Efficient Synthesis of Sugar Iminopyrrolidine Derivatives via an Intramolecular Staudinger-aza-Wittig-Type Reaction

Abstract

We report herein the first example of a Staudinger-aza-Wittig-type reaction on a substituted furanoside in which a β-azido glyco-α-aminonitrile was converted into fused iminopyrrolidines in good yields, and the following hydrolysis gave the corresponding conformationally restricted glycoamino acids.

aza-sugars - Wittig reactions - glycoamino nitrile - ­glycoamino acids - iNOS

References and Notes

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12

(1 R ,3 R ,4 R ,5 R )-5,6-Diamino-3,4- O -isopropylidene-7-aza-2-oxabicyclo[3.3.0]oct-6-ene ( 8).
To a solution of compound 2 (0.20 g, 0.85 mmol) in 10 mL of THF-H₂O (4:1) was added 0.25 g (0.93 mmol) of PPh₃. After stirring overnight at r.t., the reaction mixture was evaporated and extracted with Et₂O and H₂O. The aqueous layer was evaporated to give 0.16 g (89%) of 8 as a slight yellow syrup; [α]_D ²⁰ 20 (c 0.17, CHCl₃). IR (ATR): 2988, 1655, 1374, 1217, 1165, 1086, 1007, 877, 733 cm^-1. ¹H NMR (CDCl₃): δ = 5.80 (d, 1 H, H-1, J _1,2 = 3.9 Hz), 4.60 (d, 1 H, H-2), 4.30 (d, 1 H, H-4, J _4,5a = 3.0 Hz), 3.72 (dd, 1 H, H-5a, J _5a,5b = 14.0 Hz), 3.67 (d, 1 H, H-5b), 1.53 (s, 3 H, CH₃), 1.35 (s, 3 H, CH₃). ¹³C NMR (CDCl₃): δ = 168.2 (C=N), 112.9 (CH₃ CCH₃), 106.1 (C-1), 85.1 (C-4), 82.2 (C-2), 74.1 (C-3), 55.5 (C-5), 27.6, 27.3 (2 × CH₃). HRMS: m/z calcd for C₉H₁₆N₃O₃ [M + H]⁺: 214.1192; found: 214.1196. Anal. Calcd for C₉H₁₅N₃O₃: C, 50.69; H, 7.09; N, 19.71. Found: C, 50.54; H, 6.95; N, 19.60.

13

Key Data for Compound 9. ¹³C NMR (CDCl₃): δ = 173.4 (C=N, J ² _C-P = 9.0 Hz), 75.4 (C-3, J ³ _C-P = 17.2 Hz), 14.4 [P(CH₃)₃, J ¹ _CH3-P = 66.0 Hz). MS: m/z = 288.14 [M + H]⁺.

14

3-Amino-3-deoxy-1,2- O -isopropylidene-α- d-ribofurano-sidurono-3,5-lactam ( 17).
White solid, mp 159-162 °C; [α]_D ²⁰ 18 (c 0.11, CHCl₃). ¹H NMR (CD₃OD): δ = 5.81 (d, 1 H, H-1, J _1,2 = 3.9 Hz), 4.60 (d, 1 H, H-2), 4.40 (d, 1 H, H-4, J _4,5a = 3.5 Hz), 3.65 (dd, 1 H, H-5a, J _5a,5b = 11.8 Hz), 3.32 (d, 1 H, H-5b), 1.56 (s, 3 H, CH₃), 1.38 (s, 3 H, CH₃). ¹³C NMR (CD₃OD): δ = 176.4 (1 C, C=O), 112.8 (1 C, CH₃ CCH₃), 106.1 (1 C, C-1), 81.9 (1 C, C-2), 81.8 (1 C, C-4), 68.8 (1 C, C-3), 45.6 (1 C, C-5), 26.4, 26.0 (2 C, CH₃). IR (ATR): ν = 2959, 2932, 1716, 1659, 1465, 1382, 1233, 1166, 1098, 1082, 1001 cm^-1. HRMS: m/z calcd for C₉H₁₄N₂O₄Na: 237.0851 [M + Na]⁺; found: 237.0850.

15

3,5-Diamino-3- C -carboxy-3,5-dideoxy-1,2- O -isopropyl-idene-α- d-ribofuranose ( 18). White solid, mp 200 °C; [α]_D ²⁰ 77 (c 0.21, H₂O). ¹H NMR (D₂O): δ = 5.88 (d, 1 H, H-1, J _1,2 = 3.6 Hz), 4.55 (d, 1 H, H-2), 3.94 (dd, 1 H, H-4, J _4,5a = 1.8 Hz), 3.13 (dd, 1 H, H-5a, J _5a,5b = 13.3 Hz), 2.78 (dd, 1 H, H-5b, J _5b,4 = 9.9 Hz), 1.44 (s, 3 H, CH₃), 1.27 (s, 3 H, CH₃). ¹³C NMR (D₂O): δ = 175.1 (1 C, C=O), 113.4 (1 C, CH₃ CCH₃), 105.9 (1 C, C-1), 83.3 (1 C, C-2), 80.3 (1 C, C-4), 68.5 (1 C, C-3), 40.1 (1 C, C-5), 26.1, 25.7 (2 C, CH₃). IR (ATR): ν = 2987, 2917, 1614, 1540, 1409, 1381, 1230, 1163, 1069, 1015, 883, 809 cm^-1. HRMS: m/z calcd for C₉H₁₆N₂O₅Na: 255.0957 [M + Na]⁺; found: 255.0950.

16

(1 R ,3 R ,4 R ,5 R )-5-{[1,2- O -Isopropylidene-α- d-xylo-furanos-5-yl]amino}-6-amino-3,4- O -isopropylidene-7-aza-2-oxabicyclo[3.3.0]oct-6-ene ( 21).
White solid, mp 125-128 °C; [α]_D ²⁰ 18.2 (c 0.36, CHCl₃). IR (ATR): 2989, 2901, 1655, 1384, 1217, 1167, 1073, 1014, 879, 858 cm^-1. ¹H NMR (CDCl₃): δ = 5.89 (d, 1 H, H-1, J _1,2 = 3.6 Hz), 5.77 (d, 1 H, H-1′, J _{1 ′ ,2 ′} = 3.7 Hz), 4.62 (d, 1 H, H-2′), 4.52 (s, 1 H, H-4), 4.38 (d, 1 H, H-2), 4.14 (d, 1 H, H-4′, J _{4 ′ ,3 ′} = 2.7 Hz), 4.05 (d, 1 H, H-3′), 3.56 (s, 2 H, H-5′), 3.06 (d, 1 H, H-5a, J _5a,5b = 11.7 Hz), 2.77 (dd, 1 H, H-5b, J _5b,4 = 3.5 Hz), 1.48 (s, 3 H, CH₃), 1.39 (s, 3 H, CH₃), 1.29 (s, 3 H, CH₃), 1.20 (s, 3 H, CH₃). ¹³C NMR (CDCl₃): δ = 164.9 (1 C, CN), 112.9, 111.5 (2 C, CH₃ CCH₃), 105.2, 104.8 (2 C, 2 C-1), 85.6 (1 C, C-2), 83.1 (1 C, C-4), 82.2 (1 C, C-2′), 77.9 (1 C, C-4′), 76.5 (2 C, C-3′, C-3), 58.2 (1 C, C-5′), 42.4 (1 C, C-5), 27.3 (1 C, CH₃), 27.1 (1 C, CH₃), 26.7 (1 C, CH₃), 26.1 (1 C, CH₃). HRMS: m/z calcd for C₁₇H₂₈N₃O₇: 386.1927 [M + H]⁺; found: 386.1908. Anal. Calcd for C₁₇H₂₇N₃O₇: C, 52.98; H, 7.06; N, 10.90. Found: C, 52.91; H, 7.04; N, 10.87.

17

3,5-Diamino-3- C -carboxy-3,5-dideoxy-3- N -[1′,2′- O -isopropylidene-α- d-xylofuranos-5′-yl]-1,2- O -isopropyl-idene-α- d-ribofuranose ( 22).
White solid, mp 254-256 °C; [α]_D ²⁵ 8.0 (c 0.21, CHCl₃). IR (ATR): 2987, 2900, 1589, 1394, 1215, 1066 cm^-1. ¹H NMR (CD₃OD): δ = 5.99 (d, 1 H, H-1′, J _{1 ′ ,2 ′} = 3.6 Hz), 5.95 (d, 1 H, H-1, J _1,2 = 3.8 Hz), 5.01 (d, 1 H, H-2), 4.49 (d, 1 H, H-2′), 4,22 (m, 2 H, H-4′, H-3′), 3.98 (t, 1 H, H-4, J _4,5 = 6.8 Hz), 3.12 (d, 2 H, H-5), 3.56 (dd, 2 H, H-5a′, J _5a,5b = 11.7 Hz, J _5a,4 = 6.3 Hz), 2.71 (dd, 1 H, H-5b′, J _5b,4 = 7.3 Hz), 1.56 (s, 3 H, CH₃), 1.47 (s, 3 H, CH₃), 1.38 (s, 3 H, CH₃), 1.31 (s, 3 H, CH₃). ¹³C NMR (CD₃OD): δ = 174.6 (1 C, C=O), 112.3, 111.6 (2 C, CH₃ CCH₃), 106.8, 105.4 (2 C, C-1′, C-1), 85.2 (1 C, C-2′), 81.2 (1 C, C-2), 80.8 (1 C, C-4′), 77.8 (1 C, C-4), 76.5 (2 C, C-3′, C-3), 43.1 (1 C, C-5′), 40.9 (1 C, C-5), 26.4 (1 C, CH₃), 26.2 (1 C, CH₃), 25.7 (1 C, CH₃), 25.5 (1 C, CH₃). HRMS: m/z calcd for C₁₇H₂₈N₂O₉Na: 427.1693
[M + Na]⁺; found: 427.1685.