Synthesis of the four stereoisomers of enprostil

The four stereoisomeric components of enprostil (1a-d) were prepared using an orthoester Claisen rearrangement of individual propargylic alcohol intermediates 8 to generate the required allene upper chain stereochemistry, followed by one-carbon homologation. All four of the key propargylic alcohols 8 were prepared by addition of ethynyl Grignard reagent to aldehyde 7 (and to its enantiomer) and chromatographic separation of the diastereomers. Isomer 8a was also prepared by asymmetric reduction of propargylic ketone 10, which was in turn efficiently prepared by the opening of lactone 3 with dichlorocerium acetylide followed by silylation. Propargylic acohol 8a was stereospecifically converted to enprostil isomer 1a via reaction of the inverted propargylic bromide 21 with the three carbon functionalized organocuprate 22, easily prepared from methyl 3-bromopropionate