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Totally Synthetic by Paul H. Docherty, 22 January 2012

Total Synthesis of Stenine


J. Chen, J. Chen, Y. Xie, H. Zhang, Angew. Chem. Int. Ed. 2012, 51, 1024-1027.

DOI: 10.1002/anie.201106587

Second coverage of Stenine - the first synthesis described was 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 of Chinese herbal medicine. That doesn’t alter the core of the synthetic strategy, though, as Hongbin Zhang seems to agree with Aube that building the cyclohexane core first is the key to this target.

Zhang, however, prefers the use of a double Michael addition, enhanced with a little catalyst control to engender asymmetry in the system. Using Evans’ work, a catalyst derived from (1R,2R)-( -)-1,2-diaminocyclohexane was employed in conjunction with some silica-bound KOH as well as ultrasound. These conditions aren’t exactly typical, and Zhang doesn’t postulate much in the way of reason. My feel is that the sonication is to break-up silica-KOH particles to provide maximum surface area for the heterogeneous reaction conditions, but I’m not speculating any further than that!

A strange reaction mixture it may be, but it delivers the goods in excellent yield and control of asymmetry. Four new stereocenters constructed with (apparent) complete diastereomeric control is no mean feat, but the next reaction proves their strategy to be a winner. Under reductive conditions, the nitro-group is activated and forms not just the azepanone but the pyrrolidine too, completing the core of the target in two steps. The change in stereoelectronics also seems to cause a tautomeric shift, as the enol now seems to prefer a β-keto-ester existance.

So often this is the point in an otherwise tasty synthesis where the wheels come-off as the synthetic team have to faff about with functional group transformations and carbon chain homologations to get to their target. However, Zhang gets to stenine quite neatly, firstly by nuking the remaining methyl ester under Krapcho conditions. An alkylation with ethyl bromoacetate adds the carbon required for the required gamma-lactone, and a bit of gentle reduction delivered the final ring.

Of course, they’re not quite there - alkylation of the lactone with methyl iodide provided the carbon skeleton in reasonable yield, whilst the extraneous oxidation on their medium ring with dealt with by firstly forming the thioamide using Lawesson’s reagent, and reduction with Raney nickel delivered the product.