Synthesis of Optically Active  Amino Alcohols Changyou Yuan Department of Chemistry Michigan State University -A survey of major developments after the year 2000

Important Free or Functionalized  Amino Alcohols

Strategies Available for the Synthesis of Optically Active  Amino Alcohols

Outline Part 1: Addition reactions  Addition of Carbanions to Imines  Radical Addition to Oximes, Hydrazones Part 2: Reduction reactions  Asymmetric Hydrogenations of α-N-substituted β- Keto Esters Part 3: Coupling Reactions  Cross-Coupling of Ferrocenylideneamine and Ferrocenecarboxaldehydes  Cross-Coupling of Benzylideneamines with Aldehydes  Proline-Catalyzed Assemble of Aldehydes, Ketones, and Amine or Azodicarboxylic Acid Esters Part 4: Kinetic Resolution of Racemic Epoxides Conclusion

Outline Part 1: Addition reactions  Addition of Carbanions to Imines  Radical Addition to Oximes, Hydrazones Part 2: Reduction reactions  Asymmetric Hydrogenations of α-N-substituted β- Keto Esters Part 3: Coupling Reactions  Cross-Coupling of Ferrocenylideneamine and Ferrocenecarboxaldehydes  Cross-Coupling of Benzylideneamines with Aldehydes  Proline-Catalyzed Assemble of Aldehydes, Ketones, and Amine or Azodicarboxylic Acid Esters Part 4: Kinetic Resolution of Racemic Epoxides Conclusion

Lithiation of O-benzyl Carbamates–imine Addition S.Arrasate, E.Lete, N.Sotomayor. Tetrahedron: Asymmetry, 2002, 13, 311–316.

Asymmetric Lithiation of O-benzyl Carbamates–imine Addition S.Arrasate, E.Lete, N.Sotomayor. Tetrahedron: Asymmetry, 2002, 13, 311– CO 2 2. CH 2 N 2

Asymmetric Lithiation of O-benzyl Carbamates–imine Addition R1R1 R2R2 TempYield(%)D.Re.e. (%) OCH 3 H -78 o C 6h >95:5 56 (96) 76 (91) S.Arrasate, E.Lete, N.Sotomayor. Tetrahedron: Asymmetry, 2002, 13, 311–316.

Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines SulfoxideT ( o C)Yield (%)De (%) (S) – 1 (R) – 1 (S) – 1 (R) >98 J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5,

Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines SulfoxideT ( o C)Yield (%)de at C(2) (%) (S) – 2 (R) – 2 (S) – 2 (R) J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, C-1C-2 (S)-sulfinyl ketimine(S)-(2) (R)-(2) RSRS SSSS

J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines-Stereocontrol

J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines - stereocontrol

J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, M.Crucianelli, P.Bravo, A.Arnone, E.Corradi, S.V.Meille, M.Zanda. J. Org. Chem. 2000, 65, Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines – Demasking Steps

Radical Addition of Hydroxymethyl and Vinyl Groups to C=N Bonds G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, G.K.Friestad, S.E.Massari. Org. Lett. 2000, 2,

Hydroxymethyl Addition to Oxime Ethers G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, G.K.Friestad, S.E.Massari. Org. Lett. 2000, 2,

Hydroxymethyl Addition to Hydrazones RMe t BuiPrPh Anti-7:syn-7 Yield (%) 79: : :4 80 >98:2 57 G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, G.K.Friestad, S.E.Massari. Org. Lett. 2000, 2,

Tandem Thiyl Addition-Cyclization: Vinyl Addition to Hydrazones RYield(%)Ratio (anti/syn) Me7790:10 t Bu6794:6 i Pr6198:2 Ph49>98:2 G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, G.K.Friestad, T.Jiang, G.M.Fioroni. Tetrahedron: Asymmetry, 2003, 14, 2853–2856.

Diastereocontrol in Radical Addition – Cyclization Beckwith-Houk Model R A Value (kcal/mol) dr of 7dr of 8 Me1.679:2190:10 t Bu1.885:1594:6 i Pr2.296:498:2 Ph2.9>98:2 G.K.Friestad, S.E.Massari. Org. Lett. 2000, 2, G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, G.K.Friestad, T.Jiang, G.M.Fioroni. Tetrahedron: Asymmetry, 2003, 14, 2853–2856.

Comparison of the Addition Reactions Stereocontrol De/ee (%) Yield (%) Anti or syn Chiral amine (additive) >95:5/ syn Sulfinylketimine and sulfinyl carbanions 60:40~ 90:10 / both Substrate control and Beckwith - Houk model 80:20~ >98:2/ anti

Outline Part 1: Addition reactions  Addition of Carbanions to Imines  Radical Addition to Oximes, Hydrazones Part 2: Reduction reactions  Asymmetric Hydrogenations of α-N-substituted β- Keto Esters Part 3: Coupling Reactions  Cross-Coupling of Ferrocenylideneamine and Ferrocenecarboxaldehydes  Cross-Coupling of Benzylideneamines with Aldehydes  Proline-Catalyzed Assemble of Aldehydes, Ketones, and Amine or Azodicarboxylic Acid Esters Part 4: Kinetic Resolution of Racemic Epoxides Conclusion

C.Mordant, P.Dünkelmann, V.R,Vidal, J.P.Genet. Eur. J. Org. Chem. 2004, Asymmetric Hydrogenations of α-N-substituted β-keto esters - Preparation the Syn  – Amino Alcohols RYield (%)de (%)ee (%) C3H7C3H BnO-C 4 H >99 C 5 H C 15 H 31 iPr

Asymmetric Hydrogenations of α-N-substituted β-keto esters - Preparation the Anti  – Amino Alcohols SubstrateSYNPHOS configurationYield (%)de anti (%)ee (%) R = C 3 H 7 R = BnO-C 4 H 8 R = C 5 H 11 R = C 15 H 31 R = iPr SRSRSRSRSRSRSRSRSRSR (2S, 3S) 93 (2R, 3R) 92 (2S, 3S) 93 (2R, 3R) 91 (2S, 3S) 91 (2R, 3R) 96 (2S, 3S) 96 (2R, 3R) 97 (2S, 3S) 96 (2R, 3R) C.Mordant, P.Dünkelmann, V.R,Vidal, J.P.Genet. Eur. J. Org. Chem. 2004,

Outline Part 1: Addition reactions  Addition of Carbanions to Imines  Radical Addition to Oximes, Hydrazones Part 2: Reduction reactions  Asymmetric Hydrogenations of α-N-substituted β- Keto Esters Part 3: Coupling Reactions  Cross-Coupling of Ferrocenylideneamine and Ferrocenecarboxaldehydes  Cross-Coupling of Benzylideneamines with Aldehydes  Proline-Catalyzed Assemble of Aldehydes, Ketones, and Amine or Azodicarboxylic Acid Esters Part 4: Kinetic Resolution of Racemic Epoxides Conclusion

Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4, Cross-Coupling of N-Tosyl Ferrocenylideneamine and Ferrocenecarboxaldehydes Imine 2 ( X ) 3 yield(%) 4 yield(%) 5 yield(%) Me Bn Ph NMe 2 NHSO 2 Ph SO 2 Ph Ts Ms Trace trace

Cross-Coupling of Planar Chiral N-Tosyl Ferrocenylideneamine and Ferrocenecarboxaldehydes aldehyde 7 (% ee)imine 89 yield (%)%ee 9 R 1 =Me (95) R 1 =Me R 1 =I (95) R 1 =Br (97) R 1 = H R 2 =Me R 2 =I R 2 =Br R 2 =Me R 2 =I R 2 =Br Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4,

Reaction Mechanism of Cross-Coupling with N-Tosyl Ferrocenylideneamines Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4,

Reaction Mechanism of Cross-Coupling with N-Tosyl Ferrocenylideneamines Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4, % enantiopure 97 % enantiopure

Cross-Coupling of Benzylideneamines with Aldehydes iminealdehydeyield (%)Syn/anti X=Ms X=Ts 11 R=H, Me, OMe 14 R=H, Me, OMe 11 R=H, Me, OMe, Cl 14 R=H, Me, OMe, Cl /50 – 54/56 60/40 – 67/33 70/30 – 87/13 95/5 – 97/3 Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4,

Cross-Coupling of Benzylideneamines with Aldehydes Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4,

Proline-Catalyzed Direct Asymmetric Mannich Reaction B.List, P.Pojarliev, W.T.Biller, H.J. Martin. J. Am. Chem. Soc. 2002, 124,

Proline-Catalyzed Assemble of Aldehydes, Ketones, and Azodicarboxylic Acid Asters N.S. Chowdari, D. B. Ramachary, C.F.Barbas. Org. Lett., 2003, 5,

StereocontrolDe/ee (%) Yield (%) Anti or syn Ferrocenylideneamines Ferrocenecarboxaldehydes >95/ anti planar chiral benzaldehyde chromium complexes 90/ > syn Proline 20-95/ 60-> syn Comparison of the Cross-Coupling Reactions

Outline Part 1: Addition reactions  Addition of Carbanions to Imines  Radical Addition to Oximes, Hydrazones Part 2: Reduction reactions  Asymmetric Hydrogenations of α-N-substituted β- Keto Esters Part 3: Coupling Reactions  Cross-Coupling of Ferrocenylideneamine and Ferrocenecarboxaldehydes  Cross-Coupling of Benzylideneamines with Aldehydes  Proline-Catalyzed Assemble of Aldehydes, Ketones, and Amine or Azodicarboxylic Acid Esters Part 4: Kinetic Resolution of Racemic Epoxides Conclusion

Aminolytic Kinetic Resolution with Amines G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6, R1R1 R2R2 T ( o C)t (h)Yield (%)Ee of 4 (%)Ee of 2 (%) H OMeOMe H OMe HH rt -10 rt 0 rt >

Aminolytic Kinetic Resolution with Amines G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6,

G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6, Aminolytic Kinetic Resolution with carbamates (S,S)-catalyst (1.5 mol%) Additive (3 mol%) 20h, rt / in air RCat. (M)AdditiveSolventConv (%)ee(%) Boc Boc Cbz COOEt Fmoc Cr(Cl) Co(OAc) Co Co None AcOH p-nitrobenzoic acid CH 2 Cl 2 TBME TBME >95 95 > >

Aminolytic Kinetic Resolution with carbamates G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6, RTime (h)Yield (%)ee(%) CH 3,, 6a (CH 2 ) 3 CH 3, 6b (CH 2 ) 4 CH=CH2, 6c c-C 6 H 11, 6d CH 2 O(1-naphthyl), 6e CH 2 Cl, 6f C 6 H 5, 6g p-BrC 6 H 4, 6h o-NO 2 C 6 H 4, 6i

StereocontrolDe/ee (%) Yield (%) Anti or syn Chiral Cr(Salen) >99/ anti Chiral Co(Salen) -/ > Comparison of the Resulution Methods

Conclusion Optically active  amino alcohols have been prepared through: Addition of carbanions, free radicals to C=N. Asymmetric hydrogenations of α-N-substituted β- keto esters Coupling of imines and aldehyes Kinetic resolution of racemic epoxides Much remains to be done: Scope of substrates Relative and absolute stereochemisry

Acknowledgement Dr. Hollingsworth Dr. Wulff Dr. Borhan Hollingsworth Group Xuezheng Carol Chang Xiaoyu Li Kun Zhen Trevor Joel Felica

Proline-Catalyzed Direct Asymmetric Three Component Mannich Reaction B.List, P.Pojarliev, W.T.Biller, H.J. Martin. J. Am. Chem. Soc. 2002, 124,

Proline-Catalyzed assemble of aldehydes, ketones, and azodicarboxylic acid esters N.S. Chowdari, D. B. Ramachary, C.F.Barbas. Org. Lett., 2003, 5,

C.Mordant, P.Dünkelmann, V.R,Vidal, J.P.Genet. Eur. J. Org. Chem. 2004, Asymmetric hydrogenations of α-N-substituted β-keto esters

J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines - stereocontrol