Modular ketal-linked prodrugs and biomaterials enabled by organocatalytic transisopropenylation of alcohols

Yu, N (Yu, Na) 1, 2, 3, 4Xu, Y (Xu, Yang) 1, 2Liu, T (Liu, Tao) 1, 2Zhong, HP (Zhong, Haiping) 1, 2Xu, ZK (Xu, Zunkai) 1, 2Ji, TJ (Ji, Tianjiao) 5Zou, H (Zou, Hui) 1, 2Mu, JQ (Mu, Jingqing) 1, 2Chen, ZQ (Chen, Ziqi) 1, 2Liang, XJ (Liang, Xing-Jie) 3, 4, 6Shi, LQ (Shi, Linqi) 1, 2Kohane, DS (Kohane, Daniel S.) 5Guo, ST (Guo, Shutao) 1, 2

NATURE COMMUNICATIONS, 2021, 12(1): Article Number 5532

DOI 10.1038/s41467-021-25856-1

Abstract

Isopropenyl ethers are critical intermediates for accessing medicinally valuable ketal-based prodrugs and biomaterials, but traditional approaches for the synthesis of isopropenyl ethers suffer from poor functional group compatibility and harsh reaction conditions. Here, we develop an organocatalytic transisopropenylation approach to solve these challenges, enabling the synthesis of isopropenyl ethers from various hydroxyl-group-containing small-molecule drugs, polymers, and functional building blocks. The method provides a straightforward and versatile synthesis of isopropenyl ethers, features excellent tolerance of diverse functional groups, applies to a wide range of substrates, and allows scalable synthesis. The development of this organocatalytic transisopropenylation approach enables access to modular preparation of various acid-sensitive ketal-linked prodrugs and functionalized ketalated biomaterials. We expect our syntheses and transformations of isopropenyl ethers will find utility in several diverse fields, including medicinal chemistry, drug delivery, and biomaterials.

Isopropenyl ethers (IPPEs) are essential intermediates for obtaining ketal-based prodrugs and biomaterials, but traditional approaches for their synthesis are limited by poor functional group compatibility and harsh reaction conditions. Here, the authors report an organocatalytic transisopropenylation approach for IPPE synthesis in mild reaction conditions and with wide range of substrates, and use it to prepare acid-sensitive ketal-linked prodrugs and biomaterials.