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31 May 2006 12,110 views 13 Comments


Fukuyama, Okano and Tokuyama. JACS, 2006, 128(22), 7136. DOI: 10.1021/ja0619455

Continuing somewhat with a heterocyclic theme, Fukuyama has published a short (20 steps), flexable and rather sweet (13% yield) synthesis of yakatemycin. Especially interesting is his use of a ring contraction to put in the cyclopropane; being a spirocyclopropane, this is a reactive beast, so his strategy is rather nice:


Completed as the final step in the synthesis, one can imagine several fingers were crossed during the reaction! This paper also includes the use of an azide displacement / Staudinger reaction to create a ß-hydroxy amine from a chlorohydrin. Monoprotection of the amine with a nosyl group then allowed them to complete a ring-closing amination.
Althougth the nosyl group is fairly well known, I thought I’d show it in full:

nosyl.jpg = Ns

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  • Joe says:

    I think Ns is usually 4-nitro.

  • Tot. Syn. says:

    That would make more sense, but not where I’ve been checking. Apparently, either multiple isomers are used, or there is some ambiguity about this.

  • Jeremiah says:

    Hmmm…. I’m in the bottom of my class so, you’ll have to forgive me, but I don’t see how the reaction to form the spirocyclopropane works. Any help here?

  • Hap says:

    Deprotonation of the phenol O-H leads to the phenolate (which is like an extended enolate) – the O- can push electrons to the 4-position of the benzene ring, which attacks the mesylate carbon (Sn2-like); intramolecular ring closure to a cyclopropane is usually fast, so hydrolysis doesn’t occur instead. The amide is protected so aziridine formation doesn’t occur instead of cyclopropane formation. I think this step (or a related one) is used in the synthesis of related compounds (CC-1065?), but the conditions might be different.

  • Tot. Syn. says:

    It’s also used in Woodward’s “Sunday Afternoon” synthesis of prostaglandin. Ughhh. Such a good synthesis.

  • Jeremiah says:

    Oh man, that’s pretty clever.

  • Tot. Syn. says:

    A quick mechanism:

  • woodward says:

    I believe Ns can stand for 2 or 4 nitrobenzenesulfonyl, but the 2 is used more often for fukuyama’s chemistry b/c it is cheaper.

  • Larry says:

    Boger has been a big player with these types of compounds and the cyclopropane formation is well known, so I wouldn’t get too excited about this step (Chem Rev 1997, 787 DOI: 10.1021/cr960095g). Also, the conditions are the same as those used during Boger’s Yatakemycin synthesis.

    In addition to the 2-nitrobenzenesulfonyl chloride being cheaper, it also does not undergo an undesired side reaction during thiolate-induced deprotection (TL 1998, 39, 3889 DOI: 10.1016/S0040-4039(98)00684-4).

  • Tot. Syn. says:

    Thanks for that – those are useful references. I knew of Boger and Woodward’s work on this before – it’s just nice to see some proper classical chemistry going on.

  • ddd says:

    Fukuyama is a cool guy, I love his syntheses. Check up his mechanism problems on his homepage http://www.f.u-tokyo.ac.jp/~fukuyama/index-e.htm

  • Tot. Syn. says:

    Not to generalise at all, but some of the suggested solutions to the problems should be taken with a pinch (or a liberal spoon in isolated cases) of salt. However, on the whole they’re great! And seriously hard-core in places!

  • Neil says:

    Welcome Ajay.