Frédéric Frébault

Catalytic Asymmetric Diastereodivergent Deracemization

Your wish is my command: Deracemization is a powerful strategy wherein a racemate is converted into a 100 % yield of a single enantiopure product. A new concept in catalytic deracemization is presented, in which a racemate with n stereogenic elements can be selectively converted into each one of 2(m) (m = number of chiral centers of the product) different enantiopure products, by simple tuning of the reaction conditions.

Stereoselective Synthesis of Dienyl-Carboxylate Building Blocks: Formal Synthesis of Inthomycin C

A direct synthesis of stereodefined halodienes is reported. Those key building blocks enable a concise access to polyenic products, as demonstrated in a modular synthesis of Inthomycin C.

An Atom-Economical and Stereoselective Domino Synthesis of Functionalised Dienes

Open sesame: A direct synthesis of functionalised and stereodefined dienes, relying on a domino allylic alkylation/electrocyclic ring-opening sequence, is reported. This method allows concise access to doubly vinylogous esters. A further systematic study of ring-opening rates of carbon-substituted cyclobutenes allowed the design of substrates amenable to sequential pericyclic reactions (see scheme).

A Concise Access to 3-Substituted 2-Pyrones

The development of a modular synthesis of 3-substituted-2-pyrones is described. The attainment of this strategy hinges on a new electrophilic pyrone derivative which can be readily prepared on a multigram scale and which performs very competently in metal-catalyzed cross-coupling reactions with a variety of nucleophiles.

Total synthesis and structural revision of the piperarborenines: when photochemistry meets C-H activation.

The piperarborenines, isolated from the stems of the creeping shrub Piper arborescens, are members of a class of quasi-dimeric monoterpene alkaloids characterized by a tetrasubstituted cyclobutane ring. Closely related to the piperarborenines, but structurally more complex, is the incarvillateine family of natural products, in which the dihydropyridone is replaced by an elaborate bicyclic piperidine moiety containing five contiguous stereocenters (Figure 1). Interestingly, structure–activity relationship studies performed on 3 and derivatives thereof suggest that the cyclobutyl moiety plays a crucial role in the expression of biological activity. In 2004, Kibayashi et al. described the first enantioselective total synthesis of ( )-incarvillateine (3). A few years later, Bergman and Ellman, as well as Jia and co-workers, reported independent total syntheses using a similar approach to construct the cyclobutane core. The synthetic focus of these different strategies was placed on the assembly of the bicyclic alkaloid moiety, whilst the construction of the tetrasubstituted cyclobutane ring relied on Kibayashi s elegant topochemical [2+2] photodimerization of the ferulic acid derivative 4 (Scheme 1). Key to the success of this strategy was the realization that subtle structural factors, at loci as remote from the reactive center as the oxygen substituents in the aryl moiety of 4 (cf. tosyl substituent), can have a dramatic impact on the crystal packing arrangement and thus on the outcome of the photodimerization process.

Direct synthesis of stereodefined and functionalized dienes as valuable building blocks.

We have reported a direct and stereoselective synthesis of functionalized dienoic carboxylates from the simple bicyclic lactone 1. The use of oxygen- or nitrogen-based nucleophiles in a domino allylic alkylation/4π-electrocyclic ring opening affords reliable access to dienes with interesting functionalities. Alternatively, halide substitution offers synthesis of other classes of functionalized dienoic acids. Herein, we demonstrate the utility of such dienoic products as key building blocks in various transformations as well as natural product synthesis.