Asymmetric total synthesis of (+)-tolterodine, a new muscarinic receptor antagonist, via copper-assisted asymmetric conjugate addition of aryl Grignard reagents to 3-phenyl-prop-2-enoyl-oxazolidinones

Full text of DOI:10.1021/jo981259r

J . Org. Chem. 1998, 63, 8067-8070
8067
Asym m etr ic Tota l Syn th esis of
(+)-Tolter od in e, a New Mu sca r in ic
Recep tor An ta gon ist, via Cop p er -Assisted
Asym m etr ic Con ju ga te Ad d ition of Ar yl
Gr ign a r d Rea gen ts to
3-P h en yl-p r op -2-en oyl-oxa zolid in on es
Pher G. Andersson,*,† Hans E. Schink,‡ and
F igu r e 1.
Krister O¨ sterlund†
Department of Organic Chemistry, University of Uppsala,
Box 531, S-751 21, Uppsala, Sweden, and
Department of Chemistry, Pharmacia & Upjohn,
S-751 82, Uppsala, Sweden
Received J une 29, 1998
In tr od u ction
F igu r e 2.
Tolterodine (Figure 1) is a new and potent competitive
muscarinic receptor antagonist. The drug is intended for
the treatment of urinary urge incontinence and other
symptoms of bladder overactivity.1 It has been shown
that Tolterodine has a more pronounced action on the
urinary bladder than on salivary glands in vivo in the
anaesthetised cat.2 This selectivity also seems to occur
in humans as demonstrated in clinical trials.3 However,
this favorable profile cannot be attributed to selectivity
for a single muscarinic receptor subtype.
The structural element with two aryl groups attached
to a chiral center, as in Tolterodine, which has the R
configuration, is unusual, and few reports in the chemical
literature deal with asymmetric synthesis of these types
of diaryl compounds.4 Retrosynthetically, there are
several ways to approach this problem. One attractive
way would be catalytic asymmetric hydrogenation of a
double bond, as pictured in eq 1, using some chiral-
ligand-metal complex. However, this requires control
of the double bond configuration in the preceding steps,
which is not a trivial problem.
Resu lts a n d Discu ssion
To find a suitable chiral auxiliary for the asymmetric
1,4-addition to the cinnamic unit, a number of substrates
were prepared and evaluated. The substrates used
(Figure 2), camphorsultam 16 or the oxazolidinones 2a ,7
2b8 or 3a ,6 3b,9 3c,8 were prepared from cinnamoyl
chloride, and the corresponding chiral auxiliary was
prepared using literature procedures.
Several aryl-magnesium and aryl-copper reagents
were evaluated in the 1,4-addition to the camphorsultam
1 (Scheme 1). It was found that none of the aryl
grignards (alone or copper-catalyzed), not homocuprates
nor arylcopper reagents, led to any reaction. On the
other hand, the reagent derived from phenylmagnesium
bromide and CuBr-Me2S (PhMgBr/Cu 2:1) smoothly
underwent a highly regioselective 1,4-addition to the
camphorsultam and gave 4a in a quantitative yield.
When the aryl group was changed from phenyl to
2-methoxy-5-methylphenyl, the adduct 4b was formed in
74% chemical yield but with a disappointingly low
diastereomeric excess10 (50%).
To improve the diastereoselectivity of the reactions
with 2-methoxy-5-methylphenyl, the sultam was replaced
by chiral oxazolidinones 2a -b and 3a -c. These sub-
strates also underwent highly regioselective 1,4-additions
when they were treated with 2-methoxy-5-methylphen-
ylmagnesium bromide and CuBr‚Me2S, as shown in
Scheme 2 and Table 1.
Oxazolidinone 2a , derived from L-valine, smoothly
underwent the 1,4-addition and furnished (S)-5 after
deprotection of the chiral auxiliary.11 The enantiomeric
On the other hand, conjugate additions of various
nucleophiles to R,â-unsaturated acid derivatives attached
to a chiral auxiliary is a well-known methodology in
asymmetric synthesis (eq 2). Oxazolidinones, for ex-
ample, have been extensively used in this context and
are also easily obtained.5 Thus, by choosing this ap-
proach we could use readily available starting materials
and reliable synthetic routes for the preparation of the
desired substrates.
† University of Uppsala.
‡ Pharmacia & Upjohn.
(6) Thom, C.; Kocie´nski, P. Synthesis 1992, 582.
(7) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am. Chem. Soc. 1988,
110, 1238.
(1) Registration applications have been filed in EU and US.
(2) Nilvebrant, L.; Andersson, K.-E.; Gillberg, P.-G.; Stahl, M.; Sparf.
B. Eur. J . Pharmacol. 1997, 327, 195.
(8) See Experimental Section.
(3) Nilvebrant, L.; Halle´n, B.; Larsson, G. Life Sci. 1997, 60, 1129.
(4) For a recent exception, see: Prat, L.; Mojovic, L.; Levacher, V.;
Dupas, G.; Que´guiner, G.; Bourguignon, J . Tetrahedron: Asymmetry
1998, 9, 2509.
(9) Nicola´s, E.; Russell, K. C.; Hruby, V. J . J . Org. Chem. 1993, 58,
766.
(10) Established by 1H NMR, absolute configuration not determined.
(11) Evans D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141.
(5) Rossiter, B. R.; Swingle, N. M. Chem. Rev. 1992, 92, 771.
10.1021/jo981259r CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/16/1998

8068 J . Org. Chem., Vol. 63, No. 22, 1998
Notes
Ta ble 1. Cu -Ca ta lyzed Con ju ga te Ad d ition to
Sch em e 4
Su bstr a tes 2a ,b a n d 3a -c
entry
substrate
R1
R2
yield (%)
de (%)
config
1
2
3
4
5
2a
2b
3a
3b
3c
i-Pr
i-Pr
Me
Ph
H
68
84
75
78
81
60
99
50
98
99
S
S
R
R
R
i-Pr
Ph
H
Ph
Ph
Sch em e 1
Sch em e 2
Since 3b, derived from commercially available phenyl-
oxazolidinone, gave good yield and high stereoselectivity
in the addition reaction, it was used for further elabora-
tion to Tolterodine according to the sequence outlined in
Scheme 4.
Changing the phenol protective group of the nucleo-
phile from methyl to the more easily removable benzyl
did not affect the stereoselectivity or the yield of the
conjugate addition reaction. Reacting 3b with the aryl
Grignard reagent, as described earlier, afforded the diaryl
derivative 9 in 84% yield. NMR analysis of the reaction
mixture suggested a high diastereomeric excess, >95%.
This was confirmed in the next step. Removal of the
chiral auxiliary11 (LiOH/H2O2 in water/THF) yielded the
acid 10, and HPLC analysis revealed the ee to be 98%.
Treating 10 with thionyl chloride followed by diisopro-
pylamine afforded the corresponding diisopropylamide
11. Subsequent reduction of the amide with lithium
aluminum hydride gave o-benzyl Tolterodine, which after
deprotection (H2/palladium on carbon) yielded Toltero-
dine in 98% ee.
Sch em e 3
Exp er im en ta l Section
Gen er a l. For general experimental information, see ref 12.
1-Methoxy-2-bromo-4-methylbenzene13 and 1-benzyloxy-2-bromo-
4-methylbenzene14 were prepared from commercially available
2-bromo-4-methylphenol and had spectral data in agreement
with those reported in the literature. Merck silica gel 60 (240-
400 mesh) was used for column chromatography. Chiral HPLC
analyses were done on a CHIRAL-AGP 100 × 2 mm column
using 2-propanol as the eluent. All reactions except those
involving water were performed in flame-dried glass charged
with nitrogen. The copper(I) bromide-dimethyl sulfide complex
was purchased from Aldrich (art. 23,050-2). Magnesium sulfate
was used for drying of organic extracts.
excess was determined by chiral HPLC and revealed that
the acid had been obtained in 60% ee.
By the introduction of a second substituent on the
oxazolidinone, as in 2b (prepared via Sharpless dihy-
droxylation of 2,4-dimethyl-3-hexene and subsequent
transformation of 6 into its amino alcohol 7, Scheme 3),
the enantiomeric excess of the acid could be raised to
99%.
Since the synthesis of Tolterodine requires the opposite
sense of chiral induction in the 1,4-addition, we studied
oxazolidinones 3 as chiral auxiliaries. As expected, the
use of oxazolidinone 3a gave rise to the opposite config-
uration, giving the acid (R)-5 in 50% ee after deprotection
of the oxazolidinone. However, the oxazolidinone 3b
derived from (R)-phenylglycine, resulted in (R)-5 with
98% ee. This shows that the phenyl group is superior to
the isopropyl group in directing the incoming nucleophile.
By introduction of a second substituent on the oxazoli-
dinone (3c), the ee could be improved to 99%.
2,5-Dim eth yl-3R,4R-h exa d iol, 6. This diol was prepared
in 95% yield and 98% ee15 according to the procedure developed
by Sharpless et. al. using (DHQD)2-PHAL as the chiral ligand.16
(12) Bedekar, A. V.; Koroleva, E. B.; Andersson, P. G. J . Org. Chem.
1997, 62, 2518.
(13) Carreno, M. C.; Ruano, J . L. G.; Sanz, G.; Toledo, M. A.; Urbano,
A. J . Org. Chem. 1995, 60, 5328.
(14) Kametani, T.; Ohkubo, K.; Takano, S. Chem. Pharm. Bull. 1968,
16, 1095.
(15) Determined for the corresponding bis Mosher ester, see: Shi-
bata, T.; Gilheany, D. G.; Blackburn, B. K.; Sharpless, K. B. Tetrahe-
dron Lett. 1990, 31, 3817.
(16) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768.

Notes
J . Org. Chem., Vol. 63, No. 22, 1998 8069
mp: 78-79 °C. 1H NMR (300 MHz) δ: 3.28 (br s, 2 H), 2.21 (br
s, 2 H), 1.78 (app oct, J ) 6.5 Hz, 2 H), 0.93 (d, J ) 6.5 Hz, 12
H). 13C NMR (75 MHz) δ: 76.3, 31.1, 30.4, 19.5, 17.4. IR: 3640,
2962, 1469, 1388, 993, 908 cm-1. MS: m/e (relative intensity)
146 (M+, 0.2), 129 (0.6), 117 (1.5%), 103 (14), 85 (9), 73 (100), 72
(37). [R]25D: 2.27 (c 2.2, EtOH). Anal. Calcd for C8H18O2: C,
65.71; H, 12.41. Found: C, 65.64; H, 12.47.
2,5-Dim eth yl-3S-am in oh exan -4R-ol, 7. 2,5-Dimethyl-3R,4R-
hexadiol 6 (3.50 g, 23.9 mmol), trimethyl orthoacetate (3.73 g,
31.1 mmol, 1.3 equiv), and pyridinium toluenesulfonic acid (60
mg, 0.24 mmol, 0.01 equiv) were dissolved in dry methylene
chloride (40 mL) and stirred at room temperature for 2 h. The
reaction mixture was evaporated in vacuo, and dry methylene
chloride (40 mL) was added. The resulting solution was cooled
to 0 °C, and acetyl bromide (3.82 g, 31.1 mmol, 1.3 equiv) was
added. After the addition, the reaction was stirred and allowed
to reach ambient temperature overnight. The reaction mixture
was evaporated in vacuo, filtered through silica (eluent: 10%
EtOAc in hexane), and evaporated to give ca. 6 g of a clear,
colorless oil.
The oil was dissolved in dry ether (40 mL) and NaOH (2.10
g, 52.7 mmol, 2.2 equiv), and MeOH (1.53 g, 47.9 mmol, 2.0
equiv) was added. The resulting mixture was then stirred at
room temperature for 24 h. Ether (100 mL) was added, and the
organic phase was washed with water (50 mL) and brine (25
mL) and dried. The solvent was removed by distillation at
atmospheric pressure to yield (2R,3R)-diisopropyloxirane (ca. 4
g ethereal solution) as a clear, colorless solution, which was used
directly in the next step.
(2R,3R)-Diisopropyloxirane (approximately 22 mmol) and
LiN3 (5.4 g, 110 mmol, 5 equiv) were dissolved in dry DMF (100
mL). The resulting mixture was stirred for 24 h at 110 °C, cooled
to room temperature, diluted with water (200 mL), and extracted
with ether (4 × 25 mL). The combined organic phases were
washed with water (25 mL) and brine (25 mL), dried, and
evaporated to give crude 2,5-dimethyl-3S-azidohexan-4R-ol (3.4
g, 20 mmol).
A slurry of 2,5-dimethyl-3S-azidohexan-4R-ol (3.4 g, 20 mmol)
and Pd/C (5% on carbon, 170 mg) in ethanol (50 mL) was stirred
under an atmosphere of H2 at room temperature for 5 h. The
slurry was filtered, and the filtrate evaporated in vacuo to give
2,5-dimethyl-3S-aminohexan-4R-ol (2.76 g, 19 mmol) as a clear,
colorless oil. 1H NMR (300 MHz) δ: 3.28 (dd, J ) 4.5, 6.7 Hz,
1 H), 2.61, (dd, J ) 3.9, 6.7), 12.05-1.83 (m, 5 H), 0.95 (d, J )
7.0 Hz, 3 H), 0.94 (d, J ) 7.0 Hz, 3 H), 0.90 (d, J ) 6.8 Hz, 3 H),
0.89 (d, J ) 6.9 Hz, 3 H). 13C NMR (75 MHz) δ: 77.1, 57.9,
29.2, 28.2, 20.9, 20.2, 16.3, 16.1. IR: 3450, 2960, 1686, 1468,
1385, 995 cm-1. MS: m/e (relative intensity) 145 (M+, 0.5), 117
(0.6), 102 (11), 73 (9), 72 (100). [R]25D: +7.07 (c 2.05, EtOH).
Anal. Calcd for C8H19NO: C, 66.16; H, 13.19; N, 9.64. Found:
C, 65.89; H, 13.24; N, 9.45.
(4S,5R)-Diisop r op yl-2-oxa zolid in on e, 8. 2,5-Dimethyl-3S-
aminohexan-4R-ol, 7 (0.30 g, 2.06 mmol, 1.0 eq.), and triethyl-
amine (0.25 g, 2.47 mmol, 1.2 equiv) were dissolved in CH2Cl2
(15 mL) and stirred at 0 °C. To this solution was added slowly
phosgene (1.3 mL, 1.93M in toluene, 1.2 equiv). After the
addition was complete, the resulting mixture was stirred for 2
h at room temperature. Methylene chloride (25 mL) was added,
and the solution was washed with 2 M hydrochloric acid (10 mL),
dried, and evaporated to give the product (0.330 g, 1.93 mmol,
94%) as colorless crystals. mp: 139-143 °C. 1H NMR (400
MHz) δ: 5.80 (br. s, 1 H), 4.18 (dd, J ) 6.9, 9.1 Hz, 1 H), 3.56
(dd, J ) 3.5, 6.9 Hz, 1 H), 2.08 (m, 1 H), 1.99, (m, 1 H), 1.10 (d,
J ) 6.5 Hz, 3 H), 0.97 (d, J ) 6.5 Hz, 3 H), 0.96 (d, J ) 6.5 Hz,
3 H), 0.94 (d, J ) 6.5 Hz, 3 H). 13C NMR (100 MHz) δ: 160.4,
85.8, 60.6, 27.5, 27.4, 20.6, 19.3, 19.1, 17.0. IR: 3458, 2967, 2878,
for 10 min. To this mixture was then added a solution of
cinnamoyl chloride (0.353 g, 2.12 mmol, 1.1 equiv) dissolved in
THF (2 mL) over 30 min. The resulting yellow slurry was stirred
for 1 h at -78 °C, after which the cooling bath was removed
and the reaction was allowed to reach ambient temperature. The
reaction was quenched with sat. NH4Cl (25 mL), and the
volatiles were evaporated. EtOAc (25 mL) was added, and the
organic layer was separated and washed with water (15 mL)
and brine (15 mL). The solution was dried and evaporated to
give the crude product (0.65 g) as a yellow semicrystalline
mixture. Flash chromatography with pentane/ether (90:10, Rf
) 0.48) gave the pure product as colorless crystals 0.49 g (1.64
mmol, 85%). mp: 95-98 °C. 1H NMR (400 MHz) δ: 7.97 (d, J
) 15.5 Hz, 1 H), 7.85 (d, J ) 15.5 Hz, 1 H), 7.63 (m, 2 H), 7.40
(m, 3 H), 4.68 (dd, J ) 1.7, 5.9 Hz, 1 H), 4.04 (dd, J ) 5.9, 11.0
Hz, 1 H), 2.20 (m, 1 H), 2.14 (m, 1 H), 1.14 (d, J ) 6.5 Hz, 3 H),
1.07 (d, J ) 6.5 Hz, 3 H), 1.00 (d, J ) 6.5 Hz, 3 H), 0.98 (d, J )
6.5 Hz, 3 H). 13C NMR (100 MHz) δ: 165.3, 154.4, 146.2, 134.7,
130.5, 128.8, 128.6, 117.1, 85.7, 60.6, 28.6, 27.0, 22.2, 19.7, 18.5,
17.0. IR: 3010, 2967, 2879, 1782, 1684, 1623, 1469, 1450, 1361,
1342, 1225, 1207, 1176, 1008 cm-1. MS: m/e (relative intensity)
301 (M+, 19), 214 (9), 190 (2), 170 (4), 132 (10), 131 (100). [R]25
:
D
+119.5 (c 1.1, CHCl3). Anal. Calcd for C18H23NO3: C, 71.73;
H, 7.69; N, 4.65. Found: C, 71.53; H, 7.47; N, 4.81.
(4R,5S)-Dip h en yl-3-(3-p h en yl-2-(E)-p r op en oyl)-2-oxa zo-
lid in on e, 3c. 3c was prepared in 93% yield from (4R,5S)-
Diphenyl-2-oxazolidinone17 by following the same procedure as
that used for 2b. mp: 271-274 °C. 1H NMR (400 MHz) δ: 8.05
(d, J ) 15.5 Hz, 1 H), 7.83 (d, J ) 15.5 Hz, 1 H), 7.64 (m, 2 H),
7.41 (m, 3 H), 7.12 (m, 6 H), 7.01 (m, 2 H), 6.92 (m, 2 H), 5.97
(d, J ) 7.5 Hz, 1 H), 5.80 (d, J ) 7.5 Hz, 1 H). 13C NMR (100
MHz) δ: 164.6, 153.8, 147.0, 134.49, 134.45, 132.8, 130.8, 128.9,
128.7, 128.4, 128.3, 128.2, 128.1, 126.6, 126.2, 116.8, 80.4, 63.1.
IR: 3021, 2972, 2875, 1785, 1681, 1468, 1358, 1227, 1210, 1180,
1010 cm-1. MS: m/e (relative intensity) 369 (M+, 6), 264 (22),
219 (79), 132 (17), 131 (87), 119 (20), 114 (9), 103 (24), 77 (25),
69 (100). [R]25D: -112.5 (c 0.48, CHCl3). Anal. Calcd for C24H19
-
NO3: C, 78.03; H, 5.18; N, 3.79. Found: C, 78.21; H, 5.05; N,
3.65.
Gen er a l P r oced u r e for th e Cu Br -Ca ta lyzed Ad d ition s
of 2-Meth oxy-5-m eth ylp h en ylm a gn esiu m Br om id e to Su l-
ta m 1 a n d Oxa zolid in on es 2 a n d 3. CuBr-Me2S (0.268 g,
1.30 mmol, 1.5 equiv) was placed in a 25 mL dried round-
bottomed flask. The solvents, THF (3 mL) and Me2S (1.5 mL),
were added, and the flask cooled to -40 °C. 2-Methoxy-5-
methyl-phenylmagnesium bromide (2.7 mL, 0.95 M, 2.61 mmol,
3.0 equiv) was added via syringe, and the temperature was
raised to -20 °C over 20 min. The color was dark-green-yellow.
The substrate (0.87 mmol, 1.0 equiv) was dissolved in THF (2
mL) and added via syringe during 1 h. The reaction mixture
was allowed to reach ambient temperature overnight. The
reaction was quenched with sat. NH4Cl (25 mL), and the
volatiles were evaporated. Water (10 mL) and EtOAc (25 mL)
were added, and the mixture was filtered through a plug of glass
wool, which was rinsed with EtOAc (25 mL). The aqueous layer
was separated. The organic layer was washed with 17% NH4-
OH (2 × 25 mL), water (30 mL), and brine (30 mL) and dried.
Evaporation of the solvent gave the crude product, which was
hydrolyzed7 to give the corresponding acid.
(5S)-P h en yl-(3R)-(2-ben zyloxy-5-m eth ylp h en yl)-3-p h en -
ylp r op a n oyl-2-oxa zolid in on e, 9. Magnesium turnings (84
mg, 3.46 mmol) were placed in a two-neck round-bottomed flask
equipped with a reflux condenser. The air in the reaction vessel
was evacuated and the flask was placed in an oil bath (75 °C).
After 5 min of stirring the magnesium turnings slowly, the
system was charged with nitrogen. Using a syringe, a solution
of 1-benzyloxy-2-bromo-4-methylbenzene (829 mg, 2.99 mmol)
in THF (5 mL) was added to the hot magnesium turnings. After
15 min of reflux, most of the magnesium had been consumed,18
the oil bath was removed, and the reaction mixture was cooled
to room temperature.
1752, 1469, 1396, 1373, 1223, 1029 cm-1
. MS: m/e (relative
intensity) 171 (M+, 0.8), 129 (8), 128 (100), 127 (28), 119, (4), 86
(24), 84 (56). [R]25D: -16.9 (c 0.35, CHCl3). Anal. Calcd for
C9H17NO2: C, 63.13; H, 10.01; N, 8.18. Found: C, 63.32; H, 9.94;
N, 8.35.
(4S,5R)-Diisop r op yl-3-(3-p h en yl-2-(E)-p r op en oyl)-2-oxa -
zolid in on e, 2b. (4S,5R)-Diisopropyl-2-oxazolidinone, 7 (0.33 g,
1.93 mmol, 1.0 equiv), was dissolved in THF (9 mL), in a 25 mL
round-bottomed flask, and then cooled to -78 °C. n-Butyl-
lithium (1.93 mmol, 1.35 mL, 1.43 M in hexanes, 1.0 equiv) was
added dropwise via syringe, and the resulting solution was tirred
(17) Akiba, T.; Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh,
T.; Nakatani, K.; Kamada, M.; Hayakawa, I.; Terashima, S. Tetrahe-
dron 1994, 50, 3905.
(18) Complete consumption of the aryl halide was confirmed by GC
analysis.

8070 J . Org. Chem., Vol. 63, No. 22, 1998
Notes
Meanwhile, copper bromide-dimethyl sulfide complex (318
mg, 1.55 mmol) was dissolved in THF (4 mL) and dimethyl
sulfide (2 mL). The orange solution was cooled to - 50 °C, and
then the solution of Grignard reagent (vide supra) was added
dropwise over approximately 3 min.
(1 mL), and the resulting mixture was filtered through a glass
wool plug. The plug was rinsed with ether (4 mL), and then
the solution was concentrated in vacuo. This gave 180 mg of a
yellow solid. This product was dissolved in dry ether, and at
room temperature, diisopropylamine (0.70 mL, 5.0 mmol) was
added over a period of 3 min. The mixture was stirred at
ambient temperature for 1.5 h and then filtered through a cotton
plug, which was rinsed with ether (6 mL). The ether solution
was washed with 1 M aqueous HCl (5 × 1 mL). The combined
aqueous phases were reextracted with ether (3 mL). The organic
extracts were pooled, washed with brine (2 mL), and dried.
Filtration followed by concentration in vacuo afforded a crude
oil, 196 mg. Purification by flash chromatography (hexane/
EtAOc 80:20) gave 11 as a pale-yellow oil, 174 mg (81%).
[R]25D:-8.3 (c 1.5, CHCl3). 1H NMR δ: 7.35-7.05 (m, 10 H), 7.02
(d, J ) 2 Hz, 1 H), 6.93 (dd, J ) 8, 2 Hz, 1 H), 6.75 (d, J ) 8 Hz,
1 H), 4.9 (m, 3 H), 3.95 (m, 1 H), 3.30 (m, 1 H), 2.99 (m, 2 H),
2.25 (s, 3 H), 1.25 (m, 6 H), 1.00 (m, 6 H). 13C NMR δ: 170.22,
154.01, 144.19, 137.32, 132.66, 129.58, 129.20, 129.14, 128.28,
128.23, 128.10, 128.05, 127.93, 127.76, 127.55, 127.36, 125.74,
111.98, 69.99, 48.58, 45.63, 41.9, 39.61, 20.7. IR: 2966, 1638,
The temperature in the cooling bath was allowed to reach -20
°C, and then a solution of 3b in THF (2 mL) was slowly added
over 35 min, while the temperature was kept between -20 and
-25 °C. The orange-red mixture was stirred for 2 h (temp 10
°C) before it was quenched with 10% aqueous NH4Cl (10 mL).
Most of the organic solvents were carefully removed in vacuo.
The residue was extracted with ethyl acetate (25 mL then 2 ×
10 mL). The combined organic extracts were washed with 17%
NH4OH (3 × 10 mL), water (10 mL), and brine (10 mL) and then
dried. Upon concentration in vacuo, 850 mg of a yellow oil was
obtained. The crude product was collected on silica and purified
by flash chromatography, hexane/EtOAc (80:20 and 70:30) to
yield 415 mg (84%) of a colorless oil. [R]25D: -76 (c 1.0, CHCl3).
1H NMR δ: 7.3-7.0 (m, 16 H, Ar), 6.91 (dd, J ) 8, 1 Hz, 1 H),
6.70 (d, J ) 8 Hz, 1 H), 5.24 (dd, J ) 8.5, 3.5 Hz, 1 H), 5.01 (dd,
J ) 8.5, 6.5 Hz, 1 H), 4.88 (s, 2 H), 4.45 (dd, J ) 8.5, 8.5 Hz, 1
H), 4.14 (dd, J ) 8.5, 3.5, 1 H), 3.85 (dd, J ) 17, 9 Hz, 1 H), 3.62
(dd, J ) 17, 6.5 Hz, 1 H), 2.25 (s, 3 H). 13C NMR δ: 170.97,
153.77, 153.72, 143.38, 138.99, 137.26, 131.86, 129.85, 129.03,
128.57, 128.39, 128.31, 128.23, 128.11, 127.78, 127.52, 127.21,
126.06, 125.58, 112.16, 70.14, 69.83, 57.49, 39.98, 39.86, 20.69.
1499, 1453, 1438, 1369, 1337, 1216, 1133, 1043, 1026 cm-1
.
MS: m/e (relative intensity) 429 (M+, 7.5), 339 (11.2), 338 (35.9),
237 (7.6), 209 (6.0), 195 (17.6), 165 (6.0), 128 (17), 91 (100), 86
(58.8).
(+)-Tolter od in e, 1. To a slurry of LiAlH4 (30 mg, 0.79 mmol)
in ether (1 mL) was added a solution of 11 in ether (1 mL). The
mixture was stirred at ambient temperature overnight. The
reaction was quenched by dropwise addition of 1 M NaOH(aq)
until evolution of gas ceased. A small spoon of MgSO4 was
added, and after 1 min of stirring, the mixture was filtered.
Concentration in vacuo afforded 115 mg of a colorless oil. The
oil was dissolved in methanol (2 mL), and 10% Pd/C (59 mg,
0.055 mmol Pd) was added. Hydrogen atmosphere (1 atm) was
applied, and the mixture was stirred at room temperature
overnight. The mixture was filtered, and the resulting solution
was concentrated in vacuo. The remaining oil was purified by
flash chromatography, (hexane/EtOAc (70:30))/Et3N-98:2, through
a short silica plug. Concentration in vacuo yielded 79 mg (74%)
of Tolteriodine as a colorless oil.
IR: 3032, 1788, 1711, 1497, 1454, 1380, 1320, 1241, 1196 cm-1
.
MS: m/e (relative intensity) 491 (M+, 1.6), 400 (3.8), 328 (2.4),
238 (6.9), 237 (24), 195 (6), 178 (2.7), 92 (7.6), 91 (100), 77 (5.2).
Anal. Calcd for C32H29NO4: C, 78.2; H, 5.95; N, 2.85. Found:
C, 78.6; H, 5.85; N, 2.9.
(3R)-(2-Ben zyloxy-5-m et h ylp h en yl)-3-p h en yl-p r op a n o-
ic Acid , 10. Compound 9 (329 mg, 0.67 mmol) was hydrolyzed
according to the general method described by Evans.11 The crude
product was purified by flash chromatography using (hexane/
EtOAc (70:30))/AcOH 99:1. The product was obtained as a
crystalline solid (209 mg, 90% yield). mp 121-122 °C. [R]25
:
D
+5.5 (c 2.1, CHCl3). 1H NMR δ: 10 (br, 1 H), 7.4-7.1 (m, 10
H), 6.99 (d, J ) 2 Hz, 1 H), 6.94 (dd, J ) 8.5, 2 Hz, 1 H), 6.76 (d,
J ) 8.5 Hz, 1 H), 4.9 (m, 3 H), 3.08 (m, 2 H), 2.25 (s, 3 H). 13C
NMR δ: 177.64, 153.76, 143.08, 137.22, 131.72, 129.92, 128.56,
128.38, 128.25, 127.96 (two carbons), 127.64, 127.20, 126.22,
112.18, 70.13, 40.34, 39.28, 20.71. IR: 3031, 2924, 1712, 1604,
The amount of the obtained product was too small to allow
for a reliable determination of the optical rotation. The absolute
configuration was determined by HPLC on a chiral column by
comparing retention times with a sample of (+)-Tolterodine
reference standard. By the same method the ee was determined
to be 98%. 1H NMR δ: 7.35-7.15 (m, 5 H, Ar), 6.84 (dd, J ) 8,
2 Hz, 1 H, Ar), 6.79 (d, J ) 8 Hz, 1 H, Ar), 6.54 (d, J ) 2 Hz, 1
H, Ar), 4.47 (dd, J ) 10, 3.5 Hz, 1 H, CHPh), 3.21 (m, 2 H, 2 ×
CHMe2), 2.70 (m, 1 H, CH2), 2.35 (m, 2 H, CH2), 2.10 (s and m,
4 H, ArC H3 + CH2), 1.10 (m, 12 H, 4 × Me). 13C NMR δ: 153.18,
144.77, 132.40, 129.35, 128.62, 128.49, 128.25, 127.70, 126.09,
118.12, 47.88, 42.13, 39.37, 33.38, 20.72, 19.94, 19.59.
1499, 1453, 1413, 1290, 1241, 1115, 1026 cm-1
. MS: m/e
(relative intensity) 347 (M+, 1.6), 346 (7.0), 328 (1.7), 255 (3.0),
238 (6.0), 237 (4.0), 195 (11.3), 178 (4.5), 165 (6.3), 92 (7.6), 91
(100), 77 (4.1). Anal. Calcd for C23H22O3: C, 79.7; H, 6.40.
Found: C,79.5; H, 6.45.
N,N-Diisp r op yl-(3R)-(2-b en zyloxy-5-m et h ylp h en yl)-3-
p h en ylp r op a n e Am id e, 11. The acid 10 (173 mg, 0.50 mmol)
was dissolved in benzene (2.5 mL). To the solution was added
pyridine (1 drop) followed by SOCl2 (0.20 mL, 2.76 mmol). The
mixture was stirred at 50 °C for 50 min and then concentrated
in vacuo. The residue was dissolved in benzene (2 mL) and
concentrated in vacuo. To the semisolid residue was added ether
J O981259R