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3 April 2008 10,477 views 14 Comments

Qin, Shen and Zhang, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800566. Article PDF Supporting Information ResearchBlogging.org

Second showing in as many months for this popular alkaloid, this route from Yong Qin at the “Department of Chemistry of Medicinal Natural Products and, Key Laboratory of Drug Targeting, West China School of Pharmacy” (can’t get the website to work…) shows a few similarities to the recently covered route by Larry Overman, along with some interesting alternatives. Eschewing Overman’s ambitious palladium cascade designs, they went a bit old-school, planning a carbene insertion into an indole. However, like Overman, they hoped that the imine formed in this reaction would be attacked by a pendant amine to form the desired aminal center. Then, a rather familiar series of reactions would lead to product.

Let’s start by looking at the carbene insertion chemistry. Building the core of the indole from some chemistry developed by a former tutor of mine (Pat Bailey), they made a variety of substituted and protected indoles, and threw a few copper salts (and one rhodium catalyst) at it. Copper (I) triflate did the trick, and led them to product with a cracking yield.

Interestingly, with some substrates they obtained the product as a mixture of ketone and enol-ether isomers, where the proportion of one to the other was apparently a function of the protecting group on the indole nitrogen. The mixture of isomers, though, was dealt with swiftly by decarboxylating under Krapcho conditions to leave the unmolested ketone. I must say I’m amazed that 7h at 130 °C didn’t nuke the Boc group, though…

They then a little bother removing the tosyl group with the ketone present. Reduction of the carbonyl, removal of the Ts group and reoxidation was required, but soon they had a substrate bearing a remarkable similarity to that of Overman’s synthesis. The same palladium chemistry (initially developed by Cook) with a slightly different catalyst lead to the same result – formation of the five-membered ring. Then (surprise), Commins’ reagent gave them the corresponding enol-triflate, allowing appendage of the hydroxymethyl group by a Stille coupling – directly in this case using tri-n-butylstannylmethanol. Hmm.

And there we are; de-Boc and they’re done.

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  • Liquidcarbon says:

    This is a pretty hindered Boc. Heat can’t make its way to torture it. :)

  • lemi says:

    maybe they should try an asymmetric copper(I)-cat. cyclopropanation fashion using chiral ligands, so they can realize an enantioselective synthesis, but i can’t say the cascade still work under that circumstance… anyway, really nice work, congratuations to Pro. Qin

  • Madforit says:

    Can anyone give some explanation about the oxidative furan opening with Vo(acac)2/TBHP,to obtain a dialdeide?
    Thanks a lot…

  • antiaromatic says:

    I’m not sure I understand the need for an oxidation if your final result is a dialdehyde. The furan ring is by its very nature a masked dialdehyde. In fact, you can open furans to 1,4 dialdehydes with aqueous acid at reflux. There is no oxidation necessary.

  • Madforit says:

    I know that the furan ring is readily opened with a various acidic condition but i can t explain too the oxidative step
    ..if you are interested:asymmetic synth of castanospermine joc,1995,60,276
    Thnk you for the infos and sorry for my english.

  • antiaromatic says:

    The oxidative conditions open the furan to a gamma-keto alpha,beta-unsaturated aldehyde that is trapped internally by the alcohol to give the lactol. The K-selectride in the third step reduces the alpha beta unsaturated ketone to the corresponding alcohol (removes the alkene unsaturation and reduces the ketone). Hope that helps!

  • Madforit says:

    i saw the paper this morning,i ve always tought that the selectride did not reduce the alpha beta unsaturated ,but only the double co.this was an exercise in the style of the org.syn.workbook and i can t get the answer..
    Thanks a lot..
    p.s did you enjoy this synthesis?

  • antiaromatic says:

    K-selectride is a borohydride reagent, so it’s not surprising that it can reduce both 1,4 and 1,2. In a similar fashion, NaBH4 reduces cyclohexenone to a mixture of cyclohexanol and the corresponding allylic alcohol. Selectride is a softer source of H- and so tends to reduce 1,4. In that particular instance, as expected, they required 2 eq. of Selectride.

  • Madforit says:

    I agree,thanks a lot..
    This is an interesting target but i don t like this approach,
    look at:joc,1993,58,3397 and from the same group tetrahedr.asymm,1999,10,765.
    If you are interested tell me what do you think about.

  • cjdquest says:

    Qin’s route is elegant and efficient, although it only provides the racemic NP.

    The quality of papers coming out of PRC seems to be increasing. Late last year the Qin group also published the first TS of Communesin F -JACS 2007, 129, 13794 – (also the racemate) – a target class that had been pursued by many high-powered groups in the US: Funk, Overman, Stoltz, and Trost.

    Anyone know much more about Prof. Qin?

  • cjdquest says:

    google translate choked on Prof. Qin’s page… but the chinese version loaded OK. could at least make out the structures of some targets: dragmacidin E and flustramine B

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