Smith Group

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Smith Group: 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 focuses upon the development of novel (asymmetric) processes using organocatalytic methods, while advancing a mechanistic understanding of these transformations. In all projects we aim to discover novel approaches to the assembly of functional molecules, with progress outlined below and referenced to our publications.

The Research

a. Catalytic enolate generation using NHCs and isothioureas:

The majority of our research focuses upon the employment of NHCs and isothioureas as Lewis base catalysts. We have engaged NHCs to catalytically generate azolium enolates from ketenes,1,2 while recent work has used α-aroyloxyaldehydes as bench-stable ketene surrogates under NHC-mediated catalysis for a range of formal [2+2] and [4+2] cycloaddition processes (Fig 1).3

Smith group research

Alternatively, isothioureas 1 and 2 catalyse the asymmetric 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 (Fig 2).4 The generality of this carboxylic acid functionalisation concept has led to the preparation of dihydropyridones using isothiourea and the discovery of a selective N- to C-sulfonyl photoisomerisation process (Fig 3),5 the asymmetric α-amination of carboxylic acids,6 the preparation of trifluoromethylated building blocks7 and β-lactams, as well as the bespoke one-pot preparation of pyridines that incorporates an intramolecular N- to O-Ts transfer step (Fig 4).8

Smith group research
Smith group research

In an extension of this work we have recently developed the first catalytic asymmetric [2,3]-rearrangement of allylic quaternary ammonium salts (either isolated or prepared in situ from p-nitrophenyl bromoacetate and the corresponding allylic amine), generating syn-α-amino acid derivatives with excellent diastereo- and enantioselectivity (Fig 5, up to >95:5 dr; up to >99% ee).9

Smith group research

b. The generation and exploitation of α,β-unsaturated acyl ammoniums:

The asymmetric annulation of α,β-unsaturated acyl ammonium intermediates, formed in situ from isothiourea HyperBTM and anhydrides with either 1,3-dicarbonyls, β-ketoesters or azaaryl ketones has been used to generate either functionalised esters (upon ring opening), dihydropyranones or dihydropyridones in good yields (up to 93%) and high enantioselectivity (up to 97% ee). Notably azaaryl ketone gives preferentially N-cyclised heterocycles in high ee (Fig 6).10

Smith group research

c. Physical Organic Chemistry Methods:

Through collaborative work (Mayr and O’Donoghue groups) we have developed physical organic chemistry expertise to understand mechanistically the catalytic processes we study.11 For example, we have evaluated the pKa values (16.6-18.5) of twenty commonly used triazolium salts. Notably pD-rate profiles for deuterium exchange reveal that N-protonation to give dicationic triazolium species occurs under acidic conditions.12 Recent 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. Equilibrium constants for the formation of these 3-(hydroxybenzyl)azolium salts, as well as rate constants of hydrogen-deuterium exchange (kex) of these intermediates is reported, giving insight into the intriguing role of the N-aryl substituent within the NHC (Fig 7).13

Smith group research

d. Catalytic acyl and carboxyl transfer processes using NHCs and isothioureas:

Both NHCs and isothioureas both efficiently promote the O- to C-carboxyl group transfer of heterocyclic carbonates,14,15,16,17 with the chiral isothiourea HBTM 2.1 performing this reaction with high enantioselectivity (up to 94% ee).18,19,20,21,22 Isothioureas such as 2 also show high efficiency in the kinetic resolution of secondary alcohols (S up to >100, Fig 8), and the C-acylation of silyl ketene acetals (up to 92% ee). Recent work has also developed a catalyst controlled regiodivergent O- to C- or N-carboxyl transfer of pyrazolyl carbonates (Fig 9), with DMAP giving preferential N-carboxylation and triazolinylidenes promoting selective C-carboxylation (both with up to >95:5 regioselectivity).23

Smith group research

e. An Asymmetric Pericyclic Cascade approach to 3,3-oxindoles:

We have developed an asymmetric synthesis of oxindoles from chiral N-aryl nitrones and unsymmetrical ketenes, which has been applied to the asymmetric synthesis of the 3-phenyl-hexahydropyrroloindole skeleton.24 Computational and mechanistic studies indicate this reaction proceeds through a pericyclic cascade involving stereoselective [3+2] cycloaddition and subsequent [3,3]-sigmatropic rearrangement (Fig 10).25,26

Smith group research