The Penems, a New Class of β‐Lactam Antibiotics. 6. Synthesis of 2‐alkylthiopenem carboxylic acids

Abstract

A synthesis of 2-alkylthiopenems by an intramolecular Wittig-type reaction between a phosphorane and a trithiocarbonate ester is described.In previous publications we described synthetic methods for the preparation of this new class of p-lactam antibiotics [l-41. The approaches involved routes starting from penicillin V or penicillanic acid [l] [2] and total syntheses [3] [4] from 4-acetoxyazetidin-2-one [5].The antibiotic potency and the wide spectrum of activity of the substances prepared so far warranted the search for the application of the methods to the synthesis of novel target structures. In view of the recent appearance of thienamycin [6] [7], epithienamycins [8] and PS-5 [9] we were particularly interested in combining common structural feature of these carbapenem antibiotics, an aliphatic side-chain attached in 2-position via a sulfur atom, with the penem nucleus.In the present paper we describe the assembly of this system. The key reaction involved the intramolecular Wittig-type reaction between a carbonyl-stabi-Table. Antibacterial in vitro Activities of the Penemcarboxylic Acids 8a ( R = C~H S ) and 8b (RE (CH&NHCOCH3) Microorganism 8a 8b

Carbapenems and Penems

“…Generation of the dianion of the penem (52, R = CH 3 ) using a strong base such as n-butyllithium or lithium diisopropylamide, followed by reaction with electrophiles yields 6-substituted 2-methylpenems in moderate yield (128). The enhanced acidity of the 6-proton in the bromopenem (88) [114409- has been exploited to prepare the Beecham β-lactamase inhibitor BRL 42715 [102209-75-6] (89, R = Na), C 10 H 8 N 4 O 3 SNa (105). Lithium diphenylamide, a weaker base, was used to generate the anion of (88) which on sequential treatment with 1-methyl-1,2,3-triazole-4-carbaldehyde and acetic anhydride gives a mixture of diastereomers of the bromoacetate (90).…”