Rhodium-catalyzed enantioselective and diastereoselective hydrogenation of β-ketoenamides: Efficient access to anti 1,3-amino alcohols

Full text of DOI:10.1002/anie.200902339

Communications
DOI: 10.1002/anie.200902339
Asymmetric Catalysis
Rhodium-Catalyzed Enantioselective and Diastereoselective
Hydrogenation of b-Ketoenamides: Efficient Access to anti 1,3-Amino
Alcohols**
Huiling Geng, Weicheng Zhang, Jian Chen, Guohua Hou, Le Zhou, Yaping Zou, Wenjun Wu,*
and Xumu Zhang*
Chiral 1,3-amino alcohols are interesting structural motifs
prevalent in pharmaceutical products[1] as well as in important
chiral auxiliaries and ligands for asymmetric synthesis.[2]
Currently, the most common strategy for their synthesis is
based on the diastereoselective reduction of an enantiomer-
ically pure substrate, whereby the chirality of the substrate
controls the formation of the new stereogenic center (sub-
strate-controlled asymmetric reduction).[3–5] In this context,
we wondered whether asymmetric hydrogenation[6] could be
used to afford chiral 1,3-amino alcohols from readily prepared
substrates (reagent-controlled asymmetric reduction).[7,8]
Herein, we report a rhodium-catalyzed highly enantioselec-
tive (up to 99% ee) and diastereoselective (up to d.r. 99:1)
hydrogenation of b-ketoenamides as an efficient entry to
enantiomerically pure anti 1,3-amino alcohols containing two
stereogenic centers.
The substrates were prepared in one step from readily
accessible 1,3-diketones[9] under Dean–Stark conditions
(Table 1). Owing to its operational simplicity, we recently
employed this method for the preparation of Z/E b-aryl
enamides.[10] In the present study, we further optimized the
reaction conditions. The desired substrates 2a–2n were
obtained in moderate to good yield (up to 90%) as stable
crystalline solids. In each case, only the Z enamide was
observed, probably as a result of the intramolecular hydrogen
bond.
Table 1: Preparation of b-ketoenamides 2 through the direct condensa-
tion of 1 with acetamide.[a]
Entry
1
R1
R2
2[b]
Yield [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
90
46
84
69
87
72
58
65
65
72
56
76
47
68
p-MeC6H4
p-MeOC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
p-tBuC6H4
p-CyC6H4
m-MeC6H4
o-MeC6H4
thiophen-2-yl
2-naphthyl
C6H5
Me
Me
[a] Reactions were carried out by heating a mixture of 1 (50 mmol),
acetamide (250 mmol), and p-TsOH (10 mmol) in toluene (150 mL) in a
Dean–Stark apparatus for 24 h. [b] In all cases, only the Z enamide was
observed by 1H NMR spectroscopy. [c] Yield of the isolated product. Cy=
cyclohexyl, Ts=toluenesulfonyl.
We tested 2a as the standard substrate in a series of
rhodium-catalyzed hydrogenation reactions. Our initial reac-
tion with Rh/duanphos (L1)[11a] in CH2Cl2 under 10 bar of
hydrogen pressure gave the product 3a with 97% ee and
predominant anti selectivity (d.r. 95:5), albeit accompanied
by a small amount of the monoreduction product 4a (Table 2,
entry 1). Solvent screening (Table 2, entries 1–9) revealed
that the use of EtOAc (entry 6) led to the best reactivity
(95% yield) and selectivity (99% ee, d.r. 95:5) for 3a. Thus,
EtOAc was selected as the optimal solvent. An increase in the
hydrogen pressure to 20 bar (Table 2, entry 10) led to
complete conversion into 3a, whereas a further increase in
hydrogen pressure caused a slight drop in enantioselectivity
(entries 11–13). We also tested four other commercially
available chiral ligands: tangphos (L2),[11b] Et-duphos
(L3),[11c] binapine (L4),[11d] and f-binaphane (L5).[11e] Lower
reactivity or enantioselectivity was observed with these
ligands (Table 2, entries 14–17).
[*] H. Geng, Prof. L. Zhou, Prof. W. Wu
College of Science
Northwest Agriculture & Forestry University
Yangling, Shaanxi 712100 (China)
E-mail: wenjun_wu@263.com
H. Geng, W. Zhang, J. Chen, G. Hou, Y. Zou, Prof. X. Zhang
Department of Chemistry and Chemical Biology and
Department of Pharmaceutical Chemistry
Rutgers, The State University of New Jersey
Piscataway, New Jersey 08854 (USA)
Fax: (+1)732-445-6312
E-mail: xumu@rci.rutgers.edu
Homepage: http://rutchem.rutgers.edu/~xumuweb/
[**] This research was supported by the National Institutes of Health
(GM58832), China Scholarship Council, and Northwest Agriculture
& Forestry University. Mass spectrometry was carried out by the
Washington University Mass Spectrometry Resource, an NIH
Research Resource (Grant P41RR0954).
Encouraged by our preliminary results, we subjected a
series of substrates, 2b–2n, to asymmetric hydrogenation
under the optimized conditions with the Rh/duanphos
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902339.
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Table 2: Rhodium-catalyzed asymmetric hydrogenation of 2a under
Table 3: Rhodium-catalyzed asymmetric hydrogenation of 2a–2n.[a]
various conditions.[a]
Entry
2
R1
R2 PH
[bar]
3
Yield[b] ee[c] d.r.[d]
[%] [%] (syn/anti)
2
Entry L[b] Solvent
PH
[bar]
3a
Yield[c] ee[d]
Yield of
2
4a [%][f]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2a C6H5
Me 20 3a[e] 100
99
97
95
97
99
98
97
97
99
94
99
97
96
96
5:95
7:93
8:92
4:96
4:96
6:94
8:92
8:92
4:96
14:86
5:95
<1:99
5:95
d.r.[e]
(syn/anti)
2b p-MeC6H4
2c p-MeOC6H4
2d p-FC6H4
2e p-ClC6H4
2 f p-BrC6H4
2g p-tBuC6H4
2h p-CyC6H4
Me 100 3b
Me 100 3c
Me 20 3d
Me 20 3e
Me 100 3 f
Me 100 3g
Me 100 3h
Me 20 3i
Me 20 3j
97
95
100
100
95
96
93
100
100
100
100
[%]
[%]
1
2
3
L1 CH2Cl2
L1 toluene
L1 THF
10
10
10
10
10
10
10
10
85
74
62
97
>99
98
5:95
4:96
6:94
12
19
38
71
37
5
28
4
32
0
0
0
0
0
44
32
0
4
5
6
7
L1 dioxane
L1 acetone
L1 EtOAc
L1 MeOH
L1 iPrOH
29
63
95
72
96
3
99 29:71
98 29:71
99 5:95
98 31:69
93 9:91
46 31:69
2i
2j
m-MeC6H4
o-MeC6H4
8
2k thiophen-2-yl Me 20 3k
2l 2-naphthyl Me 20 3l
Et
Me 20 3n
9
L1 CF3CH2OH 10
10
11
12
13
14
15
16
17
L1 EtOAc
L1 EtOAc
L1 EtOAc
L1 EtOAc
L2 EtOAc
L3 EtOAc
L4 EtOAc
L5 EtOAc
20
30
40
50
20
20
20
20
100
100
100
100
100
56
99
98
98
95
98
5:95
3:97
4:96
4:96
5:95
5:95
3:97
8:92
2m C6H5
2n Me
20 3m 100
100
<1:99
[a] Reactions were carried out with a substrate/catalyst ratio of 100:1 in
EtOAc at room temperature for 24 h. [b] The yield was calculated from
the 1H NMR spectrum of the crude hydrogenation product. [c] The
ee value was determined by GC or HPLC on a chiral phase. [d] The
99
17
100
>99
69
1
diastereomeric ratio was calculated from the H NMR spectrum of the
crude hydrogenation product. [e] The absolute configuration of 3a was
assigned as 1R,3S by comparison of the observed optical rotation with
reported data. The absolute configurations of 3b–3n (all samples
showing positive optical rotation) were not determined.
[a] Reactions were carried out with a substrate/catalyst ratio of 100:1 at
room temperature for 24 h. [b] L1=(SC,RP)-duanphos, L2=
(1S,1S’,2R,2R’)-tangphos, L3=(R,R)-Et-duphos, L4=(S)-binapine, L5=
1
f-binaphane. [c] The yield of 3a was determined by H NMR spectros-
copy. [d] The ee value of 3a was determined by GC on a chiral phase. The
absolute configuration of 3a was assigned by comparison of the
observed optical rotation with reported data. [e] The diastereomeric ratio
isobutylamines. When the chiral 1,3-amino alcohol precursor
3a (99% ee) was treated with Pd/C in the presence of
hydrogen gas (20 bar), g-phenylisobutylamine (97% ee) was
obtained in quantitative yield (Scheme 1). To our knowledge,
1
was calculated from the H NMR spectrum of the crude hydrogenation
product. [f] The yield of 4a was calculated from the 1H NMR spectrum of
the crude hydrogenation product. cod=cycloocta-1,5-diene; (SC,RP)-
duanphos=(1R,1’R,2S,2’S)-2,2’-di-tert-butyl-2,3,2’,3’-tetrahydro-1H,1’H-
(1,1’)-biisophosphindolyl; (1S,1’S,2R,2’R)-tangphos=1,1’-di-tert-butyl-
(2,2’)-diphospholanyl; (R,R)-Et-duphos=1,2-bis(2,5-diethylphosphola-
nyl)benzene; (S)-binapine=(3S,3’S,4S,4’S,11bS,11’bS)-4,4’-di-tert-butyl-
4,4’,5,5’-tetrahydro-3H,3’H-bidinaphtho[2,1-c:1’,2’-e]phosphepine;
f-binaphane=1,1’-bis((S)-4,5-dihydro-3H-binaphtho[2,1-c:1’,2’-e]phos-
phepino)ferrocene.
catalytic system in EtOAc. The hydrogen pressure was found
to be critical for the formation of the desired product 3 in
good yield and minimization of the amount of monoreduction
side products. Therefore, this parameter was optimized for
different substrates (Table 3). In most cases, excellent enan-
tioselectivity, diastereoselectivity, and conversion were
observed. The presence of substituents on the phenyl
moiety in 2 resulted in a slight decrease in the ee value of
the product in some cases without compromising the diaste-
reoselectivity. The only exception was the ortho-methyl-
substituted substrate 2j, for which lower enantio- and
diastereoselectivity were observed than for the para- and
meta-substituted substrates 2b and 2i. This decrease in
selectivity can presumably be attributed to increased steric
hindrance of the aryl group during hydrogenation.
Scheme 1. Synthesis of g-phenylisobutylamine through asymmetric
hydrogenation.
there is no other catalytic method available for the prepara-
tion this class of chiral amines.[12] This transformation there-
fore represents an elegant catalytic approach to these
pharmaceutically and biologically valuable chiral compounds.
For example, compound 4, an agrochemical for pest control,
could potentially be prepared by this sequence of reactions
(Scheme 2).[13]
In summary, we have shown that a variety of anti 1,3-
amino alcohols can be prepared by a highly efficient rhodium-
catalyzed asymmetric hydrogenation of readily available
b-ketoenamides. Two stereogenic centers are generated
The present transformation can be coupled to Pd/C-
catalyzed hydrogenolysis for the preparation of chiral g-aryl
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Communications
[1] M. Nogradi, Stereoselective Synthesis, VCH, Weinheim, 1987.
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[6] a) Comprehensive Asymmetric Catalysis I–III (Eds.: E. N.
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Scheme 2. Potential application of the asymmetric hydrogenation–
hydrogenolysis protocol for the preparation of a chiral pesticide.
[7] For the catalytic synthesis of chiral 1,2-amino alcohols through
asymmetric hydrogenation, see: a) M. Kitamura, T. Okuma, S.
Inoue, N. Sayo, H. Komobayashi, S. Akutagawa, T. Ohta, H.
Takaya, R. Noyori, J. Am. Chem. Soc. 1988, 110, 629; b) H.
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He, X. Zhang, J. Am. Chem. Soc. 2004, 126, 1626; f) S. Liu, J.-H.
Xie, L.-X. Wang, Q.-L. Zhou, Angew. Chem. 2007, 119, 7650;
Angew. Chem. Int. Ed. 2007, 46, 7506; g) J.-H. Xie, S. Liu, W.-L.
Kong, W.-J. Bai, X.-C. Wang, L.-X. Wang, Q.-L. Zhou, J. Am.
Chem. Soc. 2009, 131, 4222.
simultaneously with excellent enantioselectivity and diaste-
reoselectivity in this atom-economical process. Subsequent
treatment of the 1,3-amino alcohol intermediates with Pd/C
and hydrogen gas leads to the formation of protected chiral
g-aryl isobutylamines. This protocol constitutes the first
asymmetric catalytic method for the preparation of these
valuable chiral building blocks. Further exploration of this
strategy for the preparation of various chiral compounds is
currently in progress.
[8] To our knowledge, asymmetric hydrogenation has seldom been
applied in the synthesis of chiral 1,3-amino alcohols; an example
is the asymmetric hydrogenation of certain g-amino ketones:
a) reference [7d]; b) D. Liu, W. Gao, C. Wang, X. Zhang, Angew.
Chem. 2005, 117, 1715; Angew. Chem. Int. Ed. 2005, 44, 1687.
[9] For the preparation of 1,3-diketones, see: X. Han, R. A.
Widenhoefer, J. Org. Chem. 2004, 69, 1738.
[10] J. Chen, W. Zhang, H. Geng, W. Li, G. Hou, A. Lei, X. Zhang,
Angew. Chem. 2009, 121, 814; Angew. Chem. Int. Ed. 2009, 48,
800.
Experimental Section
Substrate preparation:
A solution of 1 (50 mmol), acetamide
(250 mmol), and the catalyst p-TsOH (10 mmol) in toluene
(150 mL) was placed in a Dean–Stark apparatus and heated at
reflux for 24 h. The reaction mixture was then cooled to room
temperature, the solvent was evaporated, and the residue was purified
by flash column chromatography on silica gel (eluent: EtOAc/
hexane) to give 2 as a white powder or colorless oil.
[11] a) D. Liu, X. Zhang, Eur. J. Org. Chem. 2005, 646; b) W. Tang, X.
Zhang, Angew. Chem. 2002, 114, 1682; Angew. Chem. Int. Ed.
2002, 41, 1612; c) M. J. Burk, Acc. Chem. Res. 2000, 33, 363;
d) W. Tang, W. Wang, Y. Chi, X. Zhang, Angew. Chem. 2003, 115,
3633; Angew. Chem. Int. Ed. 2003, 42, 3509; e) D. Xiao, X.
Zhang, Angew. Chem. 2001, 113, 3533; Angew. Chem. Int. Ed.
2001, 40, 3425.
[12] For strategies based on the use of chiral auxiliaries, see: a) S. E.
Denmark, T. Weber, D. W. Piotrowski, J. Am. Chem. Soc. 1987,
109, 2224; b) J. T. Colyer, N. G. Anderson, J. S. Tedrow, T. S.
Soukup, M. M. Faul, J. Org. Chem. 2006, 71, 6859; for enzyme-
assisted resolution, see: c) J. Conzalez-Sabin, W. Gotor, F.
Rebolledo, Tetrahedron: Asymmetry 2002, 13, 1315; d) M.
Nechab, N. Azzi, N. Vanthuyne, M. Bertrand, S. Gastaldi, G.
Gil, J. Org. Chem. 2007, 72, 6918.
Hydrogenation: A stock solution was made by mixing [Rh-
(cod)2]BF4 with duanphos in a 1:1.1 molar ratio in EtOAc at room
temperature for 10 min in a nitrogen-filled glovebox. A specified
amount of the catalyst solution (0.1 mL, 0.001 mmol) was transferred
by syringe into a vial containing the substrate (0.1 mmol) in EtOAc
(2.9 mL). The vial was placed in a steel autoclave, which was then
charged with hydrogen gas, and the reaction mixture was stirred at
room temperature for 24 h. The hydrogen was then released slowly,
and the solution was concentrated and passed through a short column
of silica gel to remove the metal complex. The ee value of the product
was determined by GC or HPLC of the product mixture on a chiral
phase.
Received: May 1, 2009
Published online: July 13, 2009
[13] Y. Watanabe, Y. Otsu, H.-J. Riebel, S. Lehr, U. Stelzer, E. R. F.
Gesing, R. Kirsten, A. Lender, K. Voigt, U. Wachendorff-
Neumann, C. Erdelen, Ger. Offen. DE 19825379, 1999.
Keywords: diastereoselectivity · enamides · enantioselectivity ·
.
hydrogenation · rhodium
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