Trost’s synthesis of Aflatoxin B1, might be a generic synthesis showcasing The Tsuji-Trost Asymmetric Allylic Alkylation (AAA) for a facile prep of the furobenzofuran core. It was a response to the known ways of using enzymatic kinetic resolution to afford their product. This paper goes to showcase Dynamic Kinetic Asymmetric Transformation (DYKAT).
The Synthesis:
The synthesis starts with a Pechmann condensation. The 1967 synthesis also has this step. The coumarin is Iodated to make the handle for the Tsuji-Trost/Heck. The Tsuji-Trost Asymmetric Allylic Alkylaltion sets the stereocenter thus inducing asymmetry for the rest of the synthesis. While not shown in the Chemistry By Design Synthesis, there was supposed to be an intramolecular Heck Coupling. Which completes the prep of the furobenzofuran ring and sets the second stereocenter. The synthesis proceeds to form the cyclopenteneone ring by performing a Friedel-Crafts off aromatic Coumarin scaffold. I questioned here why Trost did a DIBAL-H reduction to afford the vinyl ether instead of maybe a Hydroboration and elimination. This paper talks about accessing different Aflatoxins, which differ based on chirality and substitution on that hemiketal stereocenter. After reduction, the hemiketal is acetylated with acetic anhydride and eliminated to afford (-)-Alfatoxin B1.
Key Knowledge:
The big addition was taking a racemic γ-tert-butoxycarbonyl-2-butenolide and being able to alkylate asymmetrically. Trost talks about how there was previous work on Kinetic Asymmetric Transformation (KAT), where a chiral palladium complex would form different products depending on the chirality of the substrate. Naturally this facilitates separation of the junk product but leaves much to be desired with a cap at 50% yield. Trost shows a DYKAT where the activated palladium interconverts between from the “mis-matched” to “matched” coordination and likely is caught in transition state “valley” until the substrate is in this matched state.
Taking a look at the arguments presented for the facial interconversion mechanism, I was not impressed that they didn’t get definitive proof for their conjecture. The proposed a Ligand displacement hypothesis, and a furan aromatization. Their proof was that the yield decreased with increased palladium, which meant that the sigma complex was the favored one.
I think a better proof would have been to lock out migration by probing the change in EE with the binding of a Lewis acid. Or attempting to run the reaction in the presence of a Mukiyama silyl enol ether. Other options include, having a chiral alkyl group for the γ-acyloxybutenolide, and seeing how the enantiomeric excess changed. But I think this may not have added much to the already deep knowledge of the Tsuji-Trost reaction umbrella.
Reflections:
Thinking about the disconnects and my lack of instinct when it came to this synthesis, brings to light that I don’t have a flair for syntheses that hinge on transition metal chemistry outside the classic model systems. This synthesis reminds me that you can guess what kind of chemistry to expect, based on the difficult disconnects, the author, and the history of the class of compounds.
Originally published: November 12, 2018