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.

A protocol for the asymmetric allylic alkylation of a five-membered ring ketone derivative that employs the lithium enolate in the presence of lithium alkoxides gave high yields and enantioselectivities. This product serves as a versatile intermediate as demonstrated in a convergent total synthesis of the antiviral agent hamigeran B. The sequence involves two unusual observations. In the intramolecular Heck reaction which establishes the complete ring sytem, the beta-H elimination step occurs both endocyclic (as expected) and exocyclic, the latter most surprising since it creates an exocylic tetrasubstituted double bond. In the catalytic hydrogenation, use of Pd/C gives complete selectivity for net delivery of hydrogen to the most hindered face of the substrate, whereas use of Ir black gives complete selectivity for delivery of hydrogen to the least hindered face. Such unusual behavior speaks to the unusual chemical properties associated with hamigeran B which may be relevant to its biological activity.

A Short and Concise Asymmetric Synthesis of Hamigeran B (I). -(TROST*, B. M.; PISSOT-SOLDERMANN, C.; CHEN, I.; Chem. Eur. J. 11 (2005) 3, 951-959; Dep. Chem., Stanford Univ., Stanford, CA 94305, USA; Eng.) -Mischke

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