Synthesis of a thienamycin intermediate from 6-aminopenicillanic acid

Abstract

The introduction of hydroxyethyl group at C$_6$ of the penicillin nucleus was investigated. 6-Aminopenicillanic acid(6-APA) was first converted to 6,6-dibromopenicillanic acid and reduced to penicillanic acid by catalytic hydrogenation. Acid function was protected by converting it to benzyl ester and the resulting benzyl penicillanate was reacted with lithium diisopropylamide(LDA) and acetaldehyde. The benzyl 6-(1-hydroxyethyl)penicillanate was first separated by preparative thin layer chromatography and the isomeric mixture was separated by high performance liquid chromatography. The ratio of 6$\alpha$ to $6\beta$ isomer was about 3:1 and the $6\alpha$ isomer was consisted of 8R and 8S isomers. The control of stereochemistry at C$_6$ and C$_8$ of the penicillin nucleus was not achieved with this approach. Methyl 6-chloro-6-iodopenicillanate was reacted with methylmagnesium iodide (MeMgI) and acetaldehyde and the products were separated by column chromatography. The $\alpha$ to $\beta$ ratio of the hydroxyethyl group at C$_6$ of the penicillin nucleus was about 2:1, but the stereochemistry at C$_8$ was not clear. The chlorine atom was replaced by hydrogen with Zn-Ag couple. The ratio of $6\alpha$ to $6\beta$ isomer was about 5:1 at this stage and the stereochemistry at C$_8$ was not clear. Subsequent ring opening by using mercuric acetate, and oxidative cleavage of the double bond yielded the desired key intermediate, in overall 15-20\% yield from 6-APA. The physical and spectral properties of the key intermediate were compared with those of authentic sample, and found them to be identical.