Norcross Neil R, Melbardis John P, Solera Margarita Ferris, Sephton Mark A, Kilner Colin, Zakharov Lev N, Astles Peter C, Warriner Stuart L, Blakemore Paul R
School of Chemistry, University of Leeds, Leeds, West Yorkshire LS2 9JT, United Kingdom.
J Org Chem. 2008 Oct 17;73(20):7939-51. doi: 10.1021/jo8013512. Epub 2008 Sep 18.
The three title alkaloids were separately prepared in stereocontrolled fashion from a common tetraoxobispidine precursor, 3,7-diallyl-2,4,6,8-tetraoxo-3,7-diazabicyclo[3.3.1]nonane (16). Bisimide 16 was generated from malonate via acid promoted cyclization of the Knoevenagel condensation adduct 1,1,3,3-propanetetracarboxamide. (+/-)-alpha-Isosparteine (dl-2) was elaborated from 16 in 28% overall yield by a two-directional synthetic sequence composed of four reactions: double addition of allylmagnesium bromide, ring-closing olefin metathesis (RCM), hydrogenation, and borane mediated reduction. (+/-)-beta-Isosparteine (dl-3) was targeted along similar lines by a strategic reversal in allylation and reduction operations on the core synthon. Thus, 16 was advanced to dl-3 in five steps and 12% overall yield by a reaction sequence commencing with sodium borohydride mediated reduction and followed by double Sakurai-type allylation of the resulting bishemiaminal. The synthesis of dl-3 was concluded by RCM and then global reduction (H2, Pd/C; LiAlH4). The final target, (+/-)-sparteine (dl-1), was secured in six steps and 11% overall yield from 16 by monoreduction and Sakurai allylation, followed by allyl Grignard addition and then RCM and global reduction as before. Reasons for the inherent C2-type regioselectivity of net double nucleophilic additions to tetraoxobispidines are discussed and enantioselective oxazaborolidine mediated reduction of the N,N'-dibenzyl congener of 16 is reported.
这三种标题生物碱分别由一个共同的四氧代双哌啶前体3,7-二烯丙基-2,4,6,8-四氧代-3,7-二氮杂双环[3.3.1]壬烷（16）以立体控制的方式制备。双酰亚胺16由丙二酸酯通过Knoevenagel缩合加合物1,1,3,3-丙烷四羧酰胺的酸促进环化反应生成。（±）-α-异鹰爪豆碱（dl-2）由16通过一个由四个反应组成的双向合成序列以28%的总收率合成：烯丙基溴化镁的双加成、关环烯烃复分解反应（RCM）、氢化反应以及硼烷介导的还原反应。（±）-β-异鹰爪豆碱（dl-3）通过对核心合成子进行烯丙基化和还原操作的策略性反转，沿着类似的路线进行合成。因此，16通过一个反应序列分五步以12%的总收率转化为dl-3，该反应序列始于硼氢化钠介导的还原反应，随后是所得双半胺的双Sakurai型烯丙基化反应。dl-3的合成通过RCM反应，然后进行整体还原反应（H2，Pd/C；LiAlH4）完成。最终目标产物（±）-鹰爪豆碱（dl-1）由16通过单还原反应和Sakurai烯丙基化反应，接着进行烯丙基格氏加成反应，然后如前所述进行RCM反应和整体还原反应，分六步以11%的总收率得到。文中讨论了对四氧代双哌啶进行净双亲核加成反应时固有的C2型区域选择性的原因，并报道了对16的N,N'-二苄基类似物进行对映选择性恶唑硼烷介导的还原反应。
