A Short Synthesis of Enantiomerically Pure (2S,3R,4R,6E)-3-Hydroxy-4-methyl-2-(methylamino)-6-octenoic Acid, the Unusual C-9 Amino acid Found in the Immunosuppressive Peptide Cyclosporine

Article abstract of DOI:10.1021/jo00389a041

A new and efficient synthesis of enantiomerically pure (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoic acid (MeBmt, 2) is reported.Reaction of (2R,4E)-2-methyl-4-hexenal (6c) with p-methoxybenzyloxycarbonylsarcosine tert-butyl ester (Pmz-Sar-O-t-Bu, 5) gave MeBmt (2) in 18-20percent overall yield.The lithium enolate of the tert-butyl ester is more stable than the corresponding methyl ester at higher temperature (room temperature vs. -78 deg C) and reacts selectively with aldehydes even in the presence of impurities.Room temperatures conditions were needed in order to increase the desired anti-Cram product 9a.The Pmz group proved superior to other amino protecting groups (e.g., Cbz) because residual Pmz-sarcosine derivatives could be easily removed from products 9a and 9b by cleavage of the Pmz group by reaction with TFA/anisole.This procedure eliminated the need for column chromatography after the aldol reaction.Reaction of the lithium enolate of Pmz-Sar-O-t-Bu (5) with aldehyde 6c afforded only the two trans-substituted 2-oxazolidinones 9a and 9b and none of the cis-substituted 2-oxazolidinones.The chemically pure diastereomeric mixture of 2-oxazolidinones 9a and 9b was resolved by using (1S,2R)-(+)-ephedrine to give enantiomerically and diastereomerically pure 9a in 18-20percent overall yield (from aldehyde 6c).Hydrolysis of 9a gave the desired MeBmt (2) in quantitative yield.This amino acid was incorporated into cyclosporin A (CSA, 1) by known literature procedures.In order to demonstrate that the synthetic methodology described in this paper can be utilized in the synthesis of a number of MeBmt (2) analogues, 1'-desmethyl-2-oxazolidinone 10a was also prepared by similar procedures.