General Synthesis of Conformationally Constrained Noncanonical Amino Acids with C(sp3)-Rich Benzene Bioisosteres

• DOI: 10.1021/acs.joc.4c00225
• Publication Date: 2024-03-27T05:52:06Z
• Authors: Xiaoshen Ma; Adam M. Beard; Samantha A. Burgess; Miroslawa Darlak; Justin A. Newman; Lisa M. Nogle; Mark J. Pietrafitta; David A. Smith; Xiao Wang; Lei Yue

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 at enabling rapid access of complex bRo5 molecular entities become increasingly valuable for medicinal chemists’ tool-kits. Herein, we report the general synthesis of a new class of noncanonical amino acids (ncAA) with a cyclopropyl back-bone to achieve conformational constraint and bearing C(sp3)-rich benzene bioisosteres. We also demonstrate preliminary studies towards utilities of these ncAA as building blocks for medicinal chemistry research.