Yu-Wasa Auxiliary for C(sp3)-H Activation

Introduction

The synthesis of heteroaromatic and aromatic compounds can be utilized in order to install various functionalities onto lead compounds. Typically, the reactivity of the metal catalysts can be modified by various ligands.  A variety of ligand-metal systems have been developed for activation of C(sp2)-H bonds; however, very few methods exist for activation of the more sterically hindered methylene C(sp3)-H.  Previously, C(sp3)-H activation involved using phosphine and pyridine auxiliaries that strongly coordinate to the Pd-catalysts, which can decrease efficiency of Pd insertion into the C-H bond. Jin-Quan Yu and co-workers have developed the Yu-Wasa Auxiliary (791806), a weakly coordinating N-arylamide auxiliary for improved activation of acyclic and cyclic β–methylene C(sp3)-H bonds.

Advantages

The Yu-Wasa Auxiliary weakly coordinates the Pd-catalyst and allows for ligand control. This optimizes the substrate-catalyst complex conformation for effective metal insertion into the C(sp3)-H bond. This auxiliary has proven truly versatile as it can promote a wide range of transformations involving different catalytic cycles including Pd (II)/Pd(0), Pd(II)/Pd(IV) and Pd(0)/Pd(II).

In particular, the Yu lab has utilized this auxiliary towards the synthesis of unnatural amino acids, which are useful building blocks in drug discovery of small molecules and bioactive peptides. Using alanine, a readily available, inexpensive starting material, a plethora of unnatural amino acids have been generated through arylation, olefination, alkylation and alkynylation.   

Representative Applications

The Yu-Wasa Auxiliary is not limited in scope to unnatural amino acid synthesis, but has also proven useful in structural diversifications of other carboxylic acids.

Materials

     

To learn more about Jin-Quan Yu’s research and other products available from his lab, please visit his Professor Product Page.

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