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Combinations of E nzymatic P rocedures with M ulticomponent C ondensations

Combinations of E nzymatic P rocedures with M ulticomponent C ondensations. Ryszard Ostaszewski a ,b a Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warszawa b Institute of Organic Chemistry, PAS, Kasprzaka 44/52, 01-224 Warszawa, Poland. Substrate

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Combinations of E nzymatic P rocedures with M ulticomponent C ondensations

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  1. Combinations of Enzymatic Procedures withMulticomponent Condensations Ryszard Ostaszewskia,b aFaculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warszawa b Institute of Organic Chemistry, PAS, Kasprzaka 44/52, 01-224Warszawa, Poland

  2. Substrate (racemic) Substrate (meso) Enzymatic Reaction (1) Resolution of enantiomers Substrate (optically active) Product Reaction1 Multicomponent condensation. (2) Product Reaction 2 Final product Final product General concept. • Classical processes: Combination of Enzymatic Procedures with multicomponent condensation.

  3. General requirements for whole processes: • -         possibility to perform both reaction as a two - step one - pot procedure, • -         economy and simplicity, • -         easy control of the stereochemical course of reactions.

  4. Multicomponent Condensations • Ugi reaction Passerini reaction Petasis reaction

  5. Paroxetin • Yu, M. S.; Lantos, I.; Zhi-Qiang Peng, Yu J.; Cacchio T. Tetrahedron Lett.2000, 41, 5647. Holmann, M. J.; Vail, R.; Morgan, B., Sebesan, V.; Levy, C.; Dodds D. R.; Zaks, A.; Adv. Synth. Catal. 2001, 343, 744

  6. Synthetic strategy.

  7. The synthesis of 3-phenylglutaric anhydrides

  8. R = H R = Cl R = Me Solvent Time (h) Er Time(h/days) Er Time(days) Er 1 diethyl ether 114 7,2 -/17 2,5 2 diisopropyl ether 43 8,2 120/- 5,2 22 5,4 3 di-n-propyl ether 177 8,0 -/17 5,3 4 di-n-butyl ether 73 6,9 72/- 5,1 5 tertbutyl methyl ether 43 7,3 120/- 3,6 14 5,6 6 Cyclohexane 20 4,3 72/- 1,1 Desymmetrization of 3-phenylglutaric anhydrides

  9. R = H R = Cl R MeO Lipase Time (h/days) Er Time (h/days) Er Time (h/days) Er Novozyme 435 61/- 8,5 120/- 5,2 -/22 5,4 Chirazym A 19/- 10,8 -/4 5,9 -/12 6,4 Chirazym B -/9 0,80 -/4 0,7 Chirazym C -/18 5,2 Amano PS -/16 0,13 Amano PS imm. 19/- 0,13 -/4 1,4 -/7 267 SP 430 67/- 5,4 -/5 2,6 Candida cylindracea imm. -/46 1,62 Pseud. capacia imm. -/46 0,29 hog pancreas imm. -/18 0,88 Mucor miehei imm. -/46 0,35 The influence of enzyme type on desymmetrization reaction.

  10. The results of combination of enzymatic desymmetrization with Ugi Four-Component Condensation.

  11. Entry Product Solvent Yield (%) 1 i-Pr2O 0 2 i-Pr2O/MeOH, 2:1, v/v 6 3 i-Pr2O/MeOH 2:1, v/v 4 4 i-Pr2O/MeOH 2:1, v/v 6a 5 i-Pr2O/MeOH 2:1, v/v 13a

  12. Entry Product Solvent Yield (%) 1 i-Pr2O/MeOH 2:1, v/v 82 2 i-Pr2O/MeOH 2:1, v/v 81a 3 i-Pr2O/MeOH 2:1, v/v 70 a 4 i-Pr2O/MeOH 2:1, v/v 72 a 5 i-Pr2O/EtOH 2:1, v/v 80 a

  13. Passerini Reaction of 3-phenylglutaric monoesters

  14. Entry Product Solvent Yield (%) 1 i-Pr2O/EtOH 2:1 51 2 i-Pr2O/EtOH 2:1 46a 3 i-Pr2O/EtOH 2:1 35 4 i-Pr2O/EtOH 2:1 56 a 5 i-Pr2O/EtOH 2:1 35 6 i-Pr2O/EtOH 2:1 50a 7 i-Pr2O/EtOH 2:1 18%

  15. Summary • enzymatic reactions can be used with multicomponent Ugi and Passerini condensations as a two-step one-pot processes. Acknowledgments Katarzyna Jeziorska, Anna Fryszkowska, Marta Głażewska This work was supported by the State Commitee for Scientific Research (Grant 3 TO9A 081-19).

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