Grant: Discovery Grants Program - Individual

Introduction. This proposal describes a program to develop novel organic transformations that can be applied in the construction of complex target structures. A common thread throughout is the idea of harnessing unique reactivity that resides in transient intermediates to devise non-intuitive but generally useful bond-forming processes. HQP will build upon preliminary studies in three key areas, using a combination of mechanistic analysis, reaction optimization, and synthetic design, with a goal of demonstrating the applicability of the new chemistry that comes from this program to important problems in chemical synthesis. Chemistry of Strained Cyclic Allenes. Allenes encased within smaller rings (<8 atoms) experience significant bond angle strain that greatly elevates their reactivity. This permits their participation in a variety of cycloaddition reactions under mild conditions. We will explore transition metal-catalyzed processes to capture the cyclic allene intermediates, and to process their strained cycloadducts. We will explore methods for transferring central chirality to allene intermediates, and preserving their axial chirality to permit stereoselective trapping and optimize their asymmetric transition metal reactions. Finally, we will seek to apply our fluoride-induced desilylation method to the formation of highly strained 1,2,4,6-cycloheptatetraene and 1,2-cyclopentadiene. Applications of Carbene-Heteroatom Adducts. Having developed productive chemistry based upon capture of metallocarbenes by azides, we will survey their reactivity with other stable 1,3-dipoles. We will develop indole trapping of azide-derived C-acylimines as a selective method for the modification of tryptophan residues in peptides and proteins. We will also examine enantioselective X-H insertion reactions of meso and achiral diols and related compounds as an approach to desymmetrize readily accessible feedstocks. Dendralenes and Related Compounds. Preliminary results with the "interrupted vinylogous Nazarov reaction" using electron-deficient dendralenes prompt us to explore the effect of cumulation on one terminus of the dendralene moiety. An unexpected allylic migration with the vanadium-catalyzed Meyer-Schuster rearrangement will be expanded to exploit these conjugated products in cascade processes. We will also attempt to develop an "interrupted Meyer-Schuster reaction" to produce cycloalkenes, including enantioselective versions. This research program is complemented with a careful HQP training plan that builds upon a successful environment that has sent many graduates to high-value positions in the chemical and pharmaceutical industries.