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Chiral Amines as Nucleophilic Catalysts in Asymmetric Synthesis

Chiral Amines as Nucleophilic Catalysts in Asymmetric Synthesis. Stephen Greszler University of North Carolina March 9th, 2007. Diverse range of activity Cost, availability of starting materials Moisture and air stability of catalysts No metal byproducts or auxilliary removal steps

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Chiral Amines as Nucleophilic Catalysts in Asymmetric Synthesis

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  1. Chiral Amines as Nucleophilic Catalysts in Asymmetric Synthesis Stephen Greszler University of North Carolina March 9th, 2007

  2. Diverse range of activity Cost, availability of starting materials Moisture and air stability of catalysts No metal byproducts or auxilliary removal steps Catalyst Recovery Catalyst loading Competitive background reactions ee’s > 99% still largely elusive (pharmaceutical importance) Asymmetric Synthesis Organocatalysis Biocatalysis Transition Metal Catalysis Advantages Disadvantages

  3. Outline Acyl Ammonium Catalysis • kinetic resolution of alcohols/amines • C-acylation (quaternary centers) • β-lactone/lactam synthesis • α-halogenation • cyclopropanation • Baylis Hillman reactions Ammonium Enolate Reactions

  4. Achiral Nucleophilic Catalysts N-methylimidazole (NMI) N,N-dimethylaminopyridine (DMAP) 1,4-diazabicyclo[2.2.2]octane (DABCO)

  5. Mechanisms of Organocatalysis by Amines Acyl Ammonium Catalysis Iminium Ion Activation 1- Ammonium Enolate Catalysis Enamine Catalysis 2-Ammonium Enolate Catalysis Phase Transfer Catalysis 3-Ammonium Enolate Catalysis

  6. Mechanisms of Organocatalysis by Amines Acyl Ammonium Catalysis Iminium Ion Activation 1- Ammonium Enolate Catalysis Enamine Catalysis 2-Ammonium Enolate Catalysis Phase Transfer Catalysis 3-Ammonium Enolate Catalysis

  7. Kinetic Resolution Basics * Calculation of selectivity factor (s) Where ee is enantiomeric excess of unreacted substrate Where ee is enantiomeric excess of product Benchmark Values s = 10…….....28% theoretical yield of unreacted substrate with ee > 99% s = 60……….46% theoretical yield of unreacted substrate with ee > 99% Vedejs, E.; Jure, M. Angew. Chem. Int. Ed. 2005, 44, 3974.

  8. Enzymatic Kinetic Resolution 15 days, 33% conversion (95% ee) Advantages: high regio-, stereo-, and enantioselectivity, mild reaction conditions Disadvantages: lack of generality (defined substrate requirements), variable quantities of water/buffer/other cofactors necessary, protein denaturation and inhibition Langrand, G; Baratti, J; Buono, G; Triantaphylides, C. Tetrahedron Lett. 1986, 27, 29.

  9. Pioneering Work by Evans and Vedejs ZnCl2 Evans, D.; Anderson, J.C.; Taylor, M. Tetrahedron Lett.1993, 34, 5563. Vedejs, E.; Chen, X. J. Am. Chem. Soc.1996, 118, 1809.

  10. Parallel Kinetic Resolution • Not catalytic • Approaches enzymatic selectivity • Equivalent to having a selectivity factor >125 + A B Vedejs, E.; Chen, X. J. Am. Chem. Soc.1997, 119, 2584.

  11. Reactivity/Selectivity Dilemma DMAP as an Esterification Catalyst Reacts faster than alcohol with acylating agent (catalytic step) Acylammonium species is a better acylating agent than anhydride (asymmetric induction step) ~ rate enhancements on the order of 104 compared to the uncatalyzed reaction Chiral Acylating Agent ~preformation of acylating agent necessary

  12. Fu’s “Planar Chiral” Design 18-electron complex A planar-chiral azaferrocene 18-electron complex A planar chiral DMAP 19-electron complex Ruble, J.C.; Fu, G. C. J. Org. Chem.1996, 61, 7230. Fu, G. C. Acc. Chem. Res. 2000, 33, 412.

  13. Catalyst Synthesis • Product stable to flash chromatography; enantiomers resolved via chiral HPLC • Air/moisture stable; identical selectivities under air and inert atmosphere • High % recovery of catalyst in most systems (98%) Fu, G. C. Acc. Chem. Res. 2000, 33, 412.

  14. Catalyst Evolution Half-life (min) 50,000 <3 S = 1.7 S = 10 Ruble, J.C.; Fu, G. C. J. Org. Chem.1996, 61, 7230. Fu, G. C. Acc. Chem. Res., 2000, 33, 412.

  15. % conversion after 1.0 h 6 10 14 8 4 6 13 8 36 solvent DMF CH3CN CH2Cl2 Acetone THF EtOAc Toluene Et2O t-amyl alcohol s 3.4 3.6 7.0 8.7 9.6 11 11 13 27 Enhancing Selectivity Ruble, J.C.; Tweddell, J.; Fu, G.C. J. Am. Chem. Soc.1998, 63, 2794.

  16. Active Catalyst Structure (SbF6- as counterion) Fu, G.C.; Acc. Chem. Res., 2004, 33, 542.

  17. Kinetic Resolution of Alcohols Unreacted Enantiomer (selectivity factor) 12 29 95 10 43 20 64 Ruble, J. C.; Latham, H.A.; Fu, G.C. J. Am. Chem. Soc.1997, 119, 1492. Tao, B.; Ruble, J.C.; Hoic, D.A.; Fu, G.C. J. Am. Chem. Soc.1999, 121, 5091. Fu, G.C.; Acc. Chem. Res., 2004, 33, 542.

  18. Fuji’s “Induced Fit” Catalyst “Induced fit”-type catalysts are most effective for resolution of cyclic diols(e.g. deracemization of meso diols and kinetic resolution of monoesters) Kawabata, T.; Nagato, M.; Takusa, K.; Fuji, K. J. Am. Chem. Soc.1997, 119, 3169.

  19. X X H X H ( R ' C O ) O N N 2 N N N N R R H H R ' O O R’ R Favored DHIP Catalysts Origin of Stereoselectivity Disfavored Birman, V.B.; Li, X.; Jiang, H.; Uffman, E.W.; Kilbane, C.J. J. Am. Chem. Soc., 2004, 126, 12226. Birman, V.B.; Li, X.; Jiang, H.; Uffman, E.W. Tetrahedron, 2006, 62, 285.

  20. Catalyst Synthesis and Reactivity DHIP = dihydroimidazo[1,2-a]pyridine TA = tetramisole BTA= benzotetramisole DHIP TA BTA Selectivity Factor Selectivity Factor Catalyst DHIP s < 85 TA s < 31 BTA s < 355 s < 32 Birman, V.B.; Li, X.; Jiang, H.; Uffman, E.W.; Kilbane, C.J. J. Am. Chem. Soc.2004, 126, 12226 . Birman, V.B.; Guo, L. Org. Lett. 2006, 8, 4859. Birman, V.B.; Li, X. Org. Lett. 2006, 8, 1351.

  21. Peptides for Kinetic Resolution A Selectivities using A • Effective for cyclic and some acyclic • α-hydroxy amides • Hydrogen bonding crucial in stabilizing • transition state • Imidazole is the active acylating portion • β-hairpin turns are a common feature No selectivity Miller, S.J.; Copeland, G.T.; Papaiannou, N.; Horstman, T.E.; Ruel, E.M. J. Am. Chem. Soc.1998, 120, 1629.

  22. Stereochemical Model Favored Approach Disfavored Approach s = 28 Vasbinder, M.M.; Jarvo, E.R.; Miller, S.J. Angew. Chem. Int. Ed., 2001, 40, 2824.

  23. Representative Peptides s = 28 for s = 51 for s = 9-50 for tertiary α-hydroxy amides ~ some success in resolution of secondary aryl alcohols using alternative octapeptides Jarva, E.R.; Evans, C.A.; Copeland, G.T.; Miller, S.J. J. Org. Chem.2001, 66,5522. Vasbinder, M.M.; Jarvo, E.R.; Miller, S.J. Angew. Chem. Int. Ed., 2001, 40, 2824.

  24. acylating agent selectivity factor 1.0 1.0 (no reaction) 1.2 12 Resolution of Amines • Limited progress relative to kinetic resolution of alcohols • Nucleophilicity of amines is an issue • Balance the reactivity of the catalyst with that of the amine • (complex acylating agents) • Cyclic amine derivatives allow for the best resolution • Other methods of amine resolution involve the use of • stoichiometric quantities of a chiral acylating agent Arai, S.; Bellemin-Laponnaz, S.; Fu, G.C. Angew. Chem. Int. Ed., 2001, 40,234.

  25. Resolution of Amine Derivatives Catalyst s = 11-27 s = 9.8-31 s = 50-520 Arai, S.; Bellemin-Laponnaz, S.; Fu, G.C. Angew. Chem. Int. Ed.2001, 40,234. Arp, F.; Fu, G.C. J. Am. Chem. Soc.2006, 128, 14264. Birman, V.B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E.W. J. Am. Chem. Soc.2006, 128, 6536.

  26. common nucleophilic catalyst rare Silyl Ketene Acetals But… Product when X = CN Product when X = Br, Cl, F Wiles, C.; Watts, P.; Haswell, S.J.; Pombo-Villar, E. Tetrahedron Lett.2002, 43, 2945. Mermeria, A.H.; Fu, G.C.; J. Am. Chem. Soc.2005, 127,5604.

  27. Proposed Pathway for Nucleophile-Catalyzed Rearrangements • Dual activation of both nucleophile • and electrophile • Ion pairs are important • E/Z mixtures of silyl ketene acetals • give identical enantioselectivities Black, T.H.; Arrivo, S.M.; Schumm, J.S.; Knobeloch, J.M. J. Am. Chem. Soc., Chem. Comm. 1986, 1524. Mermeria, A.H.; Fu, G.C.; J. Am. Chem. Soc.2005, 127,5604.

  28. Representative C-Acylations 88-99% ee, 72-95% yield 5% catalyst, Ac2O 73-92% ee, 68-96% yield toluene/CH2Cl2 rt 5% catalyst 69-83% ee, 52-93% yield 1,2-DCE, rt 2 % catalyst 88-91% ee, 93-95% yield toluene, 0°C Fu, G.C.; Acc. Chem. Res. 2004, 33, 542. Mermerian, A.H.; Fu, G.C.; J. Am. Chem. Soc.2005, 127,5604. Mermerian, A.H.; Fu, G.C. Angew. Chem. Int. Ed.2005, 44, 949.

  29. Mechanisms of Organocatalysis by Amines Acyl Ammonium Catalysis Iminium Ion Activation 1- Ammonium Enolate Catalysis Enamine Catalysis 2-Ammonium Enolate Catalysis Phase Transfer Catalysis 3-Ammonium Enolate Catalysis

  30. Cinchona Alkaloids Quinine (QN) R = OMe Quinidine (QD) Cinchonidine (CD) R = H Cinchonine (CN) Cupreine (CPN) R = OH Cupreidine (CPD) • First used as an organocatalyst in the hydrocyanation of aldehydes in 1912 • Available in two pseudoenantiomeric forms • Catalytic utility stems from the bifunctionality of quinuclidine core and C6 hydroxyl group; reactivity can be difficult to predict • Approximate cost is $1/g of material Marcelli, T.; van Maarseveen, J.H.; Hiemstra, H. Angew. Chem. Int. Ed.2006, 45, 7496.

  31. X-LG Product Br-OR, Cl-OR, F-OR α-halo ester Imine β-lactam Aldehyde/Ketone β-lactone H-OR, H-NHR chiral ester, amide Ketene Substrates: The Big Picture

  32. The Wynberg Method Early Work Pracejus’s Chiral Ester Synthesis • Bronsted Base catalysis • Modest selectivities due • to high background reaction • Original method required the • use of a ketene generator • Limitations include the use of • a highly electrophilic aldehyde Pracejus, H.; Matje, H. J. Prakt. Chem. 4. Reihe. 1964, 24, 195. Wynberg, H.; Staring, E. J. Am. Chem. Soc.1982, 104, 166.

  33. Wynberg Modifications >90% ee AcQ • Allows for in situ ketene generation • Limitations still include the necessity of a highly electron deficient aldehyde • (overcome in intramolecular reactions with carboxylic acid activation) • β –lactones undergo a variety of useful transformations Tennyson, Reginald; Romo, D. J. Org. Chem. 2000, 65, 7248. Henry-Riyad, H.; Lee, C.; Purohit, V.C.; Romo, D.; Org. Lett.2006, 8, 4363.

  34. Utility of β-Lactones Yang, H.W.; Romo, D. Tetrahedron. 1999, 55, 6403. Yang, H.W.; Romo, D. J. Org. Chem.1999, 64, 7657. France, S.; Guerin, D.J.; Miller, S.J.; Lectka, T. Chem. Rev. 2003, 103, 2985.

  35. β-Lactam Synthesis The Staudinger Reaction electrophile nucleophile Nucleophilic Catalysis (Staudinger “Umpolung”) nucleophile electrophile Staudinger, H. Liebigs Ann. Chem. 1908, 356, 51.

  36. Lectka’s “Shuttle Deprotonation” Strategy • Ketene generated in situ from the corresponding acyl chloride • Requires the use of a kinetically active, nucleophilic catalyst and • a thermodynamically active, non-nucleophilic base (proton sponge) • Catalyst and base additive act in a tandem “shuttle deprotonation” mechanism • Original methodology employed expensive phosphazene bases; recent improvements • allow for NaH and K2CO3 Taggi, A.E.; Hafez, A.M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc.2002, 124, 6629.

  37. Predicting Alkaloid Reactivity Effect of the C6 Stereocenter on Facial Preference Effect of the Quinoline Substituent on Facial Preference re face approach 0.0 kcal re face approach 0.13 kcal si face approach 6.69 kcal proposed ketene adduct proposed ketene adduct si face approach 0.0 kcal re face approach 0.0 kcal proposed ketene adduct Molecular Models si face approach 6.92 kcal Molecular Models ~ the configuration of the C6 stereocenter is unimportant ~ an approximately racemic product results; MeO group is critical Taggi, A.E.; Hafez, A.M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc.2002, 124, 6629.

  38. 10 % BQ β-Lactam Products BQ • β-lactams are desirable targets because of their antimicrobial properties • Subsequent manipulations are also possible • Fu’s PPY catalyst has also been shown to be effective in catalyzing these reactions Taggi, A.E.; Hafez, A.M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc.2002, 124, 6629. Dudding, T.; Hafez, A.; Taggi, A.; Wagerle, T.; Lectka, T. Org. Lett.2002, 4, 390.

  39. *catalyst performs a dual role as both a Lewis and Bronsted base Halogenations K2CO3 * esterification must be fast enough to avoid racemization France, S.; Wack, H.; Taggi, A.E.; Hafex, A.M.; Wagerle, T.R.; Shah, M.H.; Dusich, C.L.; Lectka, T. J. Am. Chem. Soc. 2004, 126, 4245.

  40. Effect of the Halogenating Agent Chlorination 68% yield, 56% ee 65% yield, 91% ee Bromination *deterioration of yield and ee at large scale *yield and ee consistent on gram scale France, S.; Wack, H.; Taggi, A.E.; Hafez, A.M.; Wagerle, T.R.; Shah, M.H.; Dusich, C.L.; Lectka, T. J. Am. Chem. Soc. 2004, 126, 4245. Hafez, A.M.; Taggi, A.E.; Wack, H.; Esterbrook, J., Lectka T. Org. Lett. 2001, 3,2049. Dogo-Isonagie, C.; Bekele, T.; France, S.; Wolfer, J.; Weatherwax, A.; Taggi, A.E.; Lectka, T. J. Org. Chem.2006, 71, 8946.

  41. O R O 6 2 - 9 0 % y i e l d A r C l C l 6 5 - 9 4 % e e C l C l R = M e , E t , i B u , c y c l o p e n t y l B r O R O 4 1 - 6 8 % y i e l d B r B r > 9 5 % e e B r R = A r , n B u , B n , P h O C H 2 Halogenated Products with PPY catalyst: Lee, E.C.; McCauley, K.M.; Fu, G.C.; Angew. Chem. Int. Ed.2007, 46, 977. Dogo-Isonagie, C.; Bekele, T.; France, S.; Wolfer, J.; Weatherwax, A.; Taggi, A.E.; Lectka, T. J. Org. Chem.2006, 71, 8946. France, S.; Wack, H.; Taggi, A.E.; Hafez, A.M.; Wagerle, T.R.; Shah, M.H.; Dusich, C.L.; Lectka, T. J. Am. Chem. Soc. 2004, 126, 4245.

  42. Mechanisms of Organocatalysis by Amines Acyl Ammonium Catalysis Iminium Ion Activation 1- Ammonium Enolate Catalysis Enamine Catalysis 2-Ammonium Enolate Catalysis Phase Transfer Catalysis 3-Ammonium Enolate Catalysis

  43. Ammonium Ylide Cyclopropanations NR3 Bremeyer, N.; Smith, S.C.; Ley, S.V.; Gaunt, M.J.; Angew. Chem. Int. Ed.2004, 116,4641. Papageorgiou, C.D.; Cubilla de Dios, M.A.; Ley, S.V.; Gaunt, M.J. Angew. Chem. Int. Ed.2004, 43,2735.

  44. Facial preference For ylide attack X-ray crystal structure of Me-MQD salt Proposed Stereochemical Model Johansson, C.C.C.; Bremeyer, N.; Ley, S.V.; Owen, D.R.; Smith, S.C.; Gaunt, M.J.; Angew. Chem. Int. Ed.2006, 45, 6024.

  45. 65% yield (96%ee) 96% yield (86%ee) 68% yield (98%ee) 84% yield (94%ee) Substrate Scope • Increasing yield with increase • in size of cation • Poor ee in intramolecular • reaction with Cl; significant • increases with Br 50% yield 90% yield (97%ee) 84% yield (97%ee) Bremeyer, N.; Smith, S.C.; Ley, S.V.; Gaunt, M.J.; Angew. Chem. Int. Ed.2004, 116,4641. Johansson, C.C.C.; Bremeyer, N.; Ley, S.V.; Owen, D.R.; Smith, S.C.; Gaunt, M.J.; Angew. Chem. Int. Ed.2006, 45, 6024.

  46. Mechanisms of Organocatalysis by Amines Acyl Ammonium Catalysis Iminium Ion Activation 1- Ammonium Enolate Catalysis Enamine Catalysis 2-Ammonium Enolate Catalysis Phase Transfer Catalysis 3-Ammonium Enolate Catalysis

  47. Baylis-Hillman Reactions Reversibility of Michael addition allows for selective reaction with the more stable zwitterionic form (Z) NR3 + • Attractive reaction due to • high functional density • generated • Difficulties include substrate • racemization, low yields, and • side reactions • Catalysts exploit the • nucleophilicity and • hydrogen-bonding potential • of the cinchona alkaloids Stereoinduction through metal ion complexation or hydrogen-bonding in aldol step

  48. Early Work via Barrett, A.G.M.; Cook, A.S.; Kamimura, A. Chem. Comm. 1998, 2533.

  49. Hatakeyama’s ß-ICD Catalysts 31-58% yield 91-99% ee 0-25% yield 4-85% ee 11-83% yield syn:anti = 94:6 to 100:0 >98% ee 1-20% yield syn:anti = 0:100 to 100:0 >98% ee Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc.1999, 121, 10219. Nakano, A.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2006, 8, 5357.

  50. Selectivity Model si face attack re face attack Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc.1999, 121, 10219.

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