Angewandte
Chemie
DOI: 10.1002/anie.201002958
Supramolecular Ligands
PhthalaPhos: Chiral Supramolecular Ligands for Enantioselective
Rhodium-Catalyzed Hydrogenation Reactions**
Luca Pignataro, Stefano Carboni, Monica Civera, Raffaele Colombo, Umberto Piarulli,* and
Cesare Gennari*
Chemists have largely taken inspiration from Nature in the
development of new approaches to synthetic challenges.
Combinatorial chemistry stems from the concept of evolu-
tion, whereby random mutation of a chemical structure gives
rise to libraries of compounds, from which an optimal lead can
be found with high probability. On the other hand, Nature
makes wide use of noncovalent interactions to build its
complex supramolecular architectures and to achieve effi-
cient and selective transformations. In recent years, combi-
natorial and supramolecular approaches to the development
of new ligands for asymmetric catalysis has gained momen-
tum.[1,2d] The term “supramolecular ligand” encompasses all
ligands possessing, besides the atom(s) coordinating to the
catalytic metal atom, an additional functionality capable of
noncovalent interactions (mainly hydrogen[3] or coordinative
bonds[4]) which can play the following roles: 1) self-assembly
of two monodentate ligands to form a so-called supramolec-
ular bidentate ligand;[5] 2) binding the substrate(s) in prox-
imity to the catalytic metal center[2] in analogy to metal-
loenzymes.[6] Among the different kinds of noncovalent
interactions that have been used so far for developing
supramolecular ligands,[5] hydrogen bonds are arguably the
most practical and efficient[2,3] for several reasons: 1) func-
tional groups capable of hydrogen bonding (e.g., amides,
ureas, guanidines) are stable and relatively easy to introduce;
2) hydrogen bonds are created dynamically and reversibly in
the reaction medium (where catalysis is to take place), are
capable of self-repair when broken, and often coexist with
other interactions in a “noninvasive” manner.
As a result of our continued interest in developing
supramolecular ligands,[7] we report herein the design and
synthesis of a novel class of chiral monodentate phosphite
ligands, named PhthalaPhos, which contain a phthalic acid
primary diamide moiety (Scheme 1). The phthalamidic group
Scheme 1. a) Phthalic anhydride, CHCl3, reflux, 94–98%;
b) (CF3CO)2O, TEA, dioxane or THF, 08C to RT, 97–99%; c) amino
alcohol, THF, RT, 66–90%; d) (S)-binol-PCl, TEA, THF, RT, 62–78%.
TEA=triethylamine.
displays both donor and acceptor hydrogen-bonding proper-
ties that, in principle, can give rise to supramolecular
interactions both between the ligands and with the reaction
substrate. The modular nature of the PhthalaPhos ligands
allows their properties to be tuned by simply varying
structural elements such as the linker, the binol moiety, and
the ancillary amide group (i.e., the amide not connected to
the phosphite group), and thus parallel-combinatorial ligand
optimization is possible.[1a,c]
[*] Dr. L. Pignataro, Dr. M. Civera, R. Colombo, Prof. C. Gennari
Universitꢀ degli Studi di Milano, Dipartimento di Chimica Organica
e Industriale, Centro Interdipartimentale CISI, Istituto di Scienze e
Tecnologie Molecolari (ISTM) del CNR
Via G. Venezian, 21, 20133 Milano (Italy)
Fax: (+39)02-5031-4072
The PhthalaPhos ligands were easily prepared in four
steps as outlined in Scheme 1: phthalic anhydride was treated
with a primary amine to give phthalic acid mono amides 1 in
94–98% yield.[8] Dehydration of the latter in the presence of
trifluoroacetic anhydride gave phthalisoimides 2 in high
yields, whose reaction with a chosen amino alcohol led to
phthalic acid diamides 3.[9] Diamide mono-alcohols 3 were
treated with binol-derived chlorophosphites[10] to give Phtha-
laPhos ligands 4.
Although we synthesized and screened a relatively large
library of nineteen members (4a–s, see the Supporting
Information for the complete layout of the library and the
complete set of results), here we present the results obtained
with a selected subset of the most successful nine ligands (4a–
E-mail: cesare.gennari@unimi.it
S. Carboni, Prof. U. Piarulli
Universitꢀ degli Studi dell’Insubria, Dipartimento di Scienze
Chimiche e Ambientali
Via Valleggio, 11, 22100 Como (Italy)
Fax: (+39)031-238-6449
E-mail: umberto.piarulli@uninsubria.it
[**] We thank the European Commission [RTN Network (R)Evolutionary
Catalysis MRTN-CT-2006-035866] for financial support. L. Pignataro
thanks Milan University for a postdoctoral fellowship (“Assegno di
ricerca”). HRMS spectra were performed at CIGA (Milan Univer-
sity). We are grateful to Dr. Laura Belvisi of Milan University for the
helpful discussions on the computational studies.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 6633 –6637
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6633