3-Trifluoromethanesulfonamido-pyrrolidine:A General Organocatalyst foranti-Selective Mannich ReactionsMickael Pouliquen, Jerome Blanchet,* Marie-Claire Lasne, and Jacques RoudenOrg. Lett. 2008Jared HammillBackground• Classical method for β-amino ketone andaldehyde formation• Described as early as 19th century• Carl Mannich extended the chemistry in the early1900’sMannich, Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak und Antipyrin, C. Arch. Pharm. 1912, 250, 647.OH HNHRRNH HR R++OROR-+NH HR R+ORNR2RRRUtility of Mannich Bases:•Polymer chemistry (hardeners, crosslinkers,and reaction accelerators)•Plant protection•Paint•Pharmaceuticals:Arend, M.; Westermann, B.; Risch, N. Angew Chem., Int. Ed. 1998, 37, 1044-1070Early Limitations:• Formation of unwanted side productsbisketones Multiple reaction bis-Mannich base•Regioselectivity with unsymmetrical ketones•Scope: predominantly formaldehyde•Stereoselectivity: minimal to none•Low concentrations of reactive speciesOH HNHRRNH HR R++OROR-RR+Arend, M.; Westermann, B.; Risch, N. Angew Chem., Int. Ed. 1998, 37, 1044-1070Enolates & EnaminesEnolates:RegioselectivityNucleophilicity allows for aminomethylation and alkylationEnamine:Arend, M.; Westermann, B.; Risch, N. Angew Chem., Int. Ed. 1998, 37, 1044-1070D. Seebach et al., Helv. Chim. Acta, 1984, 67, 1593Preformed Mannich Reagents [electrophile] reaction times at temperaturesArend, M.; Westermann, B.; Risch, N. Angew Chem., Int. Ed. 1998, 37, 1044-1070Iminium Salts:Imines(S)-Proline leads to high syn-selectivityProposed transition state:But what about anti-selectivity?Arend, M.; Westermann, B.; Risch, N. Angew Chem., Int. Ed. 1998, 37, 1044-1070Anti-Mannich CatalystsCordova et al, Tet Lett, 2002, 43, 7749-7752Jorgensen et a, JACS, 2005, 127, 18296-18304Barbas et al, JACS, 2007, 129, 288-289Maruoka et al, Tet Let. 2006, 47, 8467-8469List et al, Agew. Chem., 2007 46, 609-611Zhang et al, JACS, 2006, 128, 9630-9631Coulombic interactionCatalyst: Year Mol% Anti:Syn %ee % YieldI 2002 2010-19:1 74-92 50-70II 2005 10 9:1 63-83 63-83III 2005 1-5 19->20:1 98->99 70-92IV 2005 0.5-2 11->20:1 97->99 92->99V 2006 10 10->20:1 90-94 88-99VI 2007 30 >19:1 90-98 50-92Syn-selectivity vs. Anti-selectivityTanaka et al, JACS, 2006, 128, 9630-9631Proposed Transition StateTest hypothesis by varying acidity of sulfonamido proton3-sulfonamidopyrrolidines2 steps from commercially available precursorvs. 14 steps to catalyst IIIaProposed T.S.R E+ Catalyst Yield % Catalyst Yield % Anti:SynMs MsCl 5a 63 6a 100 2:1Ns NsCl 5b 74 6b 92 4:1Tf Tf2O 5c 94 6c 100 9:1Nf Nf2O 5d 88 6d 100 1:1Tanaka et al, JACS, 2006, 128, 1040-1041Conclusion:•Availability: 2-step synthesis(R-3-aminopyrrolidine:$82.50/g from Sigma-Aldrich)•Scope: linear or branched aldehydes and ketonesCatalyst: Year Mol% Anti:Syn %ee % YieldI 2002 2010-19:1 74-92 50-70II 2005 10 9:1 63-83 63-83III 2005 1-5 19->20:1 98->99 70-92IV 2005 0.5-2 11->20:1 97->99 92->99V 2006 10 10->20:1 90-94 88-99VI 2007 30 >19:1 90-98 50-92Their's 2007 5 10->20:1 97-99 70-99Future Work:• Further extension of three-componentMannich Reaction• Investigation into more labile-protectinggroups (n-Boc vs PMP)• Application in enantioselective total
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