Aube, Frankowski, Golden, Zeng and Lei. JACS, 2008, ASAP. DOI: 10.1021/ja800574m.
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 AubÃ© 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 Î±-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., AubÃƒÂ©, J. (2008). Syntheses of the Stemona Alkaloids (Ã‚Â±)-Stenine, (Ã‚Â±)-Neostenine, and (Ã‚Â±)-13-Epineostenine Using a Stereodivergent DielsÃ¢â‚¬â€œAlder/Azido-Schmidt Reaction. Journal of the American Chemical Society DOI: 10.1021/ja800574m
KUQDFUBALOGJTA-WMGIKXGKBZ FWFSEYBSWVRWGL-UHFFFAOYAT BSRDYCVTHYSZET-BIAAXOCRBB BSRDYCVTHYSZET-DYNIEEOBBZ ROIHYOJMCBKEER-KRJCKNDRBC VWNHORLEZGVBKM-ZNNLQBODBO VURUKKDUFIDCFK-QMPKGSCPBG