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Stenine Pt. 2   

22 January 2012 33,384 views 16 Comments

Zhang, Chen, Chen, Xie. ACIEE, 2011, 51, 1024. DOI: 10.1002/anie.201106587 Article PDF Supporting Information Group Website

Second time around for Stenine on TotallySynthetic - 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 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-brew 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 beta-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.

Neat stuff, but I have to say, awkwardly written.  Of course, my Mandarin (or Cantonese for that matter) is non-existent, but I expect better in Angewantde.  Perhaps, though, it’s because the writing in Aube’s paper is just so nice!

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16 Comments

  • Chang, P. F. says:

    awfuly silent here, all people must be on ACS website reading new shenvi paper.

  • TMSI says:

    That paper (Shenvi) is the bee’s knees. Just lovely work that me might actually use in our group.

  • ChezHeinz says:

    I am glad to see that the tradition of self promotion at TotallySynthetic lives on in the next generation

  • HPCC says:

    Taken from Wikipedia, “Most dialects of the Chinese language spoken in Yunnan belong to the southwestern subdivision of the Mandarin group, and are therefore very similar to the dialects of neighbouring Sichuan and Guizhou provinces. Notable features found in many Yunnan dialects include the partial or complete loss of distinction between finals /n/ and /?/, as well as the lack of /y/. In addition to the local dialects, most people also speak Standard Chinese (Putonghua, commonly called “Mandarin”), which is used in the media, by the government, and as the language of instruction in education.”

    So we’ll only forgive the non-existence of your Mandarin. We don’t need to care much about your Cantonese, TotSyn! :D

  • sKraB says:

    Very nice strategy and again the incredible use of tandem and cascade processes!!! I wonder if the stereogenic control was planned… a bit of luck, some thermodynamics considerations and you’ve got the right target ;)
    Just to talk about Shenvi’s work which is of course great… should be dedicated to Ed Vedejs who really developed the amino-directed hydroboration…

  • rhino says:

    This kind of freaks me out.

  • bubblegum says:

    Has anybody seen Baran’s JOC on the Ni-catalyzed isoprene cooligomerization? Crazy stuff. If this would have worked out…

  • MPH says:

    I’m looking for a summer intern in synthetic organic chemistry. If you are in your second, third, or fourth year of undergrad, send me your CV and research summary (what you have done before). It’s at a major pharmaceutical company in San Francisco bay area.
    MPHchemistry – at – gmail – dot – com

  • MSLT says:

    Snapshot of Zhang H.
    1985, Bachelor, Yunnan University
    1988, M.Sc. Shanghai Institute of Materia Medica
    1998, Ph.D. The Australian National University
    1999, Postdoc, Eli Lilly & Company
    2000, Professor, Yunnan University

    see: http://ynunews.cuepa.cn/show_more.php?tkey=&bkey=&doc_id=221315

  • Sid says:

    The azepan-2-one ing cyclization yield was 94% rather than 81% when aluminium powder and zinc wee used in 1:9 ———– also when i added 34% formic acid it yielded an even bette (95%) yield.

    See yah later Zhang. ;)

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  • Synthetic lives on in the next generation.

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  • HPCC says:

    Alas, this seems like the last post we’ll ever see from our dear chap, TotSyn… :/

  • alex says:

    Is your german perfect for Angewandte? :)