Received 8 February 2007
aDepartment of Organic Chemistry, Chemical Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, England, and bDepartment of Chemical Crystallography, Chemical Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, England
Correspondence e-mail: firstname.lastname@example.org
The relative configuration of the title compound, C9H14NO5, formed by catalytic hydrogenation of an azidolactone, has been established by X-ray crystallographic analysis. The absolute configuration was determined by the use of 2,3-O-isopropylidene-L-lyxono-1,4-lactone as the carbohydrate starting material.
Carbohydrates have been extensively used as starting materials for the synthesis of important small biological molecules such as imino sugars. Imino sugars are analogues of carbohydrates in which the ring O atom is replaced by an N atom and the anomeric hydroxyl group is removed (Winchester & Fleet, 1992; Asano et al., 2000). They are almost always inhibitors of the corresponding glycosidases (Bruce et al., 1992) and have proved to have the potential to produce antiviral, antidiabetes and anticancer effects, as well as immune-modulatory properties (Asano et al., 1994). Lactones have provided short syntheses of novel imino sugars (Asano et al., 2000). Almost all of these targets have unbranched carbon chains. Recent results have indicated that analogues with carbon branches give rise to compounds with interesting biological activities (Ichikawa & Igarashi, 1995; Ichikawa et al., 1998). Novel imino sugars of this kind provide an opportunity for altering and, it is hoped, increasing the specificity of inhibition of individual glycosidases, and to study further the structure-activity relationships of glycosidase inhibitors. However, the chemistry of branched sugars, and in particular that of branched sugar lactones, has remained largely unexplored. The main problem is the lack of cheaply and easily available simple derivatives of monosaccharides with a carbon branch (Bols, 1996). Efficient routes to branched sugar lactones are under investigation in our laboratory. One exploits the Ho crossed-aldol reaction (Ho, 1979, 1985; Simone et al., 2005), one the Kiliani reaction on ketohexoses (Kiliani, 1886; Soengas et al., 2005; Hotchkiss et al., 2004, 2006), and one the Amadori rearrangement on sugars followed by treatment with calcium hydroxide (Hotchkiss et al., 2006). The crossed-aldol reaction was the crucial step in the synthesis of the title powerful branched intermediate (3), stereoisomeric with (4) (Newton et al., 2004). Stereochemical ambiguity may arise from the aldol reaction.
Azidolactol (1) was prepared from 2,3-O-isopropylidene-L-lyxono-1,4-lactone and submitted to the key aldol branching reaction. Oxidation of the aldol product with bromine water yielded branched lactone (2). Hydrogenation of (2) resulted in the initial formation of the corresponding amine, which underwent isomerization to the title lactam upon refluxing in the reaction solvent.
The X-ray crystal structure of (3) removes any ambiguity about the course of the aldol condensation and provides comparison of the solid-phase structures of (3) and (4) in order to rationalize their biological activity. The molecular structure shows no abnormal features. The largest differences from the Mogul norms (Bruno et al., 2004) are C6-O7 (0.02 Å; Mogul s.u. 0.02 Å) and C2-C3-O8 (-5.4°; Mogul s.u. 1.9°).
The crystal structure of (3) consists of sheets of molecules lying perpendicular to the c axis (Fig. 2), in which the molecules are linked by short hydrogen-bonded chains (O8-H10O5-H9O7). Curiously, the amine atom H13 is not involved in any strong hydrogen bonds. The closest O atoms are too distant, and the N-HO angles are too accute (Table 1) to be real hydrogen bonds.
| || Figure 1 |
The molecular structure of the title compound, with displacement ellipsoids drawn at the 50% probability level. H atoms are shown as spheres of arbitary radius.
| || Figure 2 |
A packing diagram of the title compound, showing one sheet of hydrogen-bonded molecules lying parallel to the ab plane. Note that atom H13 (bonded to nitrogen) is not involved in any hydrogen bonds. [Symmetry codes: (i) x - 1, y, z; (ii) 1 - x, y - , - z.]
5-Amino-5-deoxy-2-C-hydroxymethyl-2,3-O-isopropylidene-L-lyxono-1,5-lactam, (3), was obtained upon reduction of 5-azido-2,3-O-isopropylidene-L-lyxono-1,4-lactone, (2), using Pd-black and hydrogen gas in refluxing toluene at low concentration (2.5 mg ml-1). A 64% yield of the title compound was obtained. The compound was then crystallized via solvent evaporation (dichloromethane-methanol), appearing as colourless plates (m.p. 490-491 K). Analysis: D21 -14.0 (c 0.18 in methanol); IR (thin film, max, cm-1): 3340 (br, OH, NH), 1661 (s, CONH, six-ring lactam); 1H NMR (D2O, 400 MHz, , p.p.m.): 1.28, 1.34 [2 × 3H, 2 × s, C(CH3)2], 3.18 (1H, dd, JH5,H5' = 13.7 Hz, JH5,H4 = 5.1 Hz, H5), 3.51 (1H, dd, JH5',H5 = 13.6 Hz, JH5',H4 = 3.5 Hz, H5'), 3.63 (1H, d, JH2,H2' = 12.1 Hz, H2), 3.77 (1H, d, JH2',H2 = 12.1 Hz, H2'), 4.08-4.15 (1H, m, J = 4.9 Hz, J = 3.6 Hz, H4), 4.34 (1H, d, JH3,H4 = 4.9 Hz, H3); 13C NMR (D2O, 100 MHz, , p.p.m.): 26.2, 26.9 [C(CH3)2], 43.2 (C5), 62.7 (C2'), 65.7 (C4), 77.3 (C3), 81.9 (C2), 111.5 [C(CH3)2], 172.9 (CONH).
The H atoms were all located in a difference map, but those attached to C atoms were repositioned geometrically. The H atoms were initially refined with soft restraints on the bond lengths and angles to regularize their geometry (C-H in the range 0.93-0.98 Å, N-H = 0.86 Å and O-H = 0.82 Å) and Uiso(H) [in the range 1.2-1.5Ueq(parent)], after which the positions were refined with riding constraints. In the absence of significant anomalous scattering, Friedel pairs were merged and the absolute configuration assigned from the starting material.
Data collection: COLLECT (Nonius, 2001).; cell refinement: DENZO/SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO/SCALEPACK; program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: CRYSTALS (Betteridge et al., 2003); molecular graphics: CAMERON (Watkin et al., 1996); software used to prepare material for publication: CRYSTALS.
Financial support (to MS) provided through the European Community's Human Potential Programme under contract No. HPRN-CT-2002-00173 is gratefully acknowledged.
Altomare, A., Cascarano, G., Giacovazzo, C., Guagliardi, A., Burla, M. C., Polidori, G. & Camalli, M. (1994). J. Appl. Cryst. 27, 435.
Asano, N., Nash, R. J., Molyneux, R. J. & Fleet, G. W. J. (2000). Tetrahedron Asymmetry, 11, 1645-1680.
Asano, N., Oseki, K., Kiuz, H. & Matsui, K. (1994). J. Med. Chem. 37, 3701-3706.
Betteridge, P. W., Carruthers, J. R., Cooper, R. I., Prout, K. & Watkin, D. J. (2003). J. Appl. Cryst. 36, 1487.
Bols, M. (1996). In Carbohydrate Building Blocks. New York: John Wiley and Sons.
Bruce, I., Fleet, G. W. J., Cenci di Bello, I. & Winchester, B. (1992). Tetrahedron, 48, 10191-10200.
Bruno, I. J., Cole, J. C., Kessler, M., Luo, J., Motherwell, W. D. S., Purkis, L. H., Smith, B. R., Taylor, R., Cooper, R. I., Harris, S. E. & Orpen, A. G. (2004). J. Chem. Inf. Comput. Sci. 44, 2133-2144.
Ho, P.-T. (1979). Can. J. Chem. 57, 381-381.
Ho, P.-T. (1985). Can. J. Chem. 63, 2221-2224.
Hotchkiss, D. J., Jenkinson, S. F., Storer, R., Heinz, T. & Fleet, G. W. J. (2006). Tetrahedron Lett. 47, 315-318.
Hotchkiss, D., Soengas, R., Simone, M. I., van Ameijde, J., Hunter, S., Cowley, A. R. & Fleet, G. W. J. (2004). Tetrahedron Lett. 45, 9461-9464.
Ichikawa, Y. & Igarashi, Y. (1995). Tetrahedron Lett. 36, 4585-4586.
Ichikawa, Y., Igarashi, Y., Ichikawa, M. & Suhara, Y. (1998). J. Am. Chem. Soc. 120, 3007-3018.
Kiliani, H. (1886). Ber. Dtsch. Chem. Ges. 19, 221-227.
Newton, C. R., Michela, I. S., Fleet, G. W. J., Blériot, Y. & Watkin, D. J. (2004). Acta Cryst. E60, o909-o910.
Nonius (2001). COLLECT. Nonius BV, Delft, The Netherlands.
Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.
Simone, M. I., Soengas, R., Newton, C. R., Watkin, D. J. & Fleet, G. W. J. (2005). Tetrahedron Lett. 46, 5761-5765.
Soengas, R., Izumori, K., Simone, M. I., Watkin, D. J., Skytte, U. P., Soetaert, W. & Fleet, G. W. J. (2005). Tetrahedron Lett. 46, 5755-5759.
Watkin, D. J., Prout, C. K. & Pearce, L. J. (1996). CAMERON. Chemical Crystallography Laboratory, University of Oxford, England.
Winchester, B. & Fleet, G. W. J. (1992). Glycobiology, 2, 199-210.