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Cooperative Lewis base / Metal-Catalyzed Enantioselective Annulations

Project description

Two catalysts are better than one: greener chemistry for biologically important compounds

Synthetic chemistry is critical to the development and production of novel compounds for virtually every industry and sector. Being able to selectively produce exactly what we want quickly and efficiently is fundamental and generally relies on catalysis. The conversion of certain molecules into others often utilises or targets ring-shaped compounds and steps including ring opening, ring expansion and so-called cycloaddition. These steps can be stubborn and require harsh chemicals and reaction conditions if they are possible at all. The EU-funded COOPCAT project is developing a novel two-catalyst approach to enable the previously impossible synthesis of important biological compounds having ring structures.

Objective

We plan to make innovative use of two catalysts in combination to achieve reactivity impossible with single catalysts acting alone and so develop new synthetic methods for the synthesis of biologically important compound classes. Catalytic approaches to chemical synthesis provide great benefits in terms of reducing the demand for energy and resources, and outwork will enable a ‘greener’ approach to molecules of value in medicine and healthcare. The combination of two catalysts (one acidic, one nucleophilic) offers particular advantages, but presents challenges of compatibility that we intend to overcome. Previously, Gong has demonstrated that chiral isothiourea Lewis base catalyst may be combined with the second mode of activation, such as Lewis acid catalysis, to enable α-amination of esters and decarboxylative [4+2] annulation of 4-ethynyl dihydrobenzooxazinones. We will build on this work by developing a new class of catalytic asymmetric C1 ammonium enolates as nucleophiles for ring opening and ring expansion chemistry. A chiral Lewis base and a metal salt will work together to promote acylammonium ion formation, ring opening, ring expansion and [4+3] and [4+2] cycloaddition chemistry. The reactions will exhibit regio- and stereocontrol, and we will aim for high yield and enantiopurity. This cooperative catalytic strategy, using a chiral Lewis base and a metal salt together, provides a powerful synthetic tool for the rapid stereoselective synthesis of small ring natural products and other bioactive targets. For the first time, it will provide a method for enantioselective [3+2], [4+2] and [5+2] annulations to generate ε-lactones, dihydropyridazinone, and dihydroquinolinone structures. It remains a challenge to selectively generate diverse products from identical substrates, and we intend to demonstrate that this is possible by employing catalyst rather than substrate control.

Coordinator

UNIVERSITY OF BRISTOL
Net EU contribution
€ 224 933,76
Address
BEACON HOUSE QUEENS ROAD
BS8 1QU Bristol
United Kingdom

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Region
South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Bristol, City of
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 224 933,76