5-Amino-5-deoxy-2-C-hydroxymethyl-2,3-O-isopropylidene-l-lyxono-1,5-lactam

Simone, M.; Fleet, G.W.J.; Bream, R.; Watkin, D.J.

doi:10.1107/S1600536807007568

organic compounds

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ISSN: 2056-9890

Volume 63| Part 3| March 2007| Pages o1409-o1411

https://doi.org/10.1107/S1600536807007568

5-Amino-5-deoxy-2-C-hydroxymethyl-2,3-O-isopropylidene-L-lyxono-1,5-lactam

Michela Simone,^a ^* George W. J. Fleet,^a Richard Bream ^b and David J. Watkin ^b

^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: michela_simone@yahoo.co.uk

(Received 8 February 2007; accepted 13 February 2007; online 23 February 2007)

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.

Comment

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—H10⋯O5—H9⋯O7). Curiously, the amine atom H13 is not involved in any strong hydrogen bonds. The closest O atoms are too distant, and the N—H⋯O 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 − $[{1\over 2}]$ , $[{1\over 2}]$ − z.]

Experimental

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: [α]_D²¹ −14.0 (c 0.18 in methanol); IR (thin film, ν_max, cm⁻¹): 3340 (br, OH, NH), 1661 (s, CONH, six-ring lactam); ¹H NMR (D₂O, 400 MHz, δ, p.p.m.): 1.28, 1.34 [2 × 3H, 2 × s, C(CH₃)₂], 3.18 (1H, dd, J_H5,H5′ = 13.7 Hz, J_H5,H4 = 5.1 Hz, H5), 3.51 (1H, dd, J_H5′,H5 = 13.6 Hz, J_H5′,H4 = 3.5 Hz, H5′), 3.63 (1H, d, J_H2,H2′ = 12.1 Hz, H2), 3.77 (1H, d, J_H2′,H2 = 12.1 Hz, H2′), 4.08–4.15 (1H, m, J = 4.9 Hz, J = 3.6 Hz, H4), 4.34 (1H, d, J_H3,H4 = 4.9 Hz, H3); ¹³C NMR (D₂O, 100 MHz, δ, 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).

Crystal data

C₉H₁₅NO₅
M_r = 217.22
Orthorhombic, P 22₁ 2₁
a = 6.2423 (2) Å
b = 12.0919 (4) Å
c = 14.1651 (6) Å
V = 1069.20 (7) Å³
Z = 4
Mo Kα radiation
μ = 0.11 mm⁻¹
T = 150 K
0.70 × 0.42 × 0.39 mm

Data collection

Nonius KappaCCD area-detector diffractometer
Absorption correction: multi-scan (DENZO/SCALEPACK; Otwinowski & Minor, 1997 ) T_min = 0.84, T_max = 0.96
6832 measured reflections
1402 independent reflections
1402 reflections with I > −3σ(I)
R_int = 0.025

Refinement

R[F² > 2σ(F²)] = 0.033
wR(F²) = 0.075
S = 0.89
1402 reflections
136 parameters
H-atom parameters constrained
Δρ_max = 0.19 e Å⁻³
Δρ_min = −0.18 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O5—H9⋯O7ⁱ	0.83	1.79	2.614 (2)	170
O8—H10⋯O5ⁱⁱ	0.85	1.83	2.666 (2)	170
N5—H13⋯O8ⁱⁱⁱ	0.90	2.52	3.339 (2)	153
N5—H13⋯O11^iv	0.90	2.57	3.140 (2)	122
Symmetry codes: (i) x-1, y, z; (ii) $[-x+1, y+{\script{1\over 2}}, -z+{\script{1\over 2}}]$ ; (iii) x+1, y, z; (iv) $[-x+2, y+{\script{1\over 2}}, -z+{\script{1\over 2}}]$ .

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 U_iso(H) [in the range 1.2–1.5U_eq(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.

Supporting information

Crystal structure: contains datablocks 3, global. DOI: https://doi.org/10.1107/S1600536807007568/at2225sup1.cif

Structure factors: contains datablock 3. DOI: https://doi.org/10.1107/S1600536807007568/at22253sup2.hkl

Computing details top

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.

2-C-Hydroxymethyl-2,3-O-isopropylidene-L-lyxono-1,5-lactam top

Crystal data top

C₉H₁₅NO₅	F(000) = 464
M_r = 217.22	D_x = 1.349 Mg m⁻³
Orthorhombic, P22₁2₁	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2bc 2	Cell parameters from 1345 reflections
a = 6.2423 (2) Å	θ = 5–27°
b = 12.0919 (4) Å	µ = 0.11 mm⁻¹
c = 14.1651 (6) Å	T = 150 K
V = 1069.20 (7) Å³	Plate, colourless
Z = 4	0.70 × 0.42 × 0.39 mm

Data collection top

Nonius KappaCCD area-detector diffractometer	1402 reflections with I > −3σ(I)
Graphite monochromator	R_int = 0.025
ω scans	θ_max = 27.5°, θ_min = 5.3°
Absorption correction: multi-scan (DENZO/SCALEPACK; Otwinowski & Minor, 1997)	h = −8→8
T_min = 0.84, T_max = 0.96	k = −15→15
6832 measured reflections	l = −18→18
1402 independent reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.033	H-atom parameters constrained
wR(F²) = 0.075	w = 1/[σ²(F²) + (0.04P)² + 0.18P], where P = [max(F_o²,0) + 2F_c²]/3
S = 0.89	(Δ/σ)_max = 0.000207
1402 reflections	Δρ_max = 0.19 e Å⁻³
136 parameters	Δρ_min = −0.18 e Å⁻³
333 restraints

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.7689 (2)	0.36364 (11)	0.24059 (9)	0.0218
C2	0.6527 (2)	0.40678 (11)	0.15372 (9)	0.0244
C3	0.6634 (3)	0.53128 (11)	0.14364 (10)	0.0284
C4	0.8936 (3)	0.56994 (12)	0.14233 (11)	0.0328
N5	1.0184 (2)	0.52029 (11)	0.21867 (9)	0.0328
O5	0.45119 (17)	0.28841 (8)	0.31454 (8)	0.0361
C6	0.9726 (2)	0.42833 (12)	0.26584 (10)	0.0255
O7	1.08682 (17)	0.39314 (9)	0.33104 (8)	0.0350
C7	0.6349 (2)	0.35344 (11)	0.33024 (9)	0.0258
O8	0.5438 (2)	0.57202 (8)	0.22163 (8)	0.0356
O9	0.76720 (18)	0.35597 (8)	0.07790 (6)	0.0302
H9	0.3364	0.3237	0.3128	0.0543*
C10	0.8366 (3)	0.24932 (11)	0.10950 (9)	0.0261
H10	0.5431	0.6419	0.2170	0.0535*
O11	0.83058 (18)	0.25414 (7)	0.21157 (6)	0.0257
C12	0.6863 (3)	0.15998 (12)	0.07612 (11)	0.0373
C13	1.0646 (3)	0.23253 (17)	0.07736 (12)	0.0455
H13	1.1436	0.5518	0.2340	0.0405*
H21	0.5013	0.3829	0.1550	0.0275*
H31	0.5925	0.5537	0.0843	0.0326*
H41	0.8977	0.6510	0.1529	0.0380*
H42	0.9530	0.5510	0.0810	0.0385*
H71	0.7231	0.3183	0.3774	0.0312*
H72	0.5957	0.4294	0.3497	0.0305*
H121	0.7335	0.0879	0.0991	0.0556*
H122	0.5442	0.1776	0.0960	0.0557*
H123	0.6891	0.1601	0.0064	0.0552*
H131	1.1219	0.1634	0.1012	0.0681*
H132	1.1507	0.2953	0.0976	0.0675*
H133	1.0609	0.2316	0.0098	0.0676*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0241 (6)	0.0184 (6)	0.0228 (6)	0.0020 (5)	−0.0001 (5)	−0.0004 (5)
C2	0.0260 (6)	0.0234 (6)	0.0236 (6)	0.0005 (5)	−0.0023 (6)	0.0001 (5)
C3	0.0370 (7)	0.0219 (6)	0.0262 (6)	0.0029 (6)	0.0007 (6)	0.0020 (5)
C4	0.0431 (8)	0.0240 (7)	0.0313 (7)	−0.0056 (6)	0.0064 (7)	0.0027 (6)
N5	0.0308 (6)	0.0351 (7)	0.0327 (6)	−0.0131 (5)	0.0000 (6)	−0.0006 (5)
O5	0.0266 (5)	0.0245 (5)	0.0571 (7)	−0.0020 (4)	0.0105 (5)	−0.0005 (5)
C6	0.0229 (6)	0.0293 (7)	0.0243 (6)	0.0018 (5)	0.0012 (5)	−0.0035 (5)
O7	0.0266 (5)	0.0441 (6)	0.0344 (5)	0.0025 (5)	−0.0067 (5)	−0.0009 (5)
C7	0.0258 (6)	0.0253 (7)	0.0263 (6)	0.0003 (5)	0.0035 (6)	0.0011 (6)
O8	0.0463 (6)	0.0219 (5)	0.0388 (6)	0.0050 (5)	0.0107 (5)	0.0018 (4)
O9	0.0462 (6)	0.0235 (5)	0.0209 (4)	0.0041 (5)	0.0009 (5)	0.0007 (4)
C10	0.0341 (7)	0.0227 (6)	0.0215 (6)	0.0043 (6)	0.0015 (6)	0.0000 (5)
O11	0.0341 (5)	0.0213 (4)	0.0216 (4)	0.0063 (4)	−0.0013 (4)	−0.0010 (3)
C12	0.0511 (9)	0.0295 (7)	0.0313 (7)	−0.0039 (7)	−0.0065 (8)	−0.0023 (6)
C13	0.0388 (8)	0.0545 (10)	0.0432 (9)	0.0095 (9)	0.0132 (8)	0.0041 (8)

Geometric parameters (Å, º) top

C1—C2	1.5205 (17)	O5—H9	0.834
C1—C6	1.5355 (19)	C6—O7	1.2418 (17)
C1—C7	1.5257 (18)	C7—H71	0.964
C1—O11	1.4390 (16)	C7—H72	0.990
C2—C3	1.5137 (19)	O8—H10	0.847
C2—O9	1.4289 (16)	O9—C10	1.4322 (16)
C2—H21	0.989	C10—O11	1.4474 (16)
C3—C4	1.512 (2)	C10—C12	1.507 (2)
C3—O8	1.4211 (18)	C10—C13	1.508 (2)
C3—H31	0.988	C12—H121	0.976
C4—N5	1.462 (2)	C12—H122	0.955
C4—H41	0.992	C12—H123	0.988
C4—H42	0.972	C13—H131	0.970
N5—C6	1.3285 (19)	C13—H132	0.973
N5—H13	0.896	C13—H133	0.958
O5—C7	1.4079 (17)

C2—C1—C6	114.13 (11)	C1—C6—O7	118.31 (12)
C2—C1—C7	116.11 (11)	N5—C6—O7	122.51 (13)
C6—C1—C7	107.55 (10)	C1—C7—O5	111.11 (11)
C2—C1—O11	102.24 (10)	C1—C7—H71	107.4
C6—C1—O11	108.27 (11)	O5—C7—H71	109.2
C7—C1—O11	108.07 (10)	C1—C7—H72	107.0
C1—C2—C3	113.36 (11)	O5—C7—H72	111.2
C1—C2—O9	102.85 (10)	H71—C7—H72	111.0
C3—C2—O9	109.56 (11)	C3—O8—H10	106.8
C1—C2—H21	110.0	C2—O9—C10	107.67 (10)
C3—C2—H21	109.5	O9—C10—O11	105.55 (10)
O9—C2—H21	111.5	O9—C10—C12	111.04 (12)
C2—C3—C4	110.52 (13)	O11—C10—C12	109.02 (12)
C2—C3—O8	104.39 (11)	O9—C10—C13	108.21 (13)
C4—C3—O8	113.68 (12)	O11—C10—C13	109.37 (13)
C2—C3—H31	109.5	C12—C10—C13	113.35 (13)
C4—C3—H31	109.3	C10—O11—C1	109.23 (9)
O8—C3—H31	109.3	C10—C12—H121	110.3
C3—C4—N5	111.75 (12)	C10—C12—H122	109.0
C3—C4—H41	109.2	H121—C12—H122	112.4
N5—C4—H41	106.3	C10—C12—H123	107.6
C3—C4—H42	107.5	H121—C12—H123	109.2
N5—C4—H42	111.2	H122—C12—H123	108.1
H41—C4—H42	111.0	C10—C13—H131	111.0
C4—N5—C6	126.96 (12)	C10—C13—H132	109.1
C4—N5—H13	118.0	H131—C13—H132	111.5
C6—N5—H13	115.0	C10—C13—H133	106.3
C7—O5—H9	114.7	H131—C13—H133	110.3
C1—C6—N5	119.17 (12)	H132—C13—H133	108.5

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O5—H9···O7ⁱ	0.83	1.79	2.614 (2)	170
O8—H10···O5ⁱⁱ	0.85	1.83	2.666 (2)	170
N5—H13···O8ⁱⁱⁱ	0.90	2.52	3.339 (2)	153
N5—H13···O11^iv	0.90	2.57	3.140 (2)	122

Symmetry codes: (i) x−1, y, z; (ii) −x+1, y+1/2, −z+1/2; (iii) x+1, y, z; (iv) −x+2, y+1/2, −z+1/2.

Acknowledgements

Financial support (to MS) provided through the European Community's Human Potential Programme under contract No. HPRN-CT-2002–00173 is gratefully acknowledged.

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