Enantioselective synthesis of optically pure β-amino ketones and γ-aryl amines by Rh-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1021/jo102091f

A series of optically pure β-amino ketones have been synthesized in high enantioselectivities (ee > 99%) by Rh-DuanPhos-catalyzed asymmetric hydrogenation of readily prepared β-keto enamides. Further reduction of these β-amino ketones with hydrogen and Pd/C leads to the formation of a variety of protected enantiomerically pure γ-aryl amines (ee > 99%), which are key building blocks in many bioactive molecules.

Full text of DOI:10.1021/jo102091f

pubs.acs.org/joc
SCHEME 1. Potential Applications of Optically Pure β-Amino
Ketones
Enantioselective Synthesis of Optically Pure β-Amino
Ketones and γ-Aryl Amines by Rh-Catalyzed
Asymmetric Hydrogenation
Huiling Geng,†,‡ Kexuan Huang,‡ Tian Sun,‡ Wei Li,‡
Xiaowei Zhang,‡ Le Zhou,† Wenjun Wu,*,† and
Xumu Zhang*,‡
†College of Science, Northwest Agriculture & Forestry
University, Yangling, Shaanxi 712100, P. R. China, and
‡Department of Chemistry and Chemical Biology &
Department of Pharmaceutical Chemistry, Rutgers,
the State University of New Jersey, Piscataway,
New Jersey 08854, United States
wenjun_wu@263.com; xumu@rci.rutgers.edu
Received October 21, 2010
The development of an efficient synthesis of β-amino ketones
has received considerable attention in the last decades. Various
protocols have been developed to synthesize racemic β-amino
ketones,6 such as Lewis acid mediated hetero-Michael addition
reaction7 and the Mannich reaction.8 Recently, a stoichiometric
A series of optically pure β-amino ketones have been synthe-
sized in high enantioselectivities (ee>99%) by Rh-DuanPhos-
catalyzed asymmetric hydrogenation of readily prepared
β-keto enamides. Further reduction of these β-amino ketones
with hydrogen and Pd/C leads to the formation of a variety of
protected enantiomerically pure γ-aryl amines (ee > 99%),
which are key building blocks in many bioactive molecules.
(3) For the chiral auxiliary-based strategy, see: (a) Denmark, S. E.;
Weber, T.; Piotrowski, D. W. J. Am. Chem. Soc. 1987, 109, 2224.
(b) Colyer, J. T.; Andersen, N. G.; Tedrow, J. S.; Soukup, T. S.; Faul,
M. M. J. Org. Chem. 2006, 71, 6859. For enzyme-assisted resolution, see:
(c) Conzalez-Sabin, J.; Gotor, W.; Rebolledo, F. Tetrahedron: Asymmetry
2002, 13, 1315. (d) Nechab, M.; Azzi, N.; Vanthuyne, N.; Bertrand, M.;
Gastaldi, S.; Gil, G. J. Org. Chem. 2007, 72, 6918.
(4) (a) Couty, F.; David, O.; Durrat, F.; Evano, G.; Lakhdar, S.; Marrot,
J.; Vargas-Sanchez, M. Eur. J. Org. Chem. 2006, 3479. (b) Barluenga, J.;
ꢀ
ꢀ
Tomas, M.; Kouznetsov, V.; Jardon, J.; Rubio, E. Synlett 1991, 821.
(c) Shustov, G. V.; Denisenko, S. N.; Chervin, I. I.; Asfandiarov, N. L.;
Kostyanovsky, R. G. Tetrahedron 1985, 41, 5719.
Enantiomerically pure β-amino ketones are useful bifunctional
intermediates for the synthesis of many biologically active mole-
cules.1 Specifically, these amino ketones can serve as key precur-
sors of syn-andanti-1,3-amino alcohols,2 γ-aryl amines,3 and syn-
and anti-1,3-diamines.4 Some important pharmaceutical
products bearing these functionalities5 are illustrated in Scheme 1.
(5) (a) Clifton, J. E.; Collins, I.; Hallett, P.; Hartley, D.; Lunts, L. H. C.;
Wicks, P. D. J. Med. Chem. 1982, 25, 670. (b) Hou, F.; Zhang, X.; Zhang, G.;
Xie, D.; Chen, P.; Zhang, W.; Jiang, J.; Liang, M.; Wang, G.; Liu, Zh.; Geng,
R. New Engl. J. Med. 2006, 354, 131. (c) Kondo, S.; Shibahara, S.; Takahashi,
S.; Maeda, K.; Umezawa, H.; Ohno, M. J. Am. Chem. Soc. 1971, 93, 6305.
(d) Raju, B.; Mortell, K.; Anandan, S.; O’Dowd, H.; Gao, H.; Gomez, M.;
Hackbarth, C.; Wu, C.; Wang, W.; Yuan, Z.; White, R.; Trias, J.; Patel, D. V.
Bioorg. Med. Chem. Lett. 2003, 13, 2413. (e) Sham, H. L.; Kempf, D J.;
Molla, A. Antimicrob. Agents Chemother. 1998, 42, 3218.
(6) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: New York, 1992. (b) Rao, I. N.; Prabhakaran, E. N.; Das, S. K.;
Iqbal, J. J. Org. Chem. 2003, 68, 4079. (c) Gomtsyan, A.; Keoenig, R. J.; Lee,
C. J. Org. Chem. 2001, 66, 3613. (d) Dakin, H. D.; West, R. J. Biol. Chem.
1928, 78, 745. (e) Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91. (f ) Xu, L.;
Xia, C.; Li, L. J. Org. Chem. 2004, 69, 8482.
(7) For reviews, see: (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991.
(b) Jauristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983. For the
preparation of β-amino ketones, see: (c) Gaunt, M. J.; Spencer, J. B. Org.
Lett. 2001, 3, 25. (d) Wabnitz, T. C.; Spencer, J. B. Tetrahedron Lett. 2002, 43,
3891. (e) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109.
(8) For a comprehensive review, see: (a) Tramontini, M. Synthesis 1973,
703. For the preparation of β-amino ketones, see: (b) Blike, F. E. Org. React.
1942, 1, 303. (c) Muraoka, T.; Kamiya, S.; Matsuda, S. I.; Itoh, K. Chem.
Commun. 2003, 449. (d) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003,
125, 338. (e) Ambhaikar, N. B.; Snyder, J. P.; Liotta, D. C. J. Am. Chem. Soc.
2003, 125, 3690.
(1) (a) Houben, J. H.; Weyl, T. In Houben-Weyl Methoden der Orga-
€
nischen Chemie, 4th ed.; Muller, E., Ed.; Georg Thieme Verlag: Stuttgart,
New York, 1977. (b) Kleinnmann, E. F. In Comprehensive Organic Synthesis;
Trost, B. M., Ed; Pergamon: New York, 1991. (c) Arend, M.; Wastermann,
B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (d) Tramontini, M.;
Angiolini, L. Tetrahedron 1990, 46, 1791. For selected applications of
β-amino ketones in the synthesis of natural products and biologically active
compounds, see: (e) Guo, D.-L.; Zhu, X.-W. Chem. Ind. Eng. 2008, 25, 276.
(f ) Sham, H. L.; Kempf, D. J.; Molla, A..; et al. Antimicrob. Agents
Chemother. 1998, 42, 3218. (g) Hou, F.; Zhang, X.; Zhang, G.; Xie, D.;
Chen, P.; Zhang, W.; Jiang, J.; Liang, M.; Liu, Z.; Geng, R. N. Engl. J. Med.
2006, 354, 131.
(2) (a) Mukaiyama, T. Organic Reactions; Wiley: New York, 1982.
(b) Wanner, K. T.; Horner, G. Tetrahedron 1991, 47, 1895. (c) Tramontini,
M. Synthesis 1982, 605. (d) Brienne, M. J.; Ouannes, C.; Jacques, J. J. Bull.
Soc. Chim. Fr. 1969, 106, 2395. (e) Keck, G. E.; Truong, A. P. Org. Lett. 2002,
4, 3131. (f ) Bartoli, G.; Cimarel, C.; Palmieri, G. J. Chem. Soc., Perkin Trans.
1 1994, 537.
332 J. Org. Chem. 2011, 76, 332–334
Published on Web 12/09/2010
DOI: 10.1021/jo102091f
r
2010 American Chemical Society

Geng et al.
JOCNote
SCHEME 2. Preparation of β-Keto Enamides
TABLE 1. Rhodium-Catalyzed Asymmetric Hydrogenation of 2a under
Various Conditionsa
transformation was reported by Davis’ group, which featured
effective preparation of optically pure β-amino ketones from
a Weinreb amide.9 Hsiao’s group discovered a highly efficient
method to synthesize β-amino acid derivatives by asymmetric
hydrogenation of unprotected β-enamino esters and amides
using commercially available ligands under mild conditions.10
To the best of our knowledge, there is no research involved the
synthesis of optically pure β-amino ketones through catalytic
asymmetric hydrogenation. Herein, we present a Rh-catalyzed
highly enantioselective hydrogenation of β-keto enamides as an
efficient way to prepare enantiomerically pure β-amino ketones
and their derivatives, γ-aryl amines. Our method has the follow-
ing advantages: (a) Starting materials 1 and substrates 2 can
be readily prepared in high yields (Scheme 2). (b) A series of
optically pure β-amino ketones can be synthesized in high ee’s
through asymmetric hydrogenation.11 (c) Enantiomerically
pure β-amino ketones can be easily converted to many useful
products.
entry
L*
PH2 (atm)
solvent
EtOAc
toluene
CH2Cl2
THF
1,4-dioxane
EtOH
ClCH2CH2Cl
iPrOH
CF3CH2OH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
convb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
2.0
5.0
89
2.0
46
98
>99
94
>99
98
95
99
95
64
96
87
98
37
94
89
3.0
95
2.0
34
>99
0.2
>99
30
>99
16
0.2
15
3.0
0.1
0.3
>99
>99
>99
MeOH
MeOH
94
91
aAll reactions were carried out with a substrate/catalyst ratio of 100:1
at room temperature for 20 min. bConversions were based on 1H NMR
spectroscopy of the crude product. cDetermined by chiral GC analysis.
The absolute configuration of 3a was assigned by comparison of the
observed optical rotation with reported data.
A series of well-defined β-keto enamides were prepared by
direct condensation of readily accessible 1,3-diketones12 with
an acetamide under a Dean-Stark condition (Scheme 2).13
The desired substrates 2a-o were obtained in moderate to
good yield (up to 90%) as stable crystalline solids. Only Z
enamide was observed in all cases because of the presence of
intramolecular hydrogen bonding.
Initial evaluation of the hydrogenation of 2a was carried
out with Rh-DuanPhos (L1) catalyst14a in EtOAc under
ambient hydrogen pressure. We obtained good conversion
and excellent enantioselectivity to the desired product 3a
(Table 1, entry 1). Further examination of the solvent effect
revealed that the reaction was solvent dependent, and polar
solvents improved its performance dramatically (entries 2-10).
In contrast, the highest conversion and enantioselectivity
were achieved in MeOH (entry 10). Several commercial
available ligands including Et-DuPhos (L2),14b Me-DuPhos
(L3),14b f-binaphane (L4),14c binapine (L5),14d C3-TunePhos
(L6),14e and BINAP (L7)14f were screened for the hydro-
genation of 2a (Figure 1), and only DuanPhos, a highly rigid
electron-donating P-chiral bisphospholane ligand developed
by our group, offered the best result (entries 11-16 vs entry10).
FIGURE 1. Chiral ligands for asymmetric hydrogenation.
Increasing hydrogen pressure caused a slight drop in enantio-
selectivities (entries 17-19).
To further explore the efficiency and the applicability of
the Rh-DuanPhos catalytic system, we investigated the
asymmetric hydrogenation of a variety of substrates, 2b-o,
under the optimized conditions (Table 1, entry 10). To our
delight, all substrates were hydrogenated in full conversions
with good to excellent enantioselectivities (Table 2). Com-
pared with 2a, electron-donating groups or electron-with-
drawing groups at the para position of the phenyl moiety had
no appreciable effect on the enantioselectivities (95-99% ee,
entries 2-8). Moving the methyl group to the meta position
increased the enantioselectivity to 99% (entry 9), while the
ortho methyl group decreased the enantioselectivity to 87%
(entry 10). It is probable that the ortho substituents interfere
with the preferred coordination of the CdC bond to the metal
center and lead to lower facial selectivity. Asymmetric hydro-
genation of substrates bearing other aromatic rings, such as 2k
and 2l, afforded the corresponding products with 99% and
95% ee, respectively (entries 11 and 12). The enantioselectivities
(9) (a) Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011. (b) Davis, F. A.;
Prasd, K. R.; Nolt, M. B.; Wu, Y. Org. Lett. 2003, 5, 925.
(10) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.;
Wang, F.; Sun, Y.; Armstrong, J. D.; Grabowski, E. J. J.; Tillyer, R. D.;
Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918.
(11) (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive
Asymmetric Catalysis I-III; Springer: Berlin, 1999. (b) Noyori, R. Asym-
metric Catalysis in Organic Synthesis; Wiley: New York, 1994. (c) Ojima, I.
Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-VCH: New York, 2000.
(d) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029.
(12) For the preparation of 1,3-diketones, see: Han, X.; Widenhoefer,
R. A. J. Org. Chem. 2004, 69, 1738.
(13) Chen, J.; Zhang, W.; Geng, H.; Li, W.; Hou, G.; Lei, A.; Zhang, X.
Angew. Chem., Int. Ed. 2009, 48, 800.
(14) For selective ligands in AH, see: (a) Liu, D.; Zhang, X. Eur. J. Org.
Chem. 2005, 646. (b) Burk, M. J. Acc. Chem. Res. 2000, 33, 363. (c) Xiao, D.;
Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425. (d) Tang, W.; Wang, W.;
Chi, Y.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 3509. (e) Zhang, Z.; Qian,
H.; Longmire, J.; Zhang, X. J. Org. Chem. 2000, 65, 6223. (f ) Miyashita, A.;
Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J. Am.
Chem. Soc. 1980, 102, 7932.
J. Org. Chem. Vol. 76, No. 1, 2011 333

Geng et al.
JOCNote
TABLE 2. Asymmetric Hydrogenation of 2 with the Rh-DuanPhos
Catalytic Systema
TABLE 3. Synthesis of γ-Aryl Amines 4 via One-Pot Asymmetric
Reductiona
entry
2
R1
C6H5
R2
Me
3
eeb,c (%)
entry
2
R1
C6H5
R2
Me
4
eeb,c (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
96 (S)
97
97
98
98
95
96
95
99
87
99
95
89
81(S)
>99
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2g
2h
2i
2j
2m
2n
4a
4b
4c
4d
4g
4h
4i
4j
4m
4n
97 (S)
95
>99
96
96
96
97
89
94 (S)
79 (S)
p-MeC6H4
p-MeOC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
p-tBuC6H4
p-CyC6H4
m-MeC6H4
o-MeC6H4
2-thienyl
2-naphthyl
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
p-MeC6H4
p-MeOC6H4
p-FC6H4
p-tBuC6H4
p-CyC6H4
m-MeC6H4
o-MeC6H4
C6H5
Me
Me
Me
Me
Me
Me
Me
Et
9
9
10d
11
12
13e
14f
15
10d
C6H5
CO2Et
aAll reactions were carried out with a substrate/DuanPhos ratio of
100:1 in MeOH at room temperature for 1 h, while the ratio of substrate
to Pd/C is 10:1. In all cases, 100% conversion was observed. bDeter-
mined by chiral HPLC analysis. cThe absolute configurations of 4a, 4m,
and 4n were assigned by comparison of the observed optical rotation
with reported data. dThe first hydrogenation was performed at 30 °C
under 60 atm of H2 for 12 h.
C6H4
Me
CO2Et
Me
aAll reactions were carried out with a substrate/catalyst ratio of 100:1
in MeOH at room temperature under 1 atm of H2 for 20 min. In all cases,
100% conversion was observed. bDetermined by chiral GC or HPLC
c
analysis. The absolute configurations of 3a and 3n were assigned by
comparison of the observed optical rotation with reported data. d2.5 h.
(250 mmol), and a catalytic amount of p-TsOH (10 mmol) was
charged in a Dean-Stark apparatus and refluxed for 24 h. After
the solution was cooled to room temperature, the solvent was
evaporated, and the concentrated mixture was passed through a
flash chromatography column filled with silica gel (eluent: EtOAc/
hexane). The product 2 was collected as a stable crystalline solid.
General Procedure for the Asymmetirc Hydrogenation. A
stock solution of [Rh(COD)2]BF4 (COD = cycloocta-1,5-diene)
and DuanPhos at a 1:1.1 molar ratio was stirred in MeOH at room
temperature for 30 min in a nitrogen-filled glovebox. The required
amount of catalyst solution (0.1 mL, 0.001 mmol) was then
transferred by syringe into the vials charged with different sub-
strates (0.1 mmol for each) in MeOH (2.9 mL). All of the vials were
placed together in a steel autoclave into which hydrogen gas was
charged. After the solution was stirred at room temperature for
20 min, the hydrogen was released slowly, the solution was con-
centrated, and then the crude product was eluted by EtOAc
through a plug of silica gel to remove the metal complex. The
purified product mixture was analyzed by chiral GC or HPLC to
determine the ee value.
e24 h. f30 °C, 60 atm of H2, 12 h.
decreased from 96% to 81% when the steric bulkiness of R2
was increased from methyl to ethyl or ethyl ester group (entry 1
vs entries 13 and 14). It was noteworthy that the hydrogenation
of 2o gave ee > 99% (entry 15) when R1 was changed from an
aryl group to a methyl group. The best outcome may be
attributed to the decreased steric hindrance enhancing the
coordination of enamide to rhodium.
It is known that Pd/C-catalyzed hydrogenation has the
ability to remove the carbonyl oxygen from the aromatic
ketone derivatives,15 and we applied this method to the
reduction of optically pure β-amino arylketones to optically
pure γ-aryl amines. In a one-pot reaction, we first reduced
β-keto enamides with Rh-DuanPhos followed by Pd/C
hydrogenolysis. As shown in Table 3, a range of enantio-
merically pure γ-aryl amines were prepared in full conver-
sions with good to excellent ee values.
3a:16 96.2% ee; enantiomeric excess was determined by GC,
In summary, a series of optically pure β-amino ketones
have been synthesized with high ee values by asymmetric
hydrogenation of readily prepared β-keto enamides using
Rh-DuanPhos catalyst. Subsequent reduction of these
β-amino ketones with hydrogen and Pd/C leads to the
formation of a variety of protected enantiomerically pure
γ-aryl amines. Our strategy therefore represents an efficient
and novel catalytic approach to prepare these two kinds of
pharmaceutically and biologically valuable compounds.
chiral Beta Dex 390 column, 160 °C, 1.0 mL/min, tmajor = 72.9
D
1
min, tminor = 76.1 min; [R]20 = -6.9 (c = 1.0, EtOAc); H
NMR (400 MHz, CDCl3) δ = 7.90-7.88 (m, 2H), 7.51-7.49-
(m,1H), 7.42-7.38 (m, 2H), 6.26 (br, 1H), 4.43-4.37 (m, 1H),
3.31-3.26 (dd, J = 4.4, 16.8 Hz, 1H), 3.04-2.98 (dd, J = 6.0,
16.8 Hz,1H), 1.89 (s, 3H), 1.23-1.22 (d, J = 6.8 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ = 199.3, 169.5, 136.9, 133.5, 128.7,
128.1, 43.4, 42.6, 23.4, 20.0.
Acknowledgment. We greatly acknowledge the National
Institutes of Health (GM58832) and Northwest Agriculture
& Forestry University for financial support.
Experimental Section
General Procedure for the Substrate Preparation. A toluene
solution (150 mL) of substituted 1,3-diketone (50 mmol), acetamide
Supporting Information Available: Experimental procedures,
characterization data for new compounds, and analysis of enan-
tioselectivities of hydrogenation products. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(15) (a) Rylander, P. N. Catalytic Hydrogenation in Organic Synthesis;
Academic Press: New York, 1979. (b) Hartung, W. H.; Simonff, R. Org.
React. 1953, 7, 263. (c) Breitner, E.; Roginski, E.; Rylander, P. N. J. Org.
Chem. 1959, 24, 1855. (d) Mori, A.; Mizusaki, T.; Miyakawa, Y.; Ohashi, E.;
Haga, T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Tetrahedron 2006, 62,
11925. (e) Sajiki, H; Hattori, K.; Hirota, K. J. Org. Chem. 1998, 63, 7990.
(f ) Sajiki, H.; Hattori, K.; Hirota, K. J. Chem. Soc., Perkin Trans. 1 1998,
4043.
(16) (a) Sugiura, M.; Kumahara, M.; Nakajima, M. Chem. Commun.
2009, 3585. (b) Luo, H.-T; Kang, Y.-R.; Nie, H.-Y.; Chen, W.-Y.; Yang,
L.-M. Fenzi Cuihua 2009, 23, 392.
334 J. Org. Chem. Vol. 76, No. 1, 2011