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A Convenient Synthesis of 4-Amino-4-desoxy Sugars Abdul Malik, Michael Roosz, and Wolfgang Voelter* Abteilung für Physikalische Biochemie Physiologisch-chemisches Institut der Universität Tübingen, Hoppe-Seyler-Straße 1, D-7400 Tübingen 1, FRG

Z. Naturforsch. 40b, 559-561 (1985); received May 14, 1984

Amino Sugars, Anhydro Sugars, Triflate Sugars

Displacement of the triflyl by the amino group in benzyl-2,3-anhydro-4-triflyl-pyranosides 4—6 gives with inversion the benzyl-2,3-anhydro-4-amino-4-desoxypyranosides 7—9. The triflyl group turns out to be a reactive leaving group which can be replaced by ammonia under mild conditions.

A general synthesis of 4-azido-4-desoxy sugars has recently been communicated by one of us [1], involv-ing displacement of C-4 triflate by the azido group in 2,3-anhydro sugars. We have now discovered that the triflyl group [2] is a very reactive leaving group which can directly be displaced with inversion by ammonia, providing a one pot synthesis of 4-amino-4-desoxy sugars.

The nucleophilic substitution of the triflyl group by ammonia depends largely on the structure and geometry of the molecule on the one hand and re-activity of the leaving group on the other [3]. In 2,3-anhydro sugars the carbon atoms in the oxirane ring show sp2 hybrid character [4] and stabilize the SN 2 transition state formed at C-4. Such an effect has earlier been observed in the case of 2,3-hex-enopyranosides [5] which favour formation of the transition state at allylic position. The dipole changes affect the formation of transition states [6] but the effect of c/s-axial change at the neighbourhood of the oxirane ring in 2,3-anhydro sugars is weakened due to molecular geometry which shows a dipole moment in the direction of the C—O bond and not parrallel to the newly forming C - N bond [1],

As model substances we synthesized benzyl-2,3-anhydro-a-D-lyxopyranoside (1) [1], benzyl-2,3-anhydro-a-D-ribopyranoside (2) [7] and benzyl-2,3-anhydro-/3-L-ribopyranoside (3) [8]. The benzyl group which is easily removable by reductive cleav-age was used as protecting group for the glycosidic hydroxyl group. The anhydro sugars 1—3 were reacted with trifluoromethanesulphonic anhydride [9] and pyridine in methylene dichloride at 0 °C to afford the corresponding triflates 4—6 in excellent yields.

* Reprint requests to Prof. Dr. W. Voelter. Verlag der Zeitschrift für Naturforschung, D-7400 Tübingen 0340-5087/85/0400-0559/$ 01.00/0

JÖL RO '—' OCH2C6H5 RO Y 7 OCH2C6HS " Ö OCH2C6H5

1 : R = H 2 : R = H 8 : R = H 4 : R = S02CF3 5 : R — S02CF3 6 : R = S02CF3

Attempts to displace the triflyl group by sodamide in HMPTA proved futile as the strongly basic nature of the attacking nucleophile evidently gives birth to undesirable side reactions like /^-elimination and at-tack at the epoxide ring, resulting in a complex mix-ture of products. The triflyl group in 4—6 could, however, be displaced selectively by reacting with a 2N solution of ammonia in chloroform at 50 °C for 5 h. The products were worked up according to the procedure described in the experimental to yield benzyl-2,3-anhydro-4-amino-4-desoxypyranosides 7 - 9 .

- O , OCH2C6H5 Ö OCH2C6H5 H2N ''OCH2C6H5

We further observed that displacement can also be affected by passing gaseous ammonia into acetonic sulutions of triflates 4 - 6 at - 1 0 °C for 1 h. The yields of compounds 7—9 were improved by this pro-cedure, providing a general route for the synthesis of amino desoxy sugars through the intervening tri-flates.

Experimental The melting points were recorded in a glass capil-

lary and are uncorrected. IR: Instrument Infracord 2221, Perkin-Elmer. 'H and 13C-NMR: Instruments

560 A. Malik et al. • A Convenient Synthesis of 4-Amino-4-desoxy Sugars

WH 90 and HFX 90, Bruker-Physik AG. MS: Instru-ment MAT 711, Varian. Optical rotations: In-strument Digitalpolarimeter OLD 5, Zeiss. Elemen-tal analyses: Carlo Erba Elemental Analyser Mod. 1104.

Benzyl-2,3-anhydro-4-triflyl-a-D-lyxopyranoside (4)

2.2 g (10 mmol) 1 were dissolved in 50 ml absolute methylene dichloride, added 1 ml absolute pyridine and cooled to 0 °C. A solution of 1.6 ml (10 mmol) trifluoromethanesulphonic anhydride in 50 ml abso-lute methylene dichloride was added dropwise under constant stirring keeping the temperature at 0 °C. The reaction mixture was stirred for further 30 min at this temperature, poured in crushed ice containing 200 mg sodium bicarbonate, added 250 ml methy-lene dichloride and layers separated. The organic phase was quickly washed with 1 N hydrochloric acid, water, dilute solution of sodium bicarbonate and again with water. The residue obtained on drying and removal of the solvent under reduced pressure was taken up in ethanol and cooled. Then, 2.97 g (90%) of 4 crystallized out. M. p. 32 °C, [a]o = +72.2° (c = 0.8, chloroform). IR (KBr): 1422, 1217, 1145 (OSO,), 1250 cm"1 (CF). MS: 354 (M+), 246 (M—PhCFLOH), 204 ( M - C F 3 S 0 2 0 H ) , 133 (CF3S02

+) , 108 (PhCH2OH+) , 91 (PhCH2+). 'H-

NMR (90 MHz, CDC13): <5 7.26 (5H; phenyl pro-tons), 5.02 (1H, m; H-4), 4.87 (1H, S; H-l) , 4.59 (2H, dd; 7 = 12.5 Hz, benzyl protons), 3.65 (1H, m; H-5), 3.33 (1H, d, 7 = 3.44; H-3), 3.14 (1H, d, 7 = 3.76; H-2).

C13H13F306S (354.29) Calcd C 44.07 H 3.71 S 9.05, Found C 43.79 H 3.79 S 9.10.

Benzyl-2,3-anhydro-4-triflyl-a-D-ribopyranoside (5) 2.2 g (10 mmol) 2 were reacted with triflic anhydride

as for 1. From moist ethanol 3.02 g (80.3%) 5 crystallized out. M.p. 66-67°C, [a]2D° = + 133°(c = 1, chloroform). 'H-NMR (90 MHz, CDC13): Ö 7.31 (5H, S; phenyl protons), 5.19 (1H, q, 7 = 6.75 and 7 = 8.07; H-4), 4.94 (1H, d, 7 = 2.5 Hz; H-l) , 4.65 (2H, dd, 7gem = 12.5 Hz; benzyl protons), 4.08-3.55 (3H, m; H-2, H-3, H-5).

C13H13F306S (354.29) Calcd C 44.07 H 3.71 S 9.05, Found C 44.11 H 3.64 S 9.03.

Benzyl-2,3-anhydro-4-triflyl-ß-L-ribopyranoside (6)

2.2 g (1 mmol) 3 were reacted with triflic anhydride as for 1. From moist ethanol 3.49 g (96%) 6

crystallized out. M.p. 83 -84 °C, [a]2D° = 17° (c = 1, chloroform). 'H-NMR (90 MHz, CDC13): c3 7.35 (5H, S; phenyl protons), 5.16 (1H, m; H-4), 5.09 (1H, S; H- l ) , 4.67 (2H, dd, 7gem = 12.5 Hz; benzyl protons), 4 .15-3.63 (1H, m, 7 = 4.1 and 7 = 13.3; H-5), 3.56 (1H, d, 7 = 3.52; H-3), 3.28 (1H, d, 7 = 3.81; H-2).

C13H13F306S (354.29) Calcd C 44.07 H 3.71 S 9.05, Found C 43.89 H 3.58 S 9.13.

Benzyl-2,3-anhydro-4-amino-4-desoxy-ß-L-ribopyranoside (7)

1.1 g (3 mmol) 4 were dissolved in 20 ml absolute chloroform, added 20 ml 2 N solution of ammonia in absolute chloroform and stirred at 50 °C for 5 h. The solvent was removed in vacuo, the residue taken up in ethyl acetate and exhaustively extracted out with 1 N acetic acid. The aqueous fraction was freeze dried, the residue washed with dilute solution of sodium bicarbonate and extracted out with ethyl ace-tate. Drying and removal of solvent in vacuo af-forded 420 mg (63.2%) 7. M. p. 55 °C, [a]2D° = + 54.4° (c = 3, chloroform). IR (KBr): Double bands be-tween 3300—3500 (NH2 stretchings) and prominent band between 1560—1650 cm - 1 (NH2 bending). FDMS (CHC13): 221 (M+) , 113 (M-PhCH 2 OH) , 108 (PhCH 2OH+ ) , 91 (PhCH2

+). 'H-NMR (90 MHz, CDC13): (3 7.38 (5H, S; phenyl protons), 4.99 (1H, S; H- l ) , 4.71 (2H, dd, 7gem = 12.54 Hz; benzyl pro-tons), 3.92 (1H, q, 7 = 5.14 Hz, 7 = 13.1 Hz; H-5), 3.49 (1H, t, 7 = 4.12 Hz; H-4), 3.25 (1H, m; H-2, H-3), 1.80 (2H, S; NH2 protons).

C1 2H!,N03 (221.28) Calcd C 65.13 H 6.85 N 6.33, Found C 64.91 H 6.33 N 6.41.

Benzyl-2,3-anhydro-4-amino-4-desoxy-ß-L-lyxopyranoside (8)

1.1 g (3 mmol) 5 were reacted with 2 N solution of ammonia in chloroform as 4 to yield 250 mg (52.7%) 8. M.p. 3 7 - 3 8 °C, [a]2

D° = +105° (c = 1, chloro-form). 'H-NMR (90 MHz, CDC13): (3 7.36 (5H, S; phenyl protons), 5.02 (1H, d, 7 = 2.91; H-l) , 4.69 (2H, dd, 7gem = 12.54 Hz; bezyl protons), 4.05 (1H, q, 7 = 2.94 Hz, 7gem = 10.5 Hz; H-5), 3.33 (1H, S; H-2), 3.29 (1H, S; H-3), 3.20 (1H, t, 7 = 2.93 Hz; H-4), 1.76 (2H, S; NH : protons).

C1 2H1 5N03 (221.28) Calcd C 65.13 H 6.85 N 6.33, Found C 65.27 H 6.73 N 6.19.

561 A. Malik et al. • A Convenient Synthesis of 4-Amino-4-desoxy Sugars

Benzyl-2,3-anhydro-4-amino-4-desoxy-a-D-lyxopyranoside (9)

1.1 g (3 mmol) 6 were reacted with a chloroform solution of 2 N ammonia as 4 to afford 520 mg (75.7%) 9. M.p. 48 -49 °C, [a]2£ = +91° (c = 1, chloroform). 'H-NMR (90 MHz, CDC13): <5 7.36 (5H, S; phenyl protons), 4.98 (1H, S; H- l ) , 4.68 (2H, dd, 7gem = 12.54 Hz; benzyl protons), 3.56 (1H, q, J = 4.69 Hz, 7gem = 10.02 Hz; H-5), 3.35 (1H, S; H-2), 3.24 (1H, S; H-3), 3.14 (1H, t, J = 4.7 Hz; H-4), 1.81 (2H, S; NH, protons).

C12H15N03 (221.28) Calcd C 65.13 H 6.85 N 6.33, Found C 65.01 H 6.72 N 6.14.

Reactions with gaseous ammonia in acetone 1.1 g (3 mmol) 4 were dissolved in 25 ml absolute

acetone, cooled to —10 °C and a slow stream of gase-ous ammonia under constant stirring for 1 h was pas-sed. The solvent was removed in vacuo, the residue taken up in ethyl acetate and exhaustively extracted

out with 1 N acetic acid with the addition of petro-leum ether. The acid layer was basified with conc. ammonia, common salt added, and repeatedly ex-tracted out with ether. The ethereal layer was dried over anhyd. Na2S04 and freed from solvent. The col-ourless oil thereby obtained was kept in the ice chest for several days when 7 crystallized out as a con-gealed mass which was filtered with the aid of ether/ petroleum ether (1:1). The mother liquor from the crystallizate was freed from solvent and the residue chromatographed over silica gel (Lobar B, Si 60, Merck) using the solvent system chloroform/methanol (98:2) as eluent. From ethyl acetate a second harvest of 7 crystallized out (total yield 498 mg; 75%). Simi-lar work up with 5 and 6 provided the corresponding amino sugars 8 and 9 in 63% and 79.6% yields re-spectively.

One of us (A. M.) wishes to express his gratitude to D A A D for providing a scholarship during the course of this work.

We thank the "Fonds der Chemischen Industrie" for financial support.

[1] R. Kimmich and W. Voelter, Liebigs Ann. Chem. 1100-1104 (1981).

[2] J. B. Hendrikson, D. D. Sternbach, and K. W. Bair, Acc. Chem. Res. 10, 306 (1978).

[3] D. H. Ball and F. W. Parrish, Adv. Carboh. Chem. 24, 139 (1969).

[4] A. Rosowski in Heterocyclic Compounds with Three-and Four-Membered Rings (A. Weissberger), Part 1, S. 1, Interscience, New York 1964.

[5] R. J. Ferrier, Adv. Carboh. Chem. 24, 265 (1969).

[6] L. Hough and A. C. Richardson in Rodd's Chemistry of Carbon Compounds (S. Coffey), 2nd Ed., Vol. 1 F, Chapt. 23, Elsevier, New York 1967.

[7] D. Buchmann, D. M. Clode, and N. Vethaviyasar, J. Chem. Soc. Perkin I, 1976, 1449.

[8] A. Holy and F. Sorm, Coll. Czech. Chem. Commun. 34, 3383 (1969).

[9] L. A. Carpino, C. A. Giza, and B. A. Carpino, J. Am. Chem. Soc. 81, 955 (1959).