A Convenient Route to Peracetylated 3-Deoxy-3-fluoro Analogues of d-Glucosamine and d-Galactosamine from a Černý Epoxide

Abstract

Peracetylated 3-deoxy-3-fluoro analogues of d-glucosamine and d-galactosamine 3 and 4, respectively, were prepared from 1,6:2,3-dianhydro-4-O-benzyl-β-d-mannopyranose (6). Azidolysis of 6 followed by reaction with diethylaminosulfur trifluoride gave 1,6-anhydro-2-azido-4-O-benzyl-2,3-dideoxy-3-fluoro-β-d-glucopyranose (9). Cleavage of the internal acetal, hydrogenation and acetylation yielded 3. De-O-benzylation of 9 followed by a configurational inversion at C4 gave 1,6-anhydro-2-azido-2,3-dideoxy-3-fluoro-β-d-galactopyranose (18), which provided 4 after cleavage of the 1,6-anhydro bridge, reduction, and acetylation.

Key words

carbohydrates - fluorine - antitumor agents - nucleophilic fluorination - amino sugars

• References and Notes

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• 12 Compound 3 was formed as an anomeric mixture (α/β = 83:12; estimated by ¹⁹F NMR of the crude product). The anomers were separated and purified chromatographically in an i-PrOH–CHCl₃–petroleum ether (2:5:5) solvent mixture yielding 322 mg (64%) of the α-anomer and 40 mg (12%) of the β-anomer. Analytical data for the α-anomer: mp 132–134 °C (EtOAc–heptane); [α]_D +81 (0.12, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 2.02 (s, 3 H, NHCOCH ₃), 2.08 (s, 3 H, COCH₃), 2.10 (s, 3 H, COCH₃), 2.16 (s, 3 H, COCH₃), 3.97 (m, 1 H, H-5), 4.11 (ddd, ² J _6en,6ex = 12.5 Hz, ³ J _6en,5 = 2.0 Hz, ⁵ J _6en,F = 2.0 Hz, 1 H, H-6en), 4.29 (dd, ² J _6en,6ex = 12.5 Hz, ³ J _6ex,5 = 4.2 Hz, 1 H, H-6ex), 4.62 (ddd, overlap with H-3, ² J _3,F = 55.8 Hz, ³ J _3,2 = 10.2 Hz, 1 H, H-2), 4.65 (ddd, overlap with H-2, ³ J _3,2 = 10.2 Hz, ³ J _4,3 = 8.6 Hz, 1 H, H-3), 5.33 (ddd, ³ J _4,F = 12.5 Hz, ³ J _4,5 = 10.3 Hz, ³ J _4,3 = 8.6 Hz, 1 H, H-4), 5.52 (d, ² J _2,NH = 8.1 Hz, 1 H, NH), 6.20 (dd, ³ J _2,1 = 3.6 Hz, ⁴ J _1,F = 3.6 Hz, 1 H, H-1). ¹³C NMR (75 MHz, CDCl₃): δ = 20.30 (s, COCH₃), 20.33 (s, COCH₃), 20.50 (s, COCH₃), 22.80 (s, NHCOCH₃), 50.73 (d, ² J _C,F = 18.0 Hz, C-2), 61.24 (s, C-6), 68.04 (d, ² J _C,F = 18.4 Hz, C-4), 69.46 (d, ³ J _C,F = 6.8 Hz, C-5), 89.64 (d, ¹ J _C,F = 189.9 Hz, C-3), 91.05 (d, ³ J _C,F = 9.2 Hz, C-1), 168.92 (s, COCH₃), 169.57 (s, COCH₃), 170.62 (s, COCH₃), 171.24 (s, COCH₃). ¹⁹F NMR (282 MHz, CDCl₃): δ = –199.77 (m). Anal. Calcd for C₁₄H₂₀FNO₈: C, 48.1; H, 5.8; N, 4.0. Found: C, 48.0; H, 5.7; N, 3.9. Analytical data for the β-anomer: mp 172–174 °C (EtOAc–heptane); [α]_D +5 (c 0.18, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 2.00 (s, 3 H, NHCOCH ₃), 2.08 (s, 3 H, COCH₃), 2.10 (s, 3 H, COCH₃), 2.12 (s, 3 H, COCH₃), 3.77 (m, 1 H, H-5), 3.88 (m, 1 H, H-2), 4.11 (ddd, ² J _6ex,6en = 12.5 Hz, ³ J _6en,5 = 2.0 Hz, ⁵ J _6en,F = 1.5 Hz, 1 H, H-6en), 4.27 (dd, ² J _6en,6ex = 12.5 Hz, ³ J _6ex,5 = 4.5 Hz, 1 H, H-6ex), 4.90 (ddd, ² J _3,F = 50.9 Hz, ³ J _3,2 = 10.0 Hz, ³ J _4,3 = 8.8 Hz, 1 H, H-3), 5.18 (ddd, ³ J _4,F = 12.5 Hz, ³ J _4,5 = 10.0 Hz, ³ J _4,3 = 8.8 Hz, 1 H, H-4), 5.68 (d, ² J _2,NH = 8.3 Hz, 1 H, NH), 5.99 (d, ³ J _2,1 = 8.6 Hz, 1 H, H-1). ¹³C NMR (75 MHz, CDCl₃): δ = 20.34 (s, COCH₃), 20.38 (s, COCH₃), 20.52 (s, COCH₃), 23.05 (s, NHCOCH₃), 54.73 (d, ² J _C,F = 18.5 Hz, C-2), 61.40 (s, C-6), 68.26 (d, ² J _C,F = 18.8 Hz, C-4), 71.74 (d, ³ J _C,F = 8.0 Hz, C-5), 90.23 (d, ¹ J _C,F = 188.9 Hz, C-3), 91.07 (d, ³ J _C,F = 10.1 Hz, C-1), 169.70 (s, COCH₃), 169.85 (s, COCH₃), 171.07 (s, COCH₃), 171.22 (s, COCH₃). ¹⁹F NMR (282 MHz, CDCl₃): δ = –194.24 (dt, ² J _H3,F = 50.9 Hz, ³ J _H4,F = 12.5 Hz, ³ J _H2,F = 12.4 Hz). Anal. Calcd for C₁₄H₂₀FNO₈: C, 48.1; H, 5.8; N, 4.0. Found: C, 47.7; H, 5.8; N, 3.8.
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• 18 Preparation of Compounds 17 and 18 from 9: A solution of NaBrO₃ (725 mg, 4.80 mmol) in H₂O (16 mL) was added to a solution of 9 (439 mg, 1.57 mmol) in EtOAc (22.5 mL). A solution of Na₂S₂O₄ (836, 4.79 mmol) in H₂O (32 mL) was added dropwise in 10 min under stirring. TLC (EtOAc–petroleum ether, 1:2) indicated absence of 9 after 2 h of vigorous stirring at r.t. The organic phase was separated and washed with aq Na₂S₂O₃. The aqueous phase was extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, dried (Na₂SO₄) and concentrated. Chromatography in heptane–EtOAc–25% aq NH₃–H₂O (40:40:9:2) yielded 17 (240 mg, 81%); mp 102–105 °C (MeOH); [α]_D –6.0 (c 0.18, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 2.60 (d, ² J _4,OH = 10.7 Hz, 1 H, OH), 3.62 (ddddd, ³ J _2,1 = 1.9 Hz, ³ J _2,3 = 1.7 Hz, ³ J _2,F = 13.9 Hz, ⁴ J _2,4 = 1.7 Hz, 1 H, H-2), 3.77 (ddddd, ² J _4,OH = 10.7 Hz, ³ J _4,F = 13.9 Hz, ³ J _4,5 = 1.8 Hz, ³ J _4,3 = 1.7 Hz, ⁴ J _2,4 = 1.7 Hz, 1 H, H-4), 3.84 (ddd, ² J _6en,6ex = 7.7 Hz, ³ J _6ex,5 = 5.8 Hz, ⁵ J _6ex,F = 2.5 Hz, 1 H, H-6ex), 4.11 (dd, ² J _6ex,6en = 7.7 Hz, ³ J _6en,5 = 1.3 Hz, 1 H, H-6en), 4.59 (dddd, ³ J _6en,5 = 1.3 Hz, ³ J _6ex,5 = 5.8 Hz, ³ J _4,5 = 1.8 Hz, 1 H, H-5), 4.62 (ddddd, ⁴ J _3,1 = 1.9 Hz, ³ J _2,3 = 1.7 Hz, ³ J _4,3 = 1.7 Hz, ³ J _3,F = 44.2 Hz, 1 H, H-3), 5.50 (dd, ³ J _2,1 = 1.9 Hz, ⁴ J _3,1 = 1.9 Hz, 1 H, H-1). ¹³C NMR (75 MHz, CDCl₃): δ = 58.75 (d, ² J _C,F = 25.4 Hz, C-2), 64.87 (d, ⁴ J _C,F = 4.7 Hz, C-6), 67.74 (d, ² J _C,F = 26.6 Hz, C-4), 75.69 (s, C-5), 89.93 (d, ¹ J _C,F = 185.5 Hz, C-3), 99.78 (s, C-1). ¹⁹F NMR (282 MHz, CDCl₃): δ = –180.50 (dddd, ² J _H3,F = 44.2 Hz, ³ J _H4,F = 13.9 Hz, ³ J _H2,F = 13.9 Hz, ⁵ J _6ex,F = 2.5 Hz). Anal. Calcd for C₆H₈FN₃O₃: C, 38.1; H, 4.3; N, 22.2. Found: C, 38.3; H, 4.2; N, 21.8. Product 17 was dissolved in CH₂Cl₂ (2.7 mL) containing pyridine (0.7 mL). Trifluoromethanesulfonic acid anhydride (0.45 mL, 2.73 mmol) was added under cooling (–40 °C) and stirring. The temperature was allowed to reach 0 °C, the reaction mixture was poured onto ice and extracted into CH₂Cl₂ (4 ×). The combined extracts were dried (Na₂SO₄) and concentrated to afford crude triflate (390 mg, 96%), which was immediately dissolved in anhyd DMF (4.0 mL). Tetrabutylammonium nitrite (0.9 g, 3.12 mmol) was added and stirring at r.t. was continued for 12 h. The reaction mixture was concentrated in vacuo to about 1/3 its volume and chromatographed (EtOAc–petroleum ether 1:2) to afford 18 (161 mg, 67%); mp 44–46 °C; [α]_D +47 (c 0.14, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 2.41 (dd, ² J _4,OH = 8.8 Hz, ³ J _F,OH = 4.0 Hz, 1 H, OH), 3.70 (ddd, ³ J _2,1 = 1.5 Hz, ³ J _2,3 = 1.5 Hz, ³ J _2,F = 14.7 Hz, 1 H, H-2), 3.73 (ddd, ² J _6en,6ex = 7.9 Hz, ³ J _6ex,5 = 4.5 Hz, ⁵ J _6ex,F = 1.2 Hz, 1 H, H-6ex), 4.06 (dddd, ² J _4,OH = 8.8 Hz, ³ J _4,F = 26.4 Hz, ³ J _4,5 = 4.5 Hz, ³ J _4,3 = 4.5 Hz, 1 H, H-4), 4.20 (dd, ² J _6ex,6en = 7.9 Hz, ³ J _6en,5 = 1.5 Hz, 1 H, H-6en), 4.51 (dddd, ³ J _6en,5 = 1.5 Hz, ³ J _6ex,5 = 4.5 Hz, ³ J _4,5 = 4.5 Hz, ⁴ J _3,5 = 1.5 Hz, 1 H, H-5), 4.80 (ddddd, ⁴ J _3,1 = 1.5 Hz, ³ J _2,3 = 1.5 Hz, ³ J _4,3 = 4.5 Hz, ³ J _3,F = 48.2 Hz, ⁴ J _3,5 = 1.5 Hz, 1 H, H-3), 5.48 (dd, ³ J _2,1 = 1.5 Hz, ⁴ J _3,1 = 1.5 Hz, 1 H, H-1). ¹³C NMR (75 MHz, CDCl₃): δ = 60.83 (d, ² J _C,F = 25.1 Hz, C-2), 63.77 (d, ⁴ J _C,F = 3.4 Hz, C-6), 64.99 (d, ² J _C,F = 17.7 Hz, C-4), 74.18 (s, C-5), 88.91 (d, ¹ J _C,F = 183.0 Hz, C-3), 99.51 (s, C-1). ¹⁹F NMR (282 MHz, CDCl₃): δ = –199.79 (ddddd, ² J _H3,F = 48.2 Hz, ³ J _H4,F = 26.4 Hz, ³ J _H2,F = 14.7 Hz, ⁵ J _6ex,F = 1.2 Hz, ³ J _F,OH = 4.0 Hz). HRMS (APCI): m/z [M + H – N₂] calcd for C₆H₉FNO₃: 162.0561; found: 162.0564.
• 19 Compound 4 was obtained after chromatography in EtOAc in 86% yield as an anomeric mixture (α/β = 72:28, ¹⁹F NMR) which contained about 7% of unknown fluorine-containing by-products (¹⁹F NMR). Recrystallization from CH₂Cl₂–Et₂O yielded 46% of the pure α-anomer. Crystallization of the mother liquor provided additional 19% of a mixture of both anomers (β/α = 89:11, estimated by ¹⁹F NMR) without contaminating by-products. Analytical data for α-anomer: mp 177–178 °C (EtOAc); [α]_D +133 (c 0.09, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 2.01 (s, 3 H, NHCOCH ₃), 2.04 (s, 3 H, COCH₃), 2.15 (s, 3 H, COCH₃), 2.17 (s, 3 H, COCH₃), 4.10 (m, 3 H, H-5, H-6en, H-6ex), 4.74 (overlap 2 × ddd, ³ J _3,2 = 11.1 Hz, ³ J _4,3 = 3.4 Hz, 2 H, H-3, H-2), 5.47 (d, ² J _2,NH = 8.7 Hz, 1 H, NH), 5.62 (m, 1 H, H-4), 6.25 (dd, ² J _2,1 = 3.9 Hz, ⁴ J _1,3 = 3.7 Hz, 1 H, H-1). ¹³C NMR (75 MHz, CDCl₃): δ = 20.30 (s, COCH₃), 20.32 (s, COCH₃), 20.54 (s, COCH₃), 22.91 (s, NHCOCH₃), 47.45 (d, ² J _C,F = 19.2 Hz, C-2), 61.21 (d, ⁴ J _C,F = 2.1 Hz, C-6), 66.43 (d, ² J _C,F = 16.9 Hz, C-4), 68.37 (d, ³ J _C,F = 5.5 Hz, C-5), 86.37 (d, ¹ J _C,F = 192.1 Hz, C-3), 91.64 (d, ³ J _C,F = 9.3 Hz, C-1), 169.07 (s, COCH₃), 170.50 (s, COCH₃), 170.71 (s, COCH₃), 170.94 (s, COCH₃). ¹⁹F NMR (282 MHz, CDCl₃): δ = –202.53 (ddd, ² J _H3,F = 46.7 Hz, ³ J _H2,F = 12.4 Hz, ³ J _H4,F = 5.2 Hz). HRMS (ESI): m/z [M + Na] calcd for C₁₄H₂₀FNO₈Na: 372.1071; found: 372.1065. Analytical data for β-anomer: ¹H NMR (300 MHz, CDCl₃): δ = 1.99 (s, 3 H, NHCOCH ₃), 2.04 (s, 3 H, COCH₃), 2.12 (s, 3 H, COCH₃), 2.15 (s, 3 H, COCH₃), 3.99 (ddd, ³ J _4,5 = 1.4 Hz, ³ J _6ex,5 = 6.5 Hz, ³ J _6en,5 = 3.2 Hz, 1 H, H-5), 4.16 (m, 3 H, H-6ex, H-6en, H-2), 4.97 (ddd, ² J _3,F = 46.8 Hz, ³ J _3,2 = 10.6 Hz, ³ J _4,3 = 3.7 Hz, 1 H, H-3), 5.57 (ddd, ³ J _4,5 = 1.4 Hz, ³ J _4,3 = 3.7 Hz, ³ J _4,F = 5.5 Hz, 1 H, H-4), 5.70 (d, ² J _2,NH = 8.3 Hz, 1 H, NH), 5.91 (d, ² J _2,1 = 8.7 Hz, 1 H, H-1). ¹³C NMR (75 MHz, CDCl₃): δ = 20.30 (s, COCH₃), 20.32 (s, COCH₃), 20.53 (s, COCH₃), 23.10 (s, NHCOCH₃), 51.76 (d, ² J _C,F = 19.6 Hz, C-2), 61.23 (d, ⁴ J _C,F = 2.8 Hz, C-6), 66.25 (d, ² J _C,F = 16.6 Hz, C-4), 70.88 (d, ³ J _C,F = 6.2 Hz, C-5), 87.41 (d, ¹ J _C,F = 193.1 Hz, C-3), 91.57 (d, ³ J _C,F = 10.5 Hz, C-1), 169.77 (s, COCH₃), 170.41 (s, COCH₃), 170.95 (s, COCH₃), 171.22 (s, COCH₃). ¹⁹F NMR (282 MHz, CDCl₃): δ = –198.59 (ddd, ² J _H3,F = 46.8 Hz, ³ J _H2,F = 10.3 Hz, ³ J _H4,F = 5.5 Hz). HRMS (ESI): m/z [M + Na] calcd for C₁₄H₂₀FNO₈Na: 372.1071; found: 372.1066.