On the Synthesis of Breitfussins. Toward the total synthesis of Breitfussin A and analogues

Abstract

The Breitfussins are a series of closely related heterocyclic compounds originated from the marine organism Thelia Breitfussi. The core is a 5(indol-3-yl)-2-(pyrrol-2-yl)oxazole, which has not been observed prior to its isolation in 2007. The divergence of the Breitfussins lies in the halogenation pattern and methoxy substitution. Breitfussin A is of synthetic interest because of its novel structural features, as a final proof of its structure (since it was determined using nonstandard techniques) and to provide material for biological testing.

In this thesis, efforts towards a synthesis of Breitfussin A are described as well as application of the synthetic strategy for making an analogue library. The synthesis features a Leimgruber-Batcho indole synthesis to prepare the correctly substituted indole. Two procedures were tested for introduction of the oxazole moiety: the Schöllkopf protocol and a Suzuki-Miyaura coupling. Development of iodination protocols are given much attention, and a novel regioselective oxazole iodination is presented.

The synthesis of a late stage intermediate of Breitfussin A was performed in a shortest sequence of 11 steps from the commercially available starting material 2,6-DNP, in 12 % total yield. The whole strategy was successfully tested on a model compound with an unsubstituted indole, with the exception of the final deprotection. A range of compounds (at different stages in the synthesis) were produced for an analogue library.