title: Stereoselective Synthesis and Modelling-Driven Optimisation of Carane-Based Aminodiols and 1,3-Oxazines as Catalysts for the Enantioselective Addition of Diethylzinc to Benzaldehyde.
abstract: The reductive amination of (-)-2-carene-3-aldehyde, prepared in two steps from (-)-perillaldehyde, furnished 2-carene-based allylamines. tert-Butyloxycarbonyl (Boc) or carbobenzyloxy (Cbz) protection of the resulting amines, followed by stereoselective dihydroxylation in highly stereospecific reactions with OsO4 and subsequent deprotection, resulted in N-benzylaminodiols, which were transformed to primary and tertiary aminodiols. The reactions of the N-benzyl- and N-(1-phenylethyl)-substituted derivatives with formaldehyde led to highly regioselective ring closure, resulting in carane-fused 1,3-oxazines. The aminodiols and their 1,3-oxazine derivatives were applied as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. The best (R) enantioselectivity was observed in the case of the N-((R)-1-phenylethyl)-substituted aminodiol, whereas the opposite chiral direction was preferred when the 1,3-oxazines were applied. Through the use of molecular modelling at an ab initio level, this phenomenon was interpreted in terms of competing reaction pathways. Molecular modelling at the RHF/LANL2DZ level of theory was successfully applied for a mechanism-based interpretation of the stereochemical outcome of the reactions leading to the development of further 1,3-oxazine-based ligands, which display excellent (S) enantioselectivity (95 and 98 % ee) in the examined transformation.
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, 6720, Szeged, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szakonyi
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, 6720, Szeged, Hungary.
authors.forename: Árpád
authors.initials: Á
authors.lastname: Csőr
authors.affiliation: Institute of Chemistry, Eötvös Loránd University, P.O. Box 32, 1518, Budapest-112, Hungary.
authors.forename: Antal
authors.initials: A
authors.lastname: Csámpai
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, 6720, Szeged, Hungary. fulop@pharm.u-szeged.hu.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
mesh_terms: D000586:Amination; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry*; D001547:Benzaldehydes / Q000138:chemical synthesis / Q000737:chemistry*; D000081008:Bicyclic Monoterpenes; D002384:Catalysis; D008958:Models, Molecular; D039821:Monoterpenes / Q000138:chemical synthesis / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000588:Amines; D001547:Benzaldehydes; D000081008:Bicyclic Monoterpenes; D039821:Monoterpenes; D009942:Organometallic Compounds; D010078:Oxazines; C113988:2-carene; C033342:perillaldehyde; C454811:diethylzinc; C032175:benzaldehyde
keywords: aminodiol; diethylzinc; molecular modelling; perillaldehyde; stereoselective catalysis