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Manassantin A   

26 October 2006 11,450 views 15 Comments

manassantin_a.jpg
Hanessian, Reddy and Chahal. Org. Lett.,2006, ASAP. DOI: 10.1021/ol0621710.

This C2 symmetric target shows an opportunity for a two directional synthesis, but as the other members of the family lack this feature, Hanessian et al used a more linear route for part of this synthesis. Most impressive (although by no means novel) was the methylation of the alkene, delivering two methyl groups in excellent d.r. Addition of lithium dimethylcuprate with TMSCl gave the anti product, which was enolised and alkylated with methyl iodide to give the syn diastereoisomer as the major product.

manassantin_a_2.jpg

Other than that, this is a really nice synthesis of a structurally interesting target, utilising the aforementioned symmetry to their advantage later in this paper for the title compound.

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15 Comments

  • Prelim Passed says:

    How much do you think the potassium cation played a role in that second alkylation? I wonder if they tried just throwing MeI into the first pot. I’m too lazy to read the ref’s to his own papers he puts for that step.

  • Alastair says:

    Agree, thought there would have been some method for trapping the enolate with a methyl. Maybe it had more to do with the selectivity of the addition, rather than that they couldn’t actually methylate.

  • regular chem says:

    I may beg to disagree here. The first addition may actually produced silyketeneacetal first before it was hydrolyzed to the ester. However, for conjugated addition, many times you need TMSCl to activate the conjugated acceptor in order for the transformation to proceed. I don’t know which is the case here.

  • synthon says:

    The TMSCl (or BF3 – Yamamoto cuprate) is needed to achieve conjugate addition to unsaturated esters; in this case nearly 20 equiv TMSCl and 6 equiv Gilman reagent! You can indeed trap that enolate with electrophiles, my guess is the selectivity stinks. The kinetics of the K-enolate (nucleophilicity) are far better than lithium, especially at -78, which translates into better selectivity. There is a paper which describes the mechansm of conjugate addition of cuprates vs alkyl copper species which I will try and dig up.

  • Tot. Syn. says:

    Cheers for that Synthon – I’m sure we’ll all appreciate the paper too…

  • aa says:

    when is sharpless going to come up with the asymmetric dimethylation so we can avoid this kind of tedious preparation. forget about “click” chemistry barry, put that gigantic cranium to some real use.

  • diketene says:

    The author had two DIBAL reduction of esters. Once was reduced to an aldehyde and the other was reduced to an alcohol. Is the outcome of DIBAL reduction substrate dependent or condition dependent? Any idea?

  • Tot. Syn. says:

    I’ve done a few recductions of esters with DIBAL, and if you control the temperature well (eg. -78, addition of cold DIBAL), you can isolate the aldehyde in good yield. Otherwise, nuke it down to the alcohol no problem at zero.

  • synthon says:

    The review I was thinking of was done by Simon Woodward, Chem. Soc. Rev. (2000), 29, 393. A couple other of my favorite copper reviews: Nakamura, Angew. Chem. Int. Ed. (2000), 39, 3750 and Krause, Angew. Chem. Int. Ed. (1997), 39, 186.

    For a related review on Yamamoto cuprates (very cool stuff): Yamamoto, Angew. Chem. Int. Ed. Engl. (1986), 25, 947

    Cheers!

  • DIBAL says:

    To diketene. If the ester has a coordinating group in alpha-position (usually OBn, OPMB or OMe better than OSiR3), the intermediate from the DIBAL addition to the C=O is stable until quench. A breakdown of this intermediate leads to the aldehyde, which is more reactive than the ester -> overreduction.
    If no stabilizing group is close enough, one usually goes down to the alcohol and then oxidizes to the aldehyde.
    So the answer is; Yes, it is substrate dependent.

  • WillisWill says:

    You can often (not always) reduce an ester to an aldehyde using DIBAL in the absence of the co-ordinating group if you’re careful with your equivalents and keep the reaction temp

  • WillisWill says:

    below -78 degrees (cold bath and slow addition)

    hmm, server squirrel seems to have gotten the end of my earlier post

  • KUN says:

    Here is one more publication from Evans-Himgaline syntheis i 2007,In his paper he reports the ester redution to alcohol.at -78 C,can any body tell me why is it?

  • pm says:

    Can DIBAL reduce amides?

  • Saiful Islam says:

    I think it is authentic