A stereoselective approach to the azaspiro[5.5]undecane ring system using a conjugate addition/dipolar cycloaddition cascade: application to the total synthesis of (+/-)-2,7,8-epi-perhydrohistrionicotoxin

The Journal of Organic Chemistry
Michael Wilson, Albert Padwa

Abstract

An efficient stereocontrolled route to the spirocyclic perhydrohistrionicotoxin derivative (+/-)-2,7,8-epi-PHTx (4) is described. The reaction of 2-butyl-3-(methoxymethoxy)cyclohexanone oxime with 2,3-bis(phenylsulfonyl)-1,3-butadiene gives rise to a 7-oxa-1-azanorbornane cycloadduct in high yield. The formation of the bicyclic isoxazolidine arises from conjugate addition of the oxime onto the diene to give a transient nitrone which then undergoes an intramolecular dipolar cycloaddition. Treatment of the cycloadduct with 5% Na/Hg results in reductive nitrogen-oxygen bond cleavage to furnish an azaspiro[5.5]undecane. Elaboration to the dihydropyridin-4(1H)-one 24 was followed by stereoselective conjugate addition using n-pentyl cuprate to give azaspirocycle 25. The stereochemistry of the product was deduced from an X-ray crystal structure of the corresponding N-tosylhydrazone derivative. The dominant factor controlling the stereochemistry of the conjugate addition is the A(1,3)-strain present in the planar vinylogous amide. A stereoelectronically preferred axial attack by the organocuprate at the beta-position leads to the observed diastereoselectivity. Azaspirocycle 25 was transformed into 2,7,8-epi-PHTx (4) in five additional ...Continue Reading

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Citations

May 11, 2016·Journal of the American Chemical Society·Pernille H PoulsenKarl Anker Jørgensen
Dec 17, 2016·Chemical Reviews·Mathéo BerthetJean Martinez
Mar 16, 2017·Organic Letters·Chunyu WangLiansuo Zu
Jun 2, 2017·The Journal of Organic Chemistry·Rungroj SaruengkhanphasitIain Coldham
Jan 24, 2017·Journal of Computational Chemistry·Haiyan Yuan, Jingping Zhang
Jul 12, 2018·Organic & Biomolecular Chemistry·Samuel D GriggsPaul A Clarke
Mar 2, 2013·Chemical & Pharmaceutical Bulletin·Satoshi Yokoshima
Nov 8, 2016·Organic & Biomolecular Chemistry·Rachel C FurnivalIain Coldham
Mar 6, 2009·Journal of Combinatorial Chemistry·Xin KuHong Liu
Sep 3, 2010·The Journal of Organic Chemistry·James J Sahn, Daniel L Comins
Jul 29, 2011·Organic Letters·Yohei AdachiTohru Fukuyama
Sep 3, 2014·The Journal of Organic Chemistry·Sergey V Tsukanov, Daniel L Comins
Jul 22, 2017·The Journal of Organic Chemistry·Nicolas D SpicciaAndrea J Robinson

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