UMD Theses and Dissertations
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Item ADVANCES IN SILOXANE-BASED COUPLING TECHNOLOGIES: APPROACHES TOWARD PANCRATISTATIN AND STREPTONIGRIN(2014) Nytko, III, Frederick Emil; DeShong, Philip; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The ability to form carbon-carbon bonds, arguably the most important transformation in synthetic chemistry, has been critically facilitated via the implementation of transition metal catalysts with main group element-associated carbon moieties. Specifically, organosilane coupling technology previously reported in the DeShong group provides ease of access to a wide variety of structurally important carbon-carbon bond motifs. The stability, tolerance of numerous implicit functional groups, simplicity of use, and ease of synthetic access to a multitude of organosilane coupling partners, makes the coupling technology developed in the DeShong lab markedly attractive for implementation in syntheses of complex natural product targets. Two targets of specific interest are pancratistatin and streptonigrin. Synthetic approaches toward pancratistatin via complex organosilane coupling precursors proved promising, however mechanistic studies performed in the DeShong group determined that standard 18-electron palladium(0) catalysts fail in transmetallation. Therefore, a new class of 16-electron Pd(0) catalysts have been developed and surveyed for applications in siloxane based allyl-aryl coupling protocols. The ability to "tune" these catalysts' activity by varying either the cone angle or the electronic characteristics of the alkene ligands attached to palladium has also been demonstrated. Unfortunately, attempts to prepare chiral adducts in the coupling reaction utilizing chiral bicyclooctadiene derivatives as a ligand for palladium provided no significant enantioenrichment in the coupled product. Similarly, previous work in the DeShong lab toward the synthesis of streptonigrin has been reported. Particularly, the synthesis of the structurally congested pyridyl C-ring proved difficult, requiring numerous steps at low yields. Development of new synthetic pathways toward the pyridyl C-ring was undertaken, exploiting the electronically withdrawn nature of the pyridone intermediate in order to brominate and alcohol, as well as change a methyl group to an aldehyde, via an enamine intermediate. The specific goals of this work were (1) to investigate new palladium(0) catalysts for the coupling of analogues of pancratistatin precursors, and (2) to improve upon problematic portions of our previous synthesis of streptonigrin's pyridyl C-ring.Item PALLADIUM-CATALYZED ALLYLIC-ARYLATION: MECHANISTIC STUDIES AND APPLICATION TO THE TOTAL SYNTHESIS OF (+/-)-7-DEOXYPANCRATISTATIN DERIVATIVES(2009) Shukla, Krupa; DeShong, Philip; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)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.