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. 2018 Aug 27;9(42):8094-8098.
doi: 10.1039/c8sc02948b. eCollection 2018 Nov 14.

Catalytic enantioselective radical coupling of activated ketones with N-aryl glycines

Yang Liu  1 , Xiangyuan Liu  1 , Jiangtao Li  1 , Xiaowei Zhao  1 , Baokun Qiao  1 , Zhiyong Jiang  1   2
Affiliations

Catalytic enantioselective radical coupling of activated ketones with N-aryl glycines

Yang Liu et al. Chem Sci. .

Abstract

Asymmetric H-bonding catalysis as a viable strategy for enantioselective radical coupling of ketones is demonstrated. With a visible-light-mediated dual catalytic system involving a dicyanopyrazine-derived chromophore (DPZ) photosensitizer and a chiral phosphoric acid (CPA), N-aryl glycines with a variety of 1,2-diketones and isatins underwent a redox-neutral radical coupling process and furnished two series of valuable chiral 1,2-amino tertiary alcohols in high yields with good to excellent enantioselectivities (up to 97% ee). In this catalysis platform, the formation of neutral radical intermediates between ketyl and H-bonding catalyst CPA is responsible for presenting stereocontrolling factors. Its success in this work should provide inspiration for expansion to other readily accessible ketones to react with various radical species, thus leading to a productive approach to access chiral tertiary alcohol derivatives.

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Figures

Scheme 1
Scheme 1. Outline of this work.
Scheme 2
Scheme 2. Design plan based on mechanistic considerations.
Scheme 3
Scheme 3. Reactions of N-aryl glycines with 1,2-diketones. Reaction conditions: 1 (0.15 mmol), 2 (0.1 mmol), DPZ (1.5 mol%), C1 (10 mol%), TBPB (30 mol%), Na2S2O4 (0.5 equiv.), 5 Å MS (50 mg), degassed CPME (2.0 mL), 10 °C, irradiation with a blue LED (3 W, 450 nm), 36 h. The yield amount was isolated by flash column chromatography on a silica gel. ee was determined by HPLC analysis on a chiral stationary phase. aOn a 1.0 mmol scale, 48 h, yield of 3a = 87%, ee of 3a = 93%. bThe ee value was obtained after a single recrystallization. Initial data: 85% ee. cReaction conditions: 1 (0.15 mmol), 2 (0.1 mmol), DPZ (1.5 mol%), C2 (10 mol%), 4 Å MS (50 mg), degassed CPME (2.0 mL), –5 °C, 36 h. Under the previous reaction conditions, ee = 34%.
Scheme 4
Scheme 4. Reactions of N-aryl glycine with isatins. +Reaction conditions: 1h (0.15 mmol), 4 (0.1 mmol), DPZ (1.0 mol%), C1 (20 mol%), degassed THF (2.0 mL), 10 °C, irradiation with a blue LED (3 W, 450 nm), 36 h. The yield amount was isolated by flash column chromatography on silica gel. ee was determined by HPLC analysis on a chiral stationary phase.
Scheme 5
Scheme 5. Synthetic applications. (a) TCCA (0.5 equiv.), H2SO4 (1 M, aq., 2.0 equiv.), CH3CN/H2O = 1 : 1, 16 h. (b) HCHO (2.0 equiv.), OHC–CHO (2.0 equiv.), NH4OAc (2.0 equiv.), MeOH, 80 °C, 5 h, 65% yield, 92% ee. (c) (Boc)2O (1.1 equiv.), DMAP (0.2 equiv.), DCM, 0 °C, 0.5 h, 98% yield, 91% ee. (d) TCCA (0.5 equiv.), H2SO4 (1 M, aq., 2.0 equiv.), CH3CN/H2O = 1 : 1, 16 h. (e) TsCl (2.0 equiv.), Et3N (2.0 equiv.), EtOAc, 0 °C to r.t., 5 h, 72% yield in two steps, 91% ee. PMP = para-methoxyphenyl; TCCA = N,N′,N′′-trichloroisocyanuric acid; (Boc)2O = di-tert-butyl dicarbonate; Boc = tert-butyl carbonate; DMAP = 4-dimethylaminopyridine; TsCl = p-toluenesulfonyl chloride; Ts = tosyl.
Scheme 6
Scheme 6. Transformation of 10 and 2a.
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