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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 its 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 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 silica-bound KOH as well as ultrasound. These conditions aren’t exactly typical, and Zhang doesn’t give details. The sonication maybe breaks up silica-KOH particles to provide maximum surface area for the heterogeneous reaction conditions.

This strange reaction mixture delivers excellent yield and good control of asymmetry including four new stereocenters constructed with (apparent) complete diastereomeric control. However, 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.

Zhang gets to stenine quite neatly, firstly by removing the remaining methyl ester under Krapcho conditions. An alkylation with ethyl bromoacetate adds the carbon for the required gamma-lactone, and a 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 was reduced by firstly forming the thioamide using Lawesson’s reagent, and reduction with Raney nickel delivered the product.