Asymmetric Michael Addition in Synthesis of β-Substituted GABA Derivatives

Han, Jianlin; Escorihuela, Jorge; Fustero, Santos; Landa, Aitor; Soloshonok, Vadim A.; Sorochinsky, Alexander E.

doi:10.3390/molecules27123797

Cited by 21 publications

(14 citation statements)

References 131 publications

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“…[21] Employing NahE for the production of (R)-γ-nitro acids also has the benefit of producing precursors which lead to the more biologically active R enantiomer of GABA analogues. [5] In conclusion, we have shown that NahE is able to catalyze the Michael addition of pyruvate to various βnitrostyrenes, in very high yield and enantioselectivity in some cases, forming valuable intermediates for the synthesis of known active pharmaceutic ingredients. To our knowledge, this is the first report of an aldolase-catalyzed Michael addition.…”

Section: Methodsmentioning

confidence: 82%

“…The use of pyruvate as the nucleophile in the NahE reaction avoids problems with oligomerization that are sometimes observed when acetaldehyde is used [21] . Employing NahE for the production of ( R )‐γ‐nitro acids also has the benefit of producing precursors which lead to the more biologically active R enantiomer of GABA analogues [5] …”

Section: Methodsmentioning

confidence: 99%

“…[2][3][4] These reactions have been particularly useful for forming γ-nitroaldehydes, which serve as valuable precursors for γaminobutyric acid (GABA) derivatives, including phenibut, baclofen, pregabalin and rolipram (Figure 1). [5] These precursors are typically formed by Michael addition of nitroalkanes to iminium-activated α,β-unsaturated aldehydes, or less commonly by Michael addition of enamine-activated aldehydes to β-nitrostyrenes. [2,3,[6][7][8][9] However, current examples employing organocatalysts require high catalyst loadings or suffer from low stereochemical selectivity, and therefore there is a need to develop analogous biocatalytic reactions.…”

mentioning

confidence: 99%

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A Type 1 Aldolase, NahE, Catalyzes a Stereoselective Nitro‐Michael Reaction: Synthesis of β‐Aryl‐γ‐nitrobutyric Acids

Fansher

Palmer

2022

Angewandte Chemie

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Michael addition reactions are highly useful in organic synthesis and are commonly accomplished using organocatalysts. However, the corresponding biocatalytic Michael additions are rare, typically lack synthetically useful substrate scope, and suffer from low stereoselectivity. Herein we report a biocatalytic nitro‐Michael addition, catalyzed by NahE, that proceeds with low catalyst loading at room temperature in moderate to excellent enantioselectivity and high yields. A series of β‐nitrostyrenes reacted with pyruvate in the presence of NahE to give, after oxidative decarboxylation, β‐aryl‐γ‐nitrobutyric acids in up to 99 % yield without need for chromatography, providing a simple preparative‐scale route to chiral GABA analogues. This reaction represents the first example of an aldolase displaying promiscuous Michaelase activity and opens the use of nitroalkenes in place of aldehydes as substrates for aldolases.

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Section: Methodsmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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A Type 1 Aldolase, NahE, Catalyzes a Stereoselective Nitro‐Michael Reaction: Synthesis of β‐Aryl‐γ‐nitrobutyric Acids

Fansher

Palmer

2022

Angewandte Chemie

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“…Under these conditions, the corresponding α-quaternary aldehydes 84 were obtained in good yields and usually high diastereo- and enantioselectivity. The resulting adducts could be easily converted into 4,4-disubstituted pyrrolidine-3-carboxylic acids, including gabapentin analogues, through hydrogenolysis [ 131 ].…”

Section: Methods Based On Combined Use Of α-Amino Acid Catalysts and ...mentioning

confidence: 99%

Catalytic Asymmetric α-Functionalization of α-Branched Aldehydes

et al. 2023

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Aldehydes constitute a main class of organic compounds widely applied in synthesis. As such, catalyst-controlled enantioselective α-functionalization of aldehydes has attracted great interest over the years. In this context, α-branched aldehydes are especially challenging substrates because of reactivity and selectivity issues. Firstly, the transient trisubstituted enamines and enolates resulting upon treatment with an aminocatalyst or a base, respectively, would exhibit attenuated reactivity; secondly, mixtures of E- and Z-configured enamines/enolates may be formed; and third, effective face-discrimination on such trisubstituted sp2 carbon intermediates by the incoming electrophilic reagent is not trivial. Despite these issues, in the last 15 years, several catalytic approaches for the α-functionalization of prostereogenic α-branched aldehydes that proceed in useful yields and diastereo- and enantioselectivity have been uncovered. Developments include both organocatalytic and metal-catalyzed approaches as well as dual catalysis strategies for forging new carbon–carbon and carbon–heteroatom (C-O, N, S, F, Cl, Br, …) bond formation at Cα of the starting aldehyde. In this review, some key early contributions to the field are presented, but focus is on the most recent methods, mainly covering the literature from year 2014 onward.

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“…γ-Amino acids and their cyclic derivatives (pyrrolidin-2-ones) are known to affect the central nervous system. 20 The adamantane fragment constitutes a privileged framework found in the structure of many drugs, since it increases their bioavailability. In this context, Sibiryakova et al developed in 2019 the synthesis of novel adamantylated chiral GABA derivatives on the basis of enantioselective Michael addition of diethyl malonate to 1-(adamant-1-yl)-2-nitroethene.…”

Section: Conjugate Additions To Nitroalkenesmentioning

confidence: 99%