Home » Guest Post, Still In The RBF


6 August 2011 16,730 views 17 Comments

Romo, Liu. ACIEE, 2011, 50, 7537-7540. DOI: 10.1002/anie.201102289 Article PDF Group Website

Guest Blogger: SPF

What if I’d ask you to synthesize this little molecule with six neighbouring stereocenters from biologically available material? Oh, by the way you can’t use any protecting groups and keep it short! Sounds impossible? Not according to Romo et al.. They’ve achieved the synthesis of this stereo-dense molecule in 10 steps from (R)-carvone (Mmmhhh spearmint). (+)-Omphadiol belongs to the africanane (guess where they grow) family of sesquiterpenes. Its brothers and sisters show some significant bioactivity, but due to insufficient amounts from extraction of natural sources, no further study was possible. There’s hope to change that with some synthetic effort. The synthesis starts off with a previously reported, Mn+III catalyzed, chemo- and regioselective, formal hydration of the enone in (-)-carvone. The resultant mixture of α-hydroxy ketone diastereoisomers was then cleaved to ketoacid with periodic acid.

Activation of carboxylic acid with tosylchloride and use of 4-pyrrolidinopyridine as nucleophilic promoter enabled aldol lactonization to a bicyclic β-lactone. The high diastereocontrol is explained by a chair-like transition state, where pseudo-equatorial is the best, no-clash, position for the isoproprenyl substitutent.

They then solve the problem of the required four carbon homologation quite elegantly, by reducing the β-lactone to the diol, converting it to the bromide, employing an intramolecular alkylation and quenching it with methyl iodide (Puuhhh…, that must have taken some time to figure out).

The original idea was to reduce the lactone, add vinyl magnesium bromide and use of a metathesis reaction to couple both olefins together. A subsequent Simmons-Smith would then give them their product. But surprise, surprise their product didn’t match NMR data. A crystal structure confirmed that they’ve actually made the 5-epi-product. This is due to a magnesium alkoxide on C9 forming an 8-membered metallocycle with the C5 Aldehyde, giving the undesired stereochemistry.

So, don’t use the diol? That proved to be troublesome and was only possible by finding a way around the DIBAL reduction/Grignard sequence above. The solution was the addition of an allyllithium which they had to make from transmetallation with allyltriphenyltin before adding the lactone. High yielding tandem isomerization/RCM of the diene, without any unfavoured 8-membered ring formation, afforded the enone.

After that, they regio- and stereoselectively reduced this enone to the right allylic alcohol and a Simmons-Smith cycolopropanation later they finally were holding (+)-omphadiol in their hands.

All in all, they’ve finished this sweet total synthesis in 10 steps, 5 of which are C-C bond forming, from (R)-carvone in 18% yield. Plus, they didn’t use a single protecting group to construct the 6 adjacent stereocenters.

(Editorial – another cracking Guest-Post, this time by SPF. Remember, if you’d like to give it a go, just contact me!)

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  • See Arr Oh says:

    Hey SPF! Great effort….who woulda thought Romo could build in all those contiguous stereocenters just using the original isopropylidene of carvone? (Awesome)

    By the way, you may wish to contact Paul to have hum scrub out all the greek letters in favor of their anglicizations (e.g. “gamma,” “beta”). They didn’t port over, so all I see are ?-marks.

    • Tot. Syn. says:

      Nuts – they appear okay in the editor, but then don’t show when I post. Okay, time to hack into the HTML again…

      Terpenes are absolutely amazing. Tasty, smelly and biological-active-y. A good friend works for a fragrance company, and has a rack of around 50 bottled terpenes. He smell the difference between all of them, but I could only manage about half. Awesome stuff.

    • gippgig says:

      Try Firefox (free download). The Greek letters display fine on my iMac.

      • Tot. Syn. says:

        Oh, that’s not Firefox getting it right – that was me sorting the HTML. Used to like Firefox, but Chrome is far better in my opinion. I see that Firefox is starting to ape Chrome’s simplicity, but it’s just too big and slow.

  • gippgig says:

    Speaking of Greek letters, that’s an alpha-hydroxy ketone & beta-lactone.

  • zeazunwoo says:

    how about the the ?-lactone was forged vis a [2+2] between the ketone and olefine ketone?

  • SPF says:

    Thanks SeeArrOh!
    Greek letters seem to be fine now. (Thanks for fixing Paul!)

    I guess I need to find some terpenes to smell.

    • chinstrap says:

      In the text you state, “This is due to 1, 5 chelation control during the metathesis reaction, causing both hydroxy groups to point to the same face of the molecule.'”

      Don’t you mean the 1,5 chelation control took place during the grignard addition and not the metathesis? Maybe I am missing something but I don’t see how the metathesis process could set the relative configuration between the 2 hydroxyl groups….Am I missing something here?

      • SPF says:

        Yes, you are right. Thanks for seeing this.
        During the grignard addition a magnesium alkoxide on C9 is formed (left hand part of the molecule). Together with the C5 Aldehyde, this forms an 8-membered metallocycle giving the (undesired) stereochemistry.

        Will be corrected.

  • Bierhoff says:

    This work seems to be important for syntheses of the africanane-type sesquiterpenoids!

    But, very recently, the synthesis of the other africananes was reported(see below).

    J. Org. Chem., 2011, 76 (15), pp 6258–6263
    DOI: 10.1021/jo2010186

    Let’s compare both reports!

  • Philip says:

    On the propiolactone formation, is there any evidence that this doesn’t go through a ketene intermediate? Those are “sort of” ketene forming conditions and the product is a ketene looking product.

    Just a thought. Maybe I should read the article.

  • BRSM says:

    I’m still getting all the greek letters as question marks in IE and Chrome on Win 7. If it helps, what I usually I do (which works for those two and Firefox, but not on my HTC) is just type a, b, g etc. and change the font to Symbol for that letter (easily done in the WordPress editor without resorting to HTML). Or you could do as See Arr Oh suggested and go for their English names.

  • gya says:

    Welwitindolinone C has fallen!
    Congrats to Garg and coworkers!

  • nicho says:

    SPF…my hats off to you for an excellent post!!! Great to see people getting excited about Total Synthesis.

    The Romo group really knows how to get around “roadblocks” so often encountered during a synthesis…great job guys! I had the opportunity to see Prof. Romo speak during my graduate years at the Univ of Alabama. Good to see that LA RAZA can also compete at making molecules in short order. Romo is a powerful inspiration to all hispanics and underrepresented minorities interested in organic chemistry!

  • LoveOChem says:

    Kinda curious how they can obtain 14:1 d.r. in converting 6 to 21. And why tBuLi is needed?

  • Ryan Mercer says:

    Doesn’t sound so much impossible but more a pain in the rear.