Research Summary

Synthetic organic chemistry and catalysis has applications that span the breadth of contemporary science, ranging from materials chemistry to chemical biology. Within this remit, our research programme is focused in the areas of enantioselective homogeneous catalysis and organocatalysis, alongside mechanistic studies of these processes. Current major research themes involve the development of novel catalytic strategies involving NHCs and isothioureas as enantioselective Lewis base catalysts and their application to the development of approaches for the assembly of functional molecules. We have developed a comprehensive mechanistic understanding of these transformations, and have enjoyed successful collaborations with physical organic chemists (A-M. O’Donoghue (AOD), Durham; G. C. Lloyd-Jones, Edinburgh, H. Mayr, LMU). We have also developed a long-standing collaboration with theorists who support our work computationally (P. Cheong, Oregon State, USA).

Significant progress in the areas of isothiourea and NHC-mediated catalysis is outlined below:

1. Developing Isothioureas as Versatile Enantioselective Catalysts:

We have developed a research programme that uses Lewis basic isothioureas to promote a range of selective transformations. We have developed strategies that use isothioureas to generate three key intermediates; acyl ammonium, C(1)-ammonium enolate and related ylidic species, as well as α,β-unsaturated acyl ammonium derivatives, and harness them in catalysis (Figure 2). Comprehensive mechanistic studies (including temporal concentration and kinetic analysis, labelling studies, KIE and natural abundance 13C experiments), have allowed unique insight to these reaction processes. The isothiourea catalyst developed in the ADS group, “HyperBTM”, is commercially available (CAS-1203507-02-1; Apollo Scientific) and used for industrial applications on scale. A key structural motif that leads to selectivity in these transformations is a 1,5-S•••O chalcogen bonding (n —> σ*) interaction (Angew. Chem. Int. Ed. 2020, 59, 3705).

Selected key advances that utilise each of these intermediates are summarised below:

Acyl ammonium catalysis:

HyperBTM performs the effective catalytic kinetic resolution of challenging heterocyclic (Angew. Chem. Int. Ed. 2018, 57, 3200) and acyclic (Angew. Chem. Int. Ed. 2020, 59, 16572) tertiary alcohols, aryl-alkenyl secondary alcohols (Chem. Eur. J. 2016, 22, 18916), with the kinetic resolution / desymmetrisation of axially chiral biaryl diols also achieved (Chem. Eur. J. 2019, 25, 2816; Angew. Chem. Int. Ed. 2020, 59, 7897). Through collaboration with the Pericas group the successful attachment of isothioureas to a polymer support (i) facilitates catalyst recycling and (ii) allows catalytic acylative kinetic resolutions in flow using a fixed bed reactor (ACS. Catalysis. 2018, 8, 1067; Green. Chem. 2018, 21, 18944). Collaboration with the Bressy group has applied Horeau amplification to resolve 1,2- and 1,3-diols in flow (Org. Biomol. Chem. 2021, 19, 3620).

C(1)-Ammonium enolate catalysis:

We have developed protocols to access C(1)-ammonium enolates from carboxylic acids (J. Am. Chem. Soc. 2011, 133, 2710), anhydrides (Chem. Sci. 2019, 10, 6162) and esters (ACS. Catalysis 2018, 8, 1153). These strategies have been applied to a variety of inter- and intramolecular processes to generate functional heterocyclic products (for select examples see Angew. Chem. Int. Ed. 2012, 51, 3653; Chem. Commun. 2017, 53, 2555; Org. Lett. 2018, 20, 5482; Chem. Sci. 2020, 11, 3885) as well as valuable achiral building blocks such as pyridines (Angew. Chem. Int. Ed. 2013, 52, 11642) and pyrones (Org. Lett. 2014, 16, 964). This process allows the direct enantioselective functionalization of SiOx surfaces (Angew. Chem. Int. Ed. 2018, 57, 9377). Employing acyl imidazoles, isothiourea hydrochloride salts can be used to provide enolate reactivity (Angew. Chem. Int. Ed. 2016, 55, 14394) with mechanistic studies implicating imidazole inhibition. Base free enantioselective ammonium enolate catalysis has recently been exploited (Angew. Chem. Int. Ed. 2019, 58, 15111), while co-operative isothiourea-Brønsted base catalysis allows the preparation of enantiopure β-amino esters (Angew. Chem. Int. Ed. 2021, 60, 11892).

Ammonium ylides in catalysis:

We developed and exploited the concept of aryloxide turnover to allow the first catalytic enantioselective 2,3-rearrangement of allylic ammonium ylides from ester precursors (J. Am. Chem. Soc. 2014, 136, 4476). Further work has probed the mechanism of this process in full (J. Am. Chem. Soc. 2017, 139, 4366), developed a dual-catalytic process to simplify the protocol (J. Am. Chem. Soc. 2017, 139, 11895), and applied this process to the preparation of bespoke amino acid derivatives containing tertiary fluoride substituents (Org. Lett. 2017, 19, 5182).

α,β-Unsaturated acyl ammonium catalysis:

The enantioselective exploitation of a,b-unsaturated acyl ammoniums ions through annulation with 1,3-dicarbonyls, β-ketoesters or azaaryl ketones generates high value products with excellent enantioselectivity (Chem. Sci. 2013, 4, 2193), with 1,5-S•••O interactions identified as key for selectivity (Chem. Sci. 2016, 7, 6919). This methodology has been exploited in complex cascade reactions (Chem. Eur. J. 2016, 14, 8068), and allows the enantioselective addition of nitroalkane pronucleophiles to a,b-unsaturated esters (Angew. Chem. Int. Ed. 2017, 56, 12282). Recent work has highlighted the key multiple roles that aryloxides play in annulations employing acylbenzothiazoles or acylbenzoxazoles with α,β-unsaturated acyl ammoniums ions (Chem. Sci. 2018, 9, 4909) and allowed the addition of N-heterocycles in an enantioselective process (Chem. Sci. 2020, 11, 241).

2. NHC Catalysis:

We have exploited the Lewis basic nature of NHCs to catalytically promote carboxyl group transfer. For example, catalyst controlled regiodivergent O- to C- or N-carboxyl transfer of pyrazolyl carbonates has been developed, with DMAP giving preferential N-carboxylation and NHCs promoting selective enantioselective C-carboxylation (Chem. Sci. 2014, 5, 3651). In further work we have demonstrated a number of routes to azolium enolate precursors including disubstituted ketenes and α-aroyloxyaldehydes, and showcased their application in a range of enantioselective formal [2+2] and [4+2] cycloaddition reaction processes (Chem. Commun. 2011, 47, 373; Org. Lett. 2013, 15, 6058; ACS Catalysis, 2014, 4, 2696; Chem. Eur. J. 2015, 21, 18944; Beilstein. J. Org. Chem. 2020, 16, 1572).

Mechanistic Understanding of NHC-catalysed Processes:

Working with AOD, we have developed a fundamental mechanistic understanding of the archetypal benzoin (Org. Biomol. Chem. 2021, 19, 387) and Stetter reaction processes (Eur. J. Org. Chem. 2021, 3670) that proceed under NHC catalysis. This encompasses evaluation of the pKa values (16.6-18.5) of twenty commonly used triazolium salts, with pD-rate profiles for deuterium exchange revealing that N-protonation to give dicationic triazolium species occurs under acidic conditions (J. Am. Chem. Soc. 2012, 134, 20421; J. Phys. Org. Chem. 2015, 28, 108). Further work has described the in situ observation, isolation and reversible formation of intermediate 3-(hydroxybenzyl)azolium salts (TI) derived from NHC addition to substituted benzaldehydes (Chem. Sci. 2013, 4, 1514). Recent work has highlighted the diverse roles of 2-substituents in both N-aryl triazolium catalysts and aryl aldehydes in controlling product outcomes in cross-benzoin reactions (Angew. Chem. Int. Ed. 2015, 54, 6887). The presence of 2-substituents, in either the aldehyde or N-aryl group of triazolylidene catalyst, both kinetically favours addition of NHC to aldehyde and increases K values for adduct (TI) formation, in contrast with the commonly assumed unfavourable steric effect of ortho-substituents.