Thioimidate N-Oxides: From Nature to Synthetic Pathways

Abstract

Inspired by the unexpected reactivity of desulfated naturally occurring glucoraphenin, methods to synthesize thioimidate N-oxides (TIO) have been devised on simple or carbohydrate templates. Either through halocyclization or under Mitsunobu conditions, the starting thiohydroximates cyclized to generate efficiently the corresponding TIO.

carbohydrates - cyclization - heterocycles - azasugars - thio function

References and Notes

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Preparation of the Thiohydroximate 19
NCS (0.88 g, 6.6 mmol) was added to a solution of aldoxime 18 (1.75 g, 6 mmol) in DMF (5 mL), and the mixture was left at r.t. for 4 h. After cooling to -78 °C, ethanethiol (1.33 mL, 18 mmol) then Et₃N (2.5 mL, 18 mmol) were added dropwise. The reaction mixture was slowly allowed to reach r.t. and stirred for a further 12 h. After hydrolysis (H₂O, 100 mL) and extraction with CH₂Cl₂ (3 ¥ 100 mL), the combined organic phases were washed with brine (3 ¥ 50 mL), dried over MgSO₄, filtered, and then evaporated. Purification of the residue over silica gel (PE-EtOAc, 7:3) afforded the 4-O-silylated derivative of 24 as an oil. This intermediate was dissolved in THF (20 mL) and reacted with TBAT (1.2 equiv) at r.t. for 14 h. H₂O (20 mL) was then added and the mixture was extracted with CH₂Cl₂ (3 ¥ 30 mL). The combined organic phases were washed with brine, dried over MgSO₄, then evaporated under reduced pressure. S-Ethyl 2,3-O-isopropylidene-l-erythronimidothioate (19) was isolated as a colorless solid (1.2 g, 84% yield) by silica gel flash chromatography (PE-EtOAc, 1:1). Mp 40-41 °C; R _f  = 0.18 (PE-EtOAc, 1:1); [a]_D ^²0 -54 (c 1.0, CHCl₃). IR (KBr): 3356, 2992, 1688, 1451, 1375, 1269, 1223, 1208, 1056, 998, 895, 859, 806, 740 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): d = 1.33 (t, 3 H, J = 7.6 Hz, CH₃CH₂), 1.40 and 1.53 [2 s, 6 H, C(CH₃)₂], 3.11 (m, 2 H, CH₃CH₂), 3.68 (m, 1 H, H-4b), 3.79 (m, 1 H, H-4a), 4.40 (dd, 1 H, J _2,3 = 6.0 Hz, J _3,4 = 4.4 Hz, H-3), 4.89 (d, 1 H, J _2,3 = 6.0 Hz, H-2), 9.40 (s, 1 H, NOH). ^¹³C NMR (100 MHz, CDCl₃) : d = 15.1 (CH₃CH₂), 25.6 (CH₃CH₂), 25.4, 27.3 [C(CH₃)₂], 61.7 (C-4), 76.9 (C-2), 78.6 (C-3), 109.5 (C(CH₃)₂), 150.8 (C=N). MS (IS): m/z = 236.0 [M + H]⁺. ESI-HRMS: m/z [M + H]⁺ calcd for C₉H₁₈NO₄S: 236.0957; found: 236.0968.

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Preparation of the Thioimidate N -Oxide 21
Ph₃P (55 mg, 0.21 mmol) was added to a solution of DEAD (40% in toluene, 95 mL, 0.21 mmol) in THF (10 mL). After 10 min of stirring, the thiohydroximate 19 (50 mg, 0.21 mmol) was added, and the reaction mixture was kept at reflux overnight. After hydrolysis (H₂O, 20 mL) and extraction with CH₂Cl₂ (3 ¥ 30 mL), the combined organic phases were dried over MgSO₄, filtered, and then evaporated. (3S,4S)-2-Ethylsulfanyl-3,4-isopropylidene-dioxy-3,4-dihydro-5H-pyrrole-1-oxide (21) was isolated as a colorless solid (45 mg, 98% yield) after silica gel flash chromatography (EtOAc). Mp 145-150 °C; R _f  = 0.5 (EtOAc); [a]_D ^²0 -136.5 (c 1.0, MeOH). IR (neat): 1570, 1422, 1383, 1261, 1234, 1204, 1154, 1076, 1021, 864, 836, 706, 663 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): d = 1.37 (t, 3 H, J = 7.6 Hz, CH₃CH₂), 1.39 and 1.44 [2 s, 6 H, C(CH₃)₂], 3.13 (q, 2 H, J = 7.6 Hz, CH₃CH₂), 4.06 (dt, 1 H, ^² J _5b,5a = 14.7 Hz, J _5b,4 = ⁵ J _5b,3 = 1.2 Hz, H-5b), 4.13 (dd, 1 H, ^² J _5b,5a = 14.7 Hz, J _5a,4 = 5.3 Hz, H-5a), 4.90 (ddd, 1 H, J _4,3 = 6.5 Hz, J _4,5a = 5.3 Hz, J _4,5b = 1.4 Hz, H-4), 5.34 (d, 1 H, J _4,3 = 6.5 Hz, H-3). ^¹³C NMR (100 MHz, CDCl₃): d = 15.6 (CH₃CH₂), 23.4 (CH₃CH₂), 26.0, 27.2 [C(CH₃)₂], 66.4 (C-5), 73,1 (C-4), 81.7 (C-3); 112.8 [C(CH₃)₂], 144.0 (C-2). MS (IS): m/z = 218.0 [M + H]⁺. ESI-HRMS: m/z [M + H]⁺ calcd for C₉H₁₆NO₃S: 218.0851; found: 218.0841.

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