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

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Presentation on theme: "Synthesis of Optically Active  Amino Alcohols Changyou Yuan Department of Chemistry Michigan State University -A survey of major developments after the."— Presentation transcript:

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

2 Important Free or Functionalized  Amino Alcohols

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

4 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

5 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

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

7 Asymmetric Lithiation of O-benzyl Carbamates–imine Addition S.Arrasate, E.Lete, N.Sotomayor. Tetrahedron: Asymmetry, 2002, 13, 311–316. 1. CO 2 2. CH 2 N 2

8 Asymmetric Lithiation of O-benzyl Carbamates–imine Addition R1R1 R2R2 TempYield(%)D.Re.e. (%) OCH 3 H -78 o C 6h 84 67 >95:5 56 (96) 76 (91) S.Arrasate, E.Lete, N.Sotomayor. Tetrahedron: Asymmetry, 2002, 13, 311–316.

9 Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines SulfoxideT ( o C)Yield (%)De (%) (S) – 1 (R) – 1 (S) – 1 (R) - 1 -78 0 82 85 67 65 60 80 >98 J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, 4454 - 4463. J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, 4513-4516.

10 Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines SulfoxideT ( o C)Yield (%)de at C(2) (%) (S) – 2 (R) – 2 (S) – 2 (R) - 2 -78 0 77 75 73 70 20 80 54 J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, 4454 - 4463. J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, 4513-4516. C-1C-2 (S)-sulfinyl ketimine(S)-(2) (R)-(2) RSRS SSSS

11 J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, 4454 - 4463. J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, 4513-4516. Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines-Stereocontrol

12 J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, 4454 - 4463. J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, 4513-4516. Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines - stereocontrol

13 J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, 4454 - 4463. J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, 4513-4516. M.Crucianelli, P.Bravo, A.Arnone, E.Corradi, S.V.Meille, M.Zanda. J. Org. Chem. 2000, 65, 2965-2971. Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines – Demasking Steps

14 Radical Addition of Hydroxymethyl and Vinyl Groups to C=N Bonds G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, 863 - 875. G.K.Friestad, S.E.Massari. Org. Lett. 2000, 2, 4237-4240.

15 Hydroxymethyl Addition to Oxime Ethers G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, 863 - 875. G.K.Friestad, S.E.Massari. Org. Lett. 2000, 2, 4237-4240.

16 Hydroxymethyl Addition to Hydrazones RMe t BuiPrPh Anti-7:syn-7 Yield (%) 79:21 76 85:15 68 96:4 80 >98:2 57 G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, 863 - 875. G.K.Friestad, S.E.Massari. Org. Lett. 2000, 2, 4237-4240.

17 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, 863 - 875. G.K.Friestad, T.Jiang, G.M.Fioroni. Tetrahedron: Asymmetry, 2003, 14, 2853–2856.

18 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, 4237-4240. G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, 863-875. G.K.Friestad, T.Jiang, G.M.Fioroni. Tetrahedron: Asymmetry, 2003, 14, 2853–2856.

19 Comparison of the Addition Reactions Stereocontrol De/ee (%) Yield (%) Anti or syn Chiral amine (additive) >95:5/ 56-76 67-84syn Sulfinylketimine and sulfinyl carbanions 60:40~ 90:10 /- 70-77both Substrate control and Beckwith - Houk model 80:20~ >98:2/- 50-80anti

20 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

21 C.Mordant, P.Dünkelmann, V.R,Vidal, J.P.Genet. Eur. J. Org. Chem. 2004, 3017-3026. Asymmetric Hydrogenations of α-N-substituted β-keto esters - Preparation the Syn  – Amino Alcohols RYield (%)de (%)ee (%) C3H7C3H7 817175 BnO-C 4 H 8 5393>99 C 5 H 11 779899 C 15 H 31 iPr 82 92 98 97

22 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 90 94 93 85 90 83 85 90 96 86 92 93 96 98 99 97 92 (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, 30173026.

23 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

24 Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, 9227 - 9237. Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4, 835-838.. 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 0 92 88 94 95 96 98 92 Trace trace 0 95 0

25 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 92 93 90 93 91 96 95 97 92 94 97 Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, 9227 - 9237. Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4, 835-838..

26 Reaction Mechanism of Cross-Coupling with N-Tosyl Ferrocenylideneamines Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, 9227 - 9237. Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4, 835-838.

27 Reaction Mechanism of Cross-Coupling with N-Tosyl Ferrocenylideneamines Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, 9227 - 9237. Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4, 835-838. 92 % enantiopure 97 % enantiopure

28 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 70-93 63-89 52-81 33-73 50/50 – 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, 9227 - 9237. Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4, 835-838.

29 Cross-Coupling of Benzylideneamines with Aldehydes Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, 9227 - 9237. Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4, 835-838.

30 Proline-Catalyzed Direct Asymmetric Mannich Reaction B.List, P.Pojarliev, W.T.Biller, H.J. Martin. J. Am. Chem. Soc. 2002, 124,827-833.

31 Proline-Catalyzed Assemble of Aldehydes, Ketones, and Azodicarboxylic Acid Asters N.S. Chowdari, D. B. Ramachary, C.F.Barbas. Org. Lett., 2003, 5,1685-1688.

32 StereocontrolDe/ee (%) Yield (%) Anti or syn Ferrocenylideneamines Ferrocenecarboxaldehydes >95/ 92-97 90-95anti planar chiral benzaldehyde chromium complexes 90/ >99 33-81syn Proline 20-95/ 60->99 60-90syn Comparison of the Cross-Coupling Reactions

33 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

34 Aminolytic Kinetic Resolution with Amines G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6, 2173-2176. R1R1 R2R2 T ( o C)t (h)Yield (%)Ee of 4 (%)Ee of 2 (%) H OMeOMe H OMe HH rt -10 rt 0 rt-10 18 36 18 24 1224 91 47 89 60 9893 86 >99 88 93 8394 30 80 81

35 Aminolytic Kinetic Resolution with Amines G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6, 2173-2176.

36 G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6, 3973-3975.. 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 0 45 65 80>95 95 >95 75 96 >9999 99.5 99 99.5

37 Aminolytic Kinetic Resolution with carbamates G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6, 3973-3975.. 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 24 36 48 99 84 95 87 90 76 62 99.3 99.2 99.7 99.9 99.5 99.9 99.8

38 StereocontrolDe/ee (%) Yield (%) Anti or syn Chiral Cr(Salen) >99/ 74-99.5 44-98anti Chiral Co(Salen) -/ >99 62-99- Comparison of the Resulution Methods

39 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

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

41 Proline-Catalyzed Direct Asymmetric Three Component Mannich Reaction B.List, P.Pojarliev, W.T.Biller, H.J. Martin. J. Am. Chem. Soc. 2002, 124,827-833.

42 Proline-Catalyzed assemble of aldehydes, ketones, and azodicarboxylic acid esters N.S. Chowdari, D. B. Ramachary, C.F.Barbas. Org. Lett., 2003, 5,1685-1688.

43 C.Mordant, P.Dünkelmann, V.R,Vidal, J.P.Genet. Eur. J. Org. Chem. 2004, 30173026. Asymmetric hydrogenations of α-N-substituted β-keto esters

44 J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, 4454 - 4463. J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, 4513-4516. Addition of  -Sulfinyl Carbanions to N-p- Tolylsulfinylketimines - stereocontrol

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