Supramolecular Ligands DOI: 10.1002/ange.201002958 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 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] 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– Scheme 1. a) Phthalic anhydride, CHCl 3 , reflux, 94–98 %; b) (CF 3 CO) 2 O, TEA, dioxane or THF, 0 8C to RT, 97–99%; c) amino alcohol, THF, RT, 66–90%; d) (S)-binol-PCl, TEA, THF, RT, 62–78%. TEA = triethylamine. [*] Dr. L. Pignataro, Dr. M. Civera, R. Colombo, Prof. C. Gennari Università 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 E-mail: cesare.gennari@unimi.it S. Carboni, Prof. U. Piarulli Università 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 under http://dx.doi.org/10.1002/anie.201002958. Angewandte Chemie 6783 Angew. Chem. 2010, 122, 6783 –6787  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim