The Research
Smith Group: Research Summary
Synthetic organic chemistry has applications that span the breadth of contemporary science, ranging from materials chemistry to chemical biology. Within this remit, our research focuses upon the development of new, small molecule, designer catalysts and novel asymmetric processes, the advancement of a mechanistic understanding of these transformations, and their application in synthesis. Our independent progress in these fields is outlined below and referenced to our publications which can be accessed by clicking on the relevant link.
a. Catalytic acyl and carboxyl transfer processes using NHCs and isothioureas: Much of our research has focused upon the employment of NHCs and isothioureas as Lewis bases in catalysis. For example, both catalyst architectures efficiently promote the O- to C-carboxyl group transfer of a variety of heterocyclic carbonates. (link, link, link, link) This work has been used as the cornerstone of the synthesis of the natural product (±)-horsfiline, (link) and has been incorporated in domino multi-step synthetic procedures using NHC 1. (link) Recent work has shown that chiral isothiourea 2 performs this reaction with high enantioselectivity (up to 94% ee), and a model to understand the asymmetry in this reaction has been developed. (link) Isothioureas such as 2 also show high efficiency in the kinetic resolution of secondary alcohols (S up to >100, Fig 1), (link) and the C-acylation of silyl ketene acetals (up to 92% ee). (link, link)
b. Catalytic enolate generation using NHCs and isothioureas: We have also engaged NHCs to catalytically generate azolium enolates from ketenes, and have employed this methodology in asymmetric beta-lactam synthesis, (link, link) the asymmetric addition of phenols to unsymmetrical ketenes, (link) and the asymmetric chlorination of ketenes (Fig 2). (link) Further work has established an array of alternative formal asymmetric cycloaddition pathways using this methodology. Notably, recent work has shown that isothioureas such as 2 and 3 catalyse the asymmetric inter- and intramolecular Michael addition-lactonisation of carboxylic acids, generating stereodefined products in high yield and with excellent stereoselectivity (typically >95:5 dr and 97% ee) via an ammonium enolate intermediate (Fig 3). (link)
Alongside these branches of research we are developing expertise in physical organic chemistry methods in order to develop a true mechanistic understanding of the catalytic processes we study. (link) In all our research projects we aim to discover novel methods and approaches to the assembly of complex functional molecules. For example, we have developed a simple and efficient asymmetric synthesis of oxindoles 5 from chiral N-aryl nitrone 4 and unsymmetrical ketenes, which has been applied to the asymmetric synthesis of the 3-phenyl- hexahydropyrroloindole skeleton 6 (Fig 4). (link) Notably, through a collaborative programme with the Houk group, we have been able to optimise the levels of asymmetry in this reaction process, and have shown that this reaction proceeds through a novel pericyclic cascade process involving an initial stereoselective [3+2] cycloaddition and subsequent [3,3]-sigmatropic rearrangement. (link)
