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. 2021 Dec 1;143(47):19643-19647.
doi: 10.1021/jacs.1c09828. Epub 2021 Nov 16.

Photoenzymatic Synthesis of α-Tertiary Amines by Engineered Flavin-Dependent "Ene"-Reductases

Xin Gao  1 , Joshua R Turek-Herman  1   2 , Young Joo Choi  1 , Ryan D Cohen  3 , Todd K Hyster  1   2
Affiliations

Photoenzymatic Synthesis of α-Tertiary Amines by Engineered Flavin-Dependent "Ene"-Reductases

Xin Gao et al. J Am Chem Soc. .

Abstract

α-Tertiary amines are a common motif in pharmaceutically important molecules but are challenging to prepare using asymmetric catalysis. Here, we demonstrate engineered flavin-dependent 'ene'-reductases (EREDs) can catalyze radical additions into oximes to prepare this motif. Two different EREDs were evolved into competent catalysts for this transformation with high levels of stereoselectivity. Mechanistic studies indicate that the oxime contributes to the enzyme templated charge-transfer complex formed between the substrate and cofactor. These products can be further derivatized to prepare a variety of motifs, highlighting the versatility of ERED photoenzymatic catalysis for organic synthesis.

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Figures

Figure 1.
Figure 1.
Preparing enantioenriched α-tertiary amines
Figure 2.
Figure 2.
Optimization of Radical Addition to Oximes
Figure 3:
Figure 3:
Substrate scope a Substrate (15 mM), Enzyme (1 mol %), NADP+ (1 mol %), GDH-105 (20% w/w), Glucose (6 equiv.), KPi (100 mM, pH 7.0), 25 °C, 18 h, c ERED A = NCR D294W Y343W, ERED B = GluER-T36A-F269V-K317M-Y343F, ERED C = GluER-T36A-F269W-K317M-Y343F, c 2 mol% ERED
Figure 4.
Figure 4.
Product Derivatization
Figure 5.
Figure 5.
Mechanistic Experiments
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References

    1. Oprea TI, Property distribution of drug-related chemical databases. J. Comput.-Aided Mol. Des 2000, 14 (3), 251–264. - PubMed
    1. Meanwell NA, Improving Drug Candidates by Design: A Focus on Physicochemical Properties As a Means of Improving Compound Disposition and Safety. Chem. Res. Toxicol 2011, 24 (9), 1420–1456. - PubMed
    1. Walters WP; Murcko A; Murcko MA, Recognizing molecules with drug-like properties. Current Opinion in Chemical Biology 1999, 3 (4), 384–387. - PubMed
    1. Stereoselective Formation of Amines. Stereoselective Formation of Amines 2014, 343, 1–286. - PubMed
    1. For examples of asymmetric hydrogenation of enamines in industry see: a)Shultz CS; Dreher SD; Ikemoto N; Williams JM; Grabowski EJJ; Krska SW; Sun Y; Dormer PG; DiMichele L, Asymmetric hydrogenation of N-sulfonylated-alpha-dehydroamino acids: Toward the synthesis of an anthrax lethal factor inhibitor. Org. Lett 2005, 7 (16), 3405–3408. - PubMed
    2. Clausen AM; Dziadul B; Cappuccio KL; Kaba M; Starbuck C; Hsiao Y; Dowling TM, Identification of ammonium chloride as an effective promoter of the asymmetric hydrogenation of a beta-enamine amide. Organic Process Research & Development 2006, 10 (4), 723–726.
    3. Allwein SP; McWilliams JC; Secord EA; Mowrey DR; Nelson TD; Kress MH, Efficient synthesis of chiral phenethylamines: preparation, asymmetric hydrogenation, and mild deprotection of enetrifluoroacetamides. Tetrahedron Letters 2006, 47 (36), 6409–6412.

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