Total Synthesis of (+)-Mycotrienol and (+)-Mycotrienin I: Application of Asymmetric Crotylsilane Bond Constructions

Abstract

A highly convergent asymmetric synthesis of the ansamycin antibiotics (+)-mycotrienin I (1c) and (+)-mycotrienol (1d) has been achieved through the synthesis and coupling of the C9−C16 subunit 3b and the aromatic subunit 4b, respectively. This article describes the complete details of that work as it illustrates the utility of our developing chiral (E)-crotylsilane bond construction methodology in total synthesis. All four stereogenic centers were introduced using chiral allylsilane bond construction methodology. In the synthesis of subunit 3b, the C12 and C13 stereocenters were installed using an asymmetric crotylsilylation reaction to α-keto dibenzyl acetal 5. The C11 stereocenter was subsequently installed via a chelate-controlled addition of allyltrimethylsilane to establish the anti-1,3-diol system. The C14−C15 trisubstituted double bond was then installed via a reductive opening of α,β-unsaturated lactone 10b. Aromatic subunit 4b was chosen on the basis of its synthon equivalency to the amidobenzoquinone system of (+)-1c and (+)-1d. Subunit 4b was constructed in a concise six-step sequence which incorporates the C3 stereogenic center of the C1−C5 side chain. The C3 stereogenic center was established using a Weinreb amidation of aniline 18 with lactone (+)-16, whose absolute stereochemistry was derived using the crotylsilane methodology. The union of subunit 3b with aromatic subunit 4b was accomplished using a sulfone-based coupling strategy. Coupling product 21 was transformed through a sequence of steps to triene 24. Divergence from this advanced intermediate allows access to both natural products. The successful completion of the synthesis included the incorporation of the (E,E,E)-triene unit with simultaneous macrocyclization through a palladium (0)-catalyzed (Stille-type) coupling macrocyclization.