title: Zn-catalyzed enantio- and diastereoselective formal [4 + 2] cycloaddition involving two electron-deficient partners: asymmetric synthesis of piperidines from 1-azadienes and nitro-alkenes.
abstract: We report a catalytic asymmetric synthesis of piperidines through [4 + 2] cycloaddition of 1-azadienes and nitro-alkenes. The reaction uses earth abundant Zn as catalyst and is highly diastereo- and regioselective. A novel BOPA ligand (F-BOPA) confers high reactivity and enantioselectivity in the process. The presence of ortho substitution on the arenes adjacent to the bis(oxazolines) was found to be particularly impactful, due to limiting the undesired coordination of 1-azadiene to the Lewis acid and thus allowing the reaction to be carried out at lower temperature. A series of secondary kinetic isotope effect studies using a range of ligands implicates a stepwise mechanism for the transformation, involving an initial Michael-type addition of the imine to the nitro-alkene followed by a cyclization event. The stepwise mechanism obviates the electronic requirement inherent to a concerted mechanism, explaining the successful cycloaddition between two electron-deficient partners.
authors.affiliation: Department of Chemistry, Colorado State University, Ft. Collins, Colorado 80523, United States.
authors.forename: John C K
authors.initials: JC
authors.lastname: Chu
authors.affiliation: Department of Chemistry, Colorado State University, Ft. Collins, Colorado 80523, United States.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Dalton
authors.affiliation: Department of Chemistry, Colorado State University, Ft. Collins, Colorado 80523, United States.
authors.forename: Tomislav
authors.initials: T
authors.lastname: Rovis
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000577:Amides / Q000737:chemistry; D002384:Catalysis; D061565:Cycloaddition Reaction; D004583:Electrons; D008024:Ligands; D009574:Nitro Compounds / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry*
chemical_list: D000475:Alkenes; D000577:Amides; D008024:Ligands; D009574:Nitro Compounds; D010880:Piperidines; D015032:Zinc
references.citation: Angew Chem Int Ed Engl. 2013 Apr 2;52(14):3822-63
references.pmid: 23447554
references.citation: J Am Chem Soc. 2007 Feb 14;129(6):1480-1
references.pmid: 17283978
references.citation: J Am Chem Soc. 2006 Mar 1;128(8):2587-93
references.pmid: 16492042
references.citation: Angew Chem Int Ed Engl. 2005 Aug 5;44(31):4981-3
references.pmid: 16007721
references.citation: Chem Soc Rev. 2013 Feb 7;42(3):902-23
references.pmid: 23172010
references.citation: Acc Chem Res. 2012 Sep 18;45(9):1491-500
references.pmid: 22716926
references.citation: Chemistry. 2010 Dec 3;16(45):13330-4
references.pmid: 21038334
references.citation: Org Lett. 2006 May 11;8(10):2115-8
references.pmid: 16671795
references.citation: J Am Chem Soc. 2006 Jul 5;128(26):8418-20
references.pmid: 16802805
references.citation: Angew Chem Int Ed Engl. 2012 Apr 10;51(15):3653-7
references.pmid: 22383389
references.citation: Angew Chem Int Ed Engl. 2002 May 17;41(10):1650-67
references.pmid: 19750685
references.citation: Chem Commun (Camb). 2013 May 11;49(38):4024-6
references.pmid: 23549346
references.citation: Chem Commun (Camb). 2011 Feb 28;47(8):2381-3
references.pmid: 21165498
references.citation: Angew Chem Int Ed Engl. 2012 Dec 3;51(49):12330-3
references.pmid: 23124903
references.citation: Angew Chem Int Ed Engl. 2012 Feb 27;51(9):2084-7
references.pmid: 22271371
references.citation: Angew Chem Int Ed Engl. 2000 Oct 16;39(20):3558-3588
references.pmid: 11091406
references.citation: Angew Chem Int Ed Engl. 2002 May 17;41(10):1668-98
references.pmid: 19750686
references.citation: Chem Commun (Camb). 2012 Dec 14;48(96):11790-2
references.pmid: 23111410
references.citation: Chem Rev. 2013 Jul 10;113(7):5515-46
references.pmid: 23521039
references.citation: Chem Asian J. 2008 Jul 7;3(7):1111-21
references.pmid: 18494013
references.citation: Angew Chem Int Ed Engl. 2009;48(30):5474-7
references.pmid: 19554588
references.citation: Angew Chem Int Ed Engl. 2013 Oct 11;52(42):11088-91
references.pmid: 24038965