Formal total synthesis of aspergillide A

The formal total synthesis of aspergillide A 1 is described. The cross-metathesis of enone 6 with 6-hepten-2-ol derivative 5 provided E-olefin 15 corresponding to the C4–C14 backbone of 1. The CBS asymmetric reduction of 15 gave allyl alcohol 16, which was transformed into β-alkoxyacrylate 4 which had a formyl group. SmI2-induced reductive cyclization of 4 gave a 2,6-syn-2,3-trans THP derivative 3 in good yield. After methoxymethylation of 3, the resulting compound 19 was submitted to desilylation and hydrolysis, to afford Fuwa’s key intermediate 2 for the total synthesis of 1.

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(9S,4E)-9-(tert-Butyldimethylsilyloxy)-1-(1,3-dithian-2-yl)dec-4-en-3-oneC20H38O2SiS2[α]D25=+9.8 (c 1.08, CHCl3)Absolute configuration: (3R,9S,4E)Source of chirality: chiral pool

(3R,9S,4E)-9-(tert-Butyldimethylsilyloxy)-1-(1,3-dithian-2-yl)dec-4-en-3-olC20H40O2SiS2[α]D25=+12.1 (c 1.02, CHCl3)Absolute configuration: (3R,9S,4E)Source of chirality: asymmetric reduction and chiral pool

(2E)-Ethyl 3-((3R,9S,4E)-9-(tert-butyldimethylsilyloxy)-1-(1,3-dithian-2-yl)dec-4-en-3-yloxy)prop-2-enoateC25H46O4SiS2[α]D24=+19.8 (c 1.33, CHCl3)Absolute configuration: (9S,4E)Source of chirality: asymmetric reduction and chiral pool

(2E)-Ethyl 3-((4R,10S,5E)-10-(tert-butyldimethylsilyloxy)-1-oxoundec-5-en-4-yloxy)prop-2-enoateC22H40O5Si[α]D25=+38.8 (c 1.12, CHCl3)Absolute configuration: (4R,10S,5E)Source of chirality: asymmetric reduction and chiral pool

Ethyl 2-((2R,3S,6R)-6-((6S,1E)-6-(tert-butyldimethylsilyloxy)hept-1-enyl)-3-methoxymethyloxy-tetrahydro-2H-pyran-2-yl)acetateC24H46O6Si[α]D24=+41.9 (c 1.07, CHCl3)Absolute configuration: (2R,3S,6R)(6S,1E)Source of chirality: asymmetric reduction and chiral pool