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A Short and Concise Asymmetric Synthesis of Hamigeran B
Author(s) -
Trost Barry M.,
PissotSoldermann Carole,
Chen Irwin
Publication year - 2005
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200400558
Subject(s) - stereocenter , chemistry , intramolecular force , regioselectivity , stereochemistry , heck reaction , isopropyl , aryl , trifluoromethanesulfonate , ketone , alkylation , combinatorial chemistry , enantioselective synthesis , medicinal chemistry , catalysis , alkyl , organic chemistry
The interesting biological properties of the hamigerans wherein hamigeran B is a potent antiviral agent with low cytotoxicity to host cells make these deceptively simple looking structures challenging synthetic targets. A strategy to hamigeran B evolved wherein the three contiguous stereocenters are established ultimately from a Pd catalyzed asymmetric allylic alkylation (AAA). The latter involves an asymmetric allylation of a non‐stabilized ketone enolate in 77 % yield and 93 % ee . By using this process, ( S )‐5‐allyl‐2‐isopropyl‐5‐methyl‐1‐trifluoromethanesulfonyloxycyclopentene becomes available in four steps from 2‐methylcyclopentanone. Introduction of the aryl unit by cross‐coupling proceeded intermolecularly but failed intramolecularly. On the other hand, reductive removal of the triflate permitted a Heck reaction to effect intramolecular introduction of the aryl ring. The unusual conformational properties of this molecular architecture are revealed by the regioselectivity of the β‐hydrogen elimination in the Heck reaction and the diastereoselectivity of the reduction establishing the stereochemistry of the carbon bearing the isopropyl group. The successful route consists of 15 steps from 2‐methylcyclopentanone and dimethylorcinol illustrating the efficiency of the route based upon the Pd AAA.