Asymmetric Synthesis of Allenes using Chiral Hypervalent Reagents - Application to the Total Synthesis of Protoilludane Natural Products. – HYPE4ALL

Numerous synthetic strategies, based on reactions such as additions, eliminations, substitutions, prototropies, or even Wittig olefinations, have been used for the synthesis of allenes. However, despite this clear bibliographic abundance, still very few methods allow to access to these synthons from simple (and non-functionalized) alkynes in a single step, and without the use of (non-sustainable) transition metals catalysts.
The HYPE4ALL project proposes to address this problem by developing heteroatomic (chiral) reagents allowing the conversion of simple alkynes known to be poorly reactive (i.e. non-activated) under oxidizing conditions.

Our efforts have recently led to the development of a chiral organoselenium reagent capable of performing this transformation with enantiomeric excesses up to 99%. This has been demonstrated through the allenylation of 11 simple alkynes, and with chemical yields ranging from 50 to 98%.

With this synthetic methodology optimized, we are now turning our attention to its application within the total synthesis of two biologically active protoilludanes via a key allenylation/[2+2] cycloaddition reaction sequence. This should allow us to efficiently generate the tricyclic [5.6.4] core of these natural substances.

3 manuscripts in the pipeline.

Synthetic organic chemistry is at the crossroads of several other disciplines such as engineering, biology, and medicine. It aims at producing targeted molecules from simple building blocks, and through sequences of appropriate transformations. One of the major challenges of this research area is related to the structural complexity of these targeted molecules. Today, novel, efficient and sustainable synthetic methodologies with high levels of stereocontrol, and using cheap and easy-to-transform chemical feedstock, are thus in high demand. The main objective of HYPE4ALL is to develop novel asymmetric methods for the synthesis of allenes from alkynes using chiral hypervalent heteroatomic reagents. These chiral allenes will then be exploited for the total synthesis of (+)-melleolide and (+)-armillasin, two complex natural products possessing diverse biological activities.