Totally Synthetic by Paul H. Docherty, 3 May 2006
Total Synthesis of Oseltamivir phosphate (Tamiflu)
Y.-Y. Yeung, S. Hong, E. J. Corey, J. Am. Chem. Soc. 2006, 128, 6310-6311.
This is not a natural product. But it’s still a very smart synthesis from the Corey labs, so deserves a mention. Corey starts this twelve-step process with an enantioselective Diels-Alder reaction (DA), setting the stereochemistry of the ester on the cyclohexene ring. He states that the DA proceeds in 97% yield at RT on a multi-gram scale, but I wonder how amenable this would be to industrial-scale using his particular catalyst. After converting to an amide, he then “moves” the olefin around the ring, substituting and setting new stereocenters progressively, in an impressive sequence.
Most impressive was the use of a regioselective aziridine-opening to set the stereochemistry of the ether and amine, moving the amine to the adjacent carbon in this process. A smart total synthesis, and, unlike Shibasaki's route (published by JACS on the same day(!), this remains unpatented; EJ's gift to the world!