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

Krzysztof Brzezinski; Ryszard Lazny; Michal Sienkiewicz; Sławomir Wojtulewski; Zbigniew Dauter

doi:10.1107/S1600536811053190

. 2011 Dec 17;68(Pt 1):o149–o150. doi: 10.1107/S1600536811053190

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

Krzysztof Brzezinski ^a,^*, Ryszard Lazny ^b, Michal Sienkiewicz ^b, Sławomir Wojtulewski ^b, Zbigniew Dauter ^a

PMCID: PMC3254493 PMID: 22259435

Abstract

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.

Related literature

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

Crystal data

C₂₁H₂₃NO₂
M _r = 321.40
Orthorhombic,
a = 5.9354 (1) Å
b = 13.3091 (2) Å
c = 22.1511 (3) Å
V = 1749.82 (5) Å³
Z = 4
Cu Kα radiation
μ = 0.61 mm⁻¹
T = 100 K
0.65 × 0.25 × 0.19 mm

Data collection

Oxford Diffraction SuperNova Dual diffractometer
Absorption correction: analytical (CrysAlis PRO; Agilent, 2011 ▶) T _min = 0.75, T _max = 0.89
32829 measured reflections
3323 independent reflections
3276 reflections with I > 2σ(I)
R _int = 0.026

Refinement

R[F ² > 2σ(F ²)] = 0.027
wR(F ²) = 0.070
S = 1.18
3323 reflections
218 parameters
H-atom parameters constrained
Δρ_max = 0.16 e Å⁻³
Δρ_min = −0.16 e Å⁻³
Absolute structure: Flack (1983 ▶), 1257 Friedel pairs
Flack parameter: 0.12 (18)

Data collection: CrysAlis PRO (Agilent, 2011 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; 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.

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536811053190/gk2429sup1.cif

e-68-0o149-sup1.cif^{(24.3KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811053190/gk2429Isup2.hkl

e-68-0o149-Isup2.hkl^{(163KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811053190/gk2429Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O9—H9⋯N8	0.84	1.99	2.7280 (13)	146
C6—H6B⋯O3ⁱ	0.99	2.61	3.3414 (15)	131
C7—H7A⋯O3ⁱ	0.99	2.52	3.2954 (15)	135
C16—H16A⋯O3ⁱ	0.99	2.60	3.5846 (16)	173

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Symmetry code: (i) Inline graphic .

Acknowledgments

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.

supplementary crystallographic information

Comment

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.

Experimental

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; R_f = 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)].