Enantioselective synthesis of (R)-tolterodine via CuH-catalyzed asymmetric conjugate reduction

Article abstract of DOI:10.1021/jo900530s

(Chemical Equation Presented) An efficient and highly enantioselective method for the preparation of (R)-tolterodine is described. The synthesis was performed by CuH-catalyzed asymmetric conjugate reduction of a β,β-diaryl-substituted unsaturated nitrile

Full text of DOI:10.1021/jo900530s

Enantioselective Synthesis of (R)-Tolterodine via CuH-Catalyzed
Asymmetric Conjugate Reduction
Kihyun Yoo, Hyohyun Kim, and Jaesook Yun*
Department of Chemistry and Institute of Basic Science, Sungkyunkwan UniVersity, Suwon 440-746, Korea
jaesook@skku.edu
ReceiVed March 11, 2009
An efficient and highly enantioselective method for the preparation of (R)-tolterodine is described. The
synthesis was performed by CuH-catalyzed asymmetric conjugate reduction of a ꢀ,ꢀ-diaryl-substituted
unsaturated nitrile as a key step, which is prepared by a stereoselective hydroarylation of alkynenitrile
with aryl boronic acid. The synthesis was accomplished without employing the protection-deprotection
sequence.
SCHEME 1. Retrosynthetic Analysis
Introduction
(R)-Tolterodine, a potent muscarinic antagonist, is an impor-
tant urological drug used for the treatment of an overactive
bladder.1 Several different approaches have been reported for
the asymmetric synthesis of tolterodine so far, utilizing asym-
metric hydrogenation,2 conjugate addition of arylboronic acids,3
and CBS reduction4 as a key step. In most of the syntheses,
cyclic precursors such as coumarins2,3a and indenones4 were
used in the key catalytic enantioselective step except for the
early approaches based on chiral auxiliaries5 or hydroformylation
reaction.6 Although some of the syntheses achieved high levels
of enantioselectivity,3,4 a more efficient method with no extra
steps for manipulating unnecessary functionalities is still
required.
of the double bond configuration and to the lack of appropriate
asymmetric reduction methods. On the other hand, asymmetric
hydrogenations of a coumarin intermediate catalyzed by rhodium
or ruthenium were reported, but only a moderate level (80%
ee) of enantioselectivity was obtained under optimized condi-
tions.2
Tolterodine has the structural element with two aryl groups
attached to a chiral center. One attractive route to this type of
target molecule would be catalytic asymmetric reduction of a
suitable acyclic alkenyl precursor (Scheme 1). However, this
approach has not been realized possibly due to a difficult control
Copper hydride (Cu-H) ligated by nonracemic ligands has
rapidly developed into a powerful catalyst for the enanti-
oselective reduction of various electron-deficient olefins,
including R,ꢀ-unsaturated carbonyl compounds, nitroalkenes,
and alkenyl sulfones.7 One of the applications of the copper
hydride catalysis is the asymmetric reduction of R,ꢀ-
(1) Nilvebrant, L. ReV. Contemp. Pharmacother. 2000, 11, 13–27.
(2) (a) Piccolo, O.; Ulgheri, F.; Marchetti, M. Enantioselective Synthesis of
Enantiomerically Enriched Compounds. International Patent WO 2005/005356,
2005. (b) Ulgheri, F.; Marchetti, M.; Piccolo, O. J. Org. Chem. 2007, 72, 6056–
6059.
(3) (a) Chen, G.; Tokunaga, N.; Hayashi, T. Org. Lett. 2005, 7, 2285–2288.
(b) So¨rgel, S.; Tokunaga, N.; Sasaki, K.; Okamoto, K.; Hayashi, T. Org. Lett.
2008, 10, 589–592.
(7) (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473–9474. (b) Lipshutz, B. H.; Noson, K.;
Chrisman, W. J. Am. Chem. Soc. 2001, 123, 12917–12918. (c) Czekelius, C.;
Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 4793–4795. (d) Llamas, T.;
Arraya´s, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2007, 46, 1–5. (e)
Desrosiers, J.-N.; Charette, A. B. Angew. Chem., Int. Ed. 2007, 46, 5955–5957.
(f) Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. ReV. 2008, 108, 2916–2927.
(4) Hedberg, C.; Andersson, P. G. AdV. Synth. Catal. 2005, 347, 662–666.
¨
(5) (a) Andersson, P. G.; Schink, H. E.; Osterlund, K. J. Org. Chem. 1998,
63, 8067–8070. (b) Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2004, 69, 9196–
9203.
(6) Botteghi, C.; Corrias, T.; Marchetti, M.; Paganelli, S.; Piccolo, O. Org.
Process Res. DeV. 2002, 6, 379–383.
4232 J. Org. Chem. 2009, 74, 4232–4235
10.1021/jo900530s CCC: $40.75 2009 American Chemical Society
Published on Web 04/27/2009

EnantioselectiVe Synthesis of (R)-Tolterodine
SCHEME 2. Preparation of (Z)- and (E)-Nitriles via Stereoselective Hydroarylation
unsaturated nitriles,8 which produce a different coordination
environment from R,ꢀ-unsaturated carbonyl compounds due
to its linear CN group. Recently, we have also reported an
efficient CuH-catalyzed enantioselective conjugate reduction
of 3-aryl-3-pyridylacrylonitriles.9 In this study, we found that
the copper system did not require a secondary coordinating
functionality for catalytic reactivity unlike Rh- and Ru-
catalyzed asymmetric hydrogenation.10
For the development of a new synthetic route to tolterodine,
we became interested in applying the CuH asymmetric
reduction method to sterically demanding 3,3-diarylacryloni-
triles having an ortho substitution on the aryl group. Herein,
we report an efficient asymmetric synthesis of (R)-tolterodine
that was successfully achieved by performing highly enan-
tioselective CuH catalysis of isomerically pure 3,3-diaryl-
substituted acrylonitriles.
partners, the coupling reactions resulted in incomplete
conversion and production of an inseparable mixture of (E)-
and (Z)-isomers.13 Then, we turned our attention to the
copper-catalyzed hydroarylation of alkynoates reported by
Yamamoto and co-workers.14 To our satisfaction, the reaction
of phenyl boronic acid with properly substituted aryl
alkynenitriles 3a and 3b gives (Z)-3,3-diarylacrylonitriles (1a
and 1b) with high stereoselectivity (Scheme 2).15 The
corresponding (E)-isomers were also prepared by the reaction
of phenyl alkynenitrile (3c) with ortho-substituted boronic
acids. However, the addition of the boronic acid possessing
an unprotected ortho-phenolic hydroxyl group proceeded very
poorly, and thus (E)-1a was obtained after deprotection of
the TMS group of the intermediate adduct. The stereochem-
istry of (Z)-1b and (E)-1b was assigned based on the
mechanism of the hydroarylation and corroborated by NOE
experiments.16
Then, we examined the conjugate reduction of these
substrates with 2 mol % of catalyst in the presence of excess
polymethylhydrosiloxane (PMHS) as a stoichiometric reduc-
ing agent in toluene. As expected, this type of diarylacry-
lonitrile with an ortho substitution (1) generates more steric
congestion around the reactive site than simple 3-phenyl-3-
pyridylacrylonitriles, and thus most of the catalyst-ligand17
combinations that had given complete conversion of the latter
substrates displayed inferior reactivity (Table 1, entries 1 and
2). However, to our delight, the reduction of (Z)-1a smoothly
proceeded to completion at room temperature in 12 h with 2
Results and Discussion
In the beginning of our study, we found that attaining
geometrically pure 3,3-diarylacrylonitriles was of great
importance because the CuH reduction of (E)- and (Z)-olefin
isomers was known to supply opposite enantiomers.8,9 Our
initial attempts to stereoselectively synthesize the unsaturated
nitrile compounds via a Heck11 or a Suzuki-Miyaura cross-
coupling12 reaction by following the known literature pro-
cedures were not successful; with ortho-substituted coupling
(8) Lee, D.; Kim, D.; Yun, J. Angew. Chem., Int. Ed. 2006, 45, 2785–2787.
(9) Lee, D.; Yang, Y.; Yun, J. Org. Lett. 2007, 9, 2749–2751.
(10) Wabnitz, T. C.; Rizzo, S.; Go¨tte, C.; Buschauer, A.; Benincori, T.; Reiser,
O. Tetrahedron Lett. 2006, 47, 3733–3736.
(13) See the Supporting Information for details.
(14) Yamamoto, Y.; Kirai, N.; Harada, Y. Chem. Commun. 2008, 2010–
2012.
(15) These are first examples of 3,3-diarylacrylonitriles synthesized from
alkynenitriles via copper-catalyzed hydroarylation with aryl boronic acids.
(16) See the Supporting Information for details.
(11) (a) Moreno-Man˜as, M.; Pleixats, R.; Roglans, A. Synlett 1997, 1157–
1158. (b) Masllorens, J.; Moreno-Man˜as, M.; Pla-Quintana, A.; Pleixats, R.;
Roglans, A. Synthesis 2002, 1903–1911.
(12) Taylor, S. J.; Netherton, M. R. J. Org. Chem. 2006, 71, 397–400.
J. Org. Chem. Vol. 74, No. 11, 2009 4233

Yoo et al.
TABLE 1. Copper-Catalyzed Asymmetric Conjugate Reduction
successive copper-catalyzed conjugate additions were stereo-
selectively carried out to give enantiomerically enriched dia-
rylpropanenitriles (2). (R)-Tolterodine was produced in 6 steps
from commercially available starting materials with an excellent
level of enantioselectivity (96% ee).
substrates
t
conversion yield
eea
(%)
Experimental Section
entry
(1)
ligand
(h)
(%)
(%)
1
2
3
4
5
6
7
(Z)-1a
(Z)-1a
(Z)-1a
(Z)-1a
(E)-1a
(Z)-1b
(E)-1b
(R)-(R)-Walphos
(R)-MeOBIPHEP
(R)-(S)-cy2PF-Pcy2 18
L1
L1
L1
L1
24
24
NR
92
For experimental details, see the Supporting Information.
General Procedure for the Copper-Catalyzed Hydroaryla-
tion (1). To a solution of alkynenitrile 3a-c (5 mmol) and
arylboronic acid (10 mmol) in methanol (10 mL) was added CuOAc
(30.5 mg, 0.25 mmol). The reaction mixture was stirred at room
temperature under a nitrogen atmosphere for 6 h. After filtration
of the reaction mixture through a pad of Celite, the filtrate was
concentrated in vacuo. The residue was purified by flash column
chromatography (SiO2, hexane/EtOAc ) 20:1).
60
83
86
91
87
85
25 (S)
41 (R)
96 (R)
86 (S)
92 (R)
90 (S)
100
100
100
100
100
12
12
12
12
a Determined by chiral HPLC analysis.
(Z)-3-(2-Hydroxy-5-methylphenyl)-3-phenylacrylonitrile ((Z)-
1a). 3a (786 mg, 5 mmol) and phenylboronic acid (1.2 g, 10 mmol)
were employed to afford 830 mg of the desired product as a pale
yellow solid (71%): 1H NMR (CDCl3, 300 MHz) δ 7.55-7.53 (m,
3H), 7.48-7.43 (m, 2H), 7.38-7.32 (m, 2H), 7.25 (s, 1H), 6.35
(s, 1H), 2.33 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ 161.1, 155.8,
152.4, 135.4, 134.0, 133.0, 129.7, 129.0, 128.5, 126.8, 118.8, 117.2,
115.3, 21.1; IR (neat) 2211 cm-1. Anal. Calcd for C16H13NO: C
81.68; H 5.57. Found: C 81.42; H 5.58. HRMS (EI) calcd for
C16H13NO 235.0997, found 235.0988.
SCHEME 3. Asymmetric Synthesis of (R)-Tolterodine
General Procedure for the Copper-Catalyzed Enantioselec-
tive Reduction. Cu(OAc)2 (1.82 mg, 0.010 mmol) and Josiphos
ligand (6.41 mg, 0.010 mmol, ethanol adduct) were placed in an
oven-dried Schlenk tube. Toluene (0.5 mL) was added under a
nitrogen atmosphere and the reaction mixture was stirred for 10
min at room temperature. PMHS (75 µL, 1.25 mmol) was added
to the reaction mixture, which was then stirred for 5 min for catalyst
activation. The unsaturated nitrile (0.5 mmol) and toluene (0.5 mL)
were added, followed by t-BuOH (191 µL, 2.0 mmol). The reaction
was sealed and stirred until the starting material was completely
consumed as judged by TLC. The reaction mixture was quenched
with water and transferred to a round-bottomed flask with the aid
of EtOAc (10 mL), then NaOH (2.5 M, 1.2 mL) was added. The
biphasic mixture was stirred vigorously for 0.5 h. The layers were
separated and the aqueous layer was extracted with EtOAc (3 ×
20 mL). The combined organic layers were washed with brine, dried
over MgSO4, and concentrated in vacuo. The product was purified
by chromatography.
mol % of Cu(OAc)2 and (R)-(S)-Josiphos (L1) as the chiral
ligand, giving the desired product (R)-2a in 86% yield and
96% ee (entry 4). The (E)-isomer of 1a gave a lower
enantioselectivity of 86% under the same conditions (entry
5). Both of the methoxy derivatives, (Z)- and (E)-1b, were
reduced with similar enantioselectivities, 92% and 90% ee,
respectively (entries 6 and 7). Overall, with Josiphos as the
ligand, the (Z)-isomers gave better enantioselectivity than
the (E)-isomers and increasing steric bulk of the ortho
substituent18 resulted in a slight decrease in ee for the (Z)-
isomer.
It turned out that the best route to the key intermediate (R)-
2a for tolterodine is the most convenient method starting from
3a bearing the free hydroxyl group without using the protection-
deprotection sequence (Scheme 3). To complete the synthesis
of (R)-tolterodine, the propionitrile (R)-2a was reduced to lactol
4 with DIBALH. The crude product was subsequently submitted
to reductive amination with diisopropylamine and NaBH(OAc)3
in 1,2-dichloroethane to give (R)-tolterodine in 63% yield for
the two steps.
(R)-3-(2-Hydroxy-5-methylphenyl)-3-phenylpropanenitrile ((R)-
2a). Using the general procedure for the enantioselective reduction,
(Z)-1a (118 mg, 0.5 mmol) was employed to afford 102 mg of the
desired product as a pale yellow oil (86%): 1H NMR (CDCl3, 300
MHz) δ 7.37-7.25 (m, 3H), 7.17-7.03 (m, 4H), 6.78 (s, 1H), 4.29
(t, J ) 6.7 Hz, 1H), 3.02 (sept, J ) 7.5 Hz, 2H), 2.25 (s, 3H); 13
C
NMR (75.4 MHz, CDCl3) δ 154.6, 141.0, 129.9, 129.4, 128.8,
128.6, 127.8, 127.0, 119.0, 110.9, 55.5, 40.9, 22.7, 20.7; IR (neat)
2245 cm-1. Anal. Calcd for C16H15NO: C 80.98; H 6.37; N 5.90.
Found: C 80.84; H 6.69; N 5.78. The ee (96% ee) was measured
by chiral HPLC on an OD-H column (i-PrOH/hexane 10:90, 0.5
mL/min); (R)-isomer tr ) 16.8 min and (S)-isomer tr ) 18.9 min.
(R)-Tolterodine. To a solution of (R)-2a (100 mg, 0.42 mmol)
in anhydrous toluene (3 mL) was added dropwise a solution of 1
M DIBAL-H in toluene (500 µL, 0.5 mmol) at 0 °C under a nitrogen
atmosphere. The reaction was quenched after 5 h with EtOAc and
a solution of sulfuric acid was added. The solution was stirred at
room temperature overnight. The aqueous phase was extracted with
EtOAc (3 × 20 mL), then the organic phases were dried over
Na2SO4, filtered, and concentrated under reduced pressure. To a
solution of the crude product in 1,2-dichloroethane (3 mL) were
added diisopropylamine (280 µL, 2 mmol) and sodium triacetoxy-
borohydride (59.4 mg, 2 mmol), then the reaction mixture was
In summary, we have developed a short, efficient catalytic
asymmetric total synthesis of (R)-tolterodine without protecting
the phenolic hydroxylic group throughout the synthesis. Two
(17) Lower conversion and enantioselectivity was obtained except for
Josiphos ligand. (R)-(R)-Walphos ) (R)-1-[(R)-2-(2′-diphenylphosphinophenyl)-
ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine; (R)-MeOBIPHEP )
(R)-(+)-(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine); (R)-(S)-cy2PF-
Pcy2
phosphine.
)
(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexyl-
(18) Increasing further the size of a protecting group of the OH resulted in
a lower reaction rate. The reaction of a benzyl-protected derivative of (Z)-1a
proceeded to 60% conversion in 24 h under the same conditions.
4234 J. Org. Chem. Vol. 74, No. 11, 2009

EnantioselectiVe Synthesis of (R)-Tolterodine
stirred at room temperature for 16 h. Aqueous NaHCO3 was added
and the mixture was extracted with EtOAc. The combined organic
extracts were dried over MgSO4, filtered, and concentrated. Flash
chromatography (SiO2, hexane/EtOAc ) 9:10) afforded 86 mg of
Acknowledgment. This work was supported by a Korea
Research Foundation Grant funded by the Korean Government
(MOEHRD, Basic Research Promotion Fund) (KRF-2008-531-
C00039). We thank Solvias for a generous supply of the ligands
used in this study.
1
product as a colorless oil (63%): H NMR (CDCl3, 300 MHz) δ
7.32-7.29 (m, 4H), 7.24-7.20 (m, 1H), 6.84 (dd, J ) 8.2, 2.0 Hz,
1H), 6.80 (d, J ) 8.1 Hz, 1H), 6.54 (s, 1H), 4.48 (dd, J ) 11.1, 3.8
Hz, 1H), 3.21 (sept, J ) 6.7 Hz, 2H), 2.72-2.69 (m, 1H),
2.40-2.30 (m, 2H), 2.11 (s, 3H), 2.11-2.04 (m, 1H), 1.12 (d, J )
6.7 Hz, 6H), 1.06 (d, J ) 6.7 Hz, 6H); 13C NMR (75.4 MHz,
CDCl3) δ 153.0, 144.7, 132.3, 129.1, 128.5, 128.3, 128.2, 127.6,
125.9, 117.8, 47.9, 42.2, 39.5, 33.5, 20.6, 19.9, 19.5; [R]23D +19.6
Supporting Information Available: Experimental details,
characterization data, and HPLC, 1H, and 13C NMR spectra for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(c 0.5, MeOH) [lit. value: [R]20 +22.0 (c 0.32, MeOH) for (R)-
D
tolterodine].
JO900530S
J. Org. Chem. Vol. 74, No. 11, 2009 4235