The Manufacture of a Homochiral 4‑Silyloxycyclopentenone Intermediate for the Synthesis of Prostaglandin Analogues

A process is described for the synthesis of kilogram quantities of homochiral 4-silyloxycyclopentenone (R)-1, a key intermediate useful for the synthesis of a plurality of prostaglandin analogue drugs. Cyclopentenone (R)-1 was synthesized in 14 isolated steps from furfural. Key steps in the synthesis include a Wittig reaction, Piancatelli rearrangement, and an enzymatic resolution featuring in situ recycling of the undesired enantiomer furnishing the desired homochiral alcohol in ≥99.5% ee. As a retort to the unsatisfactory coformation of about 8% at best of the trans-olefin in the Wittig reaction, a change to the order of several steps and the identification of a recrystallisable, amine salt derivative, 2, allowed the unwanted isomer to be controlled to as low as 0.2%.