MANUFACTURE OF 2-UNSATURATED ALKYLTHIO-PEN-2-EM-3-CARBOXYLICACIDS, SUBSTITUTED 2-THIOXOPENAM AND 2-SUBSTITUTED THIOPENEM

摘要

Disclosed is a synthesis for preparing substituted 2-thioxopenams which are useful in the synthesis of penem antibiotics 7 which may be conducted in an enantiospecific manner; said process proceeds from azetidinone 1 via the azetidinone acetic ester 2, the 4-metallothiozetidinone 3, and the 4-dithiocarbonylazetidinone 4 to the substituted 2-thioxopenam 5: +TR wherein: R6 and R7 are independently selected from: hydrogen; R6NH- (R6 is acyl or H); substituted and unsubstituted: alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein said substituents are, inter alia: halo (chloro, bromo, fluoro, iodo), hydroxyl, cyano, carboxyl, amino, and the above-recited values for R6 and R7; in functional terms, R2 is a group which potentially forms a stable carbonium ion, for example: trityl (-C(C6H5)3), bis(p-methoxyphenyl)methyl, -2,4-dimethoxybenzyl, 2-(diphenyl)isopropyl, and the like; M is a thiophilic metal such as silver, thallium, mercury, or the like; and R1 is a protecting group such as allyl, p-nitrobenzyl or a biologically removable group (pharmaceutically acceptable ester moiety), for example: pivaloyloxymethyl, pivoloyloxyethyl, ethoxycarbonyloxymethyl, phthalidyl (5-methyl-2-oxo-1,3-dioxolen-4-yl)-; and X is a methyl leaving group such as phenoxy, p-chlorophenoxy, p-nitrophenoxy, phenylthio, alkylthio, alkoxy, chloro, or the like. R8 is inter alia, substituted and unsubstituted alkyl; the final penem products 7 are known, and their various embodiments are included by this definition.