Boron Mediated Reactions for the Total Synthesis and the Late Stage Modification of Natural Products

The total synthesis and the late stage modification of natural products, analogues, and derivatives proved over the years to be one of the most reliable method for the discovery of new drugs. Our research program aims at finding methods and strategies that can be applied for efficient synthesis or editing of different classes of natural products and related biologically relevant compounds. Development of processes involving mainly radical chemistry have been selected for their mildness, broad functional group compatibility, and high versatility. The research will focus on increasing the efficiency of the syntheses by minimizing the number of synthetic steps, by opening new reaction pathways, by using mild reaction conditions compatible with a broad range of functional groups, and finally by developing environmentally friendly reagents. This last point incited us to choose to work with organoboron derivatives since, at the end of the processes, all the boron species are transformed into environmentally benign boric acid. The project has been organized according to the role played by the boron derivatives in the process. In the first part, the organoboron species are used as a source of radicals. In the second part, boron moieties are substituent enabling different types of chemistry but they are not directly used in the radical generation step.

Generation of radicals from organoboron species.
Several approaches have been developed over the years to run radical processes: non-chain reactions based on the persistent radical effect involving homolytic cleavage of a weak bond, single electron transfer processes using stoichiometric or catalytic redox active agents, photochemistry and chain processes. All these approaches are complementary and have led to significant synthetic methods. Chain reactions are particularly attractive since, beside the reagents, they only require a substoichiometric (often tiny) amount of a radical initiator to take place. The classical methods for the generation of alkyl radicals involved in a chain process is based on alkyl halides, chalcogenides, xanthates, and Barton esters. Organoboron derivatives represents a very general alternative and have been used successfully for the generation of alkyl radicals via a nucleohomolytic substitution process. For instance, trialkylboranes provide efficiently alkyl radicals but application of this type of precursor is limited to the generation of simple alkyl radicals. We have demonstrated that catechol alkylboronic esters (R–Bcat) are a very efficient source of alkyl radicals and recently radical generation was extended to the air stable and easy to handle pinacol boronic esters. Our goal is now to extend the radical generation to a broad range of functionalized radicals that can be used for the synthesis of functionalized complex (often polycyclic) frameworks. Radical chain processes involving biomimetic sources of hydrogen atoms such as catechol and thiols will be used to perform inter- and intramolecular hydroalkylation of alkenes. The development of an enantioselective hydroalkylation of unactivated alkenes is foreseen by using a highly efficient peptide-thiol catalyzed process. In another register, the fluorination of unreactive aliphatic compounds will be examined using a new class of radical fluorinating agents that we have recently developed. This process will be highly attractive for late stage modification of natural products and analogues.

Reactions involving borylated substrates
Boron containing radical and radical traps will be developed in order to couple unique features of radical chemistry, such as cyclizations, ring opening, and intermolecular addition to alkenes, with the extraordinary rich chemistry of organoboron compounds. The combination of organoboron chemistry and radical chemistry will permit the development of unique intramolecular cyclopropanation reactions giving access to the synthesis of unusual polycyclic terpenoids containing fused 3-membered ring systems. A simple procedure allowing to selectively edit complex natural products containing alkene moieties will be developed. The modifications will include simple hydromethylation as well as more sophisticated modification involving for example unique reactions enabled by the boron atom such as the Suzuki-Miyaura cross-coupling reaction and the allylboration. Starting from simple alkenylbroronic esters, a versatile multicomponent reaction (expanded Zweifel reaction) for the synthesis of polysusbtituted alkenes will be developed. Boron chemistry is particularly attractive for application in asymmetric synthesis and is expected to offer some unique opportunities for the control the relative and absolute configuration of products resulting from radical reactions.