A Short and Concise Asymmetric Synthesis of Hamigeran B

• Published in: Chemistry : a European journal 2005-01, Vol.11 (3), p.951-959
• Main Authors: Trost, Barry M., Pissot-Soldermann, Carole, Chen, Irwin
• Format: Article
• Language: English
• Subjects: alkylation; asymmetric catalysis; Heck reaction; Hydrogenation; Kinetics; Models, Chemical; Molecular Conformation; Naphthoquinones - chemical synthesis; Naphthoquinones - chemistry; palladium; Stereoisomerism; total synthesis
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200400558

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. The potent antiviral agent hamigeran B is available in 15 steps from 2‐methylcyclopentanone and dimethyl orcinol. The chirality is established by a Pd‐catalyzed asymmetric allylic alkylation (AAA). The unusual properties of this molecule are reflected in the selectivities of two other catalytic processes—the Heck reaction and hydrogenation.