Total synthesis of (+)-cladospolide D

The asymmetric total synthesis of cladospolide D, a natural 12-membered macrolide antibiotic, has been accomplished in 12-steps. Sharpless asymmetric dihydroxylation, Grubb’s cross metathesis, and Shiina lactonization have been employed as the key reactions for the installation of the desired stereocenter and the construction of the macrolactone framework.

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(2R,8S)-8-((tert-Butyldimethylsilyl)oxy)nonane-1,2-diolC15H34O3Si[α]D25 = +4.4 (c 0.5, CHCl3)Source of chirality: (S)-propylene oxide, Sharpless asymmetric dihydroxylationAbsolute configuration: (2R,8S)

(2R,8S)-8-((tert-Butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)oxy)nonan-1-olC23H42O4Si[α]D20 = −1.5 (c 1.00, CHCl3)Source of chirality: (S)-propylene oxide, Sharpless asymmetric dihydroxylationAbsolute configuration: (2R,8S)

Ethyl (5R,11S,E)-11-((tert-butyldimethylsilyl)oxy)-5-((4-methoxybenzyl)oxy)-4-oxododec-2-enoateC28H46O6Si[α]D20 = +46.8 (c 1.07, CHCl3)Source of chirality: (S)-propylene oxide, Sharpless asymmetric dihydroxylationAbsolute configuration: (5R,11S)

Ethyl (5R,11S,E)-11-hydroxy-5-((4-methoxybenzyl)oxy)-4-oxododec-2-enoateC22H32O6[α]D20 = +51.6 (c 1.5, CHCl3)Source of chirality: (S)-propylene oxide, Sharpless asymmetric dihydroxylationAbsolute configuration: (5R,11S)

(5R,11S,E)-11-Hydroxy-5-((4-methoxybenzyl)oxy)-4-oxododec-2-enoic acidC20H28O6[α]D20 = +5.0 (c 1.25, CHCl3)Source of chirality: (S)-propylene oxide, Sharpless asymmetric dihydroxylationAbsolute configuration: (5R,11S)

(6R,12S,Z)-6-((4-Methoxybenzyl)oxy)-12-methyloxacyclododec-3-ene-2,5-dioneC20H26O5[α]D20 = +45.2 (c 0.55, CHCl3)Source of chirality: (S)-propylene oxide, Sharpless asymmetric dihydroxylationAbsolute configuration: (6R,12S)