Synthesis of β-amino acid derivatives via copper-catalyzed asymmetric 1,4-reduction of β-(acylamino)acrylates

Article abstract of DOI:10.1021/ol200287z

A new set of reaction conditions has been established to facilitate the copper-catalyzed enantioselective 1,4-reduction of β-(acylamino)acrylates toward a selection of β-alkyl-β-amino acid derivatives in high yields and with uniformly high ee values (up to 99%) irrespective of the use of (E)- or (Z)-substrates.

Full text of DOI:10.1021/ol200287z

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1754–1757
Synthesis of β-Amino Acid Derivatives via
Copper-Catalyzed Asymmetric
1,4-Reduction of β-(Acylamino)acrylates
Yan Wu,† Shan-Bin Qi,† Fei-Fei Wu,† Xi-Chang Zhang,† Min Li,† Jing Wu,*,† and
Albert S. C. Chan*,‡
College of Material, Chemistry and Chemical Engineering and Key Laboratory of
Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou
Normal University, Hangzhou 310036, China, and State Key Laboratory of Chiroscience
and Institute of Creativity, Hong Kong Baptist University, Kowloon Tong, Hong Kong
jingwubc@hznu.edu.cn; ascchan@hkbu.edu.hk
Received January 28, 2011
ABSTRACT
A new set of reaction conditions has been established to facilitate the copper-catalyzed enantioselective 1,4-reduction of β-(acylamino)acrylates
toward a selection of β-alkyl-β-amino acid derivatives in high yields and with uniformly high ee values (up to 99%) irrespective of the use of (E)- or
(Z)-substrates.
Chiral β-amino acids constitute crucial structural ele-
ments of β-peptides, β-lactam antibiotics, and many other
biologically active compounds.1 Catalytic asymmetric
hydrogenation of β-(acylamino)acrylates as one of the
most facile methods toward optically enriched β-amino
acid derivatives has been intensively studied (Scheme 1).1b,2
Good to excellent enantioselectivities (up to >99% ee) have
been realized by using a variety of chiral Ru,2,3 Rh,2,4or Ir5
catalysts. In addition of the need for using precious metal
catalysts, a problem often encountered in previously studied
hydrogenation methods arises from the different catalytic
behaviors attributed to (Z)- and (E)-isomeric substrates.
Generally (E)-isomers led to higher ee values than the
† Hangzhou Normal University.
‡ Hong Kong Baptist University.
(1) (a) von Nussbaum, F.; Spiteller, P. In Highlights in Bioorganic
Chemistry: Methods and Application; Schmuck, C., Wennemers, H., Eds.;
Wiley-VCH: Weinheim, Germany, 2004; pp 63-89. (b) Enantioselective
Synthesis of β-Amino Acids; Juaristi, E., Soloshnok, V., Eds.; John Wiley &
Sons Inc: Hoboken, NJ, 2005.
(2) For some recent representative reviews, see: (a) Liu, M.; Sibi,
M. P. Tetrahedron 2002, 58, 7991–8035. (b) Ma, J.-A. Angew. Chem., Int.
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Higashi, N.; Imamoto, T. Org. Lett. 2001, 3, 1701–1704. (c) You, J.;
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Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2010, 39,
1656–1691 and references cited therein.
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Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543–554. (b) Wu, J.; Chen,
X.; Guo, R.; Yeung, C.-H.; Chan, A. S. C. J. Org. Chem. 2003, 68, 2490–
2493. (c) Qiu, L.; Wu, J.; Chan, S.; Au-Yeung, T. T.-L.; Ji, J.-X.; Guo,
R.; Pai, C.-C.; Zhou, Z.; Li, X.; Fan, Q.-H.; Chan, A. S. C. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5815–5820. (d) Qiu, L.; Kwong, F. Y.; Wu,
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Chan, A. S. C. J. Am. Chem. Soc. 2006, 128, 5955–5965.
€
Spannenberg, A.; Kostas, I. D.; Borner, A. Tetrahedron: Asymmetry
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€
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r
10.1021/ol200287z
Published on Web 03/02/2011
2011 American Chemical Society

of various γ-amino butyric acid derivatives.12 Herein, we
describe the first example of copper-catalyzed enantioselec-
tive 1,4-hydrosilylation of a selection of β-(acylamino)-
acrylates under air atmosphere in high yields and with
uniformly good to excellent ee values (up to 99%) irrespec-
tive of the use of (E)- or (Z)-substrates.
Scheme 1. Rh-, Ru-, or Ir-Catalyzed Asymmetric Hydrogena-
tion of β-Substituted β-(Acylamino)acrylates
Table 1. Effect of Additives on the Copper-Catalyzed Asym-
metric 1,4-Reduction of (Z)-2a in Aira
corresponding (Z)-substrates, which are the major isomers
formed in most current synthetic protocols.3a,4a Although
some Rh6 and Ru7catalysts can hydrogenate (Z)-sub-
strateswithcompetitivelyhighdegreesofenantioinduction
as those for (E)-isomers, the development of practical and
cost-effective catalytic systems that can perform well for
both isomers, especially for (Z)-isomers, is still highly
desirable.
In the past decade, copper-mediated asymmetric
1,4-hydrosilylation of various R,β-unsaturated Michael
acceptors has gained considerable attention8,9 owing to the
economic benefits of using nonprecious metal, the mild
reaction conditions, and the technical simplicity, whereas
the application of chiral copper catalysts in the 1,4-reduction
of β-dehydroamino acid derivatives is relatively unexplored.
Noteworthy is the elegant report in 2004 by Buchwald et al.10
on the copper-BINAP11 catalyst system, which allowed for
the asymmetric conjugate hydrosilylation of various β-ami-
no-substituted R,β-unsaturated esters to β-azaheterocyclic
acid derivatives of excellent enantiopurities. Later on, Zheng
and co-workers successfully applied this system in the synthesis
entry
alcohol
base [mol %]
t (h)
yield (%)b
ee (%)c
1
2
3d
4d
5
15
15
72
72
1
27
99
55
97e
97
29
45
87
84
88
40
13
86
60
79
79
80
91
84
81
83
81
85
85
80
72
80
84
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuONa [15]
t-BuONa [15]
t-BuONa [5]
t-BuONa [10]
t-BuONa [15]
t-BuONa [15]
t-BuONa [15]
t-BuONa [15]
t-BuOK [15]
MeONa [15]
t-BuONa [15]
6
1
7
1
8
15
1
9
i-PrOH
EtOH
10
11
12
13
14f
1
MeOH
t-BuOH
t-BuOH
t-BuOH
1
1
1
1
(6) Examples include the following: (a) Tang, W.; Zhang, X. Org.
Lett. 2002, 4, 4159–4161. (b) Lee, S.-G.; Zhang, Y. J. Org. Lett. 2002, 4,
a Reaction conditions: 0.15-1 mmol of substrate, substrate concen-
tration = 0.2-0.5 M in THF. b Determined by NMR and GC analysis.
c The ee values were determined by chiral GC analysis. The absolute
configuration was determined by comparing the retention times with known
data (see the Supporting Information). d Reaction temperature = -20 °C.
e The isolated yield was 93%. f N2 atmosphere.
~
2429–2431. (c) Pena, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L.
J. Am. Chem. Soc. 2002, 124, 14552–14553. (d) Tang, W.; Wang, W.;
Chi, Y.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 3509–3511. (e) Wu,
H.-P.; Hoge, G. Org. Lett. 2004, 6, 3645–3647. (f) Lefort, L.; Boogers,
J. A. F.; de Vries, A. H. M.; de Vries, J. G. Org. Lett. 2004, 6, 1733–1735.
(g) Hu, X.-P.; Zheng, Z. Org. Lett. 2005, 7, 419–422. (h) Tang, W.;
Capacci, A. G.; White, A.; Ma, S.; Rodriguez, S.; Qu, B.; Savoie, J.;
Patel, N. D.; Wei, X.; Haddad, N.; Grinberg, N.; Yee, N. K.; Krishna-
murthy, D.; Senanayake, C. H. Org. Lett. 2010, 12, 1104–1107. (i)
Zhang, X.; Huang, K.; Hou, G.; Cao, B.; Zhang, X. Angew. Chem.,
Int. Ed. 2010, 49, 6421–6424.
(7) Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J. Am.
Chem. Soc. 2002, 124, 4952–4953.
(8) For some recent reviews, see: (a) Riant, O.; Mostefai, N.; Cour-
marcel, J. Synthesis 2004, 2943–2958. (b) Rendler, S.; Oestreich, M.
Angew. Chem., Int. Ed. 2007, 46, 498–504. (c) Deutsch, C.; Krause, N.;
Lipshutz, B. H. Chem. Rev. 2008, 108, 2916–2927. (d) Lipshutz, B. H.
Synlett 2009, 509–524 and references cited therein.
We commenced our studies by examining the ability of
chiral dipyridylphosphine ligand P-Phos (Table1, 1a),13
which was previously demonstratedtobe highly efficient in
the Cu(II)-catalyzed asymmetric hydrosilylation of a di-
verse assortment of prochiral ketones,14 to promote the
conjugate reduction of the model substrate (Z)-2a. In the
presence of 5 mol % of Cu(OAc)2 H2O, 2 mol % of (S)-1a,
3
and 10 equiv of PMHS (polymethylhydrosiloxane), the
reaction proceeded in THF at room temperature to only
27% yield (GC and NMR) after 15 h to furnished (R)-3a in
79% ee (entry 1). Similar to previous findings,8c,9d,9e,10,15
(9) Examples include the following: (a) Moritani, Y.; Apella, D. H.;
Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 6797–
6798. (b) Lipshutz, B. H.; Servesko, J. M. Angew. Chem., Int. Ed. 2003,
42, 4789–4792. (c) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira,
E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473–9474. (d)
Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
11253–11258. (e) Lipshutz, B. H.; Servesko, J. M.; Taft, B. R. J. Am.
Chem. Soc. 2004, 126, 8352–8353. (f) Czekelius, C.; Carreira, E. M.
Angew. Chem., Int. Ed. 2003, 42, 4793–4795. (g) Czekelius, C.; Carreira,
E. M. Org. Lett. 2004, 6, 4575–4577. (h) Lee, D.; Kim, D.; Yun, J.
(12) Deng, J.; Hu, X.-P.; Huang, J.-D.; Yu, S.-B.; Wang, D.-Y.;
Duan, Z.-C.; Zheng, Z. J. Org. Chem. 2008, 73, 6022–6024.
(13) (a) Wu, J.; Chan, A. S. C. Acc. Chem. Res. 2006, 39, 711–720. (b)
Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-C.; Chan, A. S. C.; Wong,
W. T. J. Am. Chem. Soc. 2000, 122, 11513–11514.
(14) (a) Wu, J.; Ji, J.-X.; Chan, A. S. C. Proc. Natl. Acad. Sci. U.S.A.
2005, 102, 3570–3575. (b) Zhang, X.-C.; Wu, Y.; Yu, F.; Wu, F.-F.; Wu,
J.; Chan, A. S. C. Chem.;Eur. J. 2009, 15, 5888–5891.
ꢀ
Angew. Chem., Int. Ed. 2006, 45, 2785–2787. (i) Llamas, T.; Arrayas,
R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2007, 46, 3329–3332.
(10) Rainka, M. P.; Aye, Y.; Buchwald, S. L. Proc. Natl. Acad. Sci. U.
S.A. 2004, 101, 5821–5823.
(11) BINAP = 2,20-bis(diphenyllphosphino)-1,10-binaphthyl: (a)
Noyori, R.; Takaya, H. Acc .Chem. Res. 1990, 23, 345–350. (b) Noyori,
R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022.
(15) (a) Yun, J.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 5640–
5644. (b) Hays, D. S.; Fu, G. C. Tetrahedron 1999, 55, 8815–8832.
Org. Lett., Vol. 13, No. 7, 2011
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the reaction was accelerated by alcohol additives (4 equiv
of t-BuOH) although ee remained unchanged (entry 2 vs
entry 1). The lower temperature (-20 °C) did not render a
higher ee but resulted in the decrease of reaction rates
(entry 3 vs entry 2). To our delight, further introduction of
certain amounts of t-BuONa facilitated enhancements in
both yield (97%) and ee (91%, entry 4 vs entry 3). More-
over, quantitative yield was achieved within just 1 h at
room temperature with 84% ee (entry 5 vs entries 2 and 4).
Nonetheless, less than 50% yields were obtained in the
presence of 5 or 10 mol % of t-BuONa (entries 6 and 7 vs
entry 5). Additionally, if only adding t-BuONa in the
absence of alcohol, 87% yield was obtained after 15 h
(entry 8 vs entries 2 and 5). A series of alcohols of various
sizes (entries 9-11) and different bases (entries 12 and 13)
were tested. Sterically hindered t-BuOH and t-BuONa
appeared to be the preferred choice of additives in terms
of both activities and enantioselectivities. At this stage,
what is the role of the base for the increased rate and
enantioselectivity remains elusive. It appeared that in the
initial step of the catalytic cycle, a chiral Cu(II) alkoxide
(t-BuO)2CuL* or (t-BuO)CuL*(OAc) [A, L* = (S)-P-Phos]
likely formed upon combining of (S)-P-Phos with Cu-
Scheme 2. Effects of Ligand and Silane on the Copper-Cata-
lyzed Asymmetric 1,4-Reduction of (Z)-2a in Air
(OAc)2 H2O and t-BuONa. Complex A may be capable
3
of undergoing σ-bond metathesis with PMHS more ra-
pidly than Cu(OAc)2 to generate an active copper hydride
species (t-BuO)CuHL* (B), which is conjectured to be the
key intermediate responsible for discriminating between
the enantiotopic faces of the alkene substrate. Thus,
both the electronic and steric properties of the alkoxide
ion of B should have an influence on the enantioinduction
of the chiral copper hydride.8c,9d,15a Besides, when the
reaction was conducted under inert atmosphere, the reac-
tion rate was lower than that obtainable in air (entry 14 vs
entry 5).10,14,16
Furthermore, as illustrated in Scheme 2, the reaction
outcomesalsolargelyreliedon the selection ofboth ligands
and silanes. Among the chiral diphosphines screened, only
(S)-BINAP gave comparative results with those of P-Phos
at room temperature (Scheme 2 vs Table 1, entry 5).
Nevertheless, lowering the reaction temperature to
-20 °C did not lead to a higher ee in the case of the use of
(S)-BINAP (90% yield and 84% ee). Additionally, the
electronic and steric attributes of the ligands have pronounced
influences on the reaction. P-Phos showed better catalytic
properties than bulky Tol-P-Phos (1b) and Xyl-P-Phos (1c).17
As for silanes, PhSiH3,(EtO)3SiH, or (EtO)2MeSiH exhibited
inferior reactivity to the inexpensive and innocuous PMHS
although the ee values were almost the same.
set of conditions. As the findings in Scheme 3 indicated, the
extent of yields varied considerably as a function of the
counterions of copper. Although promising results were
achieved as well by applying CuCl, Cu(acac)2, Cu-
(CH3COCHCOCF3)2, or Cu(TC), Cu(OAc)2 H2O is the
3
most preferable choice because of its ease of handling and
substantially lower cost. Besides, the reaction was also
strongly solvent-dependent and THF was much more
conducive than other solvents, such as CHCl3, CH3CN,
dioxane, and toluene.
Scheme 3. Effect of Copper Salts on the Asymmetric 1,4-Re-
duction of (Z)-2a in Air
Next, the effects of various copper precursors and
solvents on the reaction were investigated under a given
(16) (a) Sirol, S.; Courmarcel, J.; Mostefai, N.; Riant, O. Org. Lett.
2001, 3, 4111–4113. (b) Mostefaı, N.; Sirol, S.; Courmarcel, J.; Riant, O.
¨
Synthesis 2007, 1265–1271.
(17) (a) Wu, J.; Chen, H.; Zhou, Z.-Y.; Yeung, C.-H.; Chan, A. S. C.
Synlett 2001, 1050–1054. (b) Wu, J.; Chen, H.; Kwok, W.-H.; Lam, K.-
H.; Zhou, Z.-Y.; Yeung, C.-H.; Chan, A. S. C. Tetrahedron Lett. 2002,
43, 1539–1543. (c) Wu, J.; Pai, C.-C.; Kwok, W. H..; Guo, R. W.; Au-
Yeung, T. T. L.; Yeung, C.-H.; Chan, A. S. C. Tetrahedron: Asymmetry
2003, 14, 987–992.
Having established the preferred conditions, we set out
to evaluate the applicable scope of the Cu-catalyzed pro-
tocol. As indicated in Table 2, the present catalytic sys-
tem worked efficiently for both (Z)- and (E)-substrates to
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Org. Lett., Vol. 13, No. 7, 2011

Table 1, entry 5). Thereaction rates for(E)-isomersin most
cases were slower than those of related (Z)-isomers under
otherwise identical conditions (for example, entry 7 vs
entry 5, entry 9 vs entry 8). Noteworthy was the observa-
tion that when the ethyl ester of 2a was changed to bulky
isopropyl (2b) or tert-butyl ester (2c), the reaction effi-
ciency and enantioselectivity suffered noticeably (entries 6
and 9 vsentry 1). Withrespect to 2dwithmethylester, up to
95% ee and reasonably high yield were obtained as
expected (entries 10 and 11). Thus, a variety of methyl
ester substrates with different β-alkyl substituents (2e-g)
were reduced completely with consistently high ee values
for both isomeric substrates (92-99%, entries 12-18).
Surprisingly, varying the β-alkyl substituents of ethyl ester
substrate (2a) distinctly influenced the reaction outcomes
(entries 20and 21vsentry 1, entry 19vsTable 1, entry 5). In
the case of 2i (R1 = t-Bu) almost no reduction took place
(entry 21).
Table 2. Cu(II)-Catalyzed Asymmetric 1,4-Reduction of
β-Substituted β-(Acylamino)acrylates 2 in Aira
In conclusion, in the presence of certain amounts of
t-BuONa and t-BuOH as additives, the combination of
Cu(OAc)2 H2O, enantiomeric P-Phos, and hydride donor
3
PMHS generated in situ an efficient catalyst system in
normal atmosphere for the asymmetric conjugate reduc-
tion of a spectrum of β-(acylamino)acrylates with uni-
formly high ee values (up to 99%) for both (Z)- and
(E)-isomeric substrates. Particularly, in most cases, (Z)-
isomers were reduced at faster rates than those of (E)-
isomers. The present catalyst system features high air-stability,
good to excellent enantioselectivity, cost efficiency, and
mild conditions and thus offers a good opportunity for the
practical preparation of β-amino acids derivatives. Studies
aimed at expanding the scope of the presentcatalyst system
and clarifying the reaction mechanism are underway in our
laboratory.
Acknowledgment. We thank the National Natural
Science Foundation of China (21032003, 20672026), the
New Century Excellent Talents in Chinese University
Program awarded to Jing Wu (NCET-07-0250), and the
Natural Science Foundation of Zhejiang Province
(R406378) for financial support of this study.
a Reaction conditions: 0.15-0.3 mmol of substrate, substrate con-
centration = 0.2 M in THF. b Determined by NMR and GC analysis.
c E/Z = 1:1. d 2 mol % of (R)-1a was used. e The isolated yield was 95%.
Supporting Information Available. Experimental de-
tails and chracterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
afford the reduction products bearing the same configura-
tion and similar enantiopurities. An E/Z mixture of 2a was
also reduced to afford the product (R)-3a quantitatively
within 2 h in 85% ee (entry 3 vs entry 1 in Table 2 and
Org. Lett., Vol. 13, No. 7, 2011
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