Sulfonyl as a Traceless Activation Group for Enantioselective Mannich Reaction Catalyzed by Thiourea to Access Chiral β-Aminophosphonates

◊ These authors contributed equally

Abstract

An efficient enantioselective Mannich reaction of N-protected α-sulfones with β-benzenesulfonyl phosphonates was developed by using a chiral cinchona alkaloid-derived thiourea as a catalyst. This method was used to obtain a series of chiral α-sulfonyl-β-aminophosphonates in yields of up to 96% with 89:11 dr and 88% ee. These compounds were further transformed into β-aminophosphonates or chiral azetidines with various functional groups by a Horner–Wadsworth–Emmons/aza-Michael addition reaction sequence.

Key words

amidosulfones - aminophosphonates - asymmetric synthesis - Mannich Reaction - thioureas - organocatalysis

• References and Notes

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• 11 Mannich Products 4 and Aminophosphonates 5; General Procedure The N-protected α-amido sulfone 1 (0.12 mmol, 1.2 equiv), 3e (10 mol%), and LiOH·H₂O (0.14 mmol, 1.4 equiv) were dissolved in toluene (1.0 mL) at –20 °C, and the mixture was stirred for 5 min. β-Benzenesulfonyl phosphate 2 (0.1 mmol, 1.0 equiv) was added at –20 °C, and the mixture was stirred for 72 h. The reaction was quenched with sat. aq NH₄Cl, and the aqueous layer was extracted with EtOAc (3 × 30 mL). The organic phases were combined, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product 4 was purified by chromatography [silica gel, EtOAc–PE]. 1,2-Dibromoethane (50 µL) was added to a mixture of product 4 and Mg turnings (30 equiv) in anhyd MeOH (0.1 mmol/mL) at 0 °C, and the mixture was stirred at r.t. for 11 h. The reaction was then quenched with sat. aq NH₄Cl and the mixture was filtered. The aqueous layer was extracted with EtOAc. The organic phases were combined, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was then purified by chromatography [silica gel, EtOAc–PE]. Diethyl ((2S)-2-Phenyl-2-{[(1,1,2-trimethylpropoxy)carbonyl]-­amino}ethyl)phosphonate (5ba) Prepared from 4ba (32 mg, 0.060 mmol), Mg turnings (44 mg, 1.80 mmol), and 1,2-dibromoethane (50 µL), as described above, as a colorless oil; yield: 19 mg (81%), [α]_D ²⁵ + 13.7 (c = 0.38, CH₂Cl₂). HPLC: Chiralpak ID column [hexane–i-PrOH (80:20), flow rate: 0.5 mL/min, λ = 254 nm]: t _minor = 25.6 min, t _major = 29.8 min. ¹H NMR (600 MHz, CDCl₃): δ = 7.31 (s, 4 H), 7.24 (s, 1 H), 5.81 (s, 1 H), 5.03 (s, 1 H), 4.03 (s, 2 H), 3.85 (d, J = 54.0 Hz, 2 H), 2.42–2.13 (m, 3 H), 1.35 (s, 6 H), 1.28 (t, J = 6.0 Hz, 3 H), 1.14 (s, 3 H), 0.93–0.73 (m, 6 H). ¹³C NMR (151 MHz, CDCl₃): δ = 154.9, 142.3, 128.5, 127.3, 126.0, 84.8, 61.8 (d, J = 7.5 Hz), 61.6 (d, J = 6.0 Hz), 50.3, 36.2, 33.2 (d, J = 140.4 Hz), 23.1, 23.0, 17.3, 16.3 (d, J = 6.0 Hz), 16.2 (d, J = 6.0 Hz). HRMS (ESI): m/z [M + Na]⁺ Calcd for C₁₉H₃₂NNaO₅P: 408.1916; found: 408.1918.