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13 September 2006 6,841 views 7 Comments


Chackalamannil, Shah, Ganguly, Chelliah, Kolotuchin, Buevich and McPhail, JACS, 2006, ASAP. DOI: 10.1021/ja065198n

An interesting synthesis by a group working at the Schering-Plough Research Institute. Certainly, this family of targets has received a load of attention by the pharma industry. Their synthesis starts with an aldehyde produced by Evans in his synthesis of (+)-A83543A, shown below:

This advanced fragment was elaborated with some nice, but fairly well-known chemistry to the cyclisation precursor. Treatment of this compound with base prompted little reaction, but heating in a microwave with HCl for one hour (quite a long time, really) allowed the aza-Michael addition to the now open unsaturated acid.


The intermediate then decarboxylated, and retro-Michael addition occured, returning to the original skeleton, sans-lactone. This is interesting, as the intermediates produced resemble the natural product very closely, but do not lead there directly. The group then resubmitted the product to an aza-Michael, this time using Sc(OTf)3 in acidic chloroform. This preformed the desired cyclisation, allowing them to complete the synthesis by reduction of the ketone. However, sodium borohydride delivered the hydride to the wrong face, resulting in epi-himgaline. They overcame this problem by using sodium (triacetoxy)borohydride, which formed a chelate to the neighbouring hydroxyl. This allowed delivery of the hydride form the correct face, and completion of the target.

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  • ramkrishna says:

    I am presented this paper in my group meeting and was wondering how can one do aza-Michael reaction in presence of 6N hydrochloric acid where the amine nitrogen will b eprotonated

  • Sam says:

    A couple of comments: the tricyclic aldehyde synthesis comes from the SPRI group (JMC 2005, 5884; ref 3c) which was originally carried out as part of a med chem project.

    Regarding Ramkrishna’s question: Protonated tertiary amine should be in a dynamic equilibrium with a small amount of free amine, even under highly acidic conditions. This free amine readily cyclizes due to entropic reasons.

    • hello chemistry says:

      aza-Michael reactions work very well in acidic conditions and the protonated form might be the cyclized one (more basic)… but I wonder why they do need to add Scandium? Brönstedt acids do not promote the intramolecular aza-Michael but Lewis acid do!! A bit surprizing but why not!!

  • ramkrishna says:

    Thank you for your reply. How about selective allylic bromination where there are two possibility…..th emore stable tertiarey readical less reactive or less stable more reactive. Do you agree with us

  • [...] 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! [...]

  • [...] was one of the first syntheses I blogged about! Another popular member is himgaline, with two (1, 2) previous blogging efforts here.  Adding to the wealth of chemistry here is going to take quite [...]

  • hello chemistry says:

    Structure of himagline is wrong! although thanks for blogging this great synthesis