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 IC50 values (IC50 500 nM and 750 nM, respectively) being only 1015 times less than that of xestobergsterol A itself (50 nM).