Selective alkylation of diethyl 3-oxoglutarate. Part X. Synthesis of .OMEGA.-chain shortened prostaglandins and their six-membered ring analogs.

Abstract

Prostaglandin Ex analogs 5a and 5b, having methyl and ethyl groups as the co-chain, were synthesized by a two-step alkylation system of diethyl 3-oxoglutarate (1) and their six-membered ring analogs 8a and 8b also derived from the first alkylation product 2 via a Michael reaction.We have been active in utilizing diethyl 3-oxoglutarate(1), DEOG, as a convenient synthetic material for the synthesis of a wide variety of compounds including natural products, because DEOG would produce useful intermediates to synthesize these products through reaction with a number of organic reactants.X) The present investigation has been undertaken in order to extend the regioselective two-step alkylation of DEOGto the synthesis of prostaglandin analogs.2) Much attention has been focused on the synthesis and medical application of diverse prostaglandin analogs possessing heteroatoms3) and/or modified side chains4) largely because of their potent and varied biological properties.Recently, Poletto et al. reported that prostaglandin E1 analogs 5a, 5b and 8a, which have a shorter alkyl group as the coside chain, exhibited inhibition to the secretion of gastric acid.5) In this paper we describe the synthesis of the co-chain shortened prostaglandins 5a and 5b and of their sixmembered ring analogs 8a and 8b starting from DEOG. DEOGwas subjected to the first alkylation with ethyl 7-bromoheptanoate in the presence of magnesiumethoxide. The product 2la) was then alkylated with chloroacetone in 1,2-dimethoxyethane to give the 2,4-dialkylated product 3a in a 73% yield. Diketone triester 3a was heated in an aqueous solution of sodium hydroxide to be decarboxylatively hydrolyzed and similtaneously cyclized to produce an acid which, on esterification, gave a five-membered ring keto ester (4a) in a 48% yield. The conjugated double bond in the a,/?-unsaturated ketone 4a was selectively hydrogenated over 5% Rh/C catalyst in ethanol and the desired keto ester 5a, an ll-deoxyprostaglandin Ex analog, was obtained in an 82% yield. GLC and *H NMRanalyses of5a showed it to be a mixture of trans and cis isomers (a/co-side chain configuration) in 70 : 30 proportions.5'6) Similarly, another prostaglandin E1 analog 5b {transIcis = 70/30) was synthesized according to the sequence described above from 3b, which had been prepared in a 75% yield utilizing l-bromo-2-butanone for the second alkylation.For the synthesis of the six-membered ring analog 8a, compound 2 was converted to a Michael adduct (6a) in an 80% yield by reaction with methyl vinyl ketone in the presence of catalytic amounts of sodium hydride. The adduct 6a was treated with an aqueous solution of sodium hydroxide as mentioned above to yield a six-membered ring carboxylic