Protecting‐Group‐Free Total Synthesis of (–)‐Pallambins A—D

Abstract

Main observation and conclusionA 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/γ‐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 β‐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.