Reagent‐Controlled Total Synthesis of Natural Anti‐Inflammatory (‐)‐Berkeleyamide A and its Seven Stereoisomers

The total synthesis of anti‐inflammatory (‐)‐berkeleyamide A (with an overall yield of 40%) and its seven stereoisomers was accomplished from inexpensive Meldrum's acid. The reagent‐controlled KO t Bu‐mediated syn ‐aldol adduct (>76% yield and >90% diastereoselectivity) afforded the natural ( 10S , 11R , 14S )‐(‐)‐berkeleyamide A. Notably, an exclusive anti‐aldol adduct, formed via LiHMDS/TMEDA‐mediated aldol reaction, produced ( 10S , 11S , 14S )‐(‐)‐11‐ epi ‐berkeleyamide A as a single crystal. While the use of LDA and NaHMDS yielded both syn ‐ and antiadducts, enabling access to all stereoisomers. The required aldol partners, chiral γ‐lactam and aliphatic aldehyde, were both produced from Meldrum's acid in 3‐ and 5‐step sequences, respectively, with high yields (each ste p >87%). The 2D NMR studies and single‐crystal X‐ray crystallographic data assisted in assigning the stereochemistry of all the stereoisomers.