). The rate constant for the intramolecular reaction decreases r a p i d l y from the six-merabered to a minimum at the eight-merabered r i n g . C y c l i z a t i o n to the nine-membered ring i s almost as slow as to the eight-membered. It i s only with greater than 12-membered - 55 -Br (CH 2 ) n C0 2 " D M S 0 ' H a ° C H 2 C«=0 + Br Figure 16. R e a c t i v i t y p r o f i l e for lactone formation. rings that the rate constant has again increased s i g n i f i c a n t l y . In summary, th i s synthetic method has proved useful for the preparation of 6- and 14-raerabered 6-keto lactones, but was not success-f u l for intermediate ring s i z e s . The intramolecular a c y l a t i o n of an u>-hydroxy Meldrum's acid derivative has yielded the f i r s t synthesis of the unsubstituted 3-oxo-5-pentanolide (123). - 56 -I I . Conformations of 14-Membered Rings The objective of th i s project has been to acquire an understand-ing of the p r i n c i p l e s which control the regio- and stereochemistry of newly introduced substituents i n the synthesis of substituted 14-membered rings. To achieve t h i s goal, the main prerequisite i s a knowledge of the conformational preferences of the compounds i n question. Towards this end the ground-state conformations were used as a f i r s t approximation to the reactive conformations. Examination of molecular models of 14-membered rings could lead one to believe that the number of possible conformations for any one compound i s countless, i f not i n f i n i t e . Indeed, i t has been pointed out by Dale (50), who did much of the pioneering work in this f i e l d , that any d e s c r i p t i o n of the p o s s i b i l i t i e s of conformations of substituted large rings would be complex. Yet, by beginning with Dale's descriptions of the conforma-tions of the simple 14-membered rings, followed by analysis of the e f f e c t s that increasing molecular complexity w i l l have on conformation, i t i s possible to l i m i t the number of conformations which need to be considered. By eliminating disfavoured conformations at each l e v e l of complexity, the number of conformations which are possible for substituted 14-membered lactones can be reduced s u b s t a n t i a l l y . Following an understanding of the conformations adopted by these molecules, explanations of the observed experimental r e s u l t s are possible. - 57 -II.A. Cyclotetradecane The simplest 14-membered ring i s the hydrocarbon c y c l o t e t r a -decane. The conformations of this and other macrocyclic alkanes as well as t h e i r simple d e r i v a t i v e s have been described by Dale (6, 31, 50). S p a c e - f i l l i n g models were used to select conformations of macrocyclic hydrocarbons which have a minimum amount of s t r a i n , and which are therefore assumed to be preferred. He found that the most compact conformations are favoured over those with a large hole in the i n t e r i o r and that those conformations which consist of two p a r a l l e l , straight chains linked by two bridges of minimum length f i l l space most e f f i c i e n t l y . This geometry leads to a d e s c r i p t i o n of "rectangular" for these conformations. The s p a c e - f i l l i n g model computer plots of cyclotetradecane shown in Figure 17 demonstrate the compact nature of th i s type of conformation. (b) (a) Figure 17. S p a c e - f i l l i n g models of cyclotetradecane: (a) top-view (b) side-view. - 58 -In addition to adopting the most compact conformations, whenever possible the hydrocarbon skeletons of large rings follow the diamond l a t t i c e (a series of chair cyclohexane rings, as shown in Figure 19). The diamond l a t t i c e provides the only p o s s i b i l i t y for conformations with l i t t l e or no angle s t r a i n . Only even-numbered carbon rings can have skeletons without torsional s t r a i n , and only 14-, 18-, 22-, 26-, etc. (4n + 2 with n >^  3) membered rings can adopt the rectangular conformation free of torsi o n a l s t r a i n (31). The id e a l conformations are not the only ones which can be adopted by these large-ring compounds, although they are favoured e n e r g e t i c a l l y . The p o s s i b i l i t i e s for macrocyclic hydrocarbons have been described by Dale (6) , using a shorthand notation which describes the conformations as two-dimensional polygons. The notation consists of a series of numbers within brackets, each giving the number of bonds i n one side of the polygon, s t a r t i n g with the shortest. The d i r e c t i o n around the ri n g i s chosen so that the following number i s the smallest possible. The sum of these numbers gives the ring s i z e . The conformations of these compounds can also be depicted using a wedge-type representation in which the view i s from above the plane of the molecule. Perspective diagrams and MM2 computer plots of the three lowest-energy conformations of cyclotetradecane, the [3434], [3344] and [3335] conformations, are shown in Figure 18. The [3434] conformation i s a rectangular, diamond-lattice conformation. It i s this conformation which was used in Figure 17 to demonstrate the compact nature of rectangular conformations. In a l l - 59 -Figure 18. The lowest-energy conformations of cyclotetradecan (a) perspective diagrams ( s t e r i c energies kcal/mole) (b) corresponding MM2 p l o t s . - 60 -three quadrangular conformations shown, there are dist inct "corner" positions. It wi l l be seen that these corner positions possess special characterist ics . Included in Figure 18 are the steric energies calculated by the MM2 computer program, which show that the [3434] conformation has the lowest energy and hence should be preferred. The [3434] conformation of cyclotetradecane in fact has the least steric energy of a l l large-ring hydrocarbons (50a)). The difference in steric energy of the [3344] and [3335] conformations (1.1 and 2.2 kcal/mole respectively) from the [3434] conformation is in agreement with the values of 1.1 and 2.4 kcal/mole calculated by Dale (50b). These latter conformations are the lowest-energy non-diamond-lattice conformations because they come closest to following the diamond-lattice. In general, i t is more favourable to keep the main portion of the ring skeleton diamond-lattice-like and to concentrate strain at a few bonds than to distribute the strain over many bonds. For example, the non-diamond-lattice [3344] conformation differs from the diamond-lattice [3434] conformation only in the position of two carbon atoms. In addition to Dale's [3434] conformation and Perun's alternate diamond-lattice conformation (see Introduction), which have been referred to as Models A and B respectively, several new diamond models have been proposed (51) for some of the more highly unsaturated 14-merabered macrolides. Models A, B, C, D and F are shown in Figure 19. A l l of these models can be placed on the diamond lat t ice and hence are assumed to be relatively free of angle s train. Models C, D and F, - 61 -however, are l e s s commonly observed than the Dale and Perun models. The high degree of transannular int e r a c t i o n in these models makes them su i t a b l e only for s p e c i f i c examples. Except for highly substituted and highly unsaturated macrolides with demanding s t e r i c and geometric A(I7.5) B (24.3) C D(20.5) F Figure 19. Diamond models A, B, C, D and F. Steric energies in kcal/mole are given for selected conformations. requirements, 14-membered macrocycles should be expected to adopt the lowest-energy [3434] conformation. Cyclotetradecane, for example, in the s o l i d state has been shown by X-ray analysis (52) to exist in this conformation as predicted by Dale. MM2 calcu l a t i o n s of s t e r i c energies of cyclotetradecane (Figure 19) show the [3434] conformation (model A) - 62 -to be preferred over models B and D. (The steric energies of models C and F were not calculated). It seems unlikely that these additional models need to be considered as possible conformations of the simpler 14-membered macrocycles. II.B. Oxacyclotetradecane The next step in the progression towards more complex systems is to consider the effects substitutions wi l l have on the conformation of cyclotetradecane. Substitution of the ring carbons of a 14-membered ring (e .g. replacement of a methylene by NH or 0) should not influence the conformation of the ring i t s e l f , according to Dale (31), as no new angular strain is introduced. However, since some hydrogens are thereby eliminated, a proper disposition of one or more such groups wi l l reduce the number of steric interactions, particularly transannular hydrogen repulsions. The preferred positions for substitution in the ring can be determined by consideration of the hydrogen interactions in cyclotetra-decane as shown in Figure 20. Due to the high degree of symmetry in Figure 20. Hydrogen interactions of cyclotetradecane in the [3434] conformation (5). The severity of each interaction i s indicated as: - • >-© >-0. - 63 -t h i s conformation, there are only four unique positions of carbon atoms. These are la b e l l e d in Figure 20. The most severe interactions r e s u l t for the C-l hydrogen which i s directed towards the centre of the r i n g . One of the hydrogens at C-4, which i s also directed into the centre of the r i n g , i s the next most hindered, followed by the a x i a l C-2 hydrogen. The hydrogen atoms at C-3, the corner position in this rectangular conformation, do not have any transannular hydrogen-hydrogen i n t e r a c t i o n s . The preference for s u b s t i t u t i o n of a ring atom should therefore follow the order C-l > C-4 > C-2 > C-3. Figure 21 i l l u s t r a t e s the four possible d i s p o s i t i o n s of the oxygen atom in oxacyclotetradecane. The accompanying s t e r i c energies 17.6 20.6 23.1 19.3 Figure 21. The four possible conformations of oxacyclotetra-decane ( s t e r i c energies in kcal/mole). - 64 -show that the r e l i e f of s t e r i c i n t e r a c t i o n i s greatest from replacement of the carbon atom C-l and i s progressively less at C-4, C-2 and C-3 as expected. 1 II.C. Cyclotetradecanone and Cyclotetradecene The introduction of a double bond which i s external to the ring (C=0, C=CH2, etc.) should leave the ring conformation unchanged because the two C-H bonds can be considered to have been simply replaced by the two "bent bonds" of the exocyclic double bond. These groups would be expected, though, to occupy positions such that transannular hydrogen in t e r a c t i o n s can be removed, in the same manner as the oxygen in oxacyclotetradecane. The s t e r i c energies of the conformations shown in Figure 22 indicate that the preferred dispostions of the carbonyl in cyclotetradecanone are also at C-l and C-4. This preference has been demonstrated by X-ray cr y s t a l l o g r a p h i c analysis (53) and i s consistent with the low temperature C nmr spectrum of cyclotetradecanone (54). The introduction of an endocyclic double bond, in contrast to an e x o c y c l i c double bond, can have a dramatic e f f e c t on the ring conforma-ti o n . An endocyclic double bond forces four successive carbon atoms into a plane, thus creating s t r a i n i n the molecule. In rings of size As mentioned in the introduction, the s t e r i c energies calculated by MM2 can be used to compare conformational isomers, but not d i f f e r e n t compounds. Hence, the s t e r i c energies of the oxocyclotetradecane isomers cannot be d i r e c t l y compared with the s t e r i c energy of cyclotetradecane. - 65 -0 16.5 14.8 Figure 22. Conformations of cyclotetradecanone (steric energies in kcal/mole). greater than 12, a trans-double bond is favoured over a cis-double bond (31), as this minimizes the strain in the r ing . II.D. 14-Membered Lactones — Tridecanolide The functional group which is of greatest interest in this study, the lactone, can now be considered. The introduction of an ester-linkage into a saturated ring system may be expected to have a much more profound effect than just the sum of a carbonyl and an ether group. This is because of the electronic conjugation which tends to keep the ester group and the two neighbouring carbon atoms planar. The preferred - 66 -conformation of an ester i s the planar s-trans conformation (55) shown in Figure 23. The planar arrangement best enables the ester oxygen to share one lone pair of electrons with the i r-orbital system and thus r e s u l t s in considerable s t a b i l i z a t i o n . The s-trans conformation 130 i s 0 0 // // R - C R— C N 0 - R ' 0 (s-trons) R 130 (s-cis) 13! Figure 23. The two planar conformations of carboxylic e s t e r s . preferred over the s - c i s conformation 131 because of a secondary e l e c t r o n i c i n t e r a c t i o n . In the s-trans conformation, the ether oxygen has an electron pair oriented antiperiplanar to the C-0 a bond of the carbonyl group. This electron pair i s thus able to overlap with the antibonding o r b i t a l (a*) of that bond (Figure 24), leading to added s t a b i l i z a t i o n of approximately 3 kcal/mole (56). This s t a b i l i z a t i o n i s much less for the s-cis conformation due to the poor overlap of the oxygen lone pair o r b i t a l and the o * c o o r b i t a l . The symbolism s- c i s and s-trans ref e r s to the o r i e n t a t i o n of the two a l k y l groups, R and R', in Figure 23. The "s" symbolizes that the isomerism i s about a single bond as opposed to ci s - t r a n s isomerism about a double bond. The opposite nomenclature, in which c i s and trans refer to the o r i e n t a t i o n of the a l k y l group R' with respect to the carbonyl oxygen atom i s also sometimes used in the l i t e r a t u r e (47). - 67 -R Figure 24. Overlap of oxygen lone pair electrons with the a* orbita l in the s-trans conformation. Lactones of 10-merabered rings and larger are large enough to adoption of this conformation was f irs t demonstrated by dipole moment measurements. Unsubstituted 10- to 16-merabered lactones have dipole moments ranging from 1.86 to 2.01 Debyes (48), consistent with those of acyclic esters which range from 1.6 to 2.0 Debyes (47). The dipole moments of s-cis esters, on the other hand, are considerably higher. For example, in 6-valerolactone (132) where the carboxyl group is held r ig id ly in the s—cis conformation the dipole moment increases to 4.22 D (Figure 25). accommodate the ester in the preferred s-trans conformation. The 132 /x = 4 .22D s - cis /x = l.86D s-trons 133 Figure 25. Comparison of the dipole moments of 6-valerolactone (132) and tridecanolide (133). - 68 -The seven possible conformations of the 14-membered lactone tridecanolide in the [3434] conformation are given in Figure 26. Dale (31) has stated that there are only three ways of accommodating a planar s-trans ester group i n a 14-membered r i n g [3434] conformation. Examination of the p o s s i b i l i t i e s given i n Figure 26 reveals that 133e and 133f have s-cis arrangements, while 133c and 133d are not planar. 0 0 133a (17.7) 133b (17.5) o 133c (24.7) 133d (25.4) I33e (25.7) I33f (25.3) I33g (17.6) Figure 26. The possible conformations of tridecanolide ( s t e r i c energies in kcal/mole). - 69 -The remaining conformations, 133a, 133b and 133g, not only have the preferred s-trans ester configuration, they also minimize hydrogen-hydrogen i n t e r a c t i o n s . Since the energies of these three are very s i m i l a r , tridecanolide i s expected to exist as a mixture of these conformations. II.E. Alkyl Substitution on Cyclotetradecane Apart from the e f f e c t s of s u b s t i t u t i o n of ring carbon atoms, the e f f e c t s on conformation r e s u l t i n g from s u b s t i t u t i o n of hydrogen atoms must be considered. The Introduction of a single substituent into medium- and large-ring cycloalkanes i s not expected to influence the ring conformation (e.g [3434] vs [3344]), since there are a number of unhindered positions for the substituent (50a). The introduction of a s i n g l e substituent should therefore lead to a complex mixture of conformers d i f f e r i n g only in the choice of the substituent p o s i t i o n on the lowest-energy ring conformation. When two r i n g atoms are each s i n g l y substituted, some r e s t r i c t i o n s are introduced both for the c i s -and the trans-isomers, but there w i l l s t i l l be many p o s s i b i l i t i e s . A geminally disubstituted carbon i s always r e s t r i c t e d to a corner position in rings of size Cg-C^g on a simple s t e r i c hindrance argument: a gem-disubstituted carbon at a non-corner position w i l l have one of i t s substituents directed towards the centre of the ring (see, for example, Figure 20), a s i t u a t i o n which i s highly disfavoured. There i s an a d d i t i o n a l factor which favours the corner position even in rings large enough to accommodate substituents in c e r t a i n non-corner pos i t i o n s . As - 70 -shown in Figure 27, gem-disubstitution at a corner position introduces one less gauche interaction than at a non-corner p o s i t i o n . non-corner corner Figure 27. D i s u b s t i t u t i o n of an R group at a corner p o s i t i o n introduces one les s gauche i n t e r a c t i o n . An i n t e r e s t i n g point about gem-disubstitution at a corner posi-t i o n of a macrocyclic hydrocarbon i s that the two substituents are equivalent. Not only does neither substituent have any serious s t e r i c i n t e r a c t i o n s , but the interactions which do exist are equivalent for each substituent. This contrasts with cyclohexane-derived systems i n which there i s an energy penalty for a substituent being a x i a l . II.F. Monosubstituted 14-Membered Lactones - 13-Tetradecanolide The next l e v e l of complexity to be considered i s the substituted lactone. There are numerous substitutions which can be made on the 14-membered lactone, and each i n combination with the lactone f u n c t i o n a l i t y w i l l provide new constraints on possible conformations. One p a r t i c u l a r substituent which could be considered i s an a l k y l group at the C-13 p o s i t i o n , since a l l of the 14-membered macrolide a n t i b i o t i c s have an a l k y l group at this p o s i t i o n . Substitution of a methyl group at C-13 provides 13-tetradecanolide (134). - 71 -134 Building on the conformational preferences already described for tri d e c a n o l i d e (133), a li m i t e d number of possible conformations for 13-tetradecanolide need be considered. These p o s s i b i l i t i e s are shown i n Figure 28. Conformation 134d can be eliminated because the methyl group 134a (18.6) 134b (18.9) 134c (18.1) I34d (20.7) I34e (18.5) I34f (18.5) Figure 28. The possible conformations of 13-tetradecanolide ( s t e r i c energies in kcal/mole). - 72 -i s a x i a l , a s i t u a t i o n which i s disfavoured at non-corner positions of large-rings j u s t as i t i s disfavoured in cyclohexane systems. Of the remaining conformations, the methyl group i s in a favourable equatorial orientation in 134c and the other conformations each have the methyl substituent at a corner p o s i t i o n . As described above, these conformations with substituents at corner positions should be s t e r i c a l l y s i m i l a r and therefore almost equally favourable. Conformation 134b has a s t e r i c i n t e r a c t i o n betwen the corner methyl group and the carbonyl which raises i t s s t e r i c energy s l i g h t l y . Nevertheless, the s t e r i c energies given in Figure 28 show that a l l of the conformations except 134d are s i m i l a r i n energy. It would appear that there should be r e l a t i v e l y l i t t l e conformational preference for 13-tetradecanolide. However, experimental r e s u l t s (which w i l l be described l a t e r ) have indicated that even simple 14-membered lactones can exist in as few as one or two conformations. This means that there must be at least one more factor which has not yet been considered. It turns out that t h i s a d d i t i o n a l conformational preference i s not unique to this system, but has been observed in a c y c l i c esters as w e l l . Using the data from X-ray c r y s t a l s t r u c t r e s , Schweizer and Dunitz (55a) examined the bond angles of many carboxylic esters and found the following conformational preferences in the attachment of substituents. Esters of primary alcohols, 135, usually have a C-O-C-C torsion angle close to 180° - that i s , the C-C bond (bond 'c' in Figure 29) i s a n t i -periplanar to the ester C-0 bond (bond 'a'). For esters of secondary alcohols, 136, the conformational pattern i s d i f f e r e n t : u s u a l l y neither of the C-C bonds ('c' or 'd') i s near the antiperiplanar p o s i t i o n , but - 73 -0 H H O H 0 C ^ O - ^ c ^ O ^ c ^ o ^ c 135 136 137 Figure 29. Conformational preferences of substituted esters. the C-O-C-H torsion angle i n v a r i a b l y l i e s in the range 0-30°. Esters of t e r t i a r y alcohols, 137 , follow the same pattern as secondary alcohols (57). This conformational preference of esters has also been studied by gas phase low res o l u t i o n microwave spectroscopy (58a). Each of the examined compounds was found to have a single preferred rotamer in agreement with the conformations shown in Figure 29. No species was observed to possess a C-O-C-H to r s i o n angle of 180° (ie C-H bond a n t i -periplanar to C-0 bond), a conformation which was estimated to be approximately 2 kcal/mole higher in energy than the rotamer with the C-H bond synperiplanar to the C-0 bond. In addition, the b a r r i e r to rot a t i o n about the O-C bond (bond 'b' in Figure 29) was estimated to be about 5 kcal/mole i n esters of secondary alcohols. These r e s u l t s were confirmed by jab i n i t i o molecular o r b i t a l c a l c u l a t i o n s (58b) , which, together with the fact that the preferred conformations cannot be distinguished by the i r s t e r i c energies ( f o r example, Figure 28), indicates that the bar r i e r to rotation i s electronic in nature. A p p l i c a t i o n of t h i s conformational preference of esters to 13-tetradecanolide eliminates 134b and 134e as possible conformations, - 74 -leaving 134a, 134c and 134f as the remaining choices. Thus 13-tetra-decanolide should exist as a mixture of only these three conformations. This p r e d i c t i o n w i l l be discussed l a t e r in terms of nmr data. The conformations 134a, 134c. and 134f are r e a d i l y interconverted, with 134a and 134c each being transformed into 134f by a simple [3434] £ [4343] ring interconversion. This interconversion a c t u a l l y r e s u l t s i n very l i t t l e change in the atomic coordinates - i n both cases, two corners s h i f t by one carbon atom each so the four bond sides become three bond sides and vice versa. The energy b a r r i e r to such an i n t e r -conversion i s low. The analogous conformational energy b a r r i e r for cyclotetradecane was measured by Anet, Cheng and Wagner (59). Low temperature nmr studies afforded a value of approximately 7 kcal/mole, which i s l e s s than the 11 kcal/mole b a r r i e r f or a c h a i r - c h a i r interconversion i n cyclohexane. The b a r r i e r for 13-tetradecanolide should be of the same order of magnitude as cyclotetradecane, so conformation interconversion should occur r e a d i l y at room temperature. III. Synthesis and Conformations of 14-Membered Lactones The preceding discussion dealt with a si n g l e monosubstituted lactone. Other monosubstituted lactones could also be considered, but the goal of proceeding to more complex systems can best be accomplished by examining the conformational e f f e c t s generated by the addition of a second substituent to the monosubstituted lactone 134. Once again there are numerous positions which can be substituted. We chose to examine the chemistry of compounds with substituents 3 to the - 75 -138 carbonyl, beginning with the 8-keto lactone 3-oxo-13-tetradecanolide (138). There are two reasons for this choice. F i r s t , 8-keto esters and 8-keto lactones have been a central area of study in our laboratory for many years. The chemistry which has been developed for these compounds could be r e a d i l y extended to the present study. Second, the 14-membered macrolide a n t i b i o t i c s frequently have an oxygen substituent at the 8 p o s i t i o n . I I I . A Synthesis of 3-Oxo-13-Tetradecanolide The synthesis of 138 was carried out in the manner previously reported from our laboratory (14). The synthetic sequence i s i l l u s t r a t e d i n Figure 30. The f i r s t step i n the sequence was the mercury(II)-catalyzed Jones oxidation (60) of the terminal o l e f i n of 10-undecenoic acid (139) to give the keto acid 140 in 93% y i e l d . The bromoketone 141 was obtained in a quantitative crude y i e l d from 140 v i a a modified Hunsdiecker reaction (61). Unfortunately, t h i s reaction was not c o n s i s t e n t l y reproducible. Varying amounts of 1,8-dibromooctane were also produced as a r e s u l t of further reaction with the ketone - 76 -Hg(OAc)2,acetone, l-L,0 II ^ ( C H 2 ) 8 C O O H J o n e s r e o g e n t - ^ 139 OH NaBH (CH 2 ) e Br (CH2)8COOH 140 HgO, Br2, 1 CCI4,A 0 (CH2)8Br 142 141 Figure 30. Synthesis of 8-keto lactone 138. - 77 -(bromoform reaction). The best y i e l d s of 141 were obtained when a l i q u i d - l i q u i d extractor was used to a z e o t r o p i c a l l y remove the water produced in the reaction. The use of fresh bromine also appears to l i m i t the amount of side reaction (62). The bromoketone decomposes r e a d i l y upon d i s t i l l a t i o n , chromatography and even upon standing. It was therefore immediately reduced with sodium borohydride to provide the bromoalcohol 142 in 78% y i e l d from the keto acid 140, following p u r i f i c a t i o n by chromatography. It may be noted that this synthetic route involves an oxidation in the preparation of keto acid 140 and a reduction of the ketone immediately following the Hunsdiecker reaction. This would appear to involve an unnecessary oxidation-reduction sequence. However, attempts to perform the Hunsdiecker reaction on the hydroxy acid 144, prepared by oxyraercuration of o l e f i n 139, resulted in almost exclusive formation of dibromide 145. 3 OH Br 1 4 4 1 4 5 This experiment was performed by Dr. R.J. Sims. - 78 -Preparation of the a c y c l i c 6-keto ester 143 was accomplished in 100% y i e l d by the intermolecular alcoholysis reaction (39) of alcohol 142 and acetyl Meldrum's acid (24) prepared i n turn in 75% y i e l d by acylation of Meldrum's acid (31). Generation of the dianion (63) of 143 and subsequent c y c l i z a t i o n gave the 8-keto lactone 138 i n modest y i e l d . Addition of a s o l u t i o n of 143 i n THF, e i t h e r dropwise or in one portion, to a s o l u t i o n of l i t h i u m diisopropylamide (LDA) at 0°C followed by warming the reaction mixture to room temperature gave yields of 20-35%. Most alternate experimental conditions ( d i f f e r e n t bases, higher d i l u t i o n , etc.) did not s i g n i f i c a n t l y improve the y i e l d of the reaction. However, deprotonation of 143 at low temperature (-78°C) with subsequent warming to room temperature resulted in the highest y i e l d of 47%. GC analysis of the reaction showed that no c y c l i z a t i o n occurred at temperatures below -10°C. Additional GC s t u d i e s 3 showed that at 0°C, the proportion of 8-keto lactone product began to diminish prior to the complete consumption of s t a r t i n g material. The maximum amount of product was observed a f t e r a reaction time of 2-3 hours in t h i s study. The desired 6-keto lactone apparently undergoes a d d i t i o n a l condensation reactions, both i n the reaction mixture and as the crude product following work-up of the reaction. The r e s u l t i n g byproduct i s a gummy substance which remains at the o r i g i n during chromatography. The p u r i f i e d product, on the other hand, i s stable and can be stored for several months without decomposition. With 6-keto lactone 138 now i n hand, the synthetic consequences of the conformational preferences of d i s u b s t i t u t e d 14-membered lactones can be examined. - 79 -III.B. Stereoselective Reduction of 3-Oxo-13-Tetradecanolide The f i r s t reaction of 138 to be studied was hydride reduction, a reac-tion which proceeded with high s t e r e o s e l e c t i v i t y . Sodium borohydride produced a 3:1 r a t i o of the diastereomeric alcohols 146 and 147, while L-Selectride (Li(_s-Bu 3) BH) 3 afforded 146 as the sole product. The stereochemistry of each of the alcohols 146 and 147 was determined by X-ray cr y s t a l l o g r a p h i c analyses of the corresponding bromoacetates 148 and 149. The X-ray c r y s t a l structures are shown in Figure 31. Additional proof of the stereochemistry of the alcohols 146 and 147 came from a c h i r a l s y n t h e s i s 5 which was completed at about the same time that the X-ray c r y s t a l structures were obtained. This synthesis i s outlined in Figure 32. The sequence of reactions i s e s s e n t i a l l y the same as that described previously f o r the preparation of the racemic alcohol 146, except that the bromoalcohol 142 was prepared in c h i r a l form s t a r t i n g from propylene oxide. Reduction of the r e s u l t i n g B-keto lactone and separation of the major isomer gave enantiomerically pure 146. Treatment of t h i s alcohol with sodium phenylselenide opened the ring by an Sjj2 type reaction, and th i s was followed by removal of the selenide group with t r i - n - b u t y l t i n hydride to give the hydroxy acid 150. The o p t i c a l rotation of t h i s hydroxy acid { [ a ] D = + 1 1 ° (CHC13) } We are grateful to Dr. M.N. Ponnuswamy and Dr. J . Trotter for these X-ray c r y s t a l structure determinations. 5 T h i s synthesis was performed by Dr. R.J. Sims. - 80 -146 R = H 148 R= C0CH 2Br (Racemates) 147 R = H l49R=C0CH 2Br (Racemates) 148 149 Figure 31. The X-ray crystal structures of bromoacetates 148 and 149. - 81 -, , M ° ^ O H T H P 0 ( C H 2 ) 7 B r — ^ T H P 0 ( C H 2 ) 7 - ^ V ^ 2) 1) AcOH-H20-THF 2) TsCI, py 3) LiBr,ocetone,A OH 0 * ' T H F ' A B r ( C H 2 ) 8 / f ^ X, 2) LDA, THF 3) NoBH4 , EtOH 4) separation 142 146 major isomer 1) *SeeNa®, HMPA 2) Bu9SnH,rf.Me, AIBN OH C H 3 ( C H 2 ) | 0 ^ ) ^ C H 2 C O O H 150 Figure 32. Chira l synthesis of alcohol 146 to prove i t s stereochemistry. - 82 -agreed with that reported (64) for (2S_)-2-hydroxytridecanoic acid { [ a ] D = +14° (CHCI3)}. Alcohol 146 must therefore have the stereo-chemistry OS, 13S_) or [(3R*. 13R*) 6 for the racemic a l c o h o l ] , i n agreement with the X-ray data. The stereochemical outcome of the reduction of 138 depends upon which face of the ketone i s open to attack. An examination of the preferred conformations i s therefore i n order. As a r e s u l t of the preceding discussions, t h i s conformational analysis of (3-keto lactone 138 i s l i m i t e d to the conformations shown i n Figure 33. These p o s s i b i l i t i e s represent the addition of a ketone to the three preferred conformations of 13-tetradecanolide (134). Since a ketone i s not expected to change the conformation, a l l three should be acceptable. However, as described previously, the correct placement of a ketone can reduce the transannular hydrogen-hydrogen interactions of a 14-membered macrocycle. Since the three preferred conformations of 13-tetradecanolide a l l have s i m i l a r energies (see Figure 28), the most favourable conformation for 138 should be the one in which the ketone most e f f e c t i v e l y minimizes these i n t e r a c t i o n s . Figure 22 indicated that the best placement of the ketone should follow the order C-4 > C-2 > C-3, corresponding to a preferred order of 138b > 138c > 138a. This i s the same order given by the MM2 calculated s t e r i c energies (Figure 33). Placement of the ketone at the corner position as i n 138a should be the least favourable as i t does not r e l i e v e any serious hydrogen-hydrogen 6The nomenclature (3R*, 13R*) i s equivalent to the d e s c r i p t i o n (3S_, 13S_), (3R, 13R) for the racemic compound. - 83 -Figure 33. The possible conformations of 3-keto lactone 138: (a) diamond l a t t i c e ( s t e r i c energies in kcal/mole) (b) corresponding stereo s p a c e - f i l l i n g p l o t s . - 84 -i n t e r a c t i o n s . In a d d i t i o n , the two carbonyls in 138a are al igned such that they w i l l have unfavourable s t e r i c and dipole i n t e r a c t i o n s . Con-formation 138b should be preferred for 6-keto lactone 138. The proportions of these conformations can be estimated using the Boltzmann d i s t r i b u t i o n law. For two isomers A and B in e q u i l i b r i u m , the e q u i l i b r i u m constant K (the r a t i o of the number of A molecules , % , to the number of B molecules , Ng) i s given by Equation 1. E A and Eg are the energies of the two isomers, R i s the gas constant and T i s the N. K . - . e x p ( E A * V RT (1) absolute temperature. Using the ca lculated s t e r i c energies of 138a, 138b and 138c an estimate of t h e i r d i s t r i b u t i o n can be obta ined . For example, consider 138a and 138b at 2 5 ° C . Equation 1 becomes N 138b N 138a = exp (16 .8 -18 .8 )x l0 3 c a l mole" 1 ~ 1.986 ca l °K m o l e - 1 x 298°K = 29.4 S i m i l a r l y , the r a t i o 138b:138c i s 3 .3 :1 .0 . The r a t i o of the three con-formations i s 138a:138b:138c = 3:74:23. For p r a c t i c a l purposes the conf irmation 138a can be ignored and 138 can be considered to ex is t as an approximately 3:1 mixture of conformations 138b and 138c. The nmr spec tra l data of 138 supports th i s conclus ion regarding conformation. In p a r t i c u l a r , the geminal coupling constant of the C-4 - 85 -hydrogens i n f e r s the conformational preference. According to B a r f i e l d and Grant (65), the geminal coupling constant of methylene protons in a fixed o r i e n t a t i o n r e l a t i v e to an adjacent ir-systera varies with the angle ((J>) subtended between the ir-orbital and one of the methylene protons 2 3 (see 152 which i s a view of 151 along the bond j o i n i n g the sp and sp hybridized carbon atoms). The v a r i a t i o n of the ir-contr ibution to geminal coupling (J^) with o) i s given in Figure 34. Figure 34. The v a r i a t i o n of the IT-contribution to geminal coupling (J 7 1) with <j> (65). - 86 -It i s apparent that J"" i s largest when both methylene protons l i e to one side of the i r - o r b i t a l , as in 152. In contrast, J 1 1 i s small when the methylene protons l i e on opposite sides of the n-o r b i t a l as in 153. The numerical value of J u can be determined once the orientation (152 or 153) of the protons and the angle (<f>) have been measured. Examination of models and the angles obtained by MM2 c a l c u l a t i o n reveals that the C-4 protons i n 138a have the o r i e n t a t i o n shown in 153 with $ = 141°. This corresponds to a i t -contribution of approximately zero. The C-4 protons of 138b both l i e on the same side of the p o r b i t a l as i n 152 and <j> = 20°, corresponding to a J 7 1 value of approxiately -4.0 Hz. S i m i l a r l y , the C-4 protons of 138c both l i e on the same side of the p - o r b i t a l and <J> = 27°, giving a i r-contribution of approximately -4.2 Hz. If the base value of the geminal coupling constant i s taken as -14 Hz, conformation 138a would lead to a geminal coupling constant of -14 Hz, while 138b and 138c would each lead to a value of -18 Hz. The observed value of -18 Hz indicates that the B-keto lactone 138 exi s t s i n conformation 138b and/or 138c but not in 138a. This i s in agreement with the prediction made e a r l i e r . Examination of the s p a c e - f i l l i n g models i n Figure 33 reveals that 138b and 138c are each open to the attack of a reagent from only one face. The other face i n each case i s blocked by the bulk of the r i n g . Both conformations thus lead to a (3S_*, 13R*) configuration of the r e s u l t i n g a lcohol, which i s the stereochemistry observed for the minor product 147. - 87 -Conformation I38a i s the only one of the three which has i t s carbonyls aligned and hence i s the only one in which chelation of the carbonyls can occur. Chelation by the metal cation of the reducing agent i n 138a should lead to the lowest-energy t r a n s i t i o n state even though i t i s normally only a minor conformation. Examination of the s p a c e - f i l l i n g model of 138a reveals that the ketone carbonyl i s open to attack from both faces of the molecule, but with chelation the metal cation e f f e c t i v e l y blocks one face. Hydride attack from the open face leads to a (3R*, 13R*) configuration of the alcohol .which i s the stereochemistry of the major product 146. Figure 35 i l l u s t r a t e s the reduction of 138 in i t s three possible conformations. Both sodium borohydride and L-Selectride produce the trans-alcohol 146 as the major product. The fact that L-Selectride r e s u l t s in exclusive formation of 146 may r e f l e c t the greater a b i l i t y of a lithium cation r e l a t i v e to a sodium cation to chelate carbonyls, and thus hold the 8-keto lactone i n conformation 138a. For convenience, the (3j3*, 13R*) and (3R*, 13R*) compounds are referred to as c i s - and trans-disubstituted lactones r e s p e c t i v e l y . It should be pointed out that the c i s (both substituents up or both substituents down) and trans (one substituent up and the other down) rel a t i o n s h i p s depend on the conformation of the r i n g . The R, j3 system i s more exact, but the c i s , trans d e s c r i p t i o n i s simpler and i s applicable to a l l molecules to be discussed. - 88 -138 b • # 147(cis or 32 ,I3R ) 138 c VI" 138 a 147 (as or 3S , I3R* ) HO 146 (trans or 3R*,I3R*) igure 35. Hydride reduction of the 3-keto lactone 138 in i t s possible conformations. Product molecules are not necessarily shown in their preferred conformations. - 89 -III.C. Conformations of 3 ,13-Dlsubstituted Lactones - Dihedral Maps In addition to proving the relative stereochemistry of the alcohols 146 and 147, the X-ray analyses of the corresponding bromo-acetates 148 and 149 provided valuable information about the conformations of the molecules. Relating the crystal structures directly to conformations, such as those in Figure 19, by visual inspection, however, is d i f f i c u l t . A more convenient method is the examination of the dihedral or torsional angles of the molecule. The value of this procedure is that the complete set of the dihedral angles formed by the ring atoms will always define the conformation. "Dihedral maps", such as those shown in Figures 37 and 38, provide a simplified two-dimensional representation of the conformation. To prepare a map, the dihedral angles of a conformation (obtained from MM2 calculation or Inspection of models) are plotted on a graph consisting of concentric circles which represent the dihedral angles. Starting from the outermost circ l e and progressing towards the centre, the circles represent angles of 180°, 120°, 60°, 0°, -60°, -120° and -180°. The dihedral angle about each bond is plotted and numbered as shown. The sign of each angle is determined from the following definition: the sign of angle A-B-C-D when looking through B towards C is positive when D is clockwise from A (Figure 36). Furthermore, an angle of +180° is equivalent to an angle of -180° so these angles are interchangeable on the map. Inversion of the sign of a l l angles results in a map of a mirror image conformation. Finally, to compare two molecules in the same conformation, the direction around the ring should be the same for - 90 -Figure 36. Dihedral angles: Angle A-B-C-D i s p o s i t i v e i f D i s clockwise from A. should be the same for each, since clockwise and counterclockwise operations r e s u l t i n mirror image maps. The dihedral map of any one conformation i s unique, so the conformation of a given molecule can be determined simply by comparison of i t s map with that of a known conformation. An added feature of the dihedral map i s that the symmetry of the conformation i s r e f l e c t e d in the symmetry of the map. Using the dihedral map as a diagnostic t o o l , the conformations revealed by the X-ray structures can e a s i l y be analyzed. The X-ray analysis of the cis-bromoacetate 149 showed that i n the c r y s t a l l i n e state t h i s molecule exists as a 1:1 mixture of two conformations. The dihedral maps of these conformations are given in Figure 37 and indicate that one i s the expected [3434] conformation and that the other i s the [3344] conformation. (Dihedral maps of the [3434] and [3344] model conformations of cyclotetradecane are given f o r comparison.) As described previously, and as can be seen in Figure 37, the [3344] conformation deviates from the [3434] conformation only i n the position of two carbon atoms and three dihedral angles. - 91 -(O (d) 37. Dihedral maps: (a) [3434] X-ray structure of 1^9 (b) [3434] cyclotetradecane model (c) [3344] X-ray structure of 149 (d) [3344] cyclotetradecane model. - 92 -The X-ray analysis of the trans-bromoacetate 148 showed that this compound exists i n only one conformation in the s o l i d state. The dihedral map given in Figure 38 shows t h i s to be the [3335] conforma-t i o n . The adoption of th i s conformation, rather than the [3434] (a) (b) Figure 38. Dihedral maps: (a) [3335] X-ray structure of 148 (b) [3335] cyclotetradecane model. conformation i s presumably due to better packing of the c r y s t a l l a t t i c e . It w i l l be seen in subsequent sections that the [3434] conformation i s preferred in so l u t i o n . - 93 -III.D. Conformations of 3,13-Disubstituted Lactones - MM2 Calculations The X-ray data c l e a r l y def ines the conformations which are adopted by the two bromoacetates in the s o l i d s tate . However, for the major i ty of synthet ic manipulations a knowledge of the preferred conformations in so lut ion i s r e q u i r e d . Since the conformations in s o l u t i o n are not n e c e s s a r i l y the same as those adopted in the s o l i d s ta t e , a d d i t i o n a l information must be obtained. MM2 c a l c u l a t i o n s , which inc lude only intramolecular s t e r i c and d ipo le i n t e r a c t i o n s , provide the preferred conformations in the gas phase. Nevertheless , these c a l c u l a t i o n s can be used to v e r i f y the pred ic t i ons of conformations in s o l u t i o n . As representat ive examples of the 3 ,13 -d i subs t i tu ted 14-membered macrol ides , the conformational preferences of the c i s - and trans-dimethyl lactones 154 and 155 w i l l be 154 155 descr ibed . Other 3 ,13 -d i subs t i tu ted lactones should have s i m i l a r preferences . The c i s -d imethy l lac tone 154 i s shown in Figure 39 in the [3434 ] (154a) and [3344] (154b) conformations observed for the cis-bromoacetate 149. As expected, the [3434] conformation i s lower i n energy. 154a (19.9) 154b (20.5) Figure 39. The [3434] and [3344] conformations of the cis-dimethyllactone 154. ( s t e r i c energies in kcal/mole). Conformer 154a i s also lower in energy than the other two possible [3434] conformations (Figure 40), since 154c has a methyl group directed 0 0 154a (19.9) 154c (24.1) I54d (21.1) Figure 40. The possible [3434] conformations of 154 ( s t e r i c energies i n kcal/mole). - 95 -int o the s t e r i c a l l y crowded centre of the ring and 154d has an a x i a l methyl group, both situations being disfavoured. The calculated s t e r i c energies lead to an approximate Boltzraann d i s t r i b u t i o n of 154a:154b:154d = 67:24:9. (The proportion of conforma-t i o n 154c i s n e g l i g i b l e . ) Compound 154 should therefore exist primarily as a 3:1 mixture of conformers 154a and 154b, the [3434] and [3344] conformations. Since these two conformations are i d e n t i c a l i n the portion of the molecule containing the f u n c t i o n a l i t y , i t w i l l s u f f i c e to describe the chemistry of the c i s - d i s u b s t i t u t e d compounds i n terms of conformation 154a. A s i m i l a r analysis shows that the [3434] conformation i s also favoured for the trans-dimethyl lactone 155. Figure 41 compares the [3434] conformation 155a with the isomer 155b which has the [3335] 155a (19.0) I55b (21.2) Figure 41. The [3434] and [3335] conformations of the trans-dimethyllactone 155 ( s t e r i c energies i n i n kcal/mole). - 96 -conformation observed for the trans-bromoacetate 148. Conformer 155a has the lower energy and hence should be pre ferred . Figure 42 compares poss ib le [3434] conformations of 155. In conformation 155c the trans-annular hydrogen in terac t ions are more serious than in 155a, while 155d has a serious raethyl-carbonyl i n t e r a c t i o n . The ca lcu la ted s t e r i c energies show 155a to be favoured over those conformations as w e l l . 1550(19.0) 155c (19.8) I55d(20.4) Figure 42. The poss ible [3434] conformations of 155 ( s t e r i c energies in kca l /mole ) . The Boltzmann d i s t r i b u t i o n of these conformations i s 155a;155b: 155c:155d = 71:4:18:7. The t r a n s - d i s u b s t i t u t e d lactones should there-fore exis t p r i m a r i l y as a 4:1 mixture of conformers 155a and 155c. As w i l l be seen, these two conformations are very s i m i l a r in t h e i r chemistry . The above d i scuss ion ind ica tes that the c i s - d i s u b s t i t u t e d lactones can be considered as a s ing le conformation about the lactone port ion of the r i n g , while the t r a n s - d i s u b s t i t u t e d lactones should ex i s t p r i m a r i l y as a mixture of two conformations. These pred ic t ions w i l l be discussed in terms of nmr s p e c t r a l data fo l lowing d e s c r i p t i o n s of the preparat ion of several members of each s e r i e s . - 97 -I I I . E . The Relative Bates of Reaction of c i s - and trans-3,13-Disub8tituted 14-Membered Lactones An experimental approach to studying the d i f f erences of the conformations adopted by the c i s - and t r a n s - d i s u b s t i t u t e d lactones i s the determination of the r e l a t i v e rates of r e a c t i v i t y of diastereomeric pa ir s of compounds. For th i s study, the r e l a t i v e rates were measured for the fo l lowing react ions: a c e t y l a t i o n of the a lcohols 146 and 147, preparat ion of the j>-toluenesulfonates of 146 and 147, hydro lys i s of the acetates , and ox idat ion of 146 and 147 to the 6-keto lactone 138. It i s well known that diastereomeric cyclohexanols ( for example, s t e r o l s ) react at much d i f f e r e n t r a t e s . F ieser and Fieser (66) made the fo l lowing genera l i za t ions regarding the react ions of diastereomeric s t e r o i d s : 1) An equator ia l hydroxyl group i s more e a s i l y acylated than an a x i a l group at the same p o s i t i o n . S i m i l a r l y , an equator ia l ester i s more r e a d i l y hydro lyzed . In each case, the equator ia l isomer has a reac t ion rate which i s two to three times greater than that of the a x i a l isomer. This d i f f erence is a t t r i b u t e d to the s t e r i c crowding of the t e t rahedra l intermediates of the a x i a l isomers r e s u l t i n g from 1 , 3 - d i a x i a l i n t e r a c t i o n s . 2) Oxidat ion of an a x i a l a lcohol i s in the order of 10 times faster than the corresponding equator ia l isomer. In ox idat ions invo lv ing chromic acid reagents, formation of the In ter -mediate chromate ester i s f a s t , while cleavage of the carbon-hydrogen bond i s the rate-determining s tep. Reaction of the a x i a l intermediate proceeds r a p i d l y to r e l i e v e s t e r i c s t r a i n . To measure the r e l a t i v e rates of r e a c t i v i t y of diastereomeric d i subs t i tu ted 14-membered lac tones , a mixture of a pa ir of diastereomers - 98 -was subjected to the appropriate reac t ion c o n d i t i o n s . The appearance of products and disappearance of s t a r t i n g mater ia l s were monitored by GC ana lys i s and the r e l a t i v e abundance of each component was then used as the concentrat ion of that component. Since the intent ion i s simply to measure the r e l a t i v e rate of r eac t ion of a mixture of diastereoraers, the r e l a t i v e concentrat ion of each reactant i s s a t i s f a c t o r y . The rate equation of t h i s type of reac t ion is given by Equation 2 log[A] = k A / k g log[B] + m (2) (See Appendix A for the d e r i v a t i o n of th i s equat ion) . The slope of a p lo t of log [A] vs log [B] , where [A] and [B] are the concentrations of A and B at time t , • w i l l be k/^/kg. Since k^ and kg are the rate constants for components A and B, k^/kg i s the r e l a t i v e rate of r e a c t i o n . P r i o r to d i scuss ing the k i n e t i c s experiments, one a d d i t i o n a l f a c t o r r e l a t i n g to conformation must be considered: the t rans -d i s u b s t i t u t e d a lcohol 146 exh ib i t s intramolecular hydrogen-bonding. Evidence of hydrogen-bonding i s provided by the fo l lowing experimental da ta . The in frared spectrum of 146 does not contain the free OH bond absorpt ion which i s observed at 3630 c m - 1 for the c i s - i somer 147. As w e l l , the carbonyl bond absorption appears at 1715 c m - 1 for 146 compared to 1725 c m - 1 for 147. The lower frequency i s expected for a hydrogen-bonded carbony l . The Rf value on thin layer chromatography ( t i c ) i s higher for 146 than for 147 - the hydrogen-bonded a lcohol of 146 i s l ess able to hydrogen-bond to the s i l i c a gel than 147, and hence t r a v e l s f a s t e r . - 99 -Of the three possible conformations for 146 (Figure 43), only 146a provides an opportunity for hydrogen-bonding. As discussed above H / \ I46a 146b 146c Figure 43. The possible conformations of alcohol 146. for the chelation of 3-keto lactone 138, the s t a b i l i z a t i o n imparted by hydrogen-bonding may lead to the adoption of a disfavoured conformation. The k i n e t i c s experiments can now be discussed and considered in terms of the preferred conformations of the compounds. Acetylation of the alcohols 146 and 147 in the presence of DMAP was accomplished in y i e l d s of 88% and 90% res p e c t i v e l y , affording acetates 156 and 157. To measure the r e l a t i v e rates of reaction, the DMAP was omitted, r e s u l t i n g i n a much slower reaction which was more suit a b l e for monitoring. The data for th i s reaction i s presented i n Table 2. Given i n Figure 44 i s a plot of the GC percentages of the diastereomeric acetates vs time. Also given i s a plot of the logarithms of the GC percentages at various times (log [157] vs log - 100 -Table 2 Ki n e t i c data for acetylation of alcohols 146 and 147 time % acetate % acetate log (% acetate log (% acetate (h) 156 157 156) 157) 0.5 1.8 - - — 1.0 4.3 1.9 0.63 0.28 1.5 5.7 2.6 0.76 0.42 2.0 9.1 3.9 0.959 0.59 2.5 10.0 4.6 1.000 0.63 3.0 12.1 5.4 1.083 0.73 4.0 17.7 7.8 1.248 0.89 5.0 19.2 8.6 1.283 0.934 6.0 26.7 11.9 1.427 1.076 10.5 44.2 19.4 1.645 1.288 21.0 66.9 26.4 1.825 1.422 23.0 68.7 26.9 1.837 1.430 - 101 -80-1 time (h) l .80- | I.60H .20-1 1 1 1 1 1 1 1 1 1 — .20 4 0 .60 .80 1.00 L20 1.40 160 L80 2 0 0 log (% ocetate 156) Figure 44. Plots of the k i n e t i c data for acetylation of alcohols 146 and 14 7. - 102 -[156] ). The slope of the l a t t e r plot (calculated by least squares analysis) i s very near unity (see Table 6) indic a t i n g that both alcohols react at the same rate under these conditions. The tetrahedral intermediates of the two diastereoraers are shown i n Figure 45. The conformation of intermediate 159 should be disfavoured according to the preceding discussions. However, this conformation i s necessary to explain the observed r e l a t i v e rates of a c e t y l a t i o n of the two alcohols. If the trans-alcohol i s deprotonated and the r e s u l t i n g alkoxide reacts without changing conformation, intermediate 159 would be obtained. In order for there to be no AcO P 158 159 Figure 45. Tetrahedral intermediates i n acetate formation. conformational change of the alkoxide, i t must be assumed that the rate determining step in the formation of 159 i s faster than any conformational change. The r e l a t i v e rate of reaction of the two alcohols should depend upon the s t e r i c crowding of the intermediates 158 and 159. But in these conformations the forming acetates are at corner positions with similar - 103 -s t e r i c i n t e r a c t i o n s . The observation that both isomers react at the same rate i s not surprising i f the reactions proceed through these intermediates. Any conformational change should a l t e r the s t e r i c environments of the intermediates and hence should modify the r e l a t i v e rate of reaction, i f only s l i g h t l y . The fact that the rates are the same indicates that a conformational change does not occur. The rates of reaction were found to be the same at both -25° and -115°C. (See Table 6 ) . The mechanism for formation of the _p_-toluenesulfonates of alcohols 146 and 147 should be similar to ace t y l a t i o n . Indeed, both alcohols reacted to form tosyLates at the same rate (see Table 6). Preparation of the i n d i v i d u a l sulfonates 160 and 161 was accomplished in 85% and 83% re s p e c t i v e l y . The ki n e t i c data for the determination of r e l a t i v e rates i s presented in Table 3, and the plots of % sulfonate vs time and log [161] vs log [160] are given in Figure 46. The alcohols 146 and 147 were obtained i n 91% y i e l d by base-catalyzed (Na 2C03) t r a n s e s t e r i f i c a t i o n of a mixture of the acetates 156 and 157 with methanol. A repeat of t h i s reaction gave the k i n e t i c data presented in Table 4. The plots of % acetate vs time and log [156] vs log [157] are given in Figure 47. The cis-isomer 157 was found to react approximately 1.2 times fas t e r than the trans-isomer. Both of the tetrahedral intermediates shown in Figure 48 have similar s t e r i c environments, but the difference - 104 -Table 3 K i n e t i c data for formation of sulfonates 160 and 161 time % alcohol % alcohol log (% alcohol log (% alcohol (h) 146 147 146) 147) 0 69.9 28.4 1.844 1.453 1 69.5 27.9 1.842 1.445 2 65.0 26.6 1.813 1.424 2.5 63.3 25.8 1.802 1.412 3 57.8 23.8 1.762 1.377 4 58.9 23.2 1.770 1.366 5 58.7 22.7 1.769 1.355 7.5 52.2 21.0 1.717 1.323 20 25.0 10.9 1.398 1.035 22 22.0 9.6 1.343 0.984 25.5 20.2 7.8 1.306 0.89 43.5 12.3 4.9 1.090 0.69 53.5 9.1 4.4 0.960 0.65 67.5 5.6 2.5 0.75 0.39 68.5 5.5 2.5 0.74 0.39 120 2.5 1.1 0.40 0.04 - 105 -K> 20 50 40 50 60 70 80 90 100 IK) 120 time(h) Figure 46. Plots of the k i n e t i c data for formation of sulfonates 160 and 161. - 106 -80 H i -I 1 1 1 1 "——i 1 1— .40 .60 BO 100 1.20 140 160 L80 £ 0 0 log (% ocetote 156) Figure 47. Plots of the k i n e t i c data for cleavage acetates 156 and 157. - 107 -Table 4 K i n e t i c data for cleavage of acetates 156 and 157 (0.18 M) time % acetate % acetate log (% acetate log (% acetate (h) 156 157 156) 157) 0 70.5 26.1 1.848 1.417 0.25 69.9 25.5 1.845 1.407 0.5 70.9 26.0 1.851 1.415 1.0 68.4 24.3 1.835 1.386 1.5 50.4 17.3 1.702 1.238 2.0 48.1 15.5 1.682 1.190 2.67 30.5 9.4 1.484 0.973 3.0 32.0 9.2 1.505 0.964 4.0 14.9 3.7 1.173 0.57 5.0 13.4 - - -6.0 4.5 - - — MeO 162 Figure 48. Tetrahedral intermediates in t r a n s e s t e r i f i c a t i o n of acetates 156 and 157. - 108 -i n reaction rates would indicate that the s t e r i c crowding i n the trans-isomer 162 i s s l i g h t l y greater. The l a s t reaction for which the r e l a t i v e rate of reaction was determined i s the oxidation of the alcohols 146 and 147 to the B-keto lactone 138. Oxidation of a mixture of the alcohols with pyridinium dichromate (PDC) in DMF (67) gave 138_ i n 78% y i e l d . Oxidation with pyridinium chlorochromate (PCC) i n dichloromethane (68) was also e f f e c t i v e . The r e l a t i v e rate of oxidation of the two alcohols with PDC was determined by monitoring a reaction which contained the hydrocarbon eicosane as an in t e r n a l standard and following the disappearance of the alcohols. This was found to be necessary because the B-keto lactone decomposes under the GC conditions employed. The k i n e t i c data obtained from t h i s reaction i s presented i n Table 5, and plots of % alcohol vs time as well as log [ 147] vs log [ 146] are given i n Figure 49. The r e l a t i v e rate calculated from the l a t t e r plot shows that the cis-isomer 147 reacts approximately 1.5 times faster than the trans-isomer 146 (see Table 6) under these conditions. Chelation of the trans-isomer as shown i n Figure 50 presumably accounts for i t s lower r e a c t i v i t y . The t r a n s i t i o n state energy of the rate-determining step of carbon-hydrogen bond breaking should be similar for each isomer, but the ground state s t a b i l i z a t i o n of the trans-chrornate ester of 147 by chelation should increase the e f f e c t i v e t r a n s i t i o n state energy b a r r i e r leading to a slower reaction for th i s isomer. - 109 -Figure 49. Plots of the k i n e t i c data for oxidation of alcohols 146 and 147. - no -Table 5 K i n e t i c data for oxidation of alcohols 146 and 147 time % alcohol % alcohol % eicosane log % log % (h) 146 147 % 146 % 147 % eicosane % eicosane x 100 x 100 0.0 60.1 21.9 15.3 2.593 2.155 0.25 60.6 21.4 16.2 2.573 2.122 0.5 60.4 20.1 18.2 2.520 2.043 0.75 59.0 18.9 18.9 2.494 1.999 1.0 57.5 17.6 20.8 2.441 1.927 1.5 57.7 16.6 22.2 2.415 1.876 2.0 57.2 14.1 24.3 2.371 1.764 3.0 51.8 12.4 27.1 2.280 1.660 4.0 48.6 9.8 32.3 2.177 1.482 5.0 44.2 8.1 36.7 2.081 1.344 6.0 42.7 7.2 35.2 2.085 1.31 7.0 41.6 6.6 39.1 2.026 1.23 11.0 33.0 4.1 46.3 1.853 0.95 25.5 24.6 2.9 53.1 1.666 0.74 1/ Cr '" A Figure 50. Intermediate chromate esters i n the oxidation of alcohols (a) 147 and (b) 146. Table 6 Experimentally determined r e l a t i v e rates of reaction Reaction Reaction Relative Standard Deviation Conditions Rate of Relative Rate acetate formation r t 147 : 146 0.96: 1.00 0.01 -25°C 147 :146 = 0.95: 1.00 0.02 -115°C 147 :146 = 1.03: 1.00 0.02 sulfonate formation 147 :146 = 0.96: 1.00 0.01 naphthalene as i n t e r n a l standard 147 :146 = 1.05: 1.00 0.06 acetate cleavage 0.18 M acetate and 0.18 M Na 2C0 3 157 :156 1.25: 1.00 0.02 157 : 156 = 1.16: 1.00 0.02 0.09 M acetate and 0.18 M Na 2C0 3 157 :156 1.18: 1.00 0.01 157 :156 = 1.22: 1.00 0.05 oxidation PDC, eicosane as i n t e r n a l standard 147 :146 1.64: 1.00 0.01 147 :146 = 1.35: 1.00 0.04 - 112 -The r e s u l t s of a l l the k i n e t i c experiments are summarized . in Table 6. Comparison of the r e l a t i v e rates of reaction of the diastereomeric pairs of compounds which were examined with those of diastereomers in systems such as sterols reveals a much lower rate d i f f e r e n c e for the large-ring p a i r s . This suggests a major difference between the chemistry of six-membered rings and that of large r i n g s . The r e l a t i v e rates of reaction f o r l a r g e - r i n g compounds are not necessa r i l y affected by stereochemistry since the placement of an asymmetric centre at a corner p o s i t i o n w i l l provide two diastereomers which have nearly equivalent s t e r i c i n t e r a c t i o n s . Even when two diastereomers do not adopt the same conformation, as i s the case for acetates 156 and 157, the diffe r e n c e i n r e l a t i v e rates i s not high because the compounds each adopt conformations that minimize s t e r i c interac t i o n s . III.F. Preparation of a,B-Unsaturated Lactones E l i m i n a t i o n of the sulfonates 160 and 161 yielded a mixture of the E_- and ^ - o l e f i n s 163 and 164. Most bases, including 1,8-diaza-bicyclo[5.4.0]undec-7-ene (DBU) , 1,8-bis(dimethylamino)naphthalene 163 164 - 113 -(Proton Sponge), potassium carbonate, and potassium carbonate with l8-crown-6, i n toluene lead to predominant formation of the E - o l e f i n 163. Freshly sublimed potassium tert-butoxide, on the other hand, reversed the r a t i o of o l e f i n s , giving primarily the Z - o l e f i n 164. If the butoxide was not freshl y sublimed, however, the major product obtained was the E_-isomer. Presumably hydroxide i s the actual base i n th i s l a s t reaction. These elimination r e s u l t s can be explained i n terms of the conformation which i s adopted by the reacting species. In the preferred conformation 160a of the Jtrans-sulfonate, H-2a i s in the plane of the carbonyl while H-2b i s perpendicular to this plane. It i s well known that a hydrogen which i s perpendicular to the plane of the carbonyl w i l l be abstracted p r e f e r e n t i a l l y since t h i s allows for the best overlap between the r e s u l t i n g carbanion and the p-or b i t a l s of the ir-bond (69). The removal of H-2b in 160a with a base such as DBU and subsequent loss of the sulfonate leaves hydrogens H-2a and H-3 in a trans r e l a t i o n s h i p leading to the E - o l e f i n 163. In the preferred conformation 161a of the ci s - s u l f o n a t e , the H-2 hydrogens each have the same o r i e n t a t i o n with respect to the carbonyl, an orientation which leaves neither hydrogen either in the plane of the 160a - 114 -carbonyl or perpendicular to i t . These two hydrogens are, however, very d i f f e r e n t s t e r i c a l l y , with H-2a being the more accessible of the two. P r e f e r e n t i a l base abstraction of the least hindered proton i s also a well-known phenomenon i n organic synthesis (70). Removal of H-2a with DBU and subsequent loss of sulfonate leaves H-2b and H-3 i n the trans o r i e n t a t i o n of the E-double bond. Potassium tert-butoxide operates in a d i f f e r e n t manner than bases such as DBU. It i s known that the potassium cation w i l l coordinate to an oxygen-containing leaving group, thus modifying the course of the reaction (71). The use of potassium tert-butoxide in the elimination of sulfonates 160 and 161 could lead to a change of conformation such that the carbonyl and the sulfonate are chelated by the potassium cation. As was indicated by the hydrogen-bond ing in alcohol 146 and by the chela-tion in the chromate ester of 146, only one conformation has the correct geometry for c h e l a t i o n . Chelation of the sulfonates should thus r e s u l t in the conformations 160b and 161b. The energy s t a b i l i z a t i o n derived from chelation should compensate for the unfavourable substituent orientations in these conformations. - 115 -K + K + 160 b 161 b Hydrogen abstraction from the sulfonates i n conformations 160b and 161 b w i l l be the same as that described for 161b ( i . e . H-2a) . Removal of hydrogen and loss of sulfonate from the compounds in these conformations w i l l r e s u l t in a trans r e l a t i o n s h i p between the carbonyl and H-3, the r e l a t i o n s h i p seen in the Z - o l e f i n . Chelation thus reverses the product d i s t r i b u t i o n . The ground state s t a b i l i z a t i o n due to chelation e f f e c t i v e l y increases the t r a n s i t i o n state energy b a r r i e r , s i m i l a r to that described for the oxidation of 146 with PDC. It i s not su r p r i s i n g then that e l i m i n a t i o n reactions which involve the use of potassium tert-butoxide as base are slower than the corresponding DBU eliminations, in the same manner as the chelated chromate ester was slower to react. The explanations proposed above a l l involve syn-eliminations of j>-toluenesulfonic a c i d . Although anti-eliminations are often favoured over syn-eliminations, either syn- or anti-pathways are possible for reactions such as those described above, which proceed through a carbanion mechanism (72). Sulfonate elimination was also conducted in methanol, since the - 116 -p o l a r i t y of the solvent can often influence the stereochemistry of elimination (72). The main difference as a r e s u l t of the change In solvent, however, was the production of three byproducts: the methoxy de r i v a t i v e s 165 and 166 and the a c y c l i c ester 167. MeOH, base 160/161 167 - 117 -The reason for the appearance of the B-methoxy lactones 165 and 166 i s not obvious. These products must have been formed, at least i n part, by the conjugate addition of methanol to the a,B-unsaturated lactones. An Sj^ 2 displacement of the sulfonate would be expected to lead to j u s t one methyl ether from each of the diastereomeric sulfonates, but each sulfonate gave a mixture of both ether isomers. The conjugate cuprate additions described below indicate that addition to the two faces of the E - o l e f i n i s possible, while the Z - o l e f i n i s unreactive towards conjugate addition. Both methyl ethers were presumably formed by addition of methanol to the E_-olefin. The stereochemistry of each of the methyl ether diastereomers was assigned by comparison of nmr spectral data with that of other c i s - and trans-d i s u b s t i t u t e d lactones. (See Tables 7 and 8, pp. 124, 125). I I I.G. Conjugate Add i t ion to the E-a, B-Unsaturated Lactone 163 Conjugate addition of dimethyllithium cuprate to the E - o l e f i n 163 resulted in the single dimethyl product 155. Numerous attempts were made to prepare a c r y s t a l l i n e d e r i v a t i v e of t h i s product so that the 163 155 - 118 -r e l a t i v e stereochemistry could be proved by X-ray a n a l y s i s . Hydrolysis of 155 gave the hydroxy acid 168 and reduction with lithium aluminum hydride provided the d i o l 169. Unfortunately, neither these compounds nor their derivatives provided c r y s t a l s suitable for X-ray a n a l y s i s . Instead, the stereochemistry of 155 was assigned by comparison of i t s nmr data with that of the preceding series of c i s - and trans-dis u b s t i t u t e d lactones. This data w i l l be discussed in the next section. Under s l i g h t l y d i f f e r e n t reaction conditions the cuprate addition was s u b s t a n t i a l l y d i f f e r e n t . In the above experiment, a solution of the o l e f i n was added slowly to a solution of the cuprate at 0°C. When the o l e f i n was added In one portion to a cuprate solution at 0°C, an approximately 1:1 mixture of the trans- and cis-dimethyl lactones 155 and 154 was obtained. (A small amount of 13-tetradecanolide (134) was also obtained, r e s u l t i n g from reduction of the double bond.) The explanation of t h i s r e s u l t requires a knowledge of the conformational preferences of the lactone 163. MM2 c a l c u l a t i o n s can be employed for this purpose, but a d i f f e r e n t approach must be used. In 168 169 - 119 -the preceding examples, the preferred [3434] conformations of substituted lactones could be determined by consideration of s t e r i c i n t e r a c t i o n s . The choice of the lowest-energy conformation was then confirmed by the c a l c u l a t i o n of s t e r i c energies. In contrast, a diamond-lattice conformation i s not possible for an a,6-unsaturated lactone which has six contiguous, planar atoms, and speculating on the best conformation becomes much more d i f f i c u l t . An alternate approach to this problem i s to begin with a low energy lactone conformation, implant a double bond in this conformation and use the MM2 method to calculate the r e s u l t i n g conformation and s t e r i c energy. Using t h i s method, the lowest-energy o l e f i n conformations were found to r e s u l t from modification of the [3434] conformation 134f and the [3335] conformation obtained from X-ray a n a l y s i s . It i s not surprising that these conformations lead to low-energy o l e f i n conformations. In the [3434] conformation s t e r i c i nteractions are minimized in the s t a r t i n g geometry while the [3335] conformation provides six atoms on one side of the molecule and hence a better opportunity for them to be planar. The r e s u l t i n g conformations, 163a and 163b, and their s t e r i c energies are given in Figure 51. Addition of cuprate to the s t e r i c a l l y unhindered face of the double bond in the lowest-energy conformation 163a provides the trans-dimethyl lactone 155. Addition to the accessible face of the s l i g h t l y higher-energy conformation 163b, on the other hand, r e s u l t s i n formation of the c i s - d imethyl lactone 154. Apparently slow addition of the lactone to the cuprate leads to the exclusive conjugate addition v i a the lowest-energy conformation. It i s possible that addition of the lactone - 120 -163b (22.9) 163a (22.6) Figure 51. Lowest-energy conformations of 163 ( s t e r i c energies i n kcal/mole). - 121 -s o l u t i o n in one portion s u f f i c i e n t l y r a i s e s the temperature of the reaction mixture such that addition to both conformations occurs, r e s u l t i n g in a mixture of the diastereomeric dimethyl lactones. However, rapid addition of the o l e f i n to a solution of dimethyllithium cuprate catalyzed by boron t r i f l u o r i d e at low temperature (-78°C) followed by slow warming to room temperature (a procedure which i s reported to lead to high s t e r e o s e l e c t i v i t y (29)) also gave a mixture of diastereomers. This cuprate reaction demonstrates two points about the chemistry of 14-membered lactones. F i r s t , addition reactions with a compound in a single conformation can be very s t e r e o s e l e c t i v e , with reaction occurring e x c l u s i v e l y from the more open face of the molecule. Second, alternate low-energy conformations which can change the stereo-chemical outcome of a reaction may also be involved. Experimental conditions can therefore play an important role in the s t e r e o s e l e c t i v i t y reactions of 14-membered compounds. The mixture of diastereomeric dimethyl lactones 155 and 154 was hydrolyzed to give the hydroxy acids 168 and 173 * (Figure 52). Hydrolysis proved to be more d i f f i c u l t than expected, in comparison with simple esters or lactones. Even after prolonged heating, some of the cis-dimethyl lactone 154 remained unreacted. Relactonization of the diastereomeric hydroxy acids, on the other hand, proceeded i n reasonable y i e l d (49% f o r the two isomers) using Gerlach's procedure (74). The d i f f i c u l t y encountered in the hydrolysis of the lactones 155 and 154 can be r a t i o n a l i z e d in terms of the s t e r i c i n t e r a c t i o n s of the - 122 -168 173 Figure 52. Hydrolysis of 155 and 154 and r e l a c t o n i z a t i o n . tetrahedral intermediates in the reaction. Hydrolysis of the trans-dimethyl lactone 155, proceeding through i t s lowest-energy conformation, would r e s u l t in the intermediate 174, while hydrolysis of the c i s -OH 0" 174 (38.7 kcol/mole) 175 (43.2 kcal/mole) - 123 -dimethyl lactone 154 should lead to 175 as an intermediate . In both 174 and 175 the charge-bearing oxygen atom i s forced into a s t e r i c a l l y crowded, hydrophobic environment. This s i t u a t i o n should lead to an increase in the energy of these intermediates and hence increase the t r a n s i t i o n state energy of r e a c t i o n . Thus the hydro lys i s reac t ion should be slow for both isomers. On a simple s t e r i c hindrance argument, the intermediate 175 for the c i s - i somer should be higher in energy, a premise which i s confirmed by the ca lcu lated s t e r i c energies shown. This isomer should be the slower of the two to r e a c t , i n agreement with experimental observat ion . III.H. Comparison of the NMR Data of c i s - and trans-Pisubstituted Lactones Tables 7 and 8 l i s t the chemical s h i f t s and the coupl ing constants of the ser ies of c i s - and t rans -3 ,13 -d i subs t i tu ted lac tones . The data for the c i s - and t r a n s - s e r i e s of compounds w i l l f i r s t be compared and contrasted . In the next s ec t i on , the impl i ca t ions of t h i s data with regard to the conformations of these compounds w i l l be cons idered . Most of the nmr data presented in Tables 7 and 8 was obtained from nmr decoupling experiments and nmr computer s imulat ions . As an example of a decoupling experiment, the data for the trans-acetate 156 i s given in Table 9. F igure 53 i l l u s t r a t e s the s imulat ion of the por t ion of the nmr spectrum of th i s compound which contains the peaks of - 124 -Table 7 The nmr data of trans-disubstituted lactones Compound R F i e l d <5H-2a <5H-2b 5H-3 number strength (MHz) (ppm) (ppm) (ppm) 155 CH 3 400 2 . 0 1 2.44 1.92 148 0C0CH 2Br 400 2.51 2.80 5.19 156 0 C 0 C H 3 400 2.45 2.78 5.13 160 OTs 400 2.51 2.90 4.82 165 OCH3 80 2.26 2.84 3.47 Compound number J2a,2b J (Hz) 2a,3 (Hz) J2b,3 (Hz) 6H-13 (ppm) H-13 ( m u l t i p l i c i t y ) 6CH3- I3 (ppm) 155 13 11 4 4.96 1 1 - l i n e 1.23 148 14 10 4 5 . 0 0 1 1 - l i n e 1.24 156 14 10 4 4.99 1 1 - l i n e 1.24 160 14 10 4 4.95 1 1 - l i n e 1.23 165 13 11 4 4.98 1.24 - 125 -Table 8 The nmr data of c i s - d i s u b s t i t u t e d lactones Compound R F i e l d 6H-2a 6H-2b 6H-3 number strength (MHz) (ppm) (ppm) (ppm) 147 OH 400 2.59 2.58 4.05 149 0C0CH 2Br 400 2.67 2.66 5.30 157 0C0CH 3 400 2.63 2.59 5.23 161 OTs 400 2.70 2.68 4.89 166 OCH3 80 2.73 2.38 3.73 154 CH 3 400 2.24 2.15 2.08 Compound number J2a,2b J (Hz) 2a,3 (Hz) J2b,3 (Hz) SH-13 (ppm) H-13 ( m u l t i p l i c i t y ) 6 C H 3 - I 3 (ppm) 147 15 3 11 5.05 11-line 1.23 149 14 5 10 5.06 11-line 1.23 157 14 5 10 5.05 11-line 1.22 161 14 5 10 5.03 11-line 1.19 166 14 4 10 5.04 - 1.23 154 14 4 10 5.07 11-line . 1.21 - 126 -Table 9 Spectral data from nmr decoupling experiments on the trans-acetate 156 Irradiated Signal Decoupled Signal 6 ( m u l t i p l i c i t y ) Assigned H 6 ( m u l t i p l i c i t y ) (before decoupling) ( m u l t i p l i c i t y ) ( a f t e r decoupling) Assigned H 5.13 (m) H-3 2.78 (dd, J = 14, 4 Hz) (d, J = 14 Hz) H-2b 2.45 (dd, J = 14, 10 Hz) (d, J - 14 Hz) H-2a 4.99 (m, J = 9, 6, 3 Hz) H-13 1.24 (d, J = 6 Hz) (s) CH3-I3 2.78 (dd, J = 14, 4 Hz) H-2b 5.13 (m) 2.45 (dd, J = 14, 10 Hz) ( t d , J = 10, 4 Hz) (d, J = 10 Hz) H-3 H-2a 2.45 (dd, J =14, 10 Hz) H-2a 5.13 (m) 2.78 (dd, J = 14, 4 Hz) (s i m p l i f i e d ) (d, J = 4 Hz) H-3 H-2b 1.24 (d, J = 6 Hz) CH3-13 4.99 (m, J = 9, 6, 3 Hz) (dd, J = 9, 3 Hz) H-13 - 127 -the H-2 protons. For comparison, the nmr simulation of the H-2 protons in the cis-acetate 157 i s also included. It i s apparent from Tables 7 and 8 that the nmr data of the dimethyl lactone 155 i s consistent with that of the series of trans-di s u b s t i t u t e d compounds. In this s e r i e s , the chemical s h i f t difference between H-2a and H-2b i s approximately 0.4 ppm, with H-2a u p f i e l d from H-2b. (See Tables 7 and 8 for the l a b e l l i n g of protons). The coupling constant between H-2a and H-3 i s always in the range of 10-11 Hz and that between H-2b and H-3 i s 4 Hz in a l l cases. In contrast, the c i s -disubstituted compounds generally exhibit a chemical s h i f t d i f f e r e n c e of les s than 0.1 ppm between H-2a and H-2b with H-2b u p f i e l d from H-2a. The coupling constant between H-2a and H-3 i s always in the range of 3-5 Hz and that between H-2b and H-3 i s 10-11 Hz. Also, H-13 i s always s l i g h t l y downfield in the cis-isomer r e l a t i v e to the trans-isomer. Additional points which can be obtained from Tables 7 and 8 are that the C-13 methyl group has a s i m i l a r chemical s h i f t i n a l l compounds, the geminal coupling constant between H-2a and H-2b i s approximately 14 Hz in a l l cases and that a l l of the compounds exhibit an 11-line m u l t i p l i c i t y f o r the H-13 proton. The l a s t point i s p a r t i c u l a r l y important as a complex mul t i p l e t i s exactly what one would expect i f each of these compounds existed primarily i n a single conformation. This m u l t i p l i c i t y can be contrasted with the simpler sextet pattern exhibited by the H-13 proton in 13-tetradecanolide (134) a compound which was described previously to e x i s t as a mixture of three - 128 -(a) (b) Figure 53. Computer simulations (upper) and actual nmr spectra' (lower) of the H-2 protons i n (a) the trans-acetate 156 and (b) the cis-acetate 157. - 129 -d i f f e r e n t conformations. The adoption of several conformations r e s u l t s in an averaging of the coupling constants between the H-13 proton and i t s f i v e neighbouring protons, hence producing a sextet. These conclusions indicate that the e a r l i e r decision to consider compounds only in their lowest-energy conformations i s v a l i d . Further support of t h i s decision w i l l be presented in the next section where the nmr data of 3,13-disubstituted lactones w i l l be discussed in terms of their preferred conformations. III.I. The NMR Data and Conformations of the Disubstituted Lactones The preferred conformations of the 3,13-disubstituted lactones were described e a r l i e r in terms of s t e r i c interactions and the calculated s t e r i c energies were used to support the suggested preferences. The nmr data of these compounds provides a d d i t i o n a l support for these proposed conformations. The f i r s t point to be considered i s whether or not the preferred r i n g geometry of these lactones i s the [3434] conformation. The X-ray data of the trans-bromoacetate 148 shows that this compound exists in the [3335] conformation in the s o l i d state, while the predicted prefer-ence in solution i s the [3434] conformation. Examination of the X-ray structure given in Figure 31 reveals that the H-3 proton bisects the angle between the two H-2 protons and hence the coupling constants between the H-3 proton and the H-2 protons should be small and similar in magnitude. Both [3434] conformations on the other hand, 155a and - 130 -155c, each with one trans and one gauche r e l a t i o n s h i p between these protons should have one large and one small coupling constant. The observed values of 10 and 4 Hz confirm that the [3434] conformations are adopted in sol u t i o n , in preference to the [3335] conformation, as predicted. The X-ray analysis of the cis-bromoacetate 149 shows that this compound exists as a 1:1 mixture of the [3434] and [3344] conformations in the s o l i d state. These two conformations cannot be distinguished by nmr since the disordered atoms are on the side of the molecule removed from the f u n c t i o n a l i t y . In both conformations, the H-3 proton has one trans and one gauche r e l a t i o n s h i p with the H-2 protons i n agreement with the observed coupling constants of 10 and 5 Hz. The trans- and c i s - d i s u b s t i t u t e d lactones are most e a s i l y distinguished by the difference in chemical s h i f t between the two H-2 protons - a diffe r e n c e of 0.3-0.4 ppm in the trans-series and only approximately 0.1 ppm in the c i s - s e r i e s (See Figure 53). S t i l l and Galynker (29) noted the same trend in the corresponding 9-, 10-, 11- and 12-membered dimethyl lactones. However, they did not provide any explanation of these observations. The difference in the 14-membered lactones (and presumably in the smaller-ring analogues as well) can be attributed to the anisotropy of the carbonyl group. The shielding (or deshielding) e f f e c t of the lactone carbonyl varies s i g n i f i c a n t l y with the distance and with the angle between the proton and the carbonyl. The e f f e c t should be most pronounced for protons which have fixed orientations r e l a t i v e to the - 131 -carbonyl, as in the case of protons in a single lactone conformation. Using Popie's data which defines the v a r i a t i o n of the anisotropy e f f e c t (73), estimates of the e f f e c t s on the H-2 protons of the lactones can be made. (Use of these shi e l d i n g values which were calculated for the anisotropy e f f e c t s of ketones assumes that the anisotropy of ester and ketone carbonyls i s similar.) Consider f i r s t the trans-disubstituted lactone in the preferred conformation 170a. Protons H-2a and H-2b are very d i f f e r e n t in t h e i r 171 - 132 -s p a t i a l relationships with the carbonyl: H-2a i s in the plane of the carbonyl, while H-2b i s perpend i c u a l r to this plane (see the above Newman pr o j e c t i o n ) . The estimated anisotropy e f f e c t s are a deshielding of H-2a by approximately 0.3 ppm, and a deshielding of H-2b by approxi-mately 0.6 ppm. Relative to a chemical s h i f t of approximately 2.2 ppm for a f r e e l y rotating methylene adjacent to a carbonyl, protons H-2a and H-2b should, therefore, have chemical s h i f t s of approximately 2.5 and 2.8 ppm, values which are in agreement with the experimental data. The other possible conformation of the trans-compounds, 170b, would r e s u l t i n similar anisotropy e f f e c t s , so the two conformations 170a and 170b cannot be distinguished on this basis. The chemical s h i f t s of the H-2 protons i n the c i s - d i s u b s t i t u t e d lactones can be explained in the same manner. The angle between the two H-2 protons in the preferred conformation 171 i s nearly bisected by the carbonyl (see the above Newman pr o j e c t i o n ) . Hence, these protons should have s i m i l a r chemical s h i f t s . The estimated e f f e c t of the anisotropy on each of these i s a deshielding of approximately 0.4 ppm leading to chemical s h i f t s of approximately 2.6 ppm. This prediction i s i n agreement with the experimental data. Another method of analyzing these conformations i s to examine the coupling constants of the H-13 proton with the H-12 protons. Decoupling of the H-13 proton and the C-13 methyl group in the trans-acetate 156 gave values of 3 and 9 Hz for these coupling constants. (See Table 9). The values are in agreement with the conformations 156a in which the H-13 proton would have one axial - e q u a t o r i a l coupling and one a x i a l - a x i a l - 133 -c o u p l i n g , but do not f i t conformation 156b in which H-13 should have two small coupling constants . This experiment thus confirms the p r e d i c t i o n that 156a i s the preferred conformation. Furthermore, i t provides a d d i t i o n a l evidence that the 3 ,13 -d i subs t i tu ted lactones ex is t p r i m a r i l y in s ing le conformations. These r e s u l t s can be compared with the decoupling experiments of CH 3 172 a 172 b This compound was prepared by Dr. J.T.B. F e r r e i r a . - 134 -conformation 172a or 172b in which the geminal methyls are placed at a corner p o s i t i o n . Coupling constants of 3 and 9 Hz indicate that 172a i s the conformation adopted i n so l u t i o n , comparable to 156a for the trans-acetate. The cis-acetate in conformation 157 a should have two small coupling constants between the H-13 proton and the H-12 protons. However, the values of 3 and 8 Hz obtained from decoupling experiments are nearly the same as i n compounds 156 and 172. Presumably t h i s deviation from the expected values r e s u l t s from a twisting of the molecule which moves the s t e r i c a l l y crowded H-12a proton out of the centre of the r i n g . The angle between this proton and H-13 would be reduced, r e s u l t i n g in a smaller coupling constant, while the angle between the H-12a proton and H-13 would be increased to give a larger coupling constant than expected. This r e s u l t means that the examination of these coupling constants i s not a good diagnostic tool for determining the conformation of cis-3,13-disubstituted lactones, although i t may be a v a l i d method in the case of the trans-lac tones. The l a s t nmr technique employed f or the examination of 3,13-disubstituted lactones was a study of spectra at low temperature. 0 157 a - 135 -P a r t i a l spectra of the trans-dimethyl lactone 155 at room temperature, -90, -110 and -130°C are given in Figure 54. The resonance peak i s that of the downfield H-2 proton. At -90°C, there i s some l i n e broadening, at -110° the resonance i s a single broad peak (the coalescence point) and at -130° there i s a separation into two broad doublets. The separa-t i o n of peaks at the lowest temperature indicates that two (or more) conformations have been "frozen out". While other nmr data indicates that each disubstituted lactone e x i s t s primarily i n a single conformation, t h i s study points out that there i s at least one rapid conformational equilibrium at room temperature. The calculated s t e r i c energies of the trans-dimethyl lactone showed that 155a i s the lowest-energy conformation and that 155c i s the next lowest. These should be the two conformations which are "frozen out" in the low temperature nmr study. (The higher-energy conformations should only be populated to a l i m i t e d extent.) The proportions of the conformations 155a and 155c can be calculated using Equation 3, where <$0t,s Is the observed chemical s h i f t 6 , = N.6. + N_6 D (3) obs A A B B . at room temperature, 6 A and 6g are the chemical s h i f t s i n the two separate conformations and N A and Ng are the mole f r a c t i o n s of the molecules i n the two conformations. The nmr data for proton H-2b of 155 provides 6 o b s = 2.43 ppm, 6 A = 2.47 ppm and 6 B = 2.40 ppm. - 136 --110° (acetone-d6/ hexafluoropropylene) -130°C (acetone-d6/ hexafluoropropylene) 2.6 25 24 2.3 ppm Figure 54. The resonance peak of the l o w - f i e l d H-2 proton in 155 at low temperature. - 137 -L e t t i n g N A = x and Ng = 1 - x, the equation can be solved to give N A = 0.4 and Ng = 0.6. The two conformations thus exist in a 60:40 r a t i o at room temperature. This i s lower than the 80:20 r a t i o calculated e a r l i e r . The discrepancy r e s u l t s from c a l c u l a t i o n s which used the s t e r i c energies (AH) of the conformations in the place of AG values. Since the entropy term (AG = AH - TAS) was not included, the calculated r a t i o i s only an approximation. The r a t i o from the low temperature nmr studies i s a more accurate determination. The b a r r i e r to inversion between the conformations 155a and 155c must be of approximately the same magnitude (6-7 kcal/mole) as the b a r r i e r s reported for cyclotetradecane and cyclotetradecanone (54, 59), since the "freezing out" process occurs i n approximately the same temperature range. Interconversion of these conformations should therefore occur very r e a d i l y at room temperature. III.J. Conjugate Addition to the _Z-a, B-Unsaturated Lactone 164 Complementary to the reaction of the _E-a,B-unsaturated lactone 163 with dimethyllithium cuprate which afforded p r i m a r i l y the trans-dimethyl lactone 155, conjugate addition to the _Z-a, B-unsaturated lactone 164 might be expected to r e s u l t primarily in the cis-dimethyl lactone 154. An example of the complementary nature of additions to E-and ^ - o l e f i n s has been reported by S t i l l and Galynker (29). Cuprate addition to the 12-membered E-a,B-unsaturated lactone 176 resulted in the trans-dimethyl lactone 177, while reaction with the Z-isomer 178 - 138 -0 Me 2 CuLi - B F 5 176 0 177 0 178 0 179 lead to the c i s - d i s u b s t i t u t e d product 179. The same r e l a t i o n s h i p may or may not ex i s t for the 14-membered compounds. As was seen for the addi t ion of a cuprate to the lE-isomer 163, the stereochemical outcome of the reac t ion depends on the conformation which i s adopted. Unfortunate ly , the ^ - o l e f i n 164 was found to be completely unreact ive towards conjugate add i t i on of d imethy l l i th ium cuprate . Instead of a dimethyl l ac tone , the react ion yielded a 6:1 mixture of the B,^-unsaturated lactones 180 and 181. Under these reac t ion c o n d i t i o n s , 180 181 - 139 -the double bond of 164 simply migrated out of conjugation. It i s assumed that the more stable isomer i s formed p r e f e r e n t i a l l y . MM2 c a l c u l a t i o n s show the E isomer to be lower in energy (15.1 vs 17.6 kcal/mole). If the double bond isomerization proceeds through a product-like t r a n s i t i o n state, the l e s s strained isomer should predominate. Not unexpectedly, the deconjugated isomers are le s s strained than t h e i r conjugated counterparts which must have six consecutive planar atoms. Deconjugation r e l i e v e s a s i g n i f i c a n t amount of s t e r i c s t r a i n . Nevertheless, the lack of r e a c t i v i t y i s surprising considering the ease with which the E_-olefin reacts with dimethyl lithium cuprate. Although esters are often found to be unreactive towards cuprates (75), one might have suspected that these two similar a,6-unsaturated lactones would have s i m i l a r r e a c t i v i t i e s . Other cuprate reagents, known for their high r e a c t i v i t y towards a, 6-unsaturated esters were t r i e d . Boron t r i f l u o r i d e - c a t a l y z e d dimethyllithium cuprate (Me 2CuLi-BF 3) (29), boron t r i f l u o r i d e - c a t a l y z e d methylcopper (MeCu-BF3) (76) and a higher order mixed cuprate (Me 2Cu(CN)Li 2) (75) a l l resulted in the same mixture of 180 and 181. The v a r i a t i o n in r e a c t i v i t y between the two o l e f i n s 163 and 164 must r e s u l t from s t r u c t u r a l differences which we did not i n i t i a l l y a n t i c i p a t e . The geometries of the double bonds confer markedly d i f f e r e n t physical c h a r a c t e r i s t i c s on the two compounds. The Z - o l e f i n - 140 -164 has a strong burnt od our. while the E — o l e f i n has l i t t l e smell. The Z-o l e f i n i s much less reactive in the charring process (10% H2S0i|/heat) used for the development of t i c plates; even in reactions i n which the ^-isomer i s the major product, t i c indicates predominantly the E_-olefin. The nmr data of the two isomers d i f f e r considerably as well, p a r t i c u l a r l y with respect to the chemical s h i f t of the a l l y l i c protons. In the _Z-olefin, one of the a l l y l i c protons i s greatly deshielded (6 = 3.04 ppm). This proton i s situated very close to the carbonyl oxygen as shown i n the lowest-energy conformation (Figure 55). The a l l y l i c protons i n the E_-isomer, on the other hand, have the same chemical s h i f t s (6 = 2.26 ppm). Figure 51 shows the lowest-energy conformations of t h i s molecule, and i t can be seen that the two a l l y l i c protons are in sim i l a r environments. Figure 55. The lowest-energy conformation 164a of the Z - o l e f i n 164. - 141 -The adoption of conformation 164a also appears to be the reason for the low reactivity of the Z-olefin. As can be seen from Figure 55, the carbonyl oxygen of this compound is buried in the hydrophobic cavity of the ring. In this environment, i t is not possible for a metal cation or solvent molecule to coordinate to the carbonyl oxygen. Since the coordination of the carbonyl is an integral part of a conjugate cuprate addition (77), reaction does not occur. In contrast, the carbonyl of the E_-a, B-unsaturated lactone 163 (Figure 51) is relatively accessible and hence the molecule is able to undergo reaction. Implicit in this explanation is the idea that molecular conformation is exceedingly important for the successful completion of reactions of 14-membered lactones. Not only does the conformation dictate the stereochemical outcome of the reaction, but i t can control whether or not the reaction actually takes place. While conjugate addition does not occur in the reaction of 164, y-deprotonation by the cuprate apparently does. The resulting conjugated enolate would force the molecule into a new conformation, a conformation requiring seven planar atoms. With half of the molecule planar, the enolate oxygen must be more exposed, better able to coordinate wih a metal cation and hence more highly stabilized than the enolate resulting from conjugate addition. Examination of the lowest-energy conformation 164a reveals that i f cuprate addition had been successful, the product obtained from addition to the accessible face of the double bond should be the trans-- 142 -dimethyl lactone 155. This i s the same product as that obtained from the E - o l e f i n 163, indicating that the cuprate addition reactions of the 14-membered a,B-unsaturated lactones may not be complementary as their 12-membered counterparts 176 and 178 are. This points out one of the po t e n t i a l differences between 14-membered and smaller lactones. A measure of the r e a c t i v i t y of the two a,B-unsaturated lactones 163 and 164 with cuprates can be obtained from the reduction potentials of the lactones, i f a two-step pathway for conjugate cuprate addition occurs (77a). This pathway, involving the r e v e r s i b l e transfer of an _ electron transfer RCH = CHCOOR +N= » RC.H — r.H= r.OR' + M-182 1 8 3 °~ I coupling N I RCHCH = COR I 0 -Figure 56. The mechanism of cuprate conjugate addition. e l e c t r o n and subsequent coupling of the r a d i c a l intermediates, i s i l l u s t r a t e d in Figure 56. The equilibrium for the f i r s t step can be estimated from the electrode potential for oxidation ( E o x ) of the nucleophile N:~, and the corresponding potential for reduction ( E r e c j ) - 143 -of the carbonyl compound 182. The electrode potentials and E j . ^ associated with this redox reaction can be measured by standard polarographic techniques against a saturated calomel electrode (SCE). The most powerful reducing agents N:- w i l l thus have the most negative E o x values and the most d i f f i c u l t l y reduced unsaturated carbonyl compounds w i l l have the most negative E r e c j values. When the value E r e d ~ Eox * s p o s i t i v e , transfer of an electron from N:~ to the carbonyl compound i s e n e r g e t i c a l l y favourable. House (77a, 77b) has reported that for reaction with a d i a l k y l -l i thium cuprate, the reduction potential of an a, g-unsaturated carbonyl compound should be within the range -1.3 to -2.4 V. Using the empirical rules f o r estimating the reduction potentials of a,B-unsaturated carbonyl compounds proposed by House, Huber and Umen (77c), the reduction potentials of the E- and _Z-a,B-unsaturated lactones 163 and 164 are each estimated to be -2.3 V, in d i c a t i n g that both should react q with d i a l k y l l i t h i u m cuprates. Measurement of the reduction potential ( E r e ( j vs SCE) of each of these compounds i n DMF with tetra-n-butyl ammonium perchlorate as supporting e l e c t r o l y t e (77c) gave values l e s s negative than the estimated values, as shown i n Table 10. (The reduction potential of cyclopentenone i s included for comparison.) Again, the in d i c a t i o n i s that both compounds should react. However, when the reduction potentials were measured in THF (a solvent s i m i l a r to the ether a c t u a l l y employed in the cuprate reactions) values of q We are gra t e f u l to Dr. T. Mashiko and Dr. D. Dolphin for the measurement of these reduction p o t e n t i a l s . - 144 -Table 10 Reduction potentials of 163, 164 and cyclopentanone Compound (estimated) (DMF) (THF) 163 -2.3 V -2.11 ± 0.05 V -2.45 ± 0.05 V 164 -2.3 V -1.97 ± 0.05 V -2.60 ± 0.05 V Cyclopentenone -2.1 V -2.04 ± 0.03 V ((77c) -2.16 V) -2.45 ± 0.05 V and -2.60 ± 0.05 V were obtained for the _E- and _Z-isomers r e s p e c t i v e l y . These r e s u l t s indicate that the E_-isomer should react with d i a l k y l l i t h i u m cuprates and that the _Z-isomer should be unreactive. The more negative Ej- e (j value for 164 presumably r e f l e c t s the i n a b i l i t y of a metal ion to s t a b i l i z e the r a d i c a l ion intermediate 183, as discussed above. The fact that 164 did not react with more powerful cuprate reagents (reagents with more negative E o x values) indicates that i t s reduction potential in ether may be more negative than that measured in THF. As a further demonstration of the d i f f e r e n t r e a c t i v i t i e s of the lactones 163 and 164, a mixture of the two compounds was treated with dimethyllithium cuprate. GC analysis showed that 163 reacted almost immediately. Upon workup of the reaction a f t e r one hour, 164, on the other hand, was recovered unchanged. This experiment adds one more piece of evidence to show that the a, B-unsaturated lactone 164 i s unreactive. - 145 -III.K. Preparation and Hydrogenation of B-Methyl-atB-Unsaturated Lactones 185 and 186 An alternate approach to the preparation of the dimethyl lactones 155 and 154 i s the hydrogenation of the dimethyl a,B-unsaturated lactones 185 and 186. Although i t i s not clear at this point which isomer should be obtained from reduction of each of the o l e f i n s , i t was hoped that only one diastereomeric dimethyl lactone might r e s u l t from each. Compounds 185 and 186 were prepared using a synthetic method which was developed i n our laboratory (78). The method involves i n i t i a l formation of the _Z- and _E-enol phosphates from a B-keto ester. Displacement of the phosphate by dimethyllithium cuprate leads to the B-methyl a,B-unsaturated ester with retention of the double bond geometry. The methodology was previously extended to the 16-membered B-keto lactone 187, as shown in Figure 57 (79), to give the _Z- and E_-enol phosphates 188 and 191 s t e r e o s e l e c t i v e l y and in quantitative y i e l d . Treatment of 188 with dimethyllithium cuprate gave a 99% crude y i e l d of a 3.3:1 mixture of 189 and 190, with the major product having - 146 -191(E) M e 2 C u L i 190 Figure 57. Preparation and react ions of the enol phosphates of the 16-membered B-keto lactone 187. - 147 -retained the double bond geometry of the enol phosphate 188. Coupling of the E-enol phosphate with dimethyllithium cuprate resulted in a 79% y i e l d of 190 with complete retention of double bond geometry. S i m i l a r l y , treatment of the 14-membered 8-keto lactone 138 with sodium hydride - diethy l chlorophosphate (78) gave the _Z-enol phosphate 192 and treatment with triethylamine - hexaraethyl phosphoramide (HMPA) -4-dimethylamino pyridine (DMAP) (80) gave the E-enol phosphate 193. Each reaction proceeded in quantitative y i e l d . The crude products of these reaction were suitable f or use in the subsequent cuprate re a c t i o n s . - 148 -The two enol phosphates are readily distinguished by their nmr spectra. The viny l proton of the E-isomer appears further downfield than that of the ^-isomer. As we l l , the E_-isomer 193 exhibits the same deshielding of one of the a l l y l i c protons as was described for 164, the a, B-unsaturated lactone with the same double bond geometry. The formation of the E-enol phosphate 193 from the B-keto lactone 138 was very slow. The preparation of the E_-enol phosphate from any 3-keto ester generally takes longer than does the preparation of the corresponding Z^isomer, but this reaction of 138 was p a r t i c u l a r l y slow: the time required for complete reaction was 28 hours compared to 4 hours for the preparation of the E_-enol phosphate of methyl acetoacetate, for example. The lower r e a c t i v i t y of 138 i s apparently a result of the higher s t e r i c energy of the E_-enolate compared to the Z-enolate. As described e a r l i e r , the ester carbonyl in this conformation leading to the E_-enolate does not s i g n i f i c a n t l y s t a b i l i z e t h i s a-enolate because of the i n a b i l i t y of solvents or metal ions to associate with the ester carbonyl. (See pl41). If the higher enolate energy i s reflected in a higher t r a n s i t i o n state energy, the rate of reaction would indeed be expected to be lower for this isomer. There must be some s t a b i l i z a t i o n of the E-enolate by the ester carbonyl, since the formation of the enol phosphate i s completely regioselective. The E-enol phosphate 193 has a higher Rf value on t i c than the corresponding Z-isomer. As with 164, the a,8-unsaturated lactone with - 149 -the same double bond geometry, the Rf value can be related to the conformation of the molecule: with the carbonyl buried in the hydrophobic cavity of the molecule, the polarity of the compound is reduced significantly. This structural similarity of 193 and 164 leads to similar reactivities as well. Just as 164 is unreactive towards conjugate cuprate addition, compound 193 is slow to be formed, since both proceed through a similar c*-enolate. Coupling of the _Z-enol phosphate 192 with dimethyllithium cuprate resulted in the product mixture shown in Figure 58. The 4:1 4 1 46% 8% II % Figure 58. Reaction of the _Z-enol phosphate 192 with dimethyllithium cuprate. - 150 -r a t i o of the E- and ^-products 185 and 186 (as determined by nmr and GC analysis) was about the same as that obtained from the reaction of the 16-membered enol phosphate 188. The two o l e f i n s are e a s i l y d i s t i n -guished by t h e i r nmf spectra, p a r t i c u l a r l y by the difference in the chemical s h i f t s of the a l l y l i c protons. Also i s o l a t e d from this reaction mixture were the gem-dimethyl ketone 194, r e s u l t i n g from two conjugate additions and one 1,2-addition of the cuprate reagent, and the t e r t i a r y alcohol 195, r e s u l t i n g from one conjugate addition and two 1,2-additions. The mixture of 185 and 186 was treated again with dimethyllithium cuprate to give the d i o l 195 as the sole product. Neither of the possible conjugate addition products 194 nor 196 was detected. This lack of conjugate addition can be attributed to the addit i o n a l 8-methyl group, which leads to a decrease of 0.1 V in the estimated reduction p o t e n t i a l of the a,B-unsaturated carbonyl (77c). Apparently the reduction potentials of compounds 185 and 186 both become s u f f i c i e n t l y - 151 -negative to preclude reaction with dimethyllithium cuprate. Since the gem-dimethyl lactone 196 was not a product of t h i s reaction, ketone 194 must be formed from the enol phosphate 192 by i n i t i a l 1,2-addition, followed by two conjugate additions to the r e s u l t i n g a c y c l i c ketone. Copper-catalyzed Grignard reagents have been shown to afford high s t e r e o s e l e c t i v i t y i n the displacement of enol phosphates (81). Treat-ment of the J-enol phosphate 192 with a copper-catalyzed Grignard reagent at low temperature resulted in increased s t e r e o s e l e c t i v i t y but a lower y i e l d . Thus, 192 was added to a mixture of methylmagnesium chloride and methylcopper in THF at -35°C, r e s u l t i n g in a 95:5 mixture of 185 and 186 i n 27% y i e l d . Also i s o l a t e d from this reaction were s t a r t i n g material (14%) and the B-keto lactone 138 (12%). Under these 95 5 27% 12% 14% - 152 -conditions, the desired reaction i s slow and cleavage of the enol phosphate to give the 8-keto lactone becomes a competing reacti o n . Longer reaction time resulted in a lower quantity of recovered starting m aterial, but gave a higher proportion of the 8-keto lactone 138. Neither 194 nor 195 was detected in t h i s product mixture. The E_-enol phosphate 193 was subjected to the same cuprate r e a c t i o n s . Coupling of 193 with dimethyllithium cuprate gave a mixture of the o l e f i n s 186 and 185 in the r a t i o 9:1 (37% y i e l d ) . The E_-enol 193 186 185 9 I phosphate was more sluggish to react than the _Z-isomer, showing once again that the isomer with t h i s double bond geometry i s less r e a c t i v e . To compare the r e a c t i v i t i e s of the two enol phosphates, a 1:6 mixture of 192 and 193 was treated with dimethyllithium cuprate (Figure 59). While some of each enol phosphate was recovered along with some 8-keto lactone 138, the products 185 and 186 were obtained in the r a t i o 10:1 - 153 -165 186 1 0 I Figure 59. Comparison of r e a c t i v i t i e s of isomeric enol phosphates with dimethyllithium cuprate. demonstrating the much greater r e a c t i v i t y of the Z^enol phosphate 192. The JE-enol phosphate 193 was l e s s r e a c t i v e with the copper-catalyzed Grignard reagent than i t was with dimethyllithium cuprate. Under the same reaction conditions as those used f o r the _Z-isomer (MeMgCl, MeCu, -35°C), 75% of 193 remained unreacted a f t e r 24 hours. When the reaction mixture was allowed to warm slowly to -5°C, a 15:85 - 154 -mixture of 193 and B-ketolactone 138 was obtained, containing no detectable amounts of the desired product 186. The coupling reaction was so slow that the enol phosphate underwent cleavage to the B-keto lactone instead. With both o l e f i n s 185 and 186 in hand, the stereochemical consequences of hydrogenating these compounds could be examined. Hydrogenation of the 93:5 mixture 185 and 186 obtained from the _Z-enol phosphate 192 gave the trans-dimethyl lactone 155 as the only detectable product. This i s the same product as was obtained from cuprate addition to the E-a,B-unsaturated lactone 163. The outcome of this reaction can be explained using the following conformational analysis. As seen above, the a,B-unsaturated lactone 163 has two low-energy conformations, with 163a lower in energy than 163b. The addition of a 8-methyl group to each of these produces 185a and 185b with s t e r i c energies of 26.0 and 25.7 kcal/mole r e s p e c t i v e l y . - 155 -These are the lowest-energy conformations of 185, but now the order of preference has been reversed r e l a t i v e to 163a and 163b. If hydrogenation proceeds through the lowest-energy conformation 185b, the r e s u l t i n g saturated dimethyl lactone w i l l have a stereochemistry opposite to that obtained from cuprate addition to 163 in the same conformation 163b. However, th i s product w i l l have the same stereochemistry as that obtained from cuprate addition to the preferred conformation 163a. Compound 185 adopts a d i f f e r e n t conformation than 163 in order to accommodate the ad d i t i o n a l methyl group. The unsubstituted a,8-unsaturated lactone reacts v i a the "a" conformation, whereas the 8-raethyl a,6-unsaturated lactone reacts v i a the "b" conformation. The MM2 c a l c u l a t i o n s v e r i f y that in each case reaction proceeds through the lowest-energy conformation. This contrasts with the chemistry of the - 156 -corresponding medium-size rings i n which cuprate - additions and hydrogenations are complementary (29). Again the difference between medium- and large-ring chemistry has been demonstrated. In medium-size rings, transannular repulsions are the major s t e r i c i n t e r a c t i o n s , so the lowest-energy conformation must be the one that minimizes these i n t e r a c t i o n s . The comparatively minor s t e r i c interactions introduced with a new substituent w i l l be accepted with retention of this conformation, since any other conformation w i l l not minimize the severe transannular i n t e r a c t i o n s . In 14-membered rings, on the other hand, transannular interactions are not as severe, so the substituted molecule can adopt a d i f f e r e n t conformation from the unsubstituted compound. The new conformation w i l l be the one which minimizes the t o t a l number of s t e r i c i n t e r a c t i o n s , including trans-annular repulsions and the s t e r i c interactions of any new substituent. Hydrogenation of the 9:1 mixture of 186 and 185 obtained from the E_-enol phosphate gave an 89% y i e l d of the cis-dimethyl lactone 154 as the only detectable product. The stereochemistry of t h i s compound 154 - 157 -was determined by comparison of i t s nmr data with the preceding series of of trans- and c i s - d i s u b s t i t u t e d lactones. (See Tables 7 and 8). Also, t h i s i s the stereochemistry which i s expected from addition of hydrogen to the more open top face of 186a the lowest-energy conformation of t h i s molecule. The hydrogenation reactions of o l e f i n s 185 and 186 were highly s t e r e o s e l e c t i v e . A further demonstration of t h i s s t e r e o s e l e c t i v i t y came from the hydrogenation of a 4:1 mixture of 185 and 186 which resulted i n a 4:1 mixture of the dimethyl lactones 155 and 154 as determined from nmr a n a l y s i s . Aside from spectral data, the cis-dimethyl lactone 154 i s d i s t i n -guished from the trans-isomer 155 by one obvious physical c h a r a c t e r i s t i c : 154 i s a s o l i d while 155 i s an o i l at room temperature. This d i s t i n c t i o n i s not r e s t r i c t e d to j u s t these two compounds. For the diastereomeric pairs of compounds which have been 186a - 158 -discussed, the melting point of the c i s - d i s u b s t i t u t e d lactone i s always higher than that of the corresponding trans-isomer. Presumably the more symmetric conformation 171 of the c is-compounds provides better molecular packing than conformation 170a of the trans-compounds, leading to higher c r y s t a l l a t t i c e energies. 1700 171 III.L. Epoxidation Reactions of a, B—Unsaturated Lactones 163 and 164 The l a s t reactions to be examined were the epoxidations of the a, B-unsaturated lactones 163 and 164. Heating a solution of 163 and - 159 -m-chloroperbenzoic acid (MCPBA) (82) resulted in a 54:46 rat i o of the epoxides 197. and 198_ in 84% y i e l d . The diastereomeric epoxides are the products which r e s u l t from attack of the peracid on the exposed faces of the two lowest-energy conformations 163a and 163b, r e s p e c t i v e l y . At the elevated temperature of t h i s reaction, the two conformations should be present in nearly equal amounts. There i s , however, a s l i g h t l y greater proportion of 197 which i s the product obtained from the lowest-energy conformation 163a, as would be expected. The stereochemistry of each epoxide was determined from the nmr data. (Tables 11 and 12 l i s t the data from decoupling experiments on each of these compounds). F i r s t , a coupling constant of 2 Hz between H-2 and H-3 for each compound indicates that both are trans-epox id es as shown (83). Second, the nmr data i s consistent with the expected conformations of the two epoxides: the conformations should be si m i l a r to the o l e f i n conformations 163a and 163b. In conformation 197a, the a x i a l proton H-4a has a geminal coupling constant of 14 Hz with H-4b, a 1970 - 160 -t r a n s - d i a x i a l r e l a t i o n s h i p with H-3 and a corresponding coupling constant of 10 Hz, and coupling constants of 11 and 3 Hz with the H-5 protons. Coupling constants of 2 Hz between H-3 and H-4b and 7 and 3 Hz between H-4b and the H-5 protons are also in agreement with this conformation. Proton H-4a s i t s d i r e c t l y over the epoxide ring and hence experiences a strong shielding e f f e c t from the epoxide anisotropy (84): the observed chemical s h i f t i s 1.12 ppm. Proton H-4b, on the other hand, l i e s in the deshielding zone and has a chemical s h i f t of 2.24 ppm. In conformation 198a of the diastereomeric epoxide, the coupling 198 a constants between H-4a and H-4b and between the H-4 and H-5 protons are the same as i n 197a. However, the d i f f e r e n t o r i e n t a t i o n of the epoxide leads to a coupling constant of 2 Hz between H-4a and H-3 and deshielding of H-3 due to i t s close proximity to the carbonyl. As w e l l , H-4b now l i e s d i r e c t l y over the epoxide and i s shielded to 1.17 ppm while H-4a i s deshielded to 2.10 ppm. The nmr data of the two epoxides i s therefore consistent with the proposed conformations. Table l l Spin decoupling on the 400 MHz nmr spectrum of compound 197 (see spectral appendix, p. 313 ) Irradiated Signal Decoupled Signal 6 ( m u l t i p l i c i t y ) Assignment 6( m u l t i p l i c i t y ) (before decoupling) ( m u l t i p l i c i t y ) ( a f t e r decoupling) Assignment 5.06 (sextet, H-13 1.54 (m) ( s i m p l i f i c a t i o n ) H-12 J = 6 Hz) 1.29 (d, Jf = 6 Hz) (s) CH 3 3.23 (d, J = 2 Hz) H-2 3.07 (dt, J_ = 10, 2 Hz) (dd, J_ = 10, 2 Hz) H-3 3.07 (dt, H-3 3.23 (d, J = 2 Hz) (s) H-2 J = 10, 2 Hz) 2.24 (dddd, (ddd, J = 14, 7, 3 Hz) H-4b J = 14, 7, 3, 2 Hz) 1.12 (dddd, (ddd, J = 14, 11, 3 Hz) H-4a J = 14, 11, 10, 3 Hz) 2.24 (dddd, H-4b 3.07 (dt, (dd, J. = 10, 2 Hz) H-3 J = 14, 7, 3, 2 Hz) J = 10, 2 Hz) 1.12 (dddd, J = 14, 11, 10, (m, J - 11, 10, 3 Hz) H-4a 3 Hz) 1.54 (m) ( s i m p l i f i c a t i o n ) H-5a 1.65 (m) + 1.54 (m) H-5a + H-12 2.24 (dddd, J = 14, 7, 3, ( s i m p l i f i c a t i o n ) H-4b 2 Hz) 1.12 (dddd, J = 14, 11, 10, (ddd, J = 14, 11, 10 Hz) H-4a 3 Hz) 5.06 (sextet, J_ = 6 Hz) (q, J_ = 6 Hz) H-13 1.29 (d, CH3 + H-5b 5.06 (sextet, J = 6 Hz) ( t , J = 6 Hz) H-13 J = 6 Hz) + (m) 2.24 (dddd, J = 14, 7, 3, ( s i m p l i f i c a t i o n ) H-4b 2 Hz) 1.12 (dddd, J_ = 14, 11, 10, ( s i m p l i f i c a t i o n ) H-4a 3 Hz) Table 12 Spin decoupling on the 400 MHz nmr spectrum of compound 198 (see spectral appendix, p. 313 ) Irradiated Signal Decoupled Signal 6 ( m u l t i p l i c i t y ) Assignment 6 ( m u l t i p l i c i t y ) (before decoupling) ( m u l t i p l i c i t y ) ( a f t e r decoupling) Assignment 5.08 (sextet, H-13 1.28 (d, J = 7 Hz) (s) CH3 J = 7 Hz) 1.65 (m) (m, J_ = 8, 6 Hz) H-12 3.29 (dt, H-3 3.21 (d, J - 2 Hz) (s) H-2 J = 10, 2 Hz) 2.10 (m, J - 14, 11, 3, (ddd, J = 14, 11, 3 Hz) H-4a 2 Hz) 1.17 (m) ( s i m p l i f i c a t i o n ) H-4b 3.21 (d, J = 2 Hz) H-2 3.29 (dt, J = 10, 2 Hz) (dd, J - 10, 2 Hz) H-3 2.10 (m, J = 14, 11, H-4a 3.29 (dt, J = 10, 2 Hz) (dd, J = 10, 2 Hz) H-3 3, 2 Hz) 1.45 (m) ( s i m p l i f i c a t i o n ) H-5 a 1.17 (m) ( s i m p l i f i c a t i o n ) H-4b 1.63 (m) + 1.45 (m) H-12a + H-5a 5.08 (sextet, J = 7 Hz) (q, J - 7 Hz) H-13 2.10 (m, J = 14, 11, 3, ( s i m p l i f i c a t i o n ) H-4a 2 Hz) 1.28 (d, J = 7 Hz) CH3 + H-5b 5.08 (sextet, J = 7 Hz) (dd, J = 7, 6 Hz) H-13 + 1.17 (m) + H-4a 3.29 (dt, J = 10, 2, Hz) ( s i m p l i f i c a t i o n ) H-3 2.10 (m, J - 14, 11, 3, ( s i m p l i f i c a t i o n ) H-4a 2 Hz) - 163 -Epoxidation of 163 at elevated temperatures provided the epoxides 197 and 198 in about equal amounts. At lower temperature a greater s t e r e o s e l e c t i v i t y could be expected. Treatment of 163 with MCPBA at room temperature resulted in a 197:198 r a t i o of 3:2, despite requiring 11 days to go to completion. For the reaction to proceed i n a more reasonable length of time at lower temperatures, a more reactive reagent i s required. T r i f l u o r o p e r a c e t i c acid was very e f f e c t i v e : reaction was complete i n one hour at room temperature. However, the s e l e c t i v i t y was only s l i g h t l y better than that obtained with MCPBA at room temperature. Reaction at 0°C with t r i f l u o r o p e r a c e t i c acid was sim i l a r to reaction at room temperature, while at -35°C, epoxidation only went 26% towards completion i n 40 hours, with an epoxide r a t i o of 7:3. Considering the conjugate cuprate addition reactions with 163, a slow rate of addition of the alkene to the reaction mixture might be expected to lead to a greater proportion of the reaction proceeding through the lowest-energy conformation 163a and hence a greater stereo-s e l e c t i v i t y i n epoxidation. Addition of a solution of the o l e f i n over a two hour period to a solu t i o n of t r i f luoroperacetic acid at room temperature lead to an epoxide r a t i o of approximately 2:1, showing a s l i g h t improvement over the reaction without slow addition. Epoxidation of 163 using hydrogen peroxide and base (Figure 60) resulted in the hydroperoxides 199 and 200 as well as the epoxides 197 and 198. The hydroperoxides 199 and 200 were i d e n t i c a l to the corresponding alcohols 146 and 147 in almost a l l respects ( i r , ms, GC). - 164 -Figure 60. Epoxidation of 163 with basic hydrogen peroxide. Only the nmr data d i f f e r e n t i a t e d the two hydroperoxides from the alcohols. Indeed, reduction of a mixture of 199 and 200 with sodium borohydride gave a mixture of the corresponding alcohols i n the same r a t i o . The large proportion of hydroperoxide obtained in t h i s reaction could r e f l e c t the s t r a i n in forming the corresponding epoxides. While conjugate addition occurs, c y c l i z a t i o n of the intermediate enolate i s retarded, presumably because of a high-energy t r a n s i t i o n state. - 165 -Epoxidation of 163 using hydrogen peroxide and base or using a peracid r e s u l t s in a greater proportion of the trans-substituted compounds 197 and 199. This i s in agreement with the expectation of addition to the lowest-energy conformation 163a. It i s also in agreement with the observed formation of the trans-dimethyl lactone 155 from cuprate addition to 163, although the s e l e c t i v i t y in epoxidation i s not as high. Epoxidation of the ^ - o l e f i n 164 should have resulted i n c i s -epoxides. However, upon treatment with MCPBA, the same epoxides were 164 163 obtained as from epoxidation of 163. Under the a c i d i c conditions employed in the reaction, or upon treatment with jp_-toluenesulfonic a c i d , the _Z-olefin 164 was found to isomerize to the E - o l e f i n 163. (No isomerization occurred under basic conditions.) Once isomerized to 163 the o l e f i n then reacts with the peracid. Again, the _Z-olefin has shown i t s lack of r e a c t i v i t y . - 166 -I I I . M . Conclusion The 14-membered lactones have been shown to exist i n d e f i n i t e , predictable conformations. Even simple lactones with as few as two substituents primarily adopt only one or two conformations. Also, i t has been shown that the preferred conformations can be determined by consideration of s t e r i c and e l e c t r o n i c i n t e r a c t i o n s . The c a l c u l a t i o n of s t e r i c energies using the MM2 program supports these predictions. The basic conformations of 14-membered lactones are often easier to predict than the conformations of medium-size rings which frequently must be calculated. However, in contrast to the smaller r i n g s , the addition of each new substituent to a 14-membered lactone can cause an a l t e r a t i o n of the r e l a t i v e energies of these conformations. The larger rings are s i m i l a r to the medium-size rings in that addition reactions occur with attack from the les s hindered outer face to give a single diastereomeric product. Obviously there i s s t i l l much work that can be done on 14-membered lactones. This thesis has only dealt with the range of compounds extending from simple 14-membered rings to 3,13-disubstituted lactones. However, using the ideas developed herein, i t should be f e a s i b l e to r a t i o n a l i z e the r e s u l t s of reactions of 14-membered lactones with a v a r i e t y of su b s t i t u t i o n patterns. Hopefully i t w i l l also be possible to use these ideas to predict the stereochemical r e s u l t s of reactions and use these predictions to plan syntheses of ever more complex systems. Eventually, i t should be possible to extend these ideas to the most complex 14-membered lactones, the macrolide a n t i b i o t i c s . - 167 -EXPERIMENTAL I . General Unless otherwise stated the following are implied. Melting points were determined on a K o f f l e r micro heating stage and are uncorrected. Kugelrohr d i s t i l l a t i o n s were performed by means of a Buchi Kugelrohr thermostat. Infrared spectra were recorded on a Perkin-Elmer model 710B spectrophotometer. Solution spectra were obtained using a * sodium chloride solution c e l l of 0.2 mm thickness. Absorption positions are given in cm - 1 and calibrated by means of the 1601 cm - 1 band of polystyrene. The proton nuclear magnetic resonance spectra were taken i n deuterochloroform solution and recorded on a Varian T-60 or Varian EM 360L (60 MHz) instrument, a Bruker WP-80 (80 MHz) instrument or a Bruker WH-400 (400 MHz) instrument. Signal positions are given i n parts per m i l l i o n downfield from tetramethyl-s i l a n e on the 6 scale. Signal m u l t i p l i c i t y , coupling constants, and integration r a t i o s are indicated i n parentheses. The chemical s h i f t s and coupling constants quoted for complicated coupling patterns are measured from the appropriate peaks in the *H nmr spectra, and hence do not exactly correspond to the true values (85). Low resol u t i o n mass spectra were determined on either a Varian MAT model CH4B or a Kratos-AEI model MS 50 mass spectrometer. Observed metastable peaks (m*) are given in the reported mass spectra, and the calculated values for the metastable peak r e s u l t i n g from the fragmentation process 2mi + •»• m2 + m3 are given by the approximate formula m* = m2/m1 In parentheses. - 168 -The major ion fragmentations are reported as percentages of the base peak. High resolution mass measurements were determined using a Kratos - AEI model MS50 mass spectrometer. A l l instruments were operated at an ionizing potential of 70eV. Gas-liquid chromatography was performed on a Hewlett Packard model 5880A gas chromatograph using a 12 m x 0.2 mm column of 3% 0V-101 or 10% Carbowax 20M, a flame i o n i z a t i o n detector and helium as the c a r r i e r gas. Microanalyses were performed by Mr. P. Borda, Mic r o a n a l y t i c a l Laboratory, Un i v e r s i t y of B r i t i s h Columbia. S i l i c a gel PF25i+ + 366 supplied by E. Merck Co. was used for preparative t i c . The plates were _ca. 1 mm in thickness. A n a l y t i c a l t i c was performed on commercial, pre-coated s i l i c a gel plates ( s i l i c a gel 60 supplied by E. Merck Co. V i s u a l i z a t i o n was effected by UV fluorescence or a 3 M s u l f u r i c acid spray followed by heating. Flash chromatography (86) was performed using s i l i c a gel 230-400 mesh ASTM, supplied by E. Merck Co. Reaction products were dried by allowing the solutions to stand over magnesium s u l f a t e , followed by f i l t r a t i o n . The petroleum ether used was of b o i l i n g range £a. 30-60°C. Dry solvents and reagents were prepared as follows: d i e t h y l ether (ether) and tetrahydrofuran (THF) by heating at r e f l u x over l i t h i u m aluminum hydride, followed by d i s t i l l a t i o n ; dichloromethane by d i s t i l l a t i o n from phosphorous pentoxide; N,N-dimethyl formamide (DMF) and hexamethyl phosphoramide (HMPA) by heating at r e f l u x over calcium hydride, followed by d i s t i l l a t i o n under reduced pressure; benzene, 1,2-dichloroethane, diisopropylamine, pyridine, triethylamine and toluene by d i s t i l l a t i o n - 169 -from calcium hydride; and ethanol and methanol by heating at reflux over magnesium ethoxide or magnesium methoxide re s p e c t i v e l y followed by d i s t i l l a t i o n . Methyllithium ( i n ether) , _n-butyllithium ( i n hexane) and methylmagnesium chloride ( i n THF) were obtained from A l d r i c h Chemical Company. The a l k y l l i t h i u m solutions were standardized either by t i t r a t i o n against 1.0 M t e r t - b u t y l alcohol i n benzene using 1,10-phenanthroline as i n d i c a t o r (87a) or by t i t r a t i o n against 1,3-diphenyl-2-propanone tosylhydrazone in THF (87b). Sodium hydride ( A l d r i c h Chemical Company) was weighed as a 60% dispersion in mineral o i l and was washed with dry ether to remove the o i l prior to use. - 170 -fi-Keto Lactone Synthesis 3-Benzyloxypropanoic Acid (98) <£CH 2 0(CH 2 ) 2 C00H A solution of 1 0 mL ( 0 . 1 6 mole) of 6-propiolactone i n 1 0 0 mL of benzyl alcohol was heated at 70°C f o r 7 4 h under a nitrogen atmosphere. The cooled reaction mixture was dilute d with ether and extracted four times with saturated sodium carbonate s o l u t i o n . The combined aqueous extracts were washed twice with ether, a c i d i f i e d with concentrated hydrochloric acid and f i n a l l y extracted three times with ether. The combined ether extracts were washed once with brine, d r i e d , and concentrated under reduced pressure to y i e l d 24 g of crude product as a pale yellow o i l . D i s t i l l a t i o n afforded 2 1 . 6 g (76%) of 98 as a col o u r l e s s o i l which c r y s t a l l i z e d on standing to give an amorphous white s o l i d ; mp 30-32°C ( l i t . (88) 3 1 . 5 - 3 3 . 5 ° C ) ; bp 130-132°C /0.05 Torr ( l i t . (88) 124-130° / 0 .01 Torr); i r ( C H C 1 3 ) : 3550-2820 (COOH) and 1720 ( C = 0 ) cm - 1; *H nmr (60 MHz, C D C I 3 ) 6: 2.63 ( t , J_= 6 Hz, 2 H ) , 3 . 7 3 ( t , J_ = 6 Hz, 2 H ) , 4 . 5 3 (s, 2 H ) , 7 . 3 5 (s, 5 H ) , 1 1 . 4 8 ( s , IH, exchangeable with D 2 0 ) ; ms m/z: 180(M+, 2 0 ) , 1 0 8 ( 1 1 ) , 1 0 7 ( 1 0 0 ) , 106(8), 105(8), 92(13), - 171 -91(63), 90(6), 89(7), 79(35), 77(16), 73(6), 65(15), 63-64(m*, 1072/180 = 63.6), 58-59(m*, 792/107 = 58.3), 51(9), 45(7) and 39(9). General Procedure A. Preparation of Benzyloxycarboxylic Acids from  Lactones (41) A mixture of the lactone, potassium hydroxide, f r e s h l y d i s t i l l e d benzyl chloride and dry toluene was heated at reflux for 14-16 h. The cooled mixture was d i l u t e d with water and the aqueous phase was washed once with ether, a c i d i f i e d with concentrated hydrochloric acid and extracted three times with ether. The combined ether extracts were washed with brine, dried and concentrated under reduced pressure. 4-Benzyloxybutanoic Acid (99) c £ C H 2 0 ( C H 2 ) 3 C O O H This compound was prepared according to general procedure A using 8.9 mL (0.12 mole) of y-butyrolactone, 32.5 g (0.58 mole) of potassium hydroxide, 40 mL (0.35 mole) of benzyl chloride and 200 mL of toluene. Work-up of the reaction mixture yielded 19.1 g of crude product as a yellow o i l . D i s t i l l a t i o n gave 16.5 g (73%) of 99_ as a colourless o i l ; bp 133-134°C/0.05 Torr [ l i t . (89) 133-134°C/0.5 Torr]; i r (CHC1 3): 3540-2850 (COOH) and 1715 (C=0) cm - 1; lE nmr (60 MHz, CDC13) 6: 1.63-2.30 (m, 2H), 2.30-2.62 (m, 2H), - 172 -3.50 ( t , J_ = 6 Hz, 2H), 4.48 (s, 2H), 7.33 (s, 5H), 11.02 (s, IH, exchangeable with D2O); ms m/z: 194(M+, 14), 108(18), 107(83), 105(7), 92(21), 91(100), 90(5), 89(7), 87(10), 85(28), 79(21), 77(12), 70(5), 65(19), 63(5), 60(7), 57.5-59.5(m*, 1072/194 = 59.0 and 79 2/107 = 58.3), 51(8), 46-47 (m*, 652/91 = 46.4), 45(13), 43(11), 42(5), 41(11) and 39(12). 5-Benzyloxypentanoic Acid (100) oj>CH20(CH2)4COOH This compound was prepared according to general procedure A using 5.0 mL (54 mmol) of 6-valerolactone, 15.1 g (0.27 mole) of potassium hydroxide, 20 mL (0.16 mole) of benzyl chloride and 125 mL of toluene. Work-up of the reaction mixture yielded 11.3 g of crude product as a yellow o i l . D i s t i l l a t i o n gave 8.5 g (75%) of 100 as a colourless o i l ; bp 140-144°C/0.1 Torr; i r ( C H C I 3 ) : 3550-2850 (COOH) and 1715 (C=0) cm - 1; XH nmr (60 MHz, CDCI3) 6: 1.40-1.80 (m, 4H), 2.07-2.42 (m, 2 H ) , 3.18-3.57 (ra, 2 H ) , 4.37 (s, 2H), 7 . 2 0 (s, 5H), 10.82 (s, IH, exchange-able with D 20); ms m/z: 208(M +, 1 2 ) , 108(17), 107(68), 1 0 1 ( 1 2 ) , 99(16), 92(22), 91 ( 1 0 0 ) , 90(5), 89(5), 83(5), 79(14), 77(8), 73(6), 71(6), 65(15), 58-59 (m*. 792/107 = 58.3), 55(13), 51(6), 46-47(m*, 652/91 = 46.4), 45(6), 43(8), 41(8) and 39(9). - 173 -Anal, calcd. for C 1 2 H 1 6 0 3 : C 69.21, H 7.74; found C 68.76, H 7.58. 6-Benzyloxyhexanoic Acid (101) o i>CH 2 0(CH 2 ) 5 COOH This compound was prepared according to general procedure A, using 10.0 ml (90 mmol) of e-caprolactone, 25 g (0.45 mole) of potassium hydroxide, 30 mL (0.27 mole) of benzyl . chloride and 200 mL of toluene. Work-up of the reaction mixture yielded 19.2 g of crude product as a yellow o i l . D i s t i l l a t i o n gave 17.0 g (85%) of 101 as a colourless o i l ; bp 148-150°C/0.07 Torr; i r (CHC1 3): 3550-2850 (COOH) and 1715 (C=0) cm"1; 1E nmr (60 MHz, CDC13) 6: 1.23-1.80 (m, 6H), 2.12-2.47 (m, 2H), 3.25-3.60 (m, 2H), 4.43 (s, 2H), 7.25 (s, 5H), 11.57 (s, IH, exchange-able with D 20); ms m/z: 222(M+, 12), 113(12), 108(13), 107(59), 105(5), 98(5), 97(5), 92(25), 91(100), 89(5), 79(12), 77(6), 73(8), 69(8), 67(6), 65(15), 58(m*. 792/107 = 58.3), 55(12), 51(6), 45(7), 43(6), 41(12) and 39(8). Exact Mass calcd. for C13H18O3: 222.1255; found(ms): 222.1255. - 174 -General Procedure B . Preparation of (1 >n)-Chloroalcohols (n = 6,8) from  (l,n)-Dlols (42) A suspension of the d i o l in concentrated hydrochloric acid was prepared in a 100 mL l i q u i d - l i q u i d extractor. The suspension was heated to 90° while being continuously extracted with toluene. The r e s u l t i n g solution was heated at this temperature and extracted for 15-17 h. The toluene extract was then cooled, washed twice with saturated aqueous sodium bicarbonate and once with brine, d r i e d , and concentrated under reduced pressure. 6-Chloro-l-hexanol ( 1 0 4 ) Cl ( C H 2 ) 6 0 H This compound was prepared according to general procedure B using 10 g (85 mmol) of 1,6-hexanediol, 20 mL of concentrated hydrochloric acid and 200 mL of toluene. Work-up of the reaction mixture gave 9.2 g of crude product as a yellow o i l . D i s t i l l a t i o n afforded 7.73 g (67%) of 104 as a colourless o i l ; bp 106-108°C/13 Torr [ l i t . (41) 107-108°C/12 Torr]; i r (CHC13): 3645 (free OH) and 3580-3300 (H-bonded OH) cm - 1; XH nmr (60 MHz, CDC13) 6: 1.18-2.12 (m, 8H), 2.47 (br s, IH, exchangeable with D 20), 3.38-3.82 (m, 4H); ms m/z: 137( 3 7C1: M+ - H, 0.4), 135( 3 5C1: M+ - H, 0.8), 120(4), - 175 -118(7), 92(12), 90(29), 83(17), 82(57), 70(10), 69(61), 67(46), 57(12), 56(37), 55(98), 54(27), 53(11), 43(28), 42(67), 41(100) and 39(28). 8-Chloro-l-octanol (105) CI (CH 2 ) 8 OH This compound was prepared according to general procedure B using 12.4 g (85 mmol) of 1,8-octanediol, 20 mL of concentrated hydrochloric acid and 200 mL of toluene. Work-up of the reaction mixture gave 12.2 g of crude product. D i s t i l l a t i o n yielded 8.4 g (60%) of 105 as a colourless o i l ; bp 114-116°C/4 Torr [ l i t . (41) 127.5-128.5°C/9 Torr]; i r (CHC1 3): 3640 (free OH) and 3580-3260 (H-bonded OH) cm - 1; *H nmr (60 MHz, CDC13) 6: 1.10-2.05 (m, 12H), 2.37 (s, IH exchangeable with D 20), 3.38-3.78 (m, 4H); ms m/z: 148( 3 7C1: M+ - H 20, 1), 146( 3 5C1: M+ - H 20, 3), 118(24), 106(11), 104(30), 91(10), 83(15), 82(32), 70(12), 69(51), 68(40), 67(28), 57(12), 56(37), 55(100), 54(16), 43(32), 42(32), 41(82) and 39(16) . General Procedure C. Formation of Benzyl Ethers of (1,n)-Chloroalcohols Sodium hydride (60% dispersion in o i l ) was washed under a nitrogen atmosphere with dry ether and the r e s u l t i n g pale grey s o l i d was - 176 -suspended i n dry THF. To this s l u r r y was added a solution of the chloroalcohol in THF and the r e s u l t i n g mixture was s t i r r e d at room temperature for 15 min. Freshly d i s t i l l e d benzyl bromide was added and the mixture was heated at reflux for 15-17 h. The reaction mixture was c a r e f u l l y quenched with water and diluted with ether. The organic phase was washed once with 1 M hydrochloric acid and twice with brine, dried, and concentrated under reduced pressure. 6-Benzyloxy-l-chiorohexane (106) oSCH 2 0(CH 2 ) 6 CI This compound was prepared according to general procedure C using 1.64 g (41 mmol) of sodium hydride dispersion, 4.00 g (29 mmol) of alcohol 104, 5.2 mL (44 mmol) of benzyl bromide and 60 mL of THF. Work-up of the reaction mixture gave 8.4 g of crude product as a yellow o i l . D i s t i l l a t i o n yielded 5.99 g (90%) of pure 106 as a colourless o i l ; bp 112-114°C/0.2 Torr; i r (CHC13): 1100 (C-0) cm - 1; *H nmr (60 MHz, CDC13) 6: 1.13-1.97 (m, 8H), 3.30-3.67 (m, 4H), 4.50 (s, 2H), 7.37 (s, 5H); - 177 -ms m/z: 228( 3 7C1: M+, 0.8), 226( 3 5C1: M+, 2), 208(1 ), 182(2), 135(1), 130(1), 119(2), 117(5), 108(10), 107(7), 105(4), 93(8), 92(71), 91(100), 81(6), 79(10), 77(8), 65(16), 55(10), 43(5), 41(16) and~39(7). Exact Mass calcd. for C 1 3 H 1 9 3 7 C 1 0 : 228.1095; found(ms): 228.1101; calcd. for C 1 3 H i g 3 5 C 1 0 : 226.1124; found(ms): 226.1130. 8-Benzyloxy-l-chlorooctane (107) o>CH20(CH2)8CI This compound was prepared according to general procedure C using 1.70 g (43 mmol) of sodium hydride dispersion, 5.00 g (30 mmol) of alcohol 105, 5.4 mL (46 mmol) of benzyl bromide and 60 mL of THF. Workup of the reaction mixture gave 9.7 g of crude product as a yellow o i l . D i s t i l l a t i o n yielded 7.48 g (97%) of pure 107 as a colourless o i l ; bp 133-135°C/0.2 Torr; i r (CHC1 3): 1100 (C-0) cm"1; *H nmr (60 MHz, CDC13) 6: 1.13-1.97 (m, 12H), 3.27-3.63 (m, 4H), 4.47 (s, 2H), 7.32 (s, 5H); ms m/z: 256( 3 7C1: M+, 0.4), 254( 3 5C1: M+, 1), 236(0.3), 208(0.7), 182(0.7), 165(1), 163(2), 145(2), 144(2), 124(2), 123(2), 110(2), 109(18), 108(9), 107(7), 93(8), 92(84), 91(100), 79(8), 77(6), 69(7), 65(12), 55(15), 46-47(m*, 652/91 =46.4), 43(7), 41(16) and 39(6). - 178 -Exact Mass calcd. f o r Ci 5H 23 3 7C10: 256.1408; found(ms): 256.1411; cal c d . for C 1 5 H 2 3 3 5 C 1 0 : 254.1438; found(ras): 254.1434. General Procedure D. Chain Extension of Benzyloxy Chlorides to Benzyloxy  Carboxylic Acids A Grignard reagent was prepared from a mixture of magnesium turnings and the appropriate chloride in dry THF under a nitrogen atmosphere. One drop of 1,2-dibromoethane was added to i n i t i a t e the reaction. The mixture was heated at reflux for 2.5 h, then was cooled to room temperature, r e s u l t i n g in a grey suspension of the Grignard reagent. In a second f l a s k , 6-propiolactone was added to a THF solution of lithium tetrachlorocuprate ( L ^ C u C l ^ ) 1 0 . This s o l u t i o n was further dilut e d with THF, then was cooled to -10°C. The above sol u t i o n of the Grignard reagent was added v i a cannulation at such a rate that the i n t e r n a l temperature of the reaction mixture remained below 0°C (43). The reaction mixture was s t i r r e d at -10°C for 1 h, then was quenched with 1 M hydrochloric acid and dilu t e d with ether. The organic phase was extracted repeatedly with 5% aqueous potassium hydroxide. The combined aqueous extracts were a c i d i f i e d with concentrated hydrochloric acid and extracted three times with ether. The combined ether layers A 0.1 M solution of lithium tetrachlorocuprate was prepared as follows: A mixture of 0.85 g (0.020 mole) of anhydrous l i t h i u m chloride and 1.34 g (0.010 mole) of anhydrous cupric chloride in a round bottom f l a s k was heated for 5 min with a bunsen burner while under vacuum (0.1 T o r r ) . The fla s k and contents were cooled, a nitrogen atmosphere was introduced and 100 mL of dry THF was added. - 179 -were washed twice with brine, d r i e d , and concentrated under reduced pressure. 9-Benzyloxynonanoic Acid (108) oSCH 2 0(CH 2 ) 8 C00H This compound was prepared according to general procedure D, using 664 mg (26.5 mmol) of magnesium turnings, 4.00 g (17.7 mmol) of chl o r i d e 106 and 20 mL of THF to generate the Grignard reagent. The second solution was prepared from 8.9 mL (0.89 mmol) of a 0.1 M so l u t i o n of l i t h i u m tetrachlorocuprate i n THF, 1.34 mL (21.2 mmol) of B-propiolactone and 20 mL of THF. Work-up of the reaction mixture gave 4.47 g of crude acid product 108 as well as 1.2 g (34%) of quenched Grignard reagent. D i s t i l l a t i o n afforded a small forerun of 3-chloropropanoic acid [54°C/0.2 Torr, l i t . (90) 203-205°C], followed by 2.77 g (59%) of \08_ as a colourless o i l ; bp 176-178°C/0.3 Torr; i r (CHC13): 3640-2850 (COOH) and 1715 (C=0) cm - 1; *H nmr (60 MHz, CDC1 3) 6: 1.10-1.90 (m, 12H), 2.33 ( t , J_= 6 Hz, 2H), 3.47 ( t , J = 6 Hz, 2H), 4.50 (s, 2H), 7.35 (s, 5H), 11.10 (br s, IH, exchangeable with D 2 O ) ; ms m/_z; 264(M+, 13), 246(2), 218(2), 155(6), 144(5), 138(5), 123(6), 108(17), 107(77), 106(9), 105(19), 97(10), 92(33), 91(100), - 180 -84(9), 83(7), 79(11), 73(15), 69(15), 68(9), 65(9), 60(18), 55(39), 51(8), 45(8), 43(15), 42(8), 41(29) and 39(8). Exact Mass calcd. for C 1 6 H 2 4 0 3 : 264.1724; found(ms): 264.1724. 11—Benzyloxyundecanoic Acid (109) <r>CH20(CH2)10C00H This compound was prepared according to general procedure D, using 860 mg (35.4 mmol) of magnesium turnings, 6.00 g (23.6 mmol) of chloride 107 and 20 mL of THF to generate the Grignard reagent. The second so l u t i o n was prepared from 11.8 mL (1.18 mmol) of a 0.1 M solut i o n of lithium tetrachlorocuprate in THF, 3.0 mL (47 mmol) of B-propiolactone and 20 mL of THF. Work-up of the reaction mixture gave 5.95 g of crude acid product 109 as well as 1.77 g (34%) of quenched Grignard reagent. D i s t i l l a t i o n afforded a forerun of 3-chloropropanoic acid (0.90 g; 54°C/0.2 To r r ) , followed by 3.89 g (56%) of 109_ as a colourless o i l which s o l i d i f i e d on standing to give a white amorphous s o l i d ; mp 30-32°C; bp 188°C/0.05 Torr; i r (CHC1 3): 3620-2820 (COOH) and 1715 (C=0) cm - 1; *H nmr (60 MHz, C D C I 3 ) 6: 1.08-1.90 (m, 16H), 2.33 ( t , J_= 7 Hz, 2H), 3.45 ( t , J = 6 Hz, 2H), 4.50 (s, 2H), 7.33 (s, 5H), 11.50 (s, IH, exchangeable with D 2 O ) ; - 181 -ms m/z; 292(M+', 12), 109(11), 108(14), 107(50), 100(10), 92(49), 91(100), 79(9), 77(8), 73(17), 71(9), 69(16), 65(9), 60(13), 55(32), 46-47(m*, 652/91 =46.4), 45(13), 43(30), 42(11), 41(25) and 39(9). Exact Mass calcd. for Ci 8H 2803: 292.2038; found(ms): 292.2038. 2,2-Dimethyl-l,3-dioxan-4,6-dione (IfeldrWs Acid) (31) (44) To a suspension of 52 g (0.50 mole) of malonic acid and 60 mL (0.60 mole) of acetic anhydride was added 1.5 mL of concentrated s u l f u r i c acid with constant s t i r r i n g . The temperature of the mixture was maintained at 20-25°C by means of an ice-water bath while 40 mL (0.55 mole) of acetone was slowly added. The mixture was then allowed to stand in the fridge overnight. The resultant c r y s t a l s were f i l t e r e d by suction, washed three times with 75 mL portions of i c e water, then allowed to a i r dry. The r e s u l t i n g white s o l i d was dissolved in 110 mL of acetone, f i l t e r e d to remove any undissolved material, then d i l u t e d with 220 mL of water. F i l t r a t i o n gave a flocculent white s o l i d which was dried in a vacuum dessicator over phosphorous pentoxide to y i e l d 0 0 37.8 g (53%) of 31; - 182 -mp 93-95°C [ l i t . (44) 94-95°C]; i r ( C H C I 3 ) : 1785 and 1755 (asymmetric. and symmetric C=0 stretches) cm - 1; JH nmr (60 MHz, CDCI3) 6: 1.77 (s, 6 H ) , 3.58 (s, 2 H ) ; ms m/z: 144CM+, 0.1), 129(10), 100(10), 61(7), 59(5), 58(5), 44(5), 43(100) and 42(43). General Procedure E. Preparation of Acid Chlorides To a solution of dry pyridine in dry dichloromethane at 0°C was added oxalyl c h l o r i d e , to give a yellow suspension. This suspension was s t i r r e d f o r 10 min, then a solution of carboxylic acid in d i c h l o r o -methane was added. The mixture was s t i r r e d at 0°C for 45 min and at room temperature for 45 min to give a yellow s o l u t i o n . General Procedure F. Acylation of 2,2-Di»ethyl-l »3-dioxan-4,6-dione  (31) <15> To a solution of _31_ in dry dichloromethane at 0°C and under a nitrogen atmosphere was added dry pyridine i n one portion and the r e s u l t i n g solution was s t i r r e d at 0°C for 30 min. A s o l u t i o n of acid chloride was then added dropwise and the reaction mixture was s t i r r e d at 0°C for 1 h and at room temperature for 1 h. The reaction mixture was washed three times with 1 M hydrochloric acid and twice with brine, d r i e d , and concentrated under reduced pressure. - 183 -5-(3'-Benzyloxy-1 '-hydroxypropylldene)-2,2-dinethyl-l t3-dloxan-4,6-dione (110) To 5 . 1 2 g (28.4 mmol) of carboxylic acid 98_ was added 5 . 0 mL (57 mmol) oxalyl chloride and the res u l t i n g solution was s t i r r e d for 2 . 5 h at room temperature. The excess oxalyl chloride was then removed under reduced pressure and the residual acid chloride was dissolved i n 30 mL of dry dichloromethane. Compound 110 was next prepared according to general procedure F, using 3.72 g (25 . 8 mmol) of 3J_, 6 . 3 mL (77 mmol) of pyridine, 50 mL of dichloromethane and the above acid chloride s o l u t i o n . Workup of the reaction mixture gave 7.72 g of crude product as a red syrup. P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate ( 4 : 1 ) as eluant afforded 5.99 g (76%) of HQ as a yellow o i l ; i r ( C H C 1 3 ) : 3600-3300 (OH), 1740 (C= 0 ) , 1680 (H-bonded C=0) and 1580 (C=C) cm"1; *H nmr (60 MHz, CDCI3) 6: 1.70 (s, 6 H ) , 2 . 6 8 - 2.92 and 3.36-3.62 (2 m u l t i p l e t s , 2H; enol and keto forms), 3 . 6 8 - 3 . 9 7 (m, 2H), 4 .57 (s, 2 H ) , 7 . 3 5 (s, 5 H ) , 15 .35 (br s, IH, exchangeable with D 2 0 ) ; ms m/z: 306(M +, 5 ) , 248 ( 9 ) , 144 ( 5 ) , 143(40), 142(8), 125 ( 2 2 ) , - 184 -124(21), 114(5), 113(5), 108(7), 107(31), 106(5), 105(6), 98(26), 96(8), 91(100), 89(6), 79(10), 77(8), 71(7), 69(8), 65(17), 59(15), 58(12), 57(6), 56(11), 55(7), 46-47(m*, 652/91 = 46.4), 45(7), 44(21), 43(9), 42(8), 41(8) and 39(11). Exact Mass calcd. for C 1 6 H 1 8 0 6 : 306.1104; found (ms): 306.1116. 5— (4'-Benzyloxy-l '-hydroxybutylidene)-2 t2-dlmethyl-l ,3-dioxan-4 ,6-dione The acid chloride of carboxylic acid 99_ was prepared according to general procedure E, using 5.0 g (26 mmol) of 99_, 2.25 mL (25.8 mmol) of oxalyl c h l o r i d e , 2.1 mL (26 mmol) of pyridine and 30 mL of d i c h l o r o -methane. Compound 111 was prepared according to general procedure F, using 3.38 g (24 mmol) of 31, 5.7 mL (71 mmol) of pyridine, 30 mL of dichloromethane and the above acid chloride s o l u t i o n . Work-up of the reaction mixture gave 7.25 g of crude product as a red syrup. P u r i f i c a -t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (2:1) as eluant afforded 6.34 g (84%) of 111 as a yellow o i l ; i r (CHC13): 3640-3300 (OH), 1740 (C=0), 1670 (H-bonded C=0) and 1580 (C=C) cm - 1; (111) QSCH 20(CH 2) 3 HO. - 185 -1K nmr (60 MHz, CDC1 3)6: 1.70 (s, 6H), 1.73-2.27 (m, 2H), 2.30-2.70 and 3.03-3.33 (2 mul t i p l e t s , 2H; enol and keto forms), 3.37-3.70 (m, 2H), 4.47 (s, 2H), 7.33 (s, 5H) 15.20-15.53 (br s, IH, exchangeable with D2O) ; ms m/z: 320(M+, 0.8), 262(7), 157(6), 155(8), 139(5), 128(14), 112(13), 111(5), 108(6), 107(29), 105(8), 92(14), 91(100), 87(6), 85(18), 84(16), 79(9), 77(9), 69(12), 65(14), 59(8), 57(10), 55(7), 51(6), 44(15), 43(38), 42(7), 41(9), and 39(9). Exact Mass calcd. f o r C 1 7H 2 0O 6: 320.1260; found (ms): 320.1278. 5-(5'-Benzyloxy-1 '-hydroxypentylidene)-2 ,2-dlmethyl-l ,3-dioxan-4 ,6-dione The acid chloride of carboxylic acid 100 was prepared according to general procedure E, using 1.00 g (4.8 mmol) of 100, 0.41 mL (4.8 mmol) of oxalyl chloride, 0.39 mL (4.8 mmol) of pyridine and 15 mL of procedure F, using 0.63 g (4.4 mmol) of 31, 1.1 mL (13 mmol) of pyridine , 10 mL of dichloromethane and the above acid chloride solu-t i o n . Work-up of the reaction mixture gave 1.53 g of crude product as a (112) 0 dichloromethane. Compound 112 was prepared according to general - 186 -red syrup. P u r i f i c a t i o n by f l a s h chromatography using petroleum ether -ethyl acetate (4:1) as eluant afforded 1.16 g (80%) of 112 as a yellow o i l ; i r (CHC1 3): 3650-3400 (OH), 1740 (C=0), 1670 (H-bonded C=0) and 1580 (C=C) cm - 1; *H nmr (60 MHz, C D C I 3 ) 6: 1.50-1.93 (ra, 4H), 1.73 (s, 6H), 2.27-2.57 and 2.90-3.25 (2 m u l t i p l e t s , 2H; enol and keto forms), 3.37-3.63 (m, 2H), 4.48 (s, 2H), 7.33 (s, 5H), 15.20-15.53 (br s, IH, exchangeable with D 20); ms m/z: 334(M+, 3), 276(7), 258(3), 208(6), 185(5), 176(4), 170(6), 169(6), 167(5), 152(8), 141(8), 124(5), 108(8), 107(32), 101(13), 99(15), 92(18), 91(100), 83(5), 79(9), 77(6), 71(8), 69(7), 65(13), 59(7), 58(14), 55(11), 46-47(m*, 652/91 =46.4), 44(24), 43(47), 42(6), 41(8) and 39(7). Exact Mass calcd. f o r C 1 8 H 2 2 0 6 : 334.1416; found (ms): 334.1428. 5-(6'-Benzyloxy-l'-hydroxyhexylidene)-2,2-diaethyl-lt3-dioxan-4,6-dtone (113) The acid chloride of carboxylic acid 101 was prepared according to general procedure E, using 2.14 g (9.6 mmol) of 101 , 0.84 mL (9.6 mmol) of oxalyl chloride, 0.78 mL (9.6 mmol) of pyridine and 20 mL of 0 - 187 -dichloromethane. Compound 113 was prepared according to general procedure F, using 1.26 g (8.7 mmol) of 31_, 2.2 mL (26 mmol) of pyridine, 20 mL of dichloromethane and the above acid chloride s o l u t i o n . Work-up of the reaction mixture gave 3.22 g of crude product as a red syrup. P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (4:1) as eluant afforded 2.53 g (83%) of 113 as a yellow o i l ; i r (CHC1 3): 3620-3420 (OH), 1740 (C=0), 1670 (H-bonded C=0) and 1575 (C=C) cm - 1; *H nmr (60 MHz, CDC13) 6: 1.40-1.90 (m, 6H), 1.72 ( s , 6H) , 2.13-2.50 and 2.90-3.27 (2 m u l t i p l e t s , 2H; enol and keto forms), 3.33-3.63 (m, 2H), 4.48 (s, 2H), 7.32 (s, 5H), 15.13-15.50 (br s, IH, exchangeable with D 2 O ) ; ms m/z: 348(M+, 0.2), 290(3), 272(0.5), 222(3), 199(3), 141(3), 115(4), 113(4), 108(4), 107(17), 97(4), 92(10), 91(55), 79(7), 77(5), 73(4), 69(7), 65(9), 59(7), 58(28), 44(34) 43(100), 42(8), 41(7) and 39(7). Exact Mass calcd. for C19H21+O6: 348.1572; found (ms): 348.1571. 5-(9 '-Benzyloxy-l '-hydroxynonylidene)-! ,2-dimethyl-l ,3—dloxan—4 ,6-dione (114) - 188 -The acid chloride of carboxylic. acid 108 was prepared according to general procedure E, using 2.0 g (7.6 mmol) of 108, 0.66 mL (7.6 mmol) of oxalyl c h l o r i d e , 0.61 mL (9.6 mmol) of pyridine and 15 mL of dichloromethane. Compound 114 was prepared according to general procedure F, using 0.99 g (6.9 mmol) of 3j_, 1.7 mL (21 mmol) of pyridine, 15 mL of dichloromethane and the above acid chloride s o l u t i o n . Work-up of the reaction mixture gave 2.49 g of crude product as a red syrup. P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (4:1) as eluant afforded 1.69 g (63%) of 114 as a yellow o i l ; i r (CHC13): 3620-3400 (OH), 1740 (C=0), 1670 (H-bonded C=0) and 1575 (C=C) cm - 1; *H nmr (60 MHz, CDC1 3) 6: 1.15-1.87 (m, 12H), 1.73 ( s , 6H) , 2.13-2.50 and 2.92-3.27 (2 m u l t i p l e t s , 2H; enol and keto forms), 3.47(t, J_ = 6 Hz, 2H), 4.50(s, 2H), 7.35 (s, 5H), 15.17-15.50 (br s, IH, exchangeable with D 20); ms m/z: 390(M +, 0.3), 375(0.3), 332(4), 265(8), 155(5), 108(13), 107(50), 97(5), 95(5), 92(24), 91(89), 79(7), 77(5), 71(9), 69(6), 65(9), 59(6), 58(33), 57(5), 55(15), 44(57), 43(100), 42(8), 41(13) and 39(17). Exact Mass ca l c d . for C 1 9 H 2 4 O 5 (M+ - acetone): 332.1623; found (ms): 332.1616. - 189 -5—(11 '-Benzyloxy-l '-hydroxyundecylldene)-2,2-dimethyl-l ,3-dioxan-4, 6-dione (115) ptCH^o > 0 HQ The acid chloride of carboxylic acid 109 was prepared according to general procedure E, using 1.46 g (5.0 mmol) of 109, 0.41 mL (5.0 mmol) of oxalyl c h l o r i d e , 0.40 mL (5.0 mmol) of pyridine and 15 mL of procedure F, using 0.79 g (5.5 mmol) of 31, 1.3 mL (17 mmol) of pyri d i n e , 15 mL of dichloromethane and the above acid chloride s o l u t i o n . Work-up of the reaction mixture gave 1.87 g of crude product as a red syrup. P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (4:1) as eluant afforded 1.05 g (50%) of 115 as a yellow o i l ; i r (CHC13): 3620-3400 (OH), 1740 (C=0), 1670 (H-bonded CO) and 1575 (C=C) cm - 1; LE nmr (60 MHz, CDC13) 6: 1.03-1.92 (m, 16H), 1.73 (s, 6H), 2.08-2.58 and 2.90-3.27 (2 mu l t i p l e t s , 2H; enol and keto forms), 3.47 ( t , J = 6 Hz, 2H), 4.50 (s, 2H), 7.35 (s, 5H), 15.17-15.50 (br s, IH, exchangeable with D 20); ms m/z: 418(M+, 1), 403(1), 401(1), 360(4), 342(1), 312(1), 293(3), 292(14), 183(3), 123(3), 108(14), 107(64), 92(28), 91(100), dichloromethane. Compound 115 was prepared according to general - 190 -85(7), 83(7), 81(8), 79(8), 77(7), 71(15), 69(11), 67(7), 65(10), 60(7), 59(8), 58(21), 57(8), 55(19), 44(39), 43(49), 42(7), 41(19) and 39(8). (ms): 360.1954. 5-(l * ,3'-Dihydroxypropylidene)-2,2-dliiethyl-l ,3-dloxan-4,6-dione (116) A mixture of 710 mg (2.32 mmol) of 110 and 70 mg of 10% palladium-on-charcoal in 10 mL of ethanol - ethyl acetate (1:1) was s t i r r e d under a hydrogen atmosphere (1 atra) at room temperature. After 57 mL (1 molar equivalent) of hydrogen had been absorbed during a period of 2 h, the uptake of hydrogen ceased. The catalyst was removed by f i l t r a t i o n and was washed with ethyl acetate. The f i l t r a t e was concentrated under reduced pressure to give 448 mg (89%) of 116 as a pale yellow o i l ; i r (CHC1 3): 3640-3350 (OH), 1740 (C=0), 1680 (H-bonded C=0) and 1580 (C=C) cm - 1; 1E nmr (60 MHz, CDC13) 6: 1.70 (s, 6H), 2.56-2.83 and 3.13-3.53 (2 m u l t i p l e t s , 2H; enol and keto forms), 3.67-4.07 (ra, 2H); Exact Mass calcd. f or C 2 1 H 2 8 0 5 ( M + - acetone): 360.1937; found 0 - 191 -ms m/z: 216CM+, 1), 159(15), 158(32), 141(14), 140(13), 114(27), 105(13), 91(12), 73(57), 69(19), 59(79), 58(14), 55(34), 45(18), 44(26), 43(100), 42(33), 41(13) and 39(13). Exact Mass calcd. for CgHi 206: 216.0634; found (ms): 216.0634. 5-(Tetrahydro-2'-furylidene)-2,2-di«ethyl-l ,3-dioxan-4,6-dione (122) 0 A mixture of 1.93 g (6.0 mmol) of 111 and 0.19 g of 5% palladium-on-charcoal in 15 mL of ethyl acetate was s t i r r e d under a hydrogen atmosphere (1 atm) at room temperature. After 208 mL (141% of 1 molar equivalent) of hydrogen had been absorbed during a period of 19 h, the uptake of hydrogen ceased. The catalyst was removed by f i l t r a t i o n and was washed with dichloromethane. The f i l t r a t e was concentrated under reduced pressure to give 1.03 g crude 122 as pale yellow c r y s t a l s . R e c r y s t a l l i z a t i o n from petroleum ether - ethyl acetate gave 0.89 g (70%) of _122 as a white s o l i d . mp 145.0-146.5°C; i r (CHC1 3): 1755 and 1715 (asymmetric and symmetric C O stretches) cm - 1 - 192 -*H nmr (60 MHz, CDC13) 6: 1.73 (s, 6H), 1.93-2.53 (m, 2H), 3.50 ( t , J_ = 8 Hz, 2H), 4.73(t, J_ = 7 Hz, 2H); ms m/z: 212(M +, 13), 197(13), 156(6), 155(55), 154(29), 113(8), 111(20), 110(100), 69(28), 53(11), 52(8), 44(7), 43(47), 42(78), 41(26), 40(8) and 39(14); Exact Mass calcd. for C 1 0 H 1 2 O 5 : 212.0685; found (ms): 212.0685. 5 - ( l ' ,5'-Dihydrc«:ypentylidene)-2,2-diiiiethyl-l t3-dioxan-4,6-dlone (118) A mixture of 2.17 g (6.48 mmol) of 112, 0.43 g of 5% palladium-on-charcoal, and 2 drops of concentrated hydrochloric acid i n 30 mL of ethanol was s t i r r e d under a hydrogen atmosphere (1 atm) at room temperature. After 159 mL (1 molar equivalent) of hydrogen had been absorbed during a period of 2 h, the uptake of hydrogen ceased. The catalyst was removed by f i l t r a t i o n and was washed with dichloromethane. The f i l t r a t e was concentrated under reduced pressure to give 1.55 g (98%) of 118 as a pale yellow o i l ; i r ( C H C I 3 ) : 3740-3350 (OH), 1740 (C=0), 1675 (H-bonded C=0) and 1580 (C=C) cm"1; *H nmr (60 MHz, CDCI3) 6: 1.43-2.08 (m, 4H), 1.78 (s, 6H), 2.20-2.50 and 2.92-3.28 (2 m u l t i p l e t s , 2H; enol and keto forms), 0 H0(CH ) 2 4 o' - 193 -3.48-3.82 (m, 2H); ms m/z: 244(M +, 1), 226(1), 186(12), 169(21), 168(39), 128(17), 124(17), 101(17), 84(11), 83(16), 82(18), 69(30), 59(47), 58(18), 55(40), 44(44), 43(100), 42(20), 41(21) and 39(12). Exact Mass calcd. f o r C^H^Og: 244.0947; found (ms) : 244.0933. 5-(l*,6'-Dihydroxyhexylidene)-2,2-dlmethyl-l,3-dioxan-4,6-dione (119) A mixture of 2.53 g (7.27 mmol) of U3_, 0.50 g of 5% palladium-on-charcoal and 2 drops of concentrated hydrochloric acid i n 30 mL of ethanol was s t i r r e d under a hydrogen atmosphere (1 atm) at room temperature. After 191 mL (107% of 1 molar equivalent) of hydrogen had been absorbed during a period of 20 min, the uptake of hydrogen ceased. The c a t a l y s t was removed by f i l t r a t i o n and was washed with dichloromethane. The f i l t r a t e was concentrated under reduced pressure to give 1.76 g (94%) of 119 as a pale yellow o i l ; i r (CHC13): 3670-3380 (OH), 1740 (C=0), 1670 (H-bonded C=0) and 1575 (C=C) cm - 1; JH nmr (60 MHz, CDC13) 6: 1.40-1 .95 (m, 6H), 1.73 (s, 6H), 0 0 - 194 -2.13-2.45 and 2.92-3.25 (2 mul triplets, 2H; enol and keto forms), 3.47-3.83 (m, 2H); ms m/z; 258(M+, 0.5), 243(0.8) 200(15), 183(10), 182(12), 156(17), 138(14), 131(11), 130(11), 128(35), 115(11), 114(14), 102(19), 97(15), 86(12), 84(21), 73(57), 70(19), 69(32), 68(17), 60(29), 59(37), 58(24), 57(11), 56(11), 55(74), 44(37), 43(100), 42(31) and 39(20). Exact Mass calcd. f o r C 1 2 H 1 8 0 6 : 258.1103; found (ms): 258.1122. 5 - ( l ' ,9 ' -D ihydroxvnony l idene ) - 2 , 2 -d inethy l - l , 3 -d ioxan-4,6-d ione (120) A mixture of 1.48 g (3.79 mmol) of 114, 0.30 g of 5% palladium-on-charcoal and 2 drops of concentrated hydrochloric acid i n 15 mL of ethanol was s t i r r e d under a hydrogen atmosphere (1 atm) at room temperature. After 93 mL (1 molar equivalent) of hydrogen had been absorbed during a period of 20 min, the uptake of hydrogen ceased. The cata l y s t was removed by f i l t r a t i o n and was washed with dichiromethane. The f i l t r a t e was concentrated under reduced pressure to give 0.96 g (85%) of 120 as a pale yellow o i l ; i r (CHC13): 3640 (free OH), 3600-3380 (H-bonded OH), 1740 (C=0), 1675 (H-bonded OH) and 1575 (C=C) cm"1; 0 - 195 -LH nmr (60 MHz, CDC13) 6: 1.08-1 .90 (m, 12H), 1.73 (s, 6H), 2.12-2.50 and 2.87-3.23 (2 m u l t i p l e t s , 2H; enol and keto forms), 3.47-3.83 (m, 2H); ms m/z: 300(M +, 0.5), 285(1), 281(0.6), 270(0.6), 242(4), 225(4), 224(5), 156(19), 138(14), 128(25), 97(13), 84(20), 73(13), 69(25), 68(12), 67(11), 60(15), 59(20), 58(24), 56(11), 55(53), 44(42), 43(100), 42(19), 41(34), and 39(10). Exact Mass calcd. for C15H211O6: 300. 1573; found (ms): 300.1536. 5 - ( l ' ,11 '-Dihydroxyundecylldene)-2 ,2-dinethyl-l ,3-dioxan-4,6-dlone A mixture of 814 mg (1.95 mmol) of 115, 160 mg of 5% palladium-on-charcoal and 1 drop of concentrated hydrochloric acid in 10 mL of ethanol was s t i r r e d under a hydrogen atmosphere (1 atm) at. room temperature. After 48 mL (1 molar equivalent) of hydrogen had been absorbed during a period of 20 min, the uptake of hydrogen ceased. The c a t a l y s t was removed by f i l t r a t i o n and was washed with dichiromethane. The f i l t r a t e was concentrated under reduced pressure to give 564 rag (88%) of 121 as a pale yellow s o l i d : (121) 0 0 - 196 -mp 35-40°C; i r (CHC13): 3600-3300 (OH), 1740 (C=0), 1675 (H-bonded C-0), and 1580 (C=C) cm - 1; *H nmr (60 MHz, CDCI3) 6: 1.08-1.90 (m, 16H), 1.73 ( s , 6H) , 2.15-2.42 and 2.90-3.25 (2 mu l t i p l e t s , 2H; enol and keto forms), 3.48-3.82 (m, 2H); ms m/z: 313(M + - CH 3, 0.1), 298(0.08), 270(0.4), 253(0.2), 252(0.4), 235(0.4), 234(0.4), 212(0.4), 200(3), 166(2), 156(3), 138(2), 128(4), 124(3), 112(4), 101(6), 98(19), 97(8), 96(7), 95(6), 89(5), 88(11), 85(5), 84(16), 83(12), 82(9), 81(7), 73(12), 71(7), 70(7), 69(22), 68(8), 60(12), 59(10), 58(35), 57(10), 56(9), 55(35), 54(6), 45(7), 44(60), 43(100), 42(13), 41(26) and 39(8). Exact Mass calcd. for C 1 6 H 2 5 0 6 (M+ - CH 3): 313.1651; found (ms): 313.1648; ca l c d . for C l l +H 2 20 5 (M+ - acetone): 270.1467; found (ms): 270.1471. 3-Oxo-5-pentanolide (123) 0 To 25 mL of dry THF heated at reflux under a nitrogen atmosphere was added a solution of 302 mg (1.40 mmol) of alcohol 116 in 15 mL of - 197 -THF over a period of 4 h, using a constant rate addition funnel. The solution was then heated at reflux for an additional 30 min. Removal of solvent gave 235 mg of a yellow o i l . D i s t i l l a t i o n 1 1 gave 139 mg (87%) of 123 as a colourless o i l , which slowly c r y s t a l l i z e d to give an amorphous white s o l i d . ( ^ B. nmr analysis indicated _ca. 95% purity.) mp 61-64°C; bp (Kugelrohr d i s t i l l a t i o n ) 130°C/0.1 Torr; i r (CHC13): 1770 (COOR) and 1740 (C=0) cm - 1; lE nmr (60 MHz, CDC13) 6 : 2.72 ( t , J_= 6 Hz, 2H), 3.60 (s, 2H) 4.63 ( t , J_ = 6 Hz, 2H); ms m/z: 114(M+, 18), 105(3), 104(3), 91(3), 85(5), 77(4), 73(3), 72(5), 71(5), 70(3), 69(5), 60(4), 58(3), 56(7), 55(51), 45(4), 44(7), 43(25), 42(100), 41(7), 40(4) and 39(5). Exact Mass calcd. for C5H6O3: 114.0317; found (ms): 114.0319. Thermolysis of 118 To 150 mL of dry THF heated at ref l u x under a nitrogen atmosphere was added a solution of 2.83 g (11.6 mmol) of alcohol 118 in 70 mL of THF over a period of 6.5 h. Removal of solvent gave 2.0 g of a yellow o i l . P u r i f i c a t i o n by fl a s h chromatography using petroleum ether - ethyl D i s t i l l a t i o n glassware was treated prior to use with a solu t i o n of t r i m e t h y l s i l y l chloride and pyridine in dichloromethane, then was rinsed with water and d r i e d . - 198 -acetate (9:1) as eluant gave in order of e l u t i o n , the following compounds: (a) 2-methylene-l,7-dioxacyclotetradecane-8,10-dione (128) (76 mg, 5%) as a white semi-solid; Rf 0.46 (petroleum ether - ethyl acetate - acetic acid 20:20:1); i r (CHC1 3): 1740 (C00R), 1720 (C=0), 1690 (C=C of enol ether) and 1645 (C=C of enol of B-keto ester) cm - 1; XH nmr (80 MHz, CDCI3) 6: 1.48-1.96 (m, 8H), 1.96-2.12 (m, 2H), 2.32-2.60 (m, 2H), 3.03 (s, 2H), 3.96-4.32 (m, 4H), 4.62-4.78 (m, 2H); ms m/z: 240(M +, 5), 142(4), 141(3), 125(7), 124(22), 101(4), 100(4), 99(50), 98(7), 97(16), 96(47), 83(5), 82(5), 69(8), 67(8), 56(3) 55(19), 54(3), 53(3), 44(4), 43(100), 42(4), 41(18) and 39(5). Exact Mass calcd. f o r C 1 3 H 2 0 O i + : 240.1362; found (ms): 240.1369. (b) l,7-dioxacyclotetradecane-2,8,10-trione (127) (181 mg, 13%) as a pale yellow o i l ; Rf 0.36 (petroleum ether - ethyl acetate - acetic acid 20:20:1); i r (CHC1 3): 1740 (COOR) and 1720 (C=0) cm - 1; *H nmr (80 MHz, CDC13) 6: 1.20-2.13 (m, 8H), 2.25-2.59 (m, 2H), 2.59-2.91 (m, 2H), 3.45 (s, 2H), 4.10-4.40 (m, 4H); ms m/z: 242(M +, 4),' 143(5), 142(11), 141(3), 129(4), 128(3), 125(5), 124(14), 115(3), 114(19), 102(7), 101(100), 100(8), 99(13), 98(7), 97(4), 96(6), 87(4), 84(5), 83(18), 82(9), 71(5), 70(4), 69(5), - 199 -59(6), 56(11), 55(37), 54(7), 44(4), 43(30), 42(27), 41(25), and 39(7). Exact Mass calcd. for C12H18O5: 242.1154; found (ms): 242.1152. (c) 1,9-dioxacyclohexadecane-l,3,10,12-tetraone (124) (184 mg, 11%) as a white s o l i d ; Rf 0.28 (petroleum ether - ethyl acetate - acetic acid 20:20:10); mp 99-102°C; i r ( C H C I 3 ) : 1745 (COOR) and 1720 (C=0) cm"1; XH nmr (60 MHz, CDCI3) 6: 1.47-2.00 (m, 8H), 2.10-2.77 (m, 4H), 3.45 (s, 4H), 3.93-4.33 (m, 4H); ms m/z: 284(M +, 6), 266(3), 198(2), 184(11), 143(68), 142(18), 125(62), 124(20), 114(23), 105(11), 101(100), 100(12), 99(22), 98(17), 97(14), 96(10), 87(12), 84(11), 83(33), 82(14), 69(14), 56(15), 55(58), 43(41), 42(33) and 41(33). Exact Mass calcd. for CH+H2006: 284.1260; found (ms): 284.1263. Thermolysis of 119 To 100 mL of dry THF heated at reflux under a nitrogen atmosphere was added a solution of 1.75 g (6.8 mmol) of alcohol 119 in 50 mL of THF over a period 3.5 h using a constant rate addition funnel. The solution was then heated at reflux for an additional 1 h. Removal of solvent gave 2.2 g of a pale yellow semi-solid. R e c r y s t a l l i z a t i o n from ethanol gave, as the only is o l a t e d product, 159 mg (15%) of 1,10-dioxacyclo-- 200 -octadecan - 2 , 4 , 1 1,13-tetraone (125) as a white s o l i d ; mp 109 -112°C; i r (CHC13): 1745 (COOR) and 1715 (C=0) cm - 1; *H nmr (60 MHz, CDCI3) 6: 1 . 2 0 - 2 . 0 0 (m, 1 2 H ) , 2.58 ( t , J_ = 6 Hz, 4 H ) , 3 . 4 3 (s, 4 H ) , 4.17 ( t , J_ = 6 H z , 4 H ) ; ms m/z; 312(M +, 8), 294 ( 3 ) , 258 ( 3 ) , 240 ( 4 ) , 216 ( 4 ) , 211(15), 198 ( 6 ) , 197 ( 4 ) , 187 ( 4 ) , 157 ( 3 3 ) , 156(18), 139(28), 138(36), 128(16), 115(81), 113 ( 1 0 ) , 1 1 2 ( 1 1 ) , 1 1 0 ( 2 1 ) , 9 7 ( 4 9 ) , 96(13), 87(13), 84(19), 7 3 ( 1 0 ) , 70 ( 1 2 ) , 69(63), 6 8(17), 67 ( 1 1 ) , 56(18), 5 5 ( 1 0 0 ) , 54(19), 43(30), 42 ( 4 5 ) , 41(69) and 3 9 ( 1 1 ) . Exact Mass calcd. for C 1 6H 2 J t0 6: 312.1573; found (ms): 312.1595. Thermolysis of 120 To 100 mL of dry THF heated at reflux under a nitrogen atmosphere was added a sol u t i o n of 568 mg (1.89 mmol) of alcohol 120 in 20 mL of THF over a 4 h period using a constant rate addition funnel. The solution was then heated at reflux for an additional 30 min. Removal of solvent gave 570 mg of a white s o l i d . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate ( 4 : 1 ) as eluant gave in order of e l u t i o n : (a) 1,ll-dioxacyclodocosane - 2,ll,13-trione (129) (29 mg, 8%) as a pale yellow o i l ; Rf 0.87 (petroleum ether - ethyl acetate 1:1); i r ( C H C I 3 ) : 1740 (COOR) and 1720 (C=0) cm - 1; - 201 -*H nmr (60 MHz, CDC13) 6: 1.07-1.97 (m, 24H), 2.07-2.70 (m, 4H), 3.40 ( s , 2H), 3.93-4.30 (m, 4H); ms m/z: 354(16), 336(11) 241(19), 199(9), 180(8), 162(14), 157(14), 139(28), 138(34), 112(12), 111(12), 110(12), 109(10), 103(12), 97(34), 96(38), 95(18), 94(18), 87(10), 85(11), 84(20), 83(16), 82(13), 81(21), 71(26), 69(56), 68(13), 67(20), 57(21), 56(24), 55(100), 54(17), 43(43), 42(22) and 41(49). Exact Mass calcd. for C ^ o ^ O s : 354.2406; found (ms): 354.2403. (b) 1,13-dioxacyclotetracosane-2,4,14,16-tetraone (126) (22 mg, 6%) as a white s o l i d ; Rf 0.82 (petroleum ether - ethyl acetate 1:1); mp 109-114°C; i r (CHCI3): 1740 (COOR) and 1720 (C=0) cm - 1; *H nmr (60 MHz, C D C I 3 ) 6: 1.07-1 .97 (m, 24 H), 2.53 ( t , J_= 6 Hz, 4H), 3.42(s, 4H), 4.15(t, J = 5 Hz, 4H); ms m/z: 396(M+, 6), 378(2), 354(4), 307(4), 283(7), 241(9), 217(5), 199(12), 185(17), 149(20), 139(18), 112(22), 97(32), 96(27), 95(21), 86(65), 85(24), 84(100), 83(31), 81(25), 71(42), 70(26), 69(51), 67(28), 57(60), 49(46), 47(34), 43(78), 42(21), 41(47) and 40(27). Exact Mass calcd. for C 2 2 H 3 6 0 6 : 396.2511; found (ms): 396.2505. - 202 -3-Oxotridecanolide (34) (15) To 250 mL of dry THF heated of reflux under a nitrogen atmosphere was added a solution of 1.02 g (3.1 mmol) of alcohol 121 in 50 mL of THF over a period of 4 h using a constant rate addition funnel. The re s u l t i n g s o l u t i o n was then heated at ref l u x for an additional 1.5 h. Removal of solvent gave 757 mg of a pale yellow s o l i d . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (9:1) as eluant gave 223 mg (32%) of 34_ as a white s o l i d . mp 37-39°C; i r (CHC1 3): 1760 (COOR) and 1740 (C=0) cm - 1; *H nmr (80 MHz, C D C I 3 ) 6: 1.08-1.90 (m, 16H), 2.58 ( t , J_= 7 Hz, 2H), 3.41 (s, 2H), 4.19 ( t , J_ = 6Hz, 2H); ms m/z: 226(M +, 10), 208(4), 149(13), 124(31) 122(10), 115(12), 103(29), 102(14), 98(21), 97(19), 96(23), 95(24), 85(15), 84(20), 83(34), 82(48), 81(28), 71(15), 70(16), 69(55), 68(30), 67(30), 58(11), 57(29), 56(23), 55(100), 54(21), 53(10), 44(13), 43(59), 42(37), 41(85) and 39(18). Exact Mass calcd. for C 1 3 H 2 2 O 3 : 226.1569; found (ms): 226.1575. - 203 -III. Synthetic Studies of 14-Membered Lactones 10-Oxoundecanoic Acid (140) 0 ^ ( C H 2 ) 8 C 0 0 H A mixture of 36.8 g (0.20 mole) of 10-undecenoic acid, 12.6 g (40 mmol) of mercuric acetate, 5 mL of water and 400 mL of acetone was s t i r r e d at room temperature (60). To t h i s mixture was added 150 mL of Jones reagent (91) over a period of 3.5 h while the temperature of the reaction mixture was maintained at 25 ± 5°C by means of an ice-water bath. The r e s u l t i n g mixture was s t i r r e d at room temperature for an a d d i t i o n a l 20 h, then the acetone layer was decanted, concentrated under reduced pressure and dilu t e d with ether. The residue of s a l t s was dissolved in water and the r e s u l t i n g aqueous layer was extracted three times with ether. The combined ether layers were washed twice with brine, dried and concentrated under reduced pressure to give 54.8 g of crude product as a pale yellow s o l i d . Two r e c r y s t a l l i z a t i o n s from petroleum ether - ether (5:1) afforded 37.2 g (93%) of 140 as a white s o l i d ; mp 55-57°C [ l i t . (92) 56-57°C]; - 204 -i r ( C H C I 3 ) : 2950 (COOH) and 1715 (CO) cm"1; !H nmr (80 MHz, CDCI3) 6: 1.10-1.93 (ra, 1 2 H ) , 2.13 (s, 3H) , 2.20-2.57 (m, 4H), 10.87 (s, IH, exchangeable with D 20); ms m/z: 200(M+,1), 182(2), 152(2), 142(2), 125(15), 124(4), 97(10), 96(5), 84(9), 83(10), 81(5), 73(6), 71(12), 69(13), 60(7), 59(14), 58(71), 55(35), 45(7), 43(100), 42(6), 41(23) and 39(5). 10—Brorao-2-decanone (141) This compound was prepared by means of a modified Hunsdiecker reaction (61). A 500 mL three-necked round bottom fla s k equipped with a pressure-equalizing dropping funnel, a heavier-than-water l i q u i d - l i q u i d extractor and condenser, and a stopper was charged with 5.0 g (25 mmol) of carboxylic acid 140 and 3.4 g (7.8 mmol) of ted mercuric oxide. A t o t a l of 200 mL of carbon tet r a c h l o r i d e was added to the l i q u i d - l i q u i d extractor and reaction f l a s k . The mixture was heated at rapid r e f l u x for 20 min and a solution of 5.0 g (32 mmol) of bromine in 5 mL of carbon tet r a c h l o r i d e was added over a period of 40 min while heating was maintained. After heating at reflux for an addit i o n a l 1 h, the mixture was cooled and f i l t e r e d . The f i l t r a t e was washed three 0 - 205 -times with 10% aqueous sodium hydroxide and twice with brine, dried and concentrated under reduced pressure to give 5.85 g (100%) of crude 141 as a yellow o i l . The crude product, containing a small amount of 1,8-dibromooctane, was used without further purification in the preparation of alcohol 142, Kugelrohr d i s t i l l a t i o n of a small amount of this material afforded 141 as a colourless o i l ; bp (Kugelrohr di s t i l l a t i o n ) 100°C/0.15 Torr; i r (CHC13): 1715 (C=0) cm-1; XH nmr (60 MHz, CDC13) 6: 1.00-2.20 (m, 12H), 2.12 (s, 3H), 2.20-2.62 (m, 2H), 3.38 ( t , J = 6 Hz, 2H); ms m/z: 236( 8 1Br: M+, 7), 234( 7 9Br: M+, 7), 221(5), 219(6), 178(16), 176(21), 155(16), 97(31), 82(21), 81(20), 80(22), 71(98), 69(68), 67(27), 59(87), 58(99), 57(29), 55(92), 44(60), 43(100), 41(85) and 39(38). Exact Mass calcd. for C 1 0H 1 9 8 1BrO: 236.0600; found (ms): 236.0617; calcd. for C 1 0H 1 9 7 9BrO: 234.0619; found (ms): 234.0625. lO-BroBO-2-decanol (142) To a solution of 8.83 g (37.6 mmol) of the ketone 141 in 75 mL of ethanol at room temperature was added 1.42 g (37.6 mmol) of sodium O H ( C H 2 ) 8 B r - 206 -borohydride . Af ter s t i r r i n g for 30 min, the reac t ion was quenched with 1 M hydroch lor ic a c i d , concentrated under reduced pressure and d i l u t e d with e ther . The organic phase was washed twice with 1 M hydrochlor ic a c i d , twice with saturated aqueous sodium bicarbonate and once with b r i n e , d r i e d , and concentrated under reduced pressure to give 7.71 g of crude 142 as a yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - e thyl acetate (4:1) as eluant gave 5.60 g (63% from carboxy l i c acid 140) of a lcohol 142 as a pale yellow o i l . D i s t i l l a t i o n of a por t ion of th i s mater ia l afforded 142 as a co lour le s s o i l ; bp 9 8 - 1 0 0 ° C / 0 . 1 5 Torr ; i r ( C H C 1 3 ) : 3630 ( free OH) and 3480 (H-bonded OH) c m - 1 ; ln nmr (60 MHz, C D C I 3 ) 6 : 1.13-2.22 (m, 14H), 1.17 ( d , J_= 6 Hz, 3H), 1.58 ( s , IH, exchangeable with D 2 0 ) , 3.38 ( t , J = 6 Hz, 2H), 3.57-3.98 (m, IH); ms m/z: 2 3 7 ( 8 1 B r : M+, 0 .3 ) , 2 3 5 ( 7 9 B r : M+, 0 .3 ) , 223(2), 221(2), 220(2), 218(2), 192(3), 190(2), 137(3), 135(3), 123(4), 97(6), 95(2), 83(5) , 81(4), 71(3), 69(9), 67(3), 57(5), 56(4), 55(16), 46(3), 45(100), 44(11), 43(10), 42(4), 41(16) and 39(3) . A n a l , c a l c d . for C 1 0 H 2 1 B r O : C 50.64, H 8.92, Br 33.69; found: C 50.88, H 9.00, Br 33.55. - 207 -5- ( l ' -Hydroxyethy l idene) -2 ,2 -d imethy l - l ,3 -d ioxan-4 ,6 -d ione (24) (Acety l Meldrum's Acid) This compound was prepared according to general procedure F, using 5.0 g (35 mmol) of 31_, 5.7 mL (70 mmol) of pyridine, 2.7 mL (39 mmol) of acetyl chloride and 100 mL of dichloromethane. Work-up of the tion from ether afforded 5.1 g (78%) of _24_ as a yellow solid; mp 81-83°C [ l i t . (93) 8 3 . 5 - 8 4 . 5 ° C ] ; i r (CHC1 3): 3600-3300 (OH), 1740 (C=0), 1650 (H-bonded C=0), and 1580 (C=C) cm - 1 ; *H nmr (80 MHz, CDCI3) 6: 1.75 (s, 6H), 2.69 (s, 3H), 15.1 (br s, IH, exchangeable with D2O); ms m/z: 186(M+, 3), 129(8), 128(1), 88(m*, 1282/186 = 88.0), 85(2), 84(4), 61(1), 59(100), 58(3), 44(6), 43(50) and 42(2). 0 0 reaction mixture gave 5.5 g of 24_ as an orange so l id . Recrystal l iza-- 208 -(10'-Bromo-2'-decyl)-3-oxobutanoate (143) 0 0 Br 2 8 A solution of 9.75 g (41 mmol) of the alcohol 142 and 9.17 g (49 mmol) of acetyl Meldrums's acid (24) in 50 mL of dry THF was heated at reflux under a nitrogen atmosphere for 4 h (39). The cooled reaction mixture was d i l u t e d with ether, washed three times with saturated aqueous sodium bicarbonate and twice with brine, d r i e d , and concentrated under reduced pressure to give 14.0 g of crude product as a red o i l . F i l t r a t i o n , with suction, of this o i l through a short column of s i l i c a using petroleum ether - ethyl acetate (9:1) as eluant followed by removal of solvent yielded 13.3 g (100%) of 143 as a pale yellow o i l . D i s t i l l a t i o n of a small amount of t h i s material gave 143 as a colourless o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 130°C/0.2 Torr; i r (CHC1 3): 1 745 (COOR) and 1720 (CO) cm"1; *H nmr (60 MHz, CDC13) 6: 1.07-2.03 (m, 17H), 2.25 (s, 3H), 3.40 ( t , J = 7 Hz, 2H), 3.40 (s, 2H), 4.77-5.17 (m, IH); ms ra/z: 322( 8 1Br: M+, 1), 320( 7 9Br: M+, 1), 220(15), 218(16), 150(6), 148(7), 104(5), 103(100), 102(13), 97(17), 87(7), 85(56), 83(22), 71(10), 69(26), 67(5), 58(7), 57(17), 56(10), 55(39), 45(13), 43(88), 42(10) and 41(28). - 209 -Anal, c a l c d . f o r C l l tH 2 5Br0 3: C 52.34, H 7.84, Br 24.87; found: C 52.59, H 8.00, Br 24.61. 3-Oxo-13-tetradecanolide (138) (14) To a solu t i o n of 1.90 mL (13.6 mmol) of diisopropylamine in 100 mL of dry THF, s t i r r e d at 0°C under a nitrogen atmosphere, was added 13.6 ml (13.6 mmol) of a 1.0 M s o l u t i o n of n-butyllithium in hexane. The r e s u l t i n g pale yellow solution was s t i r r e d at 0°C for 10 min, then was cooled to -78°C. A s o l u t i o n of 2.00 g (6.2 mmol) of the 6-keto ester 143 in 10 mL of THF was added in one portion and the mixture was allowed to warm to room temperature over a period of 3 h. The pale yellow reaction mixture was then quenched with 1 M hydrochloric acid and di l u t e d with ether. The organic layer was washed three times with 1 M hydrochloric acid and twice with brine, dried and concentrated under reduced pressure to give 1.87 g of crude product. P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (9:1) as eluant H5a H Sb - 210 -yielded 694 mg (47%) of 138 as a very pale yellow o i l . Preparative t i c of a small amount of this material using petroleum ether - ethyl acetate as solvent gave 138 as a colourless o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 80°C/0.01 Torr; i r ( C H C 1 3 ) : 1740 (COOR) and 1715 (C=0) cm - 1; *H nmr (400 MHz, CDCI3) 6: 1.17-1.81 (m, 16H), 1.26, (d, J_ = 7 Hz, 3H), 2.51 (dt, J^a.ijb = 1 8 H z • i<+a,5a = :L»a,5b = 7 H z » IH), 2.70 (dt, J „ a , i » b = 18 Hz, J^b.sa = 14b,Sb = 7 H z . 1 H ) » 3.35 (d, J2a,2b = 1 4 H z » 1 H > « 3 ' 4 6 < d » l2a,2b = 1 4 H z » 1 H > » 4.98-5.06 (m, IH); 1 3C nmr 1 2 (CDCI3 ) 6: 20.29, 21.00, 22.91, 24.66, 25.17, 26.03, 26.11, 26.27, 35.15, 40.57, 50.83, 71.95, 166.71, 202.10; ms m/z: 240(M +, 6 ) , 222(8), 181(80), 180(8), 138(22), 103(56), 102(33), 97(28), 96(39), 85(34), 83(36), 82(30), 81(30), 69(45), 68(34), 67(30), 56(22), 55(98), 54(28), 45(23), 43(100), 42(29) and 41(77). Anal, calcd. for C 1 4 H 240 3: C 69.96, H 10.07; found: C 69.77, H 10.20. The C nmr data of this compound was obtained by E. Neeland. - 211 -To a solution of 689 mg (2.87 mmol) of the B-keto lactone 138 in 15 mL of ethanol at room temperature was added 109 mg (2.87 mmol) of sodium borohydride. After s t i r r i n g at room temperature for 30 min, the reaction was quenched with 1 M hydrochloric acid and d i l u t e d with ether. The organic phase was washed twice with brine, d r i e d , and concentrated under reduced pressure to y i e l d 652 mg of a mixture of 146 and 147 as a pale orange o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (9:1) as eluant gave in order of e l u t i o n : (a) alcohol 146 (449 mg, 65%) as a pale yellow o i l . D i s t i l l a t i o n of a small amount of this material afforded a colourless o i l which c r y s t a l l i z e d very slowly to give fine white needles; Rf 0.38 (petroleum ether - ethyl acetate 4:1); mp 33-37°C; - 212 -bp (Kugelrohr d i s t i l l a t i o n ) 115°C/0.1 Torr; i r ( C H C I 3 ) : 3330 (OH) and 1715 (COOR) cm - 1; *H nmr 1 3 (400 MHz, CDC13) 6: 1.05-1.88 (m, 18H), 1.21 (d, J = 7 Hz, 3H), 2.61 (A part of an ABX system, 2 2 a ,2b = 1 5 H z » 2 2 b , 3 = 7 Hz, IH), 2.67 (B part of an ABX system, J_23j2b = 1 5 H z » i2a,3 = 3 Hz, IH), 3.01 (d, J = 9 Hz, IH, exchangeable with D 20), 3.76-3.89 (m, X part of an ABX system, J^a.3 = 3 Hz, J_2b,3 = 7 Hz, plus addi t i o n a l couplings, IH), 4.99-5.09 (m, IH); 1 3 C nmr 1 3 ( C D C I 3 ) 6: 19.56, 21.27, 22.41, 23.56, 23.70, 24.82, 25.51, 26.13, 34.09, 40.25, 68.84, 70.29, 172.83; ms m/z: 242(M +, 4), 227(2), 224(11), 164(4), 154(60), 98(18), 97(30), 96(24), 95(24), 89(100), 84(24), 83(41), 82(34), 80(30), 71(30), 70(33), 69(52), 68(30), 67(31), 57(40), 56(45), 55(98), 54(20), 45(22), 43(79), 42(32) and 41(84). Exact Mass calcd. for CmH260 3: 242.1882; found (ms): 242.1880. (b) alcohol 147 (153 mg, 22%) as a pale yellow o i l . D i s t i l l a t i o n of a small amount of t h i s material afforded a colourless o i l which c r y s t a l l i z e d slowly to give fine white needles; Rf 0.30 (petroleum ether - ethyl acetate 4:1); mp 41-45°C; bp (Kugelrohr d i s t i l l a t i o n ) 115°C/0.1 Torr; i r (CHCI3): 3630 (free OH) and 3450 (H-bonded OH) and 1725 (C=0) The H and C nmr data of t h i s compound was obtained by Dr. R.J. Sims. - 213 -cm ; 1E nmr 1 3 (400 MHz, C D C I 3 ) 6: 1.08-1.78 (m, 18H), 1.23 (d, J_ = 7 Hz, 3H), 1.78-2.00 (m, IH, exchangeable with D 20), 2.58 (A part of an ABX system, J2 a,2b = 1 5 H z » i b , 3 = 1 1 H z > 1 H ^ » 2 , 5 9 ^ B P a r t o f a n ABX system, J2a,2b = 1 5 H z » i2a,3 = 3 H z » 1 H ) » 4 » 0 2 ^ . 1 0 (m, X part of an ABX system, .J_2a,3 = ^ H z » ^.2b,3 = ^ H z > P^ u s a d d i t i o n a l couplings, IH), 4.99-5.09 (m, IH); 1 3C nmr 1 3 (CDC1 3) 6: 20.19, 21.12, 22.22, 23.63, 24.09, 25.56, 26.07, 26.09, 34.36, 34.94, 40.25, 68.77, 70.64, 171.27; ms m/z: 242(M+, 5), 224(10), 164(25), 154(16), 102(46), 98(29), 97(32), 96(28), 95(36), 89(45), 84(25), 83(42), 82(37), 81(39), 71(34), 70(27), 69(52), 68(34), 67(40), 57(45), 56(39), 55(100), 54(23), 43(82), 42(30) and 41(93). Exact Mass calcd. for C 1 4 H 2 6 O 3 : 242.1882; found (ms): 242.1880. (3R*,13R*)-3-Hydroxy-13-tetradecanolide ( 1 4 6 ) l k To a solution of 24 mg (0.1 mmol) of the B-keto lactone 138 in 2 mL of dry THF at -10°C and under a nitrogen atmosphere, was added 0.2 mL (0.2 mmol) of a 1.0 M s o l u t i o n of lithium tri-sec-butylborohydride (L-Selectride) in THF and the r e s u l t i n g mixture was s t i r r e d at -10°C for 1 h. The reaction was quenched with 2 drops of 1 M hydrochloric acid This reaction was performed by Dr. R.J. Sims. - 214 -and 2 drops of 30% H202 and the mixture was s t i r r e d for 5 min at room temperature. The mixture was then diluted with ether and the organic layer was dried and concentrated under reduced pressure to give 21 mg (87%) of 146 as a colourless o i l . GC analysis showed only the alcohol 146. None of the diastereomeric alcohol 147 was detected. (3R*,13R*)-3-Bromoacetoxy-l3-tetradecanolide (148) To a solution of 76 mg (0.32 mmol) of alcohol 146 and a s p a t u l a - t i p - f u l l of D M A P i n 1 mL of dry ether at 0°C and under a nitrogen atmosphere was added 0.16 mL (1.9 mmol) of freshl y d i s t i l l e d pyridine and 0.12 mL (1.3 mmol) of broraoacetyl bromide. The reaction mixture was s t i r r e d at 0°C for 1.5 h, then was quenched with water and diluted with ether. The organic phase was washed three times with 1 M hydrochloric acid, repeatedly with saturated aqueous sodium bicarbonate and twice with brine, dried and concentrated under reduced pressure to give 101 mg of crude product as a pale yellow o i l . P u r i f i c a t i o n by H 2 a H 2 b - 215 -f l a s h chromatography using petroleum ether - ethyl acetate (9:1) as eluant yielded 98 mg (84%) of pure 148 as a colourless o i l which c r y s t a l l i z e d slowly to give, white needles; mp 35-45°C; i r (CHC1 3): 1725 (COOR) cm - 1; XH nmr (400 MHz, CDCI3) 6: 1.17-1.82 (m, 18H), 1.24 (d, J_= 7 Hz, 3H), 2.51 (dd, J2a,2b = 1 4 H z » 22a,3 = 1 0 H z » 1 H > » 2 ' 8 0 ( d d » 22a,2b = 1 4 H z » 22b,3 = 4 H z « 1 H ) > 3 * 8 1 < d » 2 = 1 3 H z » 1 R ) » 3 * 8 4 (d, J = 13 Hz, IH), 4.95-5.05 (m, IH), 5.15-5.24 (m, J 2 a > 3 = 10 Hz, 22b,3 = 4 H z » P^ u s a d d i t i o n a l couplings, IH); ms m/z: 349( 8 1Br: M+ - CH 3, 0.4), 347( 7 9Br: M + - CH 3, 0.5), 224(16), 164(33), 138(25), 123(34), 121(29), 110(29), 109(28), 97(28), 96(56), 95(57), 83(36), 82(61), 81(77), 71(29), 69(72), 68(49), 67(55), 57(23), 56(22), 55(100), 54(36), 43(86), 42(40), 41(99) and 39(23). Exact Mass calcd. for C 1 5H 2 1 + 8 1Br0 1 + (M + - CH 3): 349.0837; found (ms): 349.0802; c a l c d . for C 1 5 H 2 l 4 7 9 B r 0 4 (M + - CH 3): 347.0858; found (ms): 347.0860; X-ray d a t a 1 5 unit c e l l parameters (standard e r r o r s ) ; a = 11.868(3), b = 13.904(2), c = 5.482(1) A°; a = 90.51(1), 6 = 98.82(1), Y = 98.48 (1)°; formula: Ci6H27Br04; formula weight; 363.30; number of formula units in the unit c e l l : Z = 2; density: d c a ^ c u ^ a t e c ] = 1.365 g We are g r a t e f u l to Dr. M.N. Ponnuswamy and Dr. J . Trotter for t h i s X-ray crystallographic structure determination. - 216 -cm- ; space group: T r i c l i n i c PI; wavelength used: X = 1.54056 A° (CuKa); number of r e f l e c t i o n s observed: 3330; number of r e f l e c t i o n s included for refinement: 2394; method of c o l l e c t i o n of i n t e n s i t y data; CAD4 d i f fractometer, CuKa r a d i a t i o n , CD-2 6 scan, solved by d i r e c t methods, refined by ORFLS (94); f i n a l R value = 5.7%. (3R*,13S*)-3-Bromoacetoxy-13-tetradecanolide (149) This compound was prepared according to the procedure employed for the preparation of the bromoacetate 148 using 38 mg (0.16 mmol) of alcohol 147, a s p a t u l a - t i p - f u l l of DMAP, 0.08 mL (0.96 mmol) of pyridine and 0.06 mL (0.64 mmol) of bromoacetylbromide. Work-up of the reaction mixture yielded 40 mg (69%) of pure 149 as white c r y s t a l s . R e c r y s t a l l i z a t i o n of a small amount of t h i s material from petroleum ether (bp 65-110°C) gave 149 as white c r y s t a l s ; mp 69.5-70.0°C; i r (CHC1 3): 1730 (COOR) cm - 1; *H nmr (400 MHz, CDC13)<5: 1.18-1.80 (m, 18H), 1.23(d, J. = 7Hz, - 217 -IH), 2.66 (A part of an ABX system, J^2a,2b = * 4 H z » ^2b,3 = ^ H z » IH), 2.67 (B part of an ABX system, _J_2a,2b = 1 4 H z » ^2a,3 = 5 Hz, IH), 3.80 (d, J - 12 Hz, IH), 3.81 (d, J = 12 Hz, IH), 5.01-5.10 (m, IH), 5.25-5.34 (m, X part of an ABX system, .J_2 b ) 3 = 10 Hz, J.2a,3 = 5 Hz, IH); ms m/z: 349( 8 1Br: M + - CH 3, 1), 347( 7 9 B r : M + - CH 3, 0.8), 320(0.6), 318(0.6), 283(4), 224(46), 164(35), 138(29), 123(24), 121(23), 110(26), 109(26), 97(23), 96(50), 95(45), 83(32), 82(51), 81(61), 71(27), 69(45), 68(46), 67(46), 57(23), 56(22), 55(100), 54(35), 43(69), 42(34) and 41(74). Anal, calcd. f o r C 1 6H 2 7Br0 1 +: C 52.90, H 7.49, Br 22.00; found C 53.03, H 7.44, Br 21.85. X-ray d a t a 1 6 unit c e l l parameters (standard e r r o r s ) : a = 11.546(4), b = 14.478(5), c = 5.283(2) A°; a - 92.42(2), B = 96.93(2), Y = 92.81(2)°; formula: Ci6H27Br0it; formula weight: 363.30; number of 3 formula units i n the unit c e l l : Z = 2; density: 1.380 g cm- ; space group: T r i c l i n i c PI; wavelength used: X = 0.70930 A° (MoKa); number of We are gr a t e f u l to Dr. M.N. Ponnuswamy and Dr. J. Trotter for t h i s X-ray cr y s t a l l o g r a p h i c structure determination. - 218 -r e f l e c t i o n s observed: 2730; number of r e f l e c t i o n s included for refinement: 1101; method of c o l l e c t i o n of i n t e n s i t y data; CAD4 d i f f T a c t o m e t e r , MoKa r a d i a t i o n , o>-2 6 scan, solved by d i r e c t methods, refined by ORFLS (94); f i n a l R value = 5.4%. (3R*,13R*)-3-Acetoxy-13-tetradecanolide (156) To a solution of 50 mg (0.21 mmol) of alcohol 146 and a s p a t u l a - t i p - f u l l of DMAP in 1 mL of dry ether at room temperature and under a nitrogen atmosphere was added 0.04 mL (0.4 mmol) of f r e s h l y d i s t i l l e d pyridine and 0.08 mL (0.84 mmol) of acetic anhydride. The reaction mixture was s t i r r e d at room temperature for 30 min, then was di l u t e d with ether, washed three times with 1 M hydrochloric a c i d , twice with saturated aqueous sodium bicarbonate and twice with brine, and dr i e d . Removal of solvent under reduced pressure gave 52 mg (88%) of pure 156 as a colourless o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 140°C/0.2 Torr; i r (CHC1 3): 1730 (COOR) cm - 1; *H nmr (400 MHz, CDCI3) <5: 1.14-1.76 (m, 18H), 1.24 (d,J_= 6 Hz, H 2o H 2b - 219 -3H), 2.05 (s, 3H), 2.45 (dd, 22a,2b = 1 4 H z » i2a,3 " 1 0 H z » 1 H>. 2.78 (dd, J2a,2b = 1 4 H z . J2b,3 = 4 H z » 1 H > » 4.95-5.02 (m, IH), 5.07-5.16 (m, J2a,3 = ^ H z » ^2b,3 = 4 l* z > P^ u s a d d i t i o n a l couplings, IH); 1 3 C nmr (CDC1 3) 6: 20.18, 21.01, 22.30, 22.43, 23.77, 24.06, 25.69, 25.72, 25.96, 30.88, 35.09, 40.55, 70.53, 70.89, 169.49, 170.40; ms m/z: 284(M +, 0.06), 269(0.4), 224(17), 180(8), 164(16), 138(13), 110(12), 109(14), 98(11), 97(12), 96(23), 95(19), 83(14), 82(23), 81(26), 71(14), 69(20), 68(20), 67(21), 57(10), 56(10), 55(40), 54(16), 43(100), 42(11) and 41(34). Exact Mass ca l c d . for Ci6H 2 80i+: 284.1988; found (ms): 284.1982. (3R*,13S*)-3-Acetoxy-l3-tetradecanolide (157) 2o u 2 b This compound was prepared according to the procedure employed f o r the preparation of the acetate 156 using 55 mg (0.23 mmol) of alcohol 147, a s p a t u l a - t i p - f u l l of DMAP, 0.04 mL of pyridine, 0.08 mL of acetic anhydride and 1 mL of ether. Work-up of the reaction mixture - 220 -gave 58 mg (90%) of pure 157 as a colourless o i l which c r y s t a l l i z e d slowly to y i e l d fine white needles; bp (Kugelrohr d i s t i l l a t i o n ) 140°C/0.2 Torr; i r (CHC1 3): 1735 (COOR) cm - 1; *H nmr (400 MHz, CDCI3) 6: 1.17-1.75 (m, 18H), 1.22 (d, J_ = 7 Hz, 3H), 2.04 (s, 3H), 2.59 (A part of an ABX system, .J_2a,2b = Hz, 22b, 3 = 1 0 H z » 1 H ) 2 , 6 3 ( B P a r t o f a n ^ X system, J_2a 2b = 1 4 H z ' J 2 a > 3 = 5 Hz, IH), 5.00-5.09 (m, IH), 5.18-5.27 (m, X part of an ABX system, 3 = 10 Hz, J2a,3 = 5 Hz, plus a d d i t i o n a l couplings, IH); 1 3 C nmr (CDCI3) 6: 20.07, 20.83, 21.01, 22.10, 24.11, 24.59, 25.74, 26.13, 26.23, 31.02, 34.71, 38.82, 70.59, 70.77, 170.02 (2C). ms m/_z: 284(M +, 0.4), 269(1), 241(4), 224(17), 180(9), 164(16), 138(14), 109(12), 108(13), 98(10), 97(12), 96(21), 95(18), 83(15), 82(23), 81(27), 71(13), 69(19), 68(21), 67(21), 57(10), 56(10), 55(38), 54(15), 43(100), 42(11) and 41(31). Exact Mass calcd. f o r C 1 6H2 8 0 i 4 : 284.1988; found(ms): 284.1996. Acetylation of Alcohols 146 and 147 - Relative Rates of Reaction This reaction was performed according to the procedure given previously except that no DMAP was added. For th i s reaction 50 mg (0.21 mmol) of a 2:1 mixture of the alcohols 146 and 147 was used. Aliquots were removed at i n t e r v a l s , quenched with water, d i l u t e d with ether and analyzed by gas chromatography. The r e s u l t s of t h i s experiment are given in Table 6, p. 111. - 221 -(3R*,13R*)-3-(4-Toluenesulfonyloxy)-l3-tetradecanollde (160) To a solution of 508 mg (2.1 mmol) of alcohol 146 in 10 mL of f r e s h l y d i s t i l l e d pyridine s t i r r e d at 0°C under a nitrogen atmosphere was added 1.60 g (8.4 mmol) of p-toluenesulfonyl chloride (95). The so l u t i o n was then stored at 7°C f o r 5 days, r e s u l t i n g in an orange mixture containing a p r e c i p i t a t e of pyridinium hydrochloride. The reaction mixture was poured into a mixture of ice and water which was then extracted with ether. The combined ether layers were washed repeatedly with i c e - c o l d 1 M hydrochloric acid and twice with brine, and drie d . Removal of solvent under reduced pressure gave 8% mg of crude product as a yellow semi-solid. P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (9:1) as eluant yielded 706 mg (85%) of 160 as a colourless o i l which, on standing, afforded white c r y s t a l s ; mp 62.5-65.5°C; i r (CHC1 3): 1735 (COOR), 1370 (S0 2-0) and 1180 (S0 2-0) cm - 1; lR nmr (400 MHz, CDC13) 6: 1.05-1.74 (m, 18H), 1.23 (d, J_= 6 H z » - 222 -3H), 2.46 (s, 3H), 2.51 (dd, J[2a,2b = 1 4 H z » 22a,3 * 1 0 H z » 1 H)» 2.90 (dd, J2a,2b = 1 4 H z » 22b,3 = 4 H z . 1 H ) » 4.79-4.87 (m, J.2a,3 = 10 Hz, J2b,3 = 4 H z> P l u s additional couplings), 4.91-5.01 (m, IH), 7.35 (d, J. = 8 Hz, 2H), 7.84 (d, J_ = 8 Hz, 2H); ms m/z: 396(M +, 4), 225(20), 224(100), 180(15), 164(23), 155(37), 138(29), 124(15), 109(18), 98(15), 97(18), 96(35), 95(29), 91(87), 83(24), 82(38), 81(39), 71(34), 69(39), 68(33), 67(32), 65(17), 57(15), 55(66), 54(27), 43(38) and 41(51). Anal, c a l c d . for C21H32O5S: C 63.61, H 8.13, S 8.09; found: C 63.50, H 8.23, S 8.20. (3R*,13S*)-3-(4'-Toluenesulfonyloxy)-l3-tetradecanolide (161) This compound was prepared according to the procedure employed f o r the preparation of 160 using 228 mg (0.94 mmol) of alcohol 147, 5 mL of pyridine and 720 mg (3.8 mmol) of p-toluenesulfonyl c h l o r i d e . Work-up of the reaction mixture yielded 333 mg 161 as a yellow s o l i d . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (9:1) as eluant gave 309 mg (83%) of 161 as a white s o l i d ; H 2 o H 2 b - 223 -mp 96.5-99.5°C; i r (CHCI3): 1725 (COOR), 1365 (S0 2-0) and 1180 (S0 2-0) cm - 1; JH nmr (400 MHz, CDCI3) 6: 1.06-1.68 (m, 18H), 1.19 (d, J_ = 6 Hz, 3H), 2.46 (s, 3H), 2.68 (A part of an ABX system, 22a,2b = 1 4 H z » 22b,3 = 10 Hz, IH), 2.70 (B part of an ABX system, J^a, 2b = 1 4 H z » 228,3 = 5 H z » 1 H ) » 4« 85-4.94 (m, 22b,3 = 1 0 H z » i.2a ,3 = 5 H z ' P l u s a d d i t i o n a l couplings, IH), 4.98-5.08 (m, IH), 7.35 (d, 2 = 8 H z» 2 H>» 7.82 (d, J = 8 Hz, 2H); ms m/z: 396(M +, 4), 241(17), 225(16), 224(77), 180(16), 164(21), 155(40), 138(29), 124(15), 91(100), 83(27), 82(39), 81(42), 71(46), 69(41), 68(35), 67(36), 65(20), 57(18), 55(77), 54(18), 43(43), 42(16) and 41(58). Anal, c a l c d . f o r C 2 1H 3 20 5S: C 63.61, H 8.13, S 8.09; found: C 63.89, H 8.16, S 8.00. Sulfonylation of Alcohols 146 and 147 — Relative Rates of Reaction This reaction was performed according to the procedure given previously, using 50 mg (0.21 mmol) of a 2.5:1 mixture of the alcohols 146 and 147 , 79 mg (0.41 mmol) of p-toluenesulfonyl chloride and 1 mL of pyridine. Aliquots were removed at i n t e r v a l s , quenched with water, d i l u t e d with ether and analyzed by gas chromatography. The r e s u l t s of this experiment are given in Table 6, p. 111. - 224 -3-Hydroxy-13-tetradecanolides 146 and 147 via Hydrolysis of Acetates 156 and 157 To a solution of 390 mg (1.37 mmol) of a 2:1 mixture of the acetates 156 and 157 in 15 mL of dry methanol was added 300 mg (2.8 mmol) of anhydrous sodium carbonate and the r e s u l t i n g mixture was s t i r r e d at room temperature under a nitrogen atmosphere for 7 h. The mixture was then d i l u t e d with ether, washed twice with 1 M hydrochloric acid and twice with brine, d r i e d , and concentrated, under reduced pressure to give 302 mg (91%) of a mixture of the alcohols 146 and 147 as a pale yellow o i l . The spectral data of the alcohol mixture i s i n good agreement with that obtained previously. Hydrolysis of Acetates 156 and 157 - Relative Sates of Reaction This reaction was performed according to the procedure given previously for acetate hydrolysis using 50 mg (0.18 mmol) of mixture (2.7:1) of the acetates 156 and 157 , 20 mg (0.18 mmol) of sodium carbonate and 1 mL of methanol. Aliquots were removed at i n t e r v a l s , quenched with water, dilut e d with ether and analyzed by gas chromatography. The r e s u l t s of th i s experiment are given in Table 6, p. 111. 3-Oxo-13-tetradecanolide (138) via PDC Oxidation of 13-Methyl-3-hydroxy-tetradecanolide (146 and 147) To a solu t i o n of 20 mg (0.08 mmol) of a mixture of the diastereomeric alcohols 146 and 147 (146:147 = 2.5:1) in 1 mL of dry DMF - 225 -was added 93 mg (0.25 mmol) of pyridinium dichromate (67) and the r e s u l t i n g mixture was s t i r r e d at room temperature under a nitrogen atmosphere for 37 h. The reaction mixture was d i l u t e d with water and extracted with ether'. The combined ether extracts were washed three times with brine, dried, and concentrated under reduced pressure to give 15 mg (78%) of 138 as a colourless o i l . The spectral data of t h i s compound i s i n good agreement with that obtained previously. PDC Oxidation of Alcohols 146 and 147 - Relative Rates of Reaction This reaction was performed according to the procedure given previously, using the same quantities of reagents. As an i n t e r n a l standard, 5 mg of the hydrocarbon eicosane was added. Aliquots were removed at i n t e r v a l s , quenched with water d i l u t e d with ether, and analyzed by gas chromatography. The r e s u l t s of t h i s experiment are given in Table 6, p. 111. Z-2-Tetradecen-13-olide (164) and E-2-Tetradecen-13-olide (163) via Elimination of p-Toluenesulfonic Acid from 160 H 3 C °J 164 163 - 226 -Method A DBU as base To a solution of 947 mg (2.4 mmol) of 160 in 30 mL of dry toluene at room temperature and under a nitrogen atmosphere was added 0.54 mL (3.6 mmol) of DBU. The reaction mixture was s t i r r e d for 1 h, then was di l u t e d with ether, washed three times with 1 M hydrochloric acid, three times with saturated aqueous sodium bicarbonate and twice with brine, and d r i e d . Removal of solvent under reduced pressure gave 509 mg of a yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (9:1) as eluant gave in order of e l u t i o n : (a) _Z-alkene 164 (72 mg, 13%) as a pale yellow o i l with a strong burnt odour. D i s t i l l a t i o n of a small amount of t h i s material gave 164 as a colourless o i l ; Rf 0.75 (petroleum ether - ethyl acetate 9:1); bp (Kugelrohr d i s t i l l a t i o n ) 100°C/0.01 Torr; i r (CHCI3): 1705 (a, B-unsaturated COOR) and 1645 (conjugated C=C) cm - 1; XH nmr (400 MHz, CDCI3) 6: 0.98-1.72 (m, 16H), 1.25 (d, J_= 7 Hz, 3H), 2.28-2.38 (m, J.<+a,4b = 14 Hz, J 3 > 1 + a = 6 Hz, = 2 Hz, plus a d d i t i o n a l couplings, IH), 2.98-3.11 (m, J ^ a ^ b = 14 Hz, 23,Hb = 10 Hz, Z_2 ,kb ^ * H z » p l u s a d d i t i o n a l couplings, IH), 5.14-5.24 (m, IH), 5.83 (ddd, J ^ 3 - 11 Hz, J_2fka = 2 Hz, J 2 ^ b < 1 Hz), 6.03 (ddd, ^2,3 = 1 1 H z » 2.3, *t a = 6 H z » J 3 > l 4 b = 10 Hz, IH); ms m/z: 224(M+, 15), 164(33), 142(24), 109(23), 99(40), 98(20), 97(29), 96(34), 95(40), 94(25), 86(30), 85(28), 84(20), 83(31), 82(35), 81(63), 69(42), 68(43), 67(49), 57(24), 56(22), 55(87), 54(23), 53(26), 43(47), 42(23), 41(100) and 39(31). - 227 -Exact Mass calcd. for C 1 1 +H 2 i t0 2: 224.1777; found (ms): 224. 1777. (b) E-alkene 163_ (317mg, 59%) as a pale yellow o i l . D i s t i l l a t i o n of a small amount of this material gave 163 as a colourless o i l ; Rf 0.68 (petroleum ether - ethyl acetate 9:1); bp (Kugelrohr d i s t i l l a t i o n ) 100°C/0.01 Torr; i r (CHCI3): 1700 (a, B-unsaturated COOR) and 1640 (conjugated C=C) cm - 1; lE nmr (400 MHz, C D C I 3 ) 6: 1.14-1.72 (m, 16H), 1.28 (d, J_= 7 Hz, 3H), 2.26(ddt, J 2 > 1 + = 3 Hz, J 3 J l t = 8 Hz, Jj+^ 5 = 7 Hz, 2H), 4.97-5.07 (m, IH), 5.84 (dt, J ^ g = 16 Hz, J_2,i+ = 3 Hz, IH), 6.96 (dt, J _ 2 > 3 = 16 Hz, _J_3,it= 8 H z » IH); ms m/_z: 224(M +, 1), 164(10), 99(19), 97(24), 96(18), 95(24), 86(15), 83(20), 82(21), 81(47), 43(53), 42(23), 41(100), 40(19) and 39(38). Exact Mass ca l c d . for Cn,H 2 i t0 2: 224.1777; found (ms): 224.1777. Method B Potassium tert-butoxide as base A s o l u t i o n of 50 mg (0.13 mmol) of 160 and 29 mg (0.26 mmol) of f r e s h l y sublimed potassium tert-butoxide in 2 mL of dry toluene was s t i r r e d for 1.5 h at room temperature under a nitrogen atmosphere. The reaction mixture was then d i l u t e d with ether and water. The organic phase was washed once with 1 M hydrochloric a c i d , three times with saturated aqueous sodium bicarbonate and once with brine, d r i e d , and concentrated under reduced pressure to give 26 mg of a mixture of 164 - 228 -and 163. P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (9:1) as eluant afforded 18 mg (61%) of a mixture of the _Z-alkene 164 and the E-alkene 163 in the r a t i o 97:3 (as determined by GC a n a l y s i s ) , as a pale yellow o i l . The spectral data of the alkene mixture i s in good agreement with that obtained previously. Method C Lithium methoxide as base To 1 mL of dry methanol at room temperature and under a nitrogen atmosphere was added 0.22 mL (0.26 mmol) of a 1.2 M solu t i o n of methyllithium in ether. After a few minutes, a solution of 50 mg (0.13 mmol) of 160 in 1 mL of methanol was added and the r e s u l t i n g solution was s t i r r e d at room temperature for 1 h. The reaction mixture was quenched with 1 M hydrochloric acid and diluted with ether. The organic phase was washed once with 1 M hydrochloric a c i d , three times with saturated aqueous sodium bicarbonate and once with brine, d r i e d , and concentrated under reduced pressure to give 20 mg of a yellow o i l . This sample was subjected to GC analysis, then was combined with the product mixures of several comparable reactions f o r p u r i f i c a t i o n . Flash chromatography using 2% ethyl acetate in petroleum ether as eluant gave in order of e l u t i o n : (a) Z-alkene 164_ (14% GC y i e l d ) ; Rf 0.68 (petroleum ether - ethyl acetate 9:1); The spectral data of th i s compound i s in good agreement with that obtained previously. - 229 -(b) E-alkene 163_ (21% GC y i e l d ) ; Rf 0.63 (petroleum ether - ethyl acetate 9:1); The spectral data of th i s compound i s in good agreement with that obtained previously. (c) (3R*,13S^)-3-methoxy-13-tetradecanolide (166) (6% GC yie l d ) as a colourless o i l ; Rf 0.50 (petroleum ether - ethyl acetate 9:1); i r (CHC1 3): 1700 (COOR) cm - 1; lE nmr (80 MHz, CDCI3) 6: 1.20-1.82 (m, 18H), 1.23 (d, J_= 6 Hz, 3H), 2.38 (dd, J ^ ^ b = 1 4 H z » £2a,3 = 1 0 H z » 1 H ) > 2 , 7 3 ( d d » 22a,2b = 1 4 H z » i2a,3 = 4 Hz, IH) , 3.38 (s, 3H), 3.49-3.78 (m, IH) 4.90-5.18 (m, IH); m/z: 256(M +, 12), 241(39), 224(25), 164(28), 138(20), 129(36), 116(33), 103(46), 97(25), 96(26), 95(32), 83(32), 82(32), 81(39), 71(71), 70(20), 69(41), 68(27), 67(37), 61(33), 58(32), 56(36), 55(88), 45(33), 43(71), 42(34) and 41(100). Exact Mass ca l c d . for 0^2503 (M+ - CH3): 241.1804; found (ms): 241.1804; c a l c d . for C l l tH 2 i +0 2 (M+ - CH3OH): 224. 1776; found (ms): 224.1778. (d) (3R*,13R*)-3-methoxy-13-tetradecanolide (165; 15% GC y i e l d ) as a colourless o i l ; Rf 0.45 (petroleum ether - ethyl acetate 9:1); i r (CHCI3): 1720 (COOR) era"1; - 230 -lE nmr (80 MHz, CDC13) 6: 1.04-1.78 (m, 18H), 1.24 (d, J_= 6 Hz, 3H), 2.26 (dd, J 2 a , 2 b = 1 4 H z » ±Za,3 = 1 0 Hz» 1H)» 2 , 8 4 (dd» 22a,2b = 1 4 H z > J 2 b , 3 = 4 H z » 1 H ) » 3 ' 3 9 ( s> 3H) , 3.35-3.69 (m, IH), 4.81-5.15 (m, IH); ms m/z: 256(M +, 5), 241(13), 224(32), 196(15), 164(33), 138(29), 109(25), 103(63), 97(31), 96(36), 95(40), 85(26), 82(41), 81(46), 71(100), 70(25), 69(49), 68(34), 67(41), 61(35), 58(33), 57(22), 56(39), 55(100), 54(20), 45(43), 43(72), 42(31) and 41(94). Exact Mass ca l c d . for C i 4 H 2 5 0 3 (M+ - CH 3): 241.1804; found (ms): 241.1811; c a l c d . f o r C m H 2 i t 0 2 (M + - C H 3 0 H ) : 224.1776; found (ms): 224.1787. (e) methyl E-13-hydroxy-2-tetradecenoate (167; 44% GC y i e l d ) Rf 0.08 (petroleum ether-ethyl acetate 9:1); i r (CHCI3): 3620 (free OH), 3480 (H-bonded OH), 1715 (COOR) and 1660 (C=C) cm - 1; *H nmr (80 MHz, CDCI3) 6: 1.05-1 .69 (m, 19H), 1.18 (d, J_= 6 Hz, 3H), 1.98-2.35 (ra, 2H), 3.58-3.93 (m, IH), 3.73 (s, 3H), 5.80(dt, J = 16,1 Hz, IH), 6.98 (dt, 2 = i 6 . 1 H z » 1H>'> ms m/z: 256(M+, 0.5), 255(0.4), 241(3), 239(1), 238(6), 213(5), 212(22), 209(14), 164(13), 138(13), 113(63), 109(20), 100(24), 96(28), 95(38), 87(39), 83(25), 82(27), 81(55), 74(32), 69(29), 68(25), 67(33), 55(72), 45(100), 43(31) and 41(57). Exact Mass calcd. for C 1 4 H 2 5 O 3 (M + - CH3): 241.1804; found (ms): 241.1800; ca l c d . for C 1 5 H 2 6 0 2 (M + - H 2 0 ) : 238.1933; found (ms): 238.1950. - 231 -Z-2-Tetradecen-13-olide (164) and E-2-Tetradecen-l3-olide (163) via Elimination of p-Toluenesulfonlc Acid from 161 Method A DBU as base This reaction was performed according to the procedure employed for the reaction of 160 with DBU, using 166 mg (0.42 mmol) of 161, 0.2 mL (1.3 mmol) of DBU, and 5 mL of toluene. Work-up of the reaction mixture af t e r 5 h afforded 89 mg of 163 as a yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethylacetate (9:1) as eluant gave 81 mg (86%) of the sole product 163 as a pale yellow o i l . The spectral data of th i s compound i s in good agreement with that obtained previously. Method B Potassium tert-butoxide as base This reaction was performed according to the procedure employed for the reaction of 160 with potassium tert-butoxide, using 50 mg (0.13 mmol) of 161 , 29 mg (0.26 mmol) of potassium tert-butoxide and 2 mL of toluene. Work-up of the reaction mixture after 16 h gave 24 mg of a - 232 -mixture of 164 and 163 as a yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (9:2) as eluant afforded 16 mg (55%) of a mixture of _Z-alkene 164 and E-alkene 163 in the r a t i o 80:20 (as determined by GC an a l y s i s ) , as a pale yellow o i l . The spectral data of the alkene mixture i s in good agreement with that obtained previously. Method C Lithium methoxide as base This reaction was performed according to the procedure employed for the reaction of 160 with l i t h i u m methoxide, using 0.22 mL (0.26 mmol) of a 1.2 M so l u t i o n of methyllithium in ether, 50 mg (0.13 mmol) of 161 and 2 mL of methanol. Work-up of the reaction mixture gave 21 mg of a yellow o i l , which was shown by GC analysis to contain in order of e l u t i o n : (a) Z-alkene 164 (41% GC y i e l d ) ; (b) E-alkene 163_ 912% GC y i e l d ) ; (c) methyl ether \66_ (4% GC y i e l d ) : (d) methyl ether 165_ (11% GC y i e l d ) (e) ester 167 (32% GC y i e l d ) ; - 233 -(3R*,13R*)-3-Methyl-13-tetradecanollde (155) Method A A suspension of 380 mg (2.0 mmol) of pu r i f i e d (96) cuprous iodide in 2.5 mL of dry ether was s t i r r e d at 0°C under a nitrogen atmosphere. To t h i s mixture 2.7 mL (4.0 mmol) of a 1.5 M s o l u t i o n of methyllithium in ether was added dropwise, and the res u l t i n g colourless suspension was s t i r r e d at 0° for 20 min. A solu t i o n of 112 mg (0.50 mmol) of the E_-alkene 163 in 0.25 mL of ether was added in 25 uL portions over a period of 1 h (19). After s t i r r i n g for an addit i o n a l 1 h at 0°C, the yellow reaction mixture was poured into an ice-cold saturated ammonium chlor i d e s o l u t i o n . This mixture was di l u t e d with petroleum ether, s t i r r e d for 10 min, and extracted with petroleum ether. The combined extracts were washed twice with brine, d r i e d , and concentrated under reduced pressure to give 106 mg of 155 as a pale yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using 2% ethyl acetate in petroleum ether as eluant yielded 90 mg (75%) of 155 as a colourless o i l . GC and *H nmr analysis showed only 155. None of the diastereomeric dimethyl lactone 154 was detected. - 234 -i r (CHCI3): 1715 (C=0) cm - 1; *H nmr (400 MHz, CDCI3) 6: 0.96 (d, J = 7 Hz, 3H), 1.22 (d, J = 7 Hz, 3H), 1.05-1.69 (m, 18H), 1.85-1 .96 (m, 22a,3 = 1 1 H z » 2.2b, 3 = 4 Hz, plus addi t i o n a l couplings, IH), 2.01 (dd, .J_2a,2b = 1 3 H z > J2 a >3 = 1 Hz, 1 H), 2.43 (dd, J_2a,2b = 1 3 H z » 2.2b,3 = 4 H z» 1 H ) ' 4.90-5.02 (m, IH); ms m/z: 240(M +, 2), 222(10), 180(46), 138(11), 125(12), 112(17), 111(17), 98(18), 97(30), 96(24), 95(15), 85(15), 56(32), 55(96), 43(60), 42(30), 41(100) and 39(18). Exact Mass calcd. f o r C 1 5 H 2 8 0 2 : 240.2089; found (ms): 240.2092. Method B This reaction was performed according to the preceding procedure for the preparation of 155, except that the solution of the alkene 163 was added in one portion. In th i s reaction 107 mg (0.56 mmol) of cuprous iodide, 0.70 mL (1.1 mmol) of a 1.6 M solution of methyllithium i n ether, 63 mg (0.28 mmol) of alkene 163 and 5 mL of ether were used. Work-up of the reaction mixture gave 61 mg of a yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using 1% ether in petroleum ether as eluant gave i n order of e l u t i o n : (a) (3R*,13R*)-3-methyl-13-tetradecanolide (155) (25 rag, 37%) as a pale yellow o i l ; Rf 0.38 (5% ether in petroleum ether); The spectral data of t h i s compound i s in good agreement with that obtained previously. - 235 -(b) a mixture of (3R* ,13S_*)-3-methyl-l 3-tetradecanolide (154) and 13-tetradecanolide (134) (22 mg, 33%) as a pale yellow o i l ; 0.27 (5% ether in petroleum ether); The spectral data of this mixture i s in good agreement with that reported on p. 252 for 154 and that reported for 134 1 7. 13-Hydroxy-3-methyltetradecanoic Acid (168) OH CH 3 ^ ^ ( C H J ^ O c O O H 2 9 To a sol u t i o n of 30 mg (0.13mmol) of a mixture of the diastereomers 155 and 154 in 2 mL of methanol was added a solution of 40 Spectral data and an authentic sample of 13-tetradecanolije (134) were kindly provided by Roman Kaiser, Givaudan Forschungsgesellschaft A.G., Zurich (97). i r (CHC13): 1730 (COOR) cm - 1; *H nmr (400 MHz, CDC1 3) 6: 1.14-1.50 (m, 16H), 1.21 (d, J_= 6 Hz, 3H), 1.50-1.64 (m, 3H), 1.64-1.76 (m, IH), 2.26 (ddd, J = 13,10,4 Hz, IH), 2.40 (ddd, J = 13,7,4 Hz, IH), 5.00 (sextet, J = 6 Hz, IH). - 236 -mg (0.71 mmol) of potassium hydroxide in 1 mL of water and the re s u l t i n g mixture was heated at reflux for 40 h. The cooled reaction mixture was a c i d i f i e d with 1 M hydrochloric acid and extracted with ether. The combined extracts were washed twice with brine, d r i e d , and concentrated under reduced pressure to give 25 mg,of a yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (9:1) to elute the les s polar components and petroleum ether - ethyl acetate (2:1) to elute the more polar components gave, in order of e l u t i o n , the following: (a) (3R*,13S*)-3-methyl-13-tetradecanolide (154) (2 mg, 7%) as a colourless o i l ; Rf 0.93 (petroleum ether - ethyl acetate 2:1); The spectral data of t h i s compound i s i n good agreement with that reported on p. 252. (b) 13-hydroxy-3-methyltetradecanoic acid (168 and 173) (22 mg, 68%) as a colourless o i l ; R£ 0.22 and 0.14 (petroleum ether - ethyl acetate 2:1); i r (CHC1 3): 3620-2400 (COOH and OH) and 1715 (C=0) cm - 1; *H nmr (80 MHz, CDC13) 6: 0.90 (d, J_ = 6 Hz, 3H), 1.18-1.55 (m, 18H), 1.20 (d, J. = 6 Hz, 3H), 1.78-2.06 (m, IH), 2.10-2.35 (m, 2H) , 3.58-3.95 (m, IH), 4.90-5.38 (m, 2H, exchangeable with D 20); ms m/z: 258(M+, 0.4), 243(1), 241(1), 240(2), 225(7), 214(27), 180(16), 112(10), 111(10), 97(17), 88(11), 87(100), 85(11), 83(22), 82(10), 71(13), 70(11), 69(44), 68(10), 60(14), 57(22), 56(17), 55(41), 45(44), 43(26) and 41(30). - 237 -Exact Mass calcd. for C 1 5H 3 o 0 3 : 258.2195; found (ms): 258.2200. (3R*,13R*)-1,13-Dihydroxy-3-methyltetradecane (169) H OH H C H 3 A suspension of 8 mg (0.20 mmol) of lithium aluminum hydride in 2 mL of dry ether was s t i r r e d at room temperature under a nitrogen atmosphere. A solution of 25 mg (0.10 mmol) of the lactone 155 in 1 mL of ether was added dropwise and the r e s u l t i n g mixture was s t i r r e d at room temperature for 30 min, then was quenched with 1 M hydrochloric a c i d . The ether layer was washed once with 1 M hydrochloric acid and twice with brine, dried, and concentrated under reduced pressure to give 22 mg of 169 as a pale yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (1:1) as eluant yielded 18 mg (74%) of 169_ as a white s o l i d ; mp 28.0-29.5°C; i r (CHC1 3): 3625 (free OH) and 3350-3550 (H-bonded OH) cm - 1; *H nmr (80 MHz, CDC1 3) 6: 0.86 (d, J_= 6 Hz, 3H), 1.09-1.88 (m, 21H), 1.19(d, J = 6 Hz, 3H), 1.48 (s, 2H, exchangeable with D 20), 3.69 ( t , J = 6.5 Hz, 2H), 3.70-3.96 (m, IH); ms m/z: 229(M+ - CH 3, 2), 226(0.2), 211(0.8), 208(5), 153(10), 138(6), 111(15), 110(17), 109(17), 97(38), 96(34), 95(27), 83(51), - 238 -82(39), 81(65), 71(49), 70(74), 69(68), 68(29), 67(23), 57(47), 56(47), 55(100), 45(100), 43(69) and 41(58). Exact Mass calcd. for C 1 i +H 2 90 2 (M + - CH 3): 229.2167; found (ms): 229.2161; calcd. for C i 5 H 3 0 O (M + - H 20): 226.2297; found (ms): 226.2292. 3-Methyl-13-tetradecanolide (155 and 154) via Lactonization of 168 and 173 To a solu t i o n 22 mg (0.085 mmol) of the hydroxy acid 168 in 0.5 mL of dry benzene was added 22 mg (0.10 mmol) of 2 , 2 ' - d i p y r i d y l d i s u l f i d e and 27 mg (0.10 mmol) of triphenylphosphine (74). The r e s u l t i n g solution was s t i r r e d at room temperature under a nitrogen atmosphere for 30 min, then was di l u t e d with 4 mL of benzene. A second f l a s k was equipped with a condenser and was charged with 10 mL of dry benzene and 0.6 mL of a 1 M solu t i o n of anhydrous s i l v e r perchlorate in toluene (74). The solution was heated such that the benzene returned from the condenser at a rate of 5 to 10 drops per second. The benzene solution of the thioester was added down the wall of the condenser over a period of 4 h, using a syringe and syringe pump. The mixture was heated at reflux for an additional 15 min then was cooled to room temperature and 3 mL of a 0.5 M potassium cyanide solution was added. After the mixture had s t i r r e d for 20 min, the benzene layer was separated, and the aqueous layer was extracted three times with benzene. The combined benzene layers were washed once with brine, d r i e d , and concentrated under reduced pressure to give 45 mg of a colourless serai-solid. P u r i f i c a t i o n - 239 -by f l a s h chromatography using 1% ether in petroleum ether as eluant gave, in order of e l u t i o n , the following: (a) (3R*,13R*)-3-methyl-13-tetradecanolide (155) (9 mg, 44%) as a colourless o i l ; Rf 0.38 (5% ether in petroleum ether); The spectral data of t h i s compound i s in good agreement with that obtained previously. (b) a mixture of (3R* ,13S_*)-3-methyl-13-tetradecaolide (154) and 13-tetradecanolide (134) (1 mg, 5%) as a colourless o i l ; Rf 0.29 (5% ether in petroleum ether); The spectral data of these compounds i s in good agreement with that reported on p. 252 and p. 234 r e s p e c t i v e l y . Reaction of ^ -2-Tetradecen-l3-olide (164) with Dimethyllithium Cuprate This experiment was performed according to the procedure for reaction of the E_-alkene 163 with Me 2CuLi (Method B), using 300 mg (1.6 mmol) of cuprous iodide, 2.6 mL (3.1 mmol) of a 1.2 M sol u t i o n of methyllithium in ether and 90 mg (0.40 mmol) of Z^alkene 164. Work-up of the reaction mixture gave 74 mg of a colourless o i l . GC analysis indicated t h i s to be a mixture of the following compounds: sta r t i n g material ( 4 % ) , _Z-3-tetradecen-l 3-olide (181_, 13%) and E-3-tetradecen-13-olide (180, 80%). i r ( C H C l 3 ) : 1725 (COOR) and 1665 (C=C) cm - 1; *H nmr (400MHz, CDC1 3) 6: 0.98-1.48 (m, 14H), 1.21 (d, J = 7 Hz, 3H), 2.09 (m, J = 7.5 Hz, 2H), 2.91 (dd, _J_2a, 2b " 1 3 H z » 22a,3 = - 240 -7.5 Hz, IH), 3.02 (dd, .J_2a,2b = 1 3 H z » lla,3 = 7-5 H z» 1 H) » 4.92 (sextet, J_ = 7 Hz, IH), 5.47 (m, ^ 3 , 4 = 15 Hz, J_2a, 3 = 7«5 Hz, J_2b, 3 = 7.5 Hz, IH), 5.54 (m, J 3 > l t = 15 Hz, J_k>$a = 7 , 5 H z » -it,5b 7.5 Hz, IH); ms m/z: 224(5), 164(9), 138(14), 110(12), 109(15), 97(13), 96(36), 95(34), 83(25), 82(56), 81(53), 70(13), 69(41), 68(48), 67(60), 57(18), 56(20), 55(84), 54(100), 43(51), 42(21), 41(93) and 39(25). Exact Mass calcd. for C 1 1 +H 2 l t0 2: 224.1776; found (ms): 224.1782. Reaction of E- and ^-2-Tetradecen-13-olide (163 and 164) with Dinethylllthium Cuprate This reaction was performed according to the procedure employed for the preparation of 155 v i a addition of Me 2CuLi to alkene 163 (Method B) , using 102 mg (0.54 mmol) of cuprous iodide, 0.66 mL (1.1 mmol) of a 1.6 M solu t i o n of methyllithium i n ether and 55 mg (0.25 mmol) of a mixture of Tr- and E-alkenes 164 and 163 0Z:_E = 36:64). GC analysis showed 90% of the E_-alkene to have reacted within the f i r s t 10 minutes. Work-up of the reaction mixture a f t e r 1 h gave 46 mg of a yellow o i l . GC and *H nmr analysis showed th i s to be a mixture of Z-alkene 164 and dimethyl lactone 155. Neither the E-alkene 163 nor the diastereomeric dimethyllactone 154 were detected. - 241 -Z-3-(Diethylphosphoryloxy)-2-tetradecen-l3-ollde (192) An oven-dried flask was charged with 44 mg ( l . l mmol) of sodium hydride (60% dispersion in o i l ) which was then washed once with dry ether under a nitrogen atmosphere. To this grey s o l i d was added 6 mL of fresh ether and the r e s u l t i n g suspension was cooled to 0°C. A solu t i o n of 240 mg (1.0 mmol) of the 6-keto lactone 138 in 4 mL of ether was added dropwise and the reaction mixture was s t i r r e d for 30 min at 0°C. Next was added 0.16 mL (1.1 mmol) of d i e t h y l chiorophosphate and the mixture was s t i r r e d at 0°C for 2 h (78). The reaction was quenched with aqueous ammonium chloride and the organic phase was washed twice with saturated aqueous sodium bicarbonate and once with b r i n e , and d r i e d . Removal of solvent under reduced pressure gave 398 mg of a pale yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (2:1) as eluant yielded 222 mg (59%) of 192 as a colourless o i l ; i r (CHC1 3): 1720 (COOR), 1670 (C=C), 1275 (PO) and 1035 (P-0-alkyl) cm - 1; *H nmr (400 MHz, CDC13) 6: 1.04-1.89 (m, 16H), 1.25 (d, J = 7 Hz, - 242 -3H), 1.38 (dt, J C H 2 C H 3 = 7 Hz, Jp 0 CCH 3 " 1 H z » 3 H > » 1.39(dt, 2CH 2CH 3 = 7 Hz, JpocCH3 = 1 H z » 3 H ) . 2.31 (ddd, J ^ ^ b = 14 Hz, I^a.sa = 11 Hz. i a . S b = 4 H z . 1 H >» 2.25-2.36 (m, J ^ , ^ = 14 Hz, Jj+b,5a = 1 H z » P l u s a d d i t i o n a l fine couplings, IH), 2.60-2.78 <m« icH2CH 3 = 7 Hz, J p 0 C H 2 = 8 Hz, 2H), 4.33 (dq, J C H 2 C H 3 " 7 H Z . iP0CH 2 = 8 Hz, 2H), 5.02 (m, IH), 5.56 (s, IH); ms m/z: 376(M +, 13), 239(6), 155(100), 127(23), 99(26), 81(10), 79(8), 69(7), 55(15), 43(9) and 41(14). Exact Mass calcd. for C 1 8 H 3 3 0 6 P : 376.2014; found (ms): 376.2017. &-3-(Diethylphosphoryloxy)-2-tetradecen-l3-olde (193) A solution of 100 mg (0.42 mmol) of B-keto lactone 138 in 2 mL of dry HMPA was s t i r r e d at 10° C under a nitrogen atmosphere. To th i s solution was added 0.08 mL (0.6 mmol) of triethylamine. After 15 min 0.08 mL (0.6 mmol) of diethylchlorophosphate was added and the mixture was s t i r r e d at room temperature for 28 h (78). The reaction mixture was quenched with 1 M hydrochloric acid and diluted with ether. The organic - 243 -phase was washed with saturated cupric sulfate (to remove HMPA) and with brine, d r i e d , and concentrated, to y i e l d 161 mg of crude 193 as a yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (2:1) as eluant gave 91 mg (58%) of pure 193 as a colourless o i l ; Ir (CHC1 3): 1710 (COOR), 1650 (C=C), 1275 (P=0) and 1030 (P-0-alkyl) cm - 1; XH nmr (400 MHz, CDCI3) 6: 0.85-1.70 (m, 14H), 1.22 (d, J_= 6 Hz, 3H), 1.36 (dt, J C H 2 C H 3 = 7 H Z > iP0CCH3 " 1 H z > 3H), 1.37 (dt, iCH 2CH 3 = 7 Hz, JpocCH3 = 1 H z > 3 H ) , 1.76-1.88 (m, 2H), 2.33 (dt, 2i+a,4b " 16 Hz, 2t*a,5a = ^ a , 5 b = 4 Hz IH), 3.46-3.57 (m, IH), 4.20 (dq, J CH 2CH 3 = 7 Hz, Jp 0CH 2 = 8 Hz, 2H), 4.21 (dq, i.CH2CH3 = 1 Hz, JpoCH2 = 8 Hz, 2H), 5.22-5.32 (m, IH), 5.94 (s, IH); ms ra/_z: 376(13) 239(6), 155(100), 127(25), 99(31 ), 81(10), 79(8), 67(6), 55(14), 43(7) and 41(11). Exact Mass calcd. for C 1 8H 3 30 6P: 376.2014; found (ms): 376.2008. E-3-Methyl-2-tetradecen-l3-olide (185) via Addition of Dinethyllithium Cuprate to Enol Phosphate 192 - 244 -An oven-dried round bottom f l a s k was cooled under a nitrogen atmosphere, and once coo l , was charged with 225 mg (1.18 mmol) of p u r i f i e d cuprous iodide and 10 mL of dry ether. The mixture was cooled to 0°C, 1.8 mL (2.3 mmol) of a 1.3 M solution of methyllithium in ether was added and s t i r r i n g was continued at th i s temperature for 20 min. The reaction mixture was cooled to -25°C (dry ice - calcium chloride -water bath) (98) and a solution of 222 mg (0.59 mmol) of the enol phosphate 192 in 1 mL of ether was added dropwise (78). Over a 10 min period the colour of the reaction mixture changed from pale yellow to deep maroon. After s t i r r i n g at -25°C for 1.5 h the mixture was poured into an ice-cold solution of saturated ammonium chloride - concentrated ammonium hydroxide (5:1). The r e s u l t i n g mixture was s t i r r e d for 10 min, then was extracted with ether. The combined ether extracts were washed twice with brine, dried, and concentrated under reduced pressure to give 121 mg of crude 185 as a yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (9:1) as eluant gave i n order of e l u t i o n : (a) a mixture of the E_-alkene 185 and the Z-alkene 186 in the r a t i o Er.Z = 77:21 (as determined by GC a n a l y s i s ) . The mixture (64 mg, 46%) was obtained as a colourless o i l ; Rf 0.85 (petroleum ether - ethyl acetate 9:1); The spectral data of the mixture of alkenes i s in good agreement with that reported below for the separate isomers. (b) 4,4-dimethyl-14-hydroxypentadecan-2-one (194) (12 mg, 8%) as a yellow o i l ; - 245 -Rf 0.12 (petroleum ether - ethyl acetate 9:1); i r (CHC13): 3600 (free OH), 3350-3560 (H-bonded OH) and 1705 (H-bonded C=0) cm - 1; *H nmr (80 MHz, CDC13) 6: 1.00 (s, 6H), 1.10-1.65 (m, 18H), 1.20 (d, J = 6 Hz, 3H), 2.14 (s, 3H), 2.33 (s, 2H), 3.60-3.96 (m, IH); ms ra/z: 270(M+, 1), 255(3), 252(2), 237(4), 212(11), 194(34), 138(17), 111(16), 110(13), 109(19), 99(49), 98(21), 97(23), 96(34), 95(27), 85(14), 83(47), 82(42), 81(21), 71(14), 69(52), 68(15), 67(15), 59(13), 58(18), 57(26), 56(21), 55(48), 45(33), 43(100) and 41(32); Exact Mass calcd. for Ci7H3k02: 270.2559; found (ms): 270.2553. (c) 2,4-dihydroxy-2,4-dimethylpentadec-3-ene (195) (17 mg , 11%) as a yellow o i l ; Rf 0.10 (petroleum ether - ethyl acetate 9:1); i r (CHCI3): 3600 (free OH), 3350-3550 (H-bonded OH) and 1100 (C-0) cm - 1; *H nmr (80 MHz, CDCI3) 6: 1.10-1.63 (m, 18H), 1.20 (d, J_ = 6 Hz, 3H), 1.38 (s, 6H), 1.84 (d, J_= 1 Hz, 3H), 3.60-3.% (m, IH), 5.33 (d, J_ = 1 Hz, IH); ms m/z: 270(0.7), 255(9), 252(4), 237(36), 194(6), 138(4), 123(5), 111(14), 109(19), 99(55), 98(13), 97(15), 96(35), 95(22), 85(21), 83(35), 82(14), 81(18), 71(14), 69(27), 68(60), 67(13), 59(18), 57(14), 55(32), 45(26), 43(100) and 41(24). Exact Mass calcd. for C n ^ i ^ : 270.2558; found (ms): 270.2555. - 246 -E-3-Methyl-2-tetradecen-13-olide (185) via Addition of Methylcopper -Methyl Magnesium Chloride to Enol Phosphate 192 An oven-dried 25 mL three necked round bottom flas k equipped with a thermometer, a rubber septum, a nitrogen i n l e t and a magnetic s t i r r i n g bar was cooled under a nitrogen atmosphere. Once the flask was cool 122 mg (0.64 mmol) of p u r i f i e d cuprous iodide and 5 mL of dry THF were introduced. The mixture was cooled to 0°C, 0.40 mL (0.64 mmol) of a 1.6 M s o l u t i o n of methyllithium in ether was added and the mixture was s t i r r e d for 20 min. The reaction mixture was cooled to -35°C (dry i c e - calcium chloride - water bath) and 0.37 mL (1.06 mmol) of a 2.9 M solution of methylmagnesium chloride in THF was added. After 20 min a so l u t i o n of 80 mg (0.21 mmol) of the enol phosphate 192 in 1.5 mL of THF was added v i a syringe, and the mixture was s t i r r e d at -35°C for 5 h (81). The reaction was quenched by pouring the mixture into an ice-cold s o l u t i o n of saturated ammonium chloride - concentrated ammonium hydroxide (5:1). The re s u l t i n g mixture was s t i r r e d for 10 min, then was extracted with ether. The combined ether extracts were washed twice - 247 -with brine, dried, and concentrated under reduced pressure to give 54 mg of crude 185 as a yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using 2% ethyl acetate in petroleum ether as eluant gave, in order of e l u t i o n : (a) a mixture of the JS-alkene 185 and the _Z-alkene 186 in the r a t i o E:Z_ = 93:5 (as determined by GC a n a l y s i s ) . The mixture (15 mg, 27%) was obtained as a colourless o i l ; Rf 0.78 (petroleum ether - ethyl acetate 9:1); i r (CHC13): 1705 (COOR) and 1645 (C=C) cm - 1; *H nmr (400 MHz, CDC13) 6: 1.02-1.74 (m, 16H), 1.26 (d, £13,11+ = 6 Hz, 3H), 2.15 (d, ^ 2 , 1 5 " 1 H z » 3 H > » 2.15-2.24 (m, 2H), 4.97-5.06 (m, J.i2a ,13 = 9 H z » i . 1 3 , 1 4 = 6 H z » £l2b , 1 3 = 3 H z » 1 H ) » 5 ' 7 6 < d » £2,15 = 1 Hz, IH); ms m/z: 238(M+, 27), 178(15), 139(21), 138(10), 126(12), 125(10), 111(24), 110(17), 109(23), 100(86), 97(17), 96(33), 95(79), 85(35), 83(91), 82(69), 81(36), 69(45), 68(25), 67(46), 55(87), 54(24), 53(16), 43(49), 42(16), 41(100), 40(27) and 39(27). Exact Mass calcd. for C 1 5H 260 2: 238.1933; found (ms): 238.1933. (b) B-keto lactone 138 (6 mg, 12%); Rf 0.53 (petroleum ether - ethyl acetate 9:1); The spectral data of the B-keto lactone i s in good agreement with that obtained previously. (c) s t a r t i n g material (11 mg, 14%); Rf 0.10 (petroleum ether - ethyl acetate 9:1). - 248 -Reaction of E-3-Methyl-2-tetradecen-13-olide (185) with Dimethyllithium Cuprate An oven-dried round bottom f l a s k was cooled under a nitrogen atmosphere, and once coo l , was charged with 198 mg (1.04 mmol) of pu r i f i e d cuprous iodide and 5 mL of dry ether. The mixture was cooled to 0°C, 1.58 mL (2.06 mmol) of a 1.3 M solution of methyllithium i n ether was added and the mixture was s t i r r e d for 10 min. A so l u t i o n of 63 mg (0.26 mmol) of 185 i n 3 mL of ether was then added dropwise. After s t i r r i n g at 0°C for 1.5 h, the mixture was c a r e f u l l y poured into an i c e - c o l d solution of saturated ammonium chloride - concentrated ammonium hydroxide (5:1). The r e s u l t i n g mixture was s t i r r e d for 10 min, then was extracted with ether. The combined ether extracts were washed twice with brine, d r i e d , and concentrated under reduced pressure to give 73 mg (100%) of d i o l 195. The spectral data of this compound i s in good agreement with that obtained previously. (3R*,13R*)-3-Methyl-13-tetradecanolide (155) via Hydrogenation of 185 - 249 -A suspension of 2 mg (0.01 mmol) of powdered platinum(IV) oxide in 1 mL of ethanol was s t i r r e d for 15 min umder a hydrogen atmosphere (1 atra) at room temperature to give elemental platinum as black granules. A solution of 6 mg (0.025 mmol) of alkene 185 in 1 mL of ethanol was added and the mixture was s t i r r e d at room temperature for 3 h. The catal y s t was removed by f i l t r a t i o n and was washed with ethanol. Removal of solvent under reduced pressure gave 5 mg (83%) of 155 as a colourless o i l . The spectral data of t h i s compound i s in good agreement with that obtained previously. Z-3-Methyl-2-tetradecen-13-olide (186) via Addition of Dimethyllithium Cuprate to Enol Phosphate 193 This compound was prepared according to the procedure employed for the preparation of 185 v i a addition of dimethyllithium cuprate to enol phosphate 192. For t h i s reaction 91 mg (0.48 mmol) of cuprous iodide, 0.73 mL (0.95 mmol) of a 1.3 M so l u t i o n of methyllithium in ether, 90 mg (0.24 mmol) of enol phosphate 193 and 5 mL of ether were - 250 -used. Work-up of the reaction mixture gave 40 mg of crude 186 as a yellow o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ethyl acetate (9:1) gave a mixture of the _Z-alkene 186 and the E_-alkene 185 in the r a t i o Z:E_ - 9:1 (as determined by GC a n a l y s i s ) . The mixture (21 mg, 37% y i e l d , 80% purity by GC analysis) was obtained as a colourless o i l ; i r ( C H C l 3 ) : 1700 (COOR) and 1650 (C=0) cm - 1; XH nmr (400 MHz, CDC1 3) 6: 1.00-1.71 (m, 16H), 1.22 (d, J = 6 Hz, 3H), 1.82 (d, £ 2 , 1 5 = 1 Hz, 3H), 2.06-2.15 (m, J ^ ^ b = 13 Hz, i a . S a = :L+a,5b = ^ H z » p l u s a d d i t i o n a l couplings, IH), 3.40 (ddd, J ^ ^ t = 13 Hz, = 10Hz, J ^ 5 b = 6 Hz, IH), 5.15-5.26 (m, J 1 3 , m = 6 Hz, J 1 2 a , 1 3 = 9 Hz, J 1 2b,13b = 3 H z » IH), 5.70 (d, £ 2 , 1 5 = 1 Hz, IH); ms m/z: 238(M+, 19), 223(12), 200(11), 179(15), 178(38), 153(18), 152(16), 139(20), 138(26), 126(22), 125(28), 123(26), 113(28), 112(20), 111(54), 110(39), 109(62), 108(20), 100(71), 97(37), 96(70), 95(100), 94(20), 83(65), 82(74), 81(69), 69(58), 68(34), 67(57), 57(29), 55(82), 43(44), 41(65) and 39(18). Exact Mass c a l c d . for C 1 5 H 2 6 O 2 : 238.1933; found (ms): 238.1931. Reaction of Z- and &-3-(Diethylpho8phoryloxy)-2-tetradecen-13-olide (192 and 193) with D i a e t h y l l i t h i u B Cuprate This reaction was performed according to the procedure employed for the preparation of 185 v i a addition of dimethyllithium cuprate to enol phosphate 192. The cuprate was generated using 57 mg (0.30 mmol) - 251 -of cuprous iodide and 0.39 mL (0.59 mmol) of a 1.5 M solu t i o n of methyllithium and was then reacted with a mixture of 8 mg (0.21 mmol) of Z-enol phosphate 192 and 48 mg (0.13 mmol) of E-enol phosphate 193 (a r a t i o of _Z:E_ = 1:6). Work-up of the reaction mixture a f t e r 3 h gave 26 mg of a yellow o i l . *H nmr analysis revealed some unreacted enol phosphates 192 and 193, a small a mount of 6-keto lactone 138 and a mixture of the products 185 and 186 in the r a t i o 10:1. Reaction of B-3-(Diethylpho8phoryloxy)-2-Tetradecen-13-olide (193) with Methylcopper - Methyl Magnesium Chloride This reaction was performed according to the procedure used for the preparation of 185 v i a addition of MeCu-MeMgCl to enol phosphate 192. For this reaction 76 mg (0.40 mmol) of cuprous io d i d e , 0.25 mL (0.40 mmol) of a 1.6 M solu t i o n of methyllithium in ether, 0.23 mL (0.66 mmol) of a 2.9 M solu t i o n of methlymagnesium chloride in THF, 50 mg (0.13 mmol) of enol phosphate 193 and 6 mL of THF were used. Af t e r s t i r r i n g at ca. -35°C f o r 24 h, GC analysis showed that 75% of the st a r t i n g material remained. The reaction mixture was warmed slowly (22 h) to -5°C giving a grey suspension. Work-up of the reaction mixture gave 40 mg of a colourless o i l . *H nmr analysis showed t h i s to be a 15:85 r a t i o of st a r t i n g material to 6-keto lactone 138. - 252 -(3R*,13S*)-3-Methyl-13-tetradecanollde (154) via Hydrogenation of 186 A suspension of 2 mg (0.01 mmol) of powdered platinum(IV) oxide in 1 mL of ethanol was s t i r r e d for 15 min under a hydrogen atmosphere (1 atra) at room temperature to give elemental platinum as black granules. A solution of 5 mg (0.02 mmol) of alkene 186 in 1 mL of ethanol was added and the mixture was s t i r r e d at room temperature for 9 h. The catalyst was removed by f i l t r a t i o n and was washed with ethanol. Removal of soluent under reduced pressure gave 4.5 mg (89%) of 154 as a colourless o i l ; i r (CHC1 3): 1715 (COOR) cm - 1; *H nmr 1 8 (400 MHz, CDCI3) 6: 0.95 (d, J_ = 7 Hz, 3H), 1.05-1.70 (m, 18H), 1.21 (d, J = 7 Hz, 3H), 2.04-2.11 (m, IH), 2.15 (dd, J = 14,10 Hz, IH), 2.24 (dd, J = 14,4 Hz, IH), 5.03-5.10 (m, IH); ms ra/z: 240(M+, 16), 225(4), 180(13), 143(6), 111(6), 110(6), 109(6), 98(6), 97(14), 96(9), 95(9), 87(7), 85(19), 84(5), 83(14), 82(9), 81(12), 73(100), 72(7), 71(13), 70(6), 69(26), 68(8), 67(8), The nmr spectrum of this sample was not well resolved. The nmr data reported here was taken from a spectrum of a mixture of the diastereomeric dimethyllactones 155 and 154. The spectrum of compound 155 was v i s u a l l y subtracted after comparison with the spectrum of pure 155. The mixture of diastereomers was obtained by hydrogenation of a mixture of the alkenes 185 and 186. - 253 -57(22), 56(8), 55(29), 45(22), 44(7), 43(22) and 41 (21). Exact Mass c a l c d . for C15H28O2: 240.2089; found (ms): 240.2088. aR^.SRSnR^-Z.S-Epoxy-lS-tetradecanolide (197) and (ZR*,3R*,13S*) -2,3-Epoxy-13-tetradecanolide (198) via Epoxidation of 163 197 198 Method A. MCPBA, 1,2-dichloroethane and heat A sol u t i o n of 40 mg (0.18 mmol) of the alkene 163 and 154 mg (0.89 mmol) of p u r i f i e d MCPBA (99) in 4 mL of dry 1,2-dichloroethane was heated at reflux for 15 h (99). The cooled reaction mixture was di u l t e d with dichloromethane and was washed once with saturated aqueous sodium bicarbonate, three times with saturated aqueous sodium b i s u l f i t e , twice more with saturated aqueous sodium bicarbonate, and once with brine, and was d r i e d . Removal of solvent under reduced pressure gave 53 mg of a crude mixture of the epoxides 197 and 198 as a very pale yellow o i l . P u r i f i c a t i o n by f i l t r a t i o n through a short column of s i l i c a gel using 1% ether in petroleum ether as eluant gave 36 mg (84%) of a mixture of 197 and 198 as a colourless o i l . GC analysis showed pure product i n the r a t i o 197:198 = 54:46. Separation of the isomers by f l a s h - 254 -chromatography using 1% ether in petroleum ether as eluant gave, in order of e l u t i o n : (a) epoxide 198 (5 mg, 12%) as a colourless o i l ; Rf 0.61 (petroleum ether - ethyl acetate 9:1); i r (CHC1 3): 1725 (COOR) and 1290 (epoxide) cm - 1; *H nmr (400 MHz, CDCI3) 6: 1.10-1.72 (m, 17H), 1.28 (d, J_= 7 Hz, IH), 2.05-2.15 (m, J ^ ^ b = 1 4 H z > 2.3 , 4 3 = 2 Hz» 2 .4a, 5a - 10 H z « 24b,5b = 3 H z> 1 H ) ' 3 * 2 1 ( d » 2-2,3 = 2 H z» 1 H>» 3 , 2 9 ( d t» ^2,3 = 2 Hz, J3 f k a = 10 Hz, J.3,4b = 2 H z ' 1 H > » 5 , 0 8 (sextet, J_ = 7 Hz, IH); ms m/z: 240(M +, 0.01), 211(0.1), 205(0.1), 195(3), 183(23), 165(13), 123(12), 109(42), 97(22), 96(19), 95(62), 83(45), 82(26), 81(51), 71(15), 70(17), 69(44), 68(27), 67(51), 57(41), 56(19), 55(100), 54(20), 43(59), 42(24), 41(95), 39(16) and 29(47). Exact Mass ca l c d . for C13H23O (M + - CHO2): 195.1748; found (ms): 195.1738; c a l c d . f o r C 1 2 H 2 3 0 (M+ - C 2H0 2): 183.1748; found (ms): 183.1748. (b) epoxide 197 (8 mg, 19%) as a colourless o i l ; Rf 0.56 (petroleum ether - ethylacetate 9:1); i r (CHCI3): 1740 (COOR) and 1255 (epoxide) cm - 1; *H nmr (400 MHz, CDC13) 6: 1.12 (dddd, J . 4 a , 4 b = 1 4 H z ' 2.3,4a " 1° H z » 2.43,5a - 3 H z » 2.43,5b " H H z » IH). 1-18-1.71 (m, 16H), 1.29 (d, J = 6 Hz, 3H), 2.24 (dddd, J ^ ^ b = 14 Hz, 2.3,4b - 2 H z » 24b,5s = 7 Hz, J ^ . g b - 3 Hz, IH), 3.07 (dt, 22,3 = 2 Hz, J 3 > 4 a = 10 Hz, J 3 > 4 b = 2 Hz, IH), 3.23 (d, J 2 > 3 - 255 -= 2 Hz, IH), 5.06 (sextet, J_ = 6 Hz, IH); ms m/z: 240(M +, 0.5), 217(0.8), 205(1), 195(6),183(37), 165(25), 123(16), 109(50), 97(25), 96(24), 95(75), 83(43), 82(29), 81(59), 71(16), 70(15), 69(44), 68(28), 67(55), 57(37), 56(19), 54(100), 45(25), 43(45), 42(22), 41(95) and 39 (18). Exact Mass calcd. for C13H23O (M+ - HCO2): 195.1748; found (ms): 195.1741; ca l c d . f o r C 1 2 H 2 3 0 (M+ - CH02): 183.1748; found (ms): 183.1749. Method B. MCPBA, dichloromethane, room temperature To a solution of 20 mg (0.089 mmol) of the alkene 163 in 2 mL of dichloromethane was added 17 mg (0.098 mmol) of MCPBA and the r e s u l t i n g s o l u t i o n was s t i r r e d at room temperature. Additional solvent was added as necessary. After 7 days an additional 77 mg (0.44 mmol) MCPBA was added. After 11 days the reaction mixture was d i l u t e d with dichloromethane, washed once with saturated aqueous sodium bicarbonate, twice with saturated aqueous sodium b i s u l f i t e , twice more with saturated aqueous sodium bicarbonate, and once with brine, and dried. Removal of solvent under reduced pressure gave 23 mg of a colou r l e s s o i l . P u r i f i c a t i o n by f l a s h chromatography using 5% ether in petroleum ether as eluant yielded 16 mg (75%) of a mixture of 197 and 198 as a colourless o i l . GC analysis showed pure product i n the r a t i o 197:198 = 61:39. The spectral data of th i s mixture i s in good agreement with that obtained previously. - 256 -Method C. T r i f l u o r o p e r a c e t i c acid To a solution of 6 mg (0.03 mmol) of the alkene 163 in 1 mL of dichloromethane was added 0.09 mL (0.3 mmol) of a 3 M solution of t r i f l u o r o p e r a c e t i c acid in dichloromethane (19) and the r e s u l t i n g solution was s t i r r e d at room temperature for 1 h. The reaction mixture was d i l u t e d with dichloromethane, washed once with saturated aqueous sodium bicarbonate, twice with saturated aqueous sodium b i s u l f i t e , twice more with saturated aqueous sodium b i s u l f i t e , and once with brine, and dr i e d . Removal of solvent under reduced pressure gave 10 mg of crude product as a colourless o i l . P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ether (1:1) as eluant yielded 6 mg (93%) of a mixture of 197 and 198 as a colourless o i l . GC analysis showed pure product in the r a t i o 197:198 =64:36. The spectral data of th i s mixture i s in good agreement with that obtained previously. Method D. Hydrogen peroxide - base A s o l u t i o n of 0.07 mL (0.7 mmol) of 30% hydrogen peroxide and 30 mg (0.22 mmol) of potassium carbonate i n 0.5 mL of water was added to a sol u t i o n of 20 mg (0.089 mmol) of alkene 163 in 1 mL of methanol and 1 mL of THF (100). The r e s u l t i n g mixture was s t i r r e d at room temperature for 5 h, then was d i l u t e d with ether, washed with brine, dried and concentrated under reduced pressure to give 10 mg of a colourless o i l . P u r i f i c a t i o n by f l a s h chromatography using 1% ether in petroleum ether to elute the faster-moving components followed by 5% ether In petroleum - 257 -ether to elute the slower-moving components, gave in order of e l u t i o n : (a) a mixture of the epoxides 197 and 198 (3 rag, 14% y i e l d ; GC y i e l d s of 197 and 198: 23% and 4% respectively, as a colourless o i l ; Rf 0.60 and 0.54 respectively (petroleum ether - ethyl acetate 9:1); The spectral data of these compounds i s i n good agreement with that obtained previously. (b) a mixture of (3R*,13R*)-3-hydroperoxy-l3-tetradecanolide (199) and (3R*,13S*)-3-hydroperoxy-13-tetradecanolide (200) (7 mg, 33% y i e l d ; GC y i e l d s 1 9 of _199_ .and 2 0 0 : 23% and 29% respectively) as a colourless o i l ; Rf 0.28 (petroleum ether - ethyl acetate 9 : 1 ) ; i r ( C H C 1 3 ) : 3550 (free OH), 3200-3500 (H-bonded OH) and 1720 (C=0) cm - 1; *H nmr (80 MHz, CDCI3) 6 1.05 -1.85 (m, 2 1 H ) , 2.30-3 .10 (m, 2 H ) , 4 .20-4.55 ( m, IH), 4.83-5.25 (m, IH), 7.93 and 8.51 (2 br s, IH); ms m/z: 242(M+ - 0 , 1 ) , 241 ( 1 ) , 240(3), 225 ( 2 ) , 224(4), 118 ( 1 0 ) , 163 ( 1 1 ) , 154(14), 138(14), 111(17), 109 ( 2 0 ) , 103(15), 102(25), 98(19), Chromatograms of these compounds were i d e n t i c a l to those of the corresponding alcohols. - 258 -97(42), 96(29), 95(32), 89(30), 84(21), 83(50), 82(32), 81(37), 71(28), 70(20), 69(59), 68(27), 67(32), 57(33), 56(28), 55(100), 54(16), 45(15), 43(77), 42(27) and 41(68). Exact Mass calcd. for C 1 4H 2603 (M+ - 0): 242.1881; found (ms): 242.1864. Reduction of (3R*,13R*)- and (3R*,13S*)-3-Hydroperoxy-13-tetradecanolide (199 and 200) To a so l u t i o n of 2.4 mg (0.01 mmol) of a mixture of the hydroperoxides 199 and 200 ( i n the r a t i o 48:52) in 0.5 mL of ethanol was added 2 mg (0.05 mmol) of sodium borohydride. After s t i r r i n g at room temperature for 1 h, the reaction mixture was quenched with 1 M hydrochloric acid and dilu t e d with ether. The organic phase was washed twice with brine, d r i e d , and concentrated under reduced pressure to give 1.6 mg (69%) of a mixture of the alcohols 146 and 147 (in' the r a t i o 45:55) as a colourless o i l . The spectral data of these compounds i s i n good agreement with that obtained previously. Reaction of ^ -2-Tetradecen-l3-olide (164) with MCPBA This reaction was performed according to the procedure for the preparation of the epoxides 197 and 198 from the E_-alkene 163 (Method A), using 20 rag (0.089 mmol) of Z-alkene 164, 77 mg (0.45 mmol) of MCPBA and 2 mL of 1,2-dichloroethane. Work-up of the reaction mixture a f t e r 15.5 h gave 27 mg of a colourless o i l . GC analysis showed this to be a mixture of the following: s t a r t i n g material (23%), epoxide 197 (37%), - 259 -epoxide _198_ (20%) and E-alkene JL63_ (15%). This mixture was again subjected to the above reaction conditions. After three days GC analysis showed the presence of considerable amoumts of E_-alkene 163, but no _Z-alkene 164. Isoaerization of Tr- and _E-2 -Te tr ad ec en-13-ol id e (164 and 163) Each isomer was reacted separately i n the following manner. A solution of 3 mg (0.013 mmol) of the alkene and 8 mg (0.039 mmol) of j>-toluenesulfonic acid in 1 mL of 1,2-dichloroethane was heated at re f l u x , under a nitrogen atmosphere for three days. In each case, GC analysis of the r e s u l t i n g mixture showed the presence of the E-alkene 163, but not of the Z-alkene 164. - 260 -REFERENCES 1. M. Kerschbaum. Ber. Dtsch. Chem. Ges. 60B, 902 (1927). 2. T. Back. Tetrahedron, 33_, 3041 (1977) and references therein. 3. H. Brockmann and W. Henkel. Naturwissenschaften, V_t 138 (1950). 4. (a) S. Masamune, G.S. Bates and J.W. Corcoran. Angew. Chem. Int. Ed. Engl. 1_6, 585 (1977) and references therein; (b) K.C. Nicolaou. Tetrahedron, J33_, 683 (1977) and references therein. 5. W.D. Celmer. Pure Appl. Chem. 28 , 41 3 (1971 ). 6. J . Dale. J. Chem. Soc. 93 (1963). 7. W.D. Celmer. Antimicrob. Agents Chemother. 144 (1965). 8. R. S. Egan, T.J. Perun, J.R. Martin and L. A. Mitscher. Tetrahedron, 29, 2525 (1973) and references therein. 9. Recent examples of t o t a l syntheses of macrolide natural products include the following: (a) S. Masamune, L.D.L. Lu, W.P. Jackson, T. Kaiho and T. Toyoda. J . Am. Chem. Soc. 104, 5523 (1982); (b) P.A. Grieco, J. Inanaya, N.H. Lin and T. Yanami. J . Am. Chem. Soc. 104, 5781 (1982). (c) E.J. Corey, D.H. Hua, B.C. Pan and S.P. S e i t z . J . Am. Chem. Soc. 102 , 6818 (1982); (d) G. Stork and E. Nakamura. J . Am. Chem. Soc. 105, 5510 (1983); (e) H. Tsutsui and 0. Mitsunobu. Tetrahedron L e t t . 75_, 2163 (1984); see also references 33, 34, 35 and 36. 10. For a review of high d i l u t i o n techniques see: L. Rossa and F. VSgtle. Top. Curr. Chem. _U3» 1 (1983). 11. T. Ishida and K. Wada. J. Chem. Soc. Chem. Commun. 209 (1975). 12. R.E. Ireland and F.R. Brown. J . Org. Chem. 45_, 1868 (1980). 13. S. Cas t e l l i n o and J . J . Sims. Tetrahedron L e t t . 25_, 2307 (1984). 14. R.J. Sims, S.A. Ti s c h l e r and L. Weiler. Tetrahedron L e t t . 7A_, 253 (1983). 15. S.A. T i s c h l e r . Ph.D. Thesis. University of B r i t i s h Columbia. Vancouver, B.C. 1981. 16. For example, see the following reviews: (a) P. A. B a r t l e t t . Tetrahedron, 36_, 3 (1980); (b) D.A. Evans, J.M. Takacs, L.R. McGee, M.D. Ennis, D.J. Mathre and J . B a r t r o l i . Pure and Appl. Chem. 53, 1109 (1981); see also reference 17. - 261 -17. S. Hannessian. Total Synthesis of Natural Products: The 'Chiron' Approach. Edited by J.E. Baldwin. Pergamon Press, Oxford. 1983, and references therein. 18. For example, see the following reviews: (a) J.W. ApSimon and R.P. Seguin. Tetrahedron, 3_5, 2797 (1979); (b) W.A. Szabo and H.T. Lee. Aldrichimica Acta, _13_» 1 3 (1980); see also reference 17. 19. W.C. S t i l l and I. Galynker. Tetrahedron, 3J_, 3981 (1981), and references therein. 20. For more detailed descriptions of molecular mechanics see: (a) E. Osawa and H. Musso. Top. Stereochera. _13 , 117 (1982); (b) N.L. A l l i n g e r . Adv. Phys. Org. Chem. 1_3, 1 (1976). 21. N.L. A l l i n g e r . J . Am. Chem. Soc. 99_, 8127 (1977). MM2 i s av a i l a b l e from The Quantum Chemistry Program Exchange, QCPE Program No. 395. Dept. of Chem. Indiana University, Bloomington, In. 47405. 22. N.L. A l l i n g e r and J.T. Sprague. J . Am. Chem. Soc. 9_5, 3893 (1973). 23. For a summary of conformations of germacradienes, see S. Iwasaki and S. Nozoe J J I Natural Product Chemistry. Vol. 1. Edited by K. Nakanishi, T. Goto, S. Ito, S. Natori and S. Nozoe, Academic Press, New York, N.Y. 1974, p. 98. 24. R.W. Doskotch, S.L. Keely, J r . and CD. Hufford. J . Chem. Soc. Chem. Commun. 1137 (1972). 25. W.C. S t i l l . J . Am. Chem. Soc. _101_, 2493 (1979). 26. C. Kuroda, H. Hirota and T. Takahashi. Chem. L e t t . 249 (1982). 27. W.C. S t i l l , S. Murata, G. Revial and K. Yoshihara. J . Am. Chem. Soc. 105, 625 (1983). 28. For example, see H.O. House, Modern Synthetic Reactions. W.A. Benjamin, Inc. Menlo Park, Ca. 1972, p. 588. 29. W.C. S t i l l and I. Galynker. J . Am. Chem. Soc. K)4, 1774 (1982). 30. E. Vedejs and D.M. Gapinski. J . Am. Chem. Soc. 105 , 5058 (1983). 31. J . Dale. Angew. Chem. Int. Ed. Engl. _5, 1000 (1966). 32. E. Vedejs, J.M. Dolphin and H. Mastalerz. J . Am. Chem. Soc. 105, 127 (1983). 33. E.J. Corey, P.B. Hopkins, S. Kim, S. Yoo, K.P. Nambiar, and J.R. Falck. J . Am. Chem. Soc. 101 , 7131 (1979). - 262 -34. E.J. Corey, K.C. Nicolaou and L.S. Meivin J r . J. Am. Chem. Soc. 97 , 654 (1975). 35. W.C. S t i l l , C. Gennari, J.A. Noguez and D.A. Pearson. J . Am. Chem. Soc. \06_, 260 (1984). 36. W.C. S t i l l and V.J. Novack. J . Am. Chem. Soc. J_06_, 1148 (1984). 37. J . (Hardy, J. Finer-Moore, L. Weiler and D.C. Wiley. Tetrahedron, 37, Suppl. No. 1, 91 (1981). 38. A.K. Ganguly, Y.T. L i u , 0. Sarre, R.S. Jaret, A.T. McPhail and A.T. Onan. Tetrahedron L e t t . _21_, 4699 (1980). 39. Y. Okawa, K. Sugano and D. Yonemitsu. J . Org. Chem. 43_, 2087 (1978). 40. J . J . Bloomfield. J. Org. chem. 2_7, 2742 (1962). 41. T.R. Hoye, M.J. Kurth and V. Lo. Tetrahedron L e t t . 22_, 815 (1981). 42. F.L.M. Pattison, W.C. Howell, A.J. McNamara, J.C. Schneider and J.F. Walker. J . Org. Chem. _2j_, 739 (1956). 43. (a) T. Fujisawa, T. Mori, T. Kawara and T. Sato. Chem. L e t t . 569 (1982); (b) T. Sato, T. Kawara, M. Kawashima and T. Fujisawa. Chem. Let t . 571 (1980). 44. A.N. Meldrum. J. Am. Chem. Soc. 93 , 598 (1908). 45. F.C. Uhle, J.E. Krueger and A.E. Rogers. J. Am. Chem. Soc. 78 , 1932 (1956). 46. B. Ganem. J . Am. Chem. Soc. 98_, 224 (1976), footnote 11. We are not aware of any reported syntheses of t h i s compound since 1976. 47. G.I.L. Jones and N.L. Owen. J. Mol. Struct. _18_, 1 (1973). 48. R. Huisgen and H. Ott. Tetrahedron, 6^, 253 (1959). 49. G. I l l u m i n a t i and L. Mandolini. Acc. Chem. Res. _14_, 95 (1981). 50. (a) J . Dale, Acta. Chem. Scand. 27, 1115, 1130 and 1149 (1973); (b) J. Dale. Top. Stereochem. £» 199 (1976). 51. H. Ogura, K. Furuhata, H. Kuwano and M. Suzuki. Tetrahedron, 37, Suppl. No. 1, 165 (1981), and references therein. 52. P. Groth. Acta Chem. Scand. Ser. A, 30, 155 (1976). 53. P. Groth. Acta Chem. Scand. Ser. A, 29 , 374 (1975). - 263 -54. F.A.L. Anet, A.K. Cheng and J . Krane. J . Am. Chem. Soc. 9_5_, 7877 (1973). 55. (a) W.B. Schweizer and J.D. Dunitz. Helv. Chim. Acta, 65, 1547 (1982); (b) A.G. Pinkus and E.Y. L i n . J . Mol. Struct. 24_, 9 (1975) ; see also references 47 and 48. 56. P. Deslongchamps. Stereoelectronic E f f e c t s in Organic Chemistry. Edited by J.E. Baldwin. Pergamon Press, Oxford, 1983. 57. This conformational preference has also been reported by A. McL. Mathieson. Tetrahedron Lett. 4137 (1965). 58. (a) N.S. True and R.K. Bohn. J . Mol. Struct. 3_6, 173 (1977); (b) N.S. True and R.K. Bohn. J . Am. Chem. Soc. 98, 1188 (1976). 59. F.A.L. Anet, A.K. Cheng and J . J . Wagner. J . Am. Chem. Soc. 94 , 9250 (1972). 60. H.R. Rogers, J.X. McDermott and G.M. Whitesides. J. Org. Chem. 4_0, 3577 (1975). 61. (a) S.J. C r i s t o l and W.C. F i r t h , J r . J. Org. Chem. 26, 280 (1961); (b) J.A. Davis, J . Herynk, S. C a r r o l l , J . Bunds and D. Johnson. J . Org. Chem. 30, 415 (1965); (c) J . Cason and D.M. Walba. J. Org. Chem. 37_, 669 (1972). 62. V. Yee, E. Neeland and L. Weiler, unpublished r e s u l t s , 1984. 63. S.N. Huckin and L. Weiler. J . Am. Chem. Soc. 96, 1082 (1974). 64. B. Lammek, W. Neugebauer and G. Kupryszewski. Rocz. Chem. 50, 997 (1976) . 65. M. B a r f i e l d and D.M. Grant. J. Am. Chem. Soc. 85, 1899 (1963). 66. L.F. Fieser and M. F i e s e r . Steroids. Reinhold, New York, N.Y. 1959. 67. E.J. Corey and G. Schmidt. Tetrahedron Lett. 399 (1979). 68. E.J. Corey and J.W. Suggs. Tetrahedron Lett. 2647 (1975). 69. A.S. Narula. Tetrahedron L e t t . 2_2, 4119 (1981) and references therein. 70. H.O. House. Modern Synthetic Reactions. W.A. Benjamin, Inc. Menlo Park, Ca. 1972, p. 501. 71. For example, see D.H. Hunter and D.J. Shearing. J . Am. Chem. Soc. 93, 2348 (1971). - 264 -72. T.H. Lowry and K.S. Richardson. Mechanism and Theory in Organic Chemistry. Harper and Row, New York, N.Y. 1976, pp. 357-361. 73. L.M. Jackman and S. St e r n h e l l . NMR Spectroscopy i n Organic Chemistry. Pergamon Press, Oxford, 1969, p. 88. 74. H. Gerlach. Helv. Chim. Acta. _57_> 2661 (1974) and private communication with H. Gerlach. 75. B.H. Lipshutz. Tetrahedron L e t t . 2_4, 127 (1983). 76. Y. Yamamoto, S. Yamamoto, H. Yatagai, Y. Ishihara and K. Maruyama. J. Org. Chem. 47_, 119 (1982). 77. (a) H.O. House, Acc. Chem. Res. 9_» 59 (1976); (b) H.O. House and J.M. Wilkins. J. Org. Chem. 43_, 2443 (1978); (c) H.O. House, L.E. Huber and M.J. Umen. J . An. Chem. Soc. 94_, 8471 (1972). 78. F.W. Sum and L. Weiler. Can. J. Chem. 57_, 1431 (1979). 79. W.R. McKay and L. Weiler, unpublished r e s u l t s , 1981. 80. F.W. Sum, Ph.D. Thesis. Un i v e r s i t y of B r i t i s h Columbia, Vancouver, B.C., 1979. 81. (a) J . Drouin, F. Leyendecker and J.M. Conia. Nouv. J. Chim. 2_, 267 (1978); (b) J.P. Barnier and L. Weiler, unpublished r e s u l t s , 1979; (c) M. Alderdice, C. Spino and L. Weiler. Tetrahedron L e t t . 25, 1643 (1984). 82. L.F. Fieser and M. Fi e s e r . Reagents for Organic Synthesis. V o l . 1. John Wiley and Sons, New York, N.Y. 1967, p. 137. 83. L.M. Jackman and S. St e r n h e l l . NMR Spectroscopy i n Organic Chemistry. Pergamon Press, Oxford. 1969, p. 272. 84. L.M. Jackman and S. S t e r n h e l l . NMR Spectroscopy i n Organic Chemistry. Pergamon Press, Oxford, 1969, p. 99. 85. D.H. Williams and I. Fleming. Spectroscopic Methods in Organic Chemistry. 2nd edn. McGraw-Hill Book Company (U.K.) Limited, London, 1973, pp. 96-100. 86. W.C. S t i l l , M. Kahn and A. Mitra. J. Org. Chem. 4_3, 2923 (1978). 87. (a) S.C. Watson and J.F. Eastham. J. Organoraet. Chem. 9_, 165 (1967); (b) A l f a . J. Org. Chem. 46 (9), 2A (1981). 88. J . J . Bloomfield. J . Org. Chem. 27_, 2742 (1962). 89. M. Sheehan, R.J. Spangler and C. D j e r r a s i . J . Org. Chem. _36^  3526 (1971). - 265 -90. C. Moureux and R. Chaux. Org. Synth. C o l l . V o l. 1, 166 (1941). 91. L.F. Fieser and M. Fi e s e r . Reagents for Organic Synthesis. Vol. 1, John Wiley and Sons, New York, N.Y. 1967, p. 135. 92. R. Toubiana and J. Asselineau. Ann. Chim. 7_, 9 (1962). 93. S.A. T i s c h l e r . Ph.D. Thesis. University of B r i t i s h Columbia, Vancouver, B.C., 1981, p. 226. 94. W.R. Busing, K.O. Martin and H.A. Levy. ORFLS Report ORNL-TM-305, Oak Ridge National Laboratory, Tennessee, 1962. 95. L.F. Fieser and M. Fieser. Reagents for Organic Synthesis, V o l . 1. John Wiley and Sons. New York, N.Y. 1967. p. 1180. 96. G. B. Kauffman and L.A. Teter. Inorg. Synth. ]_, 9 (1963). 97. R. Kaiser and D. Lamparsky. Helv. Chim. Acta., 61_, 2671 (1978). 98. W.P. Bryan and R.H. Byrne. J . Chem. Ed. 4J_, 361 (1970). 99. L.F. Fieser and M. Fi e s e r . Reagents for Organic Synthesis. Vol. 1. John Wiley and Sons. New York, N.Y. 1967, pp. 135-137. 100. A. Ichihara, K. Oda, M. Kobayashi and S. Sakamura. Tetrahedron, 36 , 183 (1980). - 266 -APPENDIX A DERIVATION20 OF THE RATE EQUATION log[A] = k A /k B logl»l + The rate equations which govern the reactions involving a mixture of compounds A and B are given in Equations 4 and 5. The reactions are ^AL = - y A ] [ C ( t , A0, B 0)] (4) i g L - -k [B] [C(t, A Q , B 0 ) ] (5) b not f i r s t order. They are dependent on the concentrations of the react-ants A and B, and on the concentration of C, which is a complex func-tion, i t s e l f dependent on time t, the i n i t i a l concentrations of A and B, A Q and B0, and on the concentrations of the reagents involved in the reactions. If A and B are treated under the same reaction conditions (as they are when the reaction is conducted on a mixture of the two components), the function C wi l l be identical in Equations 4 and 5. Equation 4 divided by Equation 5 gives d[A]/dt = ^A [A]_ d[B]/dt k B [B] We are grateful to Dr. E. Ogryzlo for helpful discussions of this derivation. - 267 -d [ A ] _ *k d[B] [A] " k f i [B] Integration of both sides gives £n [ A ] - £n AQ = k A/k f i (£n[B] - £n B Q) or £n [ A ] = k A/k f i £n[B] + (£n AQ - k A / k g £n B Q) (6) A p l o t of £n [ A ] vs £n[B] w i l l have a slope of k^/kg (the r e l a t i v e rate of reaction of A and B) and an intercept of (£n A - k A/k„ £n B ) . o A o O The i n t e r n a l consistency of t h i s equation can be checked by s u b s t i t u t i n g values obtained from experiment. The data in Table 2 for the formation of sulfonates 160 and 161 gives log(% alcohol 147) at time zero to be 1 .453 and log (% alcohol 146) to be 1 .844. The plot of l o g ( % alcohol 147) vs log(% alcohol 146) has a slope of 0 .96 (calculated by least squares a n a l y s i s ) . The intercept should therefore be ^ 4 7 log(% alcohol 147) - log(% alcohol 146) V46 = 1.453 - 0 . 9 6 x 1.844 = - 0 . 3 2 Least squares analysis gave the intercept to be - 0 . 3 3 , demonstrating that Equation 6 i s i n t e r n a l l y consistent. - 268 -APPENDIX B SPECTRAL APPENDIX For some compounds, both 80 and AOO MHz nmr spectra were recorded. In these cases, the 400 MHz nmr spectrum can be found on the page following the i r and 80 MHz nmr spectra of the compound. - 269 -- 270 -- 272 -- 273 -- 274 -- 275 -- 276 -- 277 -- 278 -- 279 -rntouttfCY (CM"*} - 281 -- 282 -- 283 -- 284 -- 285 -- 286 -- 287 -- 288 -- 289 - 290 -- \6Z -- 292 - 293 - 294 -- 295 -- 2 9 6 -- 297 -- 298 " PRCOUCMCr ICM 'I - 300 " - 302 -- 303 -- 304 -- 305 -- 306 -- 307 - 308 -4000 3*00 1100 1S00 3400 1000 1100 1*00 I4O0 11O0 I OOO MM *O0 PHCOUENCV icm") - ne -- 312 -- 313 -- 314 -

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