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1-Deoxynojirimycin and 1-Deoxyaltronojirimycin   

15 December 2009 13,101 views 16 Comments

deoxynojirimycin1
Davies, Bagal, Lee, Roberts, Russell, Scott, Thomson. Org. Lett., 2009, ASAP. DOI: 10.1021/ol902533b. Article PDF Supporting Information Group Website

More of a post-ette than a full post, this tasty little nugget was found buried amongst effective reposts and updates.  Out there to give you a freaky sense of de ja vous are full papers on kendomycin, spirastrellolide, nakiterpiosin… finding something new was an effort!

What we’ve got here are a pair of closely related synthese of some poly hydroxylated piperidenes; notable for their glycosidase inhibitory effects.  Huh, I hear you say (actually, probably not – there are plenty of med-chemists reading this!) – glycosidase inhibitors have been notable in both anti-cancer and HIV therapies.

The first reaction worth considering is a bis-epoxidation and in-situ opening to provide four stereocenters in one pot.  The chemistry is racemic, but does an excellent job otherwise, garnering a useful yield and excellent diastereoselectivity.

deoxynojirimycin_1

The second reaction I liked followed on directly after this.  Taking the freshly installed alcohol and mesylating under standard conditions results in a trans-annular ring closure, as the proximal amine displaces the mesylate to give an aziridine.  In the formation of the mesylate, chloride is of course displaced (soaked-up by the triethylamine).  But it now comes to the fore, opening the aziridine to complete a formal ring contraction and provide a functional handle.

deoxynojirimycin_2

A bit of silver was sufficient in hydrolysing the primary chloride, setting the group very close to the target, and demonstrating a neat sequence of reactions to produce a heavily functionalised piperidine.

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16 Comments

  • Martyn says:

    You’ve still got some benzyl ethers on those structures at the top. Back to the hydrog lab!

  • OrgL3tt says:

    Are you serious? This one (http://pubs.acs.org/doi/abs/10.1021/ol902594b) was very nice!

  • metallabenzene says:

    Anyone else having trouble accessing JACS articles? Not quite articles, actually, just my RSS feed shows papers are up, then I click on them and the JACS website says “Error” does not exist or some such… Anyone else seeing this?

    • J-ster says:

      I’ve had this problem repeatedly for some considerable time. It appears that ACS release the article titles and links in their feeds and alerts, before the link works. If you can wait for a day or so, it’s usually working by then….an annoyance, though!

  • Sergio says:

    Ohh the coolest thing I ever seen.

  • OrgLettWorthy? says:

    I’m worried; we have actually got to the point where we have to discuss Org Lett worthiness?!?! I will shut up if anyone points at a novel bit of science!

  • Pilky01 says:

    To OrgLettWorthy,

    I personally can’t think of such an elegant way to get from the starting material in step 1 to the product of step 2 in a diastereoselective manner, in just 2 steps! Plus its a pretty versatile intermediate they have got to, maybe this is why the referees deemed it “Org Lett worthy”.
    I think its a really neat idea, im sure im not the only one.

  • Gui says:

    Isn´t the stereochemistry of the resulting aziridinium ion wrong? I mean the amine should attack the mesilate at the opposite face. And shouldn´t it attack the epoxide as well? Just thoughts. :)

    • gippgig says:

      The nitrogen attacks the mesylate carbon from below so the methylene in between ends up in front of the newly formed six-membered ring, as shown. Try making a model if you’re still confused.

    • a-non says:

      also, as far as the mesylate epoxide selectivity goes, if in the event that the nitrogen attacked the epoxide it would generate an alkoxide, which would bite back down – reforming the epoxide. Making this a non-productive pathway for the reaction.

  • - says:

    Come on, Tot. Syn.! We all make mistakes, admittedly I myself make more than others… But you’re just going to leave the errors in your title graphic, even after they were pointed out to you in the first comment? You left an error that you yourself acknowledged in the article before this, too.

    What, are you writing for Angewandte Chemie now?

    • Tot. Syn. says:

      Fixed, but it does take *quite* a lot of time to write these posts (about 4-5 hours per post), and I’m a crap proof reader. Ask the chaps that proofed my thesis for me…