Optical resolution, stereoselective synthesis, and crystal structure of 9α-(3-azabicyclo[3,3,1]nonanyl)-2′cyclopentyl-2′-hydroxy- 2′-phenylacetate

Article abstract of DOI:10.1081/SCC-200057293

9α-(3-Azabicyclo[3,3,1 ]nonanyl)-2′-cyclopentyl-2′- hydroxy-2′-phenylacetate (1) was synthesized and its enantiomers were obtained by the optical resolution of racemates with the chiral host N-p-toluenesulfonylglutamic acid. Optical pure 1 was also effect

Full text of DOI:10.1081/SCC-200057293

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Optical Resolution,
Stereoselective Synthesis,
and Crystal Structure of
9α‐(3‐Azabicyclo[3,3,1]nonanyl)‐2′
Yan‐Qing Liu a , He Liu b , Bo‐hua Zhong b , Yu‐Lin
Deng a & Ke‐liang Liu b
a School of Life Science and Technology, Beijing
Institute of Technology , Beijing, China
b No. 7 Department , Beijing Institute of
Pharmacology and Toxicology , Beijing, China
Published online: 16 Aug 2006.
To cite this article: Yan‐Qing Liu , He Liu , Bo‐hua Zhong , Yu‐Lin Deng & Ke‐liang
Liu (2005) Optical Resolution, Stereoselective Synthesis, and Crystal Structure
of 9α‐(3‐Azabicyclo[3,3,1]nonanyl)‐2′‐cyclopentyl‐2′‐hydroxy‐2′‐phenylacetate,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:10, 1403-1412, DOI: 10.1081/SCC-200057293
To link to this article: http://dx.doi.org/10.1081/SCC-200057293
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Synthetic Communicationsw, 35: 1403–1412, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200057293
Optical Resolution, Stereoselective
Synthesis, and Crystal Structure of
9a-(3-Azabicyclo[3,3,1]nonanyl)-20-
cyclopentyl-20-hydroxy-20-phenylacetate
Yan-Qing Liu
School of Life Science and Technology, Beijing Institute of Technology,
Beijing, China
He Liu and Bo-hua Zhong
No. 7 Department, Beijing Institute of Pharmacology and
ToxicologyBeijing, China
Yu-Lin Deng
School of Life Science and Technology, Beijing Institute of Technology,
Beijing, China
Ke-liang Liu
No. 7 Department, Beijing Institute of Pharmacology and Toxicology,
Beijing, China
Abstract: 9a-(3-Azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-hydroxy-20-phenylace-
tate (1) was synthesized and its enantiomers were obtained by the optical resolution
of racemates with the chiral host N-p-toluenesulfonylglutamic acid. Optical pure 1
was also effective diastereoselective synthesized using benzaldehye as steric
hindrance agent from the chiral starting material, (S) or (R)-mandelic acid. The
structure of the title compound was first elucidated by X-ray analysis.
Keywords: Crystal structure, optical resolution, stereoselective synthesis
Received in Japan November 10, 2004
Address correspondence to He Liu, No. 7 Department, Beijing Institute of Pharma-
cology and Toxicology, Academy, Beijing 100850, China. Fax: þ86-10-68211626;
E-mail: hliuamms@yahoo.com
1403

1404
Y.-Q. Liu et al.
Design, development, and marketing of new chiral drugs are now major
themes in drug chirality research and industry.[1] The FDA announced it
would consider further incentives for developing single-isomer drugs for
their better pharmacokinetics prosperity, safety, and tolerability.[2] Our
recent drug candidate, 9a-(3-azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-
hydroxy-20-phenylacetate (1), is a potent muscarinic antagonist shown to be
more effective treating centric and peripheral choline dysfunctions.[3,4] It is
composed of a tertiary hydroxy acid as a key component as in many of the
muscarinic receptor antagonists.[5] It exhibits classical antimuscarine side
effects, such as dry mouth. Tertiary a-hydroxy acid esters have a stereogenic
center and the biology results suggest that the (2)-configuration of 1 displays
an improved therapeutic profile compared with its racemic counterpart. The
optical resolution of racemates via diastereoisomeric salt formation is a
common way for the preparation of optical isomers.[6,7] In our efforts to
produce the enantiopure 1, we found that inclusion crystallization with N-p-
toluenesulfonylglutamic acid (TSGA) as a chiral host is an effective method
for the resolution of the title compound with high enantiomeric excess. In
this article we also describe an efficient and scalable asymmetric synthesis
of the target molecule 1 by stereoselective a-alkylation of a-hetereosubsti-
tuted acids from the chiral starting material, (S) or (R)-mandelic acid.
See Chart 1.
Racemate 1 can be conveniently synthesized by demethylate reaction
of 9a-(N-methyl-3-azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-hydroxy-20-
phenylacetate 2.[4] Optical resolution of 1 was performed as outlined in
Scheme 1. To demethylate 2, carbamate would be desirable. 2,2,2-Trichloro-
ethyl carbamate can be removed with zinc dust in glacial HAc at room
temperature.[8] A 1:1 ratio of rac-1 and L-(2)-N-(p-toluenesulfonylglutamic)
glutamic acid (L-TSGA) were mixed in the anhydrous ethanol at 508C, then
.
cooled, and an inclusion complex of (2)-1 L-TSGA was separated out.
The precipitated inclusion complex was recrystalized three times in the
anhydrous ethanol. (2)-1 was obtained through alkaline hydrolysis of
the resolved acid. The mother liquor was concentrated and alkaline. The
residue was added to a solution of D-TSGA and then (þ)-1 was obtained
.
through alkaline hydrolysis of (þ)-1 D-TSGA salts.
Chart 1.

9a-(3-Azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-hydroxy-20-phenylacetate 1405
Scheme 1.
The final target, compound 1, can be dissected at the ester bond to give
two segments, the cabocyclic mandelic acid derivative 7 and the heterobicyc-
lic amine. Recently various asymmetric synthetic protocols for preparation of
pure enantiomers of tertiary a-hydroxy phenylacetic acid were reported in the
literature.[9] In 1999, Mitsuya reported a diastereoselective synthetic route in
which the (R)-a-cyclohexyl-a-hydroxy-a-phenylacetic acid with only 86% ee
could be obtained.[10] Recently, a new enantioselective synthesis of a-cyclo-
hexyl-a-hydroxy-a-phenylacetic acid employing the Sharpless asymmetric
dihydroxylation of a-cyclohexylstyrene as the key step was reported.[11]
Herein we present our diastereoselective synthesis results of acid 1 by using
benzaldehyde and S-mandelic acid as starting materials. Chrial mandelic
acid is inexpensive and available on a commercial scale. Diastereoselective
synthesis of the enantiomers of 1 was performed as outlined in Scheme 2
(S-mandelic acid 4 is an example). The preparation of high-yielding and
highly diastereoselective acetal 5 from mandelic acid was readily accom-
plished and is amenable to scaling. Deprotonation of pure 5 with lituium

1406
Y.-Q. Liu et al.
Scheme 2.
diisopropylamide (LDA), followed by the addition of bromocyclopentane,
affords the aldolate 6. (S)-a-Hydroxy-a-cyclopentyl-a-phenylacetic acid 7
was produced by hydrolysis of 6. Then, 7 reacted with CH2N2 to obtain
methyl (S)-a-hydroxy-a-cyclopentyl-a-phenylacetate 8. Reaction of 8
with 9a-(N-methyl-3-azabicyclo[3,3,1]nonane afforded (S)-9a-(N-methyl-3-
azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-hydroxy-20-phenylacetate (S)-2.
(S)-1 could be obtained from demethylate reaction. The optical rotation of
(S)-1 agreed with the value of (þ)-1 from the optical-resolution method.
The absolute structure of (þ)-1 adopted an (S)-configuration by two compari-
son methods. The enantiomers of (R)-1 could be obtained from (R)-mandelic
acid in a similar way.

9a-(3-Azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-hydroxy-20-phenylacetate 1407
(R)-(2)-9a-(3-Azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-hydroxy-20-
phenylacetate [(R)-(2)-1] was recrystallized from CH2Cl2 to give colorless
crystal. Its structure was elucidated by X-ray analysis. The X-ray ORTEP
structure of (R)-(2)-1 with atomic labeling is shown in Fig. 1a. X-ray
structure analytical data showed that the title compound is composed of a
3-azabicyclo[3,3,1]nonane structure and a tertiary hydroxy acid that adopted
R configuration. The bicyclic structure adopts a twin-chair conformation;
this is the most favored conformation for the bicyclo[3,3,1]nonane ring
system. In the cyclohexane ring, atoms C(3) and C(8) deviate from the
˚
C(1)-C(2)-C(4)-C(5) plane by 20.5642 and 0.7077 A. In the piperidine
Figure 1. (a) The ORTEP structure of (R)-1 with atom labeling; (b) packing diagram
showing the quasi-one-dimensional structure with hydrogen bonding.

1408
Y.-Q. Liu et al.
ring, atoms C(8) and N(1) deviate from the C(1)-C(5)-C(6)-C(7) plane by
˚
0.7661 and 20.4832 A. So, the cyclohexane and piperidine rings are depar-
tures from the ideal chair conformation.[12]
As shown in Fig. 1b, a zigzag quasi-one-dimensional liner structure was
. . .
formed through N-H O and N H-O hydrogen bonds in which two O
. . .
atoms of the carbonyl and hydroxy groups link the N atom of 3-azabicy-
. . .
clo[3,3,1]nonane in the adjacent molecule. The N O separations are in
˚
. . .
the range of 2.837–2.892 A with the H O and H N separations are in
. . .
˚
the range of 2.029–2.285 A; the bond angles are 122.15–168.368, falling
[13]
. . .
into the normal range of the N O separation for hydrogen bonding.
EXPERIMENTAL
All the reagents for syntheses were commercially available and used without
further purification or purified by standard methods prior to use. Melting
points were determined using a RY-1 apparatus and are uncorrected.
Elemental analyses were performed on a Perkin-Elmer 240C analyzer.
1H NMR spectra were measured in CDCl3 using a multinuclear FT-NMR
spectrometer ARX300 (Bruker). Mass spectra were obtained from Micromass
ZabSpec and API3000 instruments. Optical rotations were measured with
POLAX-2L polarmeter. The enantiomeric excess of the title compound was
determined by HPLC. Condition of HPLC: Hypersil BDS column and
b-cyclodextrin as chiral mobile phase additive, methanol–acetonitrile–
KH2PO4 (0.075 mol L21)–H2O ¼ 25:2:60:18 as eluent. 9a-(N-methyl-3-
.
azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-hydroxy-20-phenylacetate was
synthesized as described in the literature.[4]
9a-(N-trichloroethylformyl-3-azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-
20-hydroxy-20-phenylacetate 3: A mixture of 2 (3.6 g, 10 mmol) and 2,2,2-
trichloroethylchloroformate (2.5 g, 12 mmol) in 50 mL of anhydrous
benzene was heated under reflux for 20 h. After evaporation of the solvent
and excessive 2,2,2-trichloroethylchloroformate, the residual oil was added
.
to a solution of 50 mL of 25–28% NH3 H2O and 50 mL of ether. The
organic solution was washed with two 10 mL portions of saturated brine
and dried over anhydrous magnesium sulfate. The solution evaporated
under reduced pressure to give 3 4.7 g (91% yield) as a yellow oil. MS
(ESI): 519.2(Mþ1)þ.
9a-(3-azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-hydroxy-20-phenylacetate
rac-1: A solution of the yellow oil product in 50 ml of glacial HAc and 3.5 g
of zinc dust was stirred for 5 h at room temperature. After removal of the zinc
by filtration, the filtrate was basified with concentrated NaOH and extracted
with three 50-ml portions of ether. The solution evaporated under reduced
pressure to give 2.8 g (80% yield) of colorless solid. MS (ESI):
344.2(M þ 1)þ. Mp 131–1338C. Anal. calcd. for C21H29NO3: C, 73.44; H,
1
8.51; N, 4.08. Found: C, 73.51; H, 8.71; N, 4.18. H NMR (CDCl3): 7.69

9a-(3-Azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-hydroxy-20-phenylacetate 1409
(m, 2H), 7.33 (m, 2H), 7.26 (m, 1H), 4.93 (m, 1H), 3.86 (br, 1H), 3.18 (m, 1H),
3.08 (m, 2H), 3.00 (m, 2H), 2.18 (m, 1H), 2.00 (m, 1H), 1.90 (s, 2H), 1.30–
1.70 (m, 12H).
Optical resolution of rac-1: A solution of rac-1 (3.5 g, 10 mmol) and L-N-
toluenesulfonylglutamic acid (TSGA) (3.0 g, 10 mmol) in anhydrous ethanol
(150 mL) was kept at 508C for 12 h. After being cooled to room temperature,
.
a 1:1 inclusion complex (R)-(2)-1 L-TSGA was obtained as colorless
crystals. Recrystallization of the salts from ethanol three times gave pure
21
.
inclusion crystals. The inclusion complex was basified with 2 mol L
NaOH and extracted with ether (50 mL ꢀ 3) and dried over anhydrous
magnesium sulfate. The solution evaporated under reduced pressure to give
optical pure (R)-(2)-1 0.99 g (56% yield). [a]2D0 ¼ 2 32.18 (c ¼ 2, ethanol),
98.2% ee. Mp 132–1338C. Anal. calcd. for C21H29NO3: C, 73.44; H, 8.51;
N, 4.08. Found: C, 73.41; H, 8.61; N, 4.10.
The mother liquor was concentrated in vacuo and the residue was make
21
NaOH. The ester was extract with ether
.
alkaline with 2 mol L
(50 mL ꢀ 3) and dried over anhydrous magnesium sulfate. After evaporation
of the solvent, a solution of D-N-toluenesulfonylglutamic acid (4.0 g,
13 mmol) in anhydrous ethanol (100 mL) was added and the salt (S)-(þ)-
.
1 D-TSGA formed was purified in same process as described previously.
(S)-(þ)-1 was obtained by basified the salt 1.05 g (60% yield). [a]D20
¼
þ 32.58 (c ¼ 2, ethanol), 99.1% ee. Mp 132–1338C. Anal. calcd. for
C21H29NO3: C, 73.44; H, 8.51; N, 4.08. Found: C, 73.48; H, 8.48; N, 4.04.
cis-(2S,5S)-2,5-diphenyl-1,3-dioxolan-4-one ((S, S)-5): To a suspension of
(S)-mandelic acid (25.0 g, 164 mmol) in pentane (250 mL) was added benzal-
dehyde (20.9 g, 200 mmol), followed by addition of trifluoromethanesulfonic
acid (1.23 mL, 14 mmol) at 258C. To the reaction flask was added a Dean-
Stark trap. The mixture was warmed to 368C and allowed to reflux for 24 h.
The reaction mixture was allowed to cool to room temperature and 10 wt %
aqueous NaHCO3 was added. The organic layer was separated and the
aqueous layer was extracted with ether (50 mL ꢀ 3). The combined organic
layer was washed with water and brine, dried with Na2SO4, filtered, and concen-
trated in vacuum. The crude product was crystallized twice with diethyl ether-
pentane to give pure (S, S)-5, 31.5 g (80%). Mp 83–848C, [a]2D5 ¼ þ 66.68. 1H
NMR(CDCl3) d5.41(s, 1H), 6.55 (d, J ¼ 1 Hz, 1H), 7.30–7.65(m, 10H). Anal.
calcd. for C15H12O3: C, 74.99; H, 5.03. Found: C, 74.95; H, 4.99.
(S)-a-Cyclopentyl-a-hydroxy-a-phenylacetic acid ((S)-7): To a 2788C
solution of lithium diisopropylamide (60 g, 55 mmol, 10% in hexane
solution) in Et2O (50 mL) was added 5 (12.0 g, 62 mmol, dissolved in 50 mL
of Et2O). The reaction mixture was allowed to stir for 30 min at 2608C,
followed by the addition of neat bromocyclopentane (14.9 g, 100 mmol).
After stirring for 2 h at 2608C, saturated NaH2PO4 solution (50 mL) was
added. The reaction mixture was poured into a separatory funnel containing
saturated NH4Cl solution (100 mL). The aqueous layer was separated and
extracted with Et2O (200 mL ꢀ 3). The combined organic layers were dried

1410
Y.-Q. Liu et al.
(Na2SO4), filtered, and concentrated in vacuo to provide 11.0 g of crude aldol
product 6, which was used in the next step without purification.
To a solution of 11.0 g crude 6 in 50 mL MeOH and 100 mL water was
added solid KOH (25.0 g). The reaction was allowed to reflux for 3 h. After
cooling to room temperature, the reaction mixture was poured into 50 mL
water and extracted with Et2O (50 mL ꢀ 3) and discarded. The aqueous
layer was acidified to pH 1 with 2 N HCl, and the resulting mixtures were
extracted with ethyl acetate (100 mL ꢀ 3). The combined organic layers
were dried (Na2SO4), filtered, and concentrated in vacuo to provide 15 g of
colorless needle crystals of (S)-a-cyclopentyl-a-hydroxy-a-phenylacetic
1
acid 7, 9.8 g (73%). H NMR (CDCl3) d 1.84 (s, 3H), 7.30–7.65 (m, 5H,
Ar-H). 13C NMR d 26.0, 75.5, 76.6, 125.1, 128.2, 141.7, 180.4. Anal. calcd.
for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.81; H, 7.35.
(S)-9a-(N-Methyl-3-azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-hydroxy-
20-phenylacetate (S)-2: To a solution of 2.2 g 7 (10 mmol) in 50 mL Et2O was
added a solution of CH2N2 in Et2O (about 30 mmol); the mixture was stirred
at room temperature for 30 min and concentrated in vacuo to provide crude
(S)-methyl a-cyclopentyl-a-hydroxy-a-phenylacetate 8, which was used in
the next step without purification. 8 (2.6 g, 11 mmol) and 3-azabicyclo[3,3,1]-
nonan-9a-ol (1.5 g, 10 mmol) were dissolved in anhydrous n-heptane
(100 mL); NaH (0.5 g assay 80%) was added. The solution was refluxed for
3 h. The solvent was removed under reduced pressure; the residue was
dissolved in ether (150 mL), washed with water and brine, dried over
anhydrous sodium sulfate, and concentrated to dryness. (S)-2 was purified
by flash chromatography (chloroform/methanol, 9:1) and isolated as oil
(2.8 g, 79%). Anal. calcd. for C22H31NO3: C, 73.92; H, 8.74; N, 3.92.
1
Found: C, 73.84; H, 8.89; N, 3.90. H NMR (CDCl3): 7.63 (m, 2H), 7.35
(m, 3H), 5.00 (s, 1H), 3.76 (m, 2H), 3.15 (m, 2H), 3.00 (m, 2H), 2.89
(s, 3H), 2.287 (s, 1H), 2.07 (s, 1H), 1.94 (m, 2H), 1.30–1.75 (m, 12H). MS
(ESI): 364.2 (M þ 1)þ.
(S)-1 could be obtained from demethylate reaction by 2,2,2-trichloroethyl
carbamate in a similar way as described in optical resolution process. 92.4% ee.
Mp 132–1338C. Anal. calcd. for C21H29NO3: C, 73.44; H, 8.51; N, 4.08.
Found: C, 73.38; H, 8.45; N, 4.01.
(R)-1 could be obtained from (R)-mandelic acid as the start materials in
the same process. 91.1 % ee. Mp 132–1338C. Anal. calcd. for C21H29NO3:
C, 73.44; H, 8.51; N, 4.08. Found: C, 73.36; H, 8.53; N, 4.14.
Crystal data: C21H29NO3, Mr ¼ 343.45, orthorhombic, P212121,
3
˚
˚
˚
˚
a ¼ 8.097(3) A, b ¼ 14.856(5) A, c ¼ 15.418(5) A, V ¼ 1854.6(11) A ,
Dx ¼ 1.230 g cm23, Z ¼ 4, m ¼ 0.081 mm21, T ¼ 293(2) K. A colorless
crystal with dimensions of 0.26 mm ꢀ 0.24 mm ꢀ 0.20 mm was mounted on
a BRUKER SMART 1000 CCD diffractometer equipped with a graphite
monochromator for data collection. The determination of unit cell parameters
˚
and data collections were performed with MoKa radiation (l ¼ 0.71073 A). A
total of 8571 reflections with 3776 independent ones with Rint ¼ 0.0129 and

9a-(3-Azabicyclo[3,3,1]nonanyl)-20-cyclopentyl-20-hydroxy-20-phenylacetate 1411
1600 observed reflections with I . 2s (I) were collected in the range of
1.90 , u , 26.418 by an v 2 u scan mode. All data were corrected by
using SADABS method. The structure was solved by direct methods with
SHELXL-97 program.[14] The final refinement was performed by full-
matrix least-squares method with anisotropic thermal parameters for nonhy-
drogen atoms on F2. The hydrogen atoms were added theoretically, riding
on the parent atoms, with fixed thermal factors also riding. The weighting
scheme was w ¼ 1/[s2(Fo2) þ (0.0300P)2], where P ¼ (Fo2 þ 2F2c)/3. The
refinement converged to the final R ¼ 0.0682 and wR ¼ 0.1090. S ¼ 0.932.
Molecular graphics were drawn with the program package XP. Full crystallo-
graphic details have been deposited with the Cambridge Crystallographic Data
Center and allocated the deposition number CCDC-212449.
ACKNOWLEDGMENTS
This work was financially supported by the National Natural Science
Foundation of China (No. 30271492).
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