THE USE OF CARBANIONS IN ^-LACTAM SYNTHESIS A Thesis presented by PETER QUAYLE In Partial Fulfilment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF LONDON DEPARTMENT OF CHEMISTRY IMPERIAL COLLEGE OF SCIENCE & TECHNOLOGY LONDON SW7 2AY. OCTOBER, 1981. 2. To my Parents "It pays to speculate as widely and wildly as possible; people only remember when you are right!" Derek H.R. Barton, FRS. (Gordon Research Conference> 19£>4) 4. ACKNOWLEDGEMENTS I wish to thank my supervisor, Dr. A.G.M. Barrett, for his advice, insight and encouragement throughout the duration of this project. I wish to thank all my colleagues, past and present, for their stimulating lunch-time discussions. I would specially like to thank Az and Shabaht, Chris and Greg, Elizabeth and Dave, Carmen and Pagona for their unfailing friendship. I am indebted to the technical staff at Imperial College for their invaluable assistance. I thank the Science Research Council for financial support through- out my studies. I would also like to thank Maria Serrano-Widdowson for typing this thesis. Peter Quayle 15th October, 1981. The synthesis of carbapenem ring systems is reviewed. The phenylethynolate anion has been shown to undergo a novel cyclo- addition reaction with electron defficient Schiff's bases to afford highly substituted azetidin-2-ones,in good yields, in a stereoselective fashion. Attempts to react the phenylethynolate anion with less activated Schiff's bases were unsuccessful. The reaction of several related species is described. The Shapiro reaction has been successfully applied to the synthesis of a-methylene-3-lactams. The preparation of l-benzyl-3-phenylazetidin-2-one, from the readily available N-benzyl-3-hydroxy-3-phenylpropanamide, is described. Competing elimination reactions limit the general applicability of this methodology. The facile preparation of the synthetically important 4-(arylcarbonyl- methyl)azetidin-2-ones and related compounds from 4-acetoxy-l-trimethyl- silylazetidin-2-one and various silylenol ethers is described. The use of trimethylsilyl trifluoromethanesulphonate as catalyst in these C-4 displacement reactions was found to give optimum results. 6. LIST OF CONTENTS page ACKNOWLEDGEMENTS 4 ABSTRACT 5 REVIEW: SYNTHESIS OF CARBAPENEM RING SYSTEMS 7 Introduction 8 Structure Activity Relationships 12 Synthesis of Carbapenem Ring Systems 14 A. Synthesis of the carbapenem nucleus 14 B. Total Synthesis of Thienamycin and Related Compounds 38 References 65 RESULTS AND DISCUSSION: 72 Introduction 73 The Use of Ynolate Anions in the Synthesis of Azetidin-2-ones 73 Reaction of the phenylethynolate anion (17) with Schiff's bases 79 Miscellaneous reactions of the phenylethynolate anion (17) and the thiolate anion (14) 93 Aminoalkylation reactions of C-6 penicillanate enolate anions 97 C-4 Displacement Reactions 101 Preparation of cx-Methylene-3-lactams 128 Preparation of 3-Unsubstituted Azetidin-2-ones 141 EXPERIMENTAL: 153 Section 1: Ynolate Chemistry 156 Section 2: C-4 Displacement Reactions 170 Section 3: Shapiro Reactions 180 Section 4: Other N1-C4 Cyclisation Reactions 191 REFERENCES 201 REVIEW SYNTHESIS OF CARBAPENEM RING SYSTEMS 8. INTRODUCTION Nature continues to provide us with products containing new structural 1,2 variations, the class of 3-lactam antibiotics being no exception . In 1976, it was disclosed by Merck scientists that a novel B-lactam antibiotic had been isolated from the culture broths of a previousl3 y unrecognized species, subsequently designated Streptornycca cattleya . This natural product was the first member of a family of antibiotics containing the des-thiacarbapen- t 2-em nucleus, from which the name thienamycin was derived . Intense interest in these compounds results from their exceptional biological activity and unique structure. In the first part of this review, the structure and activity will be briefly discussed. The remainder will be concerned with the approaches to, and syntheses of the carbapenem systems. The assignment of the structure of thienamycin (1) was achieved by a combination of nmr, mass spectral fragmentation patterns, degradative t Throughout, the nomenclature adopted is based on the assignment of the term carbapen-2-em as: 9. 4 experiments and finally X-ray analysis . The absolute stereochemistry of 4 thianamycin was determined as 5R, 8R . Thienamycin contains several unique structural features:- (i) the carbapenem nucleus was hitherto unknown, (ii) the relative stereochemistry of the 5,6 protons is trans-, in contrast to the cis- relationship found in the penicillins and cephalosporins, (iii) the incorporation of a 1'-R-hydroxyethyl group in place of the customary amide side chains found in penicillins and cephalosporins. Thienamycin was found to be a potent antibiotic, with broad spectrum activity. Of particular importance was its activity against isolates 2 5 exhibiting resistance to other drugs ' . Its aerobic spectrum included most gram- negative bacilli tested, including E. ooli.j Pseudomonasj and S. aureus. Excellent activity was also exhibited against anaerobic bacteria 6. 2 A detailed account of the biological activity of thienamycin has appeared . Subsequent work by the Merck group indicated that at least six other closely related compounds, the epithienamycins (A-F), could be isolated 7 from a large number of strains of Sbreptomyces flavogri-esus . 8 A Beecham group independently isolated three novel (3-lactams from Streptomyoes olivaceUQ,m\ 4550, MM 13902 and MM 17880. Subsequently, four new metabolites, MM 22380, MM 22381, MM 22382 and MM 22383 were also iso- lated. Collectively, these metabolites were designated as olivanic acids. It has been suggested that the olivanic acids and epithienamycins 9 correspond to the same structures (Table 1). More recently, other metabo- 10 11 11 12 3 lites including 1PS-54 , PS-6 f • PS-7 , NS-5 , C-19393 S„£ , C-19393 AH* , and PA-31088-IV have been isolated (Table 1). It is interesting that the olivanic acids differ from thienamycin by virtue of the opposite confi- guration at C-8. 10. Tabic 1 R = H, R MM 22380 CH2CH2NHC0Me n = 0 ETM A (2) R = H, R1 = CH = CHNHCOMe MM 22382 n = 0 ETM B (3) 1 R = H0S02, R = CH = CHNHCOMe MM 13902 n = 0 ETM E R = HOSO , R1 = CH = CHNHCOMe MM 4450 n = 1 R = HOSO , R = CH CH NHCOMe MM 17880 A £ n = 0 ETM F R = H, R = CHCH NHCOMe m 22381 ETM C R = H, R1 = CH = CHNHCOMe MM 22383 ETM D /continued. 11. Table 1/continucd... S(CH2)2NHR S(CH2)2NHAC CO2H COOH R = Ac PS-5 R = H NS-5 PS-6 0© OR o' NHAc CO2H C0ZH C-19393 S2, R = SOgNa PS-7 C-19393 H2, R = S03H 0© CJGH)M S-(CH2)2N-CH o NHAc A—N HN COoH COoH PA-31088-IV MK-0787 12. STRUCTURE-ACTIVITY RELATIONSHIPS Structure-activity relationships will only be briefly mentioned here, 2 15 as further details can be obtained elsewhere ' . The factors affecting in vitro activity may be summarized as follows. (i) Stereochemistry at C-5, C-6 and C-8 Thienamycin, with the tra.ns -5R, 6S^, 8R stereochemistry, is the most potent natural antibiotic. The potency of the non-sulphated series appears to be trans-R > cis-S > trans-S^'. The trans-R series has the best peni- 9 cillanase resistance, trans-S moderate and that of the cis-S series is low . 2 Some metabolites (e.g. PS-5) are 3-lactamase inhibitors . The sulphated 9 compounds have an enhanced penicillanase inhibitory capacity . (ii) Effect of substructures Carbapen-2-em-2-carboxylic acid has the same potency as clinically used 15 penicillins . The presence of the basic function at C-3 in thienamycin maximizes antipseudomonal activity1^' . Various derivatives of thienamycin have been prepared and their activity evaluated. MK-0787 is being tested 15 clinicallt • n y in• man An important factor which has had to be considered in relation to both their clinical use and attempted synthesis is that the carbapen-2-em system in particular was found to be a highly reactive substrate towards 3 17 nucleophiles ' . In fact, the instability of thienamycin in solution has been ascribed to a bimolecular reaction, in which the nucleophilic nitrogen of one molecule attacks the 3-lactam moiety of a second 3 . Generally, the trans- or cis- refers to the relative stereochemistry of the C-5 and C-6 protons. R or S refers to the C-8 stereochemistry. 13. 3 carbapen-2-cms are also only stable over a narrow pH range . ' This instabi= 6 lity renders thienamycin itself unsuitable as a clinical agent . The inherent instability of the carbapen-2-em system has been attributed 18 to the departure from coplanarity of the 3-lactam N-l atom from the plane containing C-2, C-5 and C-7. The altitude h, of the apex N-l, from the base of the trigonal pyramid containing N-l, C-2, C-5 and C-7 is used as a convenient factor relating to the strain in such systems (4). Values of h have been computed from X-ray data. A qualitative agreement has been observed between 18 the values of h and the lability of the respective B-lactams , i.e. the larger the value of h, the greater the lability of the 3-lactam. 18 On this basis, Woodward argued that the carbapen-3-em system should be more reactive towards nucleophiles than the carbapen-2-ems, as a reflection of the greater degree of distortio3 n within the molecule. Curiously, this was not found to be the case. A -Thienamycin was found to be chemically more stable than the A 2 -isomer 17 . Other factors, e.g. electronic effects, may be of importance in determining the reactivity of such systems, as in the case 2 3 19 of the A - and A -cephems 14. SYNTHESIS OF CARBAPENEM RING SYSTEMS Duo to the chemical lability of the intact carbapen-2-em nucleus (vide supra), the formation of the bicyclic system is carried out in the latter stages of synthetic schemes*.