Looking through my old synthesis diary I played a game where I could make a fast route to THC. I was quickly disappointed when the best I could reasonably do was 9 or 10 steps (6 after revising and reading different syntheses Trost, Evans, Pinnick’s).
- Alpha Bromination of Orange Flavor Ether using NBS and UV light
- MOM Protection of Olivitol
- In-situ Grignard reagent generation + Palladated Olivetol to do a fancy Kumada Coupling.
- Total MOM Deprotection
- Sodium ethyl sulfate Demethylation
- ZnBr/MgSO4 mediated SN
The world record:
Takes simply (+)-p-mentha-2,8-dien-1-ol and olivetol in 1% BF3*(OEt2) and Anhydrous MgSO4 in DCM at 273K.
Simply put, Razdan does a retro-friedel crafts using BF3 etherate as the Lewis Acid, then has acidic conditions to drive the recombination forward. His paper’s goal was to elucidate the mechanism (mind you this was 1974) and had little stereocontrol.
These syntheses show how important starting materials and one’s ability to take advantage of simple reaction kinetics can improve the efficiency of your chemistry. Switching to Organge Flavor Ether from Terpineol saved me a step from my original route. And using olivetol instead of olivtollic acid saved me from doing a Krapcho Decarboxylation. Razdan’s Synthesis was fast because his choice of a relatively obscure monoterpene “(+)-p-mentha-2,8-dien-1-ol”. The terpene had an allyl cation equivalent eager to go through the retro Friedel-Crafts. He shows that all the coupling prep that I did was somewhat unnecessary. So for you next synthesis remember to choose your starting material wisely.
Originally published: November 8, 2018