Phorboxazoles A and B are marine natural products isolated from the Indian Ocean sponge Phorbas sp collected off Muiron Island, Western Australia. Preliminary biological data against the National Cancer Institute’s 60 tumor cells panel suggests phorboxazole A to be among one of the most cytotoxic compounds ever discovered. Our group reported the first total synthesis of phorboxazole A and since then our program aimed to disclose the biological mode of action of phorboxazoles. Development of optimized synthetic entry and structure activity relationship (SAR) studies are the preliminary goals in the program. Described herein is an optimized synthesis of the C18-C30 domain of phorboxazole A via a complex aldol reaction and hetero-michael addition. This reliable and efficient synthesis accumulated multigrams of the C18-C30 fragment to support further SAR studies. Based on our de novo biomimetic oxazole formation, 32-methyl-phorboxazole A C1-C32 analogs were achieved for biological evaluation.
In recent years N-Heterocyclic Carbenes (NHCs) have evoked considerable interest in both organometallic chemistry and synthetic organic chemistry. Due to its close analogy to triphenylphosphine, NHCs are well used as ligands for organometallic catalysts. More recently, interest in the role of nucelophilic NHCs in organocatalysis has been increasing because of not only their economical and environmental friendliness but also new synthetic strategies development. Described herein is an innovative NHC catalyzed β-hydroxy-lactone formation from α,β-expoxy-aldehyde and its application in natural product synthesis. Cephalosporolides E and F were first isolated in 1985 by Hanson and co-workers from the fungus Cephalosporium aphidiocla and later in 2004 by Rakachaisirikul and co-workers from the entomopathogenic fungus Cordyceps militaries BCC 2816. The unprecedented tricyclic β,γ-fused-[4.4]-spiroketal-γ-lactone structure evoked our interest in these natural products. A total synthesis of cephalosporolide E and F was achieved by employing our newly developed NHC catalyzed β-hydroxy-lactone formation strategy and a AuCl catalyzed spiroketalization.
Thuggacins A, B and C are novel antibiotics that were isolated by Jansen and co-workers from the myxobacterium Sorangium cellulosum and reported in 2007. Thuggacins were found to inhibit respiration in several Gram-positive bacteria, including Mycobacterium tuberculosis. We developed fragment syntheses via a novel Staudinger-aza-Wittig strategy to install a thiazole ring and an NHC-catalyzed acylation to generate an α-methyl-β-hydroxyester.