Sulfoxide- a novel strategy for the asymmetric C-H bond activation – Sulf-As-CH

Firstly, a direct functionalization of “activated” C-H bonds at allylic, benzylic positions or C-H bonds of cyclopropane derivatives will be studied. Subsequently our attention will turn towards even more ambitious targets such as activation of secondary and tertiary C-H bonds. With regard to the low reactivity of such aliphatic C-H bonds and possible difficult chiral induction, a design of bicoordinating sulfoxide-based directing groups is suggested. The introduction of such bidentate chiral auxiliary could simultaneously enhance the reactivity of the system and improve the chiral environment around the catalyst boosting stereodiscrimination.

-An original and recyclable chiral bidentate aniline-sulfoxide-based directing group has been developed. This auxiliary allows challenging stereoselective Pd-catalyzed direct functionalization of small cycloalkanes via C-aryl and C-alkyl bond formation. Although moderate diastereoselectivities are observed, both optically pure enantiomers of the highly functionalized products can be obtained separately by simple silica gel chromatography and cleavage of the chiral auxiliary. This strategy was further applied to the preparation of enantiomerically pure 1,2,3-substituted cyclopropane carboxylic acid derivatives, with 3 stereogenic centers, bearing both alkyl and aromatic substituents - molecular scaffolds not yet reported in the literature. The synthetic utility of this approach is validated as the chiral auxiliary is readily cleaved and recovered posteriori to the C-H activation step, without deterioration of its optical purity. Finally, an unprecedented palladacyclic intermediate generated via C-H activation of the cyclopropane moiety has been isolated and fully characterized. Initial DFT calculations shed additional light on the reactivity of this original intermediate.
-We also developed an original strategy towards direct arylation of aliphatic chains at ß–methyl position based on the use of amide-sulfoxide bicoordinat-ing directing group. Although moderate to high chiral induction (up to 9:1 dr) is achieved, diastereomerically pure compounds may be afforded by simple separation of diastereomeric products by silica gel chromatography. Accordingly, this reaction allows preparation of a large scope of high-value scaffolds in synthetically useful yields. A recyclable character of our chiral auxiliary brings an additional benefit. The potential of this methodology to build up original molecules via sequential diarylation and ex-pedient (two steps) synthesis of a biologically active compound are further disclosed.

Cu-catalyzed sulfoxide directed C-H activation.
our efforts will focus on the arylation reaction, but also on the direct C-N and C-O bond formations.
An important part of our efforts will concern mechanistic investigations.

1. Enantiopure sulfinyl aniline as removable and recyclable chiral auxiliary for asymmetric C(sp3)-H bond activation. Jerhaoui, S.; Chahdoura, F.; Rose, C.; Djukic, J-P.; Wencel-Delord, J.; Colobert, F. Chemistry, A European Journal 2016, 22, 17397-17406.
2. Stereoselective Sulfinyl Aniline Promoted Pd-catalyzed C-H Arylation Of Aliphatic Substrates. Jerhaoui, S.; Djukic, J-P.; Wencel-Delord, J.; Colobert, F. soumis à ACS Catalysis
Communications-conférences
1. Conférence-FACS XVI Santa-Barbara USA 19-24 juin 2016-Enantiopure sulfoxide, an efficient chiral directing group for stereoselective C-H bond activation.
2. Conférence-Strasbourg-Riken 20th Anniversay Workshop Strasbourg 26-28 octobre 2016 - Asymmetric C-H bond functionalization towards central and axial chirality.
3. Conférence-HKBU- Strasbourg Joint Chemistry Symposium Hong-Kong 10 février 2017 - Asymmetric C-H bond functionalization towards central and axial chirality.
4. Communication orale aux Journées de Chimie Organique à Palaiseau le 8 septembre 2016 – C(sp3)-H functionalization of cyclopropane derivatives using a bidentate directing group bearing a chiral sulfoxide
5. Séminaire CSIR-Indian Institute of Chemical Technology Hyderabad 21 octobre 2016 - Sulfoxide as handful tool for stereoselective C-H activation.
6. Séminaire Indian Institute of Technology IIT Bombay 27 octobre 2016 - Sulfoxide as handful tool for stereoselective C-H activation.
7. Séminaire CSIR-National Chemistry laboratory Pune 25 octobre 2016- Sulfoxide as handful tool for stereoselective C-H activation.
8. Séminaire 1st Chaos Cost Meeting Vienna 26 septembre 2016 - Sulfoxide as handful tool for stereoselective C-H activation.
9. Séminaire Astrazeneca, Gothenburg, 1er mars 2017 - From simple substrates to complex (chiral) molecular scaffolds by means of various activation modes of « latent » C-H bonds »

Over the decades non-activated C-H bonds have been considered as dormant functionalities, hardly exploitable in the context of multistep synthesis of complex scaffolds. However, since few years organic chemistry has been progressively metamorphosed by the tremendous discoveries in the C-H bond activation field. Indeed, the ingenious development of numerous catalytic systems unlocked the door towards direct metalation of some C-H bonds. Hence, more efficient transformations compatible with non-prefunctionalized substrates and limiting waste generation might be designed. Moreover, unprecedented retrosynthetic disconnections might be envisioned. A general use of the C-H activation is yet hampered by the need for finely designed starting material bearing, often hardly transformable, coordinating groups. Besides, a chirality induction during such transformations is also extremely appealing and ambitious. The aim of the herein presented project, Sulf-As-CH, is to address both of these challenges. We envision using a “readily removable” sulfoxide moiety as both directing group and chiral auxiliary. Encouraged by our pioneering work on diastereoselective Pd-catalyzed C(sp2)-H direct functionalization, we propose to study a panel of different Pd-catalyzed transformations, focusing, in particular, on very challenging activation of C(sp3)-H bonds.

Firstly, a direct functionalization of “activated” C-H bonds at allylic, benzylic positions or C-H bonds of cyclopropane derivatives will be studied. Subsequently our attention will turn towards even more ambitious targets such as activation of secondary and tertiary C-H bonds. With regard to the low reactivity of such aliphatic C-H bonds and possible difficult chiral induction, a design of bicoordinating sulfoxide-based directing groups is suggested. The introduction of such bidentate chiral auxiliary could simultaneously enhance the reactivity of the system and improve the chiral environment around the catalyst boosting stereodiscrimination.

The second part of this project concerns Cu-catalyzed sulfoxide directed C-H activation. The application of less expensive Cu catalyst in the context of C-H activation is of growing interest and some promising catalytic systems have already been developed. However, for the best of our knowledge, the chirality induction during such transformations remains unprecedented. Confident about a possible coordination between hard oxygen atom of the sulfoxide moiety and hard Cu-metal, our efforts will concern the design of unprecedented Cu-catalyzed diastereoselective transformations. Noteworthy, we hypothesize that different metallacyclic intermediate should be favoured in the presence of either soft Pd-catalyst or hard Cu-metal and therefore complementary reactivities should be achieved leading to a possible catalyst-directed switch of regioselectivity. In this context our efforts will focus on the arylation reaction, but also on the direct C-N and C-O bond formations.

The ambition of Sulf-As-CH is however to go beyond the development of new transformations. An important part of our efforts will concern mechanistic investigations. Indeed, a fundamental comprehension of the direct C-H transformations, and in particular, stereoselectivity issues, is still rather limited. Moreover, mechanistic considerations of the Cu-catalyzed direct metalation is almost uncharted field. We propose therefore to combine the experimental work and the in-depth mechanistic studies. In particular isolation of key metallacyclic intermediates, kinetic studies and DFT calculations will be undertaken to put some light on the nature of the stereodiscriminant step. Likewise, modelling will be undertaken to design promising bicoordinating sulfoxide-based directing groups. Such intimate combination of experimental and mechanistic studies could subsequently serve as the springboard for more rational design of original asymmetric C-H activation transformations.