Efforts toward an enantioselective total synthesis of (–)-oxazolomycin B and simplified chemical probes for proteomics studies; pharmacophore-directed retrosynthesis applied to gracilin A : simplified bioactive derivatives.


The oxazolomycins are bioactive peptide-polyketide hybrid natural products first isolated in 1985 by Uemura and co-workers from Streptomyces bacteria. Their complex structure and wide-ranging bioactivity against various human cancer cell lines, grampositive bacteria, and viruses like HIV, herpes, and vaccinia has enthralled organic chemists for three and a half decades. Many chiral pool-based, asymmetric synthetic approaches to the unique spiro- or fused-lactone γ-lactam core structure of these natural products have been reported. To the best of our knowledge no catalytic enantioselective strategies for the synthesis of the densely functionalized oxazolomycin γ-lactam exist in the literature. We have extended the utility of our previously developed enantioselective nucleophile-catalyzed Michael-proton transfer lactamization organocascade to the decagram scale production of a γ-lactam applicable to the total synthesis of the oxazolomycins and analogs thereof. An exhaustive experimental procedure is described for the synthesis of this γ-lactam starting material and a synthetic route utilizing this scalable procedure enabled access to the complete carbon skeleton of (–)-oxazolomycin B, with all seven stereogenic centers set. Issues encountered in the penultimate step of our total synthesis are discussed as well as early efforts to circumvent known redox/protecting group steps in accessing the particular γ-methoxy ester arrangement of the core of oxazolomycin. A formal synthesis of (+)-neooxazolomycin serves to support our assignment of the absolute stereochemistry in our intermediates, in addition to two Xray crystal structures. While oxazolomycin bioactivity and biosynthesis has been studied extensively, there is a dearth of studies into their cellular mode of action and protein target identification. Aligned with our interest in the total synthesis of bioactive, spiro-βlactone-containing natural products and the recent adoption of a pharmacophore-directed retrosynthesis strategy, we sought an efficient, modular synthesis of the intricate spiro-βlactone γ-lactam core of the oxazolomycins that would allow the construction of simplified derivatives bearing terminal alkynes. A small series spiro-β-lactones were made by our route and several proved to be too hydrolytically unstable for the proposed proteomics investigations, prompting computational studies in collaboration with Prof. Dean Tantillo’s group at UC Davis to understand relative spiro-β-lactone stabilities. This revealed the essential nature of the C4-OMe group of the oxazolomycins, which sterically shields the C17-carbonyl from hydrolysis. Future simplified spiro-β-lactone γ-lactams will include this and other structural features to impart enhanced stability. Our published work on the application of pharmacophore-directed retrosynthesis to the gracilin natural products is also enumerated here by virtue of the level of my personal contribution to the synthesis and the preparation of the manuscript.



Oxazolomycin. Neooxazolomycin. Curromycin. KSM-2690. Pyroglutamate. Natural product. Lactone. Lactam. Spiro-b-lactone. B-lactone. Hybrid. Peptide. Polyketide. Enantioselective. Diastereotopic group selective. Lanthanide. Organolithium. Lithium/halogen exchange. Lactonization. Proteomics. Bioactivity.