Abstract
Methyl 5-O-acetyl-5-cyano-6-deoxy-2,3-O-isopropylidene-β-l-gulofuranoside was prepared in high yield from methyl 6-deoxy-2,3-O-isopropylidene-α-d-lyxo-pentodialdo-1,4-furanoside. The configuration at the C5 atom was unambiguosly established by single crystal X-ray analysis of the corresponding 5-O-acetyl derivative. The conformation of the furanose and 1,3-dioxolane rings is also discussed.
Keywords: Saccharide cyanohydrins; methyl 2,3-O-isopropylidene-β-l-gulofuranoside; X-ray crystallography; conformation
Introduction
In the framework of our recent research on synthesis and structure determination of some C–C linked sugar α-amino acids [1,2,3,4,5], we have also prepared several carbohydrate derivatives, including sugar cyanohydrins, amino nitriles, and hydantoins, either as necessary synthetic precursors or suitable models for structural studies. For these model compounds, it is especially important to know their exact structural features with high precision and for this purpose X-ray crystallography was used. This paper reports the preparation of methyl 5-O-acetyl-5-cyano-6-deoxy-2,3-O-isopropylidene-β-l-gulo-furanoside and verification of its structure using single crystal X-ray analysis.
Results and Discussion
Application of the Kiliani cyanohydrin synthesis to methyl 6-deoxy-2,3-O-isopropylidene-α-d-lyxo-hexofuranosid-5-ulose (1) [6] (prepared from methyl 2,3-O-isopropylidene-α-d-lyxo-pentodialdo-1,4-furanoside [7,8] by the Grignard reaction with methylmagnesium iodide and subsequent oxidation of the reaction product with pyridinium dichromate) led to the formation of methyl 5-cyano-6-deoxy-2,3-O-isopropylidene-β-l-gulofuranoside (2) (Scheme 1). The almost 92% isolated yield of 2 indicates a high stereoselectivity for the cyanohydrin formation. Acetylation of 2 under usual conditions afforded methyl 5-O-acetyl-5-cyano-6-deoxy-2,3-O-isopropylidene-β-l-gulofuranoside (3).
Scheme 1.
Compounds 2 and 3 were fully characterized by 1H- and 13C-NMR, EIMS, CIMS, [α]D, mp, and elemental analysis data. Because of the obvious difficulties in unambigously establishing the configuration at C5 (d-manno versus l-gulo in this case) by NMR methods, suitable crystals of compound 3 were subjected to X-ray analysis. This revealed 5-R configuration and because the configuration on positions C1, C2, C3 and C4 did not change, it confirms a l-gulo arrangement. Perspective view and the numbering of atoms for compound 3 is depicted in Figure 1. The relevant crystallographic and structure refinement data for 3 are given in Table 1. The bond lengths and bond angles are listed in Table 2. A list of selected torsion angles is given in Table 3. The final positional parameters are summarized in Table 4. The hydrogen bond geometry for compound 3 is shown in Table 5.
Figure 1.
Thermal ellipsoids at 50% probability level and numbering of atoms for compound 3.
Table 1.
Crystal and experimental data for compound 3a
| Empirical formula | C13H19NO6 |
| Formula weight | 285.29 |
| Temperature, T (K) | 193(2) |
| Wavelength, λ (Å) | 0.71073 |
| Crystal system | orthorhombic |
| Space group | P212121 |
| Unit cell dimensions (Å) | a = 6.0926(2) |
| b = 9.6035(3) | |
| c = 25.5321(7) | |
| Unit cell volume, V (Å3) | 1493.89(8) |
| Formula units per unit cell, Z | 4 |
| Dcalcd (g/cm3) | 1.268 |
| Absorption coefficient, µ (mm-1) | 0.101 |
| F(000) | 608 |
| Crystal size (mm) | 0.80 (max) 0.35 (min) |
| Diffractometer | Siemens SMART CCD |
| θ Range (°) | 2.27–32.79 |
| Range of h | – 9→9 |
| Range of k | – 14→14 |
| Range of l | – 38→38 |
| Reflections | 23913 |
| Independent reflections | 5203 (Rint = 0.0365) |
| Completeness to θ = 32.79 (%) | 96.1 |
| Max. and min. transmission | 0.9656 and 0.9238 |
| Refinement method | Full-matrix least-squares on F2 |
| Data / restraints / parameters | 5203 / 0 / 205 |
| Goodness-of-fit (all) | 1.063 |
| Final R indices [I >2σ(I)] | R1 = 0.0454, wR2 = 0.1126 |
| R indices (all data) | R1 = 0.0581, wR2 = 0.1212 |
| Largest difference peak and hole (e/Å3) | 0.277 and –0.193 |
a Standard deviations in parentheses.
Table 2.
Selected bond lengths [Å] and bond angles [°] for compound 3a
| O1-C1 | 1.4160(16) | O1-C1-C2 | 106.88(13) |
| O1-C7 | 1.440(3) | O4-C1-C2 | 105.44(11) |
| O2-C2 | 1.4336(17) | O2-C2-C1 | 109.70(12) |
| O2-C8 | 1.4438(17) | O2-C2-C3 | 104.54(11) |
| O3-C3 | 1.4330(16) | C1-C2-C3 | 104.34(11) |
| O3-C8 | 1.4367(16) | O3-C3-C4 | 110.70(10) |
| O4-C1 | 1.4295(18) | O3-C3-C2 | 104.40(10) |
| O4-C4 | 1.4468(17) | C4-C3-C2 | 103.10(11) |
| O5-C12 | 1.3721(18) | O4-C4-C5 | 109.71(10) |
| O5-C5 | 1.4659(16) | O4-C4-C3 | 104.95(10) |
| O6-C12 | 1.209(2) | C5-C4-C3 | 116.78(11) |
| N1-C11 | 1.1476(19) | O5-C5-C11 | 110.31(11) |
| C1-C2 | 1.532(2) | O5-C5-C4 | 103.84(10) |
| C2-C3 | 1.560(2) | C11-C5-C4 | 110.95(10) |
| C3-C4 | 1.5411(19) | O5-C5-C6 | 109.02(11) |
| C4-C5 | 1.5349(18) | C11-C5-C6 | 111.87(11) |
| C5-C11 | 1.4961(18) | C4-C5-C6 | 110.54(12) |
| C5-C6 | 1.5375(19) | O3-C8-O2 | 104.43(10) |
| C8-C10 | 1.521(2) | O3-C8-C10 | 108.19(12) |
| C8-C9 | 1.526(2) | O2-C8-C10 | 108.76(12) |
| C12-C13 | 1.501(2) | O3-C8-C9 | 110.44(11) |
| C1-O1-C7 | 112.24(15) | O2-C8-C9 | 111.40(13) |
| C2-O2-C8 | 107.64(10) | C10-C8-C9 | 113.21(13) |
| C3-O3-C8 | 107.66(10) | N1-C11-C5 | 177.77(15) |
| C1-O4-C4 | 105.49(10) | O6-C12-O5 | 123.20(13) |
| C1-O5-C5 | 118.74(11) | O6-C12-C13 | 125.90(15) |
| O1-C1-O4 | 111.53(11) | O5-C12-C13 | 110.90(14) |
a Standard deviations in parentheses.
Table 3.
Selected torsion angles [°] for compound 3a
| C7-O1-C1-C2 | 177.05(12) | C1-O4-C4-C5 | 167.05(10) |
| C4-O4-C1-O1 | 76.03(14) | C1-O4-C4-C3 | 40.82(12) |
| C4-O4-C1-C2 | –39.62(12) | O3-C3-C4-O4 | 86.09(12) |
| C8-O2-C2-C1 | 130.48(12) | C2-C3-C4-O4 | –25.06(12) |
| C8-O2-C2-C3 | 19.09(14) | O3-C3-C4-C5 | –35.62(15) |
| O1-C1-C2-O2 | 152.07(11) | C2-C3-C4-C5 | –146.77(11) |
| O4-C1-C2-O2 | –89.14(13) | O4-C4-C5-O5 | 72.73(12) |
| O1-C1-C2-C3 | –96.41(12) | C3-C4-C5-O5 | –168.08(10) |
| O4-C1-C2-C3 | 22.38(13) | O4-C4-C5-C11 | –45.77(14) |
| C8-O3-C3-C4 | –131.55(11) | C3-C4-C5-C11 | 73.42(14) |
| C8-O3-C3-C2 | –21.24(14) | O4-C4-C5-C6 | –170.48(11) |
| O2-C2-C3-O3 | 1.24(14) | C3-C4-C5-C6 | –51.29(15) |
| C1-C2-C3-O3 | –113.97(11) | C3-O3-C8-O2 | 33.46(14) |
| O2-C2-C3-C4 | 116.99(11) | C2-O2-C8-O3 | –32.57(14) |
| C1-C2-C3-C4 | 1.79(13) | C4-C5-C11-N1 | –64(4) |
a Standard deviations in parentheses.
Table 4.
Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2 x 103) for compound 3a
| Atom | x | y | z | U(eq) |
| O1 | 4992(2) | 9235(1) | 9060(1) | 46(1) |
| O2 | 6664(2) | 6043(1) | 9659(1) | 38(1) |
| O3 | 7554(2) | 5008(1) | 8886(1) | 33(1) |
| O4 | 3751(2) | 7059(1) | 8757(1) | 33(1) |
| O5 | 3436(2) | 6486(1) | 7648(1) | 35(1) |
| O6 | 2411(2) | 4514(1) | 7222(1) | 47(1) |
| N1 | 3034(2) | 3574(1) | 8438(1) | 44(1) |
| C1 | 4630(3) | 7820(1) | 9191(1) | 35(1) |
| C2 | 6885(2) | 7175(1) | 9297(1) | 35(1) |
| C3 | 7528(2) | 6467(1) | 8769(1) | 32(1) |
| C4 | 5584(2) | 6829(1) | 8408(1) | 30(1) |
| C5 | 4956(2) | 5741(1) | 7994(1) | 29(1) |
| C6 | 6985(2) | 5298(2) | 7676(1) | 40(1) |
| C7 | 2989(4) | 9944(2) | 8924(1) | 60(1) |
| C8 | 7812(2) | 4861(1) | 9442(1) | 32(1) |
| C9 | 10240(3) | 4881(2) | 9590(1) | 44(1) |
| C10 | 6643(3) | 3536(2) | 9612(1) | 44(1) |
| C11 | 3833(2) | 4520(1) | 8240(1) | 31(1) |
| C12 | 2457(2) | 5772(2) | 7246(1) | 36(1) |
| C13 | 1479(3) | 6757(2) | 6853(1) | 55(1) |
a Standard deviations in parentheses.
Table 5.
Hydrogen bond geometry in compound 3a
| X-H...Y | Symmetry code | X-H (Å) | H...Y (Å) | X...Y (Å) | X-H...Y (°) |
| C4-H4...O6 | –x+1, y+1/2, –z+3/2 | 1.00 | 2.30 | 3.2752(17) | 164.9 |
| C6-H6A...O6 | 0.98 | 2.59 | 3.111(2) | 113.6 | |
| C6-H6B...O3 | 0.98 | 2.50 | 3.1202(18) | 120.7 |
a Standard deviations in parentheses.
Analysis of the molecular packing in the unit cell revealed two types of hydrogen bonds. In addition to weak intramolecular hydrogen bonds between C6 and O3 and C6 and O6, there are also stronger intermolecular hydrogen bonds involving C4 in one molecule and O6 of the carbonyl group in another molecule, related by a screw axis (Figure 2). The graph-set descriptor of this contact (chain) is C1,1(6). Assignment of the H-bond descriptors are based on the graph-set theory [9]. For convenience, the notation Xa,d(n) has also been adopted, in which (X) is the pattern descriptor, (a) is number of acceptors, (d) is number of donors and (n) is the number of atoms comprising the pattern.
Figure 2.
Crystal packing and hydrogen bonds for compound 3.
The values of calculated puckering parameters [10] Q = 0.377(1) Å, ϕ = 357.1(2)° and selected relevant torsion angles C1–C2–C3–C4 = 1.79(13)°, C2–C3–C4–O4 = –25.06(12)°, C3–C4–O4–C1 = 40.82(12)°, indicate that O4–C1–C2–C3–C4 furanoside ring adopts almost perfect OE conformation with C1, C2, C3 and C4 atoms in a plane and O4 atom directed endo to this plane. Analogously, puckering parameters Q = 0.307(1) Å, ϕ = 141.8(2)° and relevant dihedral angles O2–C2–C3–O3 = 1.24(14)°, C3–O3–C8–O2 = 33.46(14)°, C8–O2–C2–C3 = 19.09(14)° are indicative of almost perfect C-8E conformation for five-membered 1,3-dioxolane ring (O2–C2–C3–O3–C8) with C8 atom lying in the endo direction with respect to the plane defined by the atoms O2, C2, C3, and O3.
Experimental
General
1H- and 13C-NMR spectra (in CDCl3, internal standard Me4Si) were recorded on a Bruker Avance DPX 300 instrument operating at 300.13 and 75.46 MHz working frequencies, respectively. For the assignments of signals, 1D NOESY and C–H heterocorrelated experiments were used. The quaternary carbon atoms were identified on the basis of a semiselective INEPT experiment and a 1D INADEQUATE pulse sequence technique. The EI and CI (using pyridine as a reactive gas [11]) mass spectra (70 eV) were obtained on a Finnigan MAT SSQ 710 instrument. Specific rotations were determined on a Perkin–Elmer 241 polarimeter (10 cm cell). Microanalyses were performed on a Fisons EA 1108 analyzer. Melting points were determined with a Boetius PHMK 05 microscope. All reactions were monitored by TLC on Silica Gel plates (E. Merck) using 1:3 EtOAc–hexane as solvent. Visualization was affected with iodine vapour or H2SO4.
X-ray techniques
Crystal and experimental data for compound 3 are listed in Table 1. The structure was solved by direct methods and refined by a full-matrix least-squares technique. The crystallographic computations were performed with Bruker SHELXTL [12]. Molecular graphics were obtained using the program DIAMOND [13]. Suitable crystals were obtained by slow crystallization of 3 from a 2:1 (v/v) mixture of EtOAc–hexane.
Synthetic methods
Methyl 5-cyano-6-deoxy-2,3-O-isopropylidene-β-l-gulofuranoside (2): KCN (3.25 g, 50 mmol), water (15 mL) and NaHCO3 (4.2 g, 50 mmol) were sequentially added to a stirred solution of 5-ulose 1 (5.4 g, 25 mmol) in ether (150 mL) under cooling at 0 °C, and the stirring at this temperature was continued for 2 h. The ethereal layer was then separated and the water layer was extracted with ether (3 x 50 mL). The combined ethereal solutions were dried (Na2SO4), the solvent was evaporated and the crude product (Rf 0.34) was recrystallized from a 3:1 (v/v) mixture of EtOAc–hexane to afford white needles of cyanohydrin 2 (5.6 g, 92% yield); mp 119–121 °C; [α]D + 64° (c 1, MeOH); 1H-NMR: δ 5.08 (s, 1H, H-1), 4.85 (dd, 1H, J2,3 6.0 Hz, J3,4 4.0 Hz, H-3), 4.62 (d, 1H, H-2), 3.92 (d, 1H, H-4), 3.68 (s, 1H, OH), 3.36 (s, 3H, OCH3), 1.77 (s, 3H, H-6), 1.60 and 1.33 (2s, each 3H, Me2C); 13C-NMR: δ 120.4 (CN), 114.1 (CMe2), 107.0 (C-1), 84.6 (C-2), 82.5 (C-4), 79.1 (C-3), 69.6 (C-5), 55.0 (OCH3), 26.6 (C-6), 24.7 and 24.1 [(CH3)2C]; EIMS: m/z 243 [M]+, 228, 212, 185, 183, 173, 114, 113, 87, 73, 43; CIMS: m/z 323 [M + C6H5NH]+. Anal. Calcd for C11H17NO5: C, 54.31; H, 7.04; N, 5.76. Found: C, 54.24; H, 7.10; N, 5.81.
Methyl 5-O-acetyl-5-cyano-6-deoxy-2,3-O-isopropylidene-β-l-gulofuranoside (3): Acetylation of 2 (1.22 g, 5 mmol) with Ac2O (7 mL) in pyridine (15 mL) overnight followed by concentration and co-evaporation with toluene at diminished pressure gave 3 (1.28 g, 90% yield) as white needles after recrystallization from a 2:1 (v/v) mixture of EtOAc–hexane; Rf 0.48; mp 58–59 °C; [α]D + 43° (c 1, MeOH); 1H-NMR: δ 5.05 (s, 1H, H-1), 4.78 (dd, 1H, J2,3 5.9 Hz, J3,4 3.6 Hz, H-3), 4.60 (d, 1H, H-2), 4.18 (d, 1H, H-4), 3.37 (s, 3H, OCH3), 2.14 (s, 3H, OCCH3), 1.93 (s, 3H, H-6), 1.55 and 1.31 (2s, each 3H, Me2C); 13C-NMR: δ 168.4 (CO), 116.4 (CN), 113.7 (CMe2), 107.0 (C-1), 84.3 (C-2), 81.3 (C-4), 78.6 (C-3), 72.8 (C-5), 54.8 (OCH3), 24.7 and 24.3 [(CH3)2C], 21.2 (OCCH3), 20.0 (C-6); CIMS: m/z 365 [M + C6H5NH]+. Anal. Calcd for C13H19NO6: C, 54.73; H, 6.71; N, 4.91. Found: C, 54.62; H, 6.77; N, 4.96.
Acknowledgments
The authors thank K. Paule, G. Košický, A. Karovičová, A. Kanská, and Dr. V. Pätoprstý (Institute of Chemistry) for microanalyses, optical rotation, NMR and mass spectral measurements. Financial support of this work by the Scientific Grant Agency (VEGA, Slovak Academy of Sciences and Ministry of Education, Grant Nos. 2/7144/21 and 2/7204/20) is gratefully appreciated.
Footnotes
Samples Availability: The product 2 reported in this paper is available from MDPI.
References and Notes
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