Application of the LADA Strategy for the Synthesis of Unnatural Amino Acids through 1,2-Aryl Migration of Allylic Alcohols.

Unnatural amino acids are versatile building blocks. Herein, we report the application of the LADA strategy for the direct synthesis of unnatural amino acids through 1,2-aryl migration of allylic alcohols. This reaction proceeds under mild conditions, tolerates diverse functionalities, and works smoothly on different thiols.

Structure optimization and preliminary bioactivity evaluation of N-hydroxybenzamide-based HDAC inhibitors with Y-shaped cap.

Histone deacetylase inhibitors (HDACIs) are effective small molecules in the treatment of human cancers. In our continuing efforts to develop novel N-hydroxyterephthalamide-based HDACIs, herein we report the design and development of a new class of N-hydroxybenzamide-based HDACIs. In this new class of analogs, we inserted an ethylene moiety in the linker and used indole as a part of the Y-shaped cap group. Biological characterization identified compounds 4o, 4p, 4q and 4t to show improved HDAC inhibition, while no isoform selectivity for HDACs was observed. These compounds also exhibited improved anti-proliferative activity against multiple cancer cell lines when compared to their parent compound and positive control SAHA.

Decarboxylative oxidation-enabled consecutive C-C bond cleavage.

The selective cleavage of C-C bonds is of fundamental interest because it provides an alternative approach to traditional chemical synthesis, which is focused primarily on building up molecular complexity. However, current C-C cleavage methods provide only limited opportunities. For example, selective C(sp3)-C(sp3) bond cleavage generally relies on the use of transition-metal to open strained ring systems or iminyl and alkoxy radicals to induce ß-fragmentation. Here we show that by merging photoredox catalysis with copper catalysis, we are able to employ α-trisubstituted carboxylic acids as substrates and achieve consecutive C-C bond cleavage, resulting in the scission of the inert ß-CH2 group. The key transformation relies on the decarboxylative oxidation process, which could selectively generate in-situ formed alkoxy radicals and trigger consecutive C-C bond cleavage. This complicated yet interesting reaction might help the development of other methods for inert C(sp3)-C(sp3) bond cleavage.

Three-component radical homo Mannich reaction.

Aliphatic amine, especially tertiary aliphatic amine, is one of the most popular functionalities found in pharmaceutical agents. The Mannich reaction is a classical and widely used transformation for the synthesis of ß-amino-carbonyl products. Due to an ionic nature of the mechanism, the Mannich reaction can only use non-enolizable aldehydes as substrates, which significantly limits the further applications of this powerful approach. Here we show, by employing a radical process, we are able to utilize enolizable aldehydes as substrates and develop the three-component radical homo Mannich reaction for the streamlined synthesis of γ-amino-carbonyl compounds. The electrophilic radicals are generated from thiols via the desulfurization process facilitated by visible-light, and then add to the electron-rich double bonds of the in-situ formed enamines to provide the products in a single step. The broad scope, mild conditions, high functional group tolerance, and modularity of this metal-free approach for the synthesis of complex tertiary amine scaffolds will likely be of great utility to chemists in both academia and industry.