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Stereoselective Construction of Organofluorine compounds and Selective Carbon-Fluorine Bond Functionalization

Dr. Balaraman Kaluvu, Georgetown University

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Abstract:
Dr. Balaraman Kaluvu earned his Ph.D. at the Indian Institute of Technology (IIT) Madras with the thesis entitled “Development of Bidentate and Tetradentate Ligands from Tartaric acid and their Applications in Asymmetric Catalysis” in September 2012. During his doctoral research, he designed and synthesized a class of novel chiral bis(oxazoline) ligands and their metal complexes and successfully applied them in various asymmetric organic transformations and achieved up to >99% enantioselectivity.
He started working in the interface of chemistry & biology as a post-doctoral fellow (May 2013 – Jan 2015) at the Universite Paris-Sud, France, where he developed liposomal drug delivery systems of 2-alkylquinoline derivatives and performed in vivo evaluations to advance a treatment for leishmaniasis.
He continued working as a post-doctoral fellow (Apr 2015 – June 2018) under Prof. Christian Wolf at Georgetown University in Washington DC, where he has developed new catalytic methods for the enantioselective synthesis of fluorinated organic molecules (Angew. Chem. Int. Ed. 2017, 56, 1390–1395) and by generating fluoroenolates using a novel detrifluoroacetylative synthetic pathway (Synthesis, 2016, 48, 2376-2384). Another remarkable scientific achievement from his postdoctoral work at Georgetown was the development of a reaction that produces synthetically versatile 3,3-disubstituted fluorooxindole alkaloids having vicinal chirality centers in high yields and with excellent regio-, enantio- and diastereoselectivities. Recently, he has also introduced new methods that produce highly functionalized β-hydroxynitriles and bisoxindoles via environmentally benign green chemistry approaches (Adv. Synth. Catal. 2017, 359, 4165 & J. Org. Chem. 2018, 83, 1661). He also worked on chirality sensing that requires expertise in several analytical techniques and published in highly prestigious journals (Nat. Comm. 2018; 9: 5323, Angew.Chem.Int. Ed. 2020, Chem. Eur. J. 2019, 25, 11020).
Currently, he is working as Assistant Research Professor (July 2018 – Present) in the Chemistry Department at Georgetown University in Washington DC. He has been playing a leading role in anticancer, Parkinson and Alzheimer drug development projects, all providing a highly collaborative research environment, and prepared more than hundred compounds in recent years. To date, he has published 20 research papers and 1 review article in various fields which have been featured in the Organic Chemistry Portal and selected by Synfacts and also listed as an inventor on two international published patents and seven more patents that have been filed.

Stereoselective Construction of Organofluorine compounds and Selective Carbon-Fluorine Bond Functionalization

Part 1: Stereoselective Synthesis of Organofluorines

Asymmetric fluorination is increasingly being employed to make optically pure active pharmaceutical ingredients (API’s). Since incorporation of fluorine into drug molecules often enhances the biological properties of the parent compounds, development of fluorinated molecules has experienced enormous growth in drug discovery over the past two decades. In particular, 3-fluoro oxindoles have been used as valuable building blocks to make biologically useful heterocyclic frameworks. Enantioselective syntheses of 3-fluoro oxindoles have been achieved mostly by the late stage fluorination of activated oxindoles; however many of these procedures are substrate specific. In contrast, the use of 3-fluoro oxindole as a nucleophile in stereoselective transformations is less explored. Herein I present a highly stereoselective synthesis of 3-fluoro indoline alkaloids and their synthetic usefulness.

Part 2: Selective Csp3-F Activation & Functionalization

The general importance and widespread use of fluorinated organic compounds in the health, agrochemical and materials sciences are sustained by a large pool of structurally diverse fine chemicals that continues to grow at a fast pace. Although the C sp3 -F bond has become a ubiquitous moiety in countless, readily available building blocks, the huge synthetic prospect of selective carbon-fluorine bond activation remains to be exploited. This can be attributed to the paramount stability and chemical inertness of the C-F bond which necessitate the development of innovative functionalization strategies. Here I present the discovery of a reductive C sp3 -F bond activation pathway for defluorinative generation of nucleophiles or electrophiles under mild conditions. This chemistry is broad in scope, adaptable to a variety of carbon-carbon and carbon- heteroatom bond formation mechanisms, scalable, suitable for late-stage functionalization due to high functional group tolerance, and generally high-yielding.

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