Dynamic Catalytic Highly Enantioselective 1,3-Dipolar Cycloadditions.

Okan Yildirim,Michael Grigalunas,Andrey P Antonchick,Lukas Brieger,Herbert Waldmann,Carsten Strohmann

doi:10.1002/anie.202108072

Abstract

In dynamic covalent chemistry, reactions follow a thermodynamically controlled pathway through equilibria. Reversible covalent‐bond formation and breaking in a dynamic process enables the interconversion of products formed under kinetic control to thermodynamically more stable isomers. Notably, enantioselective catalysis of dynamic transformations has not been reported and applied in complex molecule synthesis. We describe the discovery of dynamic covalent enantioselective metal‐complex‐catalyzed 1,3‐dipolar cycloaddition reactions. We have developed a stereodivergent tandem synthesis of structurally and stereochemically complex molecules that generates eight stereocenters with high diastereo‐ and enantioselectivity through asymmetric reversible bond formation in a dynamic process in two consecutive Ag‐catalyzed 1,3‐dipolar cycloadditions of azomethine ylides with electron‐poor olefins. Time‐dependent reversible dynamic covalent‐bond formation gives enantiodivergent and diastereodivergent access to structurally complex double cycloadducts with high selectivity from a common set of reagents.

Highlights

The synthesis of organic compounds is dominated by kinetically controlled reactions, which enables irreversibleO
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We found that the double 1,3-dipolar cycloaddition can be catalyzed efficiently with AgOAc to yield cycloadduct rac-3 a with 82 % yield and high diastereoselectivity (d.r. > 20:1)

Summary

Introduction

In DCC the relative stability of the products (i.e., thermodynamic parameters) determines the product distribution rather than the relative magnitudes of energy barriers of each pathway (i.e., kinetic parameters) (Scheme 1 a) Since both the thermodynamic and the kinetic parameters are functions of reaction parameters, the outcome is highly dependent on reaction conditions such as temperature, catalyst and reaction time required to reach an equilibrium.[7,8] Turner et al employed DCC in enzyme catalysis. They used an aldolase for preparation of a dynamic combinatorial library through stereoselective carbon-carbon bond formation and enabled change in equilibrium in product distribution in presence of a thermodynamic trap.[9]. Double bond (Scheme 1 b), to a sequence of two subsequent enantioselectively catalyzed 1,3-dipolar cycloadditions with azomethine ylides generated in situ from imines.[21,22,23,24,25,26]

Results and Discussion

Conclusion

Conflict of Interest