Sudden Tamiflu

Hey there, JLC fans! Long time, no post.

Today's inspiration comes from a molecule I've enjoyed watching the synthetic, process, and educational chemistry communities go to town on for the past 18 years: (-)-oseltamivir, also known by the trade name Tamiflu. See that cyclohexene in the middle? This molecule mimics the transition state of a mostly-flat oxonium cation derived from sialic acid, so well that it interrupts the flu virus's ability to release further infectious particles, allowing the body to "catch up" and reduce overall time spent hovered over a steaming bowl of chicken noodle soup.

But enough about the Why, let's get to the How; as the authors of this paper pitch in their opening line: Time is Money!

Hayashi and Ogasawara, no strangers to Tamiflu themselves (syntheses in 2009, 2010, and 2013), report in Org. Lett. ASAP a synthetic economy we don't always consider: time. They claim a one-pot Tamiflu synthesis, five steps, average step yield around 70%...finished in just 1 hour.*

Compare that against the benchmark of the previous 1-pot reaction - 57 hours. Wow!

Several interesting modifications to their previous syntheses have enabled this savings. First, addition of a hydrogen-bond donor catalyst to a nitro-Michael addition, which accelerates the reaction 3x. Second, swap of a base in an HWE reaction: 3.5 hours in cesium carbonate becomes 20 mins in tBuOK. Finally, a sacrificial move - rapid epimerization of the penultimate nitrohexene, knowing that only 50% of the product will successfully reduce to the desired diastereomer.** A short silica column completes the rapid realization of this antiviral drug.

Lest you believe that I'm hornswoggled by a synthetic sprint, a quick glance at the Supporting Info*** provides a cold shower. There's some lingering impurities in those 1H NMRs, enough to make me believe that the yield, even at gram-scale, isn't really 16%. And the reagent equivalencies used to drive these nitro-boosters aren't pretty: 30 parts Zn, 3 parts phosphonate, 15 aliquots of TMSCl. To touch upon an allusion the authors themselves make - perhaps a Jamison-style flow reactor is the next logical step for this speed-demon of a route.

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*As I wrote this line, I couldn't stop comparing this to other "just 1 hour!" claims from consumer products: teeth whitening, photo development, tax preparation, LensCrafters, oil changes, and pizza delivery can all refer to the 2016 Hayashi Tamiflu synthesis as a spiritual brother of sorts.

**I don't believe that there's a spontaneous kinetic resolution here, but if any sharp-eyed reader can prove differently, I'm all ears.

***Counter-counterpoint: The one-pot is so streamlined that it now takes only 281 words to synthesize Tamiflu. 
Damn.

Brewing Up Shikimic Acid

Could preparing Tamiflu starters be as simple as making your morning cappuccino?

The lab instrument in question,
straight from the Supporting Info
(I <3 pictures in SI)

Jason Smith and coworkers from the University of Tasmania have reported a PHWE - pressurized hot water extraction - to obtain shikimic acid, a common starting material in several routes to oseltamivir phosphate (Tamiflu). In a preparation that begs repetition, they grind up up 20 g of Chinese star anise, mix with sand, and quickly wash with a hot ethanol-water mixture using a household espresso maker (see right).

The researchers claim that, after a quick silica plug, they obtain 5.5% (w/w) of "sufficiently pure"* shikimic acid. I'd encourage you to go see the NMR spectra for yourself.

Of course, pressing common kitchen tools into synthetic service isn't news. My undergraduate lab group ordered many of its smaller-bore funnels and spatulae from a kitchen supply store. And let's not forget grindstone chemistry, popularized by the late Ajay Bose at the Stevens Institute of Technology, which used a stainless-steel blender** to combine solid reagents into heterocycles.

If molecular gastronomy involves bringing the techniques of organic and biochemistry into the kitchen, perhaps this represents its antipode, some sort of 'reverse' molecular gastronomy in which kitchen appliances and techniques inform bench science. Makes perfect sense; after all (say it with me)...Chemistry is Just Like Cooking!

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*Based on the 1H NMR, I'm guessing their material hovers around 90% pure. Still good, given a 2-minute prep time. 
**Kitchen-Aid, no less - high-quality 'instruments' for high-quality chemistry : )