Chiral Dienolates for Organocatalytic control over multiple stereogenicities in Atroposelective Synthesis – DINATROP

Organocatalysis now belongs to the classic devices for the chemist’s “green toolbox”. In the context of enantioselective synthesis, if the control of central chirality is a well-established field, the same is not true for axial chirality. Therefore, the development of efficient methodologies to address the control of axial chirality is highly desirable and still timely. This project proposes a general strategy based on the use of chiral activated dienolates as a polyvalent synthetic platform for the rapid and highly stereocontrolled preparation of underexplored atropisomer families featuring multiple stereogenicities. This strategy is based on the reactivity of intermediates activated by enantioselective organocatalysis, that could be involved in formal (4 + 2) and (2 + 3) cyclizations, as dienolate or enolate partners, respectively. Firstly, the vinylogous character will be exploited in two complementary addition/substitution domino sequences giving access to atropisomers by de novo construction of an aromatic ring. This general approach should allow to meet the challenges of the enantioselective synthesis of new (hetero)biaryl atropisomers with multiple stereogenic axes, taking advantage of central/axial-to-axial chirality conversion (CACC) processes. It should also give access to originals atropisomers featuring up to two five-membered rings connected by a C–N axis, or more challenging N–N axis, via desymmetrization of prochiral substrates. Complementarily, exploiting the less explored and more challenging potential enolate reactivity could deliver a direct access to functionalized non-biaryl atropisomers of the styrenic series, by reaction with 1,3-dipolarophiles, involving CACC. In collaboration with physical and theoretical chemists, each new atropisomer will then be completely characterized from its chiroptic properties point of view, with notably experimental determination of the barriers to diastereo- and enantiomerization via chiral HPLC.