Highly enantioselective hydrogenation of styrenes directed by 2′-hydroxyl groups

Article abstract of DOI:10.1021/ol200422p

A new synthetic strategy that turns styrene-type olefins into excellent substrates for Rh-catalyzed asymmetric hydrogenation by installing a 2′-hydroxyl substituent is described. This methodology accommodates trisubstituted olefinic substrates in various E/Z mixtures, leading to valuable benzylic chiral compounds including (R)-tolterodine. It is also demonstrated that the 2′-hydroxyl groups could be readily removed in high yield without loss of ee from the products. Thus, this technology represents an attractive alternative to the Ir(P-N) catalyst system for the asymmetric hydrogenation of unfunctionalized olefins.

Full text of DOI:10.1021/ol200422p

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1881–1883
Highly Enantioselective Hydrogenation of
Styrenes Directed by 20-Hydroxyl Groups
Xiang Wang,* Anil Guram, Seb Caille, Jack Hu, J P. Preston, Michael Ronk, and Shawn
Walker
Chemical Process Research and Development, Amgen Inc., One Amgen Center Drive,
Thousand Oaks, California 91320, United States
xiangw@amgen.com
Received February 15, 2011
ABSTRACT
A new synthetic strategy that turns styrene-type olefins into excellent substrates for Rh-catalyzed asymmetric hydrogenation by installing a 20-
hydroxyl substituent is described. This methodology accommodates trisubstituted olefinic substrates in various E/Z mixtures, leading to valuable
benzylic chiral compounds including (R)-tolterodine. It is also demonstrated that the 20-hydroxyl groups could be readily removed in high yield
without loss of ee from the products. Thus, this technology represents an attractive alternative to the Ir(P-N) catalyst system for the asymmetric
hydrogenation of unfunctionalized olefins.
Many pharmaceutically important molecules, including
a number of commercial drugs, contain one or more
tertiary benzylic chiral centers (Figure 1).1 Asymmetric
hydrogenation of the corresponding styrene-type olefins
represents one of the most atom-economic approaches to
these molecules.2 However, the success of such transfor-
mations hasbeenlargely limited toolefinsdirectlyattached
to one or more polar functional groups (carbonyl, ester,
amide, etc.) or heteroatoms, which are often not present in
the target molecules.3 As a result, significant efforts have
been directed toward asymmetric hydrogenation of un-
functionalized olefins.4 Recently, Pfaltz has pioneered
the development of the Ir/P-N ligand systems that
were excellent catalysts for asymmetric hydrogenation of
unfunctionalized olefins.5 Despite this significant break-
through, for high enantioselectivity the Ir/P-N systems
require substrates isolated as a single olefinic E/Z isomer,2a
which is often difficult to achieve. Additionally, an expensive
counterion (BArF) is required and the preformed catalysts
are incompatible with high throughput ligand screening.
Herein we report an alternative strategy to this problem by
installing a removable directing group on styrene-type
olefins, which enables highly enantioselective hydrogena-
tion of unfunctionalized olefins in E/Z mixtures, catalyzed
by readily available in situ or preformed Rh complexes.6
(1) (a) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-VCH:
New York, 2000. (b) Blaser, H.-U.; Schmidt, E. Asymmetric Catalysis on
Industrial Scale; Wiley: New York, 2004.
(2) (a) Tolstoy, P.; Engman, M.; Paptchikhine, A.; Bergquist, J.;
Church, T. L.; Leung, A. W. M.; Andersson, P. G. J. Am. Chem. Soc.
2009, 131, 8855–8860. (b) RajanBabu, T. V. Chem. Rev. 2003, 103, 2845–
2860.
(3) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994. (b) Brown, J. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds; Springer-Verlag: Berlin,
Germany, 1999; Vol. 1 (c) Nugent, W. A.; Rajanbabu, T. V.; Burk, M. J.
Science 1993, 259, 479–483.
(4) (a) Cui, X.; Burgess, K. Chem. Rev. 2005, 105, 3272–3296. (b)
Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402–1411.
Figure 1. Tertriary benzylic chiral centers in pharmaceuticals.
Through our screening efforts in an internal project, we
came to realize that installing a 20-hydroxyl group on styrenes
might direct olefins to selectively bind to chiral transition
r
10.1021/ol200422p
2011 American Chemical Society
Published on Web 03/08/2011

Table 1. Condition Screening for Hydrogenation of 1
Table 2. Scope of Phenol-Directed Asymmetric Hydrogenationa,b
entry
R
H2 (psi)
solvent
conv (%)
ee (%)
1
2
3
4
5
6
7
H(1)
200
200
200
200
100
50
DCM
76
100
100
100
100
100
50
95.5
38.5
98.8
99.1
99.2
99.2
<20
H
THF
H
Me OH
toluene
toluene
toluene
toluene
H
H
H
Me (la)
50
metal complexes, transforming otherwise unreactive ole-
fins into excellent substrates for asymmetric hydrogenation
under very mild conditions. For example, 2-(1-phenylvinyl)-
phenol (1), a styrene-type olefin with a 20-hydroxyl sub-
stituent, underwent hydrogenation catalyzed by Rh(COD)-
BF4 (1 mol %) and (R,S)-DuanPhos (1.2 mol %) at 200 psi
in CH2Cl2 to give hydrogenation product (S)-2 in 76%
conversion and 95.5% ee (Table 1, entry 1).7,8 Switching
the solvent from CH2Cl2 to toluene and lowering the
pressure to 50 psi further increased the ee and conversion
(Table 1, entry 6).9 The presence of the hydroxyl group was
essential to the success of highly enantioselective hydro-
genation, and when the hydroxyl in 1 was replaced by a
methoxy group, both the conversion (∼50%) and ee
(<20%) suffered significantly (entry 7).10
We then expanded this strategy to other styrenes bear-
ing 20-hydroxyl groups and found that they were
excellent substrates for the Rh-catalyzed enantioselective
hydrogenation (Table 2). Catalyst loading as low as 0.1%
a Conditions: H2 (50 psi), Rh(COD)[(R,S)-DuanPhos]BF4 (1 mol
%), NEt3 (5 mol %), toluene, rt, 1-12 h. b Isolated yield of >95% purity
judged by GC analysis. c From crude reaction mixture measured by
HPLC. d 0.1 mol % catalyst loading. e 1 mol % Rh(COD)[(S,S)-Me-
BPEphos]BF4. f 1 mol % Rh(COD)2BF4 and 1.2 mol % Josiphos SL-
J210-1, see the Supporting Information for details.
(5) For leading references, see: (a) Bell, S.; Wuestenberg, B.; Kaiser,
S.; Menges, F.; Netscher, T.; Pfaltz, A. Science 2006, 311, 642–644. (b)
Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37,
2897–2899. (c) Perry, M. C.; Cui, X. H.; Powell, M. T.; Hou, D. R.;
Reibenspies, J. H.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 113–123. (d)
Dieguez, M.; Mazuela, J.; Pamies, O.; Verendel, J. J.; Andersson, P. G. J.
Am. Chem. Soc. 2008, 130, 7208–7209.
was well tolerated, provided 5 mol % of NEt3 was added in
the reaction mixture (entry 2). Substrates with various
electron-withdrawing and -donating groups such as methyl,
fluoro, methoxy, and methyl ester at the 4-position of
phenol all gave excellent ee (99%) and very high yield
(>95%) (entries 3-6). A methyl substituent at the ortho-
position of the phenol did not adversely affect the efficiency
of the reaction (entry 7, 99% ee). The catalyst system was
also compatible with substrates containing aryl bromide
functional groups (98% ee, entry 8) and with heteroaryls
(6) A process based on this chemistry was recently scaled up to 100 g
scale with 0.1% catalyst loading.
(7) For catatlytic reactions employing DuanPhos, see: (a) Tang, W.;
Zhang, X. Chem. Rev. 2003, 103, 3029–3069. (b) Zhang, W.; Chi, Y.;
Zhang, X. Acc. Chem. Res. 2007, 40, 1278–1290. (c) Zigterman, J. L.;
Woo, J. C. S.; Walker, S. D.; Tedrow, J. S. T.; Borths, C. J.; Bunel, E. E.;
Faul, M. M. J. Org. Chem. 2007, 72, 8870. (d) Phan, D. H. T.; Kim, B.;
Dong, V. M. J. Am. Chem. Soc. 2009, 131, 15608.
(8) Preformed catalyst Rh(DuanPhos)(COD)BF4 performed simi-
larly to the catalystformed in situ, and was used later on for convenience.
The absolute stereochemistry was established by comparing optical
rotation with literature references.
(9) For an example of Rh-catalyzed hydrogenation in the pharma-
ceutical industry, see: (a) Gridnev, I. D.; Imamoto, T.; Hoge, G.;
Kouchi, M.; Takahashi, H. J. Am. Chem. Soc. 2008, 130, 2560–2572.
(b) Hoge, G.; Wu, H.-P.; Kissel, W. S.; Pflum, D. A.; Greene, D. J.; Bao,
J. J. Am. Chem. Soc. 2004, 126, 5966–5967.
(10) For an example of N-containing heteroarenes as directing
groups in asymmetric reduction see: Rupnicki, L.; Saxena, A.; Lam,
H. W. J. Am. Chem. Soc. 2009, 131, 10386–10387.
(12) Snieckus, V. Chem. Rev. 1990, 90, 879–933.
(13) For recent asymmetric syntheses of (R)-tolterodine, see: (a)
Gallagher, B. D.; Taft, B. R.; Lipshutz, B. H. Org. Lett. 2009, 11,
5374–5377. (b) Ulgheri, F.; Marchetti, M.; Piccolo, O. J. Org. Chem.
2007, 72, 6056–6059. (c) Paras, N. A.; Simmons, B.; MacMillan,
D. W. C. Tetrahedron 2009, 65, 3232–3238.
(11) For use of Me-BPEphos in catalysis, see: (a) Burk, M. J.; Wang,
Y. M.; Lee, J. R. J. Am. Chem. Soc. 1996, 118, 5142–5143. (b) Burk, M. J.
Acc. Chem. Res. 2000, 33, 363–372.
(14) A stoichiometric amount of LiOt-Bu was needed for the success
of the hydrogenation, presumably because a strong base is needed to free
the phenol from the internal hydrogen bonding in 31.
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Org. Lett., Vol. 13, No. 7, 2011

(>99% ee, entry 10). Importantly, trisubstituted olefins in
various E/Zisomeric ratios were also well tolerated, as methyl,
ethyl, isopropyl, benzyl, and phenyl substituents on the
terminal olefin all yielded >90% ee, when Rh (COD)[(S,
S)-Me-BPEphos]BF4 was used as the catalyst (entries
11-14).11 It is worth noting that biaryl systems were not
required for high enantioselectivity, as evidenced by a cyclo-
pentenyl substrate 15 that underwent efficient hydrogenation to
give the corresponding product in 93% yield, 95% ee (entry 15).
genation catalyzed by 1 mol % Rh[(COD)(S,S)-Ph-BPE-
phos]BF4 at room temperature to give (R)-tolterodine in
89% isolated yield, 99% ee.
The ability of this hydrogenation system to employ E/Z
mixtures in trisubstituted substrates represents a major
improvement from the Ir/P-N system, which requires the
substrate isolated as a single E/Z isomer. This tolerance of
substratesasE/Z mixtures, aswell asthebeneficialroleofa
base, implies that the enantioselectivity of the hydrogena-
tion stems from the coordinating effect of the deproto-
nated phenol with rhodium, as proposed in Scheme 3.15,16
Scheme 1
Scheme 3
Styrene-type olefins bearing a 20-hydroxyl substituent
could be readily synthesized via phenol-directed ortho-lithia-
tion followed by ketone addition/elimination sequences
from the corresponding phenols.12 Also importantly, the
hydroxyl group in the hydrogenation product could be
removed in a two-step sequence in high yield without loss
of ee. Specifically, triflate protection of the phenol 19
followed by a palladium-catalyzed deoxygenation with
HSiEt3 afforded the des-hydroxyl product in 93% yield
(two-step) with full retention of stereochemistry (Scheme
1). Thus, the 20-hydroxyl group could serve as a traceless
directing group, while facilitating both the synthesis of the
This hypothesis would explain why methoxy-capped sub-
strate 1a, despite its structural similarity to 1, fails to
undergo efficient hydrogenation under the same condi-
tions (Table 1, entry 7). This argument is also corroborated
with the observation that substrate 9 gave 95% ee via Rh-
catalyzed hydrogenation, despite little steric bias between
the two olefinic pro-chiral faces (Table 2, entry 9).
In summary, we have demonstrated that styrene-type
olefins bearing a 20-hydroxyl substituent undergo highly
enantioselective Rh-catalyzed hydrogenations leading
to valuable benzylic chiral compounds including (R)-
tolterodine. As an improvement to the Ir(P-N) catalyst
system, this methodology accommodates trisubstituted
olefins in various E/Z mixtures. As 20-hydroxyl groups
could be readily removed without any loss of ee from the
products, this technology represents an attractive alter-
native for the asymmetric hydrogenation of unfunctio-
nalized olefins.
olefinic substrates and the asymmetric hydrogenation.
Finally, we successfully applied the strategy of phenol-
directed asymmetric hydrogenation to the synthesis of (R)-
tolterodine, the active ingredient of Detrol LA (Scheme 2).13
Alkene 31 was derived in 69% overall yield in 4 steps from
commercially available ketone 30, existing mostly in the Z
isomer (>50:1 Z:E ratio) due to internal hydrogen bonding.
With LiOt-Bu as the base,14 31 underwent efficient hydro-
Acknowledgment. The authors thank Amgen collea-
gues Drs. Jinkun Huang, Robert Milburn, Gary Guo,
Robert Larsen, Margaret Faul, and Jerry Murry and
Barry Friedrichsen, David Yeung, and Jun Han for their
support.
Scheme 2
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data for new compounds, and
HPLC chromatograms. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) Homoallylic hydroxyl groups are known directing groups for
diastereoselective hydrogenations, see: (a) Zhu, Y.; Burgess, K. J. Am.
Chem. Soc. 2008, 130, 8894–8895. (b) Evans, D. A.; Morrissey, M. M.;
Dow, R. L. Tetrahedron Lett. 1985, 26, 6005–6008.
(16) Enamide directed enantioselective hydrogenation is known to
tolerate E/Z mixtures, see: Burk, M. J.; Feaster, J. E.; Nugent, W. A.;
Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125–10138.
Org. Lett., Vol. 13, No. 7, 2011
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