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Stenine, Neostenine…   

10 April 2008 7,798 views 9 Comments

Aube, Frankowski, Golden, Zeng and Lei. JACS, 2008, ASAP. DOI: 10.1021/ja800574m. Article PDF Supporting Information Group Website ResearchBlogging.org

A short and concise synthesis of three members of the stemona alkaloid family by Jeffrey Aube’s group in Kansas. If you’re unaware of this class of natural products, this paper is an excellent place to start, as Aubé goes through the key disconnnection and step in the syntheses of Hart, Morimoto and Padwa. The biological activity of these little beasts is a bit of a mixed bag – to quote “insecticidal, anthelmintic, antitussive, and various neurochemical effects” – probably best not to have a stenine and lettuce sandwich.

The retrosynthesis of such a small natural product is always looks a bit complex, but matters are made worse here with so much going on in one pot! The key disconnection is a tandem diels-alder / Schmidt reaction, which they try several variants of in this paper, eventually settling for a tasty intermolecular number. The starting materials are simplicity itself – the dienophile was made using a Horner-Wadsworth-Emmons olefination from two simple precursors. A bit of Lewis acid, and hey-presto, two new rings and four stereocentres. They did isolate a mixture of diastereoisomers, but the product distribution was in their favour when using tin tetrachloride.

Next up was elaboration of that tricyclic core into the natural product. Here, nature itself lent a hand in the guise of awesome substrate control. Alkylation with ethyl 2-bromoacetate and then a reductive trans-lactonisation delivered the lactone easily, and they used substrate control again to append the missing methyl group. To illustrate how effective all this was, I’ve shown a diagram of the structure with the stereocentres coloured to indicate their source – red stereocentres were all imparted in the DA / Schmidt reaction, whilst the blue relied on a few simple substrate-controlled steps.

With the possibility of altering the stereochemical outcome of the DA / Schmidt event by changing the LA used, the group embarked on syntheses of other Stemona alkaloids featuring that stereochemistry. Using BF3.OEt2, they got the diastereomer required for Neostenine via an endo DA, and pursued the natural product. However, when it came to appending the exocyclic methyl group, substrate controlled alkylation would deliver the wrong stereochemistry, so they desided to do a substrate-controlled reduction of an exocyclic methylene group. How they installed the methylene group was what interested me:

This sequence (attributed to Greene) starts with an α-carboxylic acid formation, condensation with formaldehyde and then decarboxylation. A nice protocol.

A great little synthesis, but one of the best features of this paper is the actual writing – it’s incredibly well presented, and I learnt quite a bit reading it.


Frankowski, K.J., Golden, J.E., Zeng, Y., Lei, Y., Aubé, J. (2008). Syntheses of the Stemona Alkaloids (±)-Stenine, (±)-Neostenine, and (±)-13-Epineostenine Using a Stereodivergent Diels–Alder/Azido-Schmidt Reaction. Journal of the American Chemical Society DOI: 10.1021/ja800574m

InChiKey Dump:
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9 Comments

  • Taitauwai says:

    Wow…you changed your layout. Wooowwwww…..

  • milkshake says:

    Aube is under-rated in US. From his lecture here at the institute, he came across as an unasuming and very pleasant guy developing a simple-to use methodology. His version of intramolecular Schmidt reaction is now increasingly called Aube-Schmidt. I would not mind having him for my advisor. And there are obvious medchem implications of his work.

  • HPCC says:

    I really thought of him as a post-doc advisor. I really like his chemistry. I wonder if many other people are turned by the fact you’d have to spend 2 years in Kansas during your post-doc, though…

  • HPCC says:

    Another PI whose approach to chemistry as well as gentlemanship struck me is John L. Wood, formerly Yale, now Colorado. Really nice gentleman, and his seminar was full of unpublished data, giving credit to the students who not only think of the ideas but also spend countless hours in the lab. Someone I’d have been glad to work for.

  • milkshake says:

    Wood struck a mother lode with Brian Stoltz as one of his first student. (The guy synthesized a whole family of Staurosporine compounds, made unworkable disconnection to work, discovered few novel rearrangements in the process which he then used to make what was wanted – and then went on to work on more natural compounds because he finished Saturosporines in less than 3 years…)

  • gilgerto says:

    I love Brian Stoltz glasses…

  • shivani says:

    I like to spend 2 years with Prof. Brian Stoltz for post doc

  • shivani says:

    he is really great

  • [...] the first synthesis I blogged takes us back to 2008, and Aube’s neat work focusing around a tandem Diels-Alder / Schmidt reaction. This latest publication moves the research to Kunming, China, the home of it’s use as part [...]