DS0304 -

Merging Enantioselective Organocascades and Superacid Chemistry: Mechanistic Investigations and New Synthetic Opportunities for Medium-Sized Heterocycles – OrgaSup

Enantioselective organocatalysis and superacid medium a new approach for the synthesis of medium-sized heterocycles.

The enantioselective synthesis of aza,oxa-bridged bicyclic derivatives is realized by an organocatalytic domino sequence and their reactivity under superacidic conditions is studied for both synthetic and mechanistic purposes.

Control of the reactivity of aza,oxa-bridged bicyclic derivatives.

The OrgaSup project deals with the control of the reactivity merging the enantioselective organocatalysis and the superacidic activation. It targets the selective elaboration of new medium-sized heterocycles in the non-racemic series, otherwise difficult to access. Our strategy is based on the « temporary-bridged » concept generated by a domino sequence initiated by an enantioselective organocatalyzed Michael addition. This give access to original oxaza-bridged derivatives suffering ring expansion by selective fragmentation of either the oxa- or aza-bridge rendering 8- to 11-membered ring heterocycles. In parallel, their reactivity under superacid activation will provide access to highly functionalized derivative, especially via selective fluorination, and will constitute an efficient tool to study the intermediate cationic species and to bring crucial mechanistic informations for the development the targeted synthetic approaches.

Bridged azepanes (C7) are regularly sent to partner 2 who studies their functionalization in superacidic conditions. Thus, two very promising results allowed access to two families of azocanes (C8) with very complementary structures through a new ring extension strategy. The scope of this new transformations and the potential of the obtained heterocycles are currently under evaluation.

- Extended scope and mechanism under elucidation for enantioselective synthesis of azepanes based on the domino sequence initiated by a Michael addition.
- Post-functionalization of bridged azepanes in superacidic conditions in two complementary families of bridged azocanes triggered by a new ring expansion (C7 to C8)
- Selective fragmentation of azepanes leading to polyfunctionalized spirocyclic structure bearing 4 stereogenic centers, through the in situ rearrangement of eight-membered heterocyclic intermediates. This reactivity was not anticipated but offers a particularly attractive potential currently under evaluation.

During this first part of the project, various new reactivities have been discovered and future investigations will focus on studying the scope of the resulting new methodologies and the synthetic potential of the original scaffolds obtained.

At this time, no publication has been concretized but based on the first results various article should be written in the coming months.

Heterocycles are among the most significant pharmaceuticals and new chiral non racemic structures are crucial for both academic and industrial developments. In this field, the direct enantioselective catalytic access to highly functionalized medium-sized heterocycles from simple acyclic substrates still constitutes a daunting challenge in modern synthetic organic chemistry.
OrgaSup will take advantage of the strong scientific complementarity between the two partners in the design of enantioselective organocascades (partner 1) and superacid chemistry including selective fluorinations (partner 2). This synergistic association will provide ground-breaking advances for mechanistic investigations opening new synthetic opportunities for the elaboration of original highly substituted and fluorinated medium-sized heterocycles. OrgaSup practical applications may be essential to address the industrial issues of the future, particularly for chemical companies interested in the development of original chiral non-racemic scaffolds.

Project coordination

Jean RODRIGUEZ (CNRS Provence et Corse _ Institut des Sciences Moléculaires de Marseille)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


CNRS DR12 _ISM2 CNRS Provence et Corse _ Institut des Sciences Moléculaires de Marseille
IC2MP - CNRS DR CTRE LIMOUSIN POITOU-CHAREN Institut de Chimie des Milieux et Matériaux de Poitiers

Help of the ANR 375,563 euros
Beginning and duration of the scientific project: September 2016 - 48 Months

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