(6S)-Methyl-l-swainsonine [(1R,2S,6S,8S,8aS)-6-methyl­octa­hydro­indolizine-1,2,8-triol]

Håkansson, A.E.; Horne, G.; Fleet, G.W.J.; Watkin, D.J.

doi:10.1107/S1600536806052111

organic compounds

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ISSN: 2056-9890

Volume 63| Part 1| January 2007| Pages o210-o212

https://doi.org/10.1107/S1600536806052111

(6S)-Methyl-L-swainsonine [(1R,2S,6S,8S,8aS)-6-methyloctahydroindolizine-1,2,8-triol]

Anders E. Håkansson,^a ^* Graeme Horne,^a George W.J. Fleet ^a and David J. Watkin ^b

^aDepartment of Organic Chemistry, Chemistry 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: anders.hakansson@chem.ox.ac.uk

(Received 28 November 2006; accepted 1 December 2006; online 8 December 2006)

(6S)-Methyl-L-swainsonine, C₉H₁₇NO₃, together with the 6R-epimer, was formed in a synthetic sequence in which there was an ambiguity in configuration at position C-6. This ambiguity was resolved by establishing the relative stereochemistry of the title compound by X-ray crystallographic analysis. The absolute configuration was determined by the use of D-glycero-D-gulo-heptono-1,4-lactone as the starting material.

Comment

Imino sugars, in which the ring oxygen of a sugar is replaced, are a class of glycosidase inhibitor with a range of chemotherapeutic targets (Watson et al., 2001 ; Asano et al., 2000 ). D-Swainsonine (1), a natural product isolated from Swainsona canescens (Colegate et al., 1979 ), is a mimic of D-mannofuranose (2) and a powerful α-mannosidase inhibitor. Potential use of 1 for the chemotherapy of cancer (Lagana et al., 2006 ; Klein et al., 1999 ; Goss et al., 1997 ) has led to the publication of over 40 syntheses (Au & Pyne, 2006 ; Ceccon et al., 2006 ; Martin et al., 2005 ; Heimgaertner et al., 2005 ; Nemr, 2000 ). L-Swainsonine (4), the enantiomer of the natural product (1), is the corresponding imino sugar mimic of L-rhamnofuranose (3) and is a potent inhibitor of naringinase – an α-rhamnosidase (Davis et al., 1996 ). Very few syntheses of 4, with different therapeutic targets, have been reported (Guo & O'Doherty, 2006 ; Oishi et al., 1995 ). No carbon-branched swainsonine analogues have been described. In order to determine how such a substitution changes the structure of the swainsonine nucleus, the C6-methyl analogues (5) and (6) were prepared (Håkansson et al., 2007 ); in order to firmly establish the relative configuration at C6 of the two epimers, X-ray crystallographic analysis of (6) is reported in this paper. The absolute configuration of (6S)-methyl-L-swainsonine (6) was determined by the use of D-glycero-D-gulo-heptono-1,4-lactone as the starting material.

The molecular structure of (6) (Fig. 1) shows no unusual features. The largest differences from the MOGUL norms (Bruno et al., 2004 ) are C5—O6 (0.01 Å) and C11—C10—C1 (2.9°). As is normal in sugar derivatives, all the hydroxyl groups are involved in hydrogen bonding. Each molecule takes part in two different hydrogen-bonded helices (Fig. 2 and Table 1). The helix around ( $[1\over3]$ , $[2\over3]$ , z) only involves O12; that at ( $[2\over3]$ , $[1\over3]$ , z) involves both O7 and N2. The fact that each molecule is involved in two helices leads to a very rigid framework and explains the high melting point (422 K).

Figure 1
The molecular structure of 6, with displacement ellipsoids drawn at the 50% probability level. H atoms are shown as spheres of arbitrary radius.

Figure 2
Part of the crystal structure of 6, with hydrogen bonds shown as dotted lines. Each molecule contributes to two helices. That at ( $[1\over 3]$ , $[2\over3]$ , z) only involves O12; that at ( $[2\over3]$ , $[1\over3]$ , z) involves both O7 and N2. [Symmetry codes: (i) x, y, z − 1; (ii) −y + 1, x − y, z − $[{2\over 3}]$ ; (iv) −y + 1, x − y + 1, z − $[{2\over 3}]$ ; (vi) −x + y, −x + 1, z − $[{1\over 3}]$ ; (vii) −x + y + 1, −x + 1, z − $[{1\over 3}]$ .]

Experimental

(6S)-Methyl-L-swainsonine (6) (Håkansson et al., 2007) was purified by Dowex 50WX8–200 ion exchange resin (H⁺ form, eluent 2 M aqueous ammonia) and recrystallized from ethyl acetate and cyclohexane to yield fine colourless brittle needles (m.p. 421–423 K). [α]_D²¹ = +43.7 (c = 1.72, H₂O).

Crystal data

C₉H₁₇NO₃
M_r = 187.24
Trigonal, P 3₁
a = 11.4494 (6) Å
c = 6.1727 (2) Å
V = 700.76 (6) Å³
Z = 3
D_x = 1.331 Mg m⁻³
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 190 K
Needle, colourless
0.80 × 0.10 × 0.10 mm

Data collection

Nonius KappaCCD diffractometer
ω scans
Absorption correction: multi-scan (DENZO/SCALEPACK; Otwinowski & Minor, 1997 ) T_min = 0.81, T_max = 0.99
6022 measured reflections
1025 independent reflections
982 reflections with I > 2σ(I)
R_int = 0.044
θ_max = 27.1°

Refinement

Refinement on F²
R[F² > 2σ(F²)] = 0.028
wR(F²) = 0.069
S = 0.97
1020 reflections
118 parameters
H-atom parameters constrained
w = 1/[σ²(F²) + (0.04P)² + 0.1P], where P = [max(F_o²,0) + 2F_c²]/3
(Δ/σ)_max < 0.001
Δρ_max = 0.17 e Å⁻³
Δρ_min = −0.12 e Å⁻³

Table 1
Selected bond angles (°)

N2—C8—C9	110.76 (14)
C8—C9—C10	109.86 (15)
C8—C9—C13	112.68 (16)
C10—C9—C13	112.04 (15)
C9—C10—C11	113.00 (14)
C10—C11—C1	109.68 (13)
C10—C11—O12	110.95 (13)
C1—C11—O12	110.92 (13)

Table 2
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O12—H3⋯O12ⁱ	0.85	1.88	2.708 (2)	165
O6—H5⋯O7	0.82	1.93	2.541 (2)	131
O7—H1⋯N2ⁱⁱ	0.87	1.99	2.846 (2)	167
Symmetry codes: (i) $[-y+1, x-y+1, z+{\script{1\over 3}}]$ ; (ii) $[-y+1, x-y, z+{\script{1\over 3}}]$ .

In the absence of significant anomalous scattering, Friedel pairs were merged and the absolute configuration assigned from the starting material.

The sample consisted of fine brittle plates which could not be cut without being destroyed. The relatively large ratio of minimum to maximum corrections applied in the multiscan process (1:1.22) reflects changes in the illuminated volume of the crystal. The changes in illuminated volume were kept to a minimum, and were taken into account (Görbitz, 1999 ) by the multi-scan inter-frame scaling (DENZO/SCALEPACK; Otwinowski & Minor, 1997).

The H atoms were all located in a difference map, but those attached to carbon 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, O—H = 0.82 Å) and U_iso(H) (in the range 1.2–1.5 times U_eq of the parent atom), after which the positions were refined with riding constraints.

Data collection: COLLECT (Nonius, 2001 ); cell refinement: DENZO/SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO/SCALEPACK; program(s) used to solve structure: user defined structure solution: 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 6, global. DOI: https://doi.org/10.1107/S1600536806052111/lh2265sup1.cif

Structure factors: contains datablock 6. DOI: https://doi.org/10.1107/S1600536806052111/lh22656sup2.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: user defined structure solution; 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.

(1R,2S,6S,8S,8aS)-6-methyloctahydroindolizine-1,2,8-triol top

Crystal data top

C₉H₁₇NO₃	D_x = 1.331 Mg m⁻³
M_r = 187.24	Mo Kα radiation, λ = 0.71073 Å
Trigonal, P3₁	Cell parameters from 1020 reflections
Hall symbol: P 31	θ = 1–27°
a = 11.4494 (6) Å	µ = 0.10 mm⁻¹
c = 6.1727 (2) Å	T = 190 K
V = 700.76 (6) Å³	Plate, colourless
Z = 3	0.80 × 0.10 × 0.10 mm
F(000) = 306

Data collection top

Nonius KappaCCD diffractometer	982 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.044
ω scans	θ_max = 27.1°, θ_min = 2.1°
Absorption correction: multi-scan (DENZO/SCALEPACK; Otwinowski & Minor, 1997)	h = −14→14
T_min = 0.81, T_max = 0.99	k = −12→12
6022 measured reflections	l = −7→7
1025 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)] = 0.028	H-atom parameters constrained
wR(F²) = 0.069	w = 1/[σ²(F²) + (0.04P)² + 0.1P], where P = [max(F_o²,0) + 2F_c²]/3
S = 0.97	(Δ/σ)_max = 0.000219
1020 reflections	Δρ_max = 0.17 e Å⁻³
118 parameters	Δρ_min = −0.12 e Å⁻³
35 restraints

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

	x	y	z	U_iso*/U_eq
C1	0.53634 (17)	0.59057 (16)	0.8235 (3)	0.0242
N2	0.66713 (13)	0.60020 (14)	0.8706 (2)	0.0241
C3	0.63458 (18)	0.50300 (18)	1.0487 (3)	0.0310
C4	0.49845 (18)	0.38209 (17)	0.9851 (3)	0.0282
C5	0.44047 (17)	0.43864 (18)	0.8097 (3)	0.0273
O6	0.44492 (14)	0.38857 (13)	0.6023 (2)	0.0336
O7	0.51498 (14)	0.27798 (13)	0.8919 (2)	0.0322
C8	0.76987 (19)	0.73864 (18)	0.9248 (3)	0.0317
C9	0.79406 (18)	0.83322 (17)	0.7343 (3)	0.0321
C10	0.65986 (19)	0.82114 (17)	0.6624 (3)	0.0318
C11	0.54856 (16)	0.67521 (16)	0.6254 (3)	0.0251
O12	0.42283 (13)	0.66811 (14)	0.5784 (2)	0.0328
C13	0.86788 (19)	0.8108 (2)	0.5457 (3)	0.0366
H11	0.5121	0.6267	0.9485	0.0292*
H31	0.6278	0.5418	1.1870	0.0378*
H32	0.7014	0.4729	1.0604	0.0364*
H41	0.4386	0.3464	1.1114	0.0336*
H51	0.3485	0.4162	0.8438	0.0326*
H81	0.8522	0.7397	0.9658	0.0365*
H82	0.7392	0.7723	1.0503	0.0356*
H91	0.8513	0.9241	0.7916	0.0356*
H101	0.6293	0.8580	0.7800	0.0391*
H102	0.6720	0.8705	0.5290	0.0394*
H111	0.5694	0.6355	0.4976	0.0293*
H131	0.8958	0.8827	0.4416	0.0520*
H132	0.9472	0.8081	0.5970	0.0527*
H133	0.8066	0.7237	0.4744	0.0519*
H3	0.4063	0.7096	0.6762	0.0529*
H5	0.4670	0.3317	0.6258	0.0520*
H1	0.4862	0.2075	0.9762	0.0503*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0250 (8)	0.0264 (8)	0.0237 (7)	0.0148 (6)	−0.0011 (6)	−0.0034 (6)
N2	0.0236 (7)	0.0251 (7)	0.0241 (7)	0.0126 (6)	−0.0047 (5)	−0.0019 (5)
C3	0.0364 (9)	0.0319 (9)	0.0255 (9)	0.0178 (8)	−0.0056 (7)	0.0014 (6)
C4	0.0305 (9)	0.0283 (8)	0.0276 (8)	0.0161 (7)	0.0032 (6)	0.0027 (7)
C5	0.0240 (8)	0.0287 (8)	0.0302 (8)	0.0141 (7)	−0.0010 (6)	0.0002 (6)
O6	0.0418 (7)	0.0304 (7)	0.0324 (6)	0.0210 (6)	−0.0098 (5)	−0.0078 (5)
O7	0.0368 (7)	0.0288 (6)	0.0345 (7)	0.0190 (6)	0.0037 (5)	0.0036 (5)
C8	0.0324 (9)	0.0291 (9)	0.0303 (8)	0.0130 (8)	−0.0088 (7)	−0.0065 (7)
C9	0.0321 (9)	0.0221 (8)	0.0379 (10)	0.0105 (7)	−0.0043 (7)	−0.0031 (7)
C10	0.0360 (10)	0.0253 (8)	0.0369 (10)	0.0174 (8)	−0.0012 (7)	0.0004 (7)
C11	0.0277 (8)	0.0287 (8)	0.0248 (8)	0.0185 (7)	−0.0026 (6)	−0.0029 (6)
O12	0.0348 (7)	0.0411 (7)	0.0318 (6)	0.0260 (6)	−0.0070 (5)	−0.0069 (5)
C13	0.0318 (9)	0.0309 (9)	0.0433 (10)	0.0127 (8)	0.0020 (8)	0.0045 (8)

Geometric parameters (Å, º) top

C1—N2	1.474 (2)	C8—C9	1.527 (3)
C1—C5	1.526 (2)	C8—H81	0.971
C1—C11	1.523 (2)	C8—H82	1.004
C1—H11	0.979	C9—C10	1.538 (3)
N2—C3	1.474 (2)	C9—C13	1.534 (3)
N2—C8	1.464 (2)	C9—H91	0.978
C3—C4	1.530 (2)	C10—C11	1.529 (2)
C3—H31	0.983	C10—H101	0.988
C3—H32	0.986	C10—H102	0.968
C4—C5	1.569 (2)	C11—O12	1.430 (2)
C4—O7	1.419 (2)	C11—H111	0.997
C4—H41	0.982	O12—H3	0.845
C5—O6	1.414 (2)	C13—H131	0.964
C5—H51	0.974	C13—H132	0.977
O6—H5	0.821	C13—H133	0.990
O7—H1	0.875

N2—C1—C5	102.77 (12)	N2—C8—H81	108.8
N2—C1—C11	110.11 (13)	C9—C8—H81	111.2
C5—C1—C11	117.74 (14)	N2—C8—H82	110.3
N2—C1—H11	107.8	C9—C8—H82	107.2
C5—C1—H11	109.4	H81—C8—H82	108.6
C11—C1—H11	108.6	C8—C9—C10	109.86 (15)
C1—N2—C3	103.09 (13)	C8—C9—C13	112.68 (16)
C1—N2—C8	111.23 (13)	C10—C9—C13	112.04 (15)
C3—N2—C8	114.20 (13)	C8—C9—H91	105.3
N2—C3—C4	104.51 (13)	C10—C9—H91	108.0
N2—C3—H31	110.8	C13—C9—H91	108.7
C4—C3—H31	110.9	C9—C10—C11	113.00 (14)
N2—C3—H32	111.8	C9—C10—H101	107.5
C4—C3—H32	108.6	C11—C10—H101	107.3
H31—C3—H32	110.1	C9—C10—H102	110.4
C3—C4—C5	104.67 (13)	C11—C10—H102	108.0
C3—C4—O7	111.13 (15)	H101—C10—H102	110.7
C5—C4—O7	109.17 (14)	C10—C11—C1	109.68 (13)
C3—C4—H41	110.9	C10—C11—O12	110.95 (13)
C5—C4—H41	111.6	C1—C11—O12	110.92 (13)
O7—C4—H41	109.3	C10—C11—H111	110.9
C1—C5—C4	102.73 (13)	C1—C11—H111	108.2
C1—C5—O6	111.19 (14)	O12—C11—H111	106.1
C4—C5—O6	110.44 (13)	C11—O12—H3	108.9
C1—C5—H51	110.8	C9—C13—H131	109.7
C4—C5—H51	111.5	C9—C13—H132	111.0
O6—C5—H51	110.0	H131—C13—H132	109.1
C5—O6—H5	104.4	C9—C13—H133	109.5
C4—O7—H1	112.8	H131—C13—H133	109.2
N2—C8—C9	110.76 (14)	H132—C13—H133	108.3

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O12—H3···O12ⁱ	0.85	1.88	2.708 (2)	165
O6—H5···O7	0.82	1.93	2.541 (2)	131
O7—H1···N2ⁱⁱ	0.87	1.99	2.846 (2)	167

Symmetry codes: (i) −y+1, x−y+1, z+1/3; (ii) −y+1, x−y, z+1/3.

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