ORganoCatalyzed Asymmetric DEsymmetrization of MEso compounds – ORCADEME

The project was initially divided in 3 tasks, with intricated and complementary objectives:
1) Task 1 was conducted by a PhD candidate recruited on the ANR project. She developed the synthesis of a novel series of chiral organocatalysts and applied the strategy of desymmetrization to meso primary diols bearing a THP ring.
2) Task 2 was conducted by another PhD candidate with a MESR grant which developed the organocatalyzed desymmetrization of meso acyclic 1,3-diols, with application to several post-functionalizations and also the total synthesis of (-)-Diospongine A.
3) Task 3 was not developed due to the highly promising results obtained in Task 2. This new ambitious orientation was developed jointly with the postdoctoral researcher recruited in the context of the ANR project (12 months)
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This project allowed:
1) the development of a methodology based on organocatalyzed desymmetrization of meso primary diols bearing stereogenic quaternary centers, difficult to obtain by other synthetic pathway ;
2) the development of an efficient and general strategy to desymmetrize acyclic meso diols, known to be reluctant substrates through an approach involving an acyl transfer reaction ;
3) this study revealed a particular mechanism during the different processes studied, especially double catalytic kinetic resolution, and could be generalize to other systems ;
4) the development and the rational design of organocatalysts based on dimethylaminopyridine and isothiourea scaffolds.
These recent results offered new perspectives of research.

This ANR JCJC grant allowed to consolidate an emerging thematic in our laboratory with new directions of research, fundamental as well as applied researches.

The knowledge accumulated during the course of this project will be beneficial for the design of a new generation of organocatalysts. Their physical and chemical properties will be evaluated by our new collaborator, Pr Herbert Mayr in Munich.
Moreover the amplification effects of enantioselectivity observed during the study will be extended to other transformations in order to obtain chiral building blocks with high degree of enantiopurity.

2 articles in high impact factors journals (Angewandte Chemie International Edition and Organic Letters)
1 book chapter
> 10 oral communications

Natural products and their analogues account for nearly 60% of drugs in clinical use today. Unfortunately, interesting natural products are often difficult to extract from their natural hosts or are present in very small amount in Nature. The development of total synthesis provides a solution to this problem furnishing reasonable amount of biologically active products for testing and offering the ability to synthesize simplified analogues which conserve or even improve the initial activity with less synthetic work. Total synthesis is also the experimentation field for the development of new methodologies and new strategies for the construction of natural product substructures. However, these new tools should respect several fundamental criteria as selectivity, efficiency and eco-compatibility.

Recently, Baran and Hoffmann classified the different economies (atom, step, redox) that should serve as new guidelines for the synthetic chemist. We propose to add to those a new type of economy: the economy of enantioselective steps. Usually, the synthesis of complex targets which present numerous stereogenic centers, lead to an inflation of enantioselective steps, in particular for acyclic targets in which diastereoselective induction is often weak.
A solution to this problem is the employment of an enantioselective step creating several stereogenic centers in one time (like Diels-Alder cycloaddition), which combines every type of economies if the reaction is enantioselective. Another method to generate several stereogenic centers in a single step is the desymmetrization of meso compounds. This strategy relies on the detection in the target of a local symmetry, which we can call a hidden symmetry. In this case, the retrosynthetic plan points out a highly symmetric key intermediate, the meso compound containing stereogenic elements by pair(s). At this stage a simple enantioselective step reveals all the stereogenic elements furnishing valuable optically active building blocks in only one synthetic operation.

Alternatively, the extension of the meso desymmetrization strategy by the use of organocatalytic transformations would combine the economy of enantioselective step and an eco-compatible aspect. In our proposal, we decided to turn our attention to the optically active tetrahydropyran ring since it is present in numerous biological active natural products. Ratjadone A, Ambruticin S, Phorboxazole B or Exiguolide are only some of the many examples. The highly functionalized THP heterocyclic rings usually constitute the more challenging part of the synthetic pathways of these molecules.

In this context, Orcademe Project proposes to develop new organocatalytic tools to prepare highly substituted cis-2,6-THP heterocyclic rings from various meso precursors. Different organocatalytic reactions involving nucleophilic catalysis and aminocatalysis will be employed in the enantioselective desymmetrization process. In a first task, we will focuse on the asymmetric acyl transfer to meso primary diols bearing a THP ring. Our goal is to propose a rational design of a new class of modular chiral 4-dialkylaminopyridines used as enantioselective organocatalyst for the acyl transfer. In a second task, we will apply the hidden symmetry strategy to build important fragments of complex molecules, Exiguolide and Phorboxazole B, starting from a common and simple acyclic meso secondary 1,3-diol precursor using catalysts employed and developed in the first task. Finally the third task will be devoted to the development of a new approach for the desymmetrization of easily accessible meso cis-2,6-disubstituted pyranones. The concept rests upon the utilization of asymmetric aminocatalysis for the direct enantioselective a-hydroxylation and a-methylenation revealing up to three stereogenic centers in one step.