jo8013512_si_005.cif (16.04 kB)
Total Synthesis of (±)-α-Isosparteine, (±)-β-Isosparteine, and (±)-Sparteine from a Common Tetraoxobispidine Intermediate
datasetposted on 2008-10-17, 00:00 authored by Neil R. Norcross, John P. Melbardis, Margarita Ferris Solera, Mark A. Sephton, Colin Kilner, Lev N. Zakharov, Peter C. Astles, Stuart L. Warriner, Paul R. Blakemore
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. (±)-α-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. (±)-β-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.
Common Tetraoxobispidine Intermediatereaction sequencetitle alkaloidsallylmagnesium bromidedlTotal Synthesisnucleophilic additionsallyl Grignard additionSakurai allylationenantioselective oxazaborolidinestereocontrolled fashionRCMcore synthontetraoxobispidine precursorsodium borohydrideIsosparteinereduction operations