title: Total synthesis of (+/-)-alpha-isosparteine, (+/-)-beta-isosparteine, and (+/-)-sparteine from a common tetraoxobispidine intermediate.
abstract: 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.
authors.affiliation: School of Chemistry, University of Leeds, Leeds, West Yorkshire LS2 9JT, United Kingdom.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Norcross
authors.forename: John P
authors.initials: JP
authors.lastname: Melbardis
authors.forename: Margarita Ferris
authors.initials: MF
authors.lastname: Solera
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sephton
authors.forename: Colin
authors.initials: C
authors.lastname: Kilner
authors.forename: Lev N
authors.initials: LN
authors.lastname: Zakharov
authors.forename: Peter C
authors.initials: PC
authors.lastname: Astles
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Warriner
authors.forename: Paul R
authors.initials: PR
authors.lastname: Blakemore
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D008958:Models, Molecular; D013034:Sparteine / Q000138:chemical synthesis*; D013237:Stereoisomerism
chemical_list: C534357:3,7-diallyl-2,4,6,8-tetraoxo-3,7-diazabicyclo(3.3.1)nonane; D019086:Bridged Bicyclo Compounds, Heterocyclic; C495809:bispidine; D013034:Sparteine