Synlett 2014; 25(09): 1253-1256
DOI: 10.1055/s-0033-1341187
letter
© Georg Thieme Verlag Stuttgart · New York

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

Jindřich Karban*
Institute of Chemical Process Fundamentals of the ASCR, v. v. i., Rozvojová 135, 16502 Prague 6, Czech Republic   Fax: +420(2)20920661   Email: karban@icpf.cas.cz
,
Štěpán Horník
Institute of Chemical Process Fundamentals of the ASCR, v. v. i., Rozvojová 135, 16502 Prague 6, Czech Republic   Fax: +420(2)20920661   Email: karban@icpf.cas.cz
,
Lucie Červenková Šťastná
Institute of Chemical Process Fundamentals of the ASCR, v. v. i., Rozvojová 135, 16502 Prague 6, Czech Republic   Fax: +420(2)20920661   Email: karban@icpf.cas.cz
,
Jan Sýkora
Institute of Chemical Process Fundamentals of the ASCR, v. v. i., Rozvojová 135, 16502 Prague 6, Czech Republic   Fax: +420(2)20920661   Email: karban@icpf.cas.cz
› Author Affiliations
Further Information

Publication History

Received: 24 February 2014

Accepted after revision: 19 March 2014

Publication Date:
10 April 2014 (online)

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.

Supporting Information

 
  • 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.