We report the stereospecific synthesis of hamigeran B (1, Scheme 1), which is an important member of a group of related compounds isolated [1] from a marine sponge. Hamigeran B has been found to have strong in vitro activity against polio and herpes viruses but little cytotoxicity. [1] The compound presents a number of constructional problems, and the significant biological properties enhance the potential value of work on its synthesis. One route to hamigeran B and several congeners has been reported. [2] We aimed to deal only with the synthesis of hamigeran B itself and to do so in a stereospecific manner.
The most obvious synthetic difficulty resides in the stereochemistry at C6 (see 1), as the bulky isopropyl group extends into the more hindered concave face of the structure. This orientation probably disqualifies methods that rely on stereochemical equilibration at C6. Likewise, radical cyclization (see 2), which is a powerful method for making [4.3.0] bicyclic structures with cis ring fusion, does not [3] generate the correct stereochemistry at C6 because the required transition state is destabilized by steric interactions engendered by the isopropylidene group. Further synthetic analysis, as well as experimental work, suggested that double-bond reduction (Scheme 2, 3!4), possibly directed by a suitably placed substituent, would merit detailed investigation. We recognized, however, that the double bond in 3, being tetrasubstituted, might be resistant to hydrogenation. [4] Also, examination of Dreiding models exposed another potential difficulty: it was not obvious from the shape of 3 whether Scheme 1. Hamigeran B (1) and the radical cyclization of 2.