Synthesis and crystal structure characterization of (1R,2R,3R,5S)-3-(3-chlorophenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxa-6-azabicyclo[3.2.1]octan-7-one

Article abstract of DOI:10.1080/15421406.2014.928446

The title compound, (1R,2R,3R,5S)-3-(3-chlorophenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxa-6-azabicyclo[3.2.1]octan-7-one, was synthesized and characterized by ¹H and ¹³C NMR and HRMS spectroscopy. Its absolute molecular configuration wa

Full text of DOI:10.1080/15421406.2014.928446

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Synthesis and Crystal Structure
Characterization of (1R,2R,3R,5S)-3-
(3-chlorophenyl)-1-hydroxy-2-
methyl-6-phenyl-8-oxa-6-
azabicyclo[3.2.1]octan-7-one
Chao Wua, Yan-Jun Guoa, Xiao-Long Zhanga & Ai-Bao Xiaa
a Catalytic Hydrogenation Research Center, State Key Laboratory
Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang
University of Technology, Hangzhou, China
Published online: 26 Feb 2015.
Click for updates
To cite this article: Chao Wu, Yan-Jun Guo, Xiao-Long Zhang & Ai-Bao Xia (2015) Synthesis and Crystal
Structure Characterization of (1R,2R,3R,5S)-3-(3-chlorophenyl)-1-hydroxy-2-methyl-6-phenyl-8-
oxa-6-azabicyclo[3.2.1]octan-7-one, Molecular Crystals and Liquid Crystals, 607:1, 215-222, DOI:
10.1080/15421406.2014.928446
To link to this article: http://dx.doi.org/10.1080/15421406.2014.928446
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Mol. Cryst. Liq. Cryst., Vol. 607: pp. 215–222, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 1542-1406 print/1563-5287 online
DOI: 10.1080/15421406.2014.928446
Synthesis and Crystal Structure Characterization
of (1R,2R,3R,5S)-3-(3-chlorophenyl)-1-hydroxy-2-
methyl-6-phenyl-8-oxa-6-azabicyclo
[3.2.1]octan-7-one
CHAO WU, YAN-JUN GUO, XIAO-LONG ZHANG,
AND AI-BAO XIA∗
Catalytic Hydrogenation Research Center, State Key Laboratory Breeding Base
of Green Chemistry-Synthesis Technology, Zhejiang University of Technology,
Hangzhou, China
The title compound, (1R,2R,3R,5S)-3-(3-chlorophenyl)-1-hydroxy-2-methyl-6-phenyl-
1
8-oxa-6-azabicyclo[3.2.1]octan-7-one, was synthesized and characterized by H and
13C NMR and HRMS spectroscopy. Its absolute molecular configuration was investigated
by X-ray crystallography. The crystal structure analysis revealed that the structure
exhibits intermolecular hydrogen bonds of the type O H . . . O. The methyl group and
chlorophenyl group are located in the cis configuration. The conformation is stabilized
by weak intermolecular C H. .. O interactions.
Keywords Bicyclic lactam; chirality; single crystal; X-ray diffraction
Introduction
Bicyclic lactams have been used to synthesize iminosugars [1] and they are found to be
structural moiety of many natural products [2]. Therefore, synthetic routes to such kind of
compounds are of interest. In this paper, we describe a simple, excellently enantioselective
and diastereoselective one-pot synthesis of new bicyclic lactam at 0◦C in the presence of
TBS-protected diarylprolinol as an organocatalyst and triethylamine (TEA) as an additive.
Furthermore, the bicyclic lactam, (1R,2R,3R,5S)-3-(3-chlorophenyl)-1-hydroxy-2-methyl-
6-phenyl-8-oxa-6-azabicyclo[3.2.1]octan-7-one (Fig. 1), was characterized by 1H and 13
C
NMR, and HRMS spectroscopy. Its crystal structure was investigated by X-ray single-
crystal diffraction analysis.
Experimental
1H and 13C NMR were recorded in CDCl3 on Bruker AVANCE III (500 MHz for 1H NMR
and 125 MHz for 13C NMR). Proton chemical shifts (δ) are relative to tetramethylsilane
∗Address correspondence to Ai-Bao Xia, Catalytic Hydrogenation Research Center, State Key
Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Tech-
nology, Hangzhou, China. Tel.: +86-571-88320430. E-mail: xiaaibao@zjut.edu.cn
Color versions of one or more of the figures in the article can be found online at
www.tandfonline.com/gmcl.
215

216
C. Wu et al.
Figure 1. Structure of bicyclic lactam.
(TMS, δ = 0.0) as internal standard and expressed in parts per million. Spin multiplicities
are given as s (singlet), d (doublet), t (triplet), and q (quartet) as well as b (broad). Coupling
constants (J) are given in hertz. HRMS data were measured on an Agilent 6120 LC/TOF-MS
with ESI source.
Synthesis of 2-oxo-N-phenylbutanamide (1) [3]
To a stirred solution of 2-oxobutanoic acid (0.34 g, 3 mmol) and aniline (0.56 g, 6 mmol)
in methylene chloride (20 mL) at 0◦C was added a solution of dicyclohexylcarbodiimide
(0.6 g, 3 mmol) in methylene chloride (7 mL) dropwise over 30 min. Stirring was continued
at ambient temperature for 16 h. The white solid precipitates were filtered off and the
solution was washed with a 1 N HC1 solution and then with water and dried. The solvent
was removed under reduced pressure. This was isolated by flesh chromatographed column
using petroleum ether-ethyl acetate (20:1) as eluent to obtain 2-oxo-N-phenylbutanamide
(0.3 g, 56%).
Synthesis of (1R,2R,3R,5S)-3-(3-chlorophenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxa-6-
azabicyclo[3.2.1]octan-7-one (3)
To the solution of the chiral amine catalyst 3 g (20 mol%) and triethylamine (15 mol%)
in toluene (0.5 ml) was added sequentially α-ketoamide (1) (0.2 mmol) and (E)-3-(3-
chlorophenyl)acrylaldehyde (2) (0.24 mmol) at 0◦C with vigorous stirring. The reaction
was monitored by TLC. After completion, the reaction mixture was extracted with EtOAc
(3 × 10 mL), washed with water, dried and concentrated. The residue was purified by
flash chromatography to give the product. The enantiomeric ratio was determined by
HPLC analysis on a chiral column. Single crystals were obtained by slow evaporation of a
methanol and petroleum ether (V/V = 1:2) solution.
95% yield, >99% ee. The enantiomeric excess was determined by HPLC on Daicel
Chiralpak OD-H with hexane/i-PrOH (80:20) as the eluent. Flow: 1.0 ml/min; UV =
1
232 nm; tminor = 17.252 min, tmajor = 10.773 min; H NMR (500 MHz, CDCl3): δ =
7.546–7.544 (m, 2H), 7.369–7.336 (m, 2H), 7.250–7.143 (m, 4H), 7.045–7.030 (m, 1H),
5.920 (s, 1H), 4.997 (s, 1H), 3.252–3.206 (m, 1H), 2.413–2.357 (m, 2H), 2.024–1.984
Scheme 1. Synthesis of bicyclic lactam (3).

Synthesis and Crystal Structure Characterization
217
(m, 1H), 0.887–0.873 (d, J = 7.0Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ = 170.464,
142.068, 135.664, 134.484, 129.751, 129.437(×2), 127.742, 126.986, 125.837, 125.440,
118.600(×2), 101.903, 85.459, 37.901(×2), 25.709, and 6.776 ppm; HRMS: (ESI+) m/z
calcd for [C19H19ClNO3]+ 344.1053, found 344.1065.
Crystal Structure Analysis
The crystal structure of the title compound was solved by direct methods and was refined
by a full matrix least-squares method on F2. A summary of the salient crystallographic data
is given in Table 1.
Table 1. Crystal data and structure refinement parameters of compound (3)
Parameter
Value
CCDC deposition number
Empirical formula
Formula weight
Temperature
CCDC 988911
C19H18ClNO3
343.79
293(2) K
Wavelength
0.71073 Å
Crystal system
Space group
Monoclinic
P2(1)
Cell dimensions
a = 10.572(3) Å
b = 6.8163(19) Å
c = 11.398(3) Å
β = 97.963(6)◦
813.5(4) Å3
Volume
Z
2
Density (calculated)
Absorption coefficient
F000
1.404 Mg/m3
0.252 mm−1
360
Crystal size
Theta range for data collection
Index ranges
0.231 × 0.176 × 0.123 mm
1.80◦–26.00◦
−12 ≤ h ≤ 13
−8 ≤ k ≤ 8
−14 ≤ l ≤ 13
4817
Reflections collected
Independent reflections
Absorption correction
Refinement method
Data/restraints /parameters
Goodness of fit on F2
Final R indices [I > 2σ (I)]
R indices (all data)
2894 [Rint = 0.0342]
Tmin = 0.62665, Tmax = 1.00000
Full-matrix least-squares on F2
2894/1/220
1.068
R1 = 0.0501, ωR2 = 0.1304
R1 = 0.0474, ωR2 = 0.1270
None
0.08(9)
0.393 and −0.334 e.Å −3
Extinction correction
Flack parameter
Largest diff. peak and hole

218
C. Wu et al.
A single crystal suitable for X-ray diffraction obtained in methanol and petroleum ether
(V/V = 1:2) was colorless and block. The single crystal XRD of the crystal was collected
on a PROCESS-AUTO [4] diffractometer at 293(2) K using graphite-monochromated Mo
Kα radiation (λ = 0.71073 Å). The cell was refined on a PROCESS-AUTO [4] and the data
were reducted on a CrystalStructure [5] and corrected for absorption using multi-scan [6].
The structure was solved by direct methods using SHELXS-97 and refined by a full-matrix
least-squares procedure using the program SHELXL-97 [7]. Subsequent refinements were
carried out with anisotropic thermal parameters for nonhydrogen atoms. H atoms were
placed in calculated positions with C—H = 0.96 Å (sp3), C—H = 0.93 Å (aromatic). All H
atoms included in the final cycles of refinement using a riding model, with Uiso(H) =
1.5 Ueq(sp3) or 1.2 Ueq of the carrier atoms. A molecular plot was prepared with
ORTEP-3 for Windows [8]. The software used to prepare material for publication was
WINGX [9]. Table 2 gives the atomic coordinates and equivalent thermal parameters of
the nonhydrogen atoms. Tables 3 and 4 give the list of bond lengths and bond angles,
respectively.
Table 2. Atomic coordinates and equivalent thermal parameters of the nonhydrogen atoms
ꢀ ꢀ
(Å2). Ueq = (1/3)
i
j Uijai∗aj∗(a i .a j)
Atom
x
y
z
Ueq
Cl1
N1
O1
O2
O3
C1
C2
C3
C4
C5
C6
C7
C8
0.67919(8)
0.17386(17)
0.00657(13)
0.32959(14)
0.21071(16)
0.11940(19)
0.2300(2)
0.31419(19)
0.3655(2)
0.2903(2)
0.2700(2)
0.3857(3)
0.1137(2)
−0.0005(3)
−0.0568(3)
−0.0012(3)
0.1129(4)
0.1698(3)
0.3462(2)
0.39772(16)
0.7581(3)
0.9215(3)
0.9736(3)
1.2024(3)
0.8920(4)
1.0032(4)
0.7735(4)
0.6468(4)
0.6846(3)
0.9089(4)
1.0140(4)
0.6283(4)
0.6807(6)
0.5556(7)
0.3818(7)
0.3324(6)
0.4520(5)
0.5880(4)
0.5433(4)
0.4538(4)
0.4104(5)
0.4576(5)
0.5443(5)
0.90227(7)
0.38083(18)
0.45033(17)
0.44636(15)
0.52319(19)
0.4455(2)
0.5172(2)
0.4134(2)
0.5185(2)
0.6215(2)
0.6381(2)
0.7041(3)
0.2945(2)
0.2291(3)
0.1412(3)
0.1184(3)
0.1841(3)
0.2721(3)
0.7353(2)
0.7632(2)
0.8701(2)
0.9516(2)
0.9247(3)
0.8184(3)
0.0773(3)
0.0399(5)
0.0495(5)
0.0397(4)
0.0505(5)
0.0381(5)
0.0377(5)
0.0380(5)
0.0372(5)
0.0353(5)
0.0378(5)
0.0540(7)
0.0418(5)
0.0575(7)
0.0694(10)
0.0710(10)
0.0745(10)
0.0591(8)
0.0388(5)
0.0406(5)
0.0513(6)
0.0634(8)
0.0663(8)
0.0549(7)
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
0.4736(2)
0.5175(3)
0.4363(3)
0.3108(3)
0.2654(3)

Synthesis and Crystal Structure Characterization
219
Table 3. Bond lengths (Å)
Atoms
Length
Atoms
C6-C7
C8-C9
C8-C13
Length
Cl1-C16
N1-C1
N1-C8
N1-C3
O1-C1
O2-C3
O2-C2
O3-C2
C1-C2
C2-C6
C3-C4
C4-C5
C5-C14
C5-C6
1.741(3)
1.352(3)
1.407(3)
1.482(3)
1.218(3)
1.418(3)
1.427(3)
1.376(3)
1.531(3)
1.526(3)
1.515(3)
1.529(3)
1.501(3)
1.559(3)
1.523(3)
1.376(4)
1.379(4)
1.385(5)
1.364(6)
1.370(5)
1.366(5)
1.375(3)
1.393(4)
1.384(4)
1.382(4)
1.359(5)
1.373(4)
C9-C10
C10-C11
C11-C12
C12-C13
C14-C15
C14-C19
C15-C16
C16-C17
C17-C18
C18-C19
Table 4. Bond angles (◦)
Angle Atoms
Atoms
Angle
C1-N1-O8
C1-N1-C3
C8-N1-C3
C3-O2-C2
O1-C1-N1
O1-C1-C2
N1-C1-C2
O3-C2-O2
O3- C2-C6
O2-C2-C6
O3-C2-C1
O2-C2-C1
C6-C2-C1
O2-C3-N1
O2-C3-C4
N1-C3-C4
C3-C4-C5
C14-C5-C4
C14-C5-C6
C4-C5-C6
C7-C6-C2
128.36(19)
107.63(19)
124.0(2)
102.66(16)
129.0(2)
C7-C6-C5
C2-C6-C5
C9-C8-C13
C9-C8-N1
C13-C8-N1
C8-C9-C10
C11-C10-C9
C10-C11-C12
C13-C12-C11
C12-C13-C8
C15-C14-C19
C15-C14-C5
C19-C14-C5
C14-C15-C16
C17-C16-C15
C17-C16-C11
C15-C16-C11
C18-C17-C16
C17-C18-C19
C18-C19-C14
114.0(2)
109.21(19)
119.5(3)
119.6(3)
120.8(2)
119.3(3)
121.3(3)
118.6(3)
121.3(3)
119.9(3)
118.0(2)
123.5(2)
118.5(2)
119.9(2)
121.5(3)
119.6(2)
118.8(2)
118.4(3)
120.8(3)
121.4(3)
125.1(2)
105.89(18)
107.08(19)
113.3(2)
108.53(17)
114.0(2)
101.36(19)
111.64(19)
102.04(18)
108.88(19)
113.20(19)
110.11(18)
113.93(18)
111.72(19)
110.72(18)
110.5(2)

220
C. Wu et al.
Figure 2. ORTEP of the molecule with thermal ellipsoids drawn at 50% probability.
The ORTEP of the molecule with thermal ellipsoids drawn at 50% probabil-
ity is shown in Fig. 2. The crystal structure analysis revealed that the structure ex-
hibits intermolecular hydrogen bonds of the type O3–H3 . . . O1. The molecules are
linked by weak intermolecular C H . . . O interactions. The methyl group and chloro
phenyl group are located in the cis configuration. Furthermore, the torsion angle of
C7–C6–C5–C14 is 48.3(8)o. The six-membered ring including an oxygen atom adopts
a perfect chair conformation. C2, C3, C4, and C6 are on the same plane. The angle
is 71.0(3)o between the plane of the C2–C3–C4–C6 and the O1–C1–N1 plane. The
torsion angle of C3–N1–C1–C2 is 2.8(3)o. The N1–C3–C4 and C1–C2–C6 bond an-
gles are 113.2(0)o and 111.6(5)o, respectively. The Packing diagram of (3) is given in
Fig. 3.

Synthesis and Crystal Structure Characterization
221
Figure 3. The crystal packing of the title compound (3).

222
C. Wu et al.
Conclusion
The title compound (1R,2R,3R,5S)-3-(3-chlorophenyl)-1-hydroxy-2-methyl-6-phenyl-8-
oxa-6-azabicyclo[3.2.1]octan-7-one (3), was synthesized and characterized by 1H and 13
C
NMR and HRMS spectroscopy. We summarized the results from X-ray diffraction mea-
surements for compound (3) single crystal. X-ray analysis revealed that the methyl group
and chlorophenyl group are located in the cis configuration, and the molecules are linked
by weak intermolecular C H . . . O interactions.
Supplementary Information
CCDC 988911 contains the supplementary crystallographic data for this article. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html, or from
The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
Fax:+44(0)1223-336033. E-mail: deposit@ccdc.cam.ac.uk.
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