The ability to synthetically manipulate and prepare specific molecular structures with defined bespoke properties is the main goal of synthetic chemistry and catalysis, with applications that span the breadth of contemporary science ranging from materials chemistry to chemical biology. Catalysis provides society with efficient industrial processes that minimise energy, waste and harmful by-products. Andy’s research uses heterocyclic compounds as organocatalysts to develop new routes to prepare stereodefined materials from simple building blocks. Within this remit, our research speciality focuses upon the development of novel catalytic reaction processes using enantiopure heterocyclic Lewis base catalysts (isothioureas and N-heterocyclic carbenes), while simultaneously advancing a comprehensive mechanistic understanding of these transformations. In all projects the reactivity of heterocycles is used to discover novel approaches to the assembly of functional molecules. 

For more information see the ADS Group Website: https://ads-group.squarespace.com/

The majority of our research to date has focused upon the employment of NHCs and isothioureas as Lewis base catalysts.

1. Developing isothioureas as versatile enantioselective catalysts: Cutting-edge modern organocatalysis requires that a single catalytic architecture can be utilised to access a variety of different reactive intermediates that lead to products with significant added-value. In this context we have developed a range of simple heterocycles, isothioureas, that can be utilised under robust open flask conditions to promote a number of selective transformations that involve the generation of either an acyl ammonium, ammonium enolate, a,b-unsaturated acyl ammonium or ylide intermediate. One isothiourea catalyst developed in our laboratory, “HyperBTM”, is now commercially available¹ and is currently being used for industrial applications. For example, this catalyst performs highly selective kinetic resolutions of aryl-alkenyl substituted secondary alcohols via an acyl ammonium intermediate,² with recent work showing the unprecedented resolution of tertiary alcohols.  Notably, isothioureas alsocatalyse the first enantioselective inter- and intramolecular Michael addition-lactonisation of enone-acids from readily available carboxylic acids, generating stereodefined products with excellent stereoselectivity (typically >95:5 dr and 97% ee) via an ammonium enolate intermediate.3 This carboxylic acid functionalisation concept has led to the preparation of dihydropyridones,4 the enantioselective a-amination of carboxylic acids,⁵ as well as the bespoke one-pot preparation of pyridines.6 Through exploitation of the imidazolium effect, heterocyclic isothiourea hydrochloride salts can be used to provide base free-enolate reactivity.⁷ In further work we have exploited isothioureas in the first generation and exploitation of a,b-unsaturated acyl ammoniums ions.⁸ The asymmetric annulation of these species with either 1,3-dicarbonyls, b-ketoesters or azaaryl ketones generates either functionalised esters (upon ring opening), dihydropyranones or dihydropyridones in good yields (up to 93%) and high enantioselectivity (up to 97% ee). Notably azaaryl ketones give regioselectively N-cyclised heterocycles in high ee with the origin of selectivity in these processes due to ascribed to non-bonding 1,5-S•••O interactions.⁹ Further work has extended this concept to the generation of the first catalytic asymmetric 2,3-rearrangement of allylic ammonium ylides, with isothioureas proving uniquely reactive in this area.¹⁰

2. NHC catalysis: We have used NHCs to catalytically promote regio- and enantioselective carboxyl group transfer,¹¹ as well as harnessing a-aroyloxyaldehydes as azolium enolate precursors.¹² Recent collaborative mechanistic work has described the in-situ observation, isolation and reversible formation of intermediate 3-(hydroxybenzyl)azolium salts derived from NHC addition to substituted benzaldehydes, as well as rate constants of hydrogen-deuterium exchange (k_ex).¹³ Notably, the incorporation of a 2-substituent within benzaldehydes shows a remarkable rate accelerating effect in the formation of these 3-(hydroxybenzyl)azolium salts.14 This observation has been applied to understand the observed selectivity of cross-benzoin reactions that previously relied on inconsistent steric arguments.

References: ¹ CAS-1203507-02-1; commercially available from Apollo Scientific²Chem. E. J. 2016, 22, 18916. 3J. Am. Chem. Soc. 2011, 133, 2714. 4 Angew. Chem. Int Ed. 2012, 51, 3653. 5 Chem. Sci. 2012, 3, 2088.6 Angew. Chem. Int. Ed. 2013, 52, 11642. ⁷Angew. Chem. Int. Ed. 2016, 55, 14394. ⁸ Chem. Sci. 2013, 4, 2193. 9 Chem. Sci.2016, 7, 6919. ¹⁰ J. Am. Chem. Soc. 2014, 136, 4476; J. Am. Chem. Soc. 2017, 139, 4366; J. Am. Chem. Soc. 2017, 139, 11895. 11Chem. Sci. 2014, 5, 3651. 12 ACS Catalysis, 2014, 4, 2696. 13 Chem. Sci. 2013, 4, 1514.¹⁴ Angew. Chem. Int. Ed. 2015, 54, 6887.

Professor Smith gained a D. Phil (supervised by Prof. Steve Davies) in 2000 at the University of Oxford that was followed by further post-doctoral studies with Prof. Davies from 2000-2005. In October 2005, he was appointed as a Royal Society URF within the School of Chemistry at the University of St Andrews, was promoted to Reader in 2010, and Professor in 2012. He is currently Director of the EPSRC CRITICAT Catalysis CDT involving St Andrews, Edinburgh and Heriot Watt Universities. He was awarded an ERC Consolidator grant in 2011, the RSC Merck Prize in 2014 and RSC Charles Rees Award in 2018 and was elected FRSE in 2017. Research within the ADS group is currently directed towards the development of NHCs and isothioureas in Lewis base promoted catalytic enantioselective reaction processes and developing a mechanistic understanding of these processes.

Enantioselective catalysis using Lewis bases; kinetic and mechanistic studies; methodology development

Andy contributes to teaching at both sub-honours and honours classes, through lecturing in CH1601 Introductory Organic Chemistry (16 Lectures and 4 workshops), CH3615 Mechanism in Organic Chemistry (9 Lectures and 2 workshops, Module convenor) as well as CH5611 Asymmetric Synthesis (10 Lectures and 2 workshops). Andy contributes to tutorials for CH1601 and CH4461/5461 Integrating Chemistry, and regularly acts as an academic monitor for external placements (CH4441).