Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
J Org Chem. 2017 Sep 1;82(17):8792-8807. doi: 10.1021/acs.joc.7b01283. Epub 2017 Aug 16.
The right halves of halichondrins A-C were synthesized by coupling the common C20-C37 building block 9 with the C1-C19 building blocks 10a-c, 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 (1a-c) were synthesized in 28, 24, and 24 steps from commercial d-galactal in 13.4%, 21.1%, and 16.7% overall yield, respectively.
通过将共同的 C20-C37 构建块 9 与 C1-C19 构建块 10a-c 分别偶联，合成了卤地胆素 A-C 的右半部分。使用催化、不对称的 Ni/Cr 介导的偶联进行了三个 C-C 键的形成。在所有情况下，立体化学都是通过工具包方法确定的手性磺酰胺制备的 Cr 催化剂控制的。对于 (3 + 4)-、(6 + 7)- 和 (9 + 10)-偶联，使用由 (S)-H、(S)-I 和 (R)-L 制备的 Cr 催化剂，分别实现了 28:1、>40:1 和 ∼20:1 的立体选择性。与前两个偶联不同，第三个偶联使用了结构复杂的亲核试剂。结果表明，即使在亲电体/亲核体摩尔比 = 1.0/1.1 时，偶联效率也非常出色。此外，第三个偶联是在带有游离羟基的底物上进行的。在 Ni/Cr 介导的偶联中获得的产物以优异的总收率转化为卤地胆素 A-C 的右半部分。卤地胆素 A-C 的右半部分（1a-c）分别从商业 d-半乳糖醛酸以 13.4%、21.1%和 16.7%的总收率，经过 28、24 和 24 步合成。
