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!
Here we go:
“Our synthetic pathway has several advantages over the current Roche production method,” Corey says. “It is shorter, doesn’t involve any hazardous substances, begins with very cheap starting materials that are pennies per pound, and has excellent overall yield.” Corey’s overall yield is about 30% about twice that of the commercial route and significantly higher than the approximately 1% that can be calculated for Shibasaki’s.”
Whereas the Japanese researchers have applied for a patent, Corey and coworkers have put their process in the public domain. “I hope the work will stimulate others to work on different ways of synthesizing Tamiflu,” Corey says. “Although our route is already very efficient, it’s conceivable that when you put new developments together, you’ll have an even better and cheaper process. I think the Tamiflu supply problem is solved.”