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.

--
*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.

Encore, Encore!

Two hot areas of research served up second helpings online this week:

C-H Azidation: Remember John Hartwig's iron-meets hypervalent iodide combination from last March? It possessed the power to insert a late-stage amine equivalent into complex natural products. John Groves has raised the stakes, disclosing a "practical and complementary" Mn-porphyrin promoted version that takes solid sodium azide as the precursor. 

Source: Groves, JACS ASAP

The group finds it can enable late-stage azidation of a variety of complex bioactive substances (sclareolide, artemisinin, estrone, papaverine). Even more surprisingly, although likely a radical-induced transformation, using a chiral salen led to a single example of 70% ee material. Groves admits they have work to do, but the fact that this reaction operates with 1% loading in wet ethyl acetate at room temperature sure sounds promising!

Synthesis Machines: Over at Nature, Kobayashi published a flow reactor approach to syntheses of either enantiomer of rolipram, an anti-inflammatory. No MIDA-boronate 'handles' here; this is classic chemistry - olefination, 1,4 addition, reduction, hydrolysis, decarboxylation, cyclization - performed over heterogeneous catalyst beds encased in stainless steel tubes. The group spices up the synthesis by including their in-house chiral PyBOX-calcium catalyst to control the 1,4 addition, and developing a Pd / polysilane-catalyzed reduction for a troublesome nitro group. 

Kobayashi claims his synthetic engine can produce a gram of 96% ee material every 24 hours, and that the system remains stable and operable for about a week's time. In a complementary Commentary, Joel Hawkins of Pfizer presents a tantalizing future, where hood-sized continuous synthesis units chug through kilo quantities of drug precursors, using commercial reagents, sans column chromatography.

Friday Fun - Jobs from the Future

Who wants to help me construct a job description for the brave new world of automated synthesis?
Leave your suggestion in the comments, and I'll modify our advert as needed...

March 13, 2025 - Automated Synthesis Engineer

Our company seeks a motivated individual to work in our growing Automated Synthesis division.

Experience: Qualified candidates should have 5+ years previous experience in chemistry, mechanical engineering, or robosynthesis. Ideally, you'll have completed 10 (or more) previous multi-step total syntheses using 3D-Flow ModuloChem-XLs.

Software: Candidate should feel comfortable using the IBM SynBlox suite for fragment assembly, exploring GDB-23 for potential lead molecules, and assessing synthetic feasibility using the OPRD Engyn iPhone 9 app.

Special skills: Our synthesizers often require adjustments, thus experience in a trade - plumbing, welding, electrical - would be highly valued. Candidates interested in creating holographic "how-to" vidlets especially encouraged to apply.

Source: Burke Lab historical archives