Opening the cycle: controlled preparation of challenging polyene natural products

The synthesis of polyene natural products is a valuable endeavour in organic chemistry. Herein, we present a unified approach to tackle this problem. Building upon our own prior work, we propose to take the use of pyrones as sources of dienes a step further. After our preliminary demonstration of the use of dienyl carboxylates as lego-like building blocks for modular synthesis, we now turn towards the controlled engineering of cis-trans stereochemistry around a cyclobutene core as a means of orchestrating the synthesis of stereodefined polyenes. This will enable the total synthesis of Trichostatin A as well as several members of the Macrolactin family. The possibility of actually carrying out both the cyclobutene assembly and the ring- opening in a single step shall prove to be a valuable asset in specific, complex instances. A concise and innovative synthesis of the FR-family of natural products taking advantage of these strategic cornerstones is laid out.

In this project, we have developed a new strategy for the preparation of polyenes. Our approach relied on the use of cyclobutene scaffolds as templates around which substituents can be reliably and selectively placed. In a key step, the ring-opening of this cyclobutene then generates a diene whereby the stereochemistry of the cyclobutene is faithfully translated into the geometry of the diene product. After developing this strategy we have applied it to a successful total synthesis of the FR molecules. This is a family of interesting natural products which could not be synthesized in useful yields before this work due to difficulties in the assembly of their polyene moiety. Using the strategy originally proposed, we were able to prepare these natural products in a 10-step sequence which also allows the preparation of non-natural analogues.