Chiral Iodanes for Asymmetric Carbon–Carbon Bond Construction – IODOCHEM

The realization of the IODOCHEM project and the development of an efficient chiral organoiodine (catalytic) system rely on concerted efforts in i) experimental organic chemistry for the design, synthesis, structural analysis and evaluation of our own iodoarenes/iodanes in asymmetric synthesis), ii) quantum chemistry for the DFT calculations and topological analyses of iodoarenes/iodanes, and iii) physical organic chemistry for unprecedent X-ray and UV photoelectron spectroscopy (XPS and UPS, respectively) studies of iodoarenes/iodanes. These three approaches are complementary in the consortium efforts aimed at identifying the best structural modifications to be performed on chiral iodocompounds to make them always more efficient inducers of asymmetry. Theoretical calculations, together with XPS and UPS studies, also aim at gathering crucial information for a better understanding/rationalization of the theoretical aspects of this iodane-based chemistry. These advances will benefit to all chemists involved worldwide in hypervalent iodine chemistry.

Several new chiral iodanes bearing carbon-based ligands (e.g., alkynyl, cyano and trifluoromethyl) are now accessible by chemical synthesis. Their evaluation in diverse asymmetric ligand-transfer reactions has proved encouraging in the case of oxindole alkynylation (48% ee). The topological analysis of the bonds and the study of the orbitals of interest around the iodine(III) allowed the gathering of new information to better understand the reactivity of the iodine centers. Two new collaborations (Prof. J.N. Moorthy, IIT of Kanpur, India; Dr. S. Lakhdar, Univ. Toulouse, France) have been established.

As a 4-year project, IODOCHEM is not sufficient to cover all the aspects of this chemistry (conception, synthesis, application, rationalisation, topological analyses and physico-chemical studies) and to give answers to all questions we are asking in this context of the development of a chiral organoiodine system as an asymmetric organocatalyst... not forgetting new questions that have arisen throughout these basic-research works. New projects will thus be submitted in response to diverse funding calls with the aim of pursuing efficiently these investigations around the hypervalent iodine chemistry.

E. Valzer (ANR funding) carried out his thesis at the University of Bordeaux and obtained in July 2022 the degree of Doctor in Organic Chemistry. He is currently post-doctoral researcher in Dr. N. Girard group (LIT, Univ. Strasbourg). He has co-authored two manuscripts published in 2023, in Eur. J. Org. Chem. and Phys. Chem. Chem. Phys., respectively; two other publications from the consortium’s works are in preparation (submissions planned to Chem. Eur. J. and Synlett, respectively).

The chemistry of hypervalent iodine compounds, also referred to as iodanes, has unarguably experienced an impressive development since the early 1990s, as evidenced by both the diversity of iodane reagents that are available today and the number of chemical transformations that these reagents can promote. The initial incitement to the development of organo-lambda3- and lambda5-iodanes (i.e., I(III)- and I(V)-based compounds), which was mainly due to their useful oxidizing properties and capacity to replace heavy-metal-based reagents in dehydrogenating and oxygenative reactions, has paved the way to the exploitation of iodanes in various metal-free reactions. Major current and competing research efforts focus on the design of chiral iodane structures for asymmetric synthesis and organoiodo-catalyzed versions thereof. While remarkable progress has been made in asymmetric oxygenation, amination and halogenation of alkenes, ketones or phenols, the use of chiral iodanes in carbon-based ligand transfer events, such as asymmetric alkynylation, cyanation, phenylation and trifluorométhylation reactions, are very rare. Some explanation can be found in the lack of chiral lambda3-iodane structures bearing carbon-based ligands, but also in the fact that better understanding/rationalization of the theoretical aspects of this iodane-based chemistry (e.g., inter alia the access of organoiodine compounds to hypervalency, the reactivity of hypervalent iodine species and the ligand exchange/coupling processes) is crucial to fully exploit the potential of chiral lambda3-iodanes in transition metal-free carbon–carbon bond-forming methodologies.
In this context, the aim of this collaborative IODOCHEM project is to develop a transition metal-free and theoretically-guided chiral lambda3-iodane-based methodology, ideally catalytic, for asymmetric C–C bond constructions of value in complex organic synthesis. The realization of IODOCHEM will thus rely on concerted efforts in synthetic organic chemistry (i.e., design, preparation and evaluation of our own iodoarenes/iodanes), quantum chemistry (i.e., DFT calculations and topological analyses of our iodoarenes/iodanes) and physical organic chemistry (i.e., X-ray and UV photoelectron spectroscopy studies of our iodoarenes/iodanes). The success of IODOCHEM will permit to establish the foundations of the future of the chemistry of hypervalent organoiodine reagents and will offer new alternative tools for transition metal-free sustainable asymmetric synthesis.