Highly stereoselective alkenylation and alkynylation of 1,1-dihalo-1-alkenes and their applications to natural product synthesis
Abstract
The Pd-catalyzed cross-coupling reaction of 2-bromo-1,3-dienes derived from alkyl aldehydes, especially with Cl2Pd(DPEphos) as a catalyst, proceeds with clean stereoinversion of the Br-bearing C = C bond to produce in high yields and in high stereoselectivity (≥97–98%) conjugated Z,E dienes of potentially high utility in the synthesis of complex natural products. The observed stereoinversion cannot be readily accommodated by the widely accepted π-σ-π rearrangement mechanism for isomerization of ordinary allylpalladium derivatives. In contrast to this unexpected clean inversion of configuration in the methylation and higher alkylation of (Z)-2-bromo-1,3-dienes with organozinc reagents and Pd-phosphine catalysts containing DPEphos, etc., the use of Pd complexes containing tBu 3P or NHC almost completely prevents the stereoisomerization, thereby permitting an efficient and selective synthesis of (1E)-2-Methyl-1,3-dienes. trans-Selective (≥98%) monoalkynylation of 1,1-dibromo-1-alkenes and 1,1-dichloro-1-alkenes catalyzed by Cl2Pd(DPEphos) followed by stereospecific alkylation with alkylzincs catalyzed by Pd( tBu3P)2 provides an efficient and stereoselective (≥98%) route to (E)-3-methyl-1-trialkylsilyl-3-en-1-ynes, convertible to a wide variety of enynes and conjugated dienes. In the cases of 1,1-dibromo-1-alkenes, the Sonogashira alkynylation may also be satisfactory, but it is distinctly less satisfactory than the alkynylzinc reaction in cases where 1,1-dichloro-1-alkenes are used. In the final chapter, discussion will be focused on the total synthesis of 6,7-dehydrostipiamide, a multidrug resistance reversal agent. Several synthetic protocols have been carried out and compared in this work. The most efficient and convergent synthesis approach relies on a Zr-catalyzed enantioselective carboalumination and several Pd-catalyzed cross-coupling reactions.
Degree
Ph.D.
Advisors
Negishi, Purdue University.
Subject Area
Organic chemistry
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