DOI: 10.1002/chem.201600535
Communication
&
Reduction
A General and Selective Rhodium-Catalyzed Reduction of Amides,
N-Acyl Amino Esters, and Dipeptides Using Phenylsilane
Shoubhik Das, Yuehui Li, Liang-Qiu Lu, Kathrin Junge, and Matthias Beller*[a]
Mannich reactions offer elegant access for the synthesis of b-
Abstract: This article describes a selective reduction of
amino esters.[9]
functionalized amides, including N-acyl amino esters and
Interestingly, the straightforward direct reduction of amido
dipeptides, to the corresponding amines using simple
esters has been completely overlooked for the synthesis of
[Rh(acac)(cod)]. The catalyst shows excellent chemoselec-
chiral amino esters. Obviously, for the reduction of amido ester
tivity in the presence of different sensitive functional moi-
derivatives to the corresponding amino esters, the tolerance of
eties.
the ester moiety and racemization are of major concern. For
that purpose, the application of stoichiometric amounts of
metal hydrides failed due to their poor selectivity.[10] In addi-
The synthesis of amines and their derivatives is of key impor-
tance for the development of novel bioactive compounds, es-
pecially in today’s pharmaceutical and agrochemical indus-
tries.[1] Although numerous methodologies for their synthesis
have been reported, novel strategies are still the focus of in-
tense investigations in the scientific community.[2] Amides,
through reduction, represent a desirable feedstock for the syn-
thesis of amines due to their wide availability and facile syn-
thesis.[3] In recent years, the hydrosilylation of secondary and
tertiary amides has been intensively investigated; however se-
lective reduction of more challenging amides, such as a-amino
acid ester derivatives, is still underrepresented today.[4] Notably,
these latter substrates represent the key structural unit for
peptides and proteins, and they constitute valuable chiral pool
intermediates, which are of actual interest as building blocks
for drug discovery.[5] Apparently, chemoselective reductions of
amino acid derivatives offer straightforward access to a variety
of biologically interesting compounds for chemical biology
studies and potential pharmaceutical applications.
tion, tedious purifications, removal of concomitant byproducts
formed during the reduction might be troublesome. In con-
trast, catalytic procedures offer alternative strategies for selec-
tive reductions under milder conditions and might allow for
improved chemo- and regioselectivities.[11] Obviously, catalytic
hydrogenation would be an ideal option for this type of reduc-
tion but unfortunately lack of a general catalytic hydrogena-
tion of amides requires other methodologies.[12]
Complementary to hydrogenations, catalytic hydrosilylations
are operationally simple to perform and often allow for im-
proved chemoselectivity and regioselectivity.[13] Hence, metal-
catalyzed hydrosilylations of amides and related carboxylic
acid derivatives have received considerable interest during the
last decades.[14] More specifically, catalyst systems based on
Rh,[15] Ru,[16] Mo,[17] In,[18] Pt,[19] Zn,[20] Cu,[21] Co,[22] and Fe[23] have
proven to be effective for the reduction of amides (Scheme 1).
It should be noted that the vast majority of these metal cata-
lysts were used only for the reduction of nonchiral tertiary
amides.
Regarding the synthesis of N-alkylated amino acid deriva-
tives, the classical Strecker reaction is well documented for the
racemic products.[6] Nowadays, a plethora of asymmetric ver-
sions of this landmark reaction has been developed utilizing
both stoichiometric and catalytic amounts of chiral sources.
Additionally, the Petasis three-component reactions applying
boronic acids, amines, and glyoxylic acid are employed for the
diastereoselective synthesis of a-amino acid ester derivatives.[7]
Other versatile approaches consist of the addition of electro-
philes to glycine enolate derivatives, and conversely, of the ad-
dition of nucleophiles to electrophilic glycine templates, both
of which have been used successfully as methodologies to
access unnatural amino acid derivatives.[8] Moreover, catalytic
Recently, we established the first selective hydrosilylation of
amino acid esters and peptides using specific rhodium cata-
[a] Dr. S. Das, Dr. Y. Li, Dr. L.-Q. Lu, Dr. K. Junge, Prof. M. Beller
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert Einstein Str. 29a, 18059 Rostock (Germany)
Supporting information for this article is available on the WWW under
Scheme 1. Catalytic reduction of amides using silanes.
Chem. Eur. J. 2016, 22, 7050 – 7053
7050
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