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Conformationally controlled reactions of unsaturated macrocyclic lactones and keto lactones Fenster, Erik 2000

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C O N F O R M A T I O N A L L Y C O N T R O L L E D R E A C T I O N S O F U N S A T U R A T E D M A C R O C Y C L I C L A C T O N E S A N D K E T O L A C T O N E S by ERIK FENSTER B. Sc. (Hons.), McGill University, 1997 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard The University of British Columbia June 2000 © Erik Fenster, 2000 in presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department The University of British Columbia Vancouver, Canada Date "Xj ^SJZJCD DE-6 (2/88) II A B S T R A C T As part of a study of the chemistry of macrocyclic compounds in our laboratory, the 14-membered unsaturated lactones 29 and 30 were synthesized with high stereoselectivity (>16:1 EIZ) via the ring closing olefin metathesis (RCM) reaction of the open chain diene esters. The configuration of the double bond in these unsaturated lactones was determined by 1H homonuclear decoupling NMR experiments. Equilibrium studies demonstrated that the RCM reaction proceeds under thermodynamic control in the cases of 29 and 30. The keto lactones 67 and 68 were synthesized via the hydroboration of 30 followed by TPAP oxidation of the hydroxy lactone products. The conformationally controlled reactions of the macrocyclic lactones 29, 30, 67 and 68 were investigated. Treatment of the unsaturated lactone 29 with borane tetrahydrofuran complex, disiamylborane and 9BBN led to the formation of the hydroxy lactones 47 and 48 in a 1:1 regioisomeric ratio. Treatment of the unsaturated lactone 30 with the same hydroborating reagents led to the formation of the hydroxy lactones 51, 52, 53 and 54 in a 1:1 regioisomeric ratio but with good 7r-face selectivity (>7:1 using 9BBN). The epoxidation of 30 using MCPBA and methyl(trifluoromethyl)dioxirane, leading to epoxides 63 and 64 also showed moderate 7t-face selectivity (>3:1 using MCPBA at -78 °C). Treatment of keto lactones 67 and 68 with NaBH4 and K-Selectride under a variety of reaction conditions led to the formation of hydroxy lactones 52, 53 and 51, 54, respectively. The hydroxy lactones were obtained in good stereoselectivity (>10:1 using K-Selectride at -78 °C) in the case of 67, and in low stereoselectivity (1:1.5 using K-Selectride at -78 °C) in the case of 68. In general, the stereoselectivity exhibited in the reactions of these macrocyclic lactones could be rationalized from the conformational analysis of the starting materials or the products. The relative stereochemistry of the stereogenic centers within the compounds synthesized during the course of the project were successfully assigned with the use of chemical correlations and X-ray analysis. iv T A B L E O F C O N T E N T S ABSTRACT ii TABLE OF CONTENTS iv LIST OF SCHEMES vi LIST OF FIGURES vii LIST OF TABLES ix LIST OF ABBREVIATIONS x ACKNOWLEDGEMENTS xii CHAPTER 1 INTRODUCTION 1 1.1 Early Conformational Analysis Studies of Small Ring Systems 1 1.2 Conformational Analysis of Medium and Large Ring Compounds 5 1.3 Remote Asymmetric Induction in Medium and Large Rings 10 1.4 Conformationally Controlled Reactions in Macrolide Synthesis 15 1.5 Ring Closing Olefin Metathesis 19 CHAPTER 2 RESULTS AND DISCUSSION 22 2.1 Synthesis of (7£)-13-Tridec-7-enolide (29) and (7E)-13-Tetradec-7-enolide (30) 23 2.1.1 Synthesis of 6-Hepten-1-ol (34) 24 2.1.2 Synthesis of 7-Octenoic acid (33) 25 2.1.3 Synthesis of 7-Octen-2-ol (29) .....26 2.1.4 Ring Closing Olefin Metathesis (RCM) of 6-Heptenyl-7'-Octenoate (31) and 1-Methyl-6-Heptenyl-7'-Octenoate (32) 26 V 2.2 Regio- and Stereoselectivity Studies on (7£)-13-Tridec-7-enolide (29) and (7E)-13-Tetradec-7-enolide (30) 32 2.2.1 Hydroboration Studies on (7£)-13-Tridec-7-enolide (29) 32 2.2.2 Conformational Analysis of (7£)-13-Tridec-7-enolide (29) 35 2.2.3 Hydroboration Studies on (7£)-13-Tetradec-7-enolide (30) 37 2.2.4 Epoxidation Studies on (7£)-13-Tetradec-7-enolide (30) 44 2.2.5 Conformational Analysis of (7E)-13-Tetradec-7-enolide (30) 45 2.3 Stereoselectivity Studies on 7-Oxo-13-Tetradecanolide (67) and 8-Oxo-13-Tetradecanolide (68) 50 2.3.1 Hydride Reduction Studies on 7-Oxo-13-Tetradecanolide (67) 51 2.3.2 Hydride Reduction Studies on 8-Oxo-13-Tetradecanolide (68) 52 2.3.3 Conformational Analysis of 7-Oxo-13-Tetradecanolide (67) and of 8-Oxo-13-Tetradecanolide (68) 53 2.4 Conclusion 58 CHAPTER 3 EXPERIMENTAL 59 3.1 General 59 3.2 Conformational Analysis Methods 61 3.3 Chemical Methods 62 References 93 Appendices 98 Appendix I Description of Polar Maps 98 Appendix II Representative Chromatographs 100 Appendix III Spectral Appendix 105 vi L I S T O F S C H E M E S Scheme 1 The synthesis of 3-deoxyrosaranolide using macrocyclic stereocontrol 17 Scheme 2 Conformationally controlled reactions in the synthesis of dihydroerythronolide (24) 18 Scheme 3 Mechanism for the ring closing olefin metathesis reaction 20 Scheme 4 Retrosynthetic analysis of (7£)-13-tridec-7-enolide (29) and (7£)-13-tetradec-7-enolide (30) 24 Scheme 5 Synthesis of 6-hepten-1 -ol (34) 25 Scheme 6 Synthesis of 7-octenoic acid (33) 25 Scheme 7 Synthesis of 7-octen-2-ol (35) 26 Scheme 8 Synthesis of (7£)-13-tridec-7-enolide (29) and (7£)-13-tetradec-7-enolide (30) 27 Scheme 9 Hydroboration of (7£)-13-tridec-7-enolide (29) 32 Scheme 10 Separation of hydroxy lactones 47 and 48 33 Scheme 11 Hydroboration of (7£)-13-tetradec-7-enolide (30) 37 Scheme 12 Separation of hydroxy lactones 51, 52, 53, and 54 38 Scheme 13 Chemical correlations used in the structural identification of carbamate derivatives 55, 56, 57 and 58 40 Scheme 14 Synthesis of 7-oxo-13-tetradecanolide (67) and 8-oxo-13-tetradecanolide (68) 50 VII L I S T O F F I G U R E S Figure 1 Sachse's rigid (A) and flexible (B) conformations of cyclohexane 2 Figure 2 Interconversion of the monosubstituted rigid forms of cyclohexane, as proposed by Sachse 2 Figure 3 The structures of frans-decalin (A) and c/s-decalin (B) according to Mohr 3 Figure 4 Esterification of neomenthol (1) and menthol (2) 4 Figure 5 Conformational equilibrium for neomenthol (1) and neoisomenthol (3) • 4 Figure 6 The conformation of cis-1,6-diaminocyclodecane dihydrochloride 6 Figure 7 The diamond lattice conformation of cyclodecane 7 Figure 8 The strain-free diamond lattice conformation of cyclotetradecane 8 Figure 9 Transannular hydrogen interactions in cyclotetradecane 8 Figure 10 The definition of a corner position in a macrocyclic system 9 Figure 11 Conformations of 2,7-dimethylcyclooctanone and the enolates of 3-methylcyclooctanone 12 Figure 12 Epoxidation of the low energy conformation of unsaturated lactone 8 13 Figure 13 Diastereofacial selectivity in cyclohexene and cyclotetradecene 13 Figure 14 Local conformer effect in the epoxidation of (E)-3-methylcyclodecene (10) 14 Figure 15 Relay assembling of the reactive sites (A) and sources of unproductive complexes (B and C) in ring closing olefin metathesis 21 Figure 16 The global minimum energy conformations of tridecanolide (45) and 13-tetradecanolide (46) 30 Vlll Figure 17 Local conformation around the double bond in (7£)-13-tridec-7-enolide (29) 36 Figure 18 Polar maps of the three lowest energy conformations of (7£)-13-tridec-7-enolide (29) 36 Figure 19 ORTEP representation of (7FT, 13S*)-7-(A/-phenylcarbamoyl)oxy-13-tetradecanolide (57) 42 Figure 20 Local conformation around the olefinic double bond in (7£)-13-tetradec-7-enolide (30) 46 Figure 21 Polar maps of the three lowest energy conformations of (7E)-13-tetradec-7-enolide (30) 46 Figure 22 Low energy conformations of (7E)-13-tetradec-7-enolide (30) and the corresponding predicted hydroboration products 48 Figure 23 Low energy conformations of 7-oxo-13-tetradecanolide (67) and the corresponding predicted reduction products 55 Figure 24 Low energy conformations of 8-oxo-13-tetradecanolide (68) and the corresponding predicted reduction products 56 Figure 25 The polar map convention for a 14-membered macrocycle 98 ix L I S T O F T A B L E S Table 1 The Three Lowest Energy Conformations of Cyclotetradecane 10 Table 2 The Ring Closing Olefin Metathesis of Diene Esters 31 and 32 28 Table 3 Equilibrium Studies on Unsaturated Lactones 29 and 30 31 Table 4 Hydroboration Study on (7E)-13-Tridec-7-enolide (29) 34 Table 5 The Three Lowest Energy Conformations of 29 35 Table 6 Hydroboration Study on (7E)-13-Tetradec-7-enolide (30) 43 Table 7 Epoxidation Study on (7£)-13-Tetradec-7-enolide (30) 44 Table 8 The Three Lowest Energy Conformations of 30 45 Table 9 Hydride Reduction Study on 7-Oxo-13-tetradecanolide (67) 51 Table 10 Hydride Reduction Study on 8-Oxo-13-tetradecanolide (68) 52 Table 11 The Three Lowest Energy Conformations of 67 54 Table 12 The Three Lowest Energy Conformations of 68 54 L I S T O F A B B R E V I A T I O N S AIBN azobis(isobutyronitrile) 9BBN 9-borabicyclo[3.3.1]nonane bp boiling point Bu butyl C x carbon (where x represents the number of the carbon atom) calcd calculated CI chemical ionization cone. concentrated d doublet 8 chemical shift D C C 1,3-dicyclohexylcarbodiimide DCI desorption chemical ionization DHP dihydropyran DMAP 4-dimethylaminopyridine D M S O dimethyl sulfoxide El electron ionization Et ethyl EtOAc ethyl acetate FT Fourier transform G C gas chromatography HPLC high performance liquid chromatography HRMS high resolution mass spectrum or spectroscopy IR infrared (spectroscopy) J coupling constant Kcal kilocalorie K-Selectride potassium tri- sec-butylborohydride xi L R M S low resolution mass spectrum or spectroscopy m multiplet M moles per litre (concentration) M + parent mass (mass spectra) M C P B A mefa-chloroperbenzoic acid Me methyl MM molecular mechanics mp melting point Ms methylsulfonyl m/z mass-to-charge ratio NMO 4-methylmorpholine A/-oxide 1 H NMR nuclear magnetic resonance (proton) 1 3 C NMR nuclear magnetic resonance (carbon) Ph phenyl ppm parts per million P P T S pyridinium para-toluenesulfonate R C M ring closing olefin metathesis Rf retention factor or ratio to front rt room temperature s singlet Sia2BH disiamylborane t triplet T B D M S tert-butyldimethylsilyl T E S triethylsilyl THF tetrahydrofuran TLC thin-layer chromatography TMS trimethylsilyl T P A P tetrapropylammonium perruthenate Ts para-toluenesulfonyl Xll A C K N O W L E D G E M E N T S First and foremost, I would like to thank Professor Larry Weiler, my research supervisor, for his guidance, encouragement, insight and patience throughout the course of my studies. Although my relationship with Professor Weiler was shortened by his unexpected and unfortunate passing in April 1999, I have learnt a great amount from his teachings and his uncompromising dedication to excellence in research. Professor Weiler was an exceptional educator and I am privileged to have been a member of his research lab. In this respect, I am indebted to Dr. Michael Pungente for taking over the supervision of the Weiler lab, for helpful discussions and suggestions, and for the proofreading and the correcting of this thesis. I also thank Professor Gregory Dake for valuable insight and suggestions in the last ten months of my work, and in the writing of my thesis. Many thanks to past and present members of the Weiler group for their friendship and useful discussions. In particular, special thanks to William Goldring for answering my many questions on the metathesis section of my work and for valuable help with the molecular mechanics calculations, as well as to Hong Ping Yu for practical discussions on conformational analysis. I am indebted to the service personal of the Chemistry Department including the NMR laboratory (Liane and Marietta), Mass Spectrometry Laboratory, and Microanalysis Laboratory (Mr. Peter Borda). In addition, I am grateful for the X-ray analysis performed by Dr. Brian Patrick. Finally, I would like to thank the many friends I have had the opportunity to have known during the course of my work at the University of British Columbia, which have made my time here just a little more enjoyable. To my aunt, uncle, and grandparents 1 C H A P T E R 1 I N T R O D U C T I O N Ever since the demonstration of the importance of conformation to chemical reactivity by Hassel1 ,2 and Barton,3 conformational analysis has become an integral part of organic chemistry. Today, conformational analysis is widely used in the interpretation of steric and electronic effects in organic compounds, and of chemical transformations and mechanisms. 1.1 Early Conformational Analysis Studies of Small Ring Systems In the late 19th century, the concept of conformation in organic molecules began to develop. This originated with the tetrahedral geometry theory for the carbon atom independently reported by van't Hoff4 and Lebel5 in 1874. Baeyer further extended this hypothesis to cyclic systems in 1885.6 In his ring strain theory, carbon atoms which make up a ring are coplanar and the preferred ring angle should be 109.5° in accordance with carbon's tetrahedral geometry. Therefore, internal ring angles which deviated from this ideal angle would introduce strain into the ring system. Cyclopentane was then expected to have the least amount of ring strain (ring angle 108°), whereas smaller as well as larger rings would progressively have an increasing amount of ring strain. Heats of combustion data7 confirmed Baeyer's theory for cyclopropane up to and including cyclopentane, but larger ring systems possessed less ring strain than expected, and cyclohexane, remarkably, showed no ring strain. In addition to the concept of the tetrahedral arrangement for carbon, van't Hoff further suggested that carbon atoms connected by a single bond could freely rotate and give rise to new arrangements in space.4 Baeyer chose to ignore this theory of free rotation, 2 and the oversight led to the eventual breakdown of his theory. However, the ring strain theory was widely accepted early on. A B Figure 1. Sachse's rigid (A) and flexible (B) conformations of cyclohexane.8,9 The apparent inconsistency of cyclohexane's strain-free state was resolved by Sachse in 1890. Rejecting Baeyer's planar model, Sachse postulated that cyclohexane existed in two conformations.8,9 These were named the rigid or symmetric form and the flexible or asymmetric form (Figure 1). This postulation incorporated the ideas of the tetrahedral carbon geometry as well as bond rotation put forth by van't Hoff. Sachse further believed that two monosubstituted forms of the rigid conformation were possible and that they could be interconverted (Figure 2). Figure 2. Interconversion of the monosubstituted rigid forms of cyclohexane, as proposed by Sachse. In 1918, Mohr10 demonstrated that the Sachse conformations for cyclohexane were interchangeable by rotation about single bonds. Mohr further predicted the existence of decalin as two fused chair isomers, with the trans isomer predominating over the cis form (Figure 3). This again was in contradiction with Baeyer's theory since two planar 6-membered rings can only 3 H H H 1 H A B Figure 3. The structures of trans-decaWn (A) and c/s-decalin (B) according to Mohr. 1 0 All but the bridgehead hydrogen atoms have been omitted for clarity. be fused cis and, consequently, a planar irans-decalin molecule was not expected to exist or at the least be less favored than the cis isomer. The Baeyer strain theory was nevertheless well accepted until Huckel demonstrated in 1925 the existence of the decalin molecule as an interconvertible mixture of cis and trans isomers. 1 1 Two decades later Hassel showed experimentally the distinction between the axial and equatorial bonds. 1 However, it was Barton's work in 1950 on the conformational analysis of cyclohexanes, including the steroid nucleus, which lead to the widespread acceptance of the chair form of cyclohexane and its use in conformational analysis. 3 Barton in fact viewed the steroids as a series of fused Sachse-Mohr cyclohexane chair conformations in order to correctly explain ester hydrolysis rates, eliminations and product ratios in such systems. He was also able to explain results of reactions involving polysubstituted cyclohexanes. For example, in the case of neomenthol (1) and menthol (2), Barton suggested that the difference in rates of esterification was due to the difference in steric environment of the two reacting substituents (Figure 4). The hydroxyl substituent in neomenthol (1) occupies an axial position whereas the hydroxyl in menthol (2) occupies an equatorial position. Barton correctly predicted that since axial substituents are more hindered due to transannular interactions with other axial bonds, the equatorial hydroxyl should be more easily esterified. 4 R ^ \ ^ — - " " X slow _ - C H 3 R'COOH y ^ ~ - - V - C H 3 OH R'COO 1 — \ fast , R ^ Y " \ H O A ^ — ^ C H 3 R'COOH R ' C O O A ^ ^ ^ - CHq Figure 4. Esterif ication of neomenthol (1) and menthol (2) (R = i-Pr). However, Barton's work was limited to compounds that exist predominantly in one conformation. In 1953, Eliel demonstrated the complexi t ies that can ar ise in conformationally mobile sys tems (Figure 5 ) . 1 2 He noted that neoisomenthol (3) undergoes esterification at three t imes the rate of neomenthol (1). Th is rate difference can only be expla ined if the reaction occurs with the less stable conformations 1a and 3a. Th is is expected due to the severe crowding of the axial hydroxyl group of 3 compared to that of 1. The equil ibrium constant for 3 and 3a is expected to be larger than for 1 and 1a s ince the conformational analys is reveals two alkyl groups which must occupy axial posit ions in 3. Assum ing 1a and 3a have the same reactivity, Eliel then reasoned that 3a is esterif ied faster than 1a because of its larger equil ibrium concentrat ion. This O H — C H 3 R H C H 3 1 1a C H 3 R OH 3a Figure 5. Conformat ional equil ibrium for neomenthol (1) and neoisomenthol (3) (R = i-Pr). 5 example demonstrated that the preferred ground state conformations cannot always be used to predicted reaction rates. The relationship between ground state conformation of the reactant and the product distribution was established by Curtin a year later.13 The Curtin-Hammett Principle dictates that in a reaction that yields one product from one conformational isomer and a different product from another conformational isomer (and providing that these two isomers are rapidly interconvertible) the product composition is not solely dependent on the relative proportions of the conformational isomers in the substrate; it is controlled by the difference in the standard Gibbs free energies of the respective transition states. These early conformational studies did not take into account ring systems larger than cyclohexane since most chemists believed such larger systems behaved more closely to linear alkanes. However, the work performed by Barton, Eliel and others has allowed for a profound understanding of not only cyclic and heterocyclic chemistry, but also of chemical reactivity in general. 1.2 C o n f o r m a t i o n a l A n a l y s i s o f M e d i u m a n d L a r g e R i n g C o m p o u n d s The first macrocyclic compounds were discovered by Ruzicka in 1926, while investigating the components of musk oil. 1 4 , 1 5 Civetone 4 and Muscone 5 were isolated and their structures elucidated by careful chemical degradation and comparison of the fragments with known compounds. o 4 5 6 The discovery of these compounds further revealed the inadequacies of the Baeyer strain theory,6 since it predicted that large ring compounds would be too unstable to exist due to overextension of internal bond angles. The research into these musk oil components was of twofold importance. First, these compounds were of high commercial value in the fragrance industry, and second, little was known about the chemical and physical properties of these large ring compounds. Research into macrocyclic compounds continued through the efforts of Ruzicka1 6 , 1 7 and Prelog,18 who synthesized and investigated the properties of large ring hydrocarbons, alcohols and ketones. This research revealed an unexpected and interesting dependency of the physical and chemical properties of macrocyclic compounds on ring size. For example, the curve of melting point versus ring size did not increase steadily as for aliphatic acyclic hydrocarbons.16"18 It was not until 1961 when Dunitz and co-workers19 provided some understanding of the conformational details that control these phenomena. X-ray diffraction of a variety of cyclodecane derivatives showed that these compounds all crystallized in a common conformation (Figure 6). This was a surprising result since it was believed that the cyclodecane ring system was highly flexible and that it existed in many conformations. Dunitz concluded that this common conformation of the ring skeleton must represent a potential energy minimum. + N H 3 c r Figure 6. The conformation of cis-1,6-diaminocyclodecane dihydrochloride.19 Two years later, Dale noticed that the solid state conformation of the cyclodecane system was superimposable on the diamond lattice (Figure 7). 2 0 , 2 1 This diamond lattice represents a network of ideal bond lengths and bond angles. 7 It follows that any conformation that is superimposable on the diamond lattice exhibits a minimum in the angle and torsion strain. F i g u r e 7. The diamond lattice conformation of cyclodecane. Using molecular models, Dale was able to predict the low energy conformations of all even-membered cycloalkanes C-6 to C i 6 . In doing so, Dale arrived at two important conclusions: 1) Cycloalkanes containing an odd number of carbon ring atoms do not possess strain-free energy conformations since these cannot be superimposed on the diamond lattice. 2) Cycloalkanes possessing between 7 and 13 carbon ring atoms cannot have a strain-free conformation since a diamond lattice conformation for these systems results in too close an approach between internal hydrogens. Even though the conformation of cyclodecane was shown by Dunitz to follow the diamond lattice quite closely, it clearly demonstrated a compromise between angle strain, torsional energy, and transannular hydrogen repulsion. Subsequently, theoretical calculations and X-ray crystallography showed Dale's predictions to be accurate. For example, the strain-free conformation derived from the diamond lattice has been found experimentally to be similar to the solid state conformation for cyclotetradecane (Figure 8). 2 2 , 2 3 8 side view top view Figure 8. The strain-free diamond lattice conformation of cyclotetradecane (* denotes corner position). Dale further noticed that these low energy macrocyclic conformations exhibit a common feature. When viewed from the top, as illustrated for cyclotetradecane in Figure 8, four "corners" of a rectangular contour can be distinguished. Dale recognized that the hydrogens bonded to these corner atoms are directed away from the ring and suffer the least number of steric interactions (Figure 9). These are the only positions on the ring which can therefore accommodate two geminal substituents without causing severe transannular interactions. 2 4 Figure 9. Transannular hydrogen interactions in cyclotetradecane (* denotes corner position). 9 A corner position in a macrocycle was defined as having 2 adjoining gauche dihedral angles of the same sign flanked on either side by an antidihedral angle (Figure 10).20'25 Figure 10. The definition of a corner position in a macrocyclic system (* denotes corner position). From these observations, Dale also devised a nomenclature system to describe macrocyclic conformations.25 He used a set of brackets with a series of numbers, in which the numbers indicate the number of bonds between each corner position. The ring is named such that the smallest number is listed first within the brackets. Therefore, the diamond lattice conformation for cyclotetradecane is named [3434] (Tablel). Initially, Dale considered only those ring conformations which were superimposable on a diamond lattice. However, calculations on cyclotetradecane, first using modified Dreiding models on a semi-quantitative scale25 and then molecular mechanics,26 revealed two additional low energy conformations which were not superimposable on the diamond lattice.27 These were designated the [3344] and [3335] conformations (Table 1) and were calculated to have strain energies of 1.1 kcal/mol and 2.4 kcal/mol respectively, relative to the [3434] conformation. •10 Table 1. The Three Lowest Energy Conformations of Cyclotetradecane. Conformation [3434] [3344] [3335] a Strain energy is reported relative to the lowest energy conformation. 1.3 Remote Asymmetric Induction in Medium and Large Rings The control of newly generated stereocenters remains an interesting and challenging subject of organic chemistry. While the control of vicinal and 1 , 3 -asymmetric induction is well known, the stereocontrol of more remote centers often presents a greater challenge. The work of Barton3 and Eliel12 introduced 11 the aspects of conformationally controlled reactions in cyclohexane systems. With the realization that medium and large ring compounds also exist in well defined conformations, research into the conformationally controlled reactions of macrocycles has progressed over the last twenty years. The use of conformational control in the construction of remote asymmetric centers in medium and large rings was first studied by Still and Galynker in the early nineteen-eighties.28 With the aid of molecular mechanics calculations,29 a simple model was established to estimate product distributions. Using the Hammond postulate,30 product ratios were assumed to be closely related to the conformational energies of starting materials (early transition state) or products (late transition state). By calculating the conformational energy of the starting materials, intermediates and products, it was possible to quantitatively predict product distributions. An example of Still and Galynker's work is the alkylation of 3-methylcyclooctanone (6).28 Deprotonation with lithium diisopropylamide followed by addition of methyl iodide afforded the cis dimethylated product 7 with 98% selectivity over the trans product. This selectivity could not be explained by the strain energies of the enolate intermediate conformations since 6d, which yields the trans product, is similar in energy to 6a and 6c, which yield the cis product (Figure 11). However a Boltzman distribution for the product conformations yields a result which agrees with the observed selectivity. 6 7 12 0.0 kcal/mol 1.7 kcal/mol 2.9 kcal/mol 2.3 kcal/mol Figure 11 . Conformations of 2,7-dimethylcyclooctanone and of the enolates of 3-methylcyclooctanone. Another interesting and more recent example of conformational controlled reactions involving medium rings is the epoxidation of the unsaturated lactone 8 with MCPBA, which produced 9 as a single diastereomer in 81% yield.31 The calculated low energy conformation of 8 shows that the MCPBA reagent preferentially attacks from one face of the olefinic function (Figure 12). O O 8 9 13 8 Figure 12. Epoxidation of the low energy conformation of the unsaturated lactone 8. This result demonstrates an interesting aspect of olefinic functions in medium and large ring compounds. In contrast to cyclohexene, larger ring molecules contain sp2 centers which are usually perpendicular to the ring. This arrangement provides two diastereospecific faces which are highly different. An examination of Figure 13 illustrates that the two faces of the double bond in c/'s-cyclohexene are equivalent. On the other hand, the diamond lattice conformation of cyclotetradecene reveals that face B is severely hindered by the transannular hydrogen interactions and the carbon atoms of the ring. Therefore, Still realized that reagents should approach the n system of a macrocyclic alkene largely or perhaps exclusively from the periphery of the ring.28 Figure 13. Diastereofacial selectivity in cyclohexene and cyclotetradecene. 14 Following the work of Stills and Galynker, Vedejs and coworkers developed a modified approach in order to predict diastereoselective reactions of macrocycles containing olefinic functions.32,33 The local ring segment containing the alkene tends to adopt only certain conformations which control the stereochemical outcome of the reaction. Epoxidation and osmylation studies have shown this approach to be very successful.32,33 An example of this local conformer approach developed by Vedejs and coworkers is the epoxidation of (E)-3-methylcyclodecene (10).32 The local conformer prediction on 10a by peripheral attack of the reagent would produce epoxide 11. In fact, a 6:1 mixture of epoxides was obtained experimentally upon treatment of 10 with MCPBA, the major isomer 11 having the predicted relative stereochemistry (Figure 14). H 3 C 10a Figure 14. Local conformer effect in the epoxidation of (E)-3-methylcyclodecene (10). Our own laboratory has been studying the conformationally controlled reactions in simple 14- and 16-membered macrocyclic systems. Notably, high diastereoselectivity has been obtained for hydride reduction,34"37 alkylation,34,38,39 and hydroboration40 reactions of macrocyclic lactones and lactams. For example, the diastereoselectivity obtained in the hydride reduction of 9-oxo-13-15 tetradecanolide (12), yielding a 9:1 product mixture of 13 and 14, respectively, demonstrates the conformational control of a macrocyclic system in which the reacting center is remote from the stereogenic center.35 12 13 14 1.4 Conformationally Controlled Reactions in Macrolide Synthesis The first macrolide antibiotic to be discovered, pikromycin (15) was isolated in 1950 from a strain of streptomyces.41 Since this discovery, a number of macrolide compounds which have medicinal properties have been isolated. With the realization of the importance of macrolide antibiotics to the pharmaceutical industry, much attention has been focussed on the isolation and synthesis of macrolides in the past fifty years 4 2 O R = desosaminyl 15 16 One important sub-group of macrolide antibiotics is the polyoxo-macrolides. These are structurally characterized by a 12, 14 or 16 membered lactone ring with one or more deoxy-sugars attached and up to 12 asymmetric centers incorporated into the aglycone. The large number of stereocenters has remained a formidable challenge in the total synthesis of these molecules.43"47 However, a number of research groups have explored the use of conformational bias in large rings to control the stereochemical and regiochemical outcome in the synthesis of macrolides. Still and Novack were the first to display the use of macrocyclic stereocontrol in their synthesis of 3-deoxyrosaranolide (16) (Scheme 1) 4 8 The 16-membered ring of the target structure was first prepared by a Horner-Emmons cyclization to give the keto-macrolide 17, containing two stereogenic centers. The six remaining stereocenters necessary to achieve the target 16 were created using conformationally controlled reactions. Kinetic deprotonation of 17 at C 8 followed by methylation gave 18 with better than 95% stereoselectivity. The C 6 side chain was then introduced by alkylation of the kinetically generated enolate to give 20 with better than 95% regioselectivity and 85% stereoselectivity. Initially, an attempt to introduce the methyl substituent at C 4 yielded the incorrect 4ff diastereoisomer, although with high stereoselectivity (>97%). Alternatively, the enolate of 20 was quenched with formaldehyde, followed by dehydration via the mesolate to afford the exocyclic methylene ketone 21. Conjugate addition of thiophenolate to 21 followed by desulphurization afforded compound 22 with better than 95% stereoselectivity. Ester hydrolysis and sodium borohydride reduction of the derived mixed anhydride then gave the desired C 5 alcohol 23 with 83% stereoselectivity. Finally, oxidation at C 9 , epoxidation of the alkene at C12/C13 (83% stereoselectivity) and selective oxidation of the primary hydroxyl group gave 3-deoxyrosaranolide (16). 17 Scheme 1. The synthesis of 3-deoxyrosaranolide using macrocyclic stereocontrol. In a second example, Paterson and Rawson successfully prepared (+)-(9S)-dihydroerythronolide (24) using a combination of acyclic and macrocyclic stereocontrol.49 Scheme 2 demonstrates how four of the ten stereocenters were introduced using the conformational bias of the ring. 18 1) 0 s 0 4 , NMO 2) Na 2S 2 0 5 27 24 Scheme 2. Conformationally controlled reactions in the synthesis of dihydroerythronolide (24).49 Osmylation of the intermediate 25 occurred with 100% 71-face selectivity to yield 26. This was followed by reduction of the C 5 ketone and deprotection of the silyl ethers to yield 27 as a single product. A final osmylation to complete the synthesis gave 24, again with high selectivity. Although the complexity of the conformational behavior of macrocycles limits its use in synthesis, the literature contains a number of examples in which the conformational bias of large ring systems is employed in the assembling of natural products.50"55 In many of these recent examples, molecular mechanics calculations have been used to rationalize the outcome of the conformationally controlled reactions. 19 1.5 Ring Closing Olefin Metathesis The formation of C-C bonds is an integral part of organic synthesis. This is especially true if the C-C bond formation in a synthesis involves a cyclization to form the ring structure of the target molecule. There exists a variety of ring forming reactions for macrocycles.56 However, the yields are often disappointing due to the entropy factor of the reaction. One C-C bond forming cyclization reaction which has gained much interest in recent years, although examples have been reported since the early 1980's,57 ,58 is the ring closing olefin metathesis reaction (RCM).59"61 This reaction takes a pair of intramolecular alkenes and couples them in the presence of a transition metal alkylidene catalyst suited for such a cyclization. Although the mechanism is not completely understood, the catalytic species is known to be a metal alkylidene and there is evidence for the involvement of metallacyclobutanes.62 The overall reaction mechanism thus effectively involves a series of alternating [2+2] cycloaddition and cycloreversions between metal alkylidene and metallacyclobutane species (Scheme 3). Early uses of ring closing olefin metathesis involved transition metal alkylidene catalyst which had moderate or poor functional group tolerance, were sensitive to air, moisture or trace solvent impurities, and were thermally unstable on storage. The recent interest in ring closing olefin metathesis owes its recognition to the development of the bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst 28 by Grubbs and coworkers.63 This catalyst is easy to prepare, air stable and catalytically active without rigorous water and oxygen exclusion from the reaction system. It is also tolerant of most functional groups, which makes it attractive in the synthesis of complex natural products. 23 2 0 Scheme 3. Mechanism for the ring closing olefin metathesis reaction ([M]=CHR is a transition metal benzylidene catalyst). A problem with the ring closing olefin metathesis reaction is that stereocontrol of the resulting olefin function is difficult to predict and the reaction often proceeds to yield a mixture of E and Z isomers. Previous research in our laboratory64 has demonstrated the use of molecular mechanics calculations to predict the ratios of E and Z isomers obtained in the formation of a series of unsaturated 14-membered lactones and lactams. It has also been observed that lower yields are obtained if the forming olefinic function is located in the proximity of the carbonyl oxygen or the heteroatom in these macrocyclic lactones and lactams. This may be a result of metal-substrate chelation.65 It is believed that the carbonyl oxygen of esters or amides acts as a relay for the evolving carbene which assembles the reacting sites within the coordination sphere of the metal 21 (complex A in Figure 15). However, if such relays form 5- or 6-membered ring systems (complex B or C in Figure 15), the resulting complex may be too stable and the cyclization will not proceed. L B C A Figure 15. Relay assembling of the reactive sites (A) and sources of unproductive complexes (B and C) in ring closing olefin metathesis. 22 C H A P T E R 2 R E S U L T S A N D D I S C U S S I O N Chapter 1 provided an introduction to the methods whereby the conformation of macrocyclic rings can be used to control the stereochemistry of newly formed stereogenic centers. In this thesis, the reactivity and conformational rigidity of 14-membered lactones were investigated through a study of the selectivities obtained in the reactions of such ring systems. The macrocyclic lactones used in this work were chosen such that they contained the functional group of interest remote from the lactone linkage and any stereogenic centers in the molecule. This would ensure that any observed selectivity would be due primarily to conformational effects. Thus, the regioselectivity in the hydroboration reactions of unsaturated lactone 29 was investigated as well as the regio- and stereoselectivity in the hydroboration reactions of unsaturated lactone 30. We were also interested in comparing the regioselectivity differences, if any, between the hydroborations of 29 and 30. The stereoselectivity of the hydride reduction of keto lactones 67 and 68 was also examined. Subsequently, through X-ray analysis and chemical correlations, the relative stereochemistry of the newly formed stereocenters in the reaction products were determined. Molecular mechanics calculations were then carried out and correlations were drawn between these calculations and the experimental results. 68 r O C H 3 29 30 67 23 2.1 Synthesis of (7a-13-Tridec-7-enolide (29) and I7E)-13-Tetradec-7-enolide (30) Our retrosynthetic plan for the syntheses of the two unsaturated lactones 29 and 30 is outlined in Scheme 4. Since a relatively large quantity of macrolide was desired in both cases, simple and inexpensive starting materials were chosen. Due to the similarities in structure between lactones 29 and 30, we decided to use intermediates that were common in the synthesis of both lactones. The greatest challenge in the syntheses would be to introduce the olefin function exclusively with E stereochemistry. Also, the cyclization step would be an important component of our syntheses, as the cyclization of macrocycles usually proceeds with poor to moderate yields.56 Thus, we decided to handle both concerns in one step. Previous work in our laboratory64 has demonstrated that the ring closing olefin metathesis (RCM) to form 29 proceeds in good yield and with better than 99:1 E.Z ratio from the diene ester 31. Due to the structural similarities to 29, we believed that the RCM to form lactone 30 would also proceed in good yield and with good stereoselectivity from the diene ester 32. Another disconnection at the ester linkage in 31 and 32 leads to alcohols 34 and 35, respectively, and the common acid 33. Both acid 33 and alcohol 35 lead retrosynthetically to the alcohol 34, through a one-carbon chain extension.66 Thus, the precursor to the three intermediates 33, 34 and 35 is the inexpensive 1,6-hexanediol (36). 24 O O H R R > > 33 O H R 29 R = H 30 R = C H 3 31 R = H 32 R = C H 3 34 R = H 35 R = C H 3 OH 36 Scheme 4. Retrosynthetic analysis of (7E)-13-tridec-7-enolide (29) and (7£)-13-tetradec-7-enolide (30) 2.1.1 Synthesis of 6-Hepten-1 -ol (34) The synthesis of 6-hepten-1-ol (34) is outlined in Scheme 5. The commercially available 1,6-hexanediol (36) was monoprotected67 as its THP ether 37, and the unprotected primary hydroxyl function was subsequently oxidized under the Swern conditions68 to yield aldehyde 38. Wittig olefination69 of 38 with the anion of methyltriphenylphosphonium bromide gave the olefin 39. Finally, removal of the THP protecting group with a catalytic amount of PPTS in methanol provided the target intermediate 34 in 44% overall yield from 36. 25 , 0 H D H P a , O T H P Swern b „ 36 38 O T H P Ph 3 P CH 2< 37 . O T H P PPTSg 39 34 .OH Key: (a) DHP, H + resin, toluene, rt, 70%; (b) (COCI)2, DMSO, Et3N, CH2CI2, -78 °C, 80%; (c) Ph3P+CH3Br", n-BuLi, THF, 0 °C, 86%»; (d) PPTS, CH3OH, rt, 91%. Scheme 5. Synthesis of 6-hepten-1-ol (34). 2.1.2 Synthesis of 7-Octenoic acid (33) 7-Octenoic acid (33) was synthesized from 6-hepten-1-ol (34) using a one-carbon chain extension method (Scheme 6). The toluenesulfonate derivative 40 was formed from alcohol 34, and the tosylated substituent was displaced by cyanide anion to extend the hydrocarbon chain by one carbon unit, yielding 41. Nitrile 41 was then hydrolyzed to produce the desired acid 33 in an overall yield of 57% from 34. 41 33 Key: (a) p-MeCerUS.C^CI, pyridine, 0 °C^rt, 85%; (b) KCN, MeCN, 82 °C, 70%; (c) NaOH, ethylene glycol, 150 °C, then cone. HCI, 95%. Scheme 6. Synthesis of 7-octenoic acid (33). 26 2.1.3 Synthesis of 7-Octen-2-ol (35) The secondary alcohol 35 was also synthesized from 6-hepten-1-ol (34). The synthesis of the 7-octen-2-ol intermediate (35) is outlined in Scheme 7. Oxidation of alcohol 34 under the Swern conditions68 yielded aldehyde 42. Addition of methyllithium to 42 then produced the secondary alcohol 35 in 45% overall yield from 34. OH Swern a w M M e L i l 34 42 O 35 OH Key: (a) (COCI)2, DMSO, Et3N, CH2CI2, -78 °C, 77%; (b) MeLi, THF, 0 °C, then NH4CI, 59%. Scheme 7. Synthesis of 7-octen-2-ol (35). 2.1.4 Ring Closing Olefin Metathesis (RCM) of 6-Heptenyl-7'-Octenoate (31) and 1-Methyl-6-Heptenyl-7'-Octenoate (32) From this point on in the syntheses of lactones 29 and 30, the procedure developed previously in our laboratory64 for the synthesis of 29 was followed. Accordingly, acid 33 and alcohol 34 were coupled using DCC and DMAP to form diene ester 31 (Scheme 8). This was followed by the RCM of 31, using the bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst 28,63 to produce lactone 29 in an overall yield of 75% for the two steps. In the same manner, acid 33 and alcohol 35 were coupled to yield diene ester 32, followed by ring closing olefin metathesis to produce lactone 30 in an overall yield of 72% for the two steps. 27 44 = 7 Z Key: (a) DCC, DMAP, CH2CI2, rt, 87%; (b) 2 mol% 28, CH2CI2, rt, 86%; (c) DCC, DMAP, CH2CI2, rt, 85%; (d) 2 mol% 28, CH2CI2, rt, 85%. Scheme 8. Synthesis of (7£)-13-tridec-7-enolide (29) and (7£)-13-tetradec-7-enolide (30). Evidence for the formation of 29 and 30 via the ring closing metathesis reaction can be obtained from 1 3 C NMR spectroscopy. Four olefinic carbon peaks are apparent in the spectra of diene esters 31 (8 138.81, 138.71, 114.46, 113.30 ppm) and 32 (5 138.81, 138.73, 114.37, 113.27 ppm). However, the spectra of 29 (8 131.80, 131.49 ppm) and 30 (8 131.80, 131.49 ppm) reveal the presence of only the two downfield olefinic carbon peaks, which are indicative of internal alkene carbons. The RCM of diene esters 31 and 32 proceeded to yield mixtures of E and Z isomers. The yields of the two reactions and the EIZ ratios were found to be very similar (Table 2). The E isomers were the major products in both cases with an EIZ ratio of 95:5 for the reaction of 31 and 94:6 for the reaction of 32. In both 28 cases, the E and Z isomers were not separable by thin layer chromatography, and radial chromatography under a variety of eluant conditions allowed for only small amounts of the major isomers (29 and 30) to be isolated from the E and Z mixtures. However, repeated flash column chromatography with silver nitrate impregnated TLC grade silica gel 7 0 , 7 1 yielded adequate amounts of the isolated E isomers 29 and 30, along with a small amount of mixtures of E and Z isomers. The E and Z isomer ratios in both cases were measured by gas chromatography. Table 2. The Ring Closing Olefin Metathesis of Diene Esters 31 and 32. o . , . , . Yield Calculated74 Substrate products , 0 / . E/Z \/o) t / Z 31 29,43 86 95:5 96:4 32 30,44 85 94:6 96:4 The olefin configurations of unsaturated lactones 29 and 30 were determined by the coupling constants between the vinyl protons. This was obtained from 1H homonuclear decoupling NMR experiments on lactones 29 and 30. The coupling constant for olefinic protons of a trans double bond is usually found to be 12-18 Hz, whereas for a cis double bond this value is typically found to be in the 6-12 Hz range.72 From the 1H NMR decoupling experiments it was determined that the olefinic protons of the major isomer 29 had a coupling constant of 15.0 Hz, and the double bond was correspondingly assigned the E configuration. In the same manner, the double bond of the major isomer 30 was assigned the E configuration based on a coupling constant of 15.4 Hz between the olefinic protons. 29 The IR spectra of 29 and 30 were in agreement with the analysis from the 1H homonuclear decoupling NMR experiments. In order for a molecular vibration to give rise to an IR absorption, the molecular motion must result in a change of the dipole moment of the molecule. The IR spectra of cis alkenes typically show moderate absorptions for the carbon-carbon double bond stretching frequency. On the other hand, the corresponding absorption in the trans isomer is weaker or sometimes not visible.73 The changes in dipole moment of the carbon-carbon double bond of 29 and 30 are either very small or zero, and therefore no carbon-carbon stretch band for the double bond is visible in the IR spectra at 1640-1670 cm"1 region in either case. This can only be rationalized with the assignment of the Econfiguration for both unsaturated lactones 29 and 30. The EIZ ratio observed in the RCM of diene ester 32 was first rationalized in the same manner as for 31 previously reported in our laboratory.64 In the reported study of RCM reactions yielding unsaturated 14-membered lactones and lactams, including the reaction of 31, it was suggested that the relative transition state energies in the formation of the E and Z isomers were reflected in the strain energies of the products.64 However, the global minimum energy conformation75 of tridecanolide (45) shown in Figure 16 was'considered for the unsaturated lactone series. The EIZ ratios correlated well to the dihedral angles of structure 45 at the corresponding double bond position for each lactone investigated. This suggested that the conformation of the transition state for ring formation is similar to that of 45 and this controls the stereochemistry of the resulting double bond. This model then predicts a predominant formation of the E isomer in the metathesis of diene ester 31. The global minimum energy conformation75 of 13-tetradecanolide (46) is also shown in Figure 16. The dihedral angle at the double bond position in the conformation 46 also predicts the predominance of the E isomer in the metathesis reaction of 32. 30 H 3 C 4 5 4 6 Figure 16. The global minimum energy conformations of tridecanolide (45) and 13-tetradecanolide (46). The corresponding double bond positions for 29 and 30 are highlighted in red. The structural resemblance of the global energy minimum of 13-tetradecanolide (46) to that of tridecanolide (45) might then explain the comparable EZ ratios obtained in the metathesis reactions for 31 and 32. The above analysis for the RCM reaction of diene esters 31 and 32 suggests that the relative energies of the transition state structures for each reaction might be reflected in the global minimum energy structure of the saturated ring systems 45 and 46. However, MM3* calculations74 were performed on each of the macrocyclic lactone products in the two RCM cases. The calculated EZ ratios were comparable to the observed EZ ratios for the metathesis reactions (Table We were interested in determining whether the catalytic alkylidene species involved in the RCM reaction of 31 and 32 was capable of the ring opening, and subsequent equilibration of the products. Therefore, in order to determine the factors that control the EZ ratios obtained in the metathesis reactions, equilibrium studies were performed on the E isomers 29 and 30. This was achieved using the active form of the metathesis catalyst 28, Cl2(PCy3)2Ru=CH2. In both cases the unsaturated lactones isomerized in near quantitative yields to an EZ ratio that was similar to that obtained in the metathesis reactions (Table 3). A 64:36 mixture of 30 and 44 also isomerized to a ratio that was similar to 31 that obtained from the metathesis reaction. The calculated EIZ ratios agree closely with the equilibrium values. Table 3. Equilibrium Studies on Unsaturated Lactones 29 and 30. Substrate Products Yield (%) Equilibrium EIZ Metathesis E/Z Calculated74 EIZ 29 29, 43 98 96:4 95:5 96:4 30 30, 44 96 95:5 94:6 96:4 30, 44 (64:36) 24, 44 — 94:6 94:6 96:4 The equilibrium studies tentatively suggest that the metathesis reactions of diene esters 31 and 32 occur under thermodynamic control. These results also demonstrate the validity of molecular mechanics calculations as a predictive tool for the preferred stereochemistry of the alkene products. 32 2.2 Reqio- and Stereoselectivity Studies on (7£)-13-Tridec-7-enolide (29) and (7£V13-Tetradec-7-enolide (30) With the unsaturated macrocyclic lactones 29 and 30 in hand, an investigation of the conformational effects of the ring systems on the addition reactions to the double bond could be executed. Hydroboration reactions were performed on 29 and 30, and the regio- and stereoselectivity of these reactions were examined. The effect of the 13-methyl substituent in 30 was also investigated in the regioselectivity of the hydroboration reactions. In addition, epoxidation reactions were performed on 30, and the diastereoselectivity was examined. 2.2.1 Hydroboration Studies on (7£)-13-Tridec-7-enolide (29) Our primary objective was to isolate and characterize each of the two regioisomeric hydroboration products from 29 before performing hydroboration studies under a variety of conditions. Lactone 29 was therefore initially treated with borane tetrahydrofuran complex to give, after an oxidative work-up, a mixture of hydroxy lactones 47 and 48 (Scheme 9). O O .0 1) B H 3 T H F 2) NaOH, H 2 0 2 H 2 0 H O 2 9 4 7 4 8 Scheme 9. Hydroboration of (7£)-13-tridec-7-enolide (29). 33 The hydroxy lactones 47 and 48 were not separable by flash column, radial or gas chromatography under a variety of conditions. In order to separate the hydroxy lactones for characterization purposes, as well as for the determination of the regioisomeric ratio, the corresponding trimethylsilyl ethers were formed (Scheme 10). This strategy has previously been employed in our laboratory40 in order to separate isomeric hydroxy lactones. The silyl derivatives 49 and 50 were separable by gas chromatography and the analysis revealed a regioisomeric ratio of 49:51 for the hydroboration using borane tetrahydrofuran complex. The silyl ether derivatives were structurally identified by comparing the GC retention times with that of an authentic sample of 49 previously synthesized in our laboratory.76 The silyl derivatives were also separable by radial chromatography. The separated silyl ethers 49 and 50 were then desilylated using tetrabutylammonium fluoride to yield the hydroxy lactones 47 and 48. Scheme 10. Separation of hydroxy lactones 47 and 48 34 The initial isolation and characterization of the hydroxy lactones 47 and 48 revealed that the addition of borane tetrahydrofuran complex to 29 proceeded with no regioselectivity. This was followed by investigating the effect of temperature on the selectivity of the hydroboration. The reaction of 29 with borane tetrahydrofuran at -78 °C proceeded with no selectivity, according to the analysis of the silylated derivatives (50:50). We then turned our attention to bulkier hydroborating agents in an effort to increase selectivity. Treatment of 29 with disiamylborane proceeded to yield a 50:50 mixture of hydroxy lactones, and with 9BBN gave negligible regioselectivity, producing a 46:54 mixture of 47 and 48. The results for the hydroborations performed on 29 are summarized in Table 4. Table 4. Hydroboration Study on (7£)-13-Tridec-7-enolide (29). Hydroborating agent Temperature Selectivity Yield 47 48 (%) BH 3THF 22 °C 49 51 88 BH 3THF -78 °C 50 50 90 Sia2BH 22 °C 50 50 86 9BBN 22 °C 46 54 93 Calculated74 22 °C 50 50 35 2.2.2 Conformational Analysis of (7£)-13-Tridec-7-enolide (29) In order to rationalize the hydroboration results of macrocycle 29, we turned our attention to molecular modeling. The unsaturated macrocyclic lactone 29 was subjected to a detailed conformational analysis using MM3* calculations.74 Ab initio calculations77 performed for the reaction of alkenes with various hydroborating agents support the presence of a relatively early transition state along the reaction coordinate. Applying Hammond's postulate,30 the low energy conformations of the unsaturated lactone 29 were assumed to be good approximations for the transition states in the reaction of 29 with the various hydroborating agents. The conformational analysis, however, proved to be quite complex. Thirty-four conformations were found within 2 kcal/mol of the global minimum. The introduction of a double bond into the ring system of a macrocycle makes the adoption of a diamond lattice conformation impossible,20 thereby increasing the conformational mobility of the ring system in 29. The three lowest energy conformations of unsaturated lactone 29 are shown in Table 5. Table 5. The Three Lowest Energy Conformations of 29. Low Energy Conformat ion S t / S ~ a u m « ^ Conformat ion 0.00 [3344] 0.02 [3434] 0.09 [3344] a Strain energy is reported relative to the lowest energy conformation. 36 29a 29b 29c Figure 17. Local conformations around the double bond in (7E)-13-tridec-7-enolide (29). The three lowest energy conformations for 29 listed in Table 5 all reveal the same local conformation around the double bond (Figure 17). This is also evident from an examination of their polar maps (Figure 18). 29a 29b 29c Figure 18. Polar maps of the three lowest energy conformations of (7£)-13-tridec-7-enolide (29). 37 Microwave spectroscopy and ab initio calculations ' have shown that the preferred conformation of unsaturated hydrocarbon chains is that in which the allylic hydrogens are eclipsed with the center of the double bond. The calculated local conformations around the double bond in the three lowest energy conformations of 29 (Figure 17) agree with this preferred conformation. These conformations show C6, C7, C8 and C9, along with a hydrogen bonded to each carbon, in the same plane. In fact, all of the conformations obtained from the MM3* search within 2 kcal/mol of the global minimum reveal the same local conformation around the olefin function. Consequently, this arrangement provides for similar steric environments at C7 and C8. Accordingly, it can be expected that the boron of the hydroborating agent cannot distinguish between these two positions. The model based on the conformational search performed on 29 thus illustrates that the reaction would provide an equal amount of the two possible products. This calculated result is in agreement with the experimentally obtained ratios of regioisomers in the hydroboration reaction of 29. 2.2.3 Hydroboration Studies on (7£)-13-Tetradec-7-enolide (30) As with the hydroboration of 29, our primary objective was to isolate and characterize each of the stereoisomeric products from the hydroboration of 30 before performing hydroboration studies under a variety of conditions. Lactone 30 was therefore initially hydroborated with borane tetrahydrofuran complex to give, after an oxidative work-up, a mixture of hydroxy lactones 51, 52, 53, and 54 (Scheme 11). 30 51 52 53 Scheme 11. Hydroboration of (7£)-13-tetradec-7-enolide (30). 38 The hydroxy lactones 51, 52, 53, and 54 were not separable by flash column, radial or gas chromatography under a variety of conditions. In order to separate the hydroxy lactones for characterization purposes, as well as to determine the isomeric ratios, the respective trimethylsilyl ethers were formed in the same manner as the trimethylsilyl ethers of the hydroboration products of 29. This produced a reaction mixture of four products which separated as two spots by TLC, and as three peaks by GC. The formation of the triethylsilyl and of the tert-butyldimethylsilyl derivatives did not provide for better separations. The application of flash column chromatography using TLC grade silica gel on each of the various silylated reaction mixtures resulted in the isolation of two fractions, each of which contained two isomeric products. We decided to turn our attention to other types of derivatives in an attempt to separate the four isomeric products resulting from the hydroboration of 30. The formation of carbamate derivatives has previously been described in the separation of stereoisomeric mixtures of alcohols.82,83 The reaction of phenyl isocyanate with the product mixture from the hydroboration of 30 gave a quantitative yield of carbamates 55, 56, 57, and 58 (Scheme 12). 0 0 J Q. I I OH r HO u 51 O 5 2 J a I I L OH J + c U 5 3 5 4 1) PhNCO 2) separation O Scheme 12. Separation of hydroxy lactones 51, 52, 53, and 54 R i H 39 The phenyl carbamates could not be resolved by gas chromatography. However, the phenyl chromophore in the carbamate derivatives allowed for the relative amounts of the derivatives to be quantified using HPLC in conjunction with a UV detector. Four resolved peaks were observed from the HPLC analysis in a 37:18:31:14 ratio. Flash column chromatography using TLC grade silica gel provided pure samples of the phenyl carbamates 55 and 56. Unfortunately, the carbamates 57 and 58 were not separable by this method. We then set out to structurally identify the four isomers obtained. Each of the two sets of regioisomers was identified first in the following manner. The hydroboration of a 64:36 mixture of E/Z unsaturated lactones 59 and 60, previously synthesized in our laboratory,64 yielded four isomeric hydroxy lactones which were subsequently transformed to the phenyl carbamate derivatives. The HPLC chromatograph of the derivatives 56, 57, 61 and 62 was compared to that of the carbamate derivatives from the hydroboration of 30 (Scheme 13). This comparison revealed two peaks common to both of the HPLC traces, which had the same retention times. The stereoisomers 56 and 57 were assigned to these two peaks, which make up one of the two sets of regioisomers from the hydroboration of 30. Consequently, stereoisomers 55 and 58 were assigned as the second set of regioisomers. In order to identify the set of isomers resulting from the hydroboration on the same face of the double bond, we again utilized a chemical correlation approach. In their demonstration of local conformer control in the epoxidation and osmylation of unsaturated lactones and cyclic olefins, Vedejs and coworkers32,84 correlated the epoxidation products to known alcohols using nucleophilic hydride ring opening of the epoxides. Based on this work, we used a modified approach to identify the two sets of re-face isomers (Scheme 13). 40 Scheme 13. Chemical correlations used in the structural identification of carbamate derivatives 55, 56, 57 and 58 (triple lines represent chemical correlations). 41 Epoxidation of 30 with m-chloroperbenzoic acid at 22 °C yielded two diastereomers, 63 and 64, in a 67:33 ratio and 98% total yield. The lactone functionality prevented the epoxide ring opening using lithium aluminum hydride to obtain the hydroxy lactones directly. Alternatively, hydrochloric acid cleavage of the epoxide85 followed by the dehalogenation of the chlorohydrin86 was performed on the major diastereomer of the epoxidation (Scheme 13). Thus addition of hydrochloric acid to epoxide 63 yielded a mixture of regioisomeric chlorohydrins 65 and 66 in 94% yield. The two regioisomers were separated by radial chromatography, and the isolation revealed a 48:52 ratio of 65 and 66 for the hydrochloric acid addition. Chlorohydrins 65 and 66 were reduced with tributyltin hydride to yield the corresponding hydroxy lactones. Finally, the HPLC chromatographs of the carbamate derivatives 55 and 57 were compared to the HPLC trace for the carbamate derivatives from the hydroboration of 30. Since it is well known that alkene epoxidations with peracids occur via syn addition, we were confident that derivatives 55 and 57 contained the carbamate group on the same face of the ring system. Consequently, derivatives 56 and 58 both contained the carbamate group on the opposite face. At this point, the set of rc-face isomers, 55/57 and 56/58, had been elucidated, as well as the two sets of regioisomers 56/57 and 55/58. We could not conclusively assign the structure for each compound within these sets since it was not possible to establish the structure of the major isomer obtained from the epoxidation of 30. However, crystals suitable for an X-ray analysis were obtained for the phenyl carbamate 57 (Figure 19). This confirmed the 7R*,13S* relative stereochemistry for 57. The phenyl carbamate derivative 56 was then assigned the 7S*,13S* stereochemistry since the results from the hydroboration of 59 and 60 revealed that carbamate 56 was the diastereomer of 57. Also, the epoxidation of unsaturated lactone 30 revealed that carbamate 55 was the regioisomer of 57, and hence 55 was assigned the 8fl*,13S* stereochemistry. Finally, carbamate 58 was assigned the 8S*,13S* stereochemistry. The use of the star superscript 42 (*) indicates the presence of both enantiomers possessing the same relative stereochemistry at the numbered atoms, e.g. 7R*,13S* refers to an equal amount of 7f?,13S and 7 S, 13/3 stereoisomers. This star notation is used throughout this thesis. Figure 19. ORTEP representation of (7R*, 13S*)-7-(A/-phenylcarbamoyl)oxy-13-tetradecanolide (57), showing 50% probability ellipsoids and hydrogen atoms with arbitrary thermal parameters for clarity. The initial isolation and characterization of the hydroxy lactones revealed that the addition of the borane tetrahydrofuran complex to the unsaturated lactone 30 at 22 °C proceeded to yield a 37:18:31:14 ratio of the four isomeric products 51, 52, 53, and 54, respectively. This roughly correlates to a 2:1 7t-face selectivity. However, this also revealed no regioselectivity in the hydroboration of 43 30. The effect of lower temperature on the selectivity of the hydroboration was also investigated. The reaction of 30 with borane tetrahydrofuran at -78 °C proceeded with no regioselectivity, according to the HPLC analysis of the carbamate derivatives (50:50), but did provide for slightly better re-face selectivity (3:1 ratio for 51/53 and 52/54). We then turned our attention to bulkier hydroborating agents in the hope of obtaining increased selectivity. Hydroboration of 30 with disiamylborane proceeded with no regioselectivity and slightly lower re-face selectivity than with borane tetrahydrofuran at -78 °C. The lower selectivity obtained with disiamylborane may be a result of the higher reaction temperature required. The hydroboration of 30 with 9BBN also gave no regioselectivity, but resulted in the greatest re-face selectivity (7:1 ratio for 51/53 and 52/54). The results for the hydroborations performed on 30 are summarized in Table 6. Table 6. Hydroboration Study on (7£)-13-Tetradec-7-enolide (30). Hydroborating T Selectivity re-Face selectivity Yield . I emperature /r),» agent ^ 51 52 53 54 51/53 52/54 (%) BH 3THF 22 °C 37 18 31 14 68 32 90 BH 3THF -78 °C 42 17 33 8 75 25 93 Sia2BH 22 °C 41 18 31 10 72 28 85 9BBN 22 °C 45 8 43 4 88 12 92 Calculated74 22 °C 42 8 42 8 84 16 44 2.2.4 Epoxidation Studies on (7£)-13-Tetradec-7-enolide (30) The epoxidation of the unsaturated lactone 30 with MCPBA, used to determine the stereochemistry of the hydroxy lactones, showed moderate diastereoselectivity and we therefore decided to explore this further. The hydroxy lactones 55 and 57 obtained from the major epoxidation isomer had the 8 A T , 1 3 S * and the 7 A 7 * , 1 3 S * stereochemistry respectively. We therefore concluded that the major isomer 63 from the epoxidation of 30 must have the 7 S * , 8 S * , 1 3 S * stereochemistry. The epoxidation at 2 2 °C yielded a 2 : 1 ratio of diastereomers 63 and 64. We decided to perform this reaction a lower temperature in order to increase the selectivity. The same reaction at 0 °C gave a 2 . 2 : 1 ratio, and at - 7 8 °C the reaction was found to be the most selective with a 3 . 3 : 1 ratio. The epoxidation was also performed using methyl(trifluoromethyl)dioxirane87 at 0 °C, since this reagent had previously demonstrated increased selectivity when compared to MCPBA and other epoxidizing agents.88 However, the use of the dioxirane epoxidation agent gave a similar diastereoselectivity as MCPBA. The results for the epoxidations performed on 30 are summarized in Table 7 . Table 7. Epoxidation Study on (7£)-13-Tetradec-7-enolide (30). Epoxidation agent Temperature Selectivity 63 64 Yield (%) MCPBA 22 °C 67 33 98 MCPBA 0 °C 69 31 91 MCPBA -78 °C 77 23 100 Methyl(trifluoromethyl) dioxirane 0°C 70 30 98 Calculated74 -78 °C 90 10 — 45 2.2.5 Conformational Analysis of (7E)-13-Tetradec-7-enolide (30) In order to rationalize the hydroboration and epoxidation results of macrocycle 30, we again turned our attention to molecular modeling. The unsaturated lactone 30 was subjected to a detailed conformational analysis using MM3* calculations.74 In accordance with ab initio calculations77 and Hammond's postulate,30 it was again assumed that the transition state structure for the hydroboration resembles the low energy conformations of 30. The epoxidation of alkenes have also been determined from ab initio calculations89,90 to proceed through relatively early transition states along the reaction coordinate. Accordingly, the low energy conformations of 30 were used in the same manner to approximate the transition state structure for the epoxidation reaction. Table 8. The Three Lowest Energy Conformations of 30. Low Energy Conformation ^ Z u ! ^ ! ^ Conformation Q 30a 0.00 [3434] 30b 0.02 [3344] 30c 0.32 [3344] a Strain energy is reported relative to the lowest energy conformation. 46 30a 30b 30c Figure 20. Local conformations around the olefinic double bond in (7£)-13-tetradec-7-enolide (30). As with the unsaturated lactone 29, the conformational analysis for 30 proved to be quite complex. Twenty-four conformations were found within 2 kcal/mol of the global minimum. The three lowest energy conformations of unsaturated lactone 30 are shown in Table 8. 30 30a 30c Figure 21. Polar maps of the three lowest energy conformations of (7£)-13-tetradec-7-enolide (30). 47 The three lowest energy conformations for 30 listed in Table 8 all reveal the same local conformation around the double bond (Figure 20). This is also evident from an examination of their polar maps (Figure 21). The three lowest energy conformations of 30 show the same eclipsed conformation around the double bond as does the unsaturated lactone 29. In fact, all the conformations obtained from the MM3* search within 2 kcal/mol of the global minimum exhibit the same local conformation around the olefinic function. Hence, the steric environments at C7 and C8 are similar and, as with unsaturated lactone 29, the model based on the conformational search illustrates that the reaction would provide equal amounts of the two products. This calculated result is in agreement with the 50:50 ratios of regioisomers observed in the hydroboration reactions of 30. To rationalize the re-face selectivities observed in the hydroborations and epoxidations, a more detailed examination of the low energy conformations of 30 was carried out (Figure 22). Still and Gallynker28 have demonstrated that reagents approach the re system of a macrocyclic compound largely or perhaps exclusively from the peripheral face. This can be expected to occur in each of the three lowest energy conformations of 30 (30a, 30b, 30c), illustrated in Figure 21, to yield the hydroboration products with the 8ft*, 13S* and 7ft*,13S* stereochemistries (51 and 53). In fact, the five lowest energy conformations (up to 0.70 kcal/mol above the global minimum) are predicted to yield the 8ft*, 13S* and 7 ft*, 13S* products. The sixth and seventh lowest energy conformations (30d, 30e) are expected to yield products with the 8S*,13S* and 7S*,13S* stereochemistries (52 and 54). This analysis was expanded to the 24 conformations within 2 kcal/mol of the global minimum. A total of 18 of these conformations would give rise to the 8ft*, 13S* and 7ft*, 13S* products, whereas only six conformations would lead to the 8S*,13S* and 7S*,13S* products. This analysis suggests that 51 and 53 would be the major diastereomers resulting from the hydroboration of 30. 48 o 30a 0.00 kcal/mol 7fl*,13S* 8fl*,13S* 30b 0.02 kcal/mol 7fT,13S* 8fl*,13S* 30c 0.32 kcal/mol 7fl*,13S* 8fl*,13S* 30d 0.80 kcal/mol 7S*,1 3S* 8S*,13S* 30e 0.82 kcal/mol 7S*,13S* 8S*,1 3S* Figure 22. Low energy conformations of (7£)-13-tetradec-7-enolide (30) and corresponding predicted hydroboration products. 49 An attempt to calculate the re-face selectivity was performed. Still and Gallynker28 have used Boltzmann distributions of the low energy conformations to rationalize the selectivity of a variety of reaction types. The population fraction (pi) of conformations which lead to products 51 and 53 was calculated by introducing the energy contribution for each of these conformations (/?/), along with the energy contribution associated with all conformations (N), into a Boltzmann distribution equation:91 n . where e, is the energy of the molecular conformation, k is the Boltzmann constant (1.38066x10-23 JK"1) and Tis the temperature. This revealed a population ratio of 84:16 at 22 °C in favor of the conformations which lead to 51 and 53 over those which give rise to 52 and 54. Since the hydroboration of 30 is predicted to yield a 50:50 ratio of regioisomers based on the conformational analysis performed earlier, each of the re-face isomers should contain an equal number of regioisomers. Hence, the ratio of the products 51, 52, 53 and 54 is calculated to be 42:8:42:8. This is in agreement with the experimental results (Table 6). In the same manner, the calculations applied to the epoxidation of the unsaturated lactone 30 suggests a 90:10 ratio of diastereomers 63 and 64 at -78 °C. Although the calculated result for the epoxidation is in general agreement with the experimental result (Table 7), the epoxidations were found to be less selective than for when the bulkier hydroborating agents were employed. Thus, the re-face selectivity using MCPBA as well as methyl(trifluoromethyl)dioxirane appears to be similar to that of the borane-tetrahydrofuran complex. Although the presence of the additional methyl substituent in the structure of 30 provided for a less conformationally mobile ring system than that of 29, this did not improve the regioselectivity in the hydroboration reactions. The source of the poor regioselectivity appears to be the stable eclipsed conformation around the double bond, which is present in all the low energy conformations of unsaturated lactones 29 and 30. 50 2.3 Stereoselectivity Studies on 7-Oxo-13-Tetradecanolide (67) and 8-Oxo-13-Tetradecanolide (68) With the hydroxy lactones 51, 52, 53 and 54 from the hydroboration study in hand, the corresponding keto lactones for the hydride reduction study were obtained via oxidation of the alcohol function. These compounds allowed for further investigations into conformationally controlled reactions of these ring systems. Keto lactones 67 and 68 were synthesized using the TPAP oxidation of a 37:18:31:14 mixture of 51, 52, 53 and 54 (Scheme 14). The two resulting keto lactones, formed in a 1:1 ratio, were separated by flash column chromatography using TLC grade silica gel. Reduction reactions were then performed on of the keto lactones 67 and 68, using a variety of hydride reducing agents. The ratios of the resulting hydroxy lactones were then determined from the HPLC retention times of the carbamate derivatives, permitting a study of the stereoselectivity of the reduction reactions. 53 54 Key: (a) 10 mol% TPAP, NMO, 3 A molecular sieves, CH2CI2, rt, 86%. Scheme 14. Synthesis of 7-oxo-13-tetradecanolide (67) and 8-oxo-13-tetradecanolide (68). 51 2.3.1 Hydride Reduction Studies on 7-Oxo-13-Tetradecanolide (67) The 7-oxo-l3-tetradecanolide (67) was subjected to a variety of hydride reducing agents and reaction conditions. The NaBH4 reduction was first performed at low temperature (-78 °C), yielding a 1:1 ratio of the two diastereomeric products. The products were identified from the HPLC comparison of the phenyl carbamate derivatives with those from the hydroboration study of 30. The reduction of 67 with NaBH4 under Luche conditions92 (cerium chloride additive) gave only slight selectivity. We then turned our attention to the bulkier reducing reagent K-Selectride.93 The reaction of keto lactone 67 with K-Selectride in THF at -15 °C provided good selectivity with a better than 6.5:1 ratio for 52:53. The ease with which this reaction proceeded led us to believe that this same reaction could be performed at even lower temperature in order to further improve selectivity. Thus, the same reaction at -78 °C produced the two hydroxy lactones 52 and 53 with better than 10:1 selectivity. The results for the hydride reductions performed on 67 are summarized in Table 9. Table 9. Hydride Reduction Study on 7-Oxo-13-Tetradecanolide (67). Reducing agent Temperature Selectivity Yield 52 53 (%) NaBH4 -78 °C 50 50 80 NaBH4, CeCI3 -78 °C 55 45 86 K-Selectride -15 °C 87 13 83 K-Selectride -78 °C 91 9 91 Calculated74 -78 °C 92 8 52 2.3.2 Hydride Reduction Studies on 8-Oxo-13-Tetradecanolide (68) The 8-oxo-13-tetradecanolide (68) was subjected to the same variety of hydride reducing agents as were used with the keto lactone 67. The NaBH4 reduction was first performed at low temperature (-78 °C), yielding a 1:1 ratio of diastereomeric products 51 and 54. The two products were also identified from the HPLC comparison of the phenyl carbamate derivatives with those from the hydroboration study of 30. The reduction of 68 with NaBH4 under Luche conditions92 (cerium chloride additive) did not provide significant selectivity, nor did the reaction with the bulkier reagent K-Selectride93 at -15 °C. The reaction of keto lactone 68 with K-Selectride in THF at -78 °C produced the two hydroxy lactones 51 and 54 with low selectivity, yielding a 1:1.5 ratio, respectively. The results for the hydride reductions performed on 68 are summarized in Table 10. Table 10. Hydride Reduction Study on 8-Oxo-13-Tetradecanolide (68). Reducing agent Temperature Selectivity Yield 51 54 (%) NaBH4 -78 °C 50 50 83 NaBH4, CeCI3 -78 °C 56 44 87 K-Selectride -15 °C 47 53 90 K-Selectride -78 °C 40 60 89 Calculated74 -78 °C 8 92 53 2.3.3 Conformational Analysis of 7-Oxo-13-Tetradecanolide (67) and of 8-Oxo-13-Tetradecanolide (68) In order to rationalize the hydride reduction results for the keto lactones, we again turned our attention to molecular modeling. The keto lactones 67 and 68 were subjected to a detailed conformational analysis using MM3* calculations.74 Previous ab initio calculations94"96 have revealed that the transition state for ketone reduction lies early along the reaction coordinate. As previously in the hydroboration and epoxidation studies, it was assumed that the transition state structure for the reductions resembles the low energy conformations of the respective keto lactone. This method has previously been used in our laboratory,35,36 with the aid of the MM2* force field parameters,29 for the hydride reduction of a series of keto lactones. The conformational analysis for 67 and 68 proved to be quite complex. Twenty-two conformations for 67, and twenty-three conformations for 68, were found within 2 kcal/mol of the global minimum in each system. The three lowest conformations of keto lactones 67 and 68 are shown in Table 11 and Table 12, respectively. 54 Table 11. The Three Lowest Energy Conformations of 67. Low Energy Conformation Strain Energy3 (kcal/mol) Conformation 67a 67b 0.00 0.16 [3344] [3434] 67c 0.24 [3344] Strain energy is reported relative to the lowest energy conformation. Table 12. The Three Lowest Energy Conformations of 68. Low Energy Conformation Strain E n e r g y3 (kcal/mol) Conformation 68a 68b 0.00 [3434] 0.52 [3344] 68c \ 0.78 [3335] a Strain energy is reported relative to the lowest energy conformation. 55 The calculated selectivities were determined using the peripheral attack assumption28 of the hydride reducing reagents on the ring systems of 67 and 68. The three lowest energy conformations of 67 provide for the exclusive formation of the 7S*,13S* product (hydroxy lactone 52) (Figure 23). A total of 17 conformations within 2 kcal/mol of the global minimum were found which lead to the formation of the 7S*,13S* product (52). Only 5 conformations lead to the formation of the 7A7*,13S* product (53). o' 67a 0.00 kcal/mol "FT } o' 67b 0.16 kcal/mol "Kf o HO' 7S*,13S* 67c 0.24 kcal/mol "H" HO 7S*,13S* Figure 23. Low energy conformations of 7-oxo-13-tetradecanolide (67) and the corresponding predicted reduction products. A Boltzmann distribution91 of the conformations within 2 kcal/mol of the global minimum reveals a population ratio of 92:8 at -78 °C in favor of the conformations which lead to 52 over those which give 53. This is in good agreement with the experimentally obtained ratio of 91:9 observed in the 56 reduction of 67 with K-Selectride at -78 °C (Table 11). It is interesting to note the lack of stereoselectivity of the reduction using NaBH4. This suggests that NaBH4 may be able to reduce a carbonyl group from the inside as well as from the periphery of the ring system. Similar results using NaBH4 in the reduction of tetradecanolide keto lactones have been reported elsewere.97,98 A similar prediction was performed for the keto lactone 68. The three lowest energy conformations provide for the exclusive formation of the 8S*,13S* product (hydroxy lactone 54) (Figure 24). A total of 17 conformations within 2 kcal/mol of the global minimum were found which lead to the formation of the 8S*,13S* product (54) whereas 6 conformations lead to the formation of the 8R*,13S* product (51). 8S*,13S* 0.00 kcal/mol O OH 68b 0.52 kcal/mol 8S*,13S* O HO 'O 68c 0.78 kcal/mol 8S*,13S* Figure 24. Low energy conformations of 8-oxo-13-tetradecanolide (68) and the corresponding predicted reduction products. 57 A Boltzmann distribution of the conformations within 2 kcal/mol of the global minimum reveals a population ratio of 92:8 at -78 °C in favor of the conformations which lead to 54 over those which give 51. This calculated selectivity was not observed experimentally. The greatest selectivity observed in the reduction of 68 was 1:1.5 for 51 and 54 respectively in the reduction with K-Selectride at -78 °C. However, the conformations obtained via MM3* calculations do predict the observed major diastereomer 54. We decided to investigate whether the transition state for the reduction lies later along the reaction coordinate, in order to explain the lack of agreement between the calculated and the experimentally observed ratios. The hydroxy lactone products 51, 52, 53 and 54 were each subjected to a detailed conformational analysis using MM3* calculations. A Boltzmann distribution of the conformations of 51 and 54 was calculated and revealed a population ratio of 60:40 in favor of the conformations for 51 over of those for 54. In fact, this predicts the opposite major diastereomer as that which was observed experimentally for the reduction of 68. The Boltzmann distribution calculation for 52 and 53 reveals a ratio of 67:33 in the reduction of 67. This also predicts the opposite major diastereomer as that observed experimentally. Thus, the previous assumption of an early transition state appears more valid. However, the calculated results for the reduction of 67 do not agree as closely with the observed experimental ratios as for the reduction of 68. Further studies may be required in order to determine the source of this anomaly. 58 2.4 Conclusion The conformational behavior of unsaturated 14-membered lactones and keto lactones proved to be rather complex. In general, the selectivity exhibited in the reactions of the macrocyclic lactones was rationalized from the conformational analysis of starting materials. The hydroboration results demonstrated that the additions to the double bond proceed with low regioselectivity but with high re-face selectivity. Conformational analysis of the unsaturated macrocyclic lactones illustrated the lack of differentiation between the alkene carbons, thus explaining the lack of regioselectivity observed. High re-face selectivity was also evident in the epoxidation studies. The keto lactone hydride reduction results demonstrated that these reactions also proceed with moderate to high diastereoselectivity. The relative stereochemistries associated with the stereogenic centers of the macrocyclic lactones created throughout the thesis were successfully assigned with the use of chemical correlations and X-ray analysis. The molecular model calculations have proved useful in the rationalization of experimentally obtained product distributions. These calculations appear to have predictive value as a semiquantative tool for the stereochemical outcome of reactions to these compounds. 59 CHAPTER 3 EXPERIMENTAL 3.1 General All reactions were performed under a nitrogen atmosphere in flame- or oven-dried glassware. Elevated temperature reactions were performed in either a silicone oil bath or with a Glas-Col heating mantle at the desired temperature. Low temperature reactions were performed in a dry ice/acetone (-78 °C), a dry ice/ethylene glycol (-15 °C), or an ice water (0 °C) bath. Anhydrous solvents were obtained by distillation. Diethyl ether, tetrahydrofuran and toluene were distilled from sodium. Methylene chloride and triethylamine were distilled from calcium hydride. Methanol was distilled from magnesium methoxide. Dimethyl sulfoxide and pyridine were distilled at reduced pressure from calcium hydride. The low boiling fraction of petroleum ether (bp 35-60 °C) was used. In the case of olefin metathesis reactions, methylene chloride was deoxygenated by sparging with nitrogen for 60 min. Otherwise, the solvents were used as received from the supplier. Reagents were purified according to the procedures given in the literature." Unless otherwise noted, reagents were purchased from the Aldrich Chemical Co. Alkyllithium reagents were standardized by titration with diphenylacetic acid in THF at 0 °C. The bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (Grubbs' catalyst) reagent 28 was prepared according to the method of Schwab, Grubbs, and Ziller.100 The bis(tricyclohexylphosphine)methylidine ruthenium (IV) dichloride catalyst (the active form of the catalyst 28), was prepared by Mr. Andre Hodder64 according to the method of Schwab, Grubbs, and Ziller.100 60 The concentration or removal of solvents under reduced pressure refers to the use of a Bucchi rotary evaporator. A brine solution refers to a saturated sodium chloride solution. Thin layer chromatography (TLC) was performed on Merck silica gel 60 F254 precoated aluminium plates (0.2 mm thickness). A 1% p-anisaldehyde spray or irradiation with ultraviolet light (254 nm) were used in the visualization of TLC plates. Flash column chromatography101 was performed using silica gel 60, 230-400 mesh, supplied by E. Merck Co. TLC grade column chromatography refers to flash column chromatography with silica gel type H (10-40|i) supplied by Aldrich Chemical Co. Radial chromatography was performed using a Harrison Chromatotron model 8924. The adsorbant used was silica gel 60, PF254 with gypsum binder supplied by EM Science. Silver nitrate impregnated silica gel was prepared according to the procedure of de Vries. 7 0 , 7 1 Solvent systems used in liquid chromatography techniques were usually chosen such that the desired product had an Rf of approximately 0.20-0.30 on TLC. Analytical gas-liquid chromatography (GC) was performed on a Hewlett-Packard model 5880A gas chromatograph, equipped with a split mode capillary injection system and a flame ionization detector. The stationary phase consisted of an OV-101 capillary column of dimensions 0.20 mm x 12 m, and helium was used as the carrier gas. High performance liquid chromatography (HPLC) was carried out using a Waters silica Radial-Pak cartridge in a RCM 8 x 10 compression module containing Nova-Pak silica. Solvents were delivered through the column with the aid of a Waters 600E multisolvent delivery system, and a Waters 994 programmable photodiode array detector set at 250 to 400 nm was used. Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected. In the cases where Kugelrohr distillations were performed, boiling points are given as the oven temperature and are uncorrected. Infrared (IR) spectra were obtained using either a Bomem Michelson 100 FT-IR spectrophotometer or a Perkin Elmer 1710 FT-IR spectrophotometer. IR spectra were obtained as a neat sample of the liquid or as a deuteriochloroform solution held between two NaCl plates. 61 Proton nuclear magnetic resonance (1H NMR) spectra were recorded in deuteriochloroform solutions using either a Bruker AC-200 (200 MHz), Bruker WH-400 (400 MHz), or a Bruker AMX-500 (500 MHz) spectrometer. Carbon nuclear magnetic resonance (13C NMR) with proton decoupling spectra were recorded in deuteriochloroform solutions using a Bruker AC-200 (50 MHz). Chemical shifts for all spectra are reported in parts per million (ppm) on the 8 scale and are referenced to chloroform (8 7.24 1H NMR; 8 77.0 1 3 C NMR) as an internal standard. Low resolution mass spectra (LRMS) in electron ionization (El) mode were recorded on a Kratos-AEI model MS 50 spectrometer. LRMS in chemical ionization (CI) mode were recorded on either a Kratos MD 80 spectrometer or a Kratos Concept II HQ spectrometer. LRMS in desorption chemical ionization (DCI) mode were recorded on a Delsi Nermag R10-10 C spectrometer. Only peaks with relative intensities greater than 20% or those of analytical importance are reported. High resolution mass spectra (HRMS) in El mode were recorded on a kratos-AEI mode MS 50 spectrometer. HRMS in CI mode were recorded on either a Kratos MS 80 spectrometer or a Kratos Cocept II HQ spectrometer. Microanalyses were performed by Mr. Peter Borda in the Microanalytical Laboratory at the University of British Columbia on a Carlo Erba Elemental Analyzer Model 1106 or a fisions CHN-0 Elemental Analyzer Model 1108. 3.2 Conformational Analysis Methods BATCHMIN, a part of MACROMODEL molecular modelling program developed by Still and coworkers75 was used to calculate the global minimum conformations of the macrocyclic lactones studied in this work. The MM3* force field, based on the MM3 parameters developed by Allinger and coworkers,74 was used to minimize structures in conjunction with the Monte Carlo Multiple Minimum Search (MCMM) in order to find the global minimum conformations. 62 3.3 Chemical Methods 3.3.1 2-(6'-Hydroxyl hexoxyl) tetrahydropyran (37)1 Dowex 50W x 12 acidic resin (30.0 g) was added to a solution of 1,6-hexanediol (22.00 g, 186.2 mmol) and 3,4-dihydropyran (15.66 g, 186.2 mmol) in toluene (350 mL). The solution was stirred at rt for 4 hours and the resin was removed by vacuum filtration. The filtrate was sequentially washed with saturated NaHC03 solution and brine, and dried over anhydrous MgSCV The dried solution was filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 30% ethyl acetate in petroleum ether as eluant afforded alcohol 37 (26.37 g, 130.3 mmol) in 70% yield as a clear colourless oil. IR (neat): 3392, 2935, 2863, 1454, 1351, 1121, 1072, 1030, 904 cm"1; 1H NMR (200 MHz, CDCI3): 4.54 (t, J = 3.5 Hz, 1H), 3.26-3.93 (m, 6H), 1.29-1.94 (m, 15H); 1 3 C NMR (50 MHz, CDCI3): 5 98.86, 67.54, 62.60, 62.35, 32.65, 30.74, 29.66, 26.03, 25.55, 25.47, 19.61; LRMS (El) m/z(relative intensity): 201 (4), 101 (18), 85 (100), 55 (39); HRMS (El) m/z calculated for CnH 2 i0 3 : 201.14907, found: 201.14947; Analysis calculated forCnH 220 3: C, 65.31; H, 10.96. Found: C, 65.09; H, 10.97. 63 3.3.2 2-(6'-Oxohexoxyl)Tetrahydropyran (38)102 A solution of dimethylsulfoxide (22.1 mL, 311 mmol) in CH2CI2 (100 mL) was added via cannula to a solution of oxalyl chloride (12.4 mL, 143 mmol) in CH 2CI 2 (300 mL) at -78 °C. The solution was stirred for 5 minutes and alcohol 37 (26.20 g, 129.5 mmol) in CH2CI2 (100 mL) was added via cannula. This mixture was stirred for 15 minutes at -78°C. Triethylamine (84.8 mL, 609 mmol) was added, the mixture was stirred for 5 minutes, and warmed to rt. The reaction was quenched with water, the organic layer was collected, and the aqueous layer was extracted with CH2CI2. The organic layers were combined, sequentially washed with 1N HCI solution, water, 5% Na 2 C0 3 solution, and brine, and dried over anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 25% ethyl acetate in petroleum ether as eluant afforded aldehyde 38 (20.63 g, 103.0 mmol) in 80% yield as a clear colourless oil. IR (neat): 2937, 2864, 1727, 1450, 1356, 1265, 1129, 1077,1030, 869 cm"1; 1H NMR (200 MHz, CDCI3): 5 9.71 (s, 1H), 4.50 (s, 1H), 3.21-3.90 (m, 4H), 2.39 (t, J = 7.2 Hz, 2H), 1.23-1.88 (m, 12H); 1 3 C NMR (50 MHz, CDCI3): 5 202.64, 98.90, 67.25, 62.36, 43.83, 30.76, 29.50 25.91, 25.49, 21.93, 19.68; LRMS (El) m/z (relative intensity): 200 (M+, 3), 199 (8), 101 (75), 99 (50), 85 (100), 81 (26); HRMS (El) m/z calculated for CnH 2o0 3 (M+-1): 199.13352, found: 199.13342; Analysis calculated forCnHi 90 3 : C, 65.97; H, 10.07. Found: C, 66.02; H, 10.14. 64 3.3.3 2-(6'-Hexenoxyl) Tetrahydropyran (39)1 n-Butyllithium in hexane (1.7 M, 1.18.9 mL, 202.2 mmol) was added via syringe over 15 minutes to a solution of methyltriphenylphosphonium bromide (72.24 g, 202.2 mmol) in THF (500 mL) at 0°C. Aldehyde 38 (20.25 g, 101.1 mmol) in THF (50 mL) was added dropwise via cannula and the reaction was stirred at 0°C for 90 minutes. Water was added to the reaction, the organic layer was collected, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with brine, and dried over anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 15% diethyl ether in petroleum ether as eluant afforded alkene 39 (17.26 g, 87.04 mmol) in 86% yield as a clear colourless oil. IR (neat): cm"1: 3076, 2934, 2863, 1641, 1448, 1351, 1322, 1261, 1201, 1129, 1076, 1031, 870, 815 cm"1; 1H NMR (200 MHz, CDCI3): 5.68-5.92 (m, 1H), 4.86-5.06 (m, 2H), 4.56 (t, J = 2.9 Hz, 1H), 3.28 - 3.94 (m, 4 H), 2.04 (m, 2H), 1.25-1.92 (m, 12H); 1 3 C NMR (50 MHz, CDCI3): 6 138.79, 114.19, 98.69, 67.42, 62.12, 33.65, 30.70, 29.53, 28.69, 25.69, 25.47, 19.58; LRMS (El) m/z (relative intensity): 198 (M+, 2), 197 (6), 101 (41), 85 (100); HRMS (El) m/z calculated for C12H21O2 (M+-1): 197.15416, found: 197.15456; Analysis calculated forCnH 2 20 3 : C, 72.68; H, 11.18. Found: C, 72.68; H, 11.22. 65 3.3.4 6-Hepten-1-ol (34) 102 Pyridinium p-toluenesulfonate (1.29 g, 5.14 mmol) was added to a solution of alkene 39 (17.00 g, 85.73 mmol) in methanol, and the reaction was stirred at rt for 48 hours. The solvent was removed by rotary evaporation and the residue was dissolved in diethyl ether. The ether solution was washed sequentially with saturated NaHC03 solution and brine, and dried over anhydrous M g S 0 4 . The dried solution was filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 30% diethyl ether in petroleum ether as eluant, followed by distillation of the resulting oil afforded alcohol 34 (8.93 g, 78.2 mmol) in 91% yield as a clear colourless oil. bp: 80 ° C / 2 5 mm Hg; IR (neat): 3338, 3077, 2930, 2860, 1640, 1442, 1054, 994, 910 cm" 1; 1 H NMR (200 MHz, CDCI 3 ) : 5 5.68-5.89 (m, 1H), 4.90-5.02 (m, 2H), 3.61 (t, J = 6.5 Hz, 2H), 2.04 (m, 2H), 1.52 (m, 3H), 1.37 (m 4H); 1 3 C NMR (50 MHz, CDCI 3): 5 138.85, 113.90, 62.86, 33.69, 32.57, 28.66, 25.21; L R M S (El) m/z (relative intensity): 114 (M + , 10), 97 (20), 96 (70), 95 (25), 81 (100), 68 (68), 67 (81), 55 (66), 54 (51), 53 (20); H R M S (El) m/z calculated for C 7 H 1 4 0 : 114.10447, found: 114.10431; 3.3.5 6-Heptenyltosylate (40) Alcohol 34 (4.10 g, 35.9 mmol) was added to a solution of p-toluenesulfonyl chloride (8.90 g, 46.7 mmol) in pyridine (12 mL) at 0°C. The reaction was stirred for 60 minutes at 0°C, warmed to rt, and stirred for 3 hours at s 66 rt. Water was added to the reaction, the organic layer was collected, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, and sequentially washed with water and brine, and dried over anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 30% diethyl ether in petroleum ether as eluant afforded tosylate 40 (8.15 g, 30.4 mmol) in 85% yield as a clear pale yellow oil. IR (neat): 2931, 28.60, 1640, 15.99, 1455, 1360, 1307, 1189, 1177, 1098, 937, 820 cm'1; 1H NMR (200 MHz, CDCI3): 5 7.77 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.30 Hz, 2H), 5.62-5.83 (m, 1H), 4.86-5.00 (m, 2H), 4.00 (t, J = 6.5, 2H), 2.43 (s, 3H), 1.97 (q, 2H), 1.61 (m, 2H), 1.30 (m, 4H); 1 3 C NMR (50 MHz, CDCI3): 8 144.77, 138.56, 133.36, 129.92, 127.99, 114.72, 70.67, 35.55, 28.78, 28.25, 24.91, 21.73; LRMS (Cl(+), ammonia) m/z (relative intensity): 286 (M++18, 100), 155 (5); HRMS (Cl(+), ammonia) m/z calculated for Ci4H 2 4 N0 3 S: 286.14771, found: 286.14780; Analysis calculated for Ci 4H 2oS0 3: C, 62.66; H, 7.51; S, 11.95. Found: C, 62.86; H, 7.59; S, 11.80. 3.3.6 6-Heptenylcyanide (41) Oven dried potassium cyanide (2.91 g, 44.7 mmol) was added to a solution of tosylate 40 (8.00 g, 29.8 mmol) and 18-crown-6 (0.027 g) in acetonitrile (35 mL) and the solution was heated at reflux for 24 hours. CH2CI2 was added, the solution was filtered by vacuum filtration and the solvent was 67 removed under reduced pressure. Distillation of the resulting oil afforded nitrile 41 (2.57 g, 20.9 mmol) in 7 0 % yield as a clear colour less oil. bp: 108 ° C / 2 3 mm Hg; IR (neat): 3077, 2932, 2861 , 2246, 1641, 1428, 996, 913 cm" 1 ; 1 H N M R (200 M H z , C D C I 3 ) : 8 5.64-5.86 (m, 1H), 4.85-5.04 (m, 2H), 2.31 (t, J = 6.5 Hz , 2H), 2.05 (q, 2H), 1.60 (m, 2H), 1.40 (m, 4H); 1 3 C N M R (50 M H z , C D C I 3 ) : 8 138.37, 119.84, 114.92, 33.44, 28.17, 28.08, 25.33, 21.59, 17.18; L R M S (El) m/z (relative intensity): 123 ( M + , 10), 122 (59), 95 (30), 94 (100), 82 (22), 80 (25), 55 (44); H R M S (El) m/z calculated f o r C 8 H 1 2 N : 122.09697, found: 122.09707; Ana lys is calculated for C n H 2 2 0 3 : C , 65.97; H, 10.07. Found : C , 66.02; H, 10.14. 3.3.7 7 -Octenoic acid ( 3 3 ) 1 0 3 Potass ium hydroxide (4.34 g, 77.3 mmol) was added to a solution of nitrile 41 (2.38 g, 19.3 mmol) in ethylene glycol (25 mL) and the reaction was stirred at 150 °C for 6 hours. A second portion of potassium hydroxide (4.34 g, 77.3 mmol) was added and the reaction was stirred at 150 °C for 12 hours. Wate r was added and the reaction solution was washed with diethyl ether. The aqueous solution was acidif ied with concentrated HCI and extracted with diethyl ether. The organic layers were combined, washed with brine and dried over anhydrous M g S 0 4 . The extracts were filtered and the solvent was removed under reduced pressure. Distillation of the resulting oil afforded acid 33 (2.61 g, 18.3 mmol) in 9 5 % yield as a c lear pale yel low oil. bp: 135 ° C / 9 mm Hg; 68 IR (neat): 2979, 2865, 1711, 1641, 1425, 1282, 1231, 994, 913 cm"1; 1 H NMR (200 MHz, CDCI 3): 5 11.10 (s, w, 1H), 5.67-5.89 (m, 1H), 4.86-5.06 (m, 1H), 2.34 (t, J = 7.38 Hz, 2H), 2.03 (q, 2H), 1.63 (m, 2H), 1.63 (m, 2H), 1.37 (m, 4H); 1 3 C NMR (50 MHz, CDCI 3): 5 180.33, 138.71, 114.45, 34.02, 33.49, 28.47 (2), 24.48; LRMS (El) m/z (relative intensity): 142 (M + , 5), 124 (91), 100 (25), 96 (49), 83 (37), 82 (73), 67 (29), 60 (42), 55 (100); HRMS (El) m/z calculated for C 8 H 1 4 0 2 : 142.09938, found: 142.09912; Analysis calculated for C 8 H i 4 0 2 : C, 67.57; H, 9.92. Found: C, 67.63; H, 9.96. 3.3.8 6-Heptenal (42) A solution of dimethylsulfoxide (1.93 mL, 48.3 mmol) in CH2CI2 (15 mL) was added via cannula to a solution of oxalyl chloride (1.93 mL, 22.2 mmol) in CH2CI2 (50 mL) at -78 °C. The solution was stirred for 5 minutes and alcohol 34 (2.30 g, 20.1 mmol) in CH2CI2 (15 mL) was added via cannula. This mixture was stirred for 15 minutes at -78 °C. Triethylamine (13.2 mL, 94.7 mmol) was added, the mixture was stirred for 5 minutes, and warmed to rt. The reaction was quenched with water, the organic layer was collected, and the aqueous layer was extracted with CH2CI2. The organic layers were combined, sequentially washed with 1N HCI solution, water, 5% Na 2 C0 3 solution, and brine, and dried over anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. Distillation of the resulting oil afforded aldehyde 42 (1.92g, 17.1 mmol) in 77% yield as a clear colourless oil. bp: 80°C/30 mm Hg; IR (neat): 3077, 2930, 2721, 1725, 1641, 1425, 996, 913 cm"1; H O 69 1H NMR (200 MHz, CDCI3): 5 9.75 (s, 1H), 5.65-5.91 (m, 1H), 4.86-5.08 (m, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.06 (q, 2H), 1.20-1.79 (m, 4H); 1 3 C NMR (50 MHz, CDCI3): 8 202.47, 138.17, 114.76, 43.64, 33.35, 28.27, 21.44; LRMS (El) m/z (relative intensity): 112 (M+, 1) 94 (26), 79 (32), 69 (20), 68 (100), 67 (40), 57 (27), 56 (23), 55 (48); HRMS (El) m/z calculated forC 7H 1 20: 112.08882, found: 112.08833. 3.3.9 7 - O c t e n - 2 - o l (35) Methyllithium in diethyl ether (1.25 M, 15.7 mL, 19.6 mmol) was added dropwise to a solution of aldehyde 42 (1.83 g, 16.3 mmol) in THF (80 mL) at 0 °C. The reaction was stirred at 0 °C for 30 minutes, after which saturated NH4CI solution was added and the mixture was stirred a further 15 min at 0 °C. The reaction was diluted with diethyl ether, the organic layer was collected and the aqueous layer was extracted with diethyl ether. The organic layers were combined, and sequentially washed with water and brine, and dried over anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 30% diethyl ether in petroleum ether as eluant, followed by distillation of the resulting oil afforded alcohol 35 (1.48 g, 11.6 mmol) in 59% yield as a clear colourless oil. bp: 72 °C/10 mm Hg; IR (neat): 3349, 3078, 2969, 2931, 2858, 1642, 1462, 1374, 1122, 991, 911 cm"1; 1H NMR (200 MHz, CDCI3): 5 5.65-5.92 (m, 1H), 4.84-5.06 (m, 2H), 3.77 (m, 1H), 1.94-2.13 (m, 2H), 1.24-1.55 (m, 7H), 1.17 (d, J = 3.1 Hz, 3H); 1 3 C NMR (50 MHz, CDCI3): 8 139.02, 114.51, 68.22, 39.30, 33.85, 29.02, 25.36, HO 23.61; 70 LRMS (Cl(+), ammonia) m/z (relative intensity): 146 (M++18, 100), 144 (M++16), HRMS (Cl(+), ammonia/methane) m/z calculated for C 8 H 1 6 0: 146.15450, found: 146.15458. 3.3.10 6-Heptenyl-7'-Octenoate (31 )1 1,3-Dicyclohexylcarbodiimide (2.36 g, 11.4 mmol) was added to a solution of alcohol 34 (1.09 g, 9.53 mmol), acid 33 (1.36 g, 9.53 mmol) and 4-(dimethylamino)pyridine (140 mg, 1.14 mmol, 12 mol%) in dichloromethane (50 mL), and the reaction was stirred for 24 hours. The solvent was removed under reduced pressure, and column chromatography of the residue with 10% diethyl ether in petroleum ether as eluant followed by distillation of the resulting oil afforded diene ester 31 (1.98 g, 8.31 mmol) in 87% yield as a clear colourless oil. bp: 140 °C/ 9 mm Hg; IR (neat): 3077, 2931, 2858, 1737, 1641, 1453, 1178, 994, 911 cm"1; 1H NMR (500 MHz, CDCI3): 8 5.78 (m, 4H), 4.96 (m, 1H), 4.94 (m, 1H), 4.04 (t, J = 6.7 Hz, 2H), 2.27 (t, J = 7.6 Hz, 2H), 1.85-2.08 (m, 4H), 1.57-1.64 (m, 4H), 1.27-1.44 (m, 8H); 1 3 C NMR (50 MHz, CDCI3): 8 173.87, 138.81, 138.71, 114.46, 113.30, 64.28, 34.31, 33.58, 33.54, 28.70, 28.59, 28.48, 25.39, 24.83; LRMS (El) m/z (relative intensity): 238 (M+, 12), 125 (35), 124 (68), 97 (38), 96 (60), 83 (59), 82 (74), 81 (71), 68 (28), 67 (100), 54 (95), 53 (45); HRMS (El) m/z calculated forCi 5H 260 2: 238.19328, found: 238.19250. Analysis calculated for C i 5 H 2 6 0 2 : C, 75.58; H, 10.99. Found: C, 75.66: H, 11.07. 128 (3); .0 71 3 . 3 . 1 0 1 - M e t h y l - 6 - H e p t e n y l - 7 ' - O c t e n o a t e ( 3 2 ) 1,3-Dicyclohexylcarbodiimide (2.11 g, 10.2 mmol) was added to a solution of alcohol 35 (1.09 g, 8.51 mmol), acid 33 (1.21 g, 8.51 mmol) and 4-(dimethylamino)pyridine (125 mg, 1.02 mmol, 12 mol%) in dichloromethane (50 mL), and the reaction was stirred for 24 hours. The solvent was removed under reduced pressure, and column chromatography of the residue with 10% diethyl ether in petroleum ether as eluant followed by distillation of the resulting oil afforded diene ester 32 (1.82 g, 7.21 mmol) in 85% yield as a clear colourless oil. bp: 140 °C/7 mm Hg; IR (neat): 3077, 2932, 2859, 1734, 1641, 1462, 1178, 994, 911 cm"1; 1H NMR (500 MHz, CDCI3): 5 5.77 (m, 2H), 4.83-5.01 (m, 5H), 2.25 (t, J = 7.5 Hz, 2H), 2.02 (m, 4H), 1.23-1.64 (m, 12H), 1.17 (d, J = 6.3 Hz, 3H); 13C NMR (50 MHz, CDCI3): 5 173.44, 138.81, 138.73, 114.37, 113.27, 70.65, 35.77, 34.67, 33.60, 33.56, 28.67, 28.59, 28.53, 24.92, 24.85, 20.01; LRMS (El) m/z (relative intensity): 252 (M+, 2), 142, (21), 125 (53), 124 (41),111 (27), 110 (36), 107 (25), 96 (25), 95 (25), 83 (21), 82 (61), 81 (60), 69 (98), 68 (65), 67 (30), 55 (100), 54 (27); HRMS (El) m/z calculated for C 1 6H280 2: 252.20893, found: 252.20834; Analysis calculated forCi 6 H 2 80 2 : C, 76.14; H, 11.18. Found: C, 75.98: H, 11.38. 72 3.3.11 (7£)-13-Tridec-7-enolide (29)1 a) Ring closing olefin metathesis of 31 using the Grubbs catalyst 28 A deoxygenated solution of Grubbs' catalyst 28 (137 mg, 0.166 mmol, 2 mol%) in CH2CI2 (100 mL) was added via cannula over 30 minutes to a deoxygenated solution of diene ester 31 (1.98 g, 8.31 mmol) in CH2CI2 (3.9 L). The reaction was then stirred for 90 minutes and the reaction was quenched with 10 drops of triethylamine. The solvent was removed under reduced pressure and column chromatography of the residue with 10% diethyl ether in petroleum ether afforded a mixture of unsaturated lactones 29 and 43 (1.50 g, 7.15 mmol) in 86% yield. A GC analysis of the residue prior to chromatographic separation revealed a 95:5 E.Z composition. Further separation by silver nitrate impregnated TLC grade silica gel afforded the pure E isomer 29 (1.16g). mp: 34-35 °C; IR (neat): 2931, 2856, 1719, 1255, 976 cm"1; 1H NMR (500 MHz, CDCI3): 5 5.22 (m, 2H), 4.12 (t, J = 5.2 Hz, 1H), 2.29 (t, J = 6.1 Hz, 2H), 1.99 (m, 4H), 1.55 (m, 4H), 1.25-1.41 (m, 8H); 1H DECOUPLED NMR (500 MHz, CDCI3): Irradiation at 5 1.99, simplification of signal at 5.24 (d, J = 15.0 Hz, 1H) and at 5.21 (d, J = 15.0 Hz, 1H); 1 3 C NMR (50 MHz, CDCI3): 5 173.85, 131.49, 131.14, 63.24, 34.65, 31.47, 31.03, 28.05, 27.99, 27.24, 26.68, 25.12, 23.34; LRMS (El) m/z (relative intensity): 210 (M+,100), 82 (23); HRMS (El) m/z calculated for Ci 3H 2 20 2 : 210.16198, found: 210.16274; Analysis calculated forC 1 3H220 2: C.74.24; H, 10.54. Found: C, 74.46: H, 10.68. 73 b) Metathesis equilibrium study of 29 using Clp(PCvg)?Ru=CHp A deoxygenated solution of bis(tricyclohexylphosphine)methylidine ruthenium (IV) dichloride catalyst (2.0 mg, 0.0024 mmol, 2 mol%) in CH 2CI 2 (5 mL) was added via cannula to a deoxygenated solution of unsaturated lactone 29 (25.0 mg, 0.119 mmol) in CH2CI2 (55 mL). The reaction was then stirred for 3 hours and the reaction was quenched with 1 drop of triethylamine. The solvent was removed under reduced pressure and column chromatography of the residue with 10% diethyl ether in petroleum ether afforded a mixture of unsaturated lactones 29 and 43 (24.4 mg, 0.116 mmol) in 98% yield. A GC analysis of the residue prior to chromatographic separation revealed a 96:4 E:Z composition. 3.3.12 (7£)-13-Tetradec-7-enolide (30) a) Ring closing olefin metathesis of 32 using the Grubbs catalyst 28 A deoxygenated solution of Grubbs' catalyst 28 (112 mg, 0.136 mmol, 2 mol%) in CH2CI2 (100 mL) was added via cannula over 30 min to a deoxygenated solution of diene ester 32 (1.72 g, 6.81 mmol) in CH2CI2 (3.3 L). The reaction was then stirred for 90 minutes and the reaction was quenched with 10 drops of triethylamine. The solvent was removed under reduced pressure and column chromatography of the residue with 10% diethyl ether in petroleum ether afforded unsaturated lactones 30 and 44 (1.30 g, 5.79 mmol) in 85% yield. A GC analysis of the residue prior to chromatographic separation showed a 94:6 EZ composition. Further purification by silver nitrate impregnated TLC grade silica gel afforded the pure E isomer 30 (1.06 g). 74 IR (neat): 2928, 2854, 1729, 1446, 1334, 1248, 1207, 1132, 1095, 970 cm"1; 1H NMR (500 MHz, CDCI3): 8 5.21 (m, 2H), 5.00 (m, 1H), 2.27 (t, J = 5.35 Hz, 2H), 2.07-1.91 (m, 4H), 1.67-1.18 (m, 12H), 1.17 (d, J = 5.4 Hz, 3H); 1H DECOUPLED NMR (500 MHz, CDCI3): Irradiation at 8 1.99, simplification of signal at 5.22 (d, J = 15.4 Hz, 1H) and at 5.19 (d, J = 15.4 Hz, 1H); 1 3 C NMR (50 MHz, CDCI3): 8 173.88, 131.80, 131.49, 70.15, 35.76, 35.14, 31.64, 28.51, 28.14, 27.79, 27.06; 25.32, 23.60, 20.83; LRMS (El) m/z (relative intensity): 224(M+,37), 110 (28), 109 (33), 108 (24), 96 (86), 95 (67), 94 (69), 93 (20), 82 (76), 81 (89), 80 (24), 79 (36), 69 (23), 68 (60), 67 (100), 55 (53), 54 (40); HRMS (El) m/z calculated for C14H24O4: 224.17763, found: 224.17737; Analysis calculated f o r C i 4 H 2 4 0 2 : C, 74.95; H, 10.78. Found: C, 74.82; H, 10.95. b) Metathesis equilibrium study of 30 using Clp(PCy3)?Ru=CH? A deoxygenated solution of bis(tricyclohexylphosphine)methylidine ruthenium (IV) dichloride catalyst (1.8 mg, 0.0022 mmol, 2 mol%) in CH 2CI 2 (5 mL) was added via cannula to a deoxygenated solution of unsaturated lactone 30 (25.0 mg, 0.111 mmol) in CH2CI2 (50 mL). The reaction was then stirred for 3 hours and the reaction was quenched with 1 drop of triethylamine. The solvent was removed under reduced pressure and column chromatography of the residue with 10% diethyl ether in petroleum ether afforded a mixture of unsaturated lactones 30 and 44 (24.1 mg, 0.107 mmol) in 96% yield. A GC analysis of the residue prior to chromatographic separation revealed a 95:5 E:Z composition. c) Metathesis eguilibrium study of 30 and 44 using CI?(PCv:])?Ru=CH? A deoxygenated solution of bis(tricyclohexylphosphine)methylidine ruthenium (IV) dichloride catalyst (0.4 mg, 0.0005 mmol, 2 mol%) in CH2CI2 (1 mL) was added via cannula to a deoxygenated solution of a 64:36 mixture of unsaturated lactones 30 and 44 (5.0 mg, 0.022 mmol) in CH2CI2 (10 mL). The reaction was then stirred for 3 hours and the reaction was quenched with 1 drop 75 of triethylamine. A GC analysis of the reaction mixture revealed a 94:6 E\Z composition. 3.3.13 7-Hydroxy-13-Tridecanolide (47)101 and 8-Hydroxy-13-Tridecanolide (48) a) Hydroboration of 29 with borane-THF at rt A solution of borane-THF complex in THF (1 M, 950 u\L, 0.950 mmol) was added dropwise to a stirred solution of lactone 29 (100.2 mg, 0.4764 mmol) in THF (5 mL). The reaction was stirred for 4 hours and then cooled to 0 °C. 3N NaOH (400 uL) and 30% H 2 0 2 (800 uL) were added sequentially and the reaction was warmed to rt and stirred for 30 minutes at rt. Water was added and the reaction solution was extracted with CH2CI2. The organic extracts were combined, washed with brine, and dried over anhydrous MgSCU. The extracts were filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 3% methanol in CH2CI2 as eluant afforded a mixture of hydroxy lactones 47 and 48 (95.4 mg, 0.418 mmol) in 88% yield as a clear pale yellow oil. To a solution of hydroxy lactones 47 and 48 (95.4 mg, 0.418 mmol) and triethylamine (117 uL, 836 mmol) in THF (5mL) was added chlorotrimethylsilane (106 (iL, 836 mmol) dropwise. The reaction was stirred for 24 hours and then diluted with diethyl ether, washed with NaHC03, and dried over anhydrous MgSCU. The extracts were filtered and the solvent was removed under reduced pressure. Radial chromatography of the residue with 10% ethyl acetate in hexanes afforded separated silyl ethers 49 (57.8 mg, 0.192 mmol) and 50 (57.5 76 mg, 0.191 mmol) as a clear pale yellow oils in a total yield of 92% for 49 and 50. A GC analysis of the residue prior to chromatographic separation revealed a 50:50 composition of silyl ethers 49 and 50. A solution of tetrabutylammonium fluoride in THF (1 M, 384 |LLL, 0.384 mmol) was added to a solution of silyl ether 49 (57.8 mg, 0.192 mmol) in THF (5 mL) and the reaction was stirred for 2 hours. Water was added and the reaction mixture was extracted with diethyl ether. The organic layers were combined and dried over anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 3% methanol in CH2CI2 as eluant afforded hydroxy lactone 47 (44.2 mg, 0.182 mmol) in 95% yield as a clear colourless oil. The same procedure for silyl ether 50 (57.5 mg, 0.191 mmol) afforded hydroxy lactone 48 (43.6 mg, 0.180 mmol) in 94% yield as a white solid. 47 IR (neat): 3403, 2942, 2861, 1733, 1461, 1347, 1250, 1147, 1106, 996, 918 cm"1; 1H NMR (500 MHz, CDCI3): 8 4.28 (m, 1H), 3.95 (m, 1H), 3.69 (m, 1H), 2.42 (m, 1H), 2.24 (m, 1H), 1.10-1.82 (m, 19H); 1 3 C NMR (50 MHz, CDCI3): 8 173.64, 68.02, 63.26, 35.51, 33.96, 32.28, 27.56, 26.42, 24.96, 24.69, 23.89, 23.08, 22.54; LRMS (El) m/z (relative intensity): 228 (M+,1), 127 (100), 117 (30), 113 (25), 99 (24), 98 (41), 95 (50), 81 (47), 69 (20), 55 (38); HRMS (El) m/z calculated for C 1 4 H 2 4 0 4 : 228.17254, found: 228.17218; 48 mp: 79-80 °C; IR (KBr): 3382, 2942, 2864, 1724, 1463, 1255, 1149, 1098, 1028, 995 cm"1; 1H NMR (400 MHz, CDCI3): 8 4.28 (m, 1H), 3.96 (m, 1H), 3.69 (m, 1H), 2.43 (m, 1H), 2.26 (m, 1H), 1.11-1.88 (m, 19H); 1 3 C NMR (50 MHz, CDCI3): 8 173.79, 68.56, 63.00, 35.50, 34.34, 32.08, 27.54, 26.02, 25.77, 24.55, 23.50, 23.24, 22.59; 77 LRMS (El) m/z (relative intensity): 228 (M+,1), 127 (100), 117 (30), 113 (25), 99 (24), 98 (41), 95 (50), 81 (47), 26 (73), 69 (34), 56 (24), 55 (32); HRMS (El) m/z calculated forC 1 4 H240 4 : 228.17254, found: 228.17264; Analysis calculated for C 1 4 H 2 4 0 2 : C, 74.95; H, 10.78. Found: C, 74.82; H,10.95. b) Hydroboration of 29 with borane-THF at -78 °C A solution of borane-THF complex in T H F (271 uL, 0.271 mmol) was added dropwise to a stirred solution of lactone 29 (28.5 mg, 0.136 mmol) in T H F (2 mL) at -78 °C and the reaction was stirred for 20 hours. Standard work-up and purification, as outlined in method (a), gave hydroxy lactones 47 and 48 (27.8 mg, 0.122 mmol) in 90% yield and in a ratio of 50:50 (GC analysis of TMS ethers) as a clear pale yellow oil. c) Hydroboration of 29 with disiamylborane A solution of disiamylborane in T H F (260 uL, 0.260 mmol) was added dropwise to a stirred solution of lactone 29 (27.3 mg, 0.130 mmol) in THF (2 mL) and the reaction was stirred at rt for 24 hours. Standard work-up and purification, as outlined in method (a), yielded hydroxy lactones 47 and 48 (25.5 mg, 0.112 mmol) in 86% yield and in a ratio of 50:50 (GC analysis of TMS ethers) as a clear pale yellow oil. d) Hydroboration of 29 with 9BBN A solution of lactone 29 (25.1 mg, 0.119 mmol) in T H F (0.5 mL) was added dropwise to a solution of 9BBN dimer (29.8 mg, 0.122 mmol) dissolved in T H F (1.5 mL) and the reaction was stirred at rt for 13 hours. Standard work-up, as outlined in method (a), and purification yielded hydroxy lactones 47 and 48 (25.3 g, 0.111 mmol) in 93% yield and in a ratio of 46:54 (GC analysis of TMS ethers) as a clear pale yellow oil. 78 3.3.14 (8R*, 13S*)-8-(/V-Phenylcarbamoyl)oxy-13-Tetradecanolide (55), (7S*, 13S*)-7-(A/-Phenylcarbamoyl)oxy-13-Tetradecanolide (56), (7FT, 13S*)-7-(A/-Phenylcarbamoyl)oxy-13-Tetradecanolide (57) and (8S*, 13S*)-8-(A/-Phenylcarbamoyl)oxy-13-Tetradecanolide (58) 55 56 57 58 a) Hydroboration of 30 with borane-THF at rt A solution of borane-THF complex in THF (1.25 mL, 1.25 mmol) was added dropwise to a stirred solution of lactone 30 (140.3 mg, 0.6254 mmol) in THF (6 mL). The reaction was stirred for 4 hours and cooled to 0 °C. 3N NaOH (525 |iL) and 30% H2O2 (950 |iL) were added sequentially and the reaction was warmed to rt and stirred for 30 minutes at rt. Water was added and the reaction solution was extracted with CH2CI2. The organic extracts were combined, washed with brine, and dried over anhydrous MgS04. The extracts were filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 3% methanol in CH2CI2 as eluant afforded a mixture of hydroxy lactones 51, 52, 53 and 54 (136.3 mg, 0.5629 mmol) in 90% yield as a clear colourless oil. Phenyl isocyanate (612 JIL, 5.63 mmol) was added to a solution of hydroxy lactones 51, 52, 53 and 54 (136.3 mg, 0.5629 mmol) in pyridine at 0°C. The reaction was stirred at rt for 30 minutes and the solvent was removed under reduced pressure. The residue was taken up in diethyl ether and water was added. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic extracts were combined, washed with brine, and dried over anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. TLC grade column chromatography of the 79 residue with 20% ethyl acetate in hexanes afforded separated carbamate derived hydroxy lactones 55 (75.2 mg, 0.208 mmol) as a white solid and 56 (36.2 mg, 0.100 mmol) as a white solid, and an inseparable mixture of carbamate derived hydroxy lactones 57 and 58 (91.6 mg, 0.253 mmol) as a white solid in a total yield of 100% for 55, 56, 57 and 58. An HPLC analysis of the residue prior to chromatographic separation showed a 37:18:31:14 composition of 55, 56, 57 and 58. 55 mp: 80-82 °C; IR (KBr): 3337, 2928, 2861, 1724, 1713, 1601, 1545, 1503, 1445, 1331, 1314, 1227, 1137, 1083, 1054, 1031 cm'1; 1H NMR (400 MHz, CDCI3): 5 7.35 (d, J = 7.9 Hz, 2H), 7.27 (td, J = 7.9, 2.0 Hz, 2H), 7.01 (tt, J =7.3, 1.2 Hz, 1H), 6.53 (s, 1H), 5.01 (m, 1H), 4.86 (m, 1H), 2.21- 2.48 (m, 2H), 1.17-1.84 (m, 21H), 1.20 (d, J = 8.4 Hz, 3H); 1 3 C NMR (50 MHz, CDCI3): 8 173.50, 153.55, 138.11, 128.95, 123.13, 118.47, 72.68, 69.34, 34.91, 34.44, 32.94, 29.40, 25.93, 25.39, 24.60, 23.99, 23.08, 22.41, 20.11; LRMS (Cl(+), ammonia) m/z (relative intensity): 379 (M++18, 41), 363 (M++2, 22), 362 (M++1, 98), 361 (M+, 52), 260 (85), 242 (43), 225 (47), 207 (22), 158 (21), 155 (20), 119 (78), 95 (24), 94 (34), 93 (100); HRMS (Cl(+), ammonia/methane) m/z calculated for C 2 iH 3 2 N0 4 : 362.23312, found: 362.23292; 56 mp: 124-125 °C; IR (KBr): 3318, 2943, 2863, 1729, 1693, 1600, 1544, 1503, 1444, 1315, 1235, 1195, 1164, 1098, 1052, 1027 cm"1; 1H NMR (500 MHz, CDCI3): 5 7.37 (d, J = 7.9 Hz, 2H), 7.28 (td, J = 7.9, 2.0 Hz, 2H), 7.02 (tt, J =7.3, 1.2 Hz, 1H), 6.58 (s, 1H), 5.03 (m, 1H), 4.94 (m, 1H), 2.22- 2.48 (m, 2H), 1.15-1.83 (m, 21H), 1.21 (d, J = 6.4 Hz, 3H); 80 1 3 C NMR (50 MHz, CDCI3): 6 173.90, 153.41, 138.16, 128.98, 123.14, 118.47, 73.34, 70.74, 34.91, 34.44, 32.94, 29.40, 25.93, 25.39, 24.60, 23.99, 23.08, 22.41, 20.11; LRMS (Cl(+), ammonia) m/z (relative intensity): 379 (M++18, 29), 363 (M++2, 16), 362 (M++1, 73), 361 (M+, 44), 260 (48), 242 (35), 225 (52), 207 (20), 155 (21), 119(72), 94 (31), 93 (100); HRMS (Cl(+), ammonia/methane) m/z calculated for C21H32NO4: 362.23312, found: 362.23385; 57 mp: 148.149 °C; IR (KBr): 3341, 2927, 2857, 1725, 1708, 1600, 1543, 1501, 1444, 1315, 1226, 1084,1052,1029 cm"1; 1H NMR (400 MHz, CDCI3): 6 7.36 (d, J = 7.9 Hz, 2H), 7.27 (td, J = 7.9, 2.0 Hz, 2H), 7.01 (tt, J =7.3, 1.2 Hz, 1H), 6.53 (s, 1H), 5.01 (m, 1H), 4.86 (m, 1H), 2.22-2.46 (m, 2H), 1.15-1.86 (m, 21H), 1.20 (d, J = 6.4 Hz, 3H); 1 3 C NMR (50 MHz, CDCI3): 5 173.00, 153.38, 138.12, 128.98, 123.13, 118.46, 72.97, 69.80, 34.44, 33.94, 32.77, 29.49, 26.34, 25.63, 24.91, 24.05, 22.96, 21.76, 19.88; LRMS (Cl(+), ammonia) m/z (relative intensity): 379 (M++18, 29), 362 (M++1, 46), 361 (M+, 19), 260 (22), 225 (31), 119 (73), 94 (35), 93 (100); HRMS (Cl(+), ammonia/methane) m/z calculated for C 2 i H 3 2 N 0 4 : 362.23312, found: 362.23335; 57 and 58 mp: 135-137 °C; IR (CDCI3): 3440, 2931, 2859, 1727, 1708, 1600, 1543, 1502, 1444, 1314, 1226, 1132,1084,1053,1029 cm"1; 1H NMR (400 MHz, CDCI3): 5 7.35 (m, 2H), 7.27 (m, J = 7.9, 2H), 7.01 (m, 1H), 6.59 (s, 1H), 5.01 (m, 1H), 4.88 (m, 1H), 2.21-2.48 (m, 2H), 1.17-1.87 (m, 21H), 1.20 (m, 3H); 81 1 3 C NMR (50 MHz, CDCI3): 5 173.70, 173.02, 153.42, 153.38, 138.18, 138.15, 129.01, 128.95, 123.17, 123.08, 118.52, 118.41, 72.98, 70.74, 69.84, 69.78, 35.50, 35.07, 34.48, 33.97, 33.91, 32.82, 31.85, 29.53, 26.59, 26.44, 26.31, 25.56, 24.95, 24.77, 24.11, 24.03, 23.00, 22.92, 21.79, 21.33,19.92,19.77; LRMS (Cl(+), ammonia) m/z (relative intensity): 379 (M++18, 9), 362 (M++1, 21), 361 (M+, 10), 260 (81), 242 (24), 225 (48), 119 (100), 94 (26), 93 (44); HRMS (Cl(+), ammonia/methane) m/z calculated for C21H32NO4: 362.23312, found: 362.23336; b) Hydroboration of 30 with borane-THF at -78 °C A solution of borane-THF complex in THF (248 uL, 0.248 mmol) was added dropwise to a stirred solution of lactone 30 (30.0 mg, 0.124 mmol) in THF (2 mL) at -78 °C and the reaction was stirred for 24 hours. Standard work-up and purification, as outlined in method (a), yielded hydroxy lactones 51, 52, 53 and 54 (27.9 mg, 0.115 mmol) in 93% yield and in a ratio of 42:17:33:8 (HPLC analysis of carbamates) as a clear colourless oil. c) Hydroboration of 30 with disiamylborane A solution of disiamylborane in THF (290 u\L, 0.290 mmol) was added dropwise to a stirred solution of lactone 30 (32.5 mg, 0.145 mmol) in THF (2 mL) and the reaction was stirred at rt for 24 hours. Standard work-up and purification, as outlined in method (a), yielded hydroxy lactones 51, 52, 53 and 54 (29.7 mg, 0.123 mmol) in 85% yield and in a ratio of 41:18:31:10 (HPLC analysis of carbamates) as a clear colourless oil. d) Hydroboration of 30 with 9BBN A solution of lactone 30 (33.4 mg, 0.149 mmol) in THF (0.5 mL) was added dropwise to a solution of 9BBN dimer (36.4 mg, 0.149 mmol) dissolved in THF (1.5 mL) and the reaction was stirred at rt for 12 hours. Standard work-up and purification, as outlined in method (a), yielded hydroxy lactones 51, 52, 53 82 and 54 (33.3 mg, 0.137 mmol) in 92% yield and in a ratio of 45:8:43:4 (HPLC analysis of carbamates) as a clear colourless oil. e) Dehaloqenation of 65 with n-tributvltin hydride n-Tributyltin hydride (33 fiL, 0.12 mmol) was added to a solution of chlorohydroxy lactone 65 (31.1 mg, 0.112 mmol) and 2,2'-azobisisobutyronitrile (3 mg, 0.02 mmol, 16 mol%) in toluene (0.5 mL). The reaction was stirred at 85°C for 1 hour and then diluted with diethyl ether. The reaction was washed with water and the organic layer was dried over anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. Radial chromatography using 2% methanol in CH2CI2 as eluant afforded hydroxy lactone 51 (25.5 mg, 0.105 mmol) in 94% yield as a clear colourless oil. f) Dehaloqenation of 66 with n-tributvltin hydride n-Tributyltin hydride (36 ul , 0.13 mmol)) was added to a solution of chlorohydroxy lactone 66 (33.7 mg, 0.122 mmol) and 2,2'-azobisisobutyronitrile (3 mg, 0.02 mmol, 15 mol%) in toluene (0.5 mL). The reaction was stirred at 85°C for 1 hour and then diluted with diethyl ether. The reaction was washed with water and the organic layer was dried over anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. Radial chromatography using 2% methanol in CH2CI2 as eluant afforded hydroxy lactone 53 (27.7 mg, 0.114 mmol) as a clear colourless oil. g) Reduction of 67 with sodium borohydride at -78 °C Sodium borohydride (3.8 mg, 0.10 mmol) was added in one portion to a solution of keto lactone 67 (20.0 mg, 0.0832 mmol) in methanol (2 mL) at -78 °C. The reaction was stirred at -78 °C for 1 hour and then quenched with 2 drops of 1N HCI solution. The reaction mixture was diluted with ethyl acetate, washed with brine and the organic layer was dried over anhydrous MgS0 4. The organic layer was filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 3% methanol in CH2CI2 chloride as eluant 83 afforded a mixture of hydroxy lactones 52 and 53 (16.7 mg, 0.0689 mmol) in 80% yield and in a ratio of 50:50 (HPLC analysis of carbamates) as a clear colourless oil. h) Reduction of 6 8 with sodium borohydride at -78 °C Sodium borohydride (3.5 mg, 0.09 mmol) was added in one portion to a solution of keto lactone 6 8 (19.8 mg, 0.0823 mmol) in methanol (2 mL) at -78 °C. The reaction was stirred at -78 °C for 1 hour and then quenched with 2 drops of 1N HCI solution. Standard work-up and purification, as outlined in method (g), yielded hydroxy lactones 51 and 54 (33.3 mg, 0.137 mmol) in 83% yield and in a ratio of 50:50 (HPLC analysis of carbamates) as a clear colourless oil. i) Reduction of 6 7 with sodium borohydride in the presence of cerium chloride at -78 °C Sodium borohydride (4.6 mg, 0.12 mmol) was added in one portion to a solution of cerium chloride heptahydrate (36.2 mg, 0.120 mmol), and keto lactone 6 7 (25.4 mg, 0.106 mmol) in methanol (2 mL) at -78 °C. The reaction was stirred at -78 °C for 1 hour and then quenched with 2 drops of 1N HCI solution. The solvent was removed under reduced pressure and the residue was dissolved in diethyl ether and washed with saturated NaHC0 3 solution. The organic layer was separated and dried over anhydrous MgS04. The solution was filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 3% methanol in CH2CI2 as eluant afforded a mixture of hydroxy lactones 52 and 53 (22.3 mg, 0.0920 mmol) in 86% yield and in a ratio of 55:45 (HPLC analysis of carbamates) as a clear colourless oil. j) Reduction of 6 8 with sodium borohydride in the presence of cerium chloride at -78 °C Sodium borohydride (4.1 mg, 0.11 mmol) was added in one portion to a solution of cerium chloride heptahydrate (33.2 mg, 0.110 mmol), and keto lactone 6 8 (21.8 mg, 0.0907 mmol) in methanol (2 mL) at -78 °C. The reaction was 84 stirred at -78 °C for 1 hour and then quenched with 2 drops of 1N HCI solution. Standard work-up and purification, as outlined in method (i), yielded hydroxy lactones 51 and 54 (18.9 mg, 0.0780 mmol) in 87% yield and in a ratio of 56:44 (HPLC analysis of carbamates) as a clear colourless oil. k) Reduction of 67 with K-Selectride at -15 °C A solution of K-Selectride in THF (1M, 215 JLLL, 0.215 mmol) was added to a solution of keto lactone 67 (25.8 mg, 0.107 mmol) in THF (3 mL) at -15 °C. The reaction was stirred at -15 °C for 30 minutes and then 1N HCI solution (100 |iL) and 30% H2O2 (100 jxL) were added sequentially. The reaction was warmed to rt, diluted with diethyl ether, and washed with NaHC0 3 solution and brine. The organic layer was dried over anhydrous MgS0 4, the extracts were filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 3% methanol in CH2CI2 as eluant afforded a mixture of hydroxy lactones 52 and 53 (23.3 mg, 0.0961 mmol) in 83% yield and in a ratio of 87:13 (HPLC analysis of carbamates) as a clear colourless oil. I) Reduction of 68 with K-Selectride at -15 °C A solution of K-Selectride in THF (1M, 235 uL, 0.235 mmol) was added to a solution of keto lactone 68 (28.2 mg, 0.117 mmol) in THF (3 mL) at -15°C. The reaction was stirred at -15°C for 30 minutes and then 1N HCI solution (100 \iL) and 30% H2O2 (100 uL) were added sequentially. Standard work-up and purification, as outlined in method (k), yielded hydroxy lactones 51 and 54 (23.5 mg, 0.0970 mmol) in 90% yield and in a ratio of 47:53 (HPLC analysis of carbamates) as a clear colourless oil. m) Reduction of 67 with K-Selectride at -78 °C A solution of K-Selectride in THF (1M, 184 \iL, 0.184 mmol) was added to a solution of keto lactone 67 (22.1 mg, 0.0920 mmol) in THF (3 mL) at -78 °C. The reaction was stirred at -78 °C for 30 minutes and then 1N HCI solution (100 85 uL) and 30% H2O2 (100 uL) were added sequentially. Standard work-up and purification, as outlined in method (k), yielded a mixture of hydroxy lactones 52 and 53 (20.5 mg, 0.0846 mmol) in 91% yield and in a ratio of 91:9 (HPLC analysis of carbamates) as a clear colourless oil. n) Reduction of 68 with K-Selectride at -78 °C A solution of K-Selectride in THF (1M, 208 uL, 0.208 mmol) was added to a solution of keto lactone 68 (25.0 mg, 0.104 mmol) in THF (3 mL) at -78 °C. The reaction was stirred at -78 °C for 30 minutes and then 1N HCI solution (100 uL) and 30% H 2 0 2 (100 uL) were added sequentially. Standard work-up and purification, as outlined in method (k), yielded hydroxy lactones 21 and 22 (23.4 mg, 0.0966 mmol) in 89% yield and in a ratio of 40:60 (HPLC analysis of carbamates) as a clear colourless oil. 3.3.15 6-(/V-Phenylcarbamoyl)oxy-13-Tetradecanolide (61, 62) and 7-(/V-Phenylcarbamoyl)oxy-13-Tetradecanolide (56, 57) 56 61 57 62 A solution of borane-THF complex in THF (1M, 0.180 uL, 0.180 mmol) was added dropwise to a stirred solution of a 64:36 mixture of unsaturated lactones 59 and 60 (20.2 mg, 0.0900 mmol) in THF (2 mL). The reaction was stirred for 4 hours and cooled to 0 °C. 3N NaOH (75 uL) and 30% H 2 0 2 (150 uL) were sequentially added and the reaction was warmed to rt and stirred for 30 minutes. Water was added and the reaction solution was extracted with CH2CI2. The organic extracts were combined, washed with brine, and dried over 86 anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 3% methanol in CH2CI2 as eluant afforded a mixture of hydroxy lactones (18.6 mg, 0.0767 mmol) in 85% yield as a clear colourless oil. Phenyl isocyanate (84 [il_, 0.77 mmol) was added to the mixture of hydroxy lactones (18.6 mg, 0.0767 mmol) in pyridine at 0 °C. The reaction was stirred at rt for 30 minutes and the solvent was removed under reduced pressure. The residue was taken up in diethyl ether and water was added. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic extracts were combined, washed with brine, and dried over anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 20% ethyl acetate in hexanes afforded a mixture of carbamate derived hydroxylactones 5 6 , 6 1 , 5 7 and 6 2 (27.5 mg, 0.0761 mmol) in 99% yield as a yellow oil. An HPLC analysis of the residue prior to chromatographic separation showed a 10:25:49:16 composition. 5 6 , 6 1 , 5 7 and 6 2 IR (CDCI3): 3333, 2943, 2864, 1727, 1708, 1600, 1543, 1443, 1315, 1226, 1051, 1027 cm"1; 1H NMR (400 MHz, CDCI3): 5 7.35 (m, 2H), 7.27 (m, 2H), 7.02 (m, 1H), 6.52 (m, 1H), 5.01 (m, 1H), 4.87 (m, 1H), 2.22-2.47 (m, 2H), 1.17-1.85 (m, 21H); LRMS (El) m/z (relative intensity): 379 (M++18, 31), 362 (M++1, 65), 361 (M+, 31), 260 (38), 242 (20), 225 (57), 119 (52), 94 (25), 93 (100); HRMS (El) m/z calculated for C 1 4 H 2 4 0 4 : 362.23312, found: 362.23225; 87 3.3.17 (7S*, 8S*, 13S*)-7,8-Epoxy-13-Tetradecanolide (63) and (7FT, 8FT, 13S*)-7,8-Epoxy-13-Tetradecanolide (64) 63 64 a) Epoxidation of 30 with MCPBA at rt 57-86% MCPBA (375 mg, 1.22-1.90 mmol), was added to a solution of lactone 30 (250 mg, 1.12 mmol) in CH2CI2 (13 mL) at 0 °C. The reaction was stirred for 30 minutes at rt, and then washed with NaOH solution, water and dried over anhydrous MgS0 4. The organic layer was filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 30% diethyl ether in petroleum ether as eluant afforded a mixture of epoxy lactones 63 and 64 (264 mg, 1.10 mmol) in 98% yield as a clear colourless oil. A GC analysis of the oil revealed a 67:33 composition of 63 and 64. Further purification by TLC grade column chromatography afforded pure samples of 63 (66 mg) as a clear pale yellow oil and 64 (6 mg) as a clear pale yellow oil. 63 IR (neat): 2932, 2859, 1729, 1461, 1365, 1338, 1288, 1253, 1162, 1120, 1006, 914,816,778 cm"1; 1H NMR (500 MHz, CDCI3): 5 5.00 (m, 1H), 2.59 (m, 1H), 2.32 (m, 1H), 2.04-2.31 (m, 2H), 0.87-1.87 (m, 16H), 1.20 (d, J = 6.4 Hz, 3H); 1 3 C NMR (50 MHz, CDCI3): 5 173.66, 69.80, 59.12, 59.07, 36.51, 34.25, 32.26, 32.16, 28.08, 25.88, 25.86, 25.54, 25.41, 20.87; LRMS (El) m/z (relative intensity): 240 (M+, 4), 112 (22), 98 (28), 97 (52), 96 (35), 95 (36), 83 (20), 81 (65), 69 (29), 68 (33), 67 (43), 55 (100); HRMS (El) m/z calculated f o r C i 4 H 2 4 0 4 : 240.17254, found: 240.17191; 88 64 IR (neat): 2932, 2860, 1729, 1458, 1362, 1336, 1290, 1254, 1163, 1131, 1108, 1019, 1003, 913, 821, 768 cm"1; 1H NMR (500 MHz, CDCI3): 5 5.02 (m, 1H), 2.58 (m, 1H), 2.21 (m, 1H), 2.23-2.46 (m, 2H), 0.78-1.72 (m, 16H), 1.19 (d, J = 6.3 Hz, 3H); 1 3 C NMR (50 MHz, CDCI3): 5 173.20, 69.11, 59.44, 59.30, 35.76, 35.03, 31.89, 31.57, 28.65, 25.48, 25.09, 24.57, 24.50, 20.72; LRMS (El) m/z (relative intensity): 240 (M+, 4), 112 (22), 98 (29), 97 (53), 96 (34), 95 (36), 83 (20), 81 (65), 69 (30), 68 (33), 67 (43), 55 (100); HRMS (El) m/z calculated for C14H24O4: 240.17254, found: 240.17324; b) Epoxidation of 30 with MCPBA at 0 °C 57-86% MCPBA (75.0 mg, 0.244-0.381 mmol), was added to a solution of lactone 30 (50.0 mg, 0.223 mmol) in CH2CI2 (3 mL) at 0 °C, and the reaction was stirred for 3 hours at 0 °C. Standard work-up and purification, as outlined in method (a), yielded epoxy lactones 63 and 64 (48.8 mg, 0.203 mmol) in 91% yield and in a ratio of 69:31 (GC analysis) as a clear pale yellow oil. c) Epoxidation of 30 with MCPBA at -78 °C 57-86% MCPBA (75.0 mg, 0.244-0.381 mmol), was added to a solution of lactone 30 (50.3 mg, 0.224 mmol) in CH2CI2 (3 mL) at -78 °C, and the reaction was stirred for 22 hours at -78°C. Standard work-up and purification, as outlined in method (a), yielded epoxy lactones 63 and 64 (53.2 mg, 0.224 mmol) in 100% yield and in a ratio of 77:23 (GC analysis) as a clear pale yellow oil. c) Epoxidation of 30 with methyl(trifluoromethyl)dioxirane87 at 0 °C An aqueous solution of Na2EDTA (0.0004 M, 2.2 mL, 0.0008 mmol) was added to a solution of lactone 30 (102.1 mg, 0.4551 mmol) in acetonitrile (3.5 mL) and the reaction mixture was cooled to 0 °C. Excess 1,1,1-trifluoroacetone (0.45 mL) was added followed by a portionwise addition of Oxone (1.301 g, 2.276 89 mmol) and NaHC0 3 (325.1 mg, 3.641 mmol), and the reaction was stirred for 1.5 hours at 0°C. Excess dimethyl sulfide (1 mL) was added and the reaction was extracted with CH2CI2 and dried over anhydrous MgS0 4. The organic layer was filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 30% diethyl ether in petroleum ether as eluant yielded epoxy lactones 63 and 64 (107.2 mg, 0.446 mmol) in 98% yield and in a ratio of 70:30 (GC analysis) as a clear pale yellow oil. 3.3.18 (7FT, 8S*, 13S*)-7-Chloro-8-Hydroxy-13-Tetradecanolide (65) and (7S*, 8FT, 13S*)-8-Chloro-7-Hydroxy-13-Tetradecanolide (66) Concentrated HCI (32 uL, 0.37 mmol) was added to a solution of epoxy lactone 63 (60.0 mg, 0.250 mmol) in THF (2 mL) at 0 °C and the reaction was stirred at rt for 3 hours. Water was added and the solution was extracted with diethyl ether. The ether extracts were dried over anhydrous MgS0 4. The extracts were filtered and the solvent was removed under reduced pressure. Radial chromatography using 2% methanol in CH2CI2 as eluant afforded separated chlorohydroxy lactone 65 (31.1 mg, 0.112 mmol) as a clear yellow oil, and chlorohydroxy lactone 66 (33.7 mg, 0.122 mmol) as a clear yellow oil in a total yield of 94%. 65 IR (CDCI3): 3442, 2947, 2863, 1728, 1458, 1376, 1245, 1209, 1169, 1050, 988, 957, 732, 678 cm"1; 90 1H NMR (500 MHz, CDCI3): 8 5.06 (m, 1H), 4.20 (m, 1H), 3.89 (m, 1H), 2.13-2.47 (m, 2H), 1.11-2.00 (m, 17H) 1.19 (d, J = 6.4 Hz, 3H); 1 3 C NMR (50 MHz, CDCI3): 5 173.10, 70.34, 69.79, 68.01, 35.33, 33.16, 29.35, 27.21, 27.15, 24.35, 23.88, 23.73, 23.63, 19.36; LRMS (Cl(+), ammonia) m/z (relative intensity): 296 (M++2, 27), 294 (M+, 81), 258 (100), 241 (38), 223 (32), 126 (23), 113 (39), 95 (18); HRMS (Cl(+), ammonia/methane) m/z calculated for C i 4 H 2 9 0 3 N 3 7 C I : 296.18063, found: 296.18103; HRMS (Cl(+), ammonia/methane) m/z calculated for C i 4 H 2 9 0 3 N 3 5 C I : 294.18359, found: 294.18339; IR (CDCI3): 3397, 2931, 2857, 1729, 1463, 1376, 1330, 1254, 1213, 1137, 1037, 998, 932, 714, 685 cm"1; 1H NMR (500 MHz, CDCI3): 84.84 (m, 1H), 4.17 (m, 1H), 3.83 (m, 1H), 2.13-2.49 (m, 2H), 1.07-2.02 (m, 17H) 1.21 (d, J = 6.1 Hz, 3H); 1 3 C NMR (50 MHz, CDCI3): 8 173.41, 70.71, 69.98, 68.33, 35.24, 34.46, 28.72, 28.66, 26.69, 25.19, 24.39, 24.23, 23.23, 20.82; LRMS (Cl(+), ammonia) m/z (relative intensity): 296 (M++2, 19), 294 (M\ 57), 258 (100), 241 (21), 223 (16); HRMS (Cl(+), ammonia/methane) m/z calculated for C i 4 H 2 9 0 3 N 3 7 C I : 296.18063, found: 296.17951; HRMS (Cl(+), ammonia/methane) m/z calculated for C 1 4 H 2 9 0 3 N 3 5 C I : 294.18359, found: 294.18311; 91 3.3.16 7-Oxo-l3-Tetradecanolide (67) and 8-oxo-13-Tetradecanolide (68) 67 68 Tetrapropylammonium perruthenate (0.103 mmol, 36.2 mg, 10 mol%) was added to a solution of 4-Methylmorpholine A/-oxide (181 mg, 1.55 mmol), 3A molecular sieves (30 mg), and a mixture of approximately a 37:18:31:14 ratio of hydroxy lactones 51, 52, 53 and 54 (0.250 mg, 1.03 mmol), in CH2CI2 (15 mL). The reaction was stirred for 1 hour and filtered through Celite. The solvent was removed under reduced pressure and column chromatography of the residue with 15% ethyl acetate in hexanes afforded a mixture of keto lactones 67 and 68 (214 mg, 0.890 mmol) as a clear pale yellow oil. Further purification by TLC grade column chromatography afforded separated keto lactone 67 (106 mg, 0.445 mmol) in 86% yield as a clear pale yellow oil, and keto lactone 68 (104 mg, 0.441 mmol) as a clear pale yellow oil. 67 IR (CDCI3): 2937, 2862, 1729, 1713, 1460, 1366, 1252, 1132, 1094, 1001 cm"1; 1H NMR (400 MHz, CDCI3): 5 4.84 (m, 1H), 2.17-2.65 (m, 6H), 1.04-1.98 (m, 14H), 1.17 (d, J = 6.1 Hz, 3H); 1 3 C NMR (50 MHz, CDCI3): 5 211.54, 173.42, 69.68, 42.22, 40.66, 35.72, 35.01, 27.76, 27.42, 26.99, 24.89, 24.21, 23.78, 20.13; LRMS (El) m/z (relative intensity): 240 (M+,33), 153 (26), 143 (39), 140 (95), 126 (28), 125 (52), 112 (33), 111 (41), 99 (26), 98 (100), 97 (67), 84 (24), 83 (27), 82 (64), 81 (27), 71 (27), 69 (43), 67 (24), 55 (85); HRMS (El) m/z calculated for C 1 4 H 2 4 0 3 : 240.17254, found: 240.17263; 92 32 IR (CDCI3): 2933, 2861, 1729, 1713, 1460, 1371, 1253, 1132, 1094, 990 cm"1; 1H NMR (400 MHz, CDCI3): 5 4.97 (m, 1H), 2.13-2.64 (m, 6H), 1.03-1.97 (m, 14H), 1.17 (d, J = 6.4 Hz, 3H); 1 3 C NMR (50 MHz, CDCI3): 8 210.80, 172.97, 70.32, 41.94, 40.52, 35.24, 34.04, 27.06, 26.72, 24.97, 24.65, 24.12, 22.15, 20.49; LRMS (El) m/z (relative intensity): 240 (M\15), 157 (22), 139 (32), 129 (21), 126 (100), 111 (50), 97 (30), 84 (36), 83 (44), 69 (47), 68 (23), 56 (20), 55 (51); HRMS (El) m/z calculated for C14H24O3: 240.17254, found: 240.17271; 93 R E F E R E N C E S (1) Hassel, O. Tidsskrift for Kjemi, Bergvesen og Metallurgi 1942, 3, 32. (2) Ramsey, O. B. Stereochemistry, Heyden: London, 1981. (3) Barton, D. H. R. Experientia 1950, 6, 316. (4) van't Hoff, J. H. Bull. Soc. Chim. Fr. 1875, 23, 295. (5) LeBel, J. Bull. Soc. Chim. Fr. 1874, 22, 337. (6) Von Baeyer, A. Chem. Ber. 1885, 2277. (7) Kaarsemaker, S.; Coops, J. Rec. Trav. Chim., 1952, 71, 261. (8) Sachse, H. Chem. Ber. 1890, 23, 1363. (9) Sachse, H. Z Physik. Chem. 1892, 10, 203. (10) Mohr, E. Prakt. Chem. 1918, 98, 315. (11) Huckel, W 1925, 441, 1. (12) Eliel, E. L. Experientia 1953, 9, 91. (13) Curtin, D. Y. Rec. Chem. Prog. 1954, 15, 111. (14) Ruzicka, L. Helv. Chim. Acta 1926, 9, 715. (15) Ruzicka, L. Helv. Chim. Acta 1926, 9, 1008. (16) Ruzicka, L.; Stoll, M.; Huyser, H. W.; Boekenoogen, H. A. Helv. Chim. Acta 1930, 13, 1152. (17) Ruzicka, L; Plattner, P. A.; Wild, H. Helv. Chim. Acta 1946, 29, 1611. (18) Prelog, V. J. J. Chem. Soc. 1950, 420. (19) Huver-Buser, E.; Dunitz, J. D.; Venkatesan, K. Proc. Chem. Soc. 1961, 463. (20) Dale, J. J. Chem. Soc. 1963, 93. (21) Dale, J. Angew. Chem. Int. Ed. Engl. 1966, 5, 1000. (22) Groth, P. Acta Chemica Scand. 1976, A30, 155. (23) Dunitz, J. A.; Meyer, E. F. Helv. Chim. Acta 1965, 48, 1441. (24) Groth, P. Acta Chemica Scand. 1974, A28, 808. 94 Dale, J. Acta Chemica Scand. 1973, 27, 1115, 1130. Anet, F. A. L; Cheng, K. J. Am. Chem. Soc. 1975, 97, 2420. Dale, J. Top. In Stereochem. 1976, 9, 199. Still, W. C ; Galynker, I. Tetrahedron 1981, 37, 3981. Burkert, U.; Allinger, N. L. Molecular Mechanics; ACS Monograph 177; American Chemical Society: Washington, DC, 1982. Hamond, G. S. J. Am. Chem. Soc. 1955, 77, 334. Anderson, E. A.; Holmes, A. B.; Collins, I. Tetrahedron Lett. 2000, 41, 117. Vedejs, E.; Gapinski, D. M. J. Am. Chem. Soc. 1983, 105, 5058. Vedejs, E.; Dolphin, J. M.; Masterlerz, H. J. Am. Chem. Soc. 1983, 105, 127. Neeland, E.; Ounsworth, J. P.; Sims, R. J.; Weiler, L. Tetrahedron Letters. 1987, 28, 35. Keller, T. H.; Weiler, L. J. Am. Chem. Soc. 1990, 112, 450. Keller, T. H.; Weiler, L. Tetrahedron Lett. 1990, 31, 6307. Neeland, E. G.; Ounsworth, J. P.; Sims, R. J.; Weiler, L. J. Org. Chem. 1994, 59, 7383. Graham, R. J.; Weiler, L. Tetrahedron Lett. 1991, 32, 1027. Lermer, L. Ph.D. Thesis, University of British Columbia, 1999. Leslie, R. M.Sc. Thesis, University of British Columbia, 1991. Brockmann, H.; Henkel, W. Naturewissenschaften. 1950,37, 138. Omura, S. Macrolide Antibiotics; Academic Press: Tokyo, 1984. Massamune, S.; Bates, G. S.; Corcoran, J. W. Angew. Chem. Int. Ed. Engl. 1977, 16, 585. Nicolaou, K. C. Tetrahedron 1977, 33, 683. Back, T. G.; Tetrahedron 1977, 33, 3041. Bartlett, P. A. Tetrahedron 1980, 36, 2. Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569. Still, W. C ; Novack, V. J. J. Am. Chem. Soc. 1984, 106, 1148. Paterson, I.; Rawson, D. G. Tetrahedron Lett. 1989, 30, 7463. Still, W. C.; Romero, A. G. J. Am. Chem. Soc. 1986, 108, 2105. 95 Xu, Z; Johannes, C. W.; Salmon, S. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1996, 7 78, 10926. Nakajima, N.; Uoto, K.; Matsushima, T.; Yonemitsu, O.; Goto, H.; Osawa, E. J. Org. Chem. 1990, 55, 1129. Tatsuta, K.; Chino, M.; Kojima, N.; Shinojima, S.; Nakata, M.; Moroka, M.; Obha, S. Tetrahedron Lett. 1993, 34, 4957. Tatsuta, K.; Kobayoshi, Y.; Akimoto, K.; Kinushita, M. Chem. Lett. 1987, 187. Clark, J. S.; Hamelin, O.; Hufton, R. Tetrahedron Lett. 1998, 39, 8321. Roxburgh, C. J. Tetrahedron , 1995, 9767. Villemin, D. Tetrahedron Lett. 1980, 21, 1715. Tsuji, J.; Hashiguchi, S. Tetrahedron Lett. 1980, 21, 2955. Schuster, M.; Blechert, S. Angew. Chem. Int. Ed. Engl. 1997, 36, 2036. Armstrong, S. K. J. Chem. Soc, Perkin Trans 11998, 371. Grubbs, R. H.; Chang, S, Tetrahedron, 1998, 54, 4413. Schrock R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; Dimare, M.; O'Regan, M. J. Am. Chem. Soc. 1990, 7 72, 3875. Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem. Int. Ed. Engl. 1995, 34, 2039. Goldring, W. P. D.; Hodder, S.; Weiler, L. Tetrahedron Lett. 1998, 39, 4955. Furstner, A.; Langemann. K. Synthesis 1997, 792. Schreiber, S. L. In Comprehensive Organic Synthesis; Selectivity, Strategy and Efficiency in Modern Organic Chemistry, Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1984; Vol. 1, p 843. Nishiguchi, T.; Kuroda, M.; Saito, M.; Nishida, A; Fujisaki, S. J. Chem. Soc, Chem. Commun. 1995, 2491. Mancuso, A. J.; Swern, D. Synthesis 1981, 165. Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 87, 1318. De Vries, B. Chem. and Ind. 1962, 1049. De Vries, B. J. Amer. Oil Chem. Soc. 1963, 184. 96 (72) Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric Identification of Organic Compounds, 5th ed.; John Willey & Sons: New York, 1991; p 221. (73) Berstein, H. J.; Powling, J. J. Am. Chem. Soc. 1951, 73, 1843. (74) Allinger, N. L; Yuh, Y. H.; Lii, J.-H. J. Am. Chem. Soc. 1989, 111, 8551. (75) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440. (76) Li, S.-W Honours Thesis, University of British Columbia, 1999. (77) Wang, X.; Li, Y.; Wu, Y.-D.; Paddon-Row, M. N.; Rondan, N. G.; K. N. Houk J. Org. Chem. 1990, 55, 2601. (78) Lide, D. R.; Christensen, D. J. Chem. Phys. 1961, 35, 1374. (79) Herschbach, D. Ft.; Krisher, L. C. J. Chem. Phys. 1958, 28, 728. (80) Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035. (81) Dorigo, A. E.; Pratt, D. W.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 6591. (82) Pirkle, W. H.; Hoekstra, M. S. J. Org. Chem. 1974, 39, 3904. (83) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42, 1839. (84) Vedejs, E.; Dent, W. H.; Gapinski, D. M.; McClure, C. K. J. Am. Chem. Soc. 1987, 109, 5437. (85) Sonnet, P. E.; Oliver, J. E. J. Org. Chem. 1976, 41, 3279. (86) Kuivila, H. G. Synthesis 1970, 499. (87) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887. (88) Nicolaou, K. C ; He, Y.; Vourlousmis, D.; Vallberg, H.; F. Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960. (89) Singleton, D. A.; Merrigan, S. R.; Liu, J.; Houk, K. N. J. Am. Chem. Soc. 1997, 119, 3385. (90) Houk, K. N.; Liu, J.; DeMello, N. C ; Condroski, K. R. J. Am. Chem. Soc. 1997, 119, 10147. 97 (91) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry, 3rd ed.; Harper & Row: New York, 1987; p 248. Atkins, P. W. Physical Chemistry, 4th ed.; W. H. Freeman: New York, 1990; p 572. (92) Gemal, A. L; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454. (93) Brown, H. C ; Krishnamurthy, S. J. Am. Chem. Soc. 1972, 94, 7159. (94) Wu, Y.-D.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 908. (95) Wu, Y.-D.; Houk, K. N.; Florez, J.; Trost, B. M. d. Org. Chem. 1991, 56, 3656. (96) Ando, K.; Houk, K. N.;Busch, J; Menasse, A.; Sequin, U. J. Org. Chem. 1998, 63, 1761. (97) Neeland, E. G. PhD. Thesis, University of British Columbia, 1987. (98) Keller, T. H. PhD. Thesis, University of British Columbia, 1988. (99) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: New York, 1988. (100) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100. (101) Still, W. C.; Kahn, M.; Mirta, A. d. Org. Chem. 1978, 43, 2923. (102) This compound was first prepared in our laboratory by Hodder, A., Unpublished results. (103) This compound was first prepared in our laboratory using an alternate route by Hodder, A., Unpublished results. (104) Ogura, H.; Furuhata, K.; Kuwano, H.; Suzuki, M. Tetrahedron 1981, 37, 165. (105) Ounsworth, J. P.; Weiler, L. J. Chem. Ed. 1987, 64, 568. A P P E N D I C E S 98 Appendix I. Description of Polar Maps In order to simplify the identification and comparison of the conformations of oleandomycin, Ogura and coworkers104 introduced the use of polar maps.105 These plots have since been used to describe the three dimensional conformation of a variety of large rings in terms of a two dimensional pattern. Polar maps are essentially circular graphs that plot the magnitude and sign of the endocyclic torsional angles versus the bond number (Figure 25). These values are determined using a Newman projection along the torsional bond with the lower numbered atom closest to the observer. The sign of the torsional angle is positive if the direction of rotation is clockwise and negative if counterclockwise. Figure 25. The polar map convention for a 14-membered macrocycle 99 The torsional angles may be obtained from an examination of molecular models, X-ray crystallographic data or molecular mechanics calculations. However, complications arise when the torsional angles are obtained from X-ray crystallographic data or molecular mechanics calculations since these report angles less than 180° whether they are exocyclic or endocyclic. A simple solution to overcome this is to reverse the sign of the angle obtained and plot this value instead. Thus an exocyclic torsional angle of -175° would become +175°, when in fact it is +185°. Although this does introduce a slight error, it allows for the rapid and reproducible generation of polar maps. 100 Appendix II. Representative Chromatograms 2 mol% 28 31 29 = 7E 43 = 7Z ~2 i 8*5 jo -in L Si cc 2 o UJ " J cc z: cc cc tVi i» in « CC ft. U J M cr •r ui r- in co • i co <r> ".£1 T-< ff. * H n in •r u a > > CO (_ CO (to > CJ CJ o •r oj <si in LLI r - in oj * • • cc a- in r-. r H T f T J CO f— a: in '-i . . . »-l OJ PJ CO «-l II II <r ix UJ UJ Ct' w •r _j - J n cc i -r- _j O 13 102 1) BH3THF, RT 2) NaOH, H 2 0 2 H 20 3) PhNCO 30 55 56 57 R Waters 994 Dale Wavelength Time Range Interval Time double Minus peak Paper speed Maserine correct OFF Sample name Column Flow rate Temperature Flow cell INTEGRATOR Nov/11/99 01:38:02 M l STOP 30.04 min 5.00 -• FAST 30 OFF 5.0 30.04 min rrun/min EFC99B 8.0mmID* 10.0cm 3.00 ml/min 25.0 *C 10 mm FILENAME ERIK Smothing 15 points Minimum area 1.0E-05 A U « m i n Slope 0.01 AU/min Drift 0.01 AU/min Height 0.01 AU/min Width 0.01 min Packing material: Si Mobile phase 96/4 Hexanes/EtOAc Pressure 400.0 PSI Injection volume: 90 ul .s s s < 3 < M S 2 ? . « .S J5S 1 -S l i s • V O O > A ts. 06 Q Pi «— <N C N <N <NI 9 9 9 9 K w w w T <0 <N f*> Ol K ^ «^  2 >© ts n w r i f— tN «N1 N CO O N »/> %b *q _ U> IA S § 3 6 S 8 S 5 O O O O sssx w «n «•> 104 f ^ M l i ° 4 m i U ' ' •7Z '.1.1 i r _ 1 I'll "-• H 'Tl uT h 1 r_/i •;.'' ' L U l 1 •.. l"v ' ' . i ' J I V • I f l 1-11 I J . ' • J [• l \ l »~ I |J " l 0 j n n 1 0 5 Appendix III. Spectral Appendix 1 o -o -3 2 0 0 2 4 0 0 1 6 0 0 8 0 0 W a v e n u m b e r ( c m — 1 ) 106 9 . 5 9 . 0 8 . 5 8 . 0 7 . 5 7 . 0 6 . 5 6 . 0 5 . 5 5 . 0 4 . 5 4 . 0 3 . 5 3 . 0 2 . 5 2 . 0 1.5 1.0 0 . 5 ( PPm ) 1 o H o -i i i i i i i 1 1 1 1 1 1 1 1 — 3 2 0 0 2 4 0 0 1 6 0 0 '" 8 0 0 W a v e n u m b e r ( c m — 1 ) 107 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ( ppm ) 1 o -A o -1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 — 3 2 0 0 2 4 - 0 0 1 6 0 0 8 0 0 W a v e n u m b e r ( c m — 1 ) 108 109 1 o o H 3 0 -2 0 -1 o -o -3 2 0 0 2 4 0 0 1 6 0 0 8 0 0 W a v e n u m b e r ( c m — 1 ) ' 1 1 0 4. 0 ( PPm ) o "EE CO cz o 3 2 0 0 2 4 0 0 1 6 0 0 W a v e n u m b e r ( c m — 1 ) S O O 111 1 oo H 1 o -o -I ! ! ! I p — j j ! ! ! 1 1 1 [ 3 2 0 0 2 4 0 0 1 6 0 0 8 0 0 W a v e n u m b e r ( c m — 1 ) 112 113 3600 3100 2600 2100 1600 1100 600 W a v e n u m b e r (cm-1) 1 1 4 ( PPm ) 115 116 117 0 I 3500 3000 2500 2000 1500 1000 500 Wavenumber (cm-1) 119 48 A 4. 5 4. 0 ( PPm ) C J c CO 1 w c CO 3500 3000 2500 2000 Wavenumber (cm-1) 1500 1000 500 120 121 122 123 124 20 - M 10 - I 0 -I 1 1 1 . 1 1 1 . . . . 1 1 . 1 1 1 1 1 ^ r 3500 3000 2500 2000 1500 1000 500 Wavenumber (cm-1) 125 7 . 5 7 . 0 6 . 5 6 . 0 5 . 5 5 . 0 4 . 5 4 . 0 3 . 5 3 . 0 2 . 5 2 . 0 1 . 5 1 . 0 0 . 5 (ppm ) 3500 3000 2500 2000 1500 1000 500 Wavenumber (cm-1) 126 0 - I — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i — i 3500 3000 2500 2000 1500 1000 500 Wavenumber (cm-1) 127 128 129 130 7 . 5 7 .0 6 . 5 6 . 0 5 . 5 5 .0 4 . 5 4 . 0 3 . 5 3 . 0 2 . 5 2 . 0 1.5 1.0 0 . 5 ( PPm ) 0 "I . r—, , , 1 i i , i i , , r ~ , , , , 1 , , r—r-^ 3500 3000 2500 2000 1500 1000 500 Wavenumber (cm-1) 

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