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. 2024 Mar 16;29(6):1328.
doi: 10.3390/molecules29061328.

Chemoenzymatic Synthesis of Selegiline: An Imine Reductase-Catalyzed Approach

Yuliang Hu  1   2 , Jinping Bao  2 , Dongyu Tang  2 , Shushan Gao  2   3 , Fei Wang  1 , Zhongtao Ding  1   2 , Chengsen Cui  2   3
Affiliations

Chemoenzymatic Synthesis of Selegiline: An Imine Reductase-Catalyzed Approach

Yuliang Hu et al. Molecules. .

Abstract

(R)-Homobenzylic amines are key structural motifs present in (R)-selegiline, a drug indicated for the treatment of early-stage Parkinson's disease. Herein, we report a new short chemoenzymatic approach (in 2 steps) towards the synthesis of (R)-selegiline via stereoselective biocatalytic reductive amination as the key step. The imine reductase IR36-M5 mutant showed high conversion (97%) and stereoselectivity (97%) toward the phenylacetone and propargyl amine substrates, offering valuable biocatalysts for synthesizing alkylated homobenzylic amines.

Keywords: chemoenzymatic synthesis; homobenzylic amine; imine reductase; reductive amination; semi-rational design.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
(R)-selegiline and related drug molecules.
Figure 2
Figure 2
Prior synthesis and our synthetic strategy, 2014 [17], 2015 [18], 2021 [19].
Figure 3
Figure 3
Our previous work on IR36-M5 catalyzed reactions towards cyclic substrates and proposed linear substrates.
Figure 4
Figure 4
Docking the intermediate of reductive amination of 1 and a into the M5 (PDB: 7WNW) active cavity.
Figure 5
Figure 5
Enantioselectivity of M5 and its mutants in the reductive amination of 1 and a; (A–D) Enantioselectivity of M5 and its mutants at sites 203, 260, 264, and 268, respectively. * ee values were not determined because the mutants were almost inactive.
Scheme 1
Scheme 1
Chemoenzymatic synthesis of (R)-selegiline via IRED-catalyzed reductive amination.
Scheme 2
Scheme 2
Synthesis of (R)-selegiline from 1a through reductive amination with formaldehyde.
See this image and copyright information in PMC

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