From botanical origins to modern laboratories: 50 year journey in protoberberine alkaloid total synthesis.
Covering: up to 2025Protoberberine alkaloids (PBs) and tetrahydroprotoberberine alkaloids (THPBs) exhibit diverse pharmacological activities, driving significant interest in their efficient synthesis. This review systematically categorizes recent advances in the total synthesis of these alkaloids based on core-ring-closure strategies. For protoberberines, key methodologies include transition-metal-catalyzed coupling, C-H activation, Mannich/Friedel-Crafts reactions, and tandem cyclizations, enabling the rapid construction of the tetracyclic skeleton. In chiral THPB synthesis, asymmetric strategies, such as chiral auxiliaries, organocatalysis, and transition-metal-catalyzed asymmetric reactions, address the stereochemical challenges at the C14 position. Enzymatic and chemoenzymatic approaches further complement chemical synthesis by enhancing stereocontrol and sustainability. By critically analyzing the efficiency, scope, and limitations of existing strategies, this review highlights innovations in reaction design and underscores the importance of modular, catalytic, and bio-inspired methods for future alkaloid synthesis.