Organocatalytic asymmetric transferhydrogenation of β-nitroacrylates: Accessing β2-amino acids

Article abstract of DOI:10.1021/ja8069852

We describe a highly efficient and enantioselective Hantzsch ester mediated conjugate reduction of β-nitroacrylates that is catalyzed by a Jacobsen thiourea catalyst as a key step in a new route to optically active β²-amino acids. Copyright

Full text of DOI:10.1021/ja8069852

Published on Web 09/25/2008
Organocatalytic Asymmetric Transferhydrogenation of ꢀ-Nitroacrylates:
Accessing ꢀ2-Amino Acids
Nolwenn J. A. Martin, Xu Cheng, and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim an der Ruhr, Germany
Received September 3, 2008; E-mail: list@mpi-muelheim.mpg.de
Pioneered by Seebach et al. and Gellmann et al., ꢀ-peptides
recently emerged as a new class of peptidomimetics with potentially
widespread biological and medicinal applications.1,2 As a conse-
quence, the synthesis of ꢀ-amino acids has attracted considerable
attention.3 While ꢀ3-amino acids, which are branched in the
ꢀ-position, are now commercially available with most natural
substituents, the analogous ꢀ2-amino acids, branched in the R-posi-
tion, although particularly promising, are more difficult to obtain.4
Very recently, Gellmann et al. reported an elegant organocatalytic
Mannich reaction that furnishes ꢀ-amino aldehydes in high yields
and enantioselectivities.5 The products of this reaction can be readily
converted into ꢀ2-amino acids. Here we report an alternative
approach that relies on a catalytic asymmetric Hantzsch ester
trisubstituted nitroolefins.9 The reaction turned out to be rather
general and works well with a variety of substrates (Table 1).
Subjecting different nitroacrylates 2 to the above reaction conditions
for 24-48 h provided saturated ꢀ-nitroesters 5 in high yields and
enantioselectivities. The ester group can be varied significantly as
probed with phenyl-substituted derivatives 2a-e (entries 1-5).
While the yield is high in all cases, the enantioselectivity increases
slightly with size and bulkiness of the ester moiety. Other aryl and
heteroaryl groups can be utilized as well, furnishing the corre-
sponding products in similar high yields and enantioselectivities
(entries 6-10). Gratifyingly, branched as well as unbranched
aliphatic nitroacrylates are equally suitable substrates (entries
11-13).
mediated conjugate reduction of readily available ꢀ-nitroacrylates
to the corresponding ꢀ-nitroesters, which themselves are easily
converted into ꢀ2-amino acids via hydrogenation.6,7
Our approach to ꢀ2-amino acids takes its inspiration from nature.
We envisioned that, in analogy to an enzymatic reductive amination
of R-keto acids with ammonia,8 a hypothetic reductive amino-
methylation with nitromethane should lead to the corresponding
ꢀ2-amino acids (eq 1).
We have also investigated the effect of the nitroacrylate olefin
geometry on the outcome of the reaction (Scheme 1). In contrast
to our stereoconvergent iminium catalytic enal reductions,13 the
enantioselectivity of the nitroolefin reductions strongly depends on
substrate olefin geometry. Accordingly, nitroolefins (E)- or (Z)-2k
gave opposite enantiomers of product 5k, each with high enantio-
selectivity while a 1:1 (E)/(Z)-mixture gave essentially racemic 5k.
Remarkably though, stereoconvergence can be established upon
adding a catalytic quantity of triphenylphosphine. We propose this
additive to create a rapid equilibrium between (E)-2k and (Z)-2k
via a conjugate addition/elimination pathway. That (R)-5k is the
major product under these conditions indicates a faster reaction of
the corresponding (E)-starting material, which should also dominate
the equilibrium of the two 2k olefin isomers.
Encouragement for this design came from Jacobsen-type thiourea-
catalyzed ꢀ-nitroolefin reductions previously developed by our
group.9-11 In addition, a biocatalytic reduction of ꢀ-nitroacrylates
has been realized during our studies.12
Based on our previous results, we identified Jacobsen-type
thiourea 4 as a suitable catalyst of the highly enantioselective
conjugate reduction of ꢀ-nitroacrylates 2, for which we have
developed a simple and practical synthesis. For example, reacting
R-ketoester 1a first with nitromethane in the presence of a catalytic
amount of triethyl amine (20 mol%), followed by dehydration of
the resulting alcohol with acetic anhydride, gave the desired
nitroacrylate 2a in good yield and high (Z)-stereoselectivity (eq
2). Treating olefin 2a (1 M) with commercially available Hantzsch
ester 3 (1 equiv) and thiourea catalyst 4 (10 mol%) at 0 °C in
toluene gave saturated ester 5a in good yield and with high
enantioselectivity. Hydrogenation in the presence of Pd/C directly
gave the free ꢀ2-amino acid (R)-6a. The conjugate reduction
conditions have been optimized with regard to catalyst structure
and loading, solvent, substrate concentration, and Hantzsch ester
structure and concentration (see Supporting Information (SI)). The
resulting conditions are almost identical to those we have previously
used successfully in the analogous reductions of unfunctionalized
The absolute configuration of compounds 5a, 5b, and 5k was
determined by measuring their known optical rotation or that of
their corresponding known ꢀ2-amino acids (see SI).
In summary we have developed a short new approach to
enantiopure ꢀ2-amino acids. A key step in our sequence is a highly
enantioselective thiourea 4-catalyzed conjugate reduction of ꢀ-
nitroacrylates 2 to their saturated analogues 5. In addition we have
developed a convenient synthesis of the required nitroacrylates 2
via Henry reaction followed by an acetic anhydride mediated
dehydration. The conversion of our reduction products into ꢀ2-
amino acids is facile and direct if benzyl esters are utilized. In the
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10.1021/ja8069852 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Preliminary Scope of the Transfer Hydrogenation
case of ꢀ-nitroesters with ester groups other than benzyl, conversion
into the corresponding ꢀ2-amino acids is equally facile and involves
a hydrogenation-hydrolysis sequence as outlined in the SI. Our
organocatalytic asymmetric nitroolefin reduction complements a
recently developed biocatalytic version12 but has a significantly
broader scope. The modest atom economy of our procedure may
be counterbalanced by the practical and convenient use of bench
stable, crystalline Hantzsch esters and a readily available catalyst.
For practical considerations, it is important to note that both the
Hantzsch ester oxidation product and the catalyst are easily
separable from the less polar reaction products by flash chroma-
tography and our reaction tolerates air, moisture, and up-scaling.
Acknowledgment. We thank the DFG (Priority Program
Organocatalysis SPP1179) for funding this work. Generous support
by the Max-Planck-Society, by Novartis (Young Investigator Award
to BL), and by the Fond der Chemischen Industrie is gratefully
acknowledged. We also thank Jutta Rosentreter for several GC
measurements and Dr. Jung Woon Yang for technical assistance.
Supporting Information Available: Experimental procedures,
compound characterization, NMR spectra, and HPLC and GC traces.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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a Yields and er’s from GC. All yields are >89%.
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