DOI: 10.1002/chem.201303146
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Chiral Ligands
Highly Modular C1-Symmetric Chiral (P,N) Ligands with
a Stereolabile P Center: Experimental and Theoretical Studies
Nicolas Humbert,[a] Evgeny Larionov,[a] Luca Mantilli,[a] Pradeep Nareddy,[a] Cꢀline Besnard,[b]
Laure Guꢀnꢀe,[b] and Clꢀment Mazet*[a]
Abstract: An improved synthesis of a novel class of biden-
tate (P,N) ligands is presented, the structures of which are
characterized by three distinct elements of chirality. The ste-
reoselective installation of the elements of central chirality
(at the benzylic carbon and the phosphorus atom) depends
on the size of the phosphorus substituent. Thermal inversion
of the phosphorus center has been studied experimentally
and further correlated by DFT calculations. The potential of
these ligands and the role of the phosphorus atom in the
asymmetric a-arylation of aldehydes (Pd) and hydrogenation
of allylic alcohols (Ir) have also been investigated.
contributions,[5–7] the development of configurationally flexible
tropos ligands combined with exogenous or endogenous ele-
ments of chirality to convey asymmetric induction has received
a legitimate and increased interest. In contrast, little attention
has been paid to ligands with other types of flexible elements,
in particular to phosphine-containing ligands.
Introduction
Over the last few decades, asymmetric catalysis has had a pro-
found impact on the preparation of enantioenriched com-
pounds, driven in particular by the needs of the pharmaceuti-
cal, biological, medicinal, and materials sciences.[1] In this con-
text, the design of efficient chiral ligands occupies a central
place as they exert a direct role in controlling the small energy
increments responsible for high selectivity. The ideal chiral
ligand should be 1) cheap; 2) synthetically readily accessible;
3) easy to handle; 4) structurally highly modular to facilitate
identification of lead structures; and, more importantly, 5) ap-
plicable to a wide number of mechanistically unrelated asym-
metric transformations with invariable efficiency. Very few can-
didates fulfill all these requirements and it is recognized as
a highly difficult task to add a new entry to this restricted cate-
gory of so-called “privileged” chiral ligands and catalysts.[2] In-
dependently of the nature of the chiral ligand, catalyst optimi-
zation often requires iterative and time-consuming synthetic
modifications. Recent efforts have been directed towards the
development of alternative and complementary strategies to
facilitate optimal catalyst identification.[3] The development of
self-adaptable ligands, which ideally could adjust their struc-
ture to the substrate undergoing transformation, has been per-
ceived as an attractive goal.[4] Following Mikami’s pioneering
This is especially surprising with regard to the historical de-
velopments of homogeneous asymmetric catalysis and the
ever-growing catalogue of P-based chiral ligands and organo-
catalysts.[8] A plausible explanation might be that the well-es-
tablished configurational stability of P-stereogenic tertiary
phosphines has been exploited to prepare robust rather than
stereoflexible chiral ligands, despite the difficulty associated
with their stereoselective preparation.[9] The successful devel-
opment of self-adaptable ligands elaborated around flexible el-
ements other than tropoisomeric structures would certainly
constitute an important addition to asymmetric catalysis. Al-
though far from such an achievement, we report herein our
preliminary results in this direction for this long-term perspec-
tive.
We recently developed a novel class of C1-symmetric chiral
(P,N) ligands 1, which feature three distinct elements of chirali-
ty: 1) an axial chirality, 2) a carbon stereocenter, and 3) a phos-
phorus stereocenter (Figure 1).[10] Their potential in asymmetric
catalysis was revealed in the Pd-catalyzed intramolecular a-ary-
lation of aldehydes for which 1e displayed excellent levels of
enantioinduction in the formation of indane derivatives.[11]
Whereas the synthesis of the ligands with bulky P substituents
proved highly stereoselective (1a–g), ligand 1h (R=C6H5) was
obtained as a mixture of two separable diastereoisomers that
[a] N. Humbert, Dr. E. Larionov, L. Mantilli, P. Nareddy, Prof. Dr. C. Mazet
Department of Organic Chemistry
University of Geneva
Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
Fax: (+41)22-379-3215
differed only in the absolute configuration of the P atom.[12]
A
[b] Dr. C. Besnard, Dr. L. Guꢀnꢀe
Laboratoire de Cristallographie
formal inversion of the phosphorus stereocenter was observed
upon removal of the borane protecting group. On the basis of
a combined experimental and theoretical approach, we decid-
ed to engage in a detailed study of this phenomenon and to
explore its role in the context of asymmetric catalysis.
University of Geneva
Quai Ernest Ansermet 24, 1211 Geneva 4 (Switzerland)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303146.
Chem. Eur. J. 2014, 20, 745 – 751
745
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