title: Proton donor acidity controls selectivity in nonaromatic nitrogen heterocycle synthesis.
abstract: Piperidines are prevalent in natural products and pharmaceutical agents and are important synthetic targets for drug discovery and development. We report on a methodology that provides highly substituted piperidine derivatives with regiochemistry selectively tunable by varying the strength of acid used in the reaction. Readily available starting materials are first converted to dihydropyridines via a cascade reaction initiated by rhodium-catalyzed carbon-hydrogen bond activation. Subsequent divergent regio- and diastereoselective protonation of the dihydropyridines under either kinetic or thermodynamic control provides two distinct iminium ion intermediates that then undergo highly diastereoselective nucleophilic additions. X-ray structural characterization of both the kinetically and thermodynamically favored iminium ions along with density functional theory calculations provide a theoretical underpinning for the high selectivities achieved for the reaction sequences.
authors: Department of Chemistry, Yale University, New Haven, CT 06520, USA.
authors: Simon
authors: S
authors: Duttwyler
authors: Shuming
authors: S
authors: Chen
authors: Michael K
authors: MK
authors: Takase
authors: Kenneth B
authors: KB
authors: Wiberg
authors: Robert G
authors: RG
authors: Bergman
authors: Jonathan A
authors: JA
authors: Ellman
mesh_terms: D000143:Acids; D002384:Catalysis; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D007700:Kinetics; D008968:Molecular Conformation; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry*; D011522:Protons; D012238:Rhodium; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D000143:Acids; D004095:Dihydropyridines; D006571:Heterocyclic Compounds; D010880:Piperidines; D011522:Protons; D012238:Rhodium; D009584:Nitrogen
references: Angew Chem Int Ed Engl. 2012 Sep 3;51(36):8960-9009
references: 22887739
references: Chem Soc Rev. 2011 Apr;40(4):1855-6
references: 21390392
references: Chem Soc Rev. 2008 Dec;37(12):2593-608
references: 19020674
references: Drug Discov Today. 2009 Nov;14(21-22):1011-20
references: 19729075
references: J Am Chem Soc. 2011 Jan 12;133(1):115-22
references: 21142031
references: Chem Rev. 2012 May 9;112(5):2642-713
references: 22352938
references: Angew Chem Int Ed Engl. 2009;48(52):9975-8
references: 19943297
references: Chem Soc Rev. 2011 Jul;40(7):4217-31
references: 21566810
references: J Am Chem Soc. 2010 Mar 24;132(11):3680-1
references: 20187642
references: J Am Chem Soc. 2008 Mar 19;130(11):3645-51
references: 18302381
references: J Med Chem. 2011 Oct 13;54(19):6405-16
references: 21755928
references: Chem Rev. 2010 Feb 10;110(2):575
references: 20143875
references: J Am Chem Soc. 2002 Sep 4;124(35):10272-3
references: 12197717
references: J Am Chem Soc. 2012 Mar 7;134(9):4064-7
references: 22356093
references: J Med Chem. 2011 Oct 27;54(20):7005-22
references: 21848318
references: J Med Chem. 2009 Nov 12;52(21):6752-6
references: 19827778
references: Nat Chem. 2010 Mar;2(3):167-78
references: 21124474
references: J Am Chem Soc. 2011 Apr 27;133(16):6449-57
references: 21452842
references: Anal Chem. 2010 Jun 15;82(12):4712-22
references: 20496871
references: Nature. 2008 Jan 24;451(7177):417-24
references: 18216847
references: Acc Chem Res. 2012 Jun 19;45(6):777
references: 22709449