Enantioselective total synthesis of altohyrtin C (spongistatin 2)

The first total synthesis of a spongipyran macrolide, altohyrtin C, is desc ribed. The convergent synthesis strategy relies on a regioselective macrola ctonization, a stereoselective Wittig coupling of the two major synthetic f ragments, a complex anti aldol reaction to join the C-1-C-15 and C-16-C-28 spiroketal regions, and an anomeric sulfone acylation to join the C-29-C-37 and C-38-C-43 pyran regions. The incorporation of the C-44-C-51 sidechain in the final stages of the synthesis establishes a viable route for the con struction of variants in this pharmacologically important region. Methodolo gical developments en route to the total synthesis include a 1,5 anti-selec tive methyl ketone aldol reaction and a diastereoselective approach to Lewi s acid mediated beta-C-glycosidation. Completion of the synthesis has confi rmed the stereochemical assignments proposed in the altohyrtin series and h as established the identity of the altohyrtin and spongistatin marine macro lides. (C) 1999 Elsevier Science Ltd. Ail rights reserved.