Total Synthesis of (+)-Calyculin A and (−)-Calyculin B: Asymmetric Synthesis of the C(9−25) Spiroketal Dipropionate Subunit

Abstract

An asymmetric synthesis of the stereochemically fully endowed C(9−25) spiroketal fragment (+)-BC of the calyculins (1−8) is described. Highlights of the synthesis include: a highly diastereoselective IBr-induced iodocarbonate cyclization to introduce the C(21) stereocenter in epoxide (+)-18, fragment unions exploiting the reaction of acyl anion equivalents with epoxides to construct masked advanced aldols (−)-35 and (+)-71 as single diastereomers, chelation-controlled addition of the C(14−15) vinyl group to aldehyde (+)-38 to set the stereogenicity at C(16), selective reduction of the C(13) ketone via 1,3-induction, and development of an orthogonal protection scheme permitting both convenient installation of the C(17) phosphate group and flexibility in subsequent fragment couplings.