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2 June 2008 5,853 views 6 Comments

Bach and Selig. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800693. Article PDF Supporting Information Group Website ResearchBlogging.org

Another Overman target? I should think so; he completed back in ’89. But that doesn’t stop us mere mortals for following in his footsteps. Indeed, Bach seems to be snapping at them with this smart and original approach to this tightly functionalised natural product. There’s no mention of any biological activity in the paper, so let’s get on with the ‘synthetic challange’…

Bach kicks of with an astonishing pair of reactions to build the syn-6,5-fused ring system. First up is regio- and enatiomerically controlled [2+2] addition, using the somewhat strange ‘chiral complexing agent’ to engender asymmetry. It doesn’t come as any surprise that the group has been playing with this bad-boy for some time – and even though they have to use in quite an excess, the result is impressive, generating that cyclobutane in excellent yield. However, I don’t see a quoted e.e. – am I blind?!

The group initially planned to use a Wagner–Meerwein rearrangement to provide the desired cyclopentenone, but this failed. However, a ‘retro-benzilic ester rearrangement’ did the business in fantastic efficiency, giving them the desired product.

Three rings in, the next followed easily, requiring only deprotection of the amine and reductive amination to complete the second cyclopentane. They then used an interesting approach to provide the quaternary centre – a Johnson-Claisen rearrangement. This is a reaction with which I have some experience, and even though it required a fair-old roasting (normally 140 C, 10-18h), I’ve always managed fantastic yields (though I always used propionic acid rather than hydroquinone). The best thing (in my opinion) is the w/o – vac it down, and either do the next reaction or dump it directly onto the column. Nice.

Better still, they were able to gain some diastereomeric control, providing that key stereocenter in a decent yield. The final ring was then installed by alkylation of the freed amine with allyl bromide and RCM; only a few functional group transformations were then required to complete the target. Cracking strategy and implementation (and they even admit that the limiting step is the quantity of chiral complexing agent required early in the synthesis).

Selig, P., Bach, T. (2008). Enantioselective Total Synthesis of theMelodinus Alkaloid (+)-Meloscine. Angewandte Chemie International Edition DOI: 10.1002/anie.200800693

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  • pi* says:

    i remember seeing a paper, maybe in science?, where they used this catalyst…on some kind of related system, and got good ee’s, strange that they wouldnt put it in the paper…doesn’t take up much space (xx%ee)

  • milkshake says:

    very pretty scheme even if it was just a racemic route

    the chiral version is fairly involved to be a practical methodology though – using a photoreactor is trouble enough (and scale-limiting) and now you combine it with the long way from the expensive Kemp triacid to make the chiral photosensitiser…

  • SMILES says:


    I don’t have read this paper yet!!!

    Interestingly, the imide analogues of the catalyst, referred as derivatives of Kemp’s triacid, are extensively used in supramolecular chemistry (cf Rebek).

    Beautiful score of Bach!

  • MCC says:

    Nice 2+2. Could you estimate the %ee to be in the low to mid 90’s according to their original paper on this complexing agent?

  • milkshake says:

    Have you seen this dark 2+2, with organocatalyst and 2-alkoxy acrolein:

    JACS 129(29), 8930-1 (2007)

    The ees are reasonable and the amine organocatalysts are easy to make. The scope seems limited to el rich trialkyl subst C=C acceptor but I think it could be applied on this particular target

  • Potstirrer says:

    It is quite strange that there is no mention of the %ee anywhere in the paper although they clearly claim an enantioselective synthesis. In the supporting information they have a chiral HPLC trace that appears to be of optically pure material. Their optical rotation of the final compound is +96 whereas the isolation paper reports +134…not that I would take that to mean anything. What gives?