Blanc SIMI 7 - Blanc - SIMI 7 - Chimie moléculaire, organique, de coordination, catalyse et chimie biologique

Enantioselective synthesis of furan and pyridine atropisomers by central-to-axial chirality interconversion – SynthAx

Combinaison of organocatalysis and chirality conversion: Atroposelective synthesis of heterobiaryls

New heteroatropisomeric derivatives of the 4-aryl-furan or -pyridine series are obtained by organocatalysis allowing the control of central chirality, followed by an oxidative aromatization step triggering the formation of the corresponding atropisomers with high levels of central to axial chirality conversions.

Atropsiomeric enantiomerically enriched 4-arylfurans or -pyridines

The SynthAx project deals with the chirality control of complex atropisomeric molecular scaffolds by central-to-axial chirality conversion. Our innovative approaches are built on enantioselective catalysis for the control of central chirality coupled with an oxidative aromatization revealing the axial chirality. The main objective is the atroposelective construction of optically active heterobiaryl derivatives of the 4-aryl-furan and –pyridine series that constitute a real synthetic challenge. This is mainly due to the lack of efficient and general approaches together with lower barriers to rotation found especially with five-membered ring containing analogs. A physico-chemical study using chiral HPLC, is used to determine the key structural elements required to reach room temperature stable atropisomers. <br />The targeted applications are directed both, to the total synthesis of (+)-streptonigrine, a naturally occurring alkaloid with a 4-arylpyridine nucleus featuring interesting antitumoral and antibiotic properties and to the development of new organocatalysts by simple post-transformations.

The optimization of the two key steps (organocatalysis, oxidation) is combined with a physico-chemical study based on chiral HPLC allowing the experimental determination of the barriers to rotation of the products, to determine the crucial structural elements required for the synthesis of optically active 4-arylfurans and -pyridines. NMR studies at variable temperatures have allowed to propose a model to rationalize the observed phenomenon of central-to-axial chirality conversion.

The SynthAx project is centered in the field of chirality control of complex atropisomeric molecular scaffolds that constitute a daunting challenge in modern synthetic organic chemistry. It exploits the concept of central-to-axial chirality conversion for the atroposelective synthesis of heterobiaryl derivatives based on enantioselective organocatalyzed reactions (Michael addition and Friedel-Crafts reaction). A physico-chemical study using chiral HPLC, is used to determine the barriers to rotation in the racemic series and select the key structural elements required to reach room temperature stable optically active atropisomers in the 4-aryl-furan and –pyridine series with excellent conversion percentages. Preliminary studies concerning the synthetic utility of 4-arylpyridine atropisomers have allowed to propose a synthetic plan for the first enantioselective synthesis of naturally occurring alkaloid (+)-streptonigrine having interesting biological activities.

A rapid acces to some new potential organocatalysts should be possible by simple adapting our atroposelective furan methodology with the incorporation of a phosphonate function in the substrate, followed by a subsequent hydrolysis delivering an optically active axially chiral phosphoric acid. Moreover, an extension of the strategy has already resulted in the proposal of an innovative access to configurationnally stable [4]- and [5]heterohelicenes that are difficult to obtained by standard approaches due to their low barriers to rotation (lower than 50 kJ.mol-1). Our proposal is based on the concept of central-to-helical chirality conversion using a bidirectional organocatalyzed enantioselective Friedel-Crafts leading to centrally chiral bis-dihydrofuran intermediates. The preliminary results are very encouraging and we have designed a new way for increasing the conformational stability by adding either one central heterocycle of by preparing sulfur analogs via an alternative pathway. Indeed, replacing the furan ring by a thiophene results in a significant increase of the barriers to enantiomerization. These new directions to access small heterohelicenes have been the subject of a new project proposal submitted for evaluation to ANR-2018 call for projects within the DEFI 3 “Renouveau Industriel”.

During the 1st year of the project, after an accurate analysis of the state of the art concerning the field of the control of axial chirality, we have published a « Highlight » (Angew. Chem. Int. Ed. 2014, 53, 10861) dealing with chiral polyaromatic structures. The experimental results on the synthesis of optically active 4-arylpyridines and 4-arylfurans by a new central to axial chirality conversion strategy have been published in two subsequent articles (Angew. Chem. Int. Ed. 2016, 55, 1401; J. Am. Chem. Soc. 2017, 139, 2140) resulting in the revision of erroneous results from the literature dealing with the organocatalyzed enantioselective synthesis of 4-aryl-1,4-dihydropyridines (Org. Lett. 2017, submitted). Finally, our own expertise and a critical analysis of the state of the art have resulted in a « Feature Article » dealing with the recent progresses in the énantioselective synthesis of atropisomers featuring a five-membered ring (Chem. Comm. 2017, 53, 12385). Finally, based on the experience acquired during the project combined with a critical analysis of the state of the art we havae just submitted a review proposal dealing with the conversion of chirality during aromatization (Chem. Soc. Rev. 2017, submitted).

The control of chirality in organic molecules is of prime importance in modern organic synthesis. This is particularly true for pharmaceutical and agrochemical industries and it is well established that enantiomers may have significant different biological activities and toxicities. If control of central chirality is now well understood, very few methods in comparison allow the control of axial chirality. This is the major issue we intend to address in this project and we would like to focus our efforts on the asymmetric synthesis of hetero-biaryls atropisomers thanks to an innovative central-to-axial chirality interconversion strategy.
In this SynthAx project, we want to address the asymmetric synthesis of three classes of hetero-biaryl atropisomers thanks to the complementary expertise of the STeRéO and Chirosciences groups, belonging to the “Institut des Sciences Moléculaires de Marseille (iSm2)”, respectively in the fields of organic synthesis (heterocycles synthesis, enantioselective organocatalysis, total synthesis of natural products) and chirality (enantioselective chromatography, chemical stereodynamics, physical analysis of chiral molecules). The central focus of our proposal is to study the chirality interconversion from one or several stereogenic centers created during an asymmetric organocatalytic Michael addition, to a chiral axis between two sterically hindered aryl during an aromatization process. Our project is divided in three parts, each of them directing at the synthesis of a specific class of hetero-biaryl atropisomers: 4-arylfurans, 2-arylpyridines and 4-arylpyridines. The results will be valorized in different applications such as the first enantioselective total synthesis of (+)-streptonigrin, a natural product possessing a stereogenic axis, and the design and utilizations of two new classes of organocatalysts (N-heterocyclic carbene and Brønsted acid).

Project coordinator

Monsieur Jean RODRIGUEZ (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.


iSm2 Institut des Sciences Moléculaires de Marseille

Help of the ANR 479,120 euros
Beginning and duration of the scientific project: September 2013 - 48 Months

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