Asymmetric Michael Addition in Synthesis of β-Substituted GABA Derivatives

Abstract

γ-Aminobutyric acid (GABA) represents one of the most prolific structural units widely used in the design of modern pharmaceuticals. For example, β-substituted GABA derivatives are found in numerous neurological drugs, such as baclofen, phenibut, tolibut, pregabalin, phenylpiracetam, brivaracetam, and rolipram, to mention just a few. In this review, we critically discuss the literature data reported on the preparation of substituted GABA derivatives using the Michael addition reaction as a key synthetic transformation. Special attention is paid to asymmetric methods featuring synthetically useful stereochemical outcomes and operational simplicity.

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

“…[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.…”

“…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] …”

“…[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.…”

Catalytic Asymmetric α-Functionalization of α-Branched Aldehydes

“…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 ].…”

Recent developments in enantioselective nickel(ii)-catalyzed conjugate additions

“…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.…”