De Novo Asymmetric Approach to Aspergillide-C: Synthesis of 4-epi-seco-Aspergillide-C

An asymmetric approach toward the synthesis of the marine natural product aspergillide-C has been developed. The convergent asymmetric synthesis uses two asymmetric Noyori transfer hydrogenations to enantioselectively prepare the two key fragments, a C-1 to C-7 pyranone fragment and a C-8 to C-14 beta-keto-sulfone fragment. The absolute stereochemistry of the pyranone fragment was established by a Noyori reduction of beta-furylketoester to form a furyl alcohol. An Achmatowicz rearrangement was used to stereoselectively convert the furyl alcohol in to the key pyranone fragment. The absolute stereo- chemistry of the beta-keto-sulfone fragment was established by a Noyori reduction of an ynone to form a propargyl alcohol. An alkyne zipper isomerization was used to stereospecifically convert the propargyl alcohol in to the beta-keto-sulfone fragment. Finally, a Pd-catalyzed C-glycosylation was used to diastereoselectively couple the two fragments, which when combined with a reduction and Julia-Kocienski type elimination formed a protected variant of the 4-epi-seco-acid of aspergillide-C.

Automated summary

An asymmetric approach for synthesizing aspergillide-C has been developed, using asymmetric Noyori transfer hydrogenations to prepare the key fragments and establishing their absolute stereochemistry. The fragments were then coupled using a specific catalyzed reaction to form a protected variant of aspergillide-C.