General
The total synthesis of natural products and analogues proved over the years to be a very reliable method for the discovery of new drugs. Due the structural complexity of many natural products, efficient synthetic methods are required to synthesize them in order to make them (as well as analogues) available to scientists involved in drug discovery. Our research program aims at finding methods and strategies that can be applied for efficient synthesis of different classes of products possessing an interesting biological profile. Development of processes involving radical chemistry, organometallic chemistry and enantioselective catalysis will be investigated. Our research focus on increasing the efficiency of target molecule synthesis by minimizing the number of synthetic steps, by opening new synthetic pathways, and by developing environmentally friendly reagents.
Radical fluorination
Radical fluorination has been known for a long time, but synthetic applications were severely limited by the hazardous nature of the first generation of reagents such as F2 and the strongly electrophilic nature of the second generation of reagents such as N-fluorobenzenesulfonimide (NFSI) and Selecfluor®. Here, we report the preparation, use and properties of N-fluoro-N- arylsulfonamides (NFASs), a class of fluorinating reagents suitable for radical fluorination under mild conditions. Their N–F bond dissociation energies (BDE) are 30–45 kJ mol−1 lower than the N–F BDE of the reagents of the second generation. This favors clean radical fluor- ination processes over undesired side reactions. The utility of NFASs is demonstrated by a metal-free radical hydrofluorination of alkenes including an efficient remote C–H fluorination via a 1,5-hydrogen atom transfer. NFASs have the potential to become the reagents of choice in many radical fluorination processes.
DOI: 10.1038/s41467-018-07196-9
Radical Chain Repair
The concept of repair is widely used by nature to heal molecules such as proteins, lipids, sugars and DNA that are damaged by hydrogen atom abstraction resulting from oxidative stress. We have shown that this strategy, rather undocumented in the field of synthetic organic chemistry, can be used in a radical chain reaction to enable notoriously intractable transformations. By overcoming the radical chain inhibitor properties of substituted alkenes, the radical-mediated hydroalkylation of mono-, di-, tri-, and even tetrasubstituted unactivated olefins could be performed under mild conditions. With a remarkable functional group tolerance, this reaction provides a general coupling method for the derivatization of olefin containing natural products.
DOI: 10.1126/sciadv.aat6031.
Thiol-ene coupling (TEC) reactions emerged as one of the most useful processes for coupling different molecular units under reaction mild conditions. However, TEC reactions involving weak C–H bonds (allylic and benzylic fragments) are difficult to run and often low yielding. Mechanistic studies demonstrate that hydrogen-atom transfer processes at allylic and benzylic positions are responsible for the lack of efficiency of the radical-chain process. These competing reactions cannot be prevented, but we reported a method to repair the chain process by running the reaction in the presence of triethylborane and catechol. Under these reaction conditions, a unique repair mechanism leads to an efficient chain reaction, which is demonstrated with a broad range of anomeric O-allyl sugar derivatives including mono-, di-, and tetrasaccharides bearing various functionalities and protecting groups.
DOI: 10.1002/Anie.201309984
Water as a Source of Hydrogen Atom in Radical Reactions
This field of research has attracted a lot of attention of chemists involved in radical chemistry and in organic synthesis since the discovery by Wood and us in 2005 that water and alcohols in the presence of organoboranes may become a source of hydrogen atoms in radical reactions. However, a detailed mechanistic understanding of this process was missing. During the last five years, we have first examined the role of equilibrium associations on the hydrogen atom transfer from the triethylborane−methanol complex. Following this work, we have completely revised the mechanism of Wood reaction demonstrating that the reaction involving xanthates were in fact catalyzed by a catalytic amount of a thiol generated by hydrolysis of the xanthate. With this knowledge, we have developed a mild method for the deuteration of alkyl iodides with D2O. The publication of this work has attracted a lot of attention from the pharmaceutical industry (work highlighted on the platform F1000Prime dedicated to identifying great research in biology and medicine) since such mild and cheap deuteration methods of utmost importance for the preparation of deuterated drugs.
DOI: 10.1021/Jo302576c, DOI: 10.1021/jacs.7b12105
Radical Deiodination using catechols as sources of hydrogen atoms
We have demonstrated, that when used with trialkylboranes, catechol derivatives, which are low-cost and low toxicity, are valuable hydrogen atom donors for radical chain reactions involving alkyl iodides and related radical precursors. The system 4-tertbutylcatechol/triethylborane has been used to reduce a series of secondary and tertiary iodides, a xanthate, and a thiohydroxamate ester. Catechol derivatives are right in the optimal kinetic window for synthetic applications, as demonstrated by highly efficient radical cyclizations leading to the formation of quaternary centers. The H-donor properties of catechol derivatives can be fine-tuned by changing their substitution pattern.
DOI: 10.1002/ange.201604950
Synthesis of natural products
New strategies involving radical cascade reactions to access alkaloids from the mitomycin and the aspidospermia family of alkaloids have been developed. Both cascade processes involve an aryl azide as a radical trap.
DOI: 10.1021/acs.orglett.6b00306, DOI: 10.1021/jo4009904
A general strategy for the synthesis of aignopsanes, a new family of sesquiterpene natural products of marine origin, has been developed. The total synthesis of several members of this family of natural products such as (+)-aignopsanoic acid A has been achieved. (+)-Microcionin-1, a structurally related furanosesquiterpene was also synthesized and converted by a simple oxidation process to aignopsanoic acid A. This transformation supports our hypothesis that (+)-microcionin-1 may be an intermediate in the biosynthesis of aignopsanes.
DOI: 10.1002/chem.201404766.
Radical mediated C–H activation
An efficient and simple radical chain reaction to convert terminal alkynes into arenesulfonylmethylcyclopentanes has been developed. The reaction involves a radical addition– translocation–cyclization process and necessitates solely the use of readily available arenesulfonyl chlorides in tetrahydrofuran.Interestingly, this radical-mediated C–H activation process took place with a high level of retention of configuration when an enantiomerically pure starting material was used.
DOI: 10.1002/anie.201707791
Boron chemistry
An intramolecular cyclopropanation reaction involving B-(1-chloroalkyl)catecholborane intermediates generated from 1,4-dienes through hydroboration with catecholborane and Matteson homologation was developed. This unprecedented sequential procedure leading to bicyclo[3.1.0]hexanes involves the formation of three new sigma C–C bonds at the same carbon atom. A mechanistic study supports the involvement of carbocationic intermediates.
DOI: 10.1002/anie.201511100
An operationally simple protocol to affect a radical addition to alkenylboronates that spontaneously undergo a [1,2]‐metalate shift is described. Overall, the reaction is a three‐component coupling of an organolithium, alkenylboronic ester, and halide which takes place with broad scope and good to excellent yields. Experimental mechanistic investigations support the formation of a boron inverse ylid intermediate.
DOI: 10.1002/chem.201802384