Bridging between Organocatalysis and Biocatalysis: Asymmetric Addition of Acetaldehyde to β‐Nitrostyrenes Catalyzed by a Promiscuous Proline‐Based Tautomerase

Abstract

In recent years, organocatalysis has become one of the main areas in asymmetric catalysis of carbon-carbon bond-forming reactions.[1] The fast evolution of the organocatalysis field has been particularly fueled by aminocatalysis, in which secondary and primary amines react with carbonyl compounds to give enamine and iminium ion intermediates. The field was completely transformed during the last two decades by the seminal contributions of List, [2] MacMillan, [3] Yamaguchi, [4] and co-workers. The natural chiral amino acid proline and derivatives thereof were found to be powerful organocatalysts. These secondary amines are applied in substoichiometric quantities and afford high product yields and enantioselectivities in fundamental carbon-carbon bond-forming reactions such as aldolizations, [1, 2, 3b] Michael additions, [1, 4,5] Mannich reactions, [1,6] and Knoevenagel condensations. [1,7] Inspired by the versatile success of proline and its derivatives as organocatalysts, we examined whether the enzyme 4-oxalocrotonate tautomerase (4-OT), [8] which carries a catalytic amino-terminal proline (Pro = P), might be suitable to promiscuously catalyze carbon-carbon bondforming reactions. Herein, we describe the discovery and characterization of two 4-OT-catalyzed asymmetric carboncarbon bond-forming Michael-type addition reactions. Considering our reported 4-OT-catalyzed aldolizations, [9] this work is a pivotal step forward towards our aim to bridge organocatalysis and biocatalysis by developing a new class of biocatalysts that use the powerful proline-based enamine mechanism of organocatalysts [1] but that take advantage of the water solubility and relatively high catalytic rates available with enzymes. A few elegant studies on promiscuous enzyme-catalyzed carbon-carbon bond-forming Michael additions have been reported, but most of these reactions proceed in organic solvents and with moderate stereocontrol.

Mutations Closer to the Active Site Improve the Promiscuous Aldolase Activity of 4‐Oxalocrotonate Tautomerase More Effectively than Distant Mutations

“…In addition to its natural tautomerase activity, 4‐OT promiscuously catalyzes several carbon–carbon bond‐forming Michael‐type addition and aldol condensation reactions . This includes the aldol condensation of acetaldehyde ( 3 ) with benzaldehyde ( 4 ) to yield cinnamaldehyde ( 6 ; Scheme ) .…”

Biocatalytic Michael‐Type Additions of Acetaldehyde to Nitroolefins with the Proline‐Based Enzyme 4‐Oxalocrotonate Tautomerase Yielding Enantioenriched γ‐Nitroaldehydes

“…We herein report that the enzyme 4‐oxalocrotonate tautomerase (4‐OT),11 which carries a nucleophilic amino‐terminal proline residue (Pro1), promiscuously catalyzes the asymmetric Michael‐type addition of acetaldehyde to various aromatic and aliphatic nitroolefins yielding chiral γ‐nitroaldehydes (Scheme ) with high stereoselectivities. In combination with our previously described 4‐OT‐catalyzed addition of linear aldehydes (acetaldehyde up to octanal) to trans ‐nitrostyrene,12, 13 this is the first example of enzyme‐catalyzed carbon–carbon bond‐forming Michael‐type additions that includes a range of linear aldehyde donors and a series of aromatic and aliphatic nitroolefin acceptors 14. Furthermore, we found that catalytic activity of 4‐OT is preserved in aqueous solvent systems containing up to 50 % (v/v) of DMSO as co‐solvent.…”

Synthesis of γ-nitroaldehydes containing quaternary carbon in the α-position using a 4-oxalocrotonate tautomerase whole-cell biocatalyst

“…[27][28][29] It was proposed that the most likely catalytic mechanism of the 4-OT-catalyzed Michael-type additions also depend on proline-based catalysis and involves the formation of a nucleophilic enamine intermediate, which in turn reacts with the double bond of the nitro olen creating a new C-C bond aer which the product is released from 4-OT's Pro1 by hydrolysis. [27][28][29] It was proposed that the most likely catalytic mechanism of the 4-OT-catalyzed Michael-type additions also depend on proline-based catalysis and involves the formation of a nucleophilic enamine intermediate, which in turn reacts with the double bond of the nitro olen creating a new C-C bond aer which the product is released from 4-OT's Pro1 by hydrolysis.…”