A Tunable Class of Chiral Cp Ligands for Enantioselective Rhodium(III)-Catalyzed C-H Allylations of Benzamides

The lack of robust and tunable chiral versions of cyclopentadienyl (Cp) ligands hampers progress in the development of catalytic asymmetric versions of a myriad of reactions catalyzed by this ubiquitous ligand. Herein, we describe of a class of chiral Cp ligands with tunable steric parameters. Coordinated to transition metals, the ligand creates a well-defined chiral pocket, able to imprint its chirality onto the metal. The corresponding Rh complexes are shown to be excellent catalysts for enantioselective allylation of N-methoxybenzamides via directed C-H functionalizations at very mild conditions. The obtained enantioselectivities are excellent and demonstrate the viability of chiral Cp complexes as selective transition metal catalysts.

Enantiopure helical (supra)molecular arrays containing lanthanides

Marco Antonio Lama

The diastereoselective synthesis of chiral coordination compounds with d metals proved the effectiveness of the pinene-bipyridine approach in predetermining the chirality at the metal centre. The strong Lewis acidic character of lanthanide cations required the modification of this class of ligands in order to adapt their coordination properties to the binding affinity of Ln(III) toward hard donor atoms like oxygen. The pinene bipyridine carboxylic derivative (+)-L- (figure 1) has been designed and synthesized to form configurationally stable lanthanide complexes. This ligand proved its effectiveness as chiral building block for the synthesis of oligometallic supramolecular structures. Indeed a self-assembly process takes place with complete diastereoselectivity between the enantiomerically pure (-) or (+) L- and Ln(III) ions (Ln = La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er) in methanol, giving rise to trinuclear enantiopure structures with general formula Ln3(L)6(µ3-OH)(H2O)32 , possessing predetermined helical chirality. The ligands in this case display a new version of supramolecular helical chirality since they are wrapping around a trimetallic core instead of one single metal centre. The same components afford a second polynuclear structure if the reaction is carried out in CH3CN. In this medium a three-dimensional tetranuclear array self-assembles (with general formula Ln4(L)9(µ3-OH)2). The nine ligands are forming three distinct helical domains, two supramolecular as in the case of the trinuclear array and one classical around a single metal centre, with predetermined configuration. The two classes of compounds have been structurally characterized in solid state (X-ray and IR) and in solution (ES-MS, NMR). Their chiroptical properties were investigated by means of Circular Dichroism and Circularly Polarized Luminescence (for the emitting compounds). Trinuclear and tetranuclear arrays are shown to interconvert in CH3CN, in a process mediated by water. This process was rationalized taking into account the nature of the Ln(III) ions, the initial concentration of the components and the addition or removal of water in solution. The availability of both the enantiomers of the ligand prompted us to study the self-recognition capabilities of the two systems. 1H-NMR and CD studies reveal an almost complete chiral recognition in the self-assembly leading to the trinuclear complex. The process leading to tetranuclear species appears instead perturbed, probably due to the higher number of fundamental components involved (4 metals and 9 ligands instead of 3 metals and 6 ligands). Figure 1: Reaction conditions leading to the synthesis of trinuclear and tetranuclear Ln(III) complexes with ligand (+)-L-. The introduction of a carboxylic moiety onto the 6' posititon of the (-)-5,6- and (-)-4,5- pinene bipyridine lead to the tridentate ligands (-)-HL1 and (-)-HL2, respectively. Mononuclear neutral complexes are obtained upon reaction with Ln(ClO4)3. Different extents of diastereoselectivity are pointed out in the two systems by X-ray analysis and CD spectroscopy. In particular the ligand (-)-HL1, in which the pinene moiety is next to the binding site, seems to be more effective in predetermining the configuration at the metal centre. A low diastereoselectivity is instead expressed in the reactions with (-)-HL2 as revealed by the X-ray structure of [Pr{(-)-L2}3] (both Δ and Λ isomers detected) and by the CD spectrum void of signal.

EPFL2006

Developing Reactions of Strained Rings

Daniele Perrotta

Carbo- and heterocyclic structures containing nitrogen-substituted stereocenters are recurrent structural motifs in natural and bioactive compounds, therefore constituting a privileged class of synthetic targets. In this regard, substituted three- and four-membered carbocycles are powerful building blocks. Activation by a catalyst allows for an efficient exploitation of their ring strain, enabling a large variety of transformations. In particular, activation via oxidative addition by transition metals has been widely applied in annulations of these rings. Another common mode of activation consists in the use of Lewis acids to promote heterolytic ring opening of electron-poor strained rings, among which donor-acceptor cyclopropanes and cyclobutanes stand out for their well-established and broad chemistry. In this thesis, intermolecular annulations of three-membered carbocycles via oxidative addition by transition metals were first investigated. We mainly focused on the use of aminocyclopropanes as well as more strained aminomethylidenecyclopropanes. Despite a broad screening of transition metal complexes and modifications of the cyclopropane structure, no desired product could be formed. The use of aminomethylidene cyclopropanes in Lewis acid catalyzed intermolecular annulations was also studied. Employing aldehydes as reaction partners delivered highly functionalized 2-aminotetrahydrofurans. Instead, the use of all-carbon dipolarophiles for the synthesis of carbocycles was not successful. Subsequently, we explored enantioselective transformations of donor-acceptor cyclopropanes. We first investigated a new Lewis acid catalyzed DYKAT of donor-acceptor aminocyclopropanes with 2-siloxyfurans as dipolarophiles. After a thorough optimization, the desired product could be obtained in high er. However, the yield was not satisfactory, and any attempt to improve it by modifying the structure of the aminocyclopropane or by screening additives and reaction conditions was unsuccessful. On the other hand, we succeeded in the development of the first Lewis Acid catalyzed enantioselective desymmetrization of donor-acceptor meso-diaminocyclopropanes. The methodology consists in a copper(II) catalyzed Friedel-Crafts alkylation of indoles and a pyrrole, and delivers enantioenriched urea derivatives, which are recurrent structures in natural and bioactive compounds. The reaction tolerates electronically and sterically diverse substituents on the benzene ring of the indole. The choice of appropriate protecting groups on the cyclopropane was required to guarantee its solubility and to maintain good levels of enantioselectivity. The modification of an underexplored subclass of bisoxazoline ligands, bearing bulky diarylmethanol groups in alpha to the nitrogen atoms, was essential for obtaining high enantiomeric ratios, and led to the synthesis of several novel ligands. Finally, we developed Lewis acid catalyzed [4+2] annulations of donor-acceptor aminocyclobutanes with aromatic aldehydes, which afforded useful 2-aminotetrahydropyrans. A scandium catalyst was employed for the annulation of unsubstituted aminocyclobutanes, which delivered products in yields up to 95% and diastereoselectivities up to 17:1. On the other hand, one equivalent of a cheap and non-toxic iron Lewis acid was required for substituted aminocyclobutanes, which afforded densely functionalized six-membered heterocycles bearing three stereocenters in diastereoselectivities up to 5:1.

EPFL2018

Modular Chiral N-Heterocyclic Carbene Ligands for the Nickel-Catalyzed Enantioselective C-H Functionalization of Heterocycles

Nicolai Cramer, Johannes Diesel

N-Heterocyclic carbenes (NHCs) are the ligands of choice in a large variety of transformations entailing different transition metals. However, the number and variety of chiral NHCs suitable as stereo-controlling ligands in asymmetric catalysis remains limited. Herein we highlight the introduction of a modular NHC ligand family, consisting of a chiral version of the widely used IPr ligand. These chiral NHC ligands were applied in the nickel-catalyzed enantioselective C-H functionalization of N-heterocycles. Nickel-NHC catalysis unlocked the stereoselective C-H annulation of 2- and 4-pyridones, delivering fused bicyclic compounds found in many biologically active compounds. Applying a bulky, yet flexible ligand scaffold enabled the highly enantioselective C-H functionalization of pyridones under mild conditions. The introduction of a bulky chiral SIPr analogue enabled the nickel-catalyzed enantioselective C-H functionalization of indoles, yielding valuable tetrahydropyridoindoles. Additionally, pyrrolopyridines, pyrrolopyrimidines and pyrroles were efficiently functionalized, delivering chiral annulated azoles.