Every once in a while I’ll walk through a synthetsis on Chemistry By Design. Usually it’s to find a unique reaction, or to find out how a unique compound was made. Most of the time it will start with me looking at the molecule and seeing the obvious retrosynthetic points, and then walking through the synthesis to see how close I was.

The criteria in which I choose my syntheses is typically:

1. Does it have fused rings or an interesting macrocyclic structure?
2. Is the synthesis less than 20 linear steps?
3.  does it rely on a magic step that was discovered through serendipity?

Toady I will go through ent-Clavilactone.

Retrosynthetic Instinct:

1. 5-member lactonization
2. Sharpless asymmetric epoxidation -> asymmetric induction point
3. Grubbs II RCM.

The True Retro synthesis:

1. RCM
2. Oxidative Lactonization
3. 3-Component Benzyne Coupling
4. Sharpless Asymmetric Epoxidation -> asymmetric induction point

Evaluating the forward synthesis:

Barret’s Synthesis aims to form a constraint 10 member benzoquinone using RCM.  His goal was motivated to study SAR of tyrosine kinase inhibitors. His synthesis uses straightforward chemistry to get to his epoxide and the neat twist is on the 3-component Benzyne Coupling, and his lactone isomerization. He states that he employs Yamamoto’s bulky alumnium Complex [ I did not do it service in the synthesis] to isomerize his lactone. It shows robustness in being able to handle a crude mixture of diastereomers and yield a single diastereomer as a product in 80% yield. After affording his lactone and setting the stage for an olefin metathesis, he optimizes his Grubbs II RCM. The synthesis finished with CAN oxdiation of 1,4 dimethyoxybenzene installed during the 3-component benzyne coupling.

The aim to use this synthesis as jumping off point to evaluate SAR of Clavilactones leaves much to be desired. When designing a SAR your goal is make a generlized and robust synthetic route. Relying on Asymmetric Epoxidation, to set your stereochemistry, and then have it be part of your most complex moiety, makes it inflexible so heteroatom substitution.

However, he does leave optionality along the saturated chain for different alkyl substitutions as long as they agree with Gilman, Grignard Organo Lithium addition conditions.

I enjoyed this synthesis and I welcome any opinion and discussion!