Edinburgh Research Explorer

1 , 3-Dipolar Cycloaddition Approaches to functionalised Gamma-Lactams and Pyroglutamic Acids

Project: Research

Effective start/end date4/04/0530/09/07
Total award£110,744.00
Funding organisationEPSRC
Funder project referenceEP/C51243X/1

Layman's description

This research programme has as its objectives the design and development of new chemistry for use in the production of nitrogen-containing ring structures, which serve as precursors for a diverse array of chemical building blocks of interest. In one approach, appropriately-substituted reactive intermediates called azomethine ylides will be generated by the reaction of a nitrogen-containing ring with another reactive species called a metal carbenoid. Subsequent chemical reaction of the azomethine ylide with a suitable reacting partner will initially form a product containing two or three rings that serve as precursors for useful chemical building blocks called pyroglutamic acids. In a second approach, compounds known as thioiminocarbonates will serve as azomethine ylide precursors. A thorough understanding of the reacting preferences exhibited by our systems, as well as the factors that determine reaction efficiency and stereochemical outcome will be pursued. Application of the methodology to the synthesis of core structures of natural products, as well as important chemical building blocks is planned. If time permits, we will conduct preliminary studies to develop variants of the reactions that are able to preferentially produce one mirror image of the product over the other. It is anticipated that the chemistry described will find broad utility in organic synthesis.

Key findings

1. We have discovered novel catalytic systems for conducting reductive aldol cyclisations, based around nickel or cobalt salts. These reactions result in highly useful cyclic compounds containing a nitrogen or oxygen atom in the ring.
2. Explored the scope of these Ni/Co-based methodologies for the formation of β-hydroxy-γ-lactams and β-hydroxy-δ-lactams, and demonstrated that a Ni-catalysed reductive aldol cyclisation may be used in a route towards the marine natural product salinosporamide A.
3. Exploited our finding that zinc enolates are generated upon conjugate reduction of α,β-unsaturated amides to develop intermolecular reductive aldol and Mannich reactions, the former of which are rendered asymmetric using a chiral auxiliary.
4. Developed double Michael reactions of alkynones (compounds containing carbon-carbon triple bonds) to prepare highly functionalised pyroglutamic acid derivatives.