Lessons from Nature: Biomimetic Organocatalytic Carbon−Carbon Bond Formations

Abstract

Nature utilizes simple C2 and C3 building blocks, such as dihydroxyacetone phosphate (DHAP), phosphoenolpyruvate (PEP), and the "active aldehyde" in various enzyme-catalyzed carbon-carbon bond formations to efficiently build up complex organic molecules. In this Perspective, we describe the transition from using enantiopure chemical synthetic equivalents of these building blocks, employing our SAMP/RAMP hydrazone methodology and metalated chiral alpha-amino nitriles, to the asymmetric organocatalytic versions developed in our laboratory. Following this biomimetic strategy, the DHAP equivalent 2,2-dimethyl-1,3-dioxan-5-one (dioxanone) has been used in the proline-catalyzed synthesis of carbohydrates, aminosugars, carbasugars, polyoxamic acid, and various sphingosines. Proline-catalyzed aldol reactions involving a PEP-like equivalent have also allowed for the asymmetric synthesis of ulosonic acid precursors. By mimicking the "active aldehyde" nucleophilic acylations in Nature catalyzed by the thiamine-dependent enzyme, transketolase, enantioselective N-heterocyclic carbene-catalyzed benzoin and Stetter reactions have been developed. Finally, based on Nature's use of domino reactions to convert simple building blocks into complex and highly functionalized molecules, we report on our development of biomimetic asymmetric multicomponent domino reactions which couple enamine and iminium catalysis.

Asymmetric Self‐ and Cross‐Aldol Reactions of Glycolaldehyde Catalyzed by D‐Fructose‐6‐phosphate Aldolase

“…[1][2][3][4] Recent developments in direct aldol additions using bio-, organo-, and metal catalysts are promising since these methodologies do not require separate generation of enolate equivalents and thus improve the atom economy of the transformation. [1,2,[5][6][7][8] Aldehydes have been regarded as highly interesting donors in aldol reactions, because the products formed are themselves aldehydes that can be used in further aldol additions for the construction of complex polyfunctional molecular frameworks. [4] Hence, the direct catalytic cross-aldol reaction of aldehydes constitutes a challenge for these methodologies.…”

Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis

“…This target has inspired generations of synthetic chemists to design unique chiral catalysts able to enantioselectively forge a stereocenter α or β to a carbonyl group (1)(2)(3). In this context, intense investigations into the aldol (4,5) and Michael reactions (6, 7) have made them invaluable tools in modern organic chemistry.…”

Second generation engineering of transketolase for polar aromatic aldehyde substrates

“…Asymmetric carbon carbon bond formation is a powerful method in organic synthesis [1][2][3][4][5][6][7][8] and new routes could provide access to a wide range of novel and natural compounds that serve as building blocks for further synthesis [2]. Enzymes such as transketolase (TK) (EC 2.2.1.1) have been shown to catalyse asymmetric carbon-carbon bond formation with considerable synthetic potential due to their high selectivity and specificity [1,[9][10][11][12][13].…”