Premium
Addition of Indole to Methyl 2‐Chloro‐2‐cyclopropylideneacetate en Route to Spirocyclopropanated Analogues of Demethoxyfumitremorgine C and Tadalafil
Author(s) -
Limbach Michael,
Dalai Suryakanta,
Janssen André,
EsSayed Mazen,
Magull Jörg,
de Meijere Armin
Publication year - 2005
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200400617
Subject(s) - chemistry , yield (engineering) , indole test , tadalafil , condensation , hydantoin , stereochemistry , condensation reaction , natural product , tryptophan , medicinal chemistry , organic chemistry , catalysis , amino acid , materials science , medicine , biochemistry , physics , sildenafil , metallurgy , thermodynamics
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)