The Total Synthesis of Spirotenuipesines A and B

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja069164r.html

From Prof. Samuel J. Danishefsky’s group at Columbia University and Sloan-Kettering Institute for Cancer Research

Spectacular racemic syntheses of spirotenuipesines A and B from the Danishefsky’s group recently appeared in JACS asap. The compounds have the following biological effects: “Upon introduction to 1321N1 human astrocytoma cells, these compounds appear to facilitate the expression and release of neurotrophic factors, which promote neuronal differentiation of rat pheochromocytoma cells (PC-12)”.

The key convergent step involves the Diels-Alder reaction of the alpha-methylene bicyclic lactone with the Danishefsky’s diene. The alpha-methylene bicyclic lactone was constructed from the known cyclopentenol which in tern was constructed from the meso-alcohol in three steps (an improvement from 10 steps) with key steps involving an allylic oxidation and RCM with Grubb’s 2nd generation catalyst.

The first plan they had in mind in synthesizing the alpha-methylene lactone involved a Claisen-based strategy, which they thought was going to occur facial-selectively from the face opposite to the protected hydroxyl group. But this strategy only gave them a 1:1 diastereomeric mixture. The reason for this is under investigation in their lab.

They then resorted to something quite ingenious and intriguing involving an intramolecular cyclopropanation using copper carbenoid, followed by a selective Barton-McCombie radical cleavage of the “Walsh” bond in the cyclopropane ring (in red), hydrolysis of bicyclic lactone, iodolactonization, radical air-oxidation, hydroxymethylation, and finally elimination. All of these were performed using the same cyclopentenol they made for their failed Claisen strategy.

The Diels-Alder then proceeded uneventfully to give a 8:1 d.r. in 90% yield of the desired diastereomer. As expected, the diene approached the lactone on the convex (exo) face of the dienophile of the bicyclic core. Upon acid exposure, the DA adduct produced the 6-membered enone. This enone was subjected to protection as exocyclic methylene, followed by diastereoselective reduction of lactone with DIBAL-H and intramolecular acetal formation. The resulted compound was then subjected to the chemospecific dihydroxylation of the methylene group, followed by oxidative cleavage to give the reveal once again the enone.

Exploiting the locked conformation of the spiro center, they were able to perform cerium methyl addition diastereoselectively to afford the tertiary alcohol in 95% yield with 6:1 d.r. of the desired diastereomer. All there was left was the deprotection of the PMB ether to give spirotenuipesines A. From spirotenuipesines A, spirotenuipesines B was obtained in one step from an oxone oxidation of the double bond (90%).

This is a tremendous total synthesis performed with such a creative strategy, especially in their solution leading to the exocyclic methylene bicyclic lactone.