A Practical Synthesis of the PDE4 Inhibitor, KW-4490

Abstract

A practical and scalable synthesis of a PDE4 inhibitor KW-4490 ( 1 ) was developed. This improved synthesis features the construction of the 1-arylcyclohexene ( 9 ) by the Diels−Alder reaction followed by a newly established Brønsted acid-promoted hydrocyanation. Subsequent crystallization-induced dynamic resolution enabled the high-yield production of the desired cis -isomer ( cis-8 ). The synthesis was achieved in seven steps in 37% overall yield.