Addition of indole to methyl 2-chloro-2-cyclopropylideneacetate en route to spirocyclopropanated analogues of demethoxyfumitremorgine C and tadalafil

Abstract

Indole readily added across the double bond of the highly reactive Michael acceptor methyl 2-chloro-2-cyclopropylideneacetate (4) to yield 2-chloro-2-(3′-indolylcyclopropyl)acetate 5 (85%) which was converted in two steps into the racemic tryptophan analogue 7 in 90% yield. This in turn was transformed by a condensation and Pictet-Spengler sequence into the spirocyclopropane analogues, 11, 13 and 15, of both the natural product (demethoxy)fumitremorgine C (3b, 3 steps, 11 % yield) and the potent PDE-5 inhibitor Tadalafil (2, 3 steps, 71% yield) as well as the original lead structure with a hydantoin backbone (1, 2 steps, 79% yield). © Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.