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Himgaline   

20 March 2007 6,347 views 9 Comments

himgaline_3.jpg

Evans and Adams. JACS, 2007, 129, 1048-1049. DOI: 10.1021/ja0684996.

I somehow missed this brilliant synthesis by Evan, published online in January, though in my defense, I was moving town and University :). Anyway, it’s a fantastic piece of work on a molecule we’ve seen at Tot. Syn. Towers a few months back, published by Samuel Chackalamannil at the Schering-Plough Research Institute. As mentioned in the paper, the bark from which this target was isolated has been used by native tribes of Papua New Guinea as a medical treatment, and related compounds have shown potent muscarinic antagonist activity. Evans approach to the molecule is quite diverse, and I can see Chemist of Sorts appreciation for this work. However, the complex architecture of the molecule make a simple retro rather difficult, so on with the forward!

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The complexity of the polycyclic system was built-up very quickly, using an auxiliary-biased IMDA to generate the trans-decalin as a single isomer in great yield. A substrate-controlled dihydroxylation and protection created the material required for the next step, an (is that the correct definate article, ChemBark?) HWE to append the sidechain, which had to be reduced in the next step to the allylic alcohol to prevent IMCA.
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Reoxidation then allowed them to complete the funky Roskamp reaction to install the beta-ketoester necessary to complete that ring, but they found the reaction went further, doing a conjugate addition to provide the enol ester instead. No matter – the michael addition with allyldiazoacetate went swimmingly, and the conjugate addition reversed under basic conditions.
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The next cyclisation was more simple; deprotection of the amine, dehydration to mine, and treatment with AcOH, caused addition to give the aldol product, isolated as its iminium ion. An interesting discussion about the geometry required of the transdecalin is in the paper, and makes for a good read.
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Relatively straight-forward transformations then created GB13, a known precursor to Himgaline, which was efficiently transformed to the target molecule using triacetoxyborohydride;

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9 Comments

  • Paul says:

    A substrate-controlled dihydroxylation and protection created the material required for the next step, an (is that the correct definate article, ChemBark?) HWE to append the sidechain, which had to be reduced in the next step to the allylic alcohol to prevent IMCA.

    Yup, I’d run an HWE but he’d run a Horner-Wadsworth-Emmons. That said, “a” and “an” are indefinite articles.

    And in case he’s a TotSyn reader, congrats, Drew.

  • Tot. Syn. says:

    9:05 and I’ve learnt something already. It’s going to be a good day :)

  • pi* says:

    Took me a couple of minutes to figure out what was going on in the “micheal addition” step. Wild transformation

  • The Canadian Chromatographer says:

    And thanks for teaching me that an aldehyde to a beta-keto ester is called a Roskamp reaction. I’m about to use it (once I get my aldehyde in my RBF).

  • Liquidcarbon says:

    Good one! Heathcock’s dihydro-proto-daphniphylline looks similar and is more impressive

  • synthon says:

    I know Roskamp never got around to doing (or at least publishing) detailed mechanistic studies on the process and was curious what is the prevailing wind on the mechanism? I was able to eliminate a Darzens-type mechanism and have some of my own alternative ideas, but was curious what others thought?

  • Knorkator says:

    Seems that Evans got a little confused with the LiClO4 in the HWE (looks a little odd). In the supporting information, LiCl is used!

  • Aqib Zahoor says:

    i am very enjoy this synthesis of himgaline (a piperidine )alkaloid. HWE reaction utilization in this synthesis is very good.
    Aqib

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