An approach to the epipolythiodiketopiperazine bis(pyrroloindoline) class of antitumor antibiotics is proposed. These natural products have been found to inhibit c-fos proto-oncogene transcription, an event necessary for the cell's progression from the G0 yields G1 phase of cellular replication. Study of the role of these natural products in the cellular environment could lead to the discovery of a new therapeutic target for the fight against cancer. A synthetic route to the epidithiodiketopiperazine bis(pyrroloindoline) verticillin A is described in detail. Verticillin A is a dimeric structure composed of two pyrroloindolines connected through a bis(quaternary) linkage. The pyrroloindolines contain dithioketopiperazine rings that are derived from L-tryptophan and L-alanine, and each pyrroloindoline is further adorned with an hydroxyl group. The proposed verticillin A synthesis introduces a novel dimerization reaction whereby a siloxane tether is used to render the reaction intramolecular, thus affording an entropic advantage and introducing a regio- and stereocontroling element to an otherwise very difficult transformation.
|Chemler, S R; Danishefsky, S J (2000) Transannular macrocyclization via intramolecular B-alkyl Suzuki reaction. Org Lett 2:2695-8|