ADVANCES IN SILOXANE-BASED COUPLING TECHNOLOGIES: APPROACHES TOWARD PANCRATISTATIN AND STREPTONIGRIN

Abstract

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 Development of new synthetic pathways toward the pyridyl C-ring was undertaken, exploiting the electronically withdrawn nature of the pyridone intermediate in order to brominate and alcohol, as well as change a methyl group to an aldehyde, via an enamine intermediate.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.