Today’s synthesis is (+)-Psiguadial B by Sarah Reisman. I urge everyone to check it out, it is a testament to the dedication total synthesis requires. In the paper she details all the failed reaction pathways and the clever model systems that led to development of the final route.
Synthetic pathway high lights:
- Enantioselective Wolf Rearrangment/Ketene addition using aminoquinoline and (+)-cinchonine.
- Hoveyda Grubbs II RCM, and then a Crabtree’s tertiary Alcohol directed double olefin reduction.
- Copper Cat. Intrmolecular O-arylation.
- DDQ Oxidation, and Cl’ Phenylation.
Sticking with the Reisman Group theme of transition metal methodology development, we see that this synthesis is mostly transition metal catalyzed reactions. Their key additions were the Wolf Rearrangment chemistry, where they did a simple solvent substrate screen. Their other great aaddition was the Phenylation step towards the end of the synthesis. They talk about it being unclear whether an neutral Phenyl would be a suitable candidate. They achieved a 4.8:1 dr, which is reasonable given that they only examined 3 oxidants for this reaction.
Looking into other syntheses the fastest one I found was done by Cramer in 2017. He uses Caryophyllene to do most of the heavy lifting, and touts a bio-mimetic approach. The 1 step is a multicomponent reaction that would make a great group meeting problem. Thinking about what the role of total synthesis is in chemistry; As a context to develop new synthetic techniques, I think Reisman had the more valuable synthesis. I think further exploration into the enantioselective Wolff rearrangement has a lot of merit since photochemistry, has historically been difficult to employ asymmetrically.
Originally published September 19, 2018