MODEL STUDIES DIRECTED TOWARDS IONOMYCIN by KEVIN PAUL SHELLY B.Sc, University College Galway, 1981 A THESIS SUBMITTED IN PARTIAL FULFILMENT 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 October, 1984 © Kevin Paul Shelly, 1984 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 of The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date IS OCT ff*f- DE-6 (3/81) - ii - ABSTRACT This work is concerned with model studies directed towards the synthesis of the polyether antibiotic ionoraycin (2). HOjC This involved the synthesis of: (a) a model of the A portion of _2, namely 30a (b) a precursor to the B portion of 2, namely 31 31 30a Both of these racemic subunits were prepared from meso-2,4-diraethylglutaric anhydride (25). 25 Subsequent work comprised of investigating the coupling reaction of these two portions. Model studies using the simpler moieties 17 and - iii - .39b The use of the epoxide 40a proved more successful, providing 43a and 43b in a 39% yield. 40a 43b - iv - The conditions found for oxidation of 20 to 21. proved fruitless with 43a and 43b. However, dithiane hydrolysis followed by an oxidation 21 yielded the 6-diketones 44a and 44 b. 44a 44 b - v - TABLE OF CONTENTS Page ABSTRACT ii TABLE OF CONTENTS v LIST OF FIGURES vi LIST OF TABLES vii LIST OF ABBREVIATIONS viii ACKNOWLEDGEMENTS x INTRODUCTION A. Natural Product Synthesis.... 1 B. Polyether Antibiotics 2 C. Ionoraycin 3 D. Synthesis 4 DISCUSSION 1. Model Studies.. 19 2. Synthesis of a Common Intermediate Leading to Subunits 25 3. Dithiane Subunit 30 31 4. Epoxide Subunit 3_1_ 33 5. Dithiane Metallation 36 6. Alkylation Reaction 39 7. Route to 3-Diketones 44a and 44b 44 EXPERIMENTAL 54 BIBLIOGRAPHY 78 SPECTRAL INDEX 81 - vi - LIST OF FIGURES Figure Title Page 1 Retrosynthetic plan leading from ionoraycin (2_) 12 2 Percent product vs. time in oxidation of alcohol 20 using PCC and PCC • AI2O3 22 3 Percent product vs. time in oxidation of alcohol 20 using PDC in DMF 24 4 Correlation of ^-nmr and gc data of various crops of anhydride crystals...................... 27 - vii - LIST OF TABLES Table Title Page I Alkylation of dithiane 17_ with 1,2-epoxybutane (19)... 20 II Oxidation of alcohol 20_ using PDC in DMF 23 III Elemental analysis of anhydride 25_ containing one water of hydration 29 IV Metallation studies on dithiane 30a using _t-butyl lithium 37 V Metallation studies on dithiane 30a using n-butyllithiura 39 - viii - LIST OF ABBREVIATIONS AC2O acetic anhydride n-BuLi n_-butyllithium j:-BuLi _t-butyllithium °C degrees Celsius cone. concentration DCC dicyclohexylcarbodilmide DMF dimethylformamide DMSO dimethylsulfoxide equiv. equivalent(s) ethyl ether diethyl ether gc • gas liquid chromatography h hour ^H-nmr proton nuclear magnetic resonance HMPA hexamethylphosphoramide ir infra-red LAH lithium aluminum hydride MCPBA meta-chloroperoxybenzoic acid min minute(s) PCC pyridinium chlorochrornate PCC«Al203 pyridinium chlorochrornate on alumina (1:4) PDC pyridinium dichromate rbf round bottom flask S03*Py pyridine sulfur trioxide complex - ix - TBDMS _t-butyldiraethylsilyl TEA triethylamine THF tetrahydrofuran THP 2-tetrahydropyranyl tic thin layer chromatography TMEDA tetraraethylethylenediaraine abbreviations for multiplicities of ^-nrar signals s singlet bs broad singlet d doublet t triplet q quartet m multiplet dt doublet of triplets ddd doublet of doublets of doublets - x - ACKNOWLEDGEMENTS I wish to express my sincere thanks to Dr. Larry Weiler for his excellent guidance and invaluable suggestions throughout the course of my research and the preparation of this thesis. Numerous discussions with members of the research group, past and present, have been most beneficial and valuable. To them I extend my thanks and best wishes. The assistance of the elemental analysis, nmr, and mass spectroscopy staff, as well as the other staff in the department, is appreciated. - xi - To My Parents - 1 - INTRODUCTION A. Natural Product Synthesis "One should always be drunk, thats all that matters. but what with? ..." Following on this advice from the French poet Baudelaire (1821 - 1867), synthetic organic chemists seek out a natural product to ( synthesize and in effect get "drunk with". As organic chemistry develops and provides more synthetic methods, more natural product syntheses are attainable. While organic chemists can debate the merits of various syntheses, they can only allocate the silver and bronze medals. Nature, while providing the target, also usually provides the best solution. Indeed, some syntheses follow guidelines prompted by the biosynthetic pathway used by nature, and often the building blocks used in syntheses are supplied by nature, such as carbohydrates and amino acids. Nevertheless, once a synthesis has been achieved, the group involved will rightly feel a sense of achievement. As well as direct gains possible from the synthesis of a natural product such as an antibiotic or an insect pheromone, a real value lies in the experience gained by all involved in the project. Apprenticeship, the oldest of educational methods, is the basic concept in the learning process. Techniques, methods, and the planning skills learned in one synthesis can be ever so useful in subsequent work and - 2 - thus are an investment, available only through direct experience. There are a lot more ways to get drunk than by synthesizing a natural product. Baudelaire had these thoughts about the why and how; "One should always be drunk thats all that matters. So as not to feel Time's horrible burden that breaks your shoulders and bows you down, You must get drunk without ceasing. But what with? With wine, with poetry or with virtue as you please." B. Polyether Antibiotics The polyether antibiotics are members of a much larger class of compounds called ionophores. Ionophores can complex an ion and transport it through a lipophilic interface. Westley defines eight structural groups of ionophores based on chemical structure (1). The polyether antibiotic group is distinguished by a linear carbon framework, containing tetrahydrofurans and tetrahydropyrans, numerous asymmetric centres and often a terminal carboxylic acid. The first polyether antibiotic to be isolated was nigericin 0_) in 1951, it's structural determination was realized 17 years later (2). These antibiotics are an ever growing class of ionophores, with more than 30 having been recognized by 1978; while only 6 years later, 40 - 3 - more polyether antibiotics had been reported (3,4). •Me Ah 1 Economically, polyether antibiotics have been applied in the treatment of coccidiosis, a poultry disease. They have not gained any use in human therapy because of their high toxicity when administered parenterally. A number of laboratories are investigating other possible uses for the polyether antibiotics. C. Iononycin Liu et al. in 1978 (3) reported the production and isolation of the polyether antibiotic ionomycin (2). The antibiotic was isolated as its calcium salt from a broth concentrate which had been adjusted to pH 12 with aqueous sodium hydroxide. The high affinity for calcium ions illustrates an interesting property of ionomycin. This polyether antibiotic chelates dipositive ions as a dibasic acid, whereas the few other known ionophores which chelate such divalent cations do so as monobasic acids. - 4 - 2 The structural determination of _2 resulted from ir, nmr, x-ray and mass spectroscopic data as detailed by Toeplitz et al. in 1978 (5). The molecular structure of the calcium and cadmium salts of ionoraycin contain a cisoid B-diketone anion that together with a carboxylate group and three other oxygen atoms are octahedrally coordinated to the central divalent cation as shown by an x-ray structure (5). D. Synthesis Some of the difficulties involved in the synthesis of ionoraycin include setting up a 32 carbon linear skeleton containing 14 asymmetric centres and a variety of functional groups. While Evans has realized the synthesis of four subunits of ionomycin (6), the total synthesis of ionoraycin has not been reported to date. The synthesis planned by our group coincidentally involves a four part convergent synthesis. A convergent synthesis is inherently more efficient than a linear one (7). The linkage points chosen In such a plan are very important. We planned a strategy based on the bond disconnections shown In 3. - 5 - A_ _B_ _C_ .D 3 This thesis is concerned with model studies towards linking the A and B portions of ionoraycin, as well as preparing the groundwork for the synthesis of the B portion. A retrosynthetic analysis prompted us to consider dithiane chemistry to link the A and B subunits. Alkylation of the metallated dithiane with an epoxide and subsequent transformations might yield the desired B-diketone. - 6 - Applying the methods of Corey and Seebach, developed since 1965, alkylation of dithiane anions with various electrophiles is possible (8). Since regeneration of the carbonyl function can be achieved by a variety of methods, the thioacetal carbanions are equivalent to acyl anions and can be used effectively to reverse the characteristic electrophilicity of a carbonyl carbon. In 1972 Seebach proposed the use of the terra "urapolung" for this inversion of reactivity (9). - 7 - The use of dithiane chemistry in natural product synthesis is well documented. Seebach in his 1977 review, cites numerous applications (9).