PALLADIUM-CATALYZED ALLYLIC-ARYLATION: MECHANISTIC STUDIES AND APPLICATION TO THE TOTAL SYNTHESIS OF (+/-)-7-DEOXYPANCRATISTATIN DERIVATIVES
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Palladium-catalyzed carbon-carbon bond formation is one of the most widely used reactions for the synthesis of biologically active substances. The DeShong group has demonstrated that hypervalent silicates can be employed for allyl-aryl carbon-carbon bond couplings in the presence of a Pd(0) catalyst. The goals of this dissertation are (1) to demonstrate application of palladium-catalyzed allylic-arylation coupling to the total synthesis of (+/-)-7-deoxypancratistatin and its analogues, and (2) to study the mechanism of allyl-aryl cross coupling reactions. In spite of the potent antitumor and antiviral activity of (+)-7-deoxypancratistatin, the use of this compound is limited in clinical applications because of its low natural abundance and lack of a practical scalable synthetic route. In order to test the feasibility of siloxane-based coupling in the synthesis of 7-deoxypancratistatin, a simplified analogue of (+/-)-7-deoxypancratistatin was synthesized. The key reaction in the synthesis involved stereoselective construction of a carbon-carbon bond between A and C rings via coupling of an aryl siloxane with an allylic carbonate. While siloxane methodology was successfully applied to the synthesis of a (+/-)-7-deoxypancratistatin analogue, application of this methodology to the natural product (+/-)-7-deoxypancratistatin proved to be a significant challenge. To understand the causes of the failure of the coupling reaction, a detailed mechanistic study was undertaken. Hammett analysis of the allyl-aryl coupling reaction demonstrated that the rate of the coupling reaction was enhanced by electron-withdrawing groups on the aryl siloxane. The positive slope of the Hammett plot indicated a charged transition state in which negative charge on the aryl ring was stabilized inductively. Furthermore, this study provided useful information regarding the nature of ligands on the palladium. Based on this study, a new family of Pd(0) olefin catalysts was developed. These catalysts were found to be highly efficient and formed carbon-carbon bond even at ambient temperature. Novel Pd(0) olefin complexes were successfully employed in the synthesis of (+/-)-7-deoxypancratistatin. The key coupling reaction of allylic carbonate with aryl siloxane produced Hudlicky's intermediate, thus constituting formal total synthesis of the actual product. Though the reaction required higher catalytic loading and proceeded in moderate yields, the ability of the reaction to work at ambient temperature is advantageous for practical synthesis of the natural product. Future studies shall aim at optimization of the key coupling reaction and application of this methodology to the synthesis of pancratistatin and related derivatives.