A highly efficient and enantioselective access to tetrahydroisoquinoline alkaloids: Asymmetric hydrogenation with an iridium catalyst

Article abstract of DOI:10.1002/anie.201104476

Efficient and enantioselective: Using the iodine-bridged dimeric iridium complex [{Ir(H)[(S,S)-(f)-binaphane]}₂(μ-I)₃] ⁺I^- (1) a wide range of tetrahydroisoquinoline alkaloids, including the substructure of the pharmaceutical drug solifenacin, were obtained with excellent enantioselectivities and high turnover numbers (see scheme). Copyright

Full text of DOI:10.1002/anie.201104476

DOI: 10.1002/anie.201104476
Asymmetric Catalysis
A Highly Efficient and Enantioselective Access to
Tetrahydroisoquinoline Alkaloids: Asymmetric Hydrogenation with an
Iridium Catalyst**
Mingxin Chang, Wei Li, and Xumu Zhang*
Tetrahydroisoquinolines are an important class of alkaloids
displaying high bioactivities.[1] They are present in numerous
natural products, and in pharmaceutical drugs and drug
candidates, for example, (+)-cryptostyline II,[2a] (+)-crypto-
styline III,[2a] and solifenacin (Scheme 1).[2b] Among the
this system and modifications have taken place on all
components of this catalytic complex, such as, the diamine
ligand, the transition metal center, the coordinating h-arene,
and the counterion.[5h,6c–j] Although these titanocene, Ru/
DPEN and Rh/DPEN systems addressed the reduction of 1-
alkyl-3,4-dihydroisoquinolines effectively, the asymmetric
hydrogenation to enantiomerically pure 1-aryl-tetrahydroiso-
quinolines remains a challenge, probably owing to the
relatively rigid and space-demanding spatial features of
these imines. For example, there is no report on the
asymmetric hydrogenation of 1-phenyl-3,4-dihydroisoquino-
line, a reaction which would lead to the pharmaceutical drug
solifenacin (Scheme 1), and the industrial production of this
particular tetrahydroisoquinoline depends on an optical
resolution of the racemic mixture using tartaric acid.[7]
Herein, we report the highly efficient asymmetric hydro-
genation of 1-substituted 3,4-dihydroisoquinolines catalyzed
by an iridium/f-binaphane complex with excellent reactivity
and enantioselectivities (up to 99% ee and TONs of up to
10000). The combination of iridium and f-binaphane
(Scheme 2) was chosen based on their outstanding perfor-
mance in asymmetric hydrogenation of a variety of imines
Scheme 1. Structures of (+)-cryptostyline II, (+)-cryptostyline III, and
solifenacin.
various synthetic methods developed in recent decades to
afford enantiomerically pure tetrahydroisoquinolines,[1,3] cat-
alytic asymmetric hydrogenation of the corresponding imines
shows most promise as a highly efficient and straightforward
approach.[4]
During the past two decades, a number of catalytic
systems for asymmetric hydrogenation[5] and asymmetric
transfer hydrogenation[6] of this class of imines have been
invented. Using the chiral titanocene developed by Buchwald
and Willoughby, 1-methyl-3,4-dihydro-6,7-dimethoxyisoqui-
noline was hydrogenated with 98% ee.[5a] Noyori and co-
workers initiated research into the RuII/TsDPEN complex for
the highly enantioselective transfer hydrogenation of 3,4-
dihydroisoquinolines.[6a] This system was successfully applied
in the reduction of 1-(2’-NHR/NO2C6H4)-3,4-dihydroisoqui-
noline.[6b] Since then, intense research has been focused on
[*] M. Chang, W. Li, Prof. X. Zhang
Scheme 2. Structures of chiral phosphine ligands.
Department of Chemistry and Chemical Biology and
Department of Medicinal Chemistry
Rutgers, The State University of New Jersey
Piscataway, NJ 08854 (USA)
E-mail: xumu@rci.rutgers.edu
Homepage: http://chem.rutgers.edu/~xumuweb/
from our research.[8] Iridium/diphosphine complexes show
more potential for imine reduction in the presence of various
additives and possess better activities than other transition
metals.[9] At the same time, f-binaphane, which is a strong
electron donor and features a flexible ferrocene-based back-
bone, thus allowing the accommodation of a wide range of
substrates around the transition metal center, has been
[**] This research was supported by the National Institutes of Health
(GM58832). We thank Dr. Furong Sun for HRMS analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104476.
Angew. Chem. Int. Ed. 2011, 50, 10679 –10681
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10679

Communications
deployed successfully in asymmetric imine reduction[8] and in
To explore the scope and limitations of this Ir/f-binaphane
catalytic system, a range of 1-substituted 3,4-dihydroisoqui-
noline imines (1a–1p) were synthesized and hydrogenated
under the optimized reaction conditions. The results are
summarized in Table 2. This iridium complex reduced both 1-
alkyl- (Table 2; entries 2, 3, and 14) and 1-aryl-3,4-dihydro-
isoquinolines effectively with excellent enantioselectivities.
As for 1-aryl-3,4-dihydroisoquinoline imines, whether the
substituents are at the para (1d–1g) or meta (1h–1i) position
of the phenyl ring, all substrates afforded the corresponding
tetrahydroisoquinoline alkaloids with high enantioselectivi-
ties (ee values range from 94% to 99%), regardless of the
electronic properties of the substituents; interestingly, when
the imines bear a 1-ortho-substituted phenyl ring (1j and 1k),
the hydrogenation results vary dramatically, and a higher
catalyst loading was required (Table 2, entries 10 and 11). The
high ee value for 1-(2’-OMeC6H4) imine is probably attributed
to the coordination effect of the oxygen to the transition
metal center, while the poor result for 1-(2’-MeC6H4) imine
stems from steric reasons. This catalytic system also worked
quite well for 1-heteroaromatic imine 1l, giving 96% ee with a
full conversion (Table 2, entry 12). It is worth mentioning that
both enantiomerically pure (S)-(À)-norcryptostyline II (2o)
and (S)-(À)-norcryptostyline III (2p) were obtained in over
99% ee (Table 2, entries 15 and 16).
reductive amination.[10]
Initially two iridium precursors were explored along with
(S,S)-f-binaphane for the asymmetric hydrogenation of the
standard substrate 1-phenyl-3,4-dihydroisoquinoline (1a).
The neutral [{Ir(cod)Cl}2] (cod = 1,5-cyclooctadiene) gave
better conversion yet with limited enantioselectivity (Table 1,
entries 1 and 2). From the solvent screening (Table 1,
entries 3–7), CH2Cl2 afforded the best enantioselectivity and
a good conversion. With the addition of 10 mol% of I2[11a] the
enantiomeric excess was enhanced to 88% and a full
conversion was achieved (Table 1, entry 8). When the
amount of I2 was reduced to 1 mol%, the ee value dropped
to 81% (Table 1, entry 9). Other common additives,[11] such as
potassium carbonate, triethylamine, phthylamide, and tri-
fluoroacetic acid were also investigated and proved to have no
positive effect on this hydrogenation. In a control study, a
brief screening of other diphosphines was carried out. As
expected, none of these ligands yielded comparable results to
f-binaphane (Table 1, entries 10–12). The iodine-bridged
dimeric iridium complexes, initially reported by Genet et
al,[12] have shown excellent reactivity in our previous research
on asymmetric hydrogenation of cyclic imines.[8d] Therefore,
complex [{Ir(H)[(S,S)-(f)-binaphane]}2(m-I)3]+IÀ (A) was also
applied in our study. To our delight, the enantiomeric excess
was further improved to 95% with a complete conversion
(Table 1, entry 13). Using 0.05 mol% of this Ir catalyst, the
reaction still preceded smoothly without compromising the
enantioselectivity; when the catalyst loading was further
decreased to 0.005 mol%, a slightly lower conversion and
ee value were obtained (Table 1, entries 14 and 15).
In summary, the highly effective iodine-bridged dimeric
[{Ir(H)[(S,S)-(f)-binaphane]}2(m-I)3]+IÀ complex has been
applied in the asymmetric hydrogenation of a wide range of
3,4-dihydroisoquinolines with excellent enantioselectivities
and high turnover numbers (up to 10000). The use of I2 as an
additive enhanced the performance of this catalyst. This
catalytic system offers an efficient
Table 1: Asymmetric hydrogenation of 1-phenyl-3,4-dihydroisoquinoline.[a]
access to various enantiomerically
pure tetrahydroisoquinoline alka-
loids, including the substructure of
the pharmaceutical drug of solife-
nacin. Further applications of this
complex for the asymmetric hydro-
genation of 3,4-dihydroquinolines
and other cyclic imines are in prog-
Entry Ir precursor
Ligand
Solvent
Additive
Conv. [%][b] ee [%][b]
ress.
1
2
3
4
5
6
7
8
[Ir(cod)2BF4]
f-binaphane
EtOAc/CH2Cl2 (1:1)
EtOAc/CH2Cl2 (1:1)
EtOAc
CH2Cl2
THF
toluene
MeOH/CH2Cl2 (6:1)
CH2Cl2
CH2Cl2
CH2Cl2
–
–
–
–
–
–
–
30
52
98
86
99
84
11
22
23
32
46
22
20
35
88
81
34
–
[{Ir(cod)Cl}2] f-binaphane
[{Ir(cod)Cl}2] f-binaphane
[{Ir(cod)Cl}2] f-binaphane
[{Ir(cod)Cl}2] f-binaphane
[{Ir(cod)Cl}2] f-binaphane
[{Ir(cod)Cl}2] f-binaphane
[{Ir(cod)Cl}2] f-binaphane
[{Ir(cod)Cl}2] f-binaphane
[{Ir(cod)Cl}2] TangPhos
[{Ir(cod)Cl}2] DuanPhos
Experimental Section
Substrate preparation: All substrates
were prepared from the corresponding
2-arylethyl amine and alkyl- or arylcar-
bonyl chloride in two steps according to
literature reports.[13]
I2 (10 mol%) >99
9
I2 (1 mol%)
I2 (10 mol%)
I2 (10 mol%)
I2 (10 mol%)
I2/HI
>99
70
10
11
12
Catalyst preparation: Complex A
was prepared according to literature
reports.[8d,12] [{Ir(cod)Cl}2] (26.9 mg,
CH2Cl2
<5
<5
>99
>99
93
[{Ir(cod)Cl}2] C3*-TunePhos CH2Cl2
–
13[c,d] [{Ir(cod)Cl}2] f-binaphane
14[c,e] [{Ir(cod)Cl}2] f-binaphane
15[c,f] [{Ir(cod)Cl}2] f-binaphane
CH2Cl2
CH2Cl2
CH2Cl2
95
95
93
40 mmol)
and
(S,S)-f-binaphane
I2/HI
I2/HI
(71.0 mg, 88 mmol) in toluene (6 mL)
were stirred at room temperature for
2 h. Then an excess of aqueous HI
(55%, 34 mL) was added via a syringe.
[a] Reaction conditions: [Ir]/ligand/substrate=1:1:100, ligand/metal 1:1, 50 atm of H2, RT, 24 h.
[b] Reaction conversions and enantiomeric excess were determined by HPLC on a chiral stationary
phase after the amine products were converted into the corresponding acetamides. [c] HI was used for The resulting mixture was stirred over-
preparation of the iodine-bridged dimeric iridium complex [{Ir(H)[(S,S)-(f)-binaphane]}2(m-I)3]+IÀ (A)
according to references [8d],[12] [d] Complex A loading is 0.5 mol%. [e] Complex A loading is
0.05 mol%. [f] Complex A loading is 0.005 mol%.
night, and all volatiles were removed
under reduced pressure. The residue was
dissolved in dichloromethane, and hex-
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Angew. Chem. Int. Ed. 2011, 50, 10679 –10681

Approach, Wiley, Chichester, 2002, p. 315; e) K. W. Bentley, Nat.
Prod. Rep. 2006, 23, 444; f) M. Chrzanowska, M. D. Rozwadow-
ska, Chem. Rev. 2004, 104, 3341.
Table 2: Asymmetric hydrogenation of 3,4-dihydroisoquinolines by Ir/f-
binaphane.[a]
[2] a) A. Brossi, S. Teitel, Helv. Chim. Acta 1971, 54, 1564; b) H. M.
Kothari, M. G. Dave, B. Pandey, Patent WO 2011048607, 2011.
[3] a) D. Taniyama, M. Hasegawa, K. Tomioka, Tetrahedron:
Asymmetry 1999, 10, 221; b) K. T. Wanner, H. Beerb, G.
Hofnera, M. Ludwig, Eur. J. Org. Chem. 1998, 2019; c) K.
Kurihara, Y. Yamamoto, N. Miyauraa, Adv. Synth. Catal. 2009,
351, 260; d) K. Umetsu, N. Asao, Tetrahedron Lett. 2008, 49,
2722; e) S. Wang, M. B. Onaran, C. T. Seto, Org. Lett. 2010, 12,
2690; f) F. Louafi, J.-P. Hurvois, A. Chibani, T. Roisnel, J. Org.
Chem. 2010, 75, 5721; g) M. Amat, V. Elias, N. Llor, F. Subrizi, E.
Molins, J. Bosch, Eur. J. Org. Chem. 2010, 4017.
[4] T. Ohkuma, M. Kitamura, R. Noyori in Catalytic Asymmetric
Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley, New York, 2000, p. 1.
[5] a) C. A. Willoughby, S. L. Buchwald, J. Am. Chem. Soc. 1994,
116, 8952; b) T. Morimoto, K. Achiwa, Tetrahedron: Asymmetry
1995, 6, 2661; c) T. Morimoto, N. Suzuki, K. Achiwa, Hetero-
cycles 1996, 43, 2557; d) G. Zhu, X. Zhang, Tetrahedron:
Asymmetry 1998, 9, 2415; e) C. J. Cobley, J. P. Henschke, Adv.
Synth. Catal. 2003, 345, 195; f) E. Guiu, C. Claver, J. Benet-
Buchholz, S. Castillon, Tetrahedron: Asymmetry 2004, 15, 3365;
g) M. Jackson, I. C. Lennon, Tetrahedron Lett. 2007, 48, 1831;
h) C. Li, J. Xiao, J. Am. Chem. Soc. 2008, 130, 13208.
[6] a) N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori, J.
Am. Chem. Soc. 1996, 118, 4916; b) E. Vedejs, P. Trapencieris, E.
Suna, J. Org. Chem. 1999, 64, 6724; c) J. Mao, D. C. Baker, Org.
Lett. 1999, 1, 841; d) P. Roszkowski, K. Wojtasiewicz, A.
Leniewski, J. K. Maurin, T. Lis, Z. Czarnocki, J. Mol. Catal. A
2005, 232, 143; e) J. Wu, F. Wang, Y. Ma, X. Cui, L. Cun, J. Zhu, J.
Deng, B. Yu, Chem. Commun. 2006, 1766; f) J. Canivet, G. Sꢀss-
Fink, Green Chem. 2007, 9, 391; g) D. S. Matharu, J. E. D.
Martins, M. Wills, Chem. Asian J. 2008, 3, 1374; h) J. E. D.
Martins, G. J. Clarkson, M. Wills, Org. Lett. 2009, 11, 847; i) L.
Evanno, J. Ormala, P. M. Pihko, Chem. Eur. J. 2009, 15, 12963;
j) J. E. D. Martins, M. A. C. Redondo, M. Wills, Tetrahedron:
Asymmetry 2010, 21, 2258.
Entry R1
R2
Product Conv. [%][b]
ee [%][b]
1
2
3
4
5
6
7
8
9
H (1a)
C6H5
iPr
Cy
2a
2b
2c
2d
2e
2 f
2g
2h
2i
>99
>99
>99
>99
>99
>99
>99
>99
>99
98
95 (S)
96 (À)
95 (À)
94 (+)
96 (S)
H (1b)
H (1c)
H (1d)
H (1e)
H (1 f)
H (1g)
H (1h)
H (1i)
4-MeC6H4
4-ClC6H4
4-MeOC6H4
4-CF3C6H4
3-MeC6H4
3-ClC6H4
2-MeC6H4
2-MeOC6H4
2-furoyl
95 (S)
97 (+)
95 (+)
98 (+)
79 (+)
98 (À)
96 (+)
97 (S)
95 (S)
>99 (S)
>99 (S)
10[c] H (1j)
11[c] H (1k)
2j
2k
2l
2m
2n
>99
>99
>99
>99
99
12
13
14
15
16
H (1l)
OMe (1m) C6H5
OMe (1n) iPr
OMe (1o) 3,4-(MeO)2C6H3 2o
OMe (1p) 3,4,5- 2p
(MeO)3C6H2
99
[a] Reaction conditions: complex A/I2/substrate=0.05:10:100, 50 atm of
H2, RT, 24 h. [b] Conversions and enantiomeric excesses were deter-
mined by HPLC and GC on a chiral stationary phase after the products
were converted into the corresponding acetamides. The absolute
configuration of the product is shown in brackets and is assigned by
comparison of the rotation sign with literature data.[3b,6b] [c] Complex A/
substrate=0.25:100. Cy=cyclohexyl.
anes were added to precipitate the complex (85.0 mg, 83% yield) as a
pale yellow powder.
Hydrogenation: In
a nitrogen-filled glovebox, complex A
[7] Y. Ishii, K. Takaoka, M. Inakoshi, S. Nakagawa, K. Nagata, N.
Yorimoto, M. Takeuchi, Y. Yonetoku, Patent WO
2005075474A1, 2005.
[8] a) D. Xiao, X. Zhang, Angew. Chem. 2001, 113, 3533; Angew.
Chem. Int. Ed. 2001, 40, 3425; b) G. Hou, F. Gosselin, W. Li, J. C.
McWilliams, Y. Sun, M. Weisel, P. D. OꢁShea, C.-Y. Chen, I. W.
Davies, X. Zhang, J. Am. Chem. Soc. 2009, 131, 9882; c) G. Hou,
W. Li, M. Ma, X. Zhang, X. Zhang, J. Am. Chem. Soc. 2010, 132,
12844; d) M. Chang, W. Li, G. Hou, X. Zhang, Adv. Synth. Catal.
2010, 352, 3121.
(2.5 mg, 0.001 mmol) was dissolved in anhydrous CH2Cl2 (1.0 mL)
and equally divided into 10 vials charged with imine substrates
(0.2 mmol) in anhydrous CH2Cl2 solution (1.0 mL). Then I2 (5.1 mg,
0.02 mmol) was added and the total solution was made to 2.0 mL for
each vial. The resulting vials were transferred to an autoclave, which
was charged with 50 atm of H2, and the reaction mixtures were stirred
at room temperature for 24 h. The hydrogen gas was released slowly
and the solution was concentrated and passed through a short column
of silica gel to remove the metal complex. The chiral amine products
reacted with acetic anhydride to yield the corresponding acetamides,
which were then analyzed by HPLC and GC on a chiral stationary
phase to determine the enantiomeric excesses.
[9] a) F. Spindler, H.-U. Blaser in Handbook of Homogeneous
Hydrogenation, Vol. 3 (Eds.: J. G. de Vries, C. J. Elsevier),
Wiley-VCH, Weinheim, 2007, pp. 1193; b) J.-H. Xie, S.-F. Zhu,
Q.-L. Zhou, Chem. Rev. 2011, 111, 1713.
[10] Y. Chi, Y.-G. Zhou, X. Zhang, J. Org. Chem. 2003, 68, 4120.
[11] For reviews, see: a) K. Fagnou, M. Lautens, Angew. Chem. 2002,
114, 26; Angew. Chem. Int. Ed. 2002, 41, 26; b) E. M. Vogl, H.
Groeger, M. Shibasaki, Angew. Chem. 1999, 111, 1672; Angew.
Chem. Int. Ed. 1999, 38, 1570; c) D. J. Berrisford, C. Bolm, K. B.
Sharpless, Angew. Chem. 1995, 107, 1159; Angew. Chem. Int. Ed.
Engl. 1995, 34, 1059.
[12] T. Yamagata, H. Tadaoka, M. Nagata, T. Hirao, Y. Kataoka, V.
Ratovelomanana-Vidal, J. P. Genet, K. Mashima, Organometal-
lics 2006, 25, 2505.
Received: June 28, 2011
Published online: September 20, 2011
Keywords: asymmetric catalysis · enantioselectivity ·
.
hydrogenation · iridium · tetrahydroisoquinoline alkaloids
[1] a) R. Paul, J. A. Coppola, E. Cohen, J. Med. Chem. 1972, 15, 720;
b) The Chemistry and Biology of Isoquinoline Alkaloids (Eds.:
J. D. Phillipson, M. F. Roberts, M. H. Zenk), Springer, Berlin,
1985; c) D. Jack, R. Williams, Chem. Rev. 2002, 102, 1669;
d) P. M. Dewick, Medicinal Natural Products: A Biosynthetic
[13] a) M. Movassaghi, M. D. Hill, Org. Lett. 2008, 10, 3485; b) J. M.
Joo, R. A. David, Y. Yuan, C. Lee, Org. Lett. 2010, 12, 5704.
Angew. Chem. Int. Ed. 2011, 50, 10679 –10681
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