Scheme 1. Synthetic Route for Chiral β-Amino Nitroalkanes
and Their Derivatization
Figure 1. Key structural elements in chiral pharmaceuticals.
developed an asymmetric reduction of β-amino nitroolefins
through hydrosilylation with a simple N-sulfinyl urea as a
bifunctional catalyst.13 Nevertheless, among these methods,
there is substantial room for increasing catalytic activities and
improving the enantioselectivities.
Over the past decade, transition-metal-catalyzed enan-
tioselective hydrogenation of functionalized olefins has
attracted a great deal of attention and catalytic asymmetric
hydrogenation has emerged as a powerful and environ-
mentally friendly methodology for preparing chiral
compounds.14 With the rapid development of catalytic
systems, many types of olefins bearing functional groups
such as acylamino,14a carbonyl,14c,15 phosphate,14d,16 and
the cyano group17 were hydrogenated in high ee’s and
activities. In principle, the enantioselective hydrogenation
strategy can also be utilized for the formation of chiral β-
amino nitroalkanes from new substrates β-acylamino ni-
troolefins. However, highly enantioselective hydrogena-
tion of nitroolefins remains a challenging task. To the best
of our knowledge, there has been no successful catalytic
method reported for this transformation. This may be due
to the extremely electron-withdrawing nitrogroup that can
reduce the strength of chelation between CdC double
bond of the substrate and metal catalyst. Considering the
significant role played by transition metal complex bearing
chiral phosphine ligands in the asymmetric hydrogenation
of CdC, CdO, and CdN double bonds, we envisioned
that a Rh-catalyzed highly enantioselective hydrogenation
of β-acylamino nitroolefin may serve as an efficient way to
afford the desired enantiomerically pure β-amino nitroalk-
ane from a new substrate with highly electron-donating
bisphosphine ligands under the right conditions. Recently,
we have reported the asymmetric hydrogenation of β,β-
disubstituted nitroalkenes for the synthesis of chiral ni-
troalkanes with excellent efficiency and enantioselectivity.18
Herein, we document a new strategy to generate chiral β-
amino nitroalkanes in high yields and good enantioselec-
tivities via Rh-catalyzed asymmetric hydrogenation of β-
acylamino nitroolefins.
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β-Acylamino nitroolefins can be easily prepared in two
steps from readily accessible corresponding R-nitro ke-
tones 1 under mild conditions (Scheme 1), and only Z
isomers were observed for product 3. Initially, we used
(Z)-N-(2-nitro-1-phenylvinyl) acetamide3aas a model sub-
strate to optimize the reaction conditions. As shown in
Table 1, the solvent played a critical role in this catalytic
reaction. When the Rh-TangPhos complex was employed
as the catalyst, poor conversions were observed in MeOH,
CH2Cl2, ethyl acetate, and toluene, albeit with promising
enantioselectivities (57À85% ee, Table 1, entries 1À4). The
catalyst almost showed no activity in THF, dioxane, and EtOH
(Table 1, entries 5À7). To our delight, the transformation
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