A reductase-mimicking thiourea organocatalyst incorporating a covalently bound NADH analogue: efficient 1,2-diketone reduction with in situ prosthetic group generation and recycling

Abstract

A new class of bifunctional organocatalyst promotes the chemoselective reduction of diketone electrophiles at catalytic loadings in the presence of an inorganic co-reductant.Enzymatic manipulation of the NAD(P) + /NAD(P)H redox couple in biotransformations is a fundamental competency common to all living cells. 1 In biological systems levels of these cofactors are maintained through both continual degradation/biosynthesis 2 and the coupling of oxidation/reduction reactions to sustain a redox balance.1,2 A considerable difficulty associated with the exploitation of biocatalytic reduction in preparative chemistry has been the need for the use of stoichiometric quantities of the expensive and significantly unstable (in solution) NADH cofactor. In response to this challenge several approaches to cofactor regeneration in preparative biooxidations/reductions 3 have been developed, the most practical of which involve either a single (A, Fig. 1) 4 or binary (B, Fig. 1) 5 enzyme system using either isolated enzymes or whole cells.The excellent activity/selectivity of enzymatic reductase systems has inspired the development of de-novo designed small organic molecules for biomimetic reduction which can be categorised as being either chiral nicotinamide-based reagents 6 or chiral NADHanalogue dependant organocatalysts. [7][8][9] Benchmark systems in the former category of NADH model are reagents, capable of effecting highly enantioselective reduction of activated ketones at stoichiometric loadings in the presence of Mg 2+ ions (100 mol%) and are not regenerated, while the second class of reductase mimic can promote efficient reductions of a,b-unsaturated electrophiles 7-9 and imines 10 with impressive levels of stereoinduction at catalytic loadings (1-20 mol%) in the presence of stoichiometric loadings of an achiral Hantzsch dihydropyridine hydride donor.We have been engaged in the design of (thio)urea based bifunctional catalysts capable of activating electrophilic reaction components through hydrogen bond donation 11 and were intrigued by the possibility of extending this strategy to include organocatalytic reductions. 12 In particular, the development of a completely new class of bifunctional organocatalyst incorporating both a substrate-activating (thio)urea moiety and an organic hydride donor (as opposed to a binary catalyst system, e.g. Hantzsch ester and Mg 2+/organocatalyst) was appealing due to the increased potential for synergistic cooperation between the catalyst's functional components and for an increased measure of control (in a catalyst design context) over the catalyst-substrate interaction. To make the proposed process veritably catalytic in all organic components we also undertook to develop a conceptually novel artificial reductase system in which a NADH-model hydride donor could be both generated and recycled in situ by simple, chemical means.With this in mind we prepared (thio)ureas 3-11 and evaluated their performance as promoters of the hitherto unknown (in an organocatalytic context) reduction of be...

The Design of Novel, Synthetically Useful (Thio)urea-Based Organocatalysts

“…A range of control experiments where one of the two catalytic reaction components was removed demonstrated that significant levels of reduction occurred only when the BNA (which is reduced in situ by the dithionite) and the (thio)urea catalyst were present together ( Table 5, entries 1-7). 40 Gratifyingly, the most efficacious promoters of the reaction proved to be the bifunctional thiourea-based pyridinium salt precatalysts 37a,b, in which both the ketone-activating and ketone-reducing components are located on a single catalyst molecule separated by a reasonably rigid linker. The most active of these catalysts was capable of bringing about the clean and chemoselective (no diols or other side products were detected) reduction of 34 in 48 hours.…”

Asymmetric conjugate addition of carbonyl compounds to nitroalkenes catalyzed by chiral bifunctional thioureas

“…Typical procedure for the preparation of thioureas 1a-1e 11,12 A 50-mL round-bottomed flask was charged with benzylamine (1.07 g, 10.0 mmol), triethylamine (2.42 g, 24.0 mmol) and THF (10 mL). The mixture was cooled with an ice bath under a N 2 atmosphere.…”

Enantioselective, Organocatalytic Reduction of Ketones using Bifunctional Thiourea-Amine Catalysts

“…Whilst chiral ureas and thioureas have emerged as efficacious catalysts for a variety of nucleophilic conjugate additions11 and 1,2-carbonyl additions, e.g., hydrocyanation,12 Henry reaction,13 and Baylis-Hillman reaction,14 there are few examples of highly enantioselective hydride additions 15,16. However, the insights gained developing asymmetric oxy-Michael additions of boronic acids with α,β-unsaturated ketones17 revealed several unique attributes that we felt could be harnessed for enantioselective carbonyl reductions.…”