A Modular Synthesis of Ketones and Gem-diborylalkanes by Catalytic Carbon Insertion with Non-stabilized Diazoalkanes

Thesis advisor: Jason S. KingsburyChapter 1: The reaction of diazomethane with simple aldehydes to deliver methyl ketones has a long studied history in the art of organic synthesis. Formyl electrophiles have also been homologated with trimethylsilyldiazomethane, diazoacetates, and aryl-diazomethanes that very rarely proceed with catalytic activation. Due to the stigma of handling non-stabilized diazoalkanes this history is limited to examples utilizing αdiazoesters and entirely missing are examples of tertiary αsubstituted ketone synthesis beginning with disubstituted (internal) diazoalkanes. This work describes a general catalytic procedure for convergent ketone production using non-stabilized, mono- and disubstituted diazomethanes. The method involves mild reaction conditions, produces molecular nitrogen as the only byproduct, and includes six examples of chiral ketone synthesis from various aryl, heteroaryl, or aliphatic aldehydes. The latter feature, together with new evidence that the catalytic reaction mechanism invokes a stereospecific, intramolecular C-H migration, sets the stage for an enantioselective synthesis of acyclic ketones by asymmetric carbon insertion. The remarkable tolerance of this transformation to steric crowding in either reaction partner is showcased in a simple, five-step construction of the complete carbon framework in achyrofuran, a complex dibenzofuranoid. Chapter 2: Paraformaldehyde is an inexpensive and readily available source of carbon (~30 USD/kg). Upon heating, the polymer thermally depolymerizes to yield gaseous formaldehyde that can be bubbled through reactions or stored in solution at low temperature. In this work, a new and general strategy for complex ketone synthesis is described based on Sc-catalyzed, double diazoalkyl C-H insertion reactions with formaldehyde as a 1-C source. The method forms di-, tri-, and even tetrasubstituted acetones efficiently, and it has streamlined a synthesis of the Erythroxylon alkaloid (-)-dihydrocuscohygrine in which absolute stereochemistry in a proline-based starting material is preserved. Chapter 3: Use of geminally-substituted diorganometallics often gives new forms of reactivity that are unavailable to their monosubstituted counterparts. With the expanding use of boronic acids in many areas of synthetic organic methodology, an underappreciated research area has been full development of disubstitited gem diboronic ester derivatives for use in tandem reactions, olefination methods, metal catalyzed coupling reactions, and transmetallations to mixed gem diorganometallics. The nature of molecular boron is routinely engaged through its Lewis acidic vacant p-orbital, and, after metalation, this orbital interaction is enlisted to stabilize α-carbanion or α-carbanion like species to allow dependable reactivity in various applications. The platinum-catalyzed geminal diboration of diazoalkanes provides reliable and efficient access to a full range of disubstitited gem diboronic esters enabling the exploration of novel methodologies.Thesis (PhD) — Boston College, 2011.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Chemistry