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MSU CEM 958 - Luderer

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From Racemate to Enantiopure Compound: Recent Applications of Dynamic Kinetic Asymmetric TransformationsOctober 20th, 2010Micah LudererPresentation Overview De-racemization Techniques Dynamic Kinetic Resolution (DKR) Enantioconvergent Process (ECP) Cyclic De-racemization (CycD) Dynamic Kinetic Asymmetric Transformation (DYKAT) Metal Catalyzed DYKAT Organocatalytic DYKAT Enzyme Mediated DYKATKinetic Resolution (KR): Not a De-racemization Technique KR based on difference of reaction rates of enantiomers 50% theoretical yieldSteinreiber, J.; Faber, K.; Griengl, H. Chem. Eur. J. 2008, 14, 8060-8072.Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237-6240.De-racemization Technique:Steinreiber, J.; Faber, K.; Griengl, H. Chem. Eur. J. 2008, 14, 8060-8072. De-racemization Technique: Complete transformation of a racemate into a single enantiopure productRacemization: Conversion of an enantiopure substrate into a racemic mixtureDe-racemization Techniques: Dynamic Kinetic Resolution (DKR) Achiral TS‡ [I] 100% theoretical yieldFaber, K. Chem. Eur. J. 2001, 7, 5004-5010.Dynamic Kinetic Resolution ExamplesAllen, J. V.; Williams, J. M. J. Tetrahedron Lett. 1996, 37,1859-1862. Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, B. J. Am. Chem. Soc. 1981, 103, 6237-6240.Methods of Racemization Different racemization methods: Protonation/Deprotonation Oxidation/Reduction Schiff Bases Transition Metal RacemasesFaber, K. Chem. Eur. J. 2001, 7, 5004-5010. Huerta, F. F.; Minidis, A. B. E.; Bäckvall, J. E. Org. Lett. 2008, 10, 2027-2030.Racemization examplesHuerta, F. F.; Minidis, A. B. E.; Bäckvall, J. E. Org. Lett. 2008, 10, 2027-2030.De-racemization Techniques:Enantioconvergent Processes (ECP)Pedragosa-Moreau, S.; Archelas, R.; Furstoss, R. J. Org. Chem. 1993, 58, 5533-5536. Enantiomers react with different enzymes One pathway is retention, the other inversionDe-racemization Techniques:Cyclic De-racemization (CycD)Turner, N. J. Curr. Opin. Biotechnol. 2003, 14, 401-406.  Repeating cycle increases % eeDe-racemization Techniques:Dynamic Kinetic Asymmetric Transformation (DYKAT) Four classifications (Type I-IV) Catalytic Systems: Metal Catalyzed DYKAT Organocatalytic DYKAT Enzyme Mediated DYKATSteinreiber, J.; Faber, K.; Griengl, H. Chem. Eur. J. 2008, 14, 8060-8072. The de-symmetrization of racemic or diastereomeric mixtures involving interconverting diastereomeric intermediates – implying different equilibration rates of the stereoisomers – is termed dynamic kinetic asymmetric transformation.DYKAT Type I One diastereomeric complex (SRC*) reacts faster than the other (SSC*)Faber, K. Chem. Eur. J. 2001, 7, 5004-5010.DYKAT Type I ExampleTrost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543-3544.Match/Mismatch DYKAT Type I Match case: Higher % ee Mismatch case: Lower % eeSteinreiber, J.; Faber, K.; Griengl, H. Chem. Eur. J. 2008, 14, 8060-8072.Distinguishing DYKAT from DKR DYKAT Differences: SRC* and SSC* are diastereomers, not enantiomers Intermediate SC* is chiral, not achiral [I] kC ≠ kDFaber, K. Chem. Eur. J. 2001, 7, 5004-5010.DYKAT Type II Products formed from a single enantiomeric intermediate SC*Faber, K. Chem. Eur. J. 2001, 7, 5004-5010.DYKAT Type II ExampleTrost, B. M.; Patterson, D. E.; Hembre, E. J. J. Am. Chem. Soc. 1999, 121, 10834-10835.DYKAT Type IIISteinreiber, J.; Faber, K.; Griengl, H. Chem. Eur. J. 2008, 14, 8060-8072.  De-epimerization of a diastereomeric mixture of enantiomeric pairs.DYKAT Type III ExampleEdin, M.; Steinreiber, J.; Bäckvall, J. E. Proc. Natl. Acad. Sci. USA. 2004, 101, 5761-5766.DYKAT Type IV De-epimerization of a diastereomeric mixture of enantiomeric pairs through achiral intermediates.Steinreiber, J., Faber, K., Griengl, H. Chem. Eur. J. 2008, 14, 8060-8072.DYKAT Type IV ExampleReyes, E.; Córdova, A. Tetrahedron Lett. 2005, 46, 6605-6609.DYKAT Summary Type I and Type II: de-racemization of enantiomers Type III and Type IV: de-epimerization of diastereomers De-racemization Techniques Dynamic Kinetic Resolution (DKR) Enantioconvergent Processes (ECP) Cyclic de-racemization (CycD) Dynamic kinetic asymmetric transformation (DYKAT) Metal Catalyzed DYKAT Organocatalytic DYKAT Enzyme Mediated DYKATCu-Catalyzed Asymmetric Allylic Alkylation (AAA)Langlois, J. B.; Alexakis, A. Adv. Synth. Catal. 2010, 352, 447-457.Elucidating DYKAT Type I Mechanism Radical and DKR ruled out If X = OAc, 0% ee. If X = Br, 94% ee.Langlois, J. B.; Alexakis, A. Adv. Synth. Catal. 2010, 352, 447-457.Type I DYKAT in the α-Hydroxylation of Racemic MalonatesReddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T. Angew. Chem. Int. Ed. 2009, 48, 803-806.α-Hydoxylation of Racemic Malonates Scope tBu group important for high % eeReddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T. Angew. Chem. Int. Ed. 2009, 48, 803-806.Enantioselective Hydroxylation Transition StateReddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T. Angew. Chem. Int. Ed. 2009, 48, 803-806.α-Hydroxyl Malonates: Drug PrecursorsReddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T. Angew. Chem. Int. Ed. 2009, 48, 803-806.Type I Dynamic Kinetic Asymmetric [3+2] Cycloadditions Two specific catalyst requirements L.A. catalyzes cycloaddition of aldehyde preferentially with one enantiomer L.A. must promote racemization of cyclopropane enantiomers (otherwise it is a resolution, not a DYKAT)Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 3122-3123.De-racemization Pathway: DYKAT Type ICampbell, M. J.; Johnson, J. S.; Parsons, A. T.; Pohlhaus, P. D.; Sanders, S. D. J. Org. Chem. Soc. 2010, 75, 6317-6325.Mechanism and Model for cis- SelectivityCampbell, M. J.; Johnson, J. S.; Parsons, A. T.; Pohlhaus, P. D.; Sanders, S. D. J. Org. Chem. Soc. 2010, 75, 6317-6325.Scope of CycloadditionsParsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 3122-3123. De-racemization Techniques Dynamic Kinetic Resolution (DKR) Enantioconvergent Processes (ECP) Cyclic de-racemization (CycD) Dynamic kinetic asymmetric transformation (DYKAT) Metal Catalyzed DYKAT Organocatalytic DYKAT Enzyme Mediated DYKATCórdova, A. et al. Chem. Eur. J. 2010, 16, 1585-1591. Pd- and Amine- Catalyzed DYKAT Type IVDYKAT DiastereoselectivityCórdova, A.


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