Protecting-Group-Free Total Synthesis of (-)-Pallambins A-D

Main observation and conclusion A full account of the total synthesis of (-)-pallambins A-D (1-6) is described. The strategy was devised by simulating their biosynthetic pathway. The left-part bicyclo[3.2.1]octane system of pallambins C and D was efficiently constructed via a palladium- catalyzed oxidative cyclization. For construction of the right-part tetrahydrofuran/gamma-lactone moiety (C/D rings), initial attempts to synthesize the allylic alcohol 15 for an one-step Pd-mediated alkoxycarbonylation have failed. However, during the course of this work, an unprecedented CH3Li-mediated method for conversion of bromoisoxazoline to the corresponding beta-hydroxy nitrile has been discovered. Furthermore, a stepwise protocol was designed, namely an Eschenmoser-Claisen rearrangement/Lactonization to generate the C ring, and a non-classical Wittig reaction to form the D ring. During the course of this work, a palladium-catalyzed method for dehydrobromination of bromide ketone was developed. Finally, an individual transformation of pallambins C (3) and D (4) generated pallambins A (5) and B (6) under mild UV irradiation. Thus, the first enantioselective total syntheses of (-)-pallambins A-D have been achieved in 15 or 16 steps from the known chiral cyclohexenone 8. The described synthesis avoids protecting-group manipulations by designing highly chemo- and stereoselective transformations.

Automated summary

The total synthesis of (-)-pallambins A-D was successfully achieved by simulating the biosynthetic pathway, efficiently constructing the left and right parts of the compounds. During the process, novel methods such as CH3Li-mediated conversion and a palladium-catalyzed dehydrobromination were discovered, highlighting the importance of highly selective transformations in avoiding protection-group manipulations.