Stereoselective Uncatalyzed and Chiral Triazole Prolinamide Catalyzed Aldol Reactions in Aqueous Media: Applications Towards the Synthesis of Tubulysins

Paladhi, Sushovan (2014) Stereoselective Uncatalyzed and Chiral Triazole Prolinamide Catalyzed Aldol Reactions in Aqueous Media: Applications Towards the Synthesis of Tubulysins. PhD thesis, Indian Institute of Science Education and Research (IISER) Kolkata.

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Abstract

Water is the most abundant solvent in Nature for reasons of cost, safety, and environmental concerns and has unique properties such as H-bonding, high polarity and hydrophilic/hydrophobic interactions with the substrates. There have been continuing efforts to explore organic reactions with new reactivity and selectivity that can be executed in water that avoids the problems of pollution that are inherent with organic solvents. The discovery and development of environmentally benign processes for stereoselective synthesis of heterocyclic compounds represent an important goal of chemical and pharmaceutical research. On the other hand, a stereoselective aldol reaction is one of the most fundamental tools for carbon-carbon bond formation reaction in organic synthesis that creates the β-hydroxy carbonyl structural unit found in numerous numbers of natural products and drugs. Catalytic aldol reaction has been widely studied using organic solvents and in aqueous medium. However, examples of stereoselective uncatalyzed aldol reaction “in”, “on” or “in the presence of” water are rare. The analogues of preTuv were achieved using L-proline catalyzed direct asymmetric aldol reaction of substituted thiazole carbaldehydes with acetone. The first organocatalytic enantioselective approach to precursors of tubuvaline (preTuv) is presented employing a prolinamide catalyzed aldol reaction of easily accessible thiazole carbaldehyde with methyl isopropyl ketone “on water” in excellent yield, regio- and enantio-selectivities. A direct and flexible approach to tubavaline (Tuv) core of tubusyline has been established employing a diastereoselective reductive amination of preTuv.

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