Tuesday, July 5, 2016

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.

13 comments:

  1. I read your post and it is really good , keep writing more
    Buy Weed Seeds Online
    Buy A-796,260 Online
    Buy Phenethylamine Psychedelics online
    Buy DMT Dimethyltryptamine Online
    Buy 5-methoxy DALT online
    Cannabis Oil For Sale
    Buy enzodiazepines online you can as well text +1(646)883-3072 , Telegram: primenature or email:primepharma0@gmail.com for more details

    Buy Fentanyl powder Online
    Buy TH-PVP Powder Online
    Buy A-PVP Online
    Buy Crystal Meth Online
    Buy Acetyl Fentanyl Powder Online
    Buy Carfentanil Online
    Buy 4-MMC Online
    BUY AMPHETAMINE ONLINE
    CBD Isolate Powder 99%+

    ReplyDelete
  2. Buy nembutal online and have it shipped to your home, We supply nembutal sodium solution, nembutal pills, and powder nembutal. We ship Spain, Italy, Germany, Portugal, Mexico. We got high quality pentobarbital for sale and we ship our products worldwide .

    Contact For More Details

    Email-: gransuministros.medicine@gmail.com
    Whatsapp +1 530-517-7417

    ReplyDelete
  3. We sell and supply high quality and purity nembutal Pentobarbital Sodium in both large and small quantities worldwide. Our shipping and delivery cost is 100% safe and convenient.

    We are ready to sell minimum quantities and large deliveries to the world of our product. Below is a list of currently available on your product . Nembutal in powder Nembutal in Pills Nembutal in oral solution Nembutal in injection We have in stock and 100% guaranteed supply. Delivery takes a maximum of 2-3 days.please any one who is interested in any of our product do contact us directly .

    Email-: gransuministros.medicine@gmail.com
    Whatsapp +1 530-517-7417

    ReplyDelete
  4. bitcoin private key finder for 2019=2020 free http://allcryptosoftware.net/

    ReplyDelete
  5. 토토
    배트맨토토
    스포츠토토


    Outstanding post, keep up with this beneficial perform.

    ReplyDelete
  6. 토토사이트
    사설토토
    토토사이트추천

    What an amazing article. Genuinely love it, thank you! I really adore your blog.

    ReplyDelete
  7. 100% Refined Sunflower Oil
    Factory Price Refined Sunflower Oil
    Refined Sunflower Oil
    High Quality Refined Sunflower Oil
    Edible Refined sunflower oil
    100% Pure & nature refined sunflower oil
    Factory price cooking refined sunflower oil 5L bottle
    NEW STOCK REFINED SUNFLOWER OIL
    Latest Refined Sunflower Oil (1L, 2L, 3L, 5L, 10L PET Bottle)

    1.Type:Sunflower Oil 
    2.Processing Type: Refined 
    3.Packaging:Plastic Bottle 
    4.Use:Cooking 
    5.Origin: Tanzania

    Grade: Grade
    First Color: Light yellow 
    Purity (%): 100% Cultivation
    Type: Common Density (25º /4º ) 0, 9139/0, 9190
    Refined Type: Cold-pressed/winterized  

    Packaging
    Plastic Bottle, Bulk, Can (Tinned), Drum, Flexytank In transparent PET bottle----1L, 2L, 3L, 4L and 5L (With Handle).In jerrycan---- 5L, 10L, 20L, 25L and 220L.

    contact us and get quality products.
    Email : tanzaniasunflower6@gmail.com
    Email : vertigocompany380@gmail.com
    WhatsApp : +255 787820987
    Address : 33949, Dar es salaam, tanzania, Tanzania,33949

    ReplyDelete
  8. We produce only high-quality Registered Passports, ID Cards, Driver’s License, IELTS Certificate, VISA’s, Resident Permit, Birth Certificate, Diplomas SSN, TOEFL, Exit/Entry Stamps, etc that can be used legally both nationally and internationally. It will be produce with 100% authenticity like the original documents. We also use new biometric technologies for all types of our documents.


    Contact:
    Wickr ID:.....Spidoplug
    Email:.....firstclassdocuments20@gmail.com


    Documents duplicate service:
    Documents duplicates producing means we will clone real existing documents and replace the informations with your provided details to suit your activities, database considering on your age, sex, nationality, etc. It will contain real name of parents of the person, address, some other useful information which can be asked at the airport and customs by immigration, ect.


    Documents registration service:
    For some Countries we can offer to register your new documents in the government database after it will be produced. In fact it will be the official issued documents and you can use it like the original ones. But the price for registered documents will be higher than for the regular documents producing.


    Visa/Stamps Affixion Service:
    We provide a possibility to affix almost all kind of stamps/VISAs into the passports to fill you more confident. We don't provide this kind of service separately from passport producing.


    IELTS Certificates:
    We offer high qualitative English test certificates without exam. Certificates will be original and registered in official database. All certificates we issue carries a band scores level of your choosing (6.5-9.0). IELTS is accepted by more than 10,000 organizations in over 145 countries.
    This includes:
    Universities, Schools, Training Colleges and Tertiary Institutes
    Government departments and agencies
    Professional and industry bodies
    Companies and employers.

    Contact:
    Wickr ID:.....Spidoplug
    Email:.....firstclassdocuments20@gmail.com

    ReplyDelete