Unified Synthesis of C1-C19 Building Blocks of Halichondrins via Selective Activation/Coupling of Polyhalogenated Nucleophiles in (Ni)/Cr-Mediated Reactions.
A unified synthesis of the C1-C19 building blocks 8-10 of halichondrins A-C was developed from the common synthetic intermediates 26a,b. Acetylenic ketones 26a,b were in turn synthesized via selective activation/coupling of polyhalogenated nucleophiles 23a,b with aldehyde 11 in a (Ni)/Cr-mediated coupling reaction. Compared with Ni/Cr-mediated couplings of vinyl iodides and aldehydes, this (Ni)/Cr-mediated coupling exhibited two unique features. First, the coupling was found to proceed with a trace amount or no added Ni-catalyst. Second, TES-Cl, a dissociating agent to regenerate the Cr-catalyst, was found to give a better yield than Zr(Cp)2Cl2. An adjustment of the oxidation state was required to transform acetylenic ketones 26a,b into C1-C19 building blocks 8 and 9 of halichondrins A and B, respectively. In the halichondrin B series, a hydroxyl-directed (Me)4NBH(OAc)3 reduction of E- and Z-β-alkoxy-enones 30 was found cleanly to achieve the required transformation, whereas a DMDO oxidation of E-vinylogous ester 27 allowed to introduce the C13 hydroxyl group with a high stereoselectivity in the halichondrin A series. In the halichondrin C series, Hf(OTf)4 was used to convert the double oxy-Michael product 28 into C1-C19 building block 10.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
Jingwei
J
Li
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
Wuming
W
Yan
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
Yoshito
Y
Kishi
D000818:Animals; D002384:Catalysis; D002857:Chromium / Q000737:chemistry*; D004988:Ethers, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D054879:Halogenation; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D009532:Nickel / Q000737:chemistry*; D011161:Porifera / Q000737:chemistry*; D013237:Stereoisomerism; D000095662:Polyether Polyketides
D002857:Chromium; D004988:Ethers, Cyclic; D018942:Macrolides; D009532:Nickel; C070519:halichondrin B; D000095662:Polyether Polyketides; C572421:halichondrin C; C000597650:halichondrin A