Vinigrol vanquished

The total synthesis of the diterpene vinigrol has finally been achieved 20 years on from its isolation.

Credit: © 2009 ACS

Since the isolation of the diterpene natural product vinigrol in 1987, its synthesis has been the focus of vast effort. Although there have been nearly 20 syntheses of intermediates towards this goal, its total synthesis has not previously been accomplished because of its highly congested polycyclic structure, which contains eight contiguous stereogenic centres.

Now, Phil Baran and co-workers at The Scripps Research Institute in California have achieved¹ the complete synthesis of this challenging natural product through the novel functionalization of a late-stage polycyclic intermediate. This intermediate was synthesized using inter- and intramolecular Diels–Alder reactions as previously reported by Baran². In accordance with the findings of other groups, however, many logical approaches to the final steps to form vinigrol failed.

Baran and co-workers' approach to the transformation of this intermediate involved a Grob fragmentation to remove an unnecessary carbon–carbon bond. Another notable step was the formal cis-addition of methanol across an alkene group. This was achieved by a dipolar cycloaddition of bromonitrile oxide followed by ring-opening and removal of the unwanted amino group. Overcoming the challenges of the final functionalization steps lead to vinigrol in 3% yield over 23 steps.