5 years ago

Unified Synthesis of Right Halves of Halichondrins A–C

Unified Synthesis of Right Halves of Halichondrins A–C
Santhosh Reddy Naini, Ning Ye, Yoshito Kishi, Shuji Yamashita, Kentaro Iso, Kenzo Yahata, Yanran Ai
The right halves of halichondrins A–C were synthesized by coupling the common C20–C37 building block 9 with the C1–C19 building blocks 10ac, respectively. Catalytic, asymmetric Ni/Cr-mediated coupling was used for three C–C bond formations. For all cases, the stereochemistry was controlled with the Cr catalyst prepared from the chiral sulfonamide identified via the toolbox approach. For (3 + 4)-, (6 + 7)-, and (9 + 10)-couplings, the stereoselectivity of 28:1, >40:1, and ∼20:1 was achieved by the Cr catalysts prepared from (S)-H, (S)-I, and (R)-L, respectively. Unlike the first and second couplings, the third coupling used the structurally complex nucleophile. It was demonstrated that the coupling efficiency was excellent even with the electrophile/nucleophile molar ratio = 1.0/1.1. In addition, the third coupling was achieved with the substrate bearing a free hydroxyl group. The products obtained in the Ni/Cr-mediated couplings were converted to the right halves of halichondrins A–C in excellent overall yields. The right halves of halichondrins A–C (1ac) were synthesized in 28, 24, and 24 steps from commercial d-galactal in 13.4%, 21.1%, and 16.7% overall yield, respectively.

Publisher URL: http://dx.doi.org/10.1021/acs.joc.7b01283

DOI: 10.1021/acs.joc.7b01283

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