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Thèmes de recherche

(english version below)

Nos projets de recherche ont pour but de développer des stratégies en synthèse organique. Pour y arriver, nous comptons identifier de nouveaux moyens d'accéder rapidement à des molécules polycycliques complexes à partir de précurseurs acycliques simples. Ces précurseurs comporteront des unités réactives, disposées sur des embranchements, utilisées pour le repliement de la molécule en systèmes polycycliques. L'étape-clé fera donc appel à des réactions en cascade pour générer de manière sélective plusieurs types de squelettes de produits naturels, d'où la généralité de notre programme de recherche.

 La synthèse totale occupera donc le coeur de nos investigations, avec des buts précis d'élaborer des stratégies générales et innovatrices. Les stratégies que nous entendons développer visent de larges applications pouvant mener à des composés naturels et/ou non naturels importants d'un point de vue médicinal. Au fil des ans, nous avons développé plusieurs stratégies de cyclisations en cascade telles que (A) Cyclisation de Vilsmeier-Haack et cycloaddition (3+2) d'ylure d'azométhine en séquence, (B) Cyclisations de Vilsmeier-Haack et de Mannich en tandem, (C) cascade d'activation d'acide aminé - cycloaddition de münchnone - ouverture de cycle et (D) cycloadditions cétène-alcyne et cétène-alcène intramoléculaires.

Projets en cours

There is an undeniable interest from organic chemists and from the pharmaceutical industry to access complex alkaloids with short syntheses. While the latter is interested in the fascinating wide range of biological properties of alkaloids, the former are rather interested in finding new routes to access otherwise almost non available natural products from nature. However, classical syntheses often involve a large number of steps principally due to a sequential preparation of each cycle of the molecule. It is well established that one-pot reaction cascades or sequences are an excellent avenue to increase molecular complexity in a single operation and in a single reaction vessel. However, there are enormous challenges associated with this strategy: because all required functional groups must be present on the substrate for the key transformation, we have to address issues of chemoselectivity, diastereoselectivity, and regioselectivity. Over the past years, we generated the skeletons of a wide span of alkaloids of biological interest by successfully developing several reaction cascades such as (A) Sequential Vislmeier-Haack cyclization and azomethine ylide intramolecular (3+2) cycloaddition, (B) Tandem Vilsmeier-Haack and Mannich cyclizations, (C) Cascade of amido-acid activation – münchnone cycloaddition – ring-opening, and (D) Intramolecular ketene-alkyne and ketene-alkene cycloadditions.

Cascade of Iminium Cyclizations

In an effort to develop new ways to synthesize polycyclic alkaloids, I opted to use the great reactivity of iminium ions generated from amides. Because of their higher oxidation state, such iminiums show a yet unexploited advantage of generating another reactive product after the nucleophilic (Vilsmeier-Haack) cyclization, namely an iminium ion of lower oxidation state. Although conditions for amide activation and subsequent nucleophilic cyclization are usually not compatible with tethered nucleophiles, we reported the successful intramolecular addition of tethered non-aromatic carbon nucleophiles onto activated amides for the generation of enaminals (Org. Lett. 2005, 7, 4431). The latter are known useful moieties for the synthesis of important alkaloids.

My group also reported an expeditious application of our method to the total synthesis of a small alkaloid: tashiromine (J. Org. Chem. 2006, 71, 704). The primary impact of this contribution is the tremendous potential that arises from the iminium ion produced after the Vilsmeier-Haack cyclization: we are now using this iminium ion in subsequent cyclization reactions (see the two following contributions) to further increase the level of molecular complexity generated in a single operation. Moreover, along the way, we also had to develop a new method for the preparation of aldehyde enamines, among the tethered nucleophiles that we tested in the Vilsmeier-Haack cyclization. Aldehyde enamines are extremely sensitive and our method proved to be general and highly chemoselective (J. Org. Chem. 2006, 71, 7481). Future work in this project is aimed at developing the intermolecular version to create asymmetric all-carbon quaternary centers.

Model study and asymmetric total synthesis of Virosine A.  In this reaction cascade, we took advantage of the iminium ion generated after the first cyclization (Vilsmeier-Haack) to perform a Mannich cyclization in a one-pot procedure. Molecular complexity is thus rapidly built through this novel synthetic strategy, as exemplified with the synthesis of substituted quinolizidines (Org. Lett. 2011, 13, 4268) bearing either a tertiary or even a quaternary center at the ring junction. We also applied this strategy to the total synthesis of securinol B (and related Securinega alkaloids). This compound bears an uncommon quinolizidine skeleton fused to the azabicy-clo[2.2.2]octane subunit, is of very limited supply and has never been synthesized before. My group successfully performed the key transformation to generate two cycles of the bridged tetracyclic structure in only one operation (Org. Lett. 2008, 10, 4501) and we completed synthesis very recently in only 13 steps, in a non racemic form (J. Org. Chem. 2012, 77, 3215). This constitutes quite a formidable demonstration of the efficiency of this reaction cascade towards the construction of complex products.

Tandem Amido-Acid Activation – Münchnone Cycloaddition –
 Hemiaminal Cleavage
This synthetic strategy uses a one-pot sequence of chemoselective activation of amido acids, münchnone gerenation, intramolecular (3+2) cycloaddition and ring opening (J. Org. Chem. 2007, 72, 1104). The products are either iminium-carboxylate ylides that could be further reduced to bicyclic amino alcohols, or pyrrole-containing bicyclic systems. These bicyclic motifs are extremely abundant in alkaloids’ skeletons of high pharmaceutical interest. The study of substitution effect on the münchnone-alkene 3+2 cycloaddition brings a better understanding of that reaction and of münchnone reactivity in general. Since münchnones have captivated the interest of many renowned researchers for the construction of natural products, these new insights on their reactivity should further expand their utilization.

Sequence of Vislmeier-Haack Cyclization – Azomethine Ylide Intramolecular Cycloaddition
In the pursuit of synthetic efficiency, my research group developed an innovative one-pot transformation of linear substrates into bi- and tricyclic adducts using a cascade of Vilsmeier-Haack cyclization and azomethine ylide cycloaddition. Despite the high density and variety of functional groups on the substrates, the sequence occurred with perfect chemoselectivity with good to excellent yields (Org. Lett. 2008, 10, 4939).

The versatility of our planned synthetic strategy is noteworthy. The branches bearing the nucleophile and the dipolarophile can be attached in many different ways onto the amide group. Upon the proposed key transformation, these various possible assemblies will lead to very diverse skeletons that belong to a wide range of alkaloid families of pharmaceutical interest. Because of this new way to generate azomethine ylides, we were even able to fully control the order of reaction in the cascade, forcing the cycloaddition prior to the nucleophilic cyclization (Org. Lett. 2010, 12, 1396). This subtle change led to exactly the same product, but with a phenomenal diastereoselectivity and much higher yields, thus bringing a neat solution the very poor diastereoselectivities usually associated with azomethine ylide cycloaddition.

Applications of our strategy are quite spectacular: we were able to synthesize the tetracyclic core of daphnilactone B- and yuzurimine-type alkaloids in 33% less steps than our closest competitor (Org. Lett. 2011, 13, 6204; J. Org. Chem. 2016, 81, 9247). Despite the fact that members of these 2 classes were discovered up to 35 years ago, no synthesis is reported to date. Two other research groups work on these skeletons as well. This application of our strategy clearly establishes its efficiency and high potential, which will tremendously facilitate the construction of polycyclic natural products.

Dermière révision - last revision : 2017-09-13
La responsabilité du contenu de ce site est limité au Pr Guillaume Bélanger, le contenu n'engageant en rien l'Université de Sherbrooke.