Stereoselective transition metal-catalyzed hydrometallation of polarized C=C bonds – HydroMet

The HydroMet project is motivated by the synthetic potential of a chemo-, regio- and stereoselective hydrogermylation reaction as key step for the synthesis of more complex targets. Our approach is dedicated to the evaluation of polarized C=C bonds thanks to functional groups and/or heteroatoms in hydrometallation reaction. We hypothesize that transition metal catalysis should manage the chemo-, regio- and stereoselectivity of the reaction.

We selected ynamides as polarized alkyne and studied the hydrogermylation of these ynamides using palladium complexes. We have thus developed several sets of reaction conditions allowing perfect control of the chemo- and stereoselectivity. We also discovered that by varying the phosphorus ligand, it was also possible to control the regioselectivity and thus obtain the germylated enamides a,E and ß,E selectively in good yields. To explain this excellent regioselectivity, we performed DFT calculations, in collaboration with Prof. K. N. Houk from the University of California (USA). These calculations validated our experimental observations concerning the elementary steps of these reactions and the favored reaction pathway. These reactions take place via a hydropalladation step which is the regiodetermining step and directed mainly by the size of the phosphorus ligand used. These germylated enamides were subsequently used in Bischler-Napieralski-type cyclization for the synthesis of germylated isoquinolinones.

The current evolution of the project concerns the hydrometallation of alkynes polarized by electron-withdrawing groups with comparison of the electronic and steric influence of these groups on the regioselectivity of the reaction.

V. Debrauwer, A. Turlik, L. Rummler, A. Prescimone, N. Blanchard, K. N. Houk, V. Bizet J. Am. Chem. Soc. 2020, 142, 11153-11164 (https://pubs.acs.org/doi/10.1021/jacs.0c03556).

The ultimate goal in developing new synthetic methodologies in organic chemistry is to create molecular complexity from simple organic fragments in a minimum number of steps. Transition metal catalysis is one very powerful technique allowing difficult transformations by lowering the energy barrier and controlling the chemoselectivity and the stereochemical outcome of the reaction. During the last decades, transition metal catalysis has been well recognized by the attribution of several prestigious Nobel prizes in 2001, 2005 and 2010. Alkynes are reactive and easily accessible organic functional groups which can be functionalized by various transition metal catalyzed transformations such as pericyclic reactions, carbonylation, hydroarylation, hydroamination, and many others. However, due to their very weak polarization, the functionalization of simple alkynes is difficult to control with a high level of regio- and stereoselectivity. The HydroMet project belongs to the "Challenge 3: stimulate industrial renewal" and more particularly to axis 3: "Molecular chemistry, sustainable chemistry and associated processes" (CES 07). With this project, we would like to investigate further the transition metal-catalyzed hydrometallation of polarized triple C=C bonds and develop efficient methodologies to make this reaction regio- and stereoselective. For this project, we are particularly interested by elements from column 14 (C, Si, Ge, Sn); two metalloids (Si, Ge) and one metal (Sn) which are known in the literature to perform hydrometallation reactions of C=C bonds (with 2), but this reaction suffers from very low selectivity or is totally biased by the substrate making this reaction poorly attractive for further derivatization. The interest for germanium in organic chemistry has been underestimated since the eighties because this element was always compared to the other elements of column 14 (C, Si, Ge, Sn), and it was less efficient and/or less reactive than Si or Sn analogues in various synthetic transformations. In contrast, Ge derivatives are much more stable and non-toxic. Nowadays, germanium is widely used in material science, mainly as germanium oxide: in optic fiber (35%), in the optic infrared field (20%), in electronics (20%) and in catalysis (15%). Recently, a renewed interest for germanium in organic chemistry is rising since it proved to be a highly potent alternative in drug design. Indeed, replacement of a C atom by a Si or Ge atom gives access to bioisosteres with minimal changes in chemical structure, but with enhanced or reduced biological and/or physical properties. The objective of the HydroMet project is to broaden the scope of the hydrometallation reactions of polarized triple C=C bonds by developing regio- and stereoselective synthetic methods as key steps for the synthesis of more complex molecules.