American Chemical Society
jo8b02034_si_003.pdf (5.76 MB)

Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Preparation and Coupling of C15–C25 and C26–C40 Fragments of Tetrafibricin

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journal contribution
posted on 2018-10-29, 00:00 authored by Ryan M. Friedrich, Jay Q. Bell, Alfredo Garcia, Zican Shen, Gregory K. Friestad
Diverse classes of natural products contain chiral 1,5,9- and 1,5,7-triol stereotriads, including the novel fibrinogen receptor antagonist tetrafibricin. Biological activities associated with compounds containing these motifs warrant targeted synthetic strategies to 1,5-polyol families from cheap and easily accessible reagents while avoiding the need to determine configurations at each alcohol stereocenter. In the accompanying paper, we present a solution to these problems via an iterative configuration-encoded strategy that exploits Julia–Kocienski couplings of enantiopure α-silyloxy-γ-sulfononitrile building blocks. The stereocontrol is unambiguous, and the building blocks are available in multigram quantities via asymmetric catalysis. This approach efficiently accessed a C26–C40 subunit of tetrafibricin that contains a syn,syn-1,5,9-triol and all of the stereochemistry and functionality needed to advance toward tetrafibricin. A modification afforded the anti,syn-1,5,7-triol within the C15–C25 fragment of tetrafibricin by merging 1,5-polyol synthesis with diastereoselective intramolecular conjugate addition. The union of the C15–C25 and C26–C40 fragments was achieved via a BF3·OEt2-mediated Mukaiyama aldol construction with high 1,3-anti stereoinduction, revealing some unexpected insights on the impact of silyl protecting groups on 1,3-anti diastereocontrol by a β-siloxyaldehyde aldol acceptor. Directed 1,3-anti reduction completed the stereostructure of the C15–C40 portion of tetrafibricin, with configurations established by a combination of NMR experiments.