Studies Towards the Total Synthesis of Okaramine B
Alan W. Grubbs and Robert M. Williams
Department of Chemistry, Colorado State University
Fort Collins, CO 80523
Okaramine B (1), was isolated in 1989 by Hayashi and co-workers from cultures of Penicillium simplicissimum AK40 on okara (the insoluble residue of whole soybean). Okaramine B, the most biologically active of the family, exhibited potent insecticidal activity against the 3rd instar larvae of silkworm (LD50 = 0.2mg/g diet). Interest in the synthesis and biological activity of related compounds can be traced back to studies of toxigenic fungi isolated from strains of Aspergillus ustus. These fungi are important because they commonly infect corn products in early stages of processing. Further studies resulted in the isolation of active compounds produced by these fungi, austamide and 12,13-dihydro-12-hydroxyaustamide. Similarly, the okaramines are produced by a fungus that infects raw materials produced in the tofu industry.
We have generated a tricyclic lactone
precursor
to both the azetidine ring and diketopiperizine ring derived from vinyl
indole 2.
Aminomethylation of 2 gave a gramine equivalent that was subjected to Somei-Kametani coupling conditions and subsequent hydrolysis to give 5 in 78% overall yield through a 2-step one-pot sequence. Introduction of a trimethylphenyl nitrogen protecting group generated the precursor to a diastereoselective oxidative cyclization. Reaction of 6 with dimethyldioxirane gave an enantiomeric mixture of pyrroloindole 7 bearing the syn-relationship at all three stereocenters. Treatment of ester 7 with DBU in DMF gave exclusively the tricyclic lactone. Attempts continue to generate the key azetidine functionality and to achieve the union of both fragments of okaramine B.