Angewandte
Chemie
DOI: 10.1002/anie.201407744
Asymmetric Hydrogenation
Nickel-Catalyzed Asymmetric Transfer Hydrogenation of Olefins for
the Synthesis of a- and b-Amino Acids**
Peng Yang, Haiyan Xu, and Jianrong (Steve) Zhou*
Abstract: The field of asymmetric (transfer) hydrogenation of
prochiral olefins has been dominated by noble metal catalysts
based on rhodium, ruthenium, and iridium. Herein we report
that a simple nickel catalyst is highly active in the transfer
hydrogenation using formic acid. Chiral a- and b-amino acid
derivatives were obtained in good to excellent enantioselectiv-
ity. The key toward success was the use of the strongly donating
and sterically demanding bisphosphine Binapine.
A
symmetric olefin hydrogenation is commonly practiced in
industry for the large-scale synthesis of pharmaceutically
active ingredients.[1] Often rhodium-, ruthenium-, and iri-
dium-based catalysts are used. Excellent stereoselectivity can
be achieved by a judicious choice of suitable phosphorus
ligands and the catalyst loading can be lowered for an
economic application at large scale.[2] However, these heavy
metal catalysts are expensive, toxic, and damaging to the
environment. Furthermore, their reserves in earthꢀs crust are
depleting. Recently, there is renewed interest in developing
cheap, abundant first-row metal catalysts for the asymmetric
hydrogenation of prochiral olefins. For example, Chirik et al.
reported a cobalt-catalyzed asymmetric hydrogenation of
substituted styrenes and dehydroaminoesters with good
enantioselectivity (Figure 1).[3] Unfortunately, in the first
example, an air-sensitive cobalt complex of a bisiminopyridine
must be used and in both cases the scope of olefins was quite
limited.
Figure 1. Cobalt-catalyzed asymmetric hydrogenation of olefins by
Chirik et al.
directed hydrogenation of selected ketones such as b-ketoest-
ers.[6] Recently, Hamada et al. described a nickel-catalyzed
asymmetric hydrogenation of a-amino-b-ketoesters using
10 atm of H2 and obtained around 90% ee under conditions
of dynamic kinetic resolution.[7] At present, a highly asym-
metric (transfer) hydrogenation of prochiral olefins using
nickel catalysts has not been realized.[8]
b-Amino acids are important building blocks for the
synthesis of pharmaceuticals, e.g., b-lactam antibiotics. They
are also monomers of peptidomimetics that are resistant to
enzymatic degradation.[9] b-Amino acid derivatives have been
synthesized by Rh- or Ru-catalyzed asymmetric hydrogena-
tion of b-acetamido- and b-amidoacrylates.[10] The metal-
catalyzed asymmetric transfer hydrogenation using formic
acid or isopropanol to prepare amino acid derivatives was
rarely studied and afforded poor stereoselectivity.[11] In our
model hydrogenation reaction of a,b-dehydro-b-acetamino-
butyrate (Figure 2), we found that nickel catalysts ligated by
highly electron-rich and sterically demanding bisphosphines
were catalytically active. In particular, (S)-Binapine afforded
good conversion and 96% ee. (S)-Binapine was prepared
through the copper-mediated homocoupling of 1,1’-binaph-
thophosphepine sulfide by Xumu Zhang et al.[12] Two related
bisphosphines TangPhos and DuanPhos were less selective
(35% ee and 71% ee). Mark Burkꢀs ligands including Ph-
BPE, Me-DuPhos, and Me-DPF were also catalytic active,
but the selectivity was not good.[13] Imamotoꢀs P-chiral
bisphosphine QuinoxP* afforded 72% ee.[14] One of the
Josiphos ligands was catalytically active but the selectivity was
only moderate.[15] Other less donating phosphine ligands, such
as BINAP, Segphos, DIPAMP, and PHOX, were completely
inactive. Many other metal salts of iron, cobalt, and copper
were tested together with Binapine, but they were inactive in
the model reaction (see the Supporting Information).
Herein, we disclose a simple nickel/Binapine catalyst for
asymmetric transfer hydrogenation reactions leading to a-
and b-amino acids. Formic acid is used as the hydrogen
equivalent.[4] Thus, safety hazard associated with the storage
and handling of high-pressure hydrogen gas is avoided. In
addition, nickel is 100- to 1000-fold cheaper than ruthenium,
rhodium, and iridium, when the price of their chloride salts is
compared.[5]
Heterogeneous nickel catalysts modified by tartaric acid
have been reported to afford more than 90% ee in the
[*] Dr. P. Yang,[+] H. Xu,[+] Prof. Dr. J. (S.) Zhou
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
21 Nanyang Link 637371 (Singapore)
E-mail: jrzhou@ntu.edu.sg
[+] These authors contributed equally to this work.
[**] We thank Singapore GSK-EDB Green and Sustainable Manufactur-
ing Award and Nanyang Technological University for financial
support.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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