Convergent Synthesis of Both Enantiomers of 4-Hydroxypent-2-ynoic Acid Diphenylamide for a Thrombin Receptor Antagonist Sch530348 and Himbacine Analogues

Sch530348 and many himbacine analogues were prepared by using 4-hydroxypent-2-ynoic acid diphenylamide as the only chiral material. We developed deracemization methods to prepare both enantiomers of this propargyl alcohol. These methods involved a resolution followed by inversion. The objective for the resolution step was to obtain the desired enantiomer as an ester, and undesired enantiomer as an alcohol. With (R)-selective lipase, this was achieved by transesterifcation for (R)-alcohol, and ester hydrolysis for (S)-alcohol. The undesired enantiomer was inverted through the corresponding tosylate to yield the desired enantiomer as the ester. De-protection of the ester gave enantiopure alcohol as the product. These methods not only overcame the 50% yield limit in resolution, but also eliminated the need to remove the undesired enantiomer.