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Recent years have seen novel modalities emerge for the treatment of human diseases resulting in an increase in beyond rule of 5 (bRo5) chemical matter. As a result, synthetic innovations aiming to enable rapid access to complex bRo5 molecular entities have become increasingly valuable for medicinal chemists' toolkits. Herein, we report the general synthesis of a new class of noncanonical amino acids (ncAA) with a cyclopropyl backbone to achieve conformational constraint and bearing C( sp 3 )-rich benzene bioisosteres. We also demonstrate preliminary studies toward utilities of these ncAA as building blocks for medicinal chemistry research.

We report our efforts toward achieving C(sp 2 )-C(sp 3 ) coupling reactions with 2,2-difluorobicyclo[1.1.1]pentane (BCP-F 2 ) building blocks. By comparing the reactivities of matching pairs of bicyclo[1.1.1]pentane (BCP) and BCP-F 2 analogues, we discovered that the Barluenga coupling reaction was the only cross-coupling protocol that translated well between the two structural motifs in contrast to other reported protocols. In this chemistry, a BCP-F 2 bearing a tosylhydrazone functional group is cross-coupled with an arylboronic acid. These results further expanded the scope of BCP-F 2 building blocks for potential applications in organic chemistry as well as medicinal chemistry.

Cobalt bis(acetylacetonate) is shown to mediate hydrogen atom transfer to a broad range of functionalized alkenes; in situ oxidation of the resulting alkylradical intermediates, followed by hydrolysis, provides expedient access to ketones and esters. By modification of the alcohol solvent, different alkyl ester products may be obtained. The method is compatible with a number of functional groups including alkenyl halides, sulfides, triflates, and phosphonates and provides a mild and practical alternative to the Tamao-Fleming oxidation of vinylsilanes and the Arndt-Eistert homologation.

Ethyne is employed as coupling partner in copper-mediated cross-coupling reactions with N-tosylhydrazones and α-diazoacetate, leading to the development of a new synthetic method for terminal allenes. With this novel coupling method, the terminal allenes were obtained in good yields and with excellent functional group tolerance. Copper carbene migratory insertion is proposed as the key step in these transformations.