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Synthesis and reactions of unsaturated 14-membered lactones Leslie, Ray 1991

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SYNTHESIS A N D REACTIONS OF U N S A T U R A T E D 14-MEMBERED LACTONES  by Ray Leslie B . S c , (Honours), UMIST, 1988  A THESIS SUBMITTED I N P A R T I A L F U L F I L L M E N T OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE  in THE F A C U L T Y OF G R A D U A T E STUDIES (Department of Chemistry)  We accept this thesis as conforming to the required standard  T H E UNIVERSITY OF BRITISH C O L U M B I A September  1991  © Ray Leslie  In  presenting  degree  this  thesis  in  at the University of  partial  fulfilment  British Columbia,  of  the  I agree  requirements  for  of  -department  this or  thesis by  for scholarly  his  publication of this thesis  or  her  Qfe^'STr^/  The University of British Columbia Vancouver, Canada  Date  DE-6 (2/88)  era-  \c>  -9)  may be  representatives.  It  is  granted  for extensive  by the head  understood  that  for financial gain shall not be allowed without  permission.  Department of  purposes  advanced  that the Library shall make it  freely available for reference and study. I further agree that permission copying  an  of  my  copying  or  my written  ABSTRACT  Via a lactonization of the open chain hydroxy acid, the 14-membered unsaturated lactones 14 and 15 were synthesised. Treatment of these two lactones with borane dimethylsulphide, disiamyl borane and 9BBN led to formationof hydroxy lactones 30, 31, 32 and 33. The structures of 31 and 32 were determined by comparison with known compounds whereas structures 30 and 33 were deduced by considering the transition structures of the hydroboration reaction. Although both the regio and the stereoselectivity of the reactions were poor the 7t-face selectivity was high. Product distributions were estimated by the conformational control induced by the ring, using Houk's parameters for the hydroboration transition structures, in an MM2 force field, to calculate their relative strain energies. .0  14  15  HO*' 30  31  32  33  T A B L E OF CONTENTS  ABSTRACT TABLE  ii  OF CONTENTS  iii  LIST  OF T A B L E S  v  LIST  OF FIGURES  LIST  OF SCHEMES  vii  LIST OF ABBREVIATIONS  viii  .  ACKNOWLEDGEMENTS DEDICATION  '. .  vi  x xi  CHAPTER I INTRODUCTION 1.1 THE CONFORMATION OF MANY-MEMBERED RINGS  2  1.2 THE CONFORMATION OF UNSATURATED MACROCYCLES  6  1.3 M A C R O L I D E S  6  1.4 SYNTHESIS OF M A C R O C Y C L I C LACTONES  9  1.5 CONFORMATIONALLY CONTROLLED REACTIONS IN. MACROLIDE SYNTHESIS  11  CHAPTER II RESULTS AND DISCUSSION 2.1 SYNTHESIS OF (E) AND (ZJ-13-TETRADEC-8-ENOLIDE  15  2.1.1 Synthesis of 5-(rm-butyldimethylsiloxy)hexanal (17)  17  2.1.2 Synthesis of 7-carbomethoxyheptyltriphenyphosphonium iodide (18) 2.1.3 Preparation of macrolides 14 and 15  18 19  iv  2.2 THE CONFORMATIONAL ANALYSIS OF 14-MEMBERED LACTONES.... 21 2.2.1 The conformational analysis of cyclotetradecane  21  2.2.2 Polar  22  maps  2.2.3 The lactone linkage  24  2.3 LOW ENERGY CONFORMATIONS OF MACROLIDES 14 A N D 15 2.4 HYDROBORATION  25 OF 14 AND 15  29  2.4.1 Hydroboration of 14  32  2.4.2 Hydroboration of 15  33  2.4.3 Molecular modelling of hydroboration transition states  34  2.5 C O N C L U S I O N  35  CHAPTER IB EXPERIMENTAL 3.1 General  36  3.2 Synthesis and reactions of 13-tetradec-8-enolides  37  REFERENCES  54  SPECTRAL  57  APPENDIX  LIST OF T A B L E S  Table I.  The three lowest energy conformations of 14  Table II.  The three lowest energy conformations of 15  Table HI.  Hydroboration of (£)-13-tetradec-8-enolide (14) with various hydroborating  Table IV.  agents  Hydroboration of (Z)-13-tetradec-8-enolide (15) with various hydroborating  agents  vi LIST OF FIGURES  Figure 1.  The conformation of c/s-l,6-diaminocyclodecane dihydrochloride  Figure 2.  Low energy conformations of even membered cycloalkanes from C6 to C i 6  '•  2  3  Figure 3.  Corner positions in the strain free conformation of cyclotetradecane  4  Figure 4.  [3434] conformation of cyclotetradecane  4  Figure 5.  The [3344] and [3335] conformations of cyclotetradecane  5  Figure 6.  Celmer model for erythronolide B  7  Figure 7.  Perun model for erythronolide B  8  Figure 8.  Ogura models for kromycin and oleandomycin  8  Figure 9.  Conformations and relative strain energies for cyclotetradecane  21  Figure 10. The polar map convention  22  Figure 11. Rule for determining the sign of the anti dihedral angle  23  Figure 12. Polar maps for the three lowest energy conformations of cyclotetradecane....24 Figure 13. The two possible conformations of esters  24  Figure 14. The C-O-C-H dihedral angle of secondary esters  25  Figure 15. Polar maps of the three lowest energy conformations of 14  27  Figure 16. Polar maps of the three lowest energy conformations of 15  29  Figure 17. Peripheral attack of diborane on the C s carbon of 15  34  Figure 18. Transition structures in the hydroboration of 15  35  LIST OF SCHEMES  Scheme 1.  Corey-Nicolau double activation sequence to form macrolides  9  Scheme 2.  Dietsche-Schmidt modification of Corey-Nicolau macrolactonisation  10  Scheme 3.  Yamaguchi method for macrolactonisation  10  Scheme 4.  Synthesis of 3-deoxyrosaranolide (4) using macrocyclic stereocontrol  12  Scheme 5.  Conformationally controlled reactions in the synthesis of dihydroerythronolide (10)  13  Scheme 6.  Local conformer effects in reactions of cycloalkenes  14  Scheme 7.  Retrosynthetic analysis of macrolides 14 and 15  16  Scheme 8.  Synthesis of aldehyde 17  17  Scheme 9.  Synthesis of phosphonium salt 18  18  Scheme 10. Synthesis of macrolides 14 and 15  20  Scheme 11. Hydroboration of 14 and 15  30  Scheme 12. Separation of hydroxy lactones 30, 31, 32 and 33  31  LIST OF ABBREVIATIONS  Ac  acetyl  9BBN  9-borabicyclo[3.3. l]nonane  calcd  calculated  CD  circular dichroism  d  doublet  DMAP  4-dimethylaminopyridine  DMSO  dimethyl sulphoxide  Et  ethyl  eV  electron volts  FT  fourier transform  GC  gas chromatography  IR  infrared  J  coupling constant  LAH  lithium aluminium hydride  LRMS  low resolution mass spectroscopy  M  molar  m  multiplet  MCPBA  mera-chloroperbenzoic acid  Me  methyl  MM  molecular mechanics  Ms  mesyl  NMO  N-methylmorpholine-N-oxide  NMR  nuclear magnetic resonance  PPL  porcine pancreatic lipase  qn  quintet  ix  Ra-Ni  Raney nickel  s  singlet  Sia2BH  disiamylborane  t  triplet  TBDMS  rm-butyldimethylsilyl  tert  tertiary  THF  tetrahydrofuran  TMS  trimethylsilyl  X  ACKNOWLEDGEMENTS  I would like to thank Professor Larry Weiler for his helpful advice and comments throughout the course of this work. Thanks also to the NMR and Mass Spec, departments whose services were greatly appreciated. In addition I would like to thank my friends and colleagues in the Weiler group as well as the Friday night beer-boys who made it all worthwhile.  xi  To my parents  1 CHAPTER I  Introduction  The chemistry of macrocyclic compounds began in 1926 with the isolation and structural elucidation of the musk components, civetone 1 and muscone 2, by Ruzicka.  1  This discovery revealed the inadequacies of the Baeyer strain theory^ which had predicted that large ring compounds would be too unstable to exist, due to overextension of internal bond angles. Perhaps more important were the ensuing efforts to discover synthetic routes to these, and related compounds. A challenge which, with the further isolation of naturally occuring macrocyclic compounds, continues to attract the attention of chemists today. O  1  2  2  1.1  T H E C O N F O R M A T I O N OF M A N Y - M E M B E R E P RTNGS.  Ruzicka's work on macrocyclic compounds embodied two specific aims, those being the synthesis of the highly prized musk-like perfumes and the study of the physical and chemical properties of large ring compounds. Using the acyloin condensation as a basis, Ruzicka et al. and Prelog synthesized 3  4  5  and investigated the properties of medium and large ring hydrocarbons, alcohols and ketones. Surprisingly they found that the physical and chemical properties of these macrocyclic compounds had an unexpected dependence on ring size. In 1961 Duntiz and co-workers' demonstration, by X-ray diffraction, of a unique 6  conformation (Figure 1) of the ten-membered ring skeleton in several cyclodecane derivatives led to an understanding of the conformational effects controlling these phenomena. From his observations Dunitz concluded that this conformation must correspond to a potential energy minimum for this ring skeleton.  cr  +  cr  NH  3  Figure 1. The formation of m-l,6-diaminocyclodecane dihydrochloride.6 Two years later Dale pointed out that the aforementioned solid state conformations 7  closely resembled the diamond lattice - a network of ideal carbon-carbon bond lengths and bond angles. It follows that any conformation which can be superimposed on the diamond lattice must possess a minimum in angular and torsional strain. By using molecular models Dale was able to predict low energy conformations for all even membered cycloalkanes  from C6 to Ci6 (Figure 2). Subsequent theoretical calculations and X-ray crystallography 7  have shown these predictions to be very accurate.  8  (CH ) 2  6  (CH ) 2  (CH ) 10  g  2  (CH ) 2  16  Figure 2. Low energy conformations of even membered cycloalkanes C6 to C i 6 -  7  A typical feature of these macrocyclic conformations is that each contains four "corners." Dale realised that these corner positions are unique in that they can always carry two substituents without causing severe transannular interactions (Figure 3) and he defined  4  a comer atom as having two adjoining gauche dihedral angles of the same sign flanked on either side by an anti dihedral angle.  8  number of internal hydrogen interactions  Figure 3. Corner positions (shown with an asterisk) in the strain free conformation of cyclotetradecane. From this definition of corner atoms Dale also devised a system of nomenclature for macrocyclic compounds. Using a shorthand notation the ring is represented as a series of 9  numbers in brackets (Figure 4), each number indicating the bonds between each corner atom. The ring is named such that the smallest number is listed first within the brackets.  3  "°"  0  Figure 4. [3434] conformation of cyclotetradecane.  9  °  "°  Dale's initial work on conformational analysis was carried out on a semi-quantitative scale using modified Dreiding models.^ However, with the use of molecular mechanics calculations, demonstrated by Anet and Cheng  10a  to be applicable to large rings, Dale  discovered two other low energy conformations of cyclotetradecane that were nonsuperimposable on the diamond lattice.  10b  These were designated the [3344] and [3335]  conformations (Figure 5) and were calculated to have strain energies of 1.1 kcal/mol and 2.4 kcal/mol respectively, relative to the [3434] conformation.  o-—o»  o—^o^-o  [3344]  [3335]  Figure 5. The [3344] and [3335] conformations of cyclotetradecane (* = corner position). 1015  1.2  T H E C O N F O R M A T I O N OF UNSATURATED M A C R O C Y C L E S .  The introduction of a double bond into a cycloalkane makes strain-free conformations based on the diamond lattice impossible for any ring size and it has been shown that nearly all known cycloalkenes are liquids, reflecting their conformational flexibility. Although 7  there is a lack of molecular mechanics data on cycloalkenes, a good indication of the relative strain in a cycloalkene compared to the corresponding cycloalkane, and also the relative stabilities of cis and trans isomers, is gained from their heats of hydrogenation.  11  The evidence tends to suggest that the trans-olefin is more strained than its cis-isomer in the medium ring systems but, as ring size increases to twelve and further, the relative stabilities are reversed. These enthalpy differences are in good agreement with values obtained by equilibration of medium size cycloalkenes.  1.3  12  MACROLIDES  The chemistry of large ring compounds experienced another leap forward in 1950 when Brockmann et al. isolated the first macrolide antibiotic, pikromycin (3), from an Actinomyces culture.  13  Soon afterward Streptomyces organisms yielded several other  antibiotics which appeared to be chemically and anti-microbially related to pikromycin. The family of macrolides has expanded to more than one hundred physiologically active metabolites of which approximately half are subgrouped as polyoxo-macrolides.  o  3  The polyoxo-macrolides are characterized structurally by a 12, 14 or 16 membered lactone ring with one or more deoxy-sugars attached and up to 12 asymmetric centres incorporated into the aglycone. The complexity of conformational possibilities for these macrolides has aroused a great deal of interest. In 1965 Celmer proposed a model for a preferred conformer of 14  erythronolide B (Figure 6) based on the [3434] conformation of cyclotetradecane.  9  O  O  Figure 6. Celmer model for erythronolide B .  1 4  Although the H NMR data was in reasonable agreement with this model, earlier X l  ray analysis and CD studies 153  Perun,  15b  15b  were in conflict. A later model (Figure 7) proposed by  appeared to accommodate quite well with the *H NMR data as well as  eliminating, at the same time, the unfavourable 1,3 interaction between the C 4 and C 6 methyl groups.  Figure 7. Perun model for erythronolide B .  1 5 b  Further work in this field has been carried out by Ogura et a l . leading to new 16  diamond-lattice conformations of kromycin and oleandomycin (Figure 8). o O— desosamine  /  Et  kromycin  O—oleandrose  oleandomycin  Figure 8. Ogura models for kromycin and oleandomycin.  16  9  1.4  SYNTHESIS OF M A C R O C Y C L I C L A C T O N E S  Although many methods exist for the synthesis of macrolides by far the most 17  general and commonly used method is lactonization of a long chain hydroxy acid. For this reason it will be the only example discussed. The macrolactonization process depends upon carboxyl and/or hydroxyl activation techniques to overcome unfavourable entropic factors and competing polymerisation processes. The Corey-Nicolau method employs 2-pyridylthiol and relies upon a double 18  activation sequence (Scheme 1) to form the lactone.  O  Scheme 1. Corey-Nicolau double activation sequence to form macrolides.  18  A modification of Corey's procedure was developed by Dietsche and Schmidt  19  using l-phenyl-2-tetrazoline-5-thione and rm-butyl isocyanide as the activating agents (Scheme 2).  Scheme 2. Dietsche-Schmidt modification of Corey-Nicolau macrolactonization.  19  A more traditional approach was advanced by Yamaguchi et a l .  20  who used  trichlorobenzoyl chloride to activate the carboxylic functionality as its mixed anhydride (Scheme 3). O  Scheme 3. Yamaguchi method for macrolactonization.  20  Other notable examples of the double activation method include Mukaiyama's use of N-methyl-2-chloropyridinium iodide lactonization,  21b  213  and Masamune's thiolate ester-Hg(II) mediated  as well as enzyme catalysed lactonization.  21c  It should be emphasized,  however, that the latter technique has enjoyed limited success and tends to be substrate specific.  1.5  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 REACTIONS IN  MACROLIDE  SYNTHESIS.  In 1983 Still and Novack  22  elegantly displayed the power of macrocyclic  stereocontrol with the synthesis (Scheme 4) of 3-deoxyrosaranolide (4). First the 16-membered ring of the target structure was prepared by a Horner-Emmons cyclization to give the keto macrolide 5 which was kinetically deprotonated at C s and methylated with better than 95% stereoselectivity to give, after deprotection, 6. Introduction of the C 6 side chain was achieved by alkylation of the kinetically generated enolate to give 7 with better than 95% regioselectivity and 85% stereoselectivity. The methyl-bearing chiral centre at C 4 was then controlled by hydroxymethylation of the lithium enolate followed by elimination to the methylene ketone. Conjugate addition of thiophenol and desulphurisation with Raney nickel gave 8 with better than 95% stereoselectivity. Ester hydrolysis and sodium borohydride reduction of the derived mixed anhydride then gave the desired C5 alcohol 9 with 83% stereoselectivity. Finally oxidation at C 9 , epoxidation and selective oxidation of the primary hydroxyl group gave 3deoxyrosaranolide(4) with better than 93% stereoselectivity.  9  Scheme 4. Synthesis of 3-deoxyrosaranolide (4) using macrocyclic stereocontrol.  22  A more recent report by Paterson and Rawson describes the synthesis of (+)-9(S)23  dihydroerythronolide (10) based on a combination of acyclic and macrocyclic stereocontrol. Scheme 5 outlines how four of the ten stereocentres were generated using the conformational bias of the ring.  OTBDMS  OTBDMS  13  10  Scheme 5. Conformationally controlled reactions in the synthesis of dihydroerythronolide (10). 23  Osmylation of the intermediate 11 proceeded with essentially 100% 7i-faced selectivity to give the hydroxy ketone 12. Subsequent reduction of the carbonyl gave, after deprotection, 13 again as a single product. A second osmylation, although low yielding, proceeded with high selectivity to give 10 thereby completing the synthesis. Vedejs et a l . have also reported the use of macrocyclic control in the epoxidation 24  and osmylation of medium and large ring cycloalkenes. The local ring segment containing the alkene tends to adopt only certain conformations which control the stereochemical outcome of the reaction. Further restrictions in conformational possibilities arise for molecules having an allylic alkyl subs'tituent, the alkyl group occupying a pseudoequatorial position if possible. Attack of the reagent then occurs from the least hindered face (Scheme 6).  Scheme 6. Local conforrner effects in reactions of cycloalkenes.  24  This procedure has been used by Vedejs and co-workers in the stereocontrolled synthesis of an erythronolide fragment, the key step being the osmylation of a 9-membered ring alkene to give a single diol.  25  As demonstrated from these examples, the use of macrocyclic stereocontrol is a viable approach to the synthesis of macrolides. However, only sparse attempts have been made to analyse the factors controlling the conformational preferences in reactions of large rings, hence our interest in this field.  C H A P T E R II  Results and Discussion  2.1 SYNTHESIS OF (E)- AND f Z ) - 1 3 - T E T R A D E C - 8 - E N O L I D E  We chose to study an unsaturated macrocyclic lactone in which the double bond was remote from the lactone functional group to determine if reactions of the alkene could be controlled by the conformation of the ring. The retrosynthetic analysis of the unsaturated lactone 15 for this study is shown in Scheme 7. Since a large quantity of each lactone was required, commercially available and inexpensive starting materials were chosen. Dale's work on the conformational analysis of cycloalkenes - implied that lactone 7  11  14 would be thermodynamically more stable than 15. Accordingly, isomerisation of the cis-double bond in 15 should lead to 14 thus necessitating only one synthesis for both lactones. Previous results obtained in our laboratory, as well as a wealth of literature, " 18  21  indicated lactonization of the corresponding seco-acid 16 to be the method of choice for cyclisation. A second disconnection at the double bond leads to the protected hydroxy aldehyde 17 and the phosphonium salt 18, the precursors of which are ethyl 5oxohexanoate (19) and 8-bromooctanoic acid (20) respectively.  Scheme 7. Retrosynthetic analysis of macrolide 15.  17  2.1.1  Synthesis of 5-(7erM)utyldimethylsiloxy)hexanal  (17)  The synthesis of 17 is outlined in Scheme 8. Ethyl 5-oxohexanoate (19) was reduced using lithium aluminium hydride to give the diol 21 which was then selectively acylated under enzyme catalysed conditions to give the primary acetate 22. Protection of 26  the secondary hydroxyl function in 22 as its TBDMS ether gave 23 which in turn was deacylated to give the mono-protected diol 24. Finally, Swern oxidation of 24 gave the 27  target molecule 17 in 58% overall yield from 19. 0  0  OH  19  21  OH  OTBDMS  22  23  OTBDMS  24  OTBDMS O  ii)Et N 3  Scheme 8. Synthesis of aldehyde 17.  17  2.1.2  Synthesis of 7-carbomethoxvheptvltriphenvlphosphonium  iodide (18)  The synthesis of 18, as shown in Scheme 9, is relatively straightforward. Acid catalysed esterification of 8-bromooctanoic acid (20) gave bromo ester 25 which was then converted to iodo ester 26 via a Finkelstein reaction.  28  Treatment of 26 with  triphenylphosphine and a stoichiometric amount of Hunig's base in refluxing acetonitrile proceeded smoothly to give 18, which was used immediately in the next step without further purification. MeOH, H  +  ,OMe  Nal acetone  O  O  25  20  .OMe O  26  Scheme 9. Synthesis of phosphonium salt 18.  o  18  2.1.3  Preparation of macrolides 14 and 15  The coupling of fragments 17 and 18 was based on the Wittig olefination. High 29  selectivity for (Z) or (E) alkenes is available, depending on the particular circumstances, such as type of ylid, carbonyl compound, or reaction conditions. However, generation 30  of the ylid of 18 with sodium bis(trimethylsilyl)amide and subsequent reaction with 17 at low temperature gave the unsaturated protected hydroxy ester 27 in a disappointing cisrtrans ratio of 2.5:1. Nevertheless we were not too discouraged since both geometrical isomers of the unsaturated lactone, 14 and 15, were desired and we therefore decided to proceed with the synthesis and carry out separation of the geometric isomers at the lactone stage. Hence desilylation of 27 gave hydroxy ester 28 which was hydrolysed to the hydroxy acid 29. Cyclisation of 29 was achieved using the Dietsche-Schmidt doubleactivation method to give lactones 14 and 15 in a ratio of 1:1.25. Separation of the two lactones was carried out by flash chromatography using silver nitrate impregnated silica 31  gel thus completing the synthesis (Scheme 10). 32  2.2 THE CONFORMATIONAL ANALYSIS OF 14-MEMBERED LACTONES  2.2.1  The conformational analysis of cyclotetradecane  Dale's work on conformational analysis revealed that the [3434], [3344] and [3335] were the three lowest energy conformations for cyclotetradecane.  10b  However  Saunders, using a ring-building computer program, has reported an additional twelve 33  diamond lattice conformations that are theoretically possible.  At this stage the  conformational analysis of 14-membered rings appeared overwhelming. Fortunately calculations in our laboratory showed the majority of these conformations to have 40  significantly higher strain energies than the lowest energy [3434] conformation making many of them irrelevant to the conformational analysis of substituted derivatives (Figure 9).  [3434] °.°  [3344] 1.1  [3335] 2.3  Conf. E 6.8  Conf. F 7.1  Conf. G 7.5  Conf. D 3.0  Conf. H 7.6  /  Conf. J 7.9  Conf. B 8.5  Conf. K 11.0  Conf. L 11.1  Conf. C 5.0  Conf. I 7.7  \  Conf. M 12.0  Figure 9. Conformations and relative strain energies in kcal/mol for cyclotetradecane.  The concept of polar maps was introduced by Ogura to simplify the identification 34  and comparison of the many conformations possible for large rings. Polar maps are circular graphs that plot the magnitude and sign of the internal dihedral angles versus the bond number (Figure 10). Since the dihedral angles are unique for the three dimensional structure of a molecule, each conformation will give a distinctive pattern in a polar map.  14  isof.  12  11  Figure 10. The polar map convention.  Ambiguity arises in determining the sign of a dihedral angle as it approaches 180°. To overcome this difficulty it was proposed that only the endocyclic anti dihedral angle be considered for the generation of polar maps (Figure 1l).  35  Figure 11. Rule for determining the sign of the anti dihedral angle.  Complications arose when applying this rule since MM2 calculations or X-ray crystallographic data reported angles that are less than or equal to 180° whether formed inside or outside the ring. A simple solution to this problem is to reverse the sign of the angle obtained from the X-ray/MM2 data and plot this value instead. Thus an exocyclic dihedral angle of -175° becomes, for convenience, +175° when in fact it should be +185°. Although this convention introduces a slight error it allows for the quick and reproducible generation of polar maps.  The polar maps for the three lowest energy conformations of cyclotetradecane are shown in Figure 12.  [3434]  [3335]  [3344]  Figure 12. Polar maps for the three lowest energy conformations of cyclotetradecane.  2.2.3  The lactone linkage  The introduction of an ester linkage into a ring system would be expected to have a greater effect on its conformation than just the sum of a carbonyl and an ether group. The s-trans geometry of esters (Figure 13) is more stable than the s-cis form and since a 1436  membered ring is large enough to accomodate an s-trans lactone, any conformation containing an s-cis lactone can be eliminated from our consideration of conformational analysis. O  O  R"  s-trans  s-cis  Figure 13. The two possible conformations of esters.  Furthermore, studies carried out on the conformational preferences of esters of secondary alcohols revealed that the C-O-C-H dihedral angle was invariably in the range of 0-60° (Figure 14).  37  Application of this trend to lactones of secondary alcohols can be  used to simplify our analysis.  R  Figure 14. The C-O-C-H dihedral angle of secondary esters.  2.3 L O W E N E R G Y CONFORMATIONS OF M A C R O L I D E S 14 AND 15  In order to simplify the conformational analysis of large ring lactones the following restrictions can be applied. 1. Substituents should occupy the exterior positions of a macrolide. 2. Geminally substituted atoms must occupy a corner position. 3. The lactone linkage must have the s-trans geometry. 4. The C-O-C-H dihedral angle must be in the range of 0-60°. With this in mind we subjected our macrolides to a detailed conformational analysis using MM2 calculations.  38  As expected the introduction of an endocyclic double-bond  makes the adoption of a strain free conformation impossible, therefore increasing the 7  conformational mobility of macrolides 14 and 15.  Table I. The three lowest energy conformations of 14.  Low energy conformations  a  Strain energy  Conformation  0.00 kcal/mol  [3344]  0.06 kcal/mol  [3344]  0.17 kcal/mol  [3344]  Strain energy is reported relative to the lowest energy conformation.  The three lowest energy conformations for macrolide 14 are shown in Table I. The conformational analysis of 14 proved to be quite complex, with over thirty conformations being within 2 kcal/mol of the global minimum. The three lowest energy conformations turned out to have the [3344] geometry. A l l three conformations also had the same local conformation around the olefinic double bond, as can be seen from their polar maps (Figure 15).  9  8  14a  7  9  8  14b  7  9  8  7  14c  Figure 15. Polar maps of the three lowest energy conformations of 14.  As with 14 the conformational analysis of macrolide 15 proved complex with twenty-six conformations within 2 kcal/mol of the global minimum. As shown in Table II the lowest energy conformation is again a [3344] conformation followed by a [3434] and [3344] respectively.  Table II. The three lowest energy conformations of 15. Low energy conformations  15b  15 c  a  l~7~\  //  l^i.mmm.  Strain energy  Conformation  0.00 kcal/mol  [3344]  0.06 kcal/mol  [3434]  0.17 kcal/mol  [3344]  3  A  ^  Strain energy is reported relative to the lowest energy conformation.  The polar maps for the three conformations are shown in Figure 16. Again, the local conformation around the olefinic double bond remains constant.  29  15a  15b  15c  Figure 16. Polar maps of the three lowest energy conformations of 15. 2.4  HYDROBORATION OF 14 AND 15 With the possibility of four isomeric hydroxy lactones being formed in the  hydroboration of 14 or 15 our initial aim was to isolate and characterise each of the isomers for future reference. We therefore hydroborated a mixture of 14 and 15 with borane dimethylsulphide complex to give, after work-up, a mixture of hydroxy lactones 30,31,32 and 33 (Scheme 11),  30  1) BH -SMe 3  2  2)NaOH,H 0 HO 2  2  z  30  31  33  32  Scheme 11. Hydroboration of 14 and 15. Separation of the hydroxy lactones (Scheme 12) was achieved by initially forming their respective silyl ethers 34, 35, 36 and 37 which were then separated, by radial chromatography, into two fractions containing 34 and 35, and 36 and 37 respectively. Desilylation of 34 and 35 followed by separation, again by radial chromatography, gave hydroxy lactones 30 and 31, the latter being identified by comparison of its NMR spectrum with an original sample previously made in our laboratory.  403  Unfortunately  desilylation of 36 and 37 yielded an inseparable mixture of hydroxy lactones 32 and 33. We were however able to confirm the structure of 32 again by comparison of its NMR spectrum with that of a previously synthesized sample.  403  Scheme 12. Separation of hydroxy lactones 30, 31, 32 and 33.  2.4.1  Hydroboration of 14  Previous literature results indicated that the hydroboration of alkenes with diborane proceeded with low regio and stereoselectivity. Hydroboration of 14 using borane dimethylsulphide gave, from GC analysis of their respective TMS ethers, a 44:26:18:12 mixture of four isomeric hydroxy lactones 30, 31, 32 and 33. We therefore turned our attention to bulkier hydroborating agents in the hope of gaining increased selectivity. Unfortunately hydroboration of 14 with 9BBN, perhaps because of the elevated reaction temperature required, gave a slightly decreased 43:24:26:7 mixture of the four isomeric hydroxy lactones 30, 31, 32 and 33.  However, when 14 was treated with  disiamylborane the reaction proceeded with 100% regioselectivity to give two diastereomeric hydroxy lactones 30 and 33 in a ratio of 9:1. The results for the various hydroborations performed on 14 are summarised in Table III.  Table HI. Hydroboration of (T^-lS-tetradec-S-enolide (14) with various hydroborating agents. Hydroborating agents  Temperature 30  BH SMe  Selectivity 31 32  Yield % 33  -78 °C  44  26  18  12  96  9BBN  25 °C  43  24  26  7  93  Sia BH  25 °C  90  10  96  3  2  2  Predicted Selectivity (MM2)  37  59  4  2.4.2  Hydroboration of 15  Hydroborations of 15 were carried out with the same reagents as for 14. Again the reaction of borane dimethylsulphide with 15 proceeded with low selectivity to give four isomeric hydroxy lactones 30, 31, 32 and 33 in a ratio of 45:28:19:8. The use of the bulkier hydroborating agents resulted in an increase in selectivity although the outcome in both cases was still disappointing. Reaction of 15 with 9BBN gave four isomeric hydroxy lactones 30, 31, 32 and 33 in a ratio of 51:36:6:7, whereas with disiamylborane three hydroxy lactones 30, 31 and 33 were produced in a ratio of 53:37:10. The results for the reactions of 15 are summarised in Table IV.  Table IV. Hydroboration of (Z)- 13-tetradec-8-enolide (15) with various hydroborating agents. Hydroborating agents  Temperature 30  BH SMe  Selectivity 31 32  Yield % 33  -78 °C  45  28  19  8  96  9BBN  25 °C  51  36  6  7  93  Sia BH  25 °C  53  37  10  96  50  40  3  2  2  Predicted Selectivity (MM2)  2  8  We were now faced with the problem of assigning the relative stereochemistry of the products in the hydroboration of 14 and 15. As was previously mentioned, two hydroxy lactones 31 and 32 were identified by comparison with their original NMR spectra however there still remained the identification of lactones 30 and 33.  4 0 a  34  Still and Galynker have shown that reagents attack the 7C-system of a macrolide 42  almost exclusively from the periphary of the ring. Using this model as a basis we suggest that peripheral attack of a hydroborating agent on the Cs carbon of macrolide 15 (Figure 17) would lead to the hydroxy lactone with the 8R*, 13S* stereochemistry. Thus the major product in the hydroborations was assigned the 8R*, 13S* stereochemistry 30, and 33 the 8S*, 13S*.  Figure 17. Peripheral attack of diborane on the Cs carbon of 15.  2.4.3  Molecular modelling of hydroboration transition states  From ab initio calculations based on the transition state of the gas phase reaction between borane and ethylene, Houk and co-workers have recently developed a method 41  wherein MM2 calculations can be performed on the transition structures of the reaction between hydroborating agents and alkenes. Following this methodology we were able to perform MM2 calculations on the transition structures of the reaction between diborane and macrolides 14 or 15 (Figure 18). To accomplish this it was necessary to input a set of parameters that defined atom types and bond orders in the transition structure. The product ratio could then be determined from a Boltzmann distribution using the relative strain energies of the individual transition structures.  Figure 18. Transition structures in the hydroboration of 15.  2.5  CONCLUSION  In the conformational analysis of unsaturated 14-membered lactones we have found their behaviour to be very complex with the macrocyclic ring exhibiting a high degree of flexibility. We performed a number of hydroborations on the unsaturated lactones 14 and 15 to investigate the conformational control induced by the ring. Although the results of the hydroborations were disappointing we were able to show that the reactions proceeded with highrc-faceselectivity. Thus new applications of conformationally controlled reactions in unsaturated macrolides could be found in asymmetric osmylations and epoxidations.  CHAPTER III  Experimental  3.1  GENERAL  Unless otherwise stated, all reactions were performed under nitrogen using ovendried glassware. Cold temperature baths were maintained as follows: -78 °C (dry iceacetone) and 0 °C (ice-water). Anhydrous reagents and solvents were prepared according to literature procedure.  39  Preparative flash chromatography was performed using silica gel 60, 230-400 31  mesh, supplied by E. Merck Co. Infrared spectra were recorded on a BOMEM FT-IR Michaelson-100 connected to an IBM compatible computer. IR spectra were recorded either neat or in a chloroform solution using NaCl cells of 0.2 mm thickness. Proton nuclear magnetic resonance spectra were recorded in deuterochloroform solution on a Bruker WH-400 (400 MHz) spectrometer. Chemical shifts are given in parts per million (ppm) on the 8 scale versus tetramethylsilane (8 0) as internal standard. Signal multiplicities, coupling constants and integration ratios are given in parentheses. Low resolution mass spectra were recorded on either a Kratos-AEI model 50 or MS9 spectrometer. Only peaks with greater than 20% relative intensity or those which were analytically useful are reported. High resolution mass spectra were recorded on a Kratos AEI model MS 50 spectrometer. An ionization potential of 70 eV was used in all measurements.  3.2  SYNTHESIS AND REACTIONS OF 13-TETRADEC-8-ENOLIDES  1.5-Hexanediol  (21) OH  A solution of ethyl 4-acetylbutyrate (15.0 g, 0.095 mol) in THF (100 mL) was added to a stirred suspension of lithium aluminium hydride (10.0 g, 0.245 mol) in THF (150 mL) at 0 °C. The mixture was allowed to warm to room temperature and then heated at reflux for 24 h. The mixture was cooled to 0 °C and a saturated solution of sodium sulphate was added. The resulting slurry was filtered and the filtrate washed with ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were dried (MgS04) and the solvent was removed under reduced pressure. Flash chromatography of the crude product using methylene chloride-methanol (12:1) as eluant yielded 21 as a colourless oil (11.1 g, 99%).  IR (neat, cm" ): 3700-3100, 2940, 2855, 1458, 1374, 1071, 940, 845 1  !H NMR ( C D C I 3 , 400 MHz) 8: 3.82 (m, J= 6 Hz, 1H), 3.67 (t, J= 6 Hz, 2H),  1.56-1.66 (m, 4H), 1.39-1.56 (m, 4H), 1.21 (d, J= 6 Hz, 3H)  LRMS (m/z): 118 (M+, 0.6), 75 (27), 56 (91), 55 (22), 45 (100), 43 (40), 41 (54)  38  l-Acetoxy-5-hexanol (22)  OH  O  A solution of 1,5-hexandiol (21) (11.0 g, 0.093 mol) and acetic anhydride (13.1 mL, 0.14 mol) in diethyl ether (70 mL) was added to a suspension of PPL in Et20 (70 mL) and the mixture stirred for 30 h. The lipase was removed by filtration, washed with Et20 and the combined organic solutions washed with 1 M HC1, saturated NaHC03 and water. The aqueous layers were extracted with E12O and the combined organic extracts dried (MgSC>4). Evaporation of the solvent and flash chromatography using petroleum etherethyl acetate (3:2) as eluant yielded 22 as a colourless liquid (11.2 g, 75%).  IR (neat, cm" ): 3600-3250, 2945, 2850, 1730, 1376, 1250, 1071, 845 1  *H NMR (CDCI3, 400 MHz) 5: 4.09 (t, J=6 Hz, 2H), 3.83 (m, J=6 Hz, 1H), 2.06  (s, 3H), 1.71-1.61 (m, 2H), 1.53-1.35 (m,5H), 1.21 (d, J=6 Hz,3H)  LRMS (m/z) from CI: 178 (M++18, 53)  LRMS (m/z) from EI: 101 (25), 85 (36), 67 (22), 61 (63), 57 (24), 58 (23), 45 (68), 43 (100), 41 (43)  Exact Mass calculated for C8Hi 02: 160.1099; found: 160.1090 6  39  l-Acetoxv-5-(fer/-butvldimethvlsiloxy)hexane  (23)  OTBDMS  l-Acetoxy-5-hexanol (11.1 g, 0.069 mol) in methylene chloride (100 mL) was added to a solution of TBDMS chloride (15.7 g, 0.104 mol) in methylene chloride (200 mL). Triethylamine (19.3 mL, 0.139 mol) and a catalytic amount of DMAP were added and the mixture heated at reflux for 48 h. The reaction mixture was cooled to room temperature and quenched with 1 M HC1. The organic layer was separated, washed with saturated NaHCC>3, water and dried (MgSO"4). Evaporation of the solvent and flash chromatography using petroleum ether-ethyl acetate (20:1) as eluant gave 23 as a colourless liquid (19.0 g, 100%).  IR (neat, cm" ): 2944, 2856, 1743, 1476, 1370, 1244, 1136, 1055, 835, 775 1  1H NMR (CDC1 , 400 MHz) 5: 4.06 (t, 1=8 Hz, 2H), 3.78 (m, 1H), 2.05 (s, 3H), 3  1.67-1.55 (m, 2H), 1.23-1.52 (m, 4H), 1.12 (d, J=8 Hz, 3H), 0.88 (s, 9H), 0.08 (s, 6H)  LRMS (m/z) from CI: 292 (M++ 18, 7)  LRMS (m/z) from EI: 217 (M+-57, 9), 117 (100), 83 (56), 75 (35), 73 (21), 55 (37)  Exact Mass calculated for Ci4H o0 Si: 273.1886; found: 273.1886 3  3  5-(ferf-ButyIdimethyIsiloxy)-l-hexanol  (24)  OTBDMS  TBDMS ether 23 (7.5 g, 0.027 mol) was added to a solution of KOH (9.1 g, 0.163 mol) in methanol (60 mL) and the resulting solution was stirred for 24 h. The methanol was removed under reduced pressure and the residue dissolved in Et20. The organic layer was washed with water, saturated NaHCC>3 and dried (MgSCU). Evaporation of the solvent and flash chromatography using petroleum ether-ethyl acetate (8:1) as eluant yielded 24 as a colourless liquid (5.59 g, 88%).  IR (neat, cm" ): 3600-3150, 2941, 2859, 1466, 1371, 1253, 1138, 1104, 1056, 1  1006, 834, 775  *H NMR  ( C D C I 3 , 400 MHz) 5: 3.80 (m, 1H), 3.66 (t, J=8 Hz, 2H), 1.57  (m,  2H), 1.50-1.34 (m, 5H), 1.13 (d, 1=8 Hz, 3H), 0.90 (s, 9H), 0.06 (s, 6H)  LRMS (m/z): 175 (M+-57, 9), 159 (26), 119 (87), 93 (25), 83 (92), 75 (100), 73 (72), 55 (87)  Exact Mass calculated for Ci2H 70 Si: 231.1781; found: 231.1780 2  2  5-(ferf-ButyldimethyIsiloxy)hexanal  (17)  OTBDMS H  To a solution of oxalyl chloride (2.5 mL, 0.026 mol) in methylene chloride (50 mL) at -78 °C was added a solution of DMSO (3.8 mL, 0.052 mol) in methylene chloride (10 mL). The mixture was stirred for 15 min. and then a solution of alcohol 24 (5.5 g, 0.024 mol) in methylene chloride (10 mL) was added to the reaction mixture. Stirring was continued for another 15 min., triethylamine (16.5 mL, 0.118 mol) added and the mixture allowed to warm to room temperature. The reaction mixture was poured into water, extracted with methylene chloride and the combined organic layers dried (MgSCU). Evaporation of the solvent and flash chromatography using petroleum ether-ethyl acetate (20:1) as eluant yielded 17 as a colourless liquid (4.86 g, 89%).  IR (neat, cm" ): 2917, 2715, 1731, 1465, 1373, 1251, 1138, 1053, 834 1  !H NMR (CDCI3, 400 MHz) 8: 9.76 (t, J=2 Hz, 1H), 3.81 (m, J=4 Hz, 1H),  2.43  (dt, J=2, 4 Hz, 2H), 1.76-1.60 (m, 2H), 1.40-1.33 (m, 2H), 1.14 (d, J=4 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H)  LRMS: 230 (M+, 1), 171 (29), 143 (47), 115 (38), 99 (100), 97 (25), 83 (27), 81 (43), 75 (44), 69 (25), 55 (26)  Exact Mass calculated for Ci2H 5C>2Si: 229.1624; found: 229.1624 2  Methyl 8-bromooctanoate (25)  8-Bromooctanoic acid (7.0 g, 0.031 mol) was added to a catalytic amount of sulphuric acid in methanol (150 mL) and the mixture heated at reflux for 24 h. The solution was cooled to room temperature, poured into ice-cold water, extracted with methylene chloride and the combined organic layers dried (MgSC>4). Evaporation of the solvent and flash chromatography using hexanes-ethyl acetate (10:1) as eluant yielded 25 as a colourless liquid (6.98 g, 94%).  IR (neat, cm-l): 2928, 2875, 1738, 1442, 1213  *H NMR (CDC1 , 400 MHz) 5: 3.66 (s, 3H), 3.40 (t, J=6 Hz, 2H), 2.31 (t, J=6 3  Hz, 2H), 1.86 (qi, J=6 Hz, 2H), 1.63 (m, 2H), 1.44 (m, 2H), 1.34 (m, 6H)  LRMS (m/z): 238 ( Br, M+, 0.2), 236 ( Br, M+, 0.2), 157 (33), 125 (46), 97 81  79  (32), 87 (83), 75 (24.3), 74 (100), 69 (21), 59 (42), 55 (86), 43 (45)  Exact Mass calculated for Ci9Hi BrC>2: 236.0391; found: 236.0383 81  7  Ci9Hi 79Br0 : 236.0411; found: 236.0415 7  2  Methvl 8-iodooctanoate (26)  Bromo ester 25 (6.9 g, 0.029 mol) was added to a solution of sodium iodide (43.6 g, 0.29 mol) in acetone (200 mL) and the mixture stirred for 24 h. The solvent was then removed under reduced pressure and the residue dissolved in Et20. The organic phase was washed with water, brine and dried (MgS04). Evaporation of the solvent and flash chromatography using petroleum ether-ethyl acetate (25:1) as eluant yielded 26 as a colourless liquid (8.15 g, 99%).  IR (neat, cm" ): 3458, 2918, 1736, 1443, 1232, 1012, 866, 724 1  !H NMR (CDC1 , 400 MHz) 8: 3.66 (s, 3H), 3.2 (t, J=8 Hz, 2H), 2.32 (t, J=8 3  Hz, 2H), 1.82 (qn, J=8 Hz, 2H), 1.63 (m, 2H), 1.47-1.30 (m, 8H)  LRMS (m/z): 284 (M+, 0.1), 157 (69), 125 (81), 97 (79), 83 (84), 74 (64), 69 (29), 59 (52), 55 (100), 43 (28), 41 (37)  Exact Mass calculated for C9H17IO2: 284.0273; found: 284.0272  Methyl 13-(7ert-butyldirnethvlsiIoxv)tetradec-8-enoate (27) OTBDMS  O  Iodide 26 (6.17 g, 0.022 mol) was added to a solution of triphenyl phosphine (6.84 g, 0.026 mol) and diisopropylethylamine (3.8 mL, 0.022 mol) in acetonitrile (70 mL) and the mixture heated under reflux for 48 h. The solution was cooled, the solvent removed under reduced pressure and the crude phosphonium salt dried under high vacuum for 12 h. To a solution of the crude phosphonium salt 18 in THF (250 mL), cooled to -78 °C, was added a solution of sodium bis(trimethylsilyl)amide (3.96 g, 0.021 mol) in THF (50 mL). Stirring was continued for 30 min. and aldehyde 17 (4.50 g, 0.02 mol) in THF (25 mL) was added. The mixture was stirred for 1 h., allowed to warm to room temperature and filtered through celite. Evaporation of the solvent and column chromatography using petroleum ether-ethyl acetate (50:1) as eluant yielded 27 (4.1 g, 57%) as a colourless oil.  IR (neat, cm" ): 2935, 2851, 1740, 1451, 1369, 1251, 834, 774 1  !H NMR (CDC1 , 400 MHz) 8: 5.34 (m, 2H), 3.77 (m, 1H), 3.66 (s, 3H), 2.30 (t, 3  1=8 Hz, 2H), 2.02 (m, 4H), 1.61 (br. m, 4H), 1.51-1.24 (m, 12H), 1.12 (d, 1=6 Hz, 3 Hz), 0.90 (s, 9H), 0.06 (s, 6H)  LRMS (m/z): 370 ( M , 0.2), 313 (35), 281 (52), 262 (82), 183 (61), 159 (20), 109 +  (25), 108 (45), 107 (45), 95 (41), 81 (48), 75 (100), 73 (58), 69 (20), 67 (34), 55 (33)  Methvl 13-hvdroxvtetradec-8-enoate (28) OH  O  A I M solution of tetrabutylammonium fluoride in THF (21.6 mL, 0.022 mol) was added to the rm-butyldimethylsilyl ether 27 (4.00 g, 0.011 mol). The resulting solution was stirred for 48 h. and then the solvent was removed under reduced pressure. The residue was dissolved in methylene chloride, washed with water and dried (MgSC»4). Evaporation of the solvent and flash chromatography using petroleum ether-ethyl acetate (6:1) as eluant yielded 28 as a colourless liquid (1.98 g, 72%).  IR (neat, cm' ): 3610-3160, 2931, 2857, 1734, 1449, 1372, 1225, 1046 1  *H NMR  ( C D C I 3 , 400  MHz)  8: 5.37  (m,  2H),  3.80  (m,  1H),  3.68  (s, 3H),  2.30  (t,  J=8 Hz, 2H), 2.04 (m, 4H), 1.70-1.24 (m, 13H), 1.20 (d, J=6 Hz, 2H)  LRMS (m/z): 256 (M+ 2.1), 164 (75), 142 (45), 136 (22), 135 (26), 123 (20), 122 (43), 121 (25), 112 (21), 110 (20), 109 (35), 108 (25), 107 (24), 98 (55), 97 (34), 96 (46), 95 (60), 94 (31), 93 (23), 87 (25), 84 (23), 83 (32), 82 (57), 81 (100), 80 (28), 79 (32), 74 (25)  Exact Mass calculated for C 1 5 H 2 8 O 3 : 256.2038; found: 256.2038  13-Hydroxvtetradec-8-enoic acid (29) OH  O  A solution of hydroxy ester 28 (1.95 g, 7.62 mmol) in THF (100 mL) was added to a solution of lithium hydroxide (0.62 g, 38.6 mmol) in water (50 mL) and the resulting mixture was stirred for 6 h. The solution was neutralised with 1 M HC1, extracted with Et20 and the combined organic extracts dried. (MgSC<4). Evaporation of the solvent and flash chromatography using petroleum ether-ethyl acetate (3:2) as eluant yielded 29 as a colourless oil (1.46 g, 80%).  IR (neat,  cm-1):  3580-3530, 2929, 2857, 1712, 1459, 1408, 1374, 1252, 1126,  1081,938  1H NMR (CDC1 , 400 MHz) 5: 5.36 (m, 2H), 3.83 (m, 1H), 2.35 (t, J=8 Hz, 3  2H), 2.06 (m, 4H), 1.65 (m, 2H), 1.58-1.36 (m, 11H), 1.20 (d, J=6 Hz, 3H)  LRMS (m/z): 242 (M+, 0.4), 182 (35), 149 (22), 126 (25), 122 (50), 112 (20), 109 (28), 98 (46), 96 (33), 95 (56), 83 (21), 82 (58), 81 (89), 80 (21), 79 (22), 71 (49), 69 (35), 68 (100)  Exact Mass calculated for  C14H26O3:  224.1882; found: 224.1884  (E/Z)-13-Tetradec-8-enolide (14.15)  1-Phenyl-1 H-tetrazole-5-thiol (1.24 g, 6.94 mmol) in toluene (50 mL) was added to terf-butylisocyanide (0.8 mL, 6.94 mmol)-and the resulting mixture stirred until homogeneous. Hydroxy acid 29 (1.40 g, 5.78 mmol) was then added, the solution was diluted with toluene (1.0 L) and the mixture heated under reflux for 24 h. Removal of the solvent and flash chromatography using petroleum ether-ethyl acetate (25:1) as eluant yielded a 1:1.25 mixture of 14 and 15 as a yellow oil (901 mg, 70%). Separation of 14 and 15 was achieved by flash chromatography using silver nitrate impregnated silica gel, and petroleum ether-diethyl ether (25:1) as eluant to give 14 (402 mg) as a colourless oil and 15 (491 mg) as a pale yellow oil.  Data for 14 IR (neat, cm" ): 2927, 2855, 1730, 1447, 1368, 1273, 1211, 1178, 1142, 1101, 1  1017, 970, 868, 732  *H NMR (CDC1 , 400 MHz) 5: 5.46 (dt, J=16, 8 Hz, 1H), 5.30 (dt, J=16, 8 Hz, 3  1H), 5.06 (m, 1H), 2.28 (m, 2H), 2.15-1.98 (m, 4H), 1.90-1.72 (m, 4H), 1.64-1.18 (m, 8H), 1.20 (d, J=8 Hz, 3H)  LRMS (m/z): 224 (M+ 29), 182 (72), 164 (22), 122 (50), 109 (30), 108 (21), 96 (41), 95 (59), 94 (23), 93 (20), 82 (71), 81 (88), 80 (23), 79 (29), 69 (24), 68 (100)  Exact Mass calculated for C14H24O2: 224.1777; found: 224.1775  Data for 15 IR (neat, cm" ): 3426, 2931, 2858, 1729, 1453, 1368, 1251, 1132, 1081, 1040, 1  994, 882,714  J  H NMR (CDCI3, 400 MHz) 8: 5.45 (dt, J=ll, 8 Hz, 1H), 5.25 (dt, J=ll, 8 Hz,  1H), 4.94 (m, 1H), 2.28 (m, 4H), 1.87 (m, 2H), 1.80-1.16 (m, 11H), 1.25 (d, J=6 Hz, 3H)  LRMS (m/z): 224 (M+, 15), 182 (48), 164 (21), 122 (52), 109 (28), 96 (38), 95 (62), 94 (24), 93 (24), 82 (61), 81 (92), 80 (26), 79 (37), 69 (26), 68 (100)  Exact Mass calculated for Ci4H C>2: 224.1777; found: 224.1774 24  49  (8R*. J3S*)-8-Hvdroxv-13-tetradecanolide  (30)  (a) Hydroboration of (E/Z)-13-Tetradec-8-enolide (14.15) with boranedimethvlsulphide Borane-dimethylsulphide (70 (iL, 0.74 mmol) was added to a 1:1 mixture of 14 and 15 (150 mg, 0.67 mmol) in THF (15 mL) and the resulting solution stirred for 4 h. The solution was then cooled to 0 °C and 3 M NaOH (600 uX, 1.8 mmol) and 30% H2O2 (1.2 mL) were added sequentially. Stirring was continued for a further 30 min. then the mixture was diluted with water, extracted with methylene chloride and the combined organic layers dried (MgS04). Evaporation of the solvent and purification by chromatotron using chloroform-methanol (99:1) as eluant yielded a mixture of 30, 31, 32 and 33 (130 mg, 80%) as a colourless oil. The mixture of hydroxy lactones (130 mg, 0.54 mmol) was dissolved in THF (10 mL) and TMS chloride (169 [iL, 1.1 mmol) and triethylamine (186 fjL, 1.1 mmol) were added. The resulting solution was stirred for 24 h., diluted with diethyl ether, washed with saturated NaHC03 and dried (MgS04). Evaporation of the solvent and purification by chromatotron using petroleum ether-ethyl acetate (99:1) as eluant to give a mixture of 36 and 37 (54 mg) and 34 and 35 (98 mg), in a total yield of 90%.  A I M solution of tetrabutylammonium fluoride (340 uL, 0.34 mmol) in THF was added to a solution of 36 and 37 (54 mg, 0.17 mmol) in THF (5 mL) and the resulting mixture stirred for 2 h. The mixture was diluted with water, extracted with ether and the combined organic layers dried (MgSO-4). Evaporation of the solvent and purification by chromatotron using chloroform-methanol (99:1) as eluant yielded hydroxy lactones 32 and 33 (37 mg, 90%). Desilylation of 34 and 35 (98 mg, 0.31 mmol) followed the same procedure as above using tetrabutylammonium fluoride (620 uX, 0.62 mmol) to give hydroxy lactones 30 (40 mg) and 31 (28 mg) as colourless oils (90%).  Data for 30 IR (neat, cm" ): 3620-3120, 2936, 2859, 1719, 1452, 1371, 1243, 1141, 755 1  !H NMR ( C D C I 3 , 400 MHz) 5: 5.00 (m, 1H), 3.73 (m, 1H), 2.44 (m, 1H),  2.25  (m, 1H), 1.80-1.16 (m, 19H), 1.21 (d, J=8 Hz, 3H)  LRMS (m/z) from CI: 258 (M++18, 3)  LRMS (m/z) from EI: 224 (M+-18, 2), 141 (88), 113 (39), 95 (100), 69 (41), 68 (26), 67 (22)  Exact Mass calculated for  C14H26O3:  242.1882; found: 242.1874  Data for 31 IR (neat, cm" ): 3600-3175, 2934, 2863, 1719, 1453, 1371, 1250, 1122, 934, 755 1  *H NMR (CDC1 , 400 MHz) 5: 4.98 (m, 1H), 3.84 (m, 1H), 2.40 (m, 1H), 2.27 3  (m, 1H), .1.72-1.20 (m, 19H), 1.23 (d, J=8 Hz, 3H)  LRMS (m/z): 224 (M++18, 13), 173 (25), 156 (25), 156 (25), 155 (91), 115 (58), 109 (56), 100 (25), 99 (100), 98 (52), 97 (30), 96 (20), 95 (36), 34 (29), 83 (50), 82 (43), 81 (80), 73 (44)  Data for 32 and 33 IR (neat, cm" ): 3600-3115, 2933, 2862, 1720, 1453, 1371, 1251, 1112, 755 1  *H NMR (CDCI3, 400 MHz) 6: 5.03 (m, 1H), 4.95 (m, 1H), 3.78 (m, 2 x 1H),  2.43 (m, 2 x 1H), 2.30 (m, 2 x 1H), 1.74-1.20 (m, 2 x 19H), 1.23 (d, J=8 Hz, 2 x 3H)  LRMS (m/z): 242 (M+, 0.2), 224 (6), 155 (87), 141 (58), 115 (24), 113 (32), 109 (31), 99 (100), 98 (26), 95 (67), 83 (25), 82 (24), 81 (69), 73 (26)  b) Hydroboration offfE-tetradecen-13-olide(14) with boranedimethvlsulphide Borane-dimethylsulphide (22 |iL, 0.22 mmol) was added to a solution of lactone 14 (25 mg, 0.11 mmol) in THF (3 mL) at -78 °C and the resulting mixture stirred for 24 h. Standard work-up and purification, as outlined in method (a), yielded hydroxy lactones 30, 31, 32 and 33 (26 mg, 96%) in a ratio of 44:26:18:12 (GC analysis of TMS ethers) as a colourless oil.  (c) Hydroboration of 3E-tetradecen-13-oIide (14) with 9BBN A solution of 9BBN (54 mg, 0.22 mmol) in THF (1 mL) was added to a solution of lactone 14 (25 mg, 0.11 mmol) in THF (2 mL) and the resulting solution stirred for 10 h. Standard work-up and purification yielded hydroxy lactones 30, 31, 32 and 33 (25 mg, 93%) in a ratio of 43:24:26:7 (GC analysis of TMS ethers) as a colourless oil.  (d) Hydroboration offfE-tetradecen-13-olide(14) with disiamvlborane A 0.5 M solution of disiamylborane in THF (1.8 mL, 0.40 mmol) was added to lactone 14 (40 mg, 0.18 mmol) in THF (4 mL) and the resulting solution stirred for 30 h. Standard work-up and purification yielded hydroxy lactones 30 and 33 (42 mg, 96%) in a ratio of 89:11 (GC analysis of TMS ethers) as a colourless oil.  (e) Hydroboration of &Z-tetradecen-13-olide (15) with boranedimethylsulphide Borane-dimethylsulphide (22 |iL, 0.22 mmol) was added to a solution of lactone 15 (25 mg, 0.11 mmol) in THF (3 mL) at -78 °C and the resulting mixture stirred for 24 h. Standard work-up and purification yielded hydroxy lactones 30, 31, 32 and 33 (27 mg, 100%) in a ratio of 45:28:19:8 (GC analysis of TMS ethers) as a colourless oil.  (f) Hydroboration of 3Z-tetradecen-13-olide (15) with 9BBN A solution of 9BBN (54 mg, 0.22 mmol) in THF (1 mL) was added to a solution of lactone 15 (25 mg, 0.11 mmol) in THF (2 mL) and the resulting mixture stirred for 10 h. Standard work-up and purification yielded hydroxy lactones 30, 31, 32 and 33 (25 mg, 93%) in a ratio of 51:7:6:36 (GC analysis of TMS ethers) as a colourless oil.  (g) Hydroboration of gZ-tetradecen-13-olide (15) with disiamylborane A 0.5 M solution of disiamylborane in THF (1.5 mL, 0.34 mmol) was added to lactone 15 (30 mg, 0.14 mmol) in THF (4 mL) and the resulting mixture stirred for 18 h. Standard work-up and purification yielded hydroxy lactones 30, 31 and 33 (30 mg, 93%) in a ratio of 53:37:10 (GC analysis of TMS ethers) as a colourless oil.  54 REFERENCES  1.  a) Ruzicka, L. Helv. Chim. Acta 1926, 9, 715. b) Ruzicka, L. Helv. Chim. Acta 1926, 9, 1008.  2.  von Baeyer, A. Chem. Ber. 1885, 2277.  3.  Prelog, V.; Frenkiel, L.; Kobelt, M.; Barman, P. Helv. Chim. Acta 1947, 30, 1741.  4.  a) Ruzicka, L.; Stoll, M.; Huyser, H . W.; Boekenoogen, H. A. Helv. Chim. Acta 1930, 13, 1152. b) Ruzicka, L.; Planner, P. A.; Wild, H. Helv. Chim. Acta 1946, 29, 1611  5.  Prelog, V. J. Chem. Soc. 1950, 420.  6.  Huver-Buser, E.; Dunitz, J. D.; Venkatesan, K. Proc. Chem. Soc. 1961, 463.  7.  Dale, J. / . Chem. Soc. 1963, 63.  8.  a) Dunitz, J. D.; Meyer, E. F. Helv. Chim. Acta 1965, 48, 1441. b) Groth, P. Acta Chem. Scand. 1976, A30, 155.  9.  a) Dale, J. Acta Chem. Scand. 1973, 27, 1115. b) Dale, J. Acta Chem. Scand. 1973, 27, 1130.  10. a) Anet, F. A . L.; Cheng, A. K. J. Am. Chem. Soc. 1975, 97, 2420. b) Dale, J. Top. in Stereochem. 1976, 9, 199. 11.  Dale, J. Angew. Chem. Int. Ed. Engl. 1975, 5, 1000.  12. Cope, A. C ; Moore, P. T.; Moore, W. R. J. Amer. Chem. Soc. 1960, 82, 1744. 13. Brockmann, H.; Henkel, W. Naturwissenschaften 1950, 37, 138. 14. Celmer, W. D. Antimicrob. Agents Chemother. 1965, 144. 15. a) Harris, D. R.; M Geachin, S. G.; Mills, H.H. Tetrahedron Lett. 1965, 679. b) c  Egan, R. S.; Perun, T. J.; Martin, J. R.; Mitscher, L. A. Tetrahedron 1973, 29, 2525. 16. Ogura, H.; Furuhata, K.; Kuwano, H.; Harada, N . / . Am. Chem. Soc. 1975, 97, 1930.  55  17. a) Falbe, J.; Korte, F. Chem. Ber. 1963, 96, 919. b) Binder, N.; Tamm, C. Helv. Chim. Acta 1973, 56, 966. c) Corey, E. J.; Petrzilka, M . Tetrahedron Lett. 1975, 2537. 18. Corey, E. J.; Nicolau, K. C. / . Am. Chem. Soc. 1974, 96, 5614. 19. Schmidt, U.; Dietsche, M . Angew. Chem. Int. Ed. Engl. 1981, 20, 771. 20. Inanaga, J.; Hirata, K.; Sacka, H.; Katsuki, T.; Yamaguchi, M . Bull. Chem. Soc. Jpn. 1979, 52, 1989. 21.  a) Mukaiyama, T.; Usui, M . ; Saigo, K. Chem. Lett. 1976, 49. b) Masamune, S.; Kamata, S.; Schilling, W. / . Am. Chem. Soc. 1975, 97, 3515. c) Makita, A.; Nihira, T.; Yamada, Y. Tetrahedron Lett. 1987, 805.  22.  Still, W. C ; Novack, V. J. / . Am. Chem. Soc. 1984, 106, 1148.  23. Paterson, I.; Rawson, D. J. Tetrahedron Lett. 1989, 7463. 24. Vedejs, E.; Gapinski, D. M . / . Am. Chem. Soc. 1983, 105, 5058. 25. Vedejs, E.; Dolphin, J. M.; Masterlerz, H. J. Am. Chem. Soc. 1983, 105, 127. 26.  Ramaswamy, S.; Morgan, B.; Oehlschlager, A. C. Tetrahedron Lett. 1990, 3405.  27.  Mancuso, A . J.; Huang, S. L.; Swern, D. / . Org. Chem. 1978, 43, 2480.  28. Corey, E. J.; Reichard, G. A. Tetrahedron Lett. 1989, 5207. 29. Wittig, G.; Schollkopf, U . Chem. Ber. 1954, 87, 1318. 30. Schlosser, M . Top. in Stereochem. 1970, 5, 1. 31.  Still, W. C ; Kahn, M . ; Mirata, A. J. Org. Chem. 1978, 43, 2923.  32. De Vries, B. Chem. and Ind. 1962, 1049. 33. Saunders, M . Tetrahedron 1978, 23, 2103. 34. Ogura, H.; Furuhata, K.; Kuwano, H.; Suzuki, M . Tetrahedron 1981, 37, 165. 35. Ounsworth, J. P.; Weiler, L. /. Chem. Ed. 1987, 64, 568. 36. Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon Press: Willowdale, 1983 37. Schweizer, W. B.; Dunitz, J. D. Helv. Chim. Acta 1982, 65, 1547.  56  38.  Burkert, U.; Allinger, N. L. Molecular Mechanics, ACS Monograph 177: Washington, 1982.  39.  Perrin, D. D. and Armarego, W. L. F. Purification of Laboratory Chemicals, third ed.; Pergamon Press: Toronto, 1988.  40.  a) Keller, T. H. Ph. D. Thesis, University of British Columbia, June 1988. b) Neeland, E. G. Ph.D. Thesis, University of British Columbia, January 1988.  41. L i , Y.; Wang, X.; Wu, Y.; Houk, K. N. Preprint, 1991. 42.  Still, W. C ; Galynker, I. / . Am. Chem. Soc. 1982, 104, 1774.  SPECTRAL  APPENDIX  59  OTBDMS  23  OTBDMS  84.06-1  1  1  1 -i  1  r  1  1  1  1  i  1  1  1  1  1  1  1  1  1  '  1  r  42.6H  4000 .  1 1 1  J—i  3400.  1 1  1  000.  1 1 1  1  2200.  1  i  1  1  1600.  1 1  1000.  •  1  DM  64  67  68  5880A AREA y.  IhPl  MANUAL INJECTION 9 21:49 AREA  1.37 1.54 9.44 9.80 9.92 18.33  5.63 11.24 168.53 883.23 385.83 549.32  TOTAL AREA = 2003.84 MULTIPLIER = 1  JAN 17» 1991  TYPE  AREA '/.  BB BB BV VV VP PB  0.234 0.561 8.411 44.077 19.255 27.414  

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