supplementary materials


gk2429 scheme

Acta Cryst. (2012). E68, o149-o150    [ doi:10.1107/S1600536811053190 ]

(2R)-8-Benzyl-2-[(S)-hydroxy(phenyl)methyl]-8-azabicyclo[3.2.1]octan-3-one

K. Brzezinski, R. Lazny, M. Sienkiewicz, S. Wojtulewski and Z. Dauter

Abstract top

The crystal of the title compound, C21H23NO2, was chosen from a conglomerate formed by a racemic mixture. An intramolecular hydrogen bond is formed between hydroxy group and heterocyclic N atom of the azabicyclo[3.2.1]octan-3-one system. The crystal structure is stabilized by C-H...O interactions between aliphatic C-H groups and the carbonyl O atom. For the title chiral crystal, the highly redundant and accurate diffraction data set collected with low energy copper radiation gave a Flack parameter of 0.12 (18) for anomalous scattering effects originating from O atoms.

Comment top

Tropane (8-methyl-8-azabicyclo[3.2.1]octane) and nortropane (8-azabicyclo[3.2.1]octane) are known scaffolds of numerous natural alkaloids, many of which demonstrate a range of biological activities. Many synthetic derivatives and unnatural analogues of tropane alkaloids have been synthesized and studied as potential agrochemically or pharmaceutically useful agents (Singh, 2000). Diastereomerically and enantimerically pure aldols of tropinone were used as key intermediates in stereoselective synthesis of unnatural enantiomer of cocaine (ent-cocaine), knightinol, alkaloid KD–B and ferrugine (Sienkiewicz et al., 2009). Stereoselective syntheses of nortropinone aldols (Lazny & Nodzewska, 2003; Lazny et al., 2001) is more complicated and remains a challenge. Therefore synthetically equivalent N-benzylnortropinone aldols may open a route to synthetic availability of nor-analogues of potential pharmaceutical importance. Knowledge of the structure and reactivity of the N-benzyl analogues of tropanes is also used for modeling reactivity of nortropanes anchored through nitrogen on commonly used solid-phase supports with benzyl derived linkers. The solid-phase immobilization and subsequent transformations are typically used in combinatorial approaches to preparation of libraries of potentially bioactive substances.

The studied N-benzyl compound was prepared by a procedure analogous to method known for N-methyl aldols. The synthetic procedure gave a racemic mixture, however homochiral crystals were formed spontaneously. An enantiomorphic crystal was picked at random.

The crystal structure of the title compound contains one molecule in the asymmetric unit (Fig. 1). The Flack parameter is equal to 0.12 (18) for the crystals containing (2R)-8-benzyl-2-[(S)-hydroxy(phenyl)methyl]-8-azabicyclo[3.2.1] octan-3-one enantiomer. The intramolecular hydrogen bond is formed between hydroxyl group and heterocyclic nitrogen atom from the azabicyclo[3.2.1]octan-3-one system. The carbonyl oxygen atom is located near equatorial hydrogen atoms of C6 and C7, as well as, the H16A atom. Intra- and intermolecular interactions are shown in Fig. 2 and summarized in Table 1.

Related literature top

For recent background literature on the chemistry of related tropane-derived aldols and their applications, including stereoselective syntheses of bioactive alkaloids, see: Lazny et al. (2011); Sienkiewicz et al. (2009) and references cited therein. For stereoselective syntheses of related nortropinone aldols, see: Lazny et al. (2001); Lazny & Nodzewska (2003). For a representative review of the biological activity of tropane derivatives, see: Singh (2000).

Experimental top

A solution of n-butyllithium in hexane (2.4 M, 0.50 ml, 1.2 mmol) was added dropwise to a cooled (273 K) solution of diisopropylamine (0.168 ml, 1.2 mmol) in tetrahydrofuran (10 ml). The mixture was stirred for 30 min, then cooled to 195 K and a solution of N-benzylnortropinone (0.215 g, 1 mmol) in tetrahydrofuran (7 ml) was added dropwise. After stirring for 2 h, benzaldehyde (0.117 ml, 1.15 mmol) was added dropwise and the mixture was stirred for another 10 min. The reaction was quenched with saturated aq. NH4Cl (4 ml), allowed to warm to room temperature, and extracted with dichloromethane (3 × 10 ml). The combined extracts were dried over MgSO4 and concentrated to give the crude product. Crystallization from mixed solvent system hexane/dichloromethane gave the the major product (0.243 g, 75%) as white crystals [m.p. 372–377 K; Rf = 0.77 (10% methanol/dichloromethane); HR (MS-ESI): MNa+, found 344,1640, C21H23NNaO2 requires 344,1626; 1H NMR (CDCl3): 7.43–7.21 (m, 10H), 5.11 (d, J = 3 Hz, 1H), 3.73–3.65 (m, 3H), 3.58–3.57 (m, 1H), 2.82 (ddd, J1 = 1.5 Hz, J2 = 4.5 Hz, J3 = 6 Hz, 1H), 2.45–2.44 (m, 1H), 2.36–2.32 (m, 3H), 1.70–1.66 (m, 2H)].

Refinement top

All hydrogen atoms were constrained to idealized positions with C—H distances fixed at 0.95–1.00 Å and O—H distances fixed at 0.84 Å and Uiso(H) = 1.5Ueq(C) for hydroxyl hydrogen atom and 1.2Ueq(C) for others.

Computing details top

Data collection: CrysAlis PRO (Agilent, 2011); cell refinement: CrysAlis PRO (Agilent, 2011); data reduction: CrysAlis PRO (Agilent, 2011); program(s) used to solve structure: SHELXD (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 1997) and pyMOL (DeLano, 2002); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. The molecular structure of the title compound. Displacement ellipsoids are drawn at the 50% probability level.
[Figure 2] Fig. 2. Crystal packing viewed along the a axis. Dashed lines represent hydrogen bonds. For clarity, only hydrogen atoms involved in the intra- and intermolecular interactions are shown.
(2R)-8-Benzyl-2-[(S)-hydroxy(phenyl)methyl]-8- azabicyclo[3.2.1]octan-3-one top
Crystal data top
C21H23NO2F(000) = 688
Mr = 321.40Dx = 1.220 Mg m3
Orthorhombic, P212121Cu Kα radiation, λ = 1.54180 Å
Hall symbol: P 2ac 2abCell parameters from 23874 reflections
a = 5.9354 (1) Åθ = 3.3–73.6°
b = 13.3091 (2) ŵ = 0.61 mm1
c = 22.1511 (3) ÅT = 100 K
V = 1749.82 (5) Å3Needle, colourless
Z = 40.65 × 0.25 × 0.19 mm
Data collection top
Oxford Diffraction SuperNova Dual
diffractometer
3323 independent reflections
Radiation source: SuperNova (Cu) X-ray Source3276 reflections with I > 2σ(I)
mirrorRint = 0.026
Detector resolution: 10.4052 pixels mm-1θmax = 73.6°, θmin = 3.9°
ω scansh = 76
Absorption correction: analytical
(CrysAlis PRO; Agilent, 2011)
k = 016
Tmin = 0.75, Tmax = 0.89l = 027
32829 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.027H-atom parameters constrained
wR(F2) = 0.070 w = 1/[σ2(Fo2) + (0.0283P)2 + 0.4297P]
where P = (Fo2 + 2Fc2)/3
S = 1.18(Δ/σ)max < 0.001
3323 reflectionsΔρmax = 0.16 e Å3
218 parametersΔρmin = 0.16 e Å3
0 restraintsAbsolute structure: Flack (1983), 1257 Friedel pairs
Primary atom site location: structure-invariant direct methodsFlack parameter: 0.12 (18)
Crystal data top
C21H23NO2V = 1749.82 (5) Å3
Mr = 321.40Z = 4
Orthorhombic, P212121Cu Kα radiation
a = 5.9354 (1) ŵ = 0.61 mm1
b = 13.3091 (2) ÅT = 100 K
c = 22.1511 (3) Å0.65 × 0.25 × 0.19 mm
Data collection top
Oxford Diffraction SuperNova Dual
diffractometer
3323 independent reflections
Absorption correction: analytical
(CrysAlis PRO; Agilent, 2011)
3276 reflections with I > 2σ(I)
Tmin = 0.75, Tmax = 0.89Rint = 0.026
32829 measured reflectionsθmax = 73.6°
Refinement top
R[F2 > 2σ(F2)] = 0.027H-atom parameters constrained
wR(F2) = 0.070Δρmax = 0.16 e Å3
S = 1.18Δρmin = 0.16 e Å3
3323 reflectionsAbsolute structure: Flack (1983), 1257 Friedel pairs
218 parametersFlack parameter: 0.12 (18)
0 restraints
Special details top

Geometry. All e.s.d.'s are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry.

Refinement. Refinement of F2 against all reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > 2σ(F2) is used only for calculating R-factors etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C10.8760 (2)0.63105 (8)0.16890 (5)0.0158 (2)
H10.91720.66560.13040.019*
C20.8530 (2)0.51680 (8)0.15913 (5)0.0153 (2)
H21.00310.49030.14620.018*
C30.7921 (2)0.46720 (9)0.21973 (5)0.0169 (3)
O30.88275 (17)0.38983 (7)0.23623 (4)0.0256 (2)
C40.6185 (2)0.52123 (8)0.25898 (5)0.0177 (3)
H4A0.62930.49670.30110.021*
H4B0.46490.50660.24390.021*
C50.6612 (2)0.63510 (8)0.25734 (5)0.0164 (2)
H50.54760.67190.28230.020*
C60.9079 (2)0.65823 (10)0.27939 (6)0.0202 (3)
H6A0.96030.60670.30840.024*
H6B0.91660.72520.29870.024*
C71.0516 (2)0.65523 (9)0.21957 (6)0.0204 (3)
H7A1.12530.72080.21210.025*
H7B1.16860.60240.22180.025*
N80.65350 (19)0.66906 (7)0.19242 (4)0.0150 (2)
O90.45290 (16)0.52672 (6)0.12196 (4)0.0204 (2)
H90.46140.58080.14140.031*
C90.6768 (2)0.49154 (9)0.10786 (5)0.0165 (3)
H9C0.72690.52630.07010.020*
C100.6686 (2)0.38004 (9)0.09495 (5)0.0166 (3)
C110.8557 (3)0.33441 (10)0.06662 (5)0.0210 (3)
H110.98140.37420.05510.025*
C120.8568 (3)0.23166 (10)0.05557 (6)0.0238 (3)
H120.98330.20090.03690.029*
C130.6694 (3)0.17393 (9)0.07224 (6)0.0241 (3)
H130.66990.10350.06520.029*
C140.4813 (3)0.21910 (10)0.09918 (6)0.0226 (3)
H140.35370.17940.10930.027*
C150.4803 (2)0.32179 (9)0.11116 (5)0.0196 (3)
H150.35390.35220.13010.023*
C160.6383 (2)0.78046 (8)0.19028 (5)0.0171 (3)
H16A0.76390.80980.21380.020*
H16B0.49520.80220.20910.020*
C170.6486 (2)0.81981 (8)0.12530 (6)0.0176 (3)
C180.4719 (3)0.80051 (9)0.08410 (6)0.0212 (3)
H180.34490.76260.09690.025*
C190.4813 (3)0.83679 (10)0.02427 (6)0.0252 (3)
H190.36140.82340.00300.030*
C200.6690 (3)0.89285 (10)0.00518 (6)0.0262 (3)
H200.67630.91770.03500.031*
C210.8457 (3)0.91194 (9)0.04567 (6)0.0265 (3)
H210.97290.94940.03260.032*
C220.8362 (3)0.87590 (9)0.10572 (6)0.0227 (3)
H220.95640.88950.13280.027*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0150 (6)0.0132 (5)0.0194 (6)0.0009 (5)0.0025 (5)0.0001 (4)
C20.0143 (6)0.0129 (5)0.0186 (5)0.0017 (5)0.0010 (5)0.0008 (4)
C30.0174 (7)0.0140 (5)0.0192 (6)0.0017 (5)0.0041 (5)0.0006 (5)
O30.0324 (6)0.0175 (4)0.0269 (5)0.0076 (4)0.0038 (4)0.0032 (4)
C40.0197 (7)0.0154 (5)0.0178 (5)0.0003 (5)0.0000 (5)0.0026 (4)
C50.0180 (7)0.0157 (5)0.0156 (5)0.0014 (5)0.0006 (5)0.0002 (4)
C60.0210 (8)0.0187 (6)0.0207 (6)0.0000 (5)0.0046 (5)0.0004 (5)
C70.0147 (7)0.0183 (6)0.0283 (7)0.0003 (5)0.0008 (5)0.0043 (5)
N80.0169 (6)0.0120 (4)0.0160 (5)0.0020 (4)0.0010 (4)0.0004 (4)
O90.0178 (5)0.0165 (4)0.0269 (5)0.0037 (3)0.0038 (4)0.0048 (4)
C90.0179 (7)0.0157 (5)0.0159 (5)0.0005 (5)0.0003 (5)0.0004 (4)
C100.0207 (7)0.0166 (5)0.0126 (5)0.0006 (5)0.0028 (5)0.0009 (4)
C110.0220 (7)0.0223 (6)0.0187 (6)0.0001 (5)0.0002 (5)0.0029 (5)
C120.0260 (8)0.0246 (6)0.0209 (6)0.0072 (6)0.0024 (6)0.0065 (5)
C130.0371 (9)0.0155 (6)0.0196 (6)0.0019 (6)0.0052 (6)0.0030 (5)
C140.0309 (8)0.0194 (6)0.0175 (6)0.0055 (6)0.0018 (6)0.0006 (5)
C150.0228 (7)0.0197 (6)0.0162 (5)0.0005 (5)0.0008 (5)0.0012 (5)
C160.0188 (7)0.0118 (5)0.0206 (6)0.0014 (5)0.0005 (5)0.0013 (4)
C170.0194 (7)0.0110 (5)0.0224 (6)0.0034 (5)0.0025 (6)0.0002 (4)
C180.0228 (8)0.0171 (6)0.0238 (6)0.0003 (5)0.0003 (5)0.0034 (5)
C190.0302 (8)0.0218 (6)0.0235 (6)0.0036 (6)0.0033 (6)0.0021 (5)
C200.0369 (9)0.0192 (6)0.0226 (6)0.0066 (6)0.0074 (6)0.0049 (5)
C210.0261 (8)0.0187 (6)0.0347 (7)0.0010 (6)0.0113 (6)0.0046 (5)
C220.0226 (8)0.0153 (5)0.0303 (7)0.0009 (5)0.0020 (6)0.0007 (5)
Geometric parameters (Å, °) top
C1—N81.5071 (16)C10—C151.4068 (19)
C1—C21.5419 (15)C10—C111.4127 (19)
C1—C71.5648 (18)C11—C121.3893 (18)
C1—H11.0000C11—H110.9500
C2—C31.5390 (16)C12—C131.401 (2)
C2—C91.5801 (16)C12—H120.9500
C2—H21.0000C13—C141.401 (2)
C3—O31.2180 (15)C13—H130.9500
C3—C41.5279 (18)C14—C151.3923 (17)
C4—C51.5368 (15)C14—H140.9500
C4—H4A0.9900C15—H150.9500
C4—H4B0.9900C16—C171.5329 (16)
C5—N81.5082 (14)C16—H16A0.9900
C5—C61.5742 (18)C16—H16B0.9900
C5—H51.0000C17—C221.4091 (19)
C6—C71.5762 (18)C17—C181.4140 (19)
C6—H6A0.9900C18—C191.4116 (18)
C6—H6B0.9900C18—H180.9500
C7—H7A0.9900C19—C201.406 (2)
C7—H7B0.9900C19—H190.9500
N8—C161.4861 (14)C20—C211.403 (2)
O9—C91.4430 (16)C20—H200.9500
O9—H90.8400C21—C221.4151 (19)
C9—C101.5121 (16)C21—H210.9500
C9—H9C1.0000C22—H220.9500
N8—C1—C2107.58 (10)O9—C9—H9C107.8
N8—C1—C7105.46 (9)C10—C9—H9C107.8
C2—C1—C7111.25 (10)C2—C9—H9C107.8
N8—C1—H1110.8C15—C10—C11120.07 (11)
C2—C1—H1110.8C15—C10—C9121.20 (12)
C7—C1—H1110.8C11—C10—C9118.73 (12)
C3—C2—C1108.74 (9)C12—C11—C10120.33 (13)
C3—C2—C9112.33 (10)C12—C11—H11119.8
C1—C2—C9111.67 (9)C10—C11—H11119.8
C3—C2—H2108.0C11—C12—C13119.32 (13)
C1—C2—H2108.0C11—C12—H12120.3
C9—C2—H2108.0C13—C12—H12120.3
O3—C3—C4121.66 (11)C12—C13—C14120.62 (11)
O3—C3—C2121.38 (12)C12—C13—H13119.7
C4—C3—C2116.94 (10)C14—C13—H13119.7
C3—C4—C5109.85 (10)C15—C14—C13120.37 (13)
C3—C4—H4A109.7C15—C14—H14119.8
C5—C4—H4A109.7C13—C14—H14119.8
C3—C4—H4B109.7C14—C15—C10119.27 (13)
C5—C4—H4B109.7C14—C15—H15120.4
H4A—C4—H4B108.2C10—C15—H15120.4
N8—C5—C4108.25 (9)N8—C16—C17111.62 (9)
N8—C5—C6105.38 (10)N8—C16—H16A109.3
C4—C5—C6109.80 (10)C17—C16—H16A109.3
N8—C5—H5111.1N8—C16—H16B109.3
C4—C5—H5111.1C17—C16—H16B109.3
C6—C5—H5111.1H16A—C16—H16B108.0
C5—C6—C7103.74 (10)C22—C17—C18118.94 (12)
C5—C6—H6A111.0C22—C17—C16120.10 (12)
C7—C6—H6A111.0C18—C17—C16120.96 (12)
C5—C6—H6B111.0C19—C18—C17120.96 (13)
C7—C6—H6B111.0C19—C18—H18119.5
H6A—C6—H6B109.0C17—C18—H18119.5
C1—C7—C6104.36 (10)C20—C19—C18119.68 (13)
C1—C7—H7A110.9C20—C19—H19120.2
C6—C7—H7A110.9C18—C19—H19120.2
C1—C7—H7B110.9C21—C20—C19119.74 (12)
C6—C7—H7B110.9C21—C20—H20120.1
H7A—C7—H7B108.9C19—C20—H20120.1
C16—N8—C1112.14 (10)C20—C21—C22120.66 (13)
C16—N8—C5109.34 (9)C20—C21—H21119.7
C1—N8—C5101.69 (9)C22—C21—H21119.7
C9—O9—H9109.5C17—C22—C21120.02 (13)
O9—C9—C10109.26 (11)C17—C22—H22120.0
O9—C9—C2112.65 (9)C21—C22—H22120.0
C10—C9—C2111.47 (10)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O9—H9···N80.841.992.7280 (13)146
C6—H6B···O3i0.992.613.3414 (15)131
C7—H7A···O3i0.992.523.2954 (15)135
C16—H16A···O3i0.992.603.5846 (16)173
Symmetry codes: (i) −x+2, y+1/2, −z+1/2.
Table 1
Hydrogen-bond geometry (Å, °)
top
D—H···AD—HH···AD···AD—H···A
O9—H9···N80.841.992.7280 (13)146
C6—H6B···O3i0.992.613.3414 (15)131
C7—H7A···O3i0.992.523.2954 (15)135
C16—H16A···O3i0.992.603.5846 (16)173
Symmetry codes: (i) −x+2, y+1/2, −z+1/2.
Acknowledgements top

This work was supported in part by the University of Bialystok (BST-125), the Polish Ministry of Science and Higher Education (grant No. N N204 546939), the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN2612008000001E.

references
References top

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