First total synthesis of xestobergsterol A and active structural analogues of the xestobergsterols

The novel pentacyclic polyhydroxylated sterol, xestobergsterol A 1a , a strong inhibitor of histamine release from rat mast cells induced by anti-IgE, has been synthesized in 24 steps and good overall yield from stigmasterol 7 . The Breslow remote functionalization process has been extended to several more highly functionalized steroid derivatives, especially those with oxygen functionality in the B-ring. The key steps of the synthesis of xestobergsterol A 1a and its analogues, 7-deoxyxestobergsterol A 1d and 16,23- seco -23-deoxyxestobergsterol A 73 , are the Breslow remote functionalization of oxygenated steroids and for compounds 1a and 1d , a novel base-catalyzed epimerization-aldol condensation of a dione to give the desired CD- cis ring structure of the xestobergsterols. Thus the known alcohol 75 , prepared from stigmasterol 7 , was taken to the tetraacetate 107 which was then converted via a Breslow remote functionalization into the alkene aldehyde 114 which was transformed in 5 steps to xestobergsterol A 1a . Testing of the synthetic materials showed that the two analogues, 7-deoxyxestobergsterol A 1b and 16,23- seco -23-deoxyxestobergsterol A 73 , are also potent inhibitors of histamine release with IC 50 values (IC 50 500 nM and 750 nM, respectively) being only 1015 times less than that of xestobergsterol A itself (50 nM).