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

<A NAME="RD08106ST-1">1</A> Moncada S. Higgs EA. FASEB J.  1995,  9:  1319 

<A NAME="RD08106ST-2">2</A> Knowles RG. Moncada S. Biochem. J.  1994,  298:  249 

<A NAME="RD08106ST-3">3</A> Kawanaka Y. Kobayashi K. Kusuda S. Tatsumi T. Murot M. Nishiyama T. Hisaichi K. Fujii A. Hirai K. Nak M. Komeno M. Odagaki Y. Nakai H. Toda M. Bioorg. Med. Chem. Lett.  2003,  13:  1723 ; and references cited therein

<A NAME="RD08106ST-4A">4a</A> Ueda S. Terauchi H. Yano A. Iro M. Matsumoto M. Kawasaki M. Bioorg. Med. Chem. Lett.  2004,  14:  313 

<A NAME="RD08106ST-4B">4b</A> Atkinson RN. Moore L. Tobin J. King SB. J. Org. Chem.  1999,  64:  3467 

<A NAME="RD08106ST-5">5</A> Moore WM. Webber RK. Fok KF. Jerome GM. Connor JR. Manning PT. Wyatt PS. Misko TP. Tjoeng FS. Currie MG. J. Med. Chem.  1996,  39:  669 

<A NAME="RD08106ST-6A">6a</A> Hagen TJ. Bergmanis AA. Kramer SW. Fok KF. Schmelzer AE. Pitzele BS. Swenton L. Jerome GM. Kornmeier CM. Moore WM. Branson LF. Connor JR. Manning PT. Currie MG. Hallinan EA. J. Med. Chem.  1998,  41:  3675 

<A NAME="RD08106ST-6B">6b</A> Tsymbalov S. Hagen TJ. Moore WM. Jerome GM. Connor JR. Manning PT. Pitzele BS. Hallinan EA. Bioorg. Med. Chem. Lett.  2002,  12:  3337 

<A NAME="RD08106ST-6C">6c</A> Guthikonda NR. Shah SK. Pacholok SG. Humes JL. Mumford RA. Grant SK. Chabin RM. Green BG. Tsou N. Ball R. Fletcher DS. Luell S. MacIntyre DE. MacCoss M. Bioorg. Med. Chem. Lett.  2005,  15:  1997 

<A NAME="RD08106ST-7">7</A> Burden PM. Synth. Commun.  1993,  23:  1195 

<A NAME="RD08106ST-8A">8a</A> Shankaran K. Donnelly K. Shah SK. Guthikonda RN. MacCoss M. Humes JL. Pacholok SG. Grant SK. Kelly TM. Wong KK. Bioorg. Med. Chem. Lett.  2004,  14:  4539 

<A NAME="RD08106ST-8B">8b</A> Shankaran K. Donnelly KL. Shah SK. Caldwell CG. Chen P. Hagmann WK. MacCoss M. Humes JL. Pacholok SG. Kelly TM. Grant SK. Wong KK. Bioorg. Med. Chem. Lett.  2004,  14:  5907 

<A NAME="RD08106ST-8C">8c</A> Gadreau C. Foucaud A. Tetrahedron Lett.  1974,  48:  4243 

<A NAME="RD08106ST-9">9</A> Benati L. Bencivenni G. Leardini R. Minozzi M. Nanni D. Scialpi R. Spagnolo P. Zanardi G. Rizzoli C. Org. Lett.  2004,  6:  417 

<A NAME="RD08106ST-10A">10a</A> Postel D. Nguyen Van Nhien A. Pillon M. Villa P. Ronco G. Tetrahedron Lett.  2000,  41:  6403 

<A NAME="RD08106ST-10B">10b</A> Nguyen Van Nhien A. Ducatel H. Len C. Postel D. Tetrahedron Lett.  2002,  43:  3805 

<A NAME="RD08106ST-10C">10c</A> Postel D. Nguyen Van Nhien A. Marco JL. Eur. J. Org. Chem.  2003,  19:  3713 

<A NAME="RD08106ST-10D">10d</A> Dominguez L. Nguyen Van Nhien A. Tomassi C. Len C. Postel D. Marco-Contelles JL. J. Org. Chem.  2004,  69:  843 

<A NAME="RD08106ST-10E">10e</A> Nguyen Van Nhien A. Tomassi C. Len C. Marco-Contelles JL. Balzarini J. Pannecouque C. De Clercq E. Postel D. J. Med. Chem.  2005,  48:  4276 

<A NAME="RD08106ST-11">11</A> Ewing DF. Goethals G. MacKenzie G. Martin P. Ronco G. Vanbaelinghem L. Villa P. Carbohydr. Res.  1999,  321:  190 

<A NAME="RD08106ST-12">12</A>

(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.

<A NAME="RD08106ST-13">13</A>

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]⁺.

<A NAME="RD08106ST-14">14</A>

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.

<A NAME="RD08106ST-15">15</A>

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.

<A NAME="RD08106ST-16">16</A>

(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.

<A NAME="RD08106ST-17">17</A>

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.