A short and concise asymmetric synthesis of hamigeran B.
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 beta-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.
Trost
Barry M
BM
Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA. bmtrost@stanford.edu
Pissot-Soldermann
Carole
C
Chen
Irwin
I
D006865:Hydrogenation; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D009285:Naphthoquinones; C483756:hamigeran B