Methodologies, tools for synthesis - Catalysis


The catalytic (aza)Prins cyclization reaction between a homoallylic alcohol/amine and an aldehyde in the presence of an acidic promoter or catalyst is a powerful C-C bond forming transformation and one of the most elegant approach to access highly substituted tetrahydropyrans and piperidines with excellent diastereoselectivities.
The catalytic enantioselective Prins cyclization is a real scientific challenge since to date only two reports about this topic are known in the literature. We have been the first to disclose that the synergistic combination of a chiral Brønsted acid, namely a BINOL-derived bis-phosphoric acid with an achiral Lewis acid, CuCl, can promote the reaction in an enantioselective fashion (e.r. up to 80:20).
A detailed study devoted to the development of the aza-Prins cyclization involving non-sulfonylated homoallylic amines has not been undertaken to date. We have filled the gap by exploiting again the synergism between a Brønsted (p-TSA) and a Lewis acid (TiCl4), which can promote the aza-Prins cyclization with N-aryl, -alkyl and even non protected homoallylic amines. The piperidines are obtained in good yields and with a good cis/trans ratio dependent on the group borne by the N atom.

(aza)Prins cyclization reaction

Tandem/domino reactions starting with a Prins-type process are the object of our ongoing collaboration with the Indian Institute of Chemical Technology in Hyderabad INDIA, within the Indo-French Joint Laboratory for Natural Products and Synthesis towards Affordable Health LIA IICT/CSIR – CNRS/UR1. During the stage of the Indian PhD student I have supervised (april-july 2017), we put in evidence a competition between the classical Prins cyclization in the presence of AlCl3 delivering tetrahydropyrans substituted with a Cl atom, and a tandem Prins/intramolecular Friedel-Crafts cascade promoted by BF3.Et2O giving access to tricyclic scaffolds.

catalysis -tandem

For more information : Claudia Lalli

In a general concern to substitute precious metals with more abundant and less toxic first-row transition metals, the search for new zinc- and iron-based catalysts that are active in hydrosilylation of ketones, an important method for the synthesis of secondary alcohols, has been undertaken. In this topic, the zinc complexes are frequently stabilized by bidentate ligands featuring amine or imine functional groups. We have demonstrated the high catalytic performance of diethylzinc combined with picolinohydrazides as a new ligand class in the hydrosilylation of carbonyl compounds under mild conditions (system A). The readily available iron complex [CpFe(CO)2]2 was also identified as a simple tool for the hydrosilylation of aldehydes and ketones in the presence of diethoxymethylsilane (system B). This procedure was air-tolerant and the addition of an organic solvent was unnecessary.

Pure phosphotriesters (phosphates) are very seldom used in transition metal catalysis or as organocatalysts if compared to other phosphorus based compounds such as phosphines or phosphoric acids. We designed novel mono- and bis- BINOL derived phosphotriesters such as A and B. An intriguing reactivity has been observed in the phosphorylation of BINOL and other bis-phenols operated by chlorophosphates, which is attributable to the pKa of hydroxyl group of the bis-phenols and to the leaving group nucleofugal behavior of the chlorophosphates. By playing on these two parameters new chiral monophosphotriesters, symmetrical homo-BINOL bisphosphates and unsymmetrical non-homo-BINOL ones, were synthesized selectively and in good yields. Those new Lewis bases found application as ligands in metal-based catalytic transformations: the zinc-catalyzed hydrosilylation of ketones and diethylzinc addition to aldehydes have been performed in the presence of achiral phosphates, and then an enantioselective version has been studied with a BINOL-derived bisphosphate (up to 34% ee).

For more information : Gilles Argouarch, Claudia Lalli

The allylboration reaction constitute a powerful C-C bond forming transformation that largely satisfy the criteria of stereoselectivity and step economy for the construction of highly functionalized motifs. Application of this approach in synthesis offers a straightforward entry to complex natural products and highly functionalized pharmaceutical ingredients. Moreover this methodology permits the construction of quaternary stereocenters which represent a great challenge in organic chemistry, but also a major issue for the international community, especially in an enantioselective fashion. While the enantioselective metal catalyzed allylation of carbonyls, as well as their organocatalytic allylboration have been largely described, the organocatalytic allylboration of isatins doesn’t know the same success. Indeed only one example is described in the literature using a chiral amino-phenol as catalyst. We have reported the enantioselective BINOL-derivatives catalyzed allylboration of isatins leading to 3-allyl-3-hydroxyoxindoles in high yields (up to 99%) and excellent e.r.’s (up to 98:2). The methodology was applied at a gram-scale to the synthesis of the natural product (R)-chimonamidine and its isomer.

Synthetic applications of new aldol- and Mannich-type reactions

Our goal in this area is to develop a new version of the aldol reaction, discovered in our group. Starting from allylic alcohols and using appropriate organometallic catalysts, tandem isomerization-aldolisation and isomerization-Mannich reactions have been successfully performed. These are full atom economy-type reactions which, further occur under mild and neutral conditions. Various Fe, Rh, Ru and Ni catalytic systems can be used. Mechanistic studies strongly support a pathway where the transition metal catalyst performs only the isomerization into the enol and then, this free enol reacts with the aldehyde or the imine.

Synthetic applications

Recently we have considered the use of silicon intermediates in such aldol processes. Starting from α-hydroxy-allylsilanes this tandem process allows the preparation of new β-hydroxy-acylsilanes which are of much interest in synthesis. For instance, by using appropriate conditions it was possible to transform smoothly the acylsilane unit into an aldehyde and thus develop a new process for iterative aldol reactions. On the other hand, stereoselective syntheses of enol ethers have been performed, followed by Mukaiyama aldol-type reactions. Both approaches led to fragments of macrolides and other bioactive natural products.

Further, we have demonstrated recently for the first time that unsaturated acylsilanes can be used in Morita-Baylis-Hilman reactions. The corresponding adducts can be transformed smoothly into enals, which appear as highly versatile intermediates in organic synthesis.

This research is performed in coordination with CSIR-IICT, Hyderabad as part of our Indo-French Joint Laboratory. Our present activities in this area are dealing with new synthetic applications of acylsilanes prepared by these, and other, routes.

For more information : René Grée