With this award, the Chemical Synthesis (SYN) Program is funding Professor T.V. RajanBabu of the Department of Chemistry at Ohio State University to explore catalytic methods in synthesis. The SYN Program finds particularly notable both the efficient Ni-mediated hydrovinylation transformation, and the impressive regiodivergent Y-salen-mediated aziridine opening chemistry developed in the last cycle. Key features of the research plan in the next cycle include investigation of the mechanism of the efficient stereoselective hydrovinylation reaction and development of an unprecedented asymmetric silyl(boryl)stannylation-diyne cyclization that would give axial chiral cyclic dienes. In most ring-forming reactions, even among highly catalytic and selective ones, the number of functional groups is often depleted in going from an unsaturated starting material to a product. In the aforementioned metal-catalyzed cyclization of diynes, enynes, allenynes and allene-aldehydes mediated by various X-Y reagents (X, Y = [R3Si], [R3Sn], [R2B]), there is a net increase in the number of functional groups in the product of the reaction. Moreover, in the case of the alpha,omega-diyne cyclization, the product (ZZ)-1,2-bis-alkylidene is axially chiral, and transfer of such chirality to centers of chirality around the newly formed ring is projected to add a new dimension to stereocontrol in cyclization reactions.

These catalytic processes are part of an underlying green chemistry theme of this and related work in the RajanBabu research group. This theme carries over into the undergraduate organic teaching laboratory in which a project involving an aqueous, asymmetric biocatalytic reduction of unsymmetrical ketones has been introduced. Such a laboratory experience exposes a large undergraduate population to several aspects of modern organic synthesis (e.g., chirality, asymmetric catalysis, green chemistry, structure-activity relationships, separations by chiral stationary phase chromatography).

Project Report

Functionalized carbocyclic and heterocyclic compounds with small to medium size rings are ubiquitous among pharmaceutically relevant natural and non-natural products, and research directed towards new stereoselective methods for the synthesis of these compounds is at the heart of modern synthetic organic and medicinal chemistry. Even in the best catalytic cyclization reactions, generally functional groups are depleted in going from the starting materials to the products. The bimetallative cyclization methods, on the other hand, give facile entry into highly functionalized late-stage intermediates endowed with additional functional groups and new elements of chirality as compared to the starting materials. Development of such methods, as illustrated during this project, facilitates synthesis of complex biologically active molecules. We have completed the first total synthesis of fully functionalized dibenzocyclooctadienes, which have a broad spectrum of biological activities including anti-tumor, HIV- and type-B-hepatitis inhibition, anti-neurodegenerative properties, and NO-inhibitory activities. In another area, we work on the hydrovinylation reactions, which use one of the most abundant and renewable carbon feedstocks, ethylene (available from bio-ethanol) for the enantioselective synthesis of biologically active molecules. A recent example from our work is (arguably) the best enantioselective synthesis of widely used anti-inflammatory 2-arylpropionic acids from vinylarenes and ethylene in 3 steps (up to 7000 molecules of a key intermediate produced per molecule of the catalyst from a styrene and ethylene). Another use of ethylene is in a new protocol for a Heck reaction for the synthesis of vinyl compounds. The hydrovinylation also provided a solution to a long-standing problem in synthetic organic chemistry (the ‘exo-cyclic stereochemistry problem’) and enabled shortened synthesis of several key natural products [e. g., curcumene, psuedopterosins, trikentrins, physostigmine and several difficult-to- access steroid derivatives.] The PI has been approached by a pharma company to develop a practical synthesis of a key beta-aminoacid using an enantioselective aziridine ring-opening reaction developed in his laboratory. The interdisciplinary nature of this research makes it a very fertile ground for training students. Seven students (including one female) received PhD degrees during the past 5 years. In the past I have been associated with OSU’s NSF supported REU and REEL programs and, in 2013, an IGERT submission. For REEL, we devised a research module for a large undergraduate organic lab that involved aqueous biocatalytic reduction of arylmethyl ketones using leguminous seeds. These experiments introduced aspects of catalytic asymmetric synthesis, chiral separations and principles of green chemistry to several batches of sophomore students. This topic also became the subject of a BS Honors thesis. We hope to continue such involvement in large-scale undergraduate education in the future. I have also been involved in international outreach activities through visiting professorships in India. During the past 3 years I have given 14 invited talks, and published 4 highly visible reviews on our chemistry.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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Carol Bessel
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Ohio State University
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