Angewandte
Chemie
DOI: 10.1002/anie.201202715
Asymmetric Hydrogenation
Highly Enantioselective Hydrogenation of b,b-Disubstituted
Nitroalkenes**
Shengkun Li, Kexuan Huang, Bonan Cao, Jiwen Zhang, Wenjun Wu,* and Xumu Zhang*
Enantiomerically pure nitroalkanes are valuable intermedi-
ates in organic synthesis. They can be easily converted to
other versatile building blocks, such as amines, aldehydes,
carboxylic acids, nitrile oxides, and denitrated compounds.[1]
Structural motifs derived from chiral b-branched nitroalkanes
can be found in many small molecule pharmaceuticals, such as
catramilast, for the treatment of atopic dermatitis, the muscle
relaxant baclofen,[2] and the asthma agent NK5807.
despite the potential for high efficiency. Asymmetric hydro-
genation of nitroalkenes has been a challenging problem and
advances in this area will lead to an efficient, atom-
economical approach to chiral b-branched nitroalkanes
(Figure 1). Herein, we report the first highly enantioselective
hydrogenation of b,b-disubstituted nitroalkenes to produce
chiral b-branched nitroalkanes.
Many catalytic asymmetric methods are known to pro-
duce chiral b-branched nitroalkanes: 1) Several groups have
reported the biocatalytic reduction of nitroalkenes using
bakerꢀs yeast and reductases from Lycopersicon esculentum,
Saccharomyces carlsbergensis, Kluyveromyces lactis, and
Yersinia bercovieri.[3] 2) Carreira and Czekelius[4] have devel-
oped elegant chiral transfer hydrogenations of b,b-disubsti-
tuted nitroalkenes catalyzed by copper and iridium. The
research group of Deng has demonstrated an efficient
conjugate reduction of nitroalkenes using a chiral diamine–
rhodium catalyst.[5] 3) Chiral thiourea-based organocatalysts
have been applied in the asymmetric transfer hydrogenation
of nitroalkenes.[6] 4) Versatile, highly enantioselective conju-
gate additions of carbon or phosphorus nucleophiles to
nitroalkenes have also been reported by a number of groups.[7]
To the best of our knowledge, the direct hydrogenation of
nitroalkenes with molecular H2 has not yet been reported,
Figure 1. Different approaches to chiral b-branched nitroalkanes.
Apart from the importance of chiral nitroalkanes, the
asymmetric hydrogenation of nitroalkenes is particularly
attractive as these substrates are readily available and can
be prepared by the Henry reaction or through the nitration of
olefins (nitration of a-methylstyrene with N2O4,[4a,8] HNO3,[3e]
or CAN[3g,9]). In our preparation, b,b-disubstituted nitro-
alkenes 1a–v were synthesized from substituted acetophe-
nones through a Wittig reaction followed by CAN-catalyzed
nitration (CAN = ceric ammonium nitrate; see the Support-
ing Information for details).
Our initial evaluation began with the asymmetric hydro-
genation of model substrate 1a with a series of catalysts. Poor
results were obtained using Ru–bidentate phosphine cata-
lysts, which gave low conversion and/or low ee. A number of
Rh complexes of monodentate phosphine ligands were also
evaluated, also with poor results (see the Supporting Infor-
mation). Rh complexes with bidentate phosphines, such as
Rh-Duanphos, Et-Duphos, Tangphos, or Me-Pennphos com-
plexes (Figure 2) gave low enantioselectivities, albeit with
good conversions (Table 1, entries 1–4). In some cases, the
isomerization of 1a was detected (Table 1, entries 1 and 4).
Chiral biaryl bisphosphorus ligands (S)-Segphos and (R)-
MeO-Biphep (Table 1, entries 5 and 6) showed no activity.
(S)-C3-Tunephos showed some activity and selectivity
(31% ee, Table 1, entry 7). Other types of bidentate diphos-
phine ligands showed either significantly lower enantioselec-
tivities with higher isomerization (Table 1, entry 8, f-Ketal-
phos) or no reactivity (Table 1, entry 9, (R)-QuinoxP).
We were gratified to find that the commercially available
ferrocene ligand Josiphos-1 (Figure 2; Table 1, entry 10) gave
a promising result with 87% conversion, 56% ee, and no
[*] S. Li, J. Zhang, Prof. W. Wu
Institute of Pesticide Science and College of Science
Northwest Agriculture & Forestry University
Yangling, Shaanxi 712100 (China)
E-mail: wuwenjun@nwsuaf.edu.cn
S. Li, K. Huang, B. Cao, Prof. X. Zhang
Department of Chemistry and Chemical Biology and
Department of Pharmaceutical Chemistry
Rutgers, the State University of New Jersey
Piscataway, NJ 08854 (USA)
E-mail: xumu@rci.rutgers.edu
[**] This research was supported by the National Institutes of Health
(GM58832), the China Scholarship Council, and the National Key
S&T Research Foundation of China (2010CB126105).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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