NIH-National Institute of General Medical Sciences

Project 3

Lactam and Sulfoxamide Libraries

This project seeks to discover and then generalize new ways of generating heterocyclic scaffolds that contain lactams and the related sulfoxamide linkage. In the first part of the project, Aubé and coworkers will seek to broadly address bottlenecks that hinder the application of alkyl azides in library construction. The first aim will be to develop a suite of reactions that involve tandem sequences in which a Lewis acid-promoted reaction of an alkyl azide with a ketone is partnered with another, similarly promoted reaction like (but not limited to) the Diels–Alder reaction. A second project will broadly address the use of flow chemistry to overcome well-known practical issues encountered with using alkyl azides on scale or with using highly energetic azide intermediates. The third project will utilize reaction screening as a reaction discovery tool. Although focusing on the reactions of azidoalkyl azide sublibraries with ketones and other potential reaction partners, the techniques developed in this reaction (carried out in collaboration with the Porco group at Boston University) will be brought to bear on other reactions as well, including a set of double conjugate addition reactions of quinone ketals developed recently in the Aubé lab. The last project in this section will concern the exploration of conformation control to establish regiochemistry in library-constructing reactions, ultimately with the goal of developing efficient means to shape-diverse libraries of piperidine privileged structures.

In the second part of this project, the Hanson group will target sulfonamide and sultam libraries, which show promising potential as bioactive agents yet still constitute a rare chemical class in Pubchem. We aim to develop a generalized strategic approach that first constructs a series of sulfonamide linchpins using an underdeveloped example of a “click” reaction. Once made, a single sulfonamide linchpin will be made to diverge to multiple scaffolds using a set of orthogonal cyclization pathways. Elements of this project will involve the integration of flow technology to facilitate sultam library production and the development of facilitated protocols for late-stage annotation using ROM polymerization technology developed by the Hanson group within the first granting period. 

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