Selective Formation of 1,3-Oxazolidine-2-thiones on Ketohexose Templates

Abstract

Thiocyanic acid condensation on selectively protected ketohexose led to the isolation of five out of the seven possible 1,3-oxazolidine-2-thiones (OZT). The four isomeric spiro-OZT synthesized showed promising biological activity against d-fructose transport.

carbohydrates - bicyclic compounds - spiro compounds - d-fructose - 1,3-oxazolidine-2-thione

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12

General Protocol for the Formation of 23 and 24: 1,2-O-Isopropylidene-3,4-di-O-benzyl-β-d-fructopyranose 20 (1.1 g, 2.75 mmol) was dissolved in a cooled solution of TFA-H₂O (3:2) and stirred at r.t. overnight. The crude solution was evaporated and co-evaporated with toluene (3 times); the residue was suspended in H₂O containing KSCN (670 mg, 6.87 mmol) and 37% HCl (0.57 mL) was added. The resulting solution was heated for 3 d at 50 °C, then cooled and extracted with EtOAc (3 times). The organic phases were collected and washed with NaHCO₃ until neutral, then with brine and dried over MgSO₄. The residue obtained after evaporation was purified on column chromatography using petroleum ether-EtOAc (1:1 mixture). Spiro-furano OZT 22 (410 mg, 1.02 mmol, 37% yield) was isolated as the first fraction then spiro-pyrano OZT 21 (250 mg, 0.62 mmol, 22% yield). Each fraction was acetylated (Ac₂O 2 mL, pyridine 5 mL, 24 h); after co-evaporation with toluene, the residue was purified on column chromatography using petroleum ether-EtOAc mixtures (8:2 for furano OZT and 7:3 for pyrano OZT). Spiro-furano OZT 23α (155 mg, 0.32 mmol, 37% yield) and then 23β (150 mg, 0.31 mmol, 35% yield) was isolated. Spiro-furano OZT 23α: [α]_D ²⁵ +134.0 (c 1.0, CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 1.99 (s, 3 H, OAc), 2.70 (s, 3 H, NAc), 3.86 (dd, 1 H, J _3,4 = 8.0 Hz, J _4,5 = 9.1 Hz, H-4), 3.95 (dd, 1 H, J _5,6b = 4.4 Hz, J _6a,6b = 12.5 Hz, H-6b), 4.14 (d, 1 H, J _1a,1b = 10.0 Hz, H-1b), 4.22 (dd, 1 H, J _5,6a = 2.3 Hz, H-6a), 4.46 (ddd, 1 H, H-5), 4.50 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.63 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.63 (d, 1 H, J = 11.7 Hz, CH₂Ph), 4.73 (d, 1 H, J = 11.7 Hz, CH₂Ph), 4.94 (d, 1 H, H-1a), 5.09 (d, 1 H, H-3), 7.23-7.38 (m, 10 H, H-Ar). ¹³C NMR (62.5 MHz, CDCl₃): δ = 20.7 (OAc), 28.0 (NAc), 62.9 (C-6), 72.9 (CH₂Ph), 73.6 (C-1), 74.0 (CH₂Ph), 78.0 (C-5), 80.9 (C-4), 83.3 (C-3), 100.5 (C-2), 127.9, 128.2, 128.4, 128.6, 128.7, 128.9, 136.6, 137.4 (C-Ar), 170.4 (CO), 172.1 (CO), 185.7 (CS). MS (IS+): m/z = 508.0 [M + Na]⁺, 486 [M + H]⁺, 466.0 [M - Ac + Na]⁺. Anal. Calcd for C₂₅H₂₇NO₇S: C, 61.84; H, 5.61; N, 2.89. Found: C, 61.61; H, 5.59; N, 2.88. Spiro-furano OZT 23β: [α]_D ²⁵ +7.0 (c 1.2, CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 2.07 (s, 3 H, OAc), 2.75 (s, 3 H, NAc), 4.05 (d, 1 H, J _1a,1b = 10.1 Hz, H-1b), 4.11 (ddd, 1 H, J _4,5 = 7.5 Hz, J _5,6a = 3.4 Hz, J _5,6b = 7.6 Hz, H-5), 4.20 (d, 1 H, J _3,4 = 6.5 Hz, H-3), 4.31 (dd, 1 H, J _6a,6b = 11.8 Hz, H-6b), 4.41 (d, 1 H, H-1a), 4.43 (dd, 1 H, H-6a), 4.53 (dd, 1 H, H-4), 4.55 (d, 1 H, J = 11.7 Hz, CH₂Ph), 4.60 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.66 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.68 (d, 1 H, J = 11.7 Hz, CH₂Ph), 7.21-7.40 (m, 10 H, H-Ar). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.0 (OAc), 27.6 (NAc), 65.1 (C-6), 73.2 (CH₂Ph), 73.6 (CH₂Ph), 77.6 (C-1), 80.9 (C-5), 84.2 (C-4), 87.1 (C-3), 99.5 (C-2), 127.8, 128.2, 128.3, 128.7, 128.9, 136.6, 137.5 (C-Ar), 171.0 (CO), 172.7 (CO), 186.4 (CS). MS (IS+): m/z = 508.0 [M + Na]⁺, 466.0 [M - Ac + Na]⁺. Anal. Calcd for C₂₅H₂₇NO₇S: C, 61.84; H, 5.61; N, 2.89. Found: C, 61.48; H, 5.81; N, 2.63.
Spiro-pyrano OZT 24β (50 mg, 0.10 mmol, 27% yield) and then 24α (75 mg, 0.15 mmol, 41% yield) were also isolated. Spiro-pyrano OZT 24β: [α]_D ²⁵ -98 (c 1.0, CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 2.12 (OAc), 2.68 (NAc), 3.76 (d, 1 H, J _3,4 = 8.8 Hz, H-3), 3.90 (dd, 1 H, J _5,6b = 2.6 Hz, J _6a,6b = 12.7 Hz, H-6b), 4.06 (d, 1 H, J _1a,1b = 9.6 Hz, H-1b), 4.38 (d, 1 H, H-1a), 4.41 (dd, 1 H, J _5,6a = 1.3 Hz, H-6a), 4.42 (dd, 1 H, J _4,5 = 3.9 Hz, H-4), 4.49 (d, 1 H, J = 10.6 Hz, CH₂Ph), 4.60 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.69 (d, 1 H, J = 10.6 Hz, CH₂Ph), 4.92 (d, 1 H, J = 10.6 Hz, CH₂Ph), 5.51 (m, 1 H, H-5), 7.16-7.37 (m, 10 H, H-Ar). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.2 (OAc), 28.0 (NAc), 66.1 (C-6), 67.3 (C-5), 71.8 (CH₂Ph), 75.6 (C-3), 77.1 (C-4), 78.5 (C-1), 97.7 (C-2), 127.8, 128.1, 128.3, 128.6, 128.7, 137.3, 137.5 (C-Ar), 170.4 (CO), 174.7 (CO), 187.9 (CS). MS (IS+): m/z = 508.0 [M + Na]⁺, 466.0 [M - Ac + Na]⁺, 444.0 [M - Ac + H]⁺. Anal. Calcd for C₂₅H₂₇NO₇S: C, 61.84; H, 5.61; N, 2.89. Found: C, 61.68; H, 5.48; N, 2.85. Spiro-pyrano OZT 24α: [α]_D ²⁵ +45.0 (c 1.2, CHCl₃). ¹H NMR (250 MHz, CDCl₃): δ = 2.23 (s, 3 H, OAc), 2.65 (s, 3 H, NAc), 3.45 (dd, 1 H, J _4,3 = 10.2 Hz, J _4,5 = 2.1 Hz, H-4), 3.57 (dd, 1 H, J _5,6b = 1.3 Hz, J _6a,6b = 14.0 Hz, H-6b), 4.04 (dd, 1 H, J _5,6a = 1.3 Hz, H-6a), 4.38 (d, 1 H, J _1a,1b = 9.3 Hz, H-1b), 4.54 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.59 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.73 (d, 1 H, J = 11.4 Hz, CH₂Ph), 4.76 (d, 1 H, H-1a), 4.85 (d, 1 H, J = 11.4 Hz, CH₂Ph), 5.06 (d, 1 H, H-3), 5.34 (m, 1 H, H-5), 7.21-7.33 (m, 10 H, H-Ar). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.2 (OAc), 28.1 (NAc), 64.0 (C-6), 66.9 (C-5), 70.6 (C-1), 72.0 (CH₂Ph), 73.6 (C-3), 75.7 (CH₂Ph), 78.2 (C-4), 97.3 (C-2), 127.9, 128.1, 128.2, 128.6, 137.3, 137.6 (C-Ar), 170.7 (CO), 172.0 (CO), 186.7 (CS). MS (IS+): m/z = 508.0 [M + Na]⁺, 466.0 [M - Ac + Na]⁺, 444.0 [M - Ac + H]⁺. Anal. Calcd for C₂₅H₂₇NO₇S: C, 61.84; H, 5.60; N, 2.88. Found: C, 61.72; H, 5.57; N, 2.88.