| The phomactins, a class of diterpenes isolated by Sugano and coworkers in the early 1990s, have drawn much attention from the synthetic community over the past few years. In addition to their biological activity as platelet activating factor (PAF) antagonists, the phomactins possess a structurally unique architecture, which is marked by a highly substituted cyclohexene that is bridged by a 12-membered macrocycle. Phomactin A, arguably the most structurally complex member of the phomactin family, also contains a pyran ring and a sensitive hydrated furan ring. The objective of this research was to complete a total synthesis of (+)-phomactin A using a B-alkyl Suzuki macrocyclization.; The total synthesis strategy centered on a highly substituted cyclohexene intermediate. This key intermediate possessed the entire carbon framework and all relevant stereochemistry necessary to complete the total synthesis. A convergent route to this highly substituted cyclohexene intermediate was designed from two commercially available and inexpensive terpene starting materials, (R)-(+)-pulegone and geraniol. These two compounds were used to synthesize a cyclohexenyl lithium species and an aldehyde, respectively, which were then coupled using a nucleophilic addition reaction.; Following the addition reaction, three ring closures were carried out: an intramolecular epoxide opening to install the pyran ring, a deprotection of the primary hydroxyl group to spontaneously form the hydrated furan ring, and a B-alkyl Suzuki coupling to install the 12-membered macrocycle and complete the total synthesis. |
