Integrating Biocatalysis and Metal-Mediated Radical Cyclizations for Diversity Oriented Synthesis

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

Complex biologically-active molecules, possessing elaborate 3D forms, represent the ultimate challenge for synthetic chemists. As many of society's established and future drugs, agrochemicals, and biological probes boast intricate architectures, the ability to efficiently generate molecular complexity from simple starting materials, with precision control of 3D shape, is vital. In medicinal chemistry, in particular, a marked shift to complex drug candidates containing more saturation (sp3 centres) and chiral centres is underway with evidence that this will facilitate drug discovery.
We have developed the radical cyclizations of lactones and lactams, triggered by single electron transfer (SET),1 for the rapid generation of complex 3D scaffolds.2,3 In collaboration with the Turner group, we have recently explored the integration of biocatalytic oxidation and metal-mediated radical cyclizations in a divergent approach to molecular architectures.4 In this project we will exploit the Turner group's expertise in biocatalytic reduction and, in particular, their recent discovery of an NADPH-dependent reductive aminase.5
We propose that the integration of biocatalytic reduction/reductive amination and metal-mediated radical cyclizations, including metal-catalyzed processes, will allow expedient conversion of simple, achiral feedstocks to a range of complex, chiral, molecular architectures with precision control of 3D shape.
Biocatalytic reduction of ketones 1 (3 steps from dimethyl malonate) using oxidoreductases, will deliver lactones 2 (X = O) with control of absolute and relative stereochemistry. Furthermore, we propose that cutting-edge biocatalysis using reductive aminases5 will allow mixtures of ketones 1 and amines to be converted into enantiomerically enriched secondary amines, and subsequently to lactams 2 (X=NR).
Recent studies by the Turner group have shown the ability of an NADPH-dependent reductive aminase (AspRedAm) to convert mixtures of ketones and amines to secondary amines5a and have shed light on the mechanism by which the enzyme promotes both imine formation and reduction.5b As ketone substrates 1 represent the most functionalized substrates employed to date, we will first use simplified ketones 1' to improve our understanding of the selectivity of the new reductive aminase enzymes.
SET reduction of lactone/lactam intermediates 2 with SmI2 will allow divergent access to spirocycles 3a, heterocyclic products of a 1,4 ester-shift 3b, cyclic ketones 3c, and medium-sized heterocycles 3d. Crucially, we now know that subtle variation of the additives used in the reduction will allow manipulation of either the endo- or exocyclic carbonyl groups in 2 (green and grey highlights) (Scheme 1). For example, we will guide SET to the exocyclic carbonyl, giving rise to rad-1, hemiketal-1, and ultimately products 3a and 3b (Figure 2), or to the endocyclic carbonyl, giving rise to rad-2, hemiketal-2, and ultimately products 3c and 3d (Figure 2).
We aim to connect biocatalysis and metal-mediated radical chemistry, including metal-catalyzed radical chemistry, in an integrated, enantioselective, diversity oriented approach to 3D scaffolds. Biocatalytic reduction, and cutting-edge biocatalytic reductive amination, will be used to trigger the formation of enantioenriched heterocyclic intermediates for manipulation by a metal-reagent or metal catalyst. Technology-driven solutions will be needed to integrate the bio- and chemocatalytic stages in a telescoped, one-pot process.
1. Just-Baringo, X.; Procter, D. J. Acc. Chem. Res. 2015, 48, 1263.
2. (a) Procter and co-workers. Nat. Commun. 2018, 9, 4802. (b) Procter and co-workers. J. Am. Chem. Soc. 2012, 134, 12751.
3. (a) Huang, H. -M.; Procter, D. J. J. Am. Chem. Soc. 2017, 139, 1661. (b) Huang, H. -M.; Procter, D. J. J. Am. Chem. Soc. 2016, 138, 7770.
4. Turner, Procter and co-workers. Angew. Chem. Int. Ed. 2018, 57, 3692.
5. (a) Grogan, Turner and co-workers. Nat. Chem. 2017, 9,

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S023755/1 01/04/2019 30/09/2027
2279391 Studentship EP/S023755/1 01/10/2019 30/09/2023 Emma Louise Pye