Total Synthesis of Dolabriferol C by a Highly Stereoselective One‐Pot Coupling of a meso‐3,7‐Diketone with Two Chiral Aldehydes

Total synthesis of the noncontiguous polypropionate dolabriferol C was achieved by retro‐Claisen fragmentation of its putative contiguous precursor under mild conditions, thus establishing the former as a plausible isolation artifact. The precursor was prepared by a novel one‐pot three‐component bis...

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Bibliographic Details
Published in:Angewandte Chemie 2021-12, Vol.133 (51), p.26981-26986
Main Authors: Diddi, Naveen, Ward, Dale E.
Format: Article
Language:English
Subjects:
Absolute configuration
Aldehydes
bisenolates
Chemistry
Coupling
Diketones
Enantiomers
enantioselective desymmetrization
kinetic resolution
Precursors
stereoselective aldol reaction
Stereoselectivity
Synthesis
three-component coupling
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Summary:Total synthesis of the noncontiguous polypropionate dolabriferol C was achieved by retro‐Claisen fragmentation of its putative contiguous precursor under mild conditions, thus establishing the former as a plausible isolation artifact. The precursor was prepared by a novel one‐pot three‐component bisaldol coupling of a meso (Z,Z)‐bisenolate (generated in situ from a 3,7‐diketone) with two enantioenriched aldehydes to set the absolute configuration of seven stereocenters in one step. The first aldol reaction proceeded with enantioselective desymmetrization of the bisenolate to produce an enantiomerically pure enolate–aldolate. Quenching at this stage enabled a streamlined synthesis of dolabriferol. Addition of a racemic aldehyde to the enolate–aldolate resulted in aldol coupling with kinetic resolution of the “matched” aldehyde; overall, a sequential enantiotopic‐group‐selective (SEGS) bisaldol reaction. Because the desired adduct results from the “mismatched” aldol reaction, use of enantioenriched aldehyde was required. The total synthesis of dolabriferol C was achieved by retro‐Claisen fragmentation of its putative contiguous precursor, thus establishing the former as a plausible isolation artifact. The carbon skeleton of the precursor was assembled using a novel strategy involving a highly stereoselective three‐component bisaldol coupling that sets the absolute configuration of seven (or eight) stereocenters in a one‐pot process.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202111895