Stereoselective Synthesis of Carbohydrate-Derived N-Sulfonyl Aziridines

Abstract

A novel reaction of iodomethyllithium with a variety of sugar-derived N-sulfinyl imines, under very mild conditions, is ­described. N-Sulfonyl aziridines were easily obtained in high yields and in moderate to good stereoselectivities through an addition/­oxidation protocol. A mechanism is proposed that is ­supported by the results of X-ray diffraction studies.

Key words

aziridines - carbohydrates - imines - iodomethyllithium - sulfonamides

• References and Notes

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• 20 Synthesis of 6-Deoxy-1,2:3,4-di-O-isopropylidene-6[(4-methoxyphenyl)imino]-α-d-galactopyranose (1a): ¹⁹ N-p-Methoxyphenylimine 1a was prepared in nearly quantitative yields by stirring a solution of the corresponding aldehyde (10 mmol, 1.0 equiv) in CH₂Cl₂ with p-anisidine (10 mmol, 1.0 equiv), in the presence of MgSO₄ (2 g) for 16 h. Yield: 3.4 g (93%); orange oil; [α]_D ²⁰ +7.2 (c 0.6 in CHCl₃); R_f  = 0.62 (hexane–EtOAc, 3:1). IR (neat): 3060, 1674, 1510, 1260 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.75 (d, J = 4.0 Hz, 1 H), 7.03 (d, J = 8.6 Hz, 2 H), 6.78 (d, J = 8.6 Hz, 2 H), 5.56 (d, J = 4.9 Hz, 1 H), 4.58 (dd, J = 7.7, 2.3 Hz, 1 H), 4.45–4.22 (m, 2 H),4.28 (dd, J = 5.0, 2.4 Hz, 1 H), 3.69 (s, 3 H), 1.48 (s, 3 H), 1.39 (s, 3 H), 1.26 (s, 3 H), 1.24 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃): δ = 160.9 (CH), 158.1 (C), 143.7 (C), 121.8 (2 × CH), 113.9 (2 × CH), 109.2 (C), 108.5 (C), 96.0 (CH), 73.1 (CH), 70.3 (CH), 70.2 (CH), 55.1 (CH₃), 53.2 (CH), 25.8 (CH₃), 25.7 (CH₃), 24.6 (CH₃), 24.0 (CH₃); MS (ESI⁺): m/z (%) = 364 (100) [M + H]⁺, 338 (7), 322 (30), 306 (4); HRMS (ESI⁺-TOF): m/z [M + H]⁺ calcd for C₁₉H₂₆NO₆: 364.1760; found: 364.1755.
• 21 Synthesis of N-tert-Butylsulfinyl Imines 2: To a solution of the corresponding aldehyde (0.5 mmol, 1 equiv) in anhydrous CH₂Cl₂ (10 mL), [Ti(OEt)₄] (2 mmol, 4 equiv) was added slowly by using a syringe. N-tert-Butanesulfinamide (0.5 mmol, 1 equiv) was added in one portion and the reaction mixture was stirred at r.t. for16 h. The excess [Ti(OEt)₄] was decomposed by slow addition of the reaction mixture to a solution of brine. The resulting suspension was filtered through a pad of Celite, washed with ethyl acetate, the organic layer was separated, and the aqueous phase was extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under vacuum to yield crude N-tert-butylsulfinyl imines 2 without further purification. 6-Deoxy-6-(N-tert-butylsulfinyl)imino-1,2:3,4-di-O-isopropylidene-α-d-galactopyranose (2a): Yield: 155.8 mg (86%); yellow oil; R _f  = 0.36, 0.33 (hexane–EtOAc, 3:1). IR (neat): 3051, 1633, 1458, 1071, 735, 702 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 8.00 (d, J = 2.7 Hz, 1 H), 5.62 (d, J = 4.9 Hz, 1 H), 4.64 (dd, J = 7.8, 2.4 Hz, 1 H), 4.60 (app. t, J = 2.7 Hz, 1 H), 4.49 (dd, J = 7.8, 2.4 Hz, 1 H), 4.35 (dd, J = 4.9, 2.4 Hz, 1 H), 1.52 (s, 3 H), 1.39 (s, 3 H), 1.33 (s, 3 H), 1.28 (s, 3 H), 1.20 (s, 9 H); δ (minor isomer) = 8.00 (d, J = 2.6 Hz, 1 H), 5.65 (d, J = 5.2 Hz, 1 H), 4.64 (dd, J = 7.7, 2.4 Hz, 1 H), 4.56 (dd, J = 7.6, 2.6 Hz, 1 H), 4.40–4.37 (m, 1 H), 4.31–4.20 (m, 1 H), 1.43 (s, 3 H), 1.32 (s, 3 H), 1.29 (s, 3 H), 1.28 (s, 3 H), 1.20 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃): δ = 167.1 (CH), 109.6 (C), 109.4 (C), 96.1 (CH), 72.6 (CH), 70.4 (2 × CH), 70.2 (CH), 57.2 (C), 25.9 (CH₃), 25.6 (CH₃), 24.6 (CH₃), 24.1 (CH₃), 22.2 (3 × CH₃); δ (minor isomer) = 165.2 (CH), 109.8 (C), 109.7 (C), 96.1 (CH), 71.9 (CH), 70.4 (2 × CH), 70.1 (CH), 57.1 (C), 25.9 (CH₃), 25.6 (CH₃), 24.6 (CH₃), 24.1 (CH₃), 22.3 (3 × CH₃); MS (ESI⁺): m/z (%) = 400 (5) [M + K]⁺, 386 (9) [M + 2 + Na]⁺, 385 (20) [M + 1 + Na]⁺, 384 (100) [M +Na]⁺; HRMS (ESI⁺-TOF): m/z [M + Na]⁺ calcd for C₁₆H₂₇NO₆SNa: 384.1457; found: 384.1462.
• 22 Synthesis of N-Sulfonyl Aziridines 3: To a mixture of the corresponding N-sulfinyl mine 2 (0.4 mmol, 1 equiv) and CH₂I₂ (0.6 mmol, 1.5 equiv) in anhydrous THF (2 mL), was added a solution of MeLi (1.5 M in Et₂O, 0.48 mmol, 1.2 equiv) at –78 °C. The solution was stirred at –78 °C for 30 min, and then allowed to warm to r.t. and stirred for an additional 30 min. The reaction was then quenched with aq. NH₄Cl and the organic layer was extracted with Et₂O (3 × 10 mL). The combined extracts were dried with Na₂SO₄ and concentrated under vacuum to yield crude N-sulfinyl aziridines. Finally, to a solution of the corresponding sulfinyl aziridine in CH₂Cl₂ (1 mL), anhydrous MCPBA (0.4 mmol, 1 equiv) was added at r.t. in one portion. When the reaction was complete (less than 1 min), the reaction was diluted with CH₂Cl₂ (2 mL) and washed with sat. NaHCO₃ (3 × 3 mL). Organic layers were dried over anhydrous Na₂SO₄ and the solvents were evaporated, giving the corresponding N-sulfonyl aziridines 3, which were purified by flash chromatography on silica gel (hexane–EtOAc, 3:1). 6,7-Deoxy-6,7-(N-tert-butylsulfinyl)imino-1,2:3,4-di-O-isopropylidene-d-glycero-α-d-galacto-heptapyranose (3a): Yield: 135.1 mg (86%); white solid; m.p. 84–85 °C (Et₂O–hexane); [α]_D ²⁰ –9.2 (c 1.0, CHCl₃); R _f  = 0.30 (hexane–EtOAc, 3:1). IR (neat): 1640, 1458, 1308, 1067, 724 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 5.50 (d, J = 4.9 Hz, 1 H), 4.61 (dd, J = 7.9, 2.4 Hz, 1 H), 4.33 (dd, J = 7.9, 1.5 Hz, 1 H), 4.30 (dd, J = 4.9, 2.4 Hz, 1 H), 3.63 (dd, J = 5.2, 1.5 Hz, 1 H), 3.09 (dt, J = 6.9, 5.2 Hz, 1 H), 2.64 (d, J = 6.9 Hz, 1 H), 2.33 (d, J = 5.2 Hz, 1 H), 1.49 (s, 9 H), 1.47 (s, 3 H), 1.44 (s, 3 H), 1.34 (s, 3 H), 1.32 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃): δ = 109.3 (C), 108.4 (C), 96.0 (CH), 71.4 (CH), 70.3 (2 × CH), 67.0 (CH), 59.1 (C), 37.0 (CH), 31.2 (CH₂), 25.8 (CH₃), 25.7 (CH₃), 24.6 (CH₃), 24.1 (CH₃), 23.9 (3 × CH₃); MS (ESI⁺): m/z (%) = 430 (18) [M + K]⁺, 416 (14) [M + 2 + Na]⁺, 415 (32) [M + 1 + Na]⁺, 414 (100) [M + Na]⁺; HRMS (ESI⁺-TOF): m/z [M + Na]⁺ calcd for C₁₇H₂₉NO₇NaS: 414.1562; found: 414.1558.
• 23 CCDC 900247 contains the supplementary crystallographic data for compound 3d. This data can be obtained free of charge via: www.ccdc.cam.ac.uk/conts/retrieving.html [or the Cambridge Data Center, 12 Union Road, Cambridge CB2 1EZ, UK; fax [phone]; or [e-mail]].
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