Isothioureas in enantioselective organocatalysis

: synthetic and mechanistic investigations

Abstract

This thesis details the development of bench-stable ammonium enolate precursors and mechanistic investigations of isothiourea-catalyzed reactions.

Initial studies focussed on the investigation of esters as ammonium enolate precursors in a Michael addition-lactonization reaction. Trichlorophenyl esters were competent precursors Michael addition lactonization reactions and subsequent in situ methanolysis giving highly functionalized keto ester products in up to 86% yield, 94:6 dr and 99:1 er.

N-Acyl imidazoles were identified as ammonium enolate precursors and exploited in enantio- and diastereoselective Michael addition-cyclization reactions giving lactone and lactam products in up to 98% yield, >95:5 dr and 99:1 er. This represents the first use of acyl imidazoles in enantioselective isothiourea-catalyzed reactions and the use of base-free conditions for ammonium enolate chemistry. Notably, in some cases a Brønsted acid additive was optimal for reactivity and stereoselectivity.

The mechanism of the benzotetramisole-catalyzed reaction of N-acyl imidazoles with trifluoromethylenone was investigated revealing some clear distinctions from an analogous reaction under basic conditions. The acylation of the catalyst was promoted under acidic conditions signifying the importance of the “imidazolium effect”. The use of reaction progress kinetic analysis (RPKA) allowed the complex reaction kinetics to be probed, identifying the imidazole by-product as a source of product inhibition and the Michael addition step as turnover-rate limiting. This was further confirmed through measurement of an inverse secondary KIE kH/kD = 0.75.

Further investigations of isothioureas supported the postulate that an oxygen-sulfur interaction is important in stabilizing certain conformations of N-acylated isothioureas and that catalyst acylation varies depending on both ring size within the isothiourea and the acylating agent. Isourea and isoselenoureas ananlogues of isothiourea HyperBTM were prepared and isoselenourea was a competent enantioselective catalyst in both acyl transfer and Michael addition-lactonization reactions.

Date of Award	31 Dec 2017
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Andrew David Smith (Supervisor)