.
Angewandte
Communications
Nanocatalysts
À
Enantiospecific C H Activation Using Ruthenium Nanocatalysts
CØline Taglang, Luis Miguel Martínez-Prieto, Iker del Rosal, Laurent Maron, Romuald Poteau,
Karine Philippot, Bruno Chaudret, Serge Perato, Anaïs Sam Lone, CØline Puente,
Christophe Dugave, Bernard Rousseau, and GrØgory Pieters*
Abstract: The activation of CÀH bonds has revolutionized
rationalize the chemoselectivity, the enantiospecificity, and
the low activation energy of this intriguing reaction, DFT
calculations were performed and revealed a four-membered
dimetallacycle as the key intermediate.
modern synthetic chemistry. However, no general strategy for
enantiospecific CÀH activation has been developed to date. We
herein report an enantiospecific CÀH activation reaction
3
followed by deuterium incorporation at stereogenic centers.
Mechanistic studies suggest that the selectivity for the
a-position of the directing heteroatom results from a four-
membered dimetallacycle as the key intermediate. This work
paves the way to novel molecular chemistry on nanoparticles.
Recently, we developed a smooth and selective C(sp )ÀH
activation/deuteration process in the a-position of the nitro-
gen atom of amines using ruthenium nanoparticles dispersed
[24]
in a polyvinylpyrrolidone matrix (RuNP@PVP). However,
in all cases studied, the CÀH activation took place on methyl
or methylene groups and never at a chiral center. To study the
stereochemical outcome of such transformations, three differ-
ent chiral amines, compounds 1 to 3, were subjected to
RuNP@PVP catalyzed CÀH activation followed by deutera-
S
yntheses and modifications of functional molecules are
critical steps in many areas of research and industry, including
drug discovery and development, biochemistry, imaging
techniques, material science, and nanobiotechnology. This is
classically achieved through step-by-step functional-group
modification, which is a time-consuming and environmentally
detrimental process. Over the last decade, the revolutionary
emergence of CÀH bond activation and functionalization has
tion (Figure 1). In all cases, the corresponding deuterated
opened the way to the rapid construction and atom-economic
and late-stage diversification of functional molecules.
Historically, numerous works have been dedicated to
[1–7]
Figure 1. Enantiospecific CÀH activation/deuteration using
2
3
RuNP@PVP nanoparticles (3%) under an atmosphere of D gas
2
C(sp )ÀH activation and more recently to C(sp )ÀH activa-
(
(
2 bar) at 558C for 36 h in THF (compounds 1 and 2) or D O
compound 3).
[
8–18]
2
tion.
Among these studies, only few reported enantiose-
lective CÀH activation, and these examples all involved chiral
metal complexes. Moreover, no general enantiospecific
method has been developed to date, and only sporadic
compounds were isolated in 70–80% yield. The CÀH
deuteration at the chiral center occurred efficiently to give
highly isotopically enriched compounds (99%) with full
retention of configuration.
[19–21]
examples have been reported.
In this active field of
research, the control over the stereochemistry of CÀH
activation and the discovery of novel key mechanisms that
enable the development of new reactions remain two major
breakthroughs to be realized. Herein, we report the develop-
ment of a catalytic enantiospecific CÀH activation reaction of
We then generalized this method to the deuteration of
amino acids because they play a central role in the chemistry
of life. Furthermore, deuterated amino acids have repeatedly
[
25,26]
several classes of compounds (amines, amino acids, peptides)
been shown to have important applications.
Gratifyingly,
[22,23]
3
using ruthenium nanoparticles under mild conditions.
To
this reaction occurred enantiospecifically at the C (sp )
a
position with full retention of configuration. Efficient deute-
rium incorporation (77–99% isotopic enrichment) was
observed for amino acids with aliphatic (4 to 8), amide (9
and 10), and nitrogen-containing (11 and 12) side chains
(Figure 2), highlighting the general scope of this enantiospe-
cific CÀH activation process. For serine (13) and threonine
[
*] C. Taglang, Dr. S. Perato, A. Sam Lone, C. Puente, Dr. C. Dugave,
Dr. B. Rousseau, Dr. G. Pieters
CEA Saclay, SCBM, iBiTec-S, Building 547, PC # 108
9
1191 Gif sur Yvette (France)
E-mail: gregory.pieters@cea.fr
L. M. Martínez-Prieto, Dr. I. del Rosal, Prof. L. Maron, Prof. R. Poteau,
Dr. B. Chaudret
LPCNO; Laboratoire de Physique et Chimie de Nano-Objets
UMR 5215 INSA-CNRS-UPS, Institut National des Sciences Appli-
quØes, 135, Avenue de Rangueil, 31077 Toulouse (France)
(
14), together with the expected enantiospecific labeling at
the Ca position, an additional CÀH activation process
occurred at the Cb position. Remarkably, the latter also
proceeded with full retention of configuration for both chiral
centers of threonine (14). For histidine (15), the expected
enantiospecific labeling at the Ca position was observed.
Interestingly, full labeling of the imidazole ring occurred
owing to the high affinity of this coordinating group for the
nanocatalyst surface. For the water-soluble compounds 16 and
L. M. Martínez-Prieto, Dr. K. Philippot
CNRS; LCC (Laboratoire de Chimie de Coordination)
2
05, Route de Narbonne, 31077 Toulouse (France)
1
0474
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 10474 –10477