ABSTRACT
Total syntheses of the antimicrobial tricyclic 16-membered macrolides, (+)-tubelactomicin B, (+)-tubelactomicin D, and (+)-tubelactomicin E, have been accomplished for the first time with common synthetic approaches. These total syntheses established the relative and absolute configurations of the three tubelactomicins, for which planar structures had solely been reported. The total synthesis of (+)-tubelactomicin D included a newly developed stereoselective intramolecular Diels-Alder reaction for constructing the highly functionalized octahydronaphthalene substructures.
Subject(s)
Chemistry, Organic/methods , Lactones/chemical synthesis , Macrolides/chemistry , Cyclization , Lactones/chemistry , Macrolides/chemical synthesis , Magnetic Resonance Spectroscopy , Models, Chemical , Molecular Conformation , Naphthalenes/chemistry , Spectrophotometry, Infrared , StereoisomerismABSTRACT
[reaction: see text]. Starting from diethyl (R)-malate, synthesis of the lower-half segment of (+)-tubelactomicin A, a 16-membered macrolide antibiotic, has been achieved. The synthesis involved the highly endo- and pi-facial selective intramolecular Diels-Alder reaction achieved using a trisubstituted methacrolein derivative tethering a 10-carbon dienyne unit at the beta-carbon, which in turn was prepared from a known allylated malic acid derivative.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Macrolides/chemical synthesis , Malates/chemistry , Actinomyces/chemistry , Anti-Bacterial Agents/chemistry , Lactones/chemical synthesis , Lactones/chemistry , Macrolides/chemistry , Molecular Structure , StereoisomerismABSTRACT
[reaction: see text]. We have completed the total synthesis of natural (+)-tubelactomicin A (1), a 16-membered macrolide antibiotic. This Letter presents a highly efficient synthesis of the upper-half segment (C14-C24) and the completion of the total synthesis featuring a high-yielding Stille coupling for the connection of the upper-half and lower-half segments and Mukaiyama macrolactonization for the construction of the entire structure of 1.