Study towards palladium-catalyzed cross-coupling and zirconium-catalyzed carboalumination and their application to natural product synthesis, such as mycolactones A and B, 2'-O-methylmyxalamides D
Abstract
In the first chapter, the discussions were focused on the AlCl3 -promoted anti-selective carboalumination of 3-butyn-1-ol to give (Z)-4-iodo-3-methyl-3-buten-1-ol in a remarkably mild and highly satisfactory procedure as well as Zr-catalyzed methylalumination of heterosubstituted arylethynes containing O, S, Cl, and Si which can proceed in high yields and in a highly regio- and stereoselective manner. The low regioselectivity of 60% initially observed with o -ethynylphenol has been elevated to ≥98% through the use of either a catalytic amount of Zr(ebi)Cl2 or Zr(2-Me-Ind)2Cl 2 or the stoichiometric amount of ZrCp2Cl2, ZrCp 2MeCl, or ZrCp2Me2 in conjunction with the use of a deficient amount of I2 for subsequent iodinolysis. In the second chapter, Negishi coupling between alkenyl halide and alkenylzirconium species derived directly from hydrozirconation was realized in high yield and high regio- and stereoselectivity in the presence of PEPPSI. Also Pd-catalyzed alkenylation.carbonyl olefination synergy was developed for triene or polyene synthesis. As its application, highly efficient and selective syntheses of both (all-E) and (6E, 10Z)-isomers of 2'-O-methylmyxalamide D, in which the crucial conjugated pentaene moieties were assembled in ≥98% stereoselectivity through the use of two Pd-catalyzed alkenylation reactions, the HWE olefination, and either the CSM-modified Peterson olefination for (all-E)-isomer or the Still-Gennari olefination for (6E, 10Z)-isomers, are reported. Each of isomers was prepared in 16% overall yield over 7 steps from propargyl alcohol. Finally, unprecedentedly efficient and highly selective syntheses of mycolactone A and B sidechains mainly by using Negishi coupling in 17 longest linear steps from ethyl (S)-3-hydroxybutyrate in 16% and 15% overall yield, respectively, were reported. The synthesis of mycolactone core was realized in 4% overall yield in 19 longest linear steps by using Pd-catalyzed alkenyl–allyl coupling and trialkylalkenylaluminate mediated epoxide opening reaction as key steps. The syntheses of fully protected mycolactones A and B with ≥98% isomerical purity as well as the mixtures of mycolactones A and B, which are inseparable and reaching an equilibrium, were also reported. The overall yields to mycolactones A and B mixture are about 1% in 23 longest linear steps.
Degree
Ph.D.
Advisors
Negishi, Purdue University.
Subject Area
Organic chemistry
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