Strategies for Catalytic Asymmetric Electrophilic a alogenation of Carbonyl Compounds 1 2 Y Catalyst [X + ] 1 X! 2 Y intermann, L. ; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359 4362 amashima, Y.; Sodeoka, M. et al J. Am. Chem. Soc. 2002, 124, 14530 14531 France, S.; Lectka, T. et al J. Am. Chem. Soc. 2004, 126, 4245 4255 Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 4109 alland,. ; Jørgensen, K. A. et al J. Am.Chem. Soc. 2004, 126, 4790 4791 Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2004, 43, 5507 5510 Zhang, Y. ; Shibatomi, K.; Yamamoto,. J. Am. Chem. Soc. 2004, 126, 15038 15039 Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2005, 44, 2 5 (early view) Ali Z. Ding Advisor: Prof. W. D. Wulff May 12 2005
Introduction a-alogenated Carbonyl Compounds Linchpins for further stereospecific manipulations alogen substituents can sometimes dramatically alter its physical, chemical and biological properties Increasingly important structural motifs in medicinal chemistry and material sciences. Me F F 3 C BMS-204352 MaxiPost Currently being assessed worldwide in phase III clinical trials for treatment of acute ischemic stoke estreich, M. Angew. Chem. Int. Ed., 2005, 44, 2324-2327 Ibrahim,.; Togni, A. Chem. Commun. 2004, 1147 1155
Introduction Approaches to the Chiral a-alogenated Carbonyl Compounds (1) eagent-controlled halogenation: asymmetric halogenation of enolates using chiral electrophilic halogenating agents! 1 [X + ] Y 2 (2) Substrate-controlled halogenation: diastereoselective electrophilic halogenation of chiral enolates or enol ethers 1 X! 2 Y [X + ] 1 Y* 1 X! Y* 2 2 (3) Catalytic asymmetric halogenation of carbonyl compounds 1 2 Y Catalyst [X + ] 1 X! 2 Y estreich, M. Angew. Chem. Int. Ed., 2005, 44, 2324-2327 Taylor, S. D.; Kotoris, C. C. and um, G. Tetrahedron, 1999, 55,12431-12477
oncatalytic alogenation Substrate-controlled alogenation: Use of Chiral Auxiliaries estreich, M. Angew. Chem. Int. Ed., 2005, 44, 2324-2327 Taylor, S. D.; Kotoris, C. C. and um, G. Tetrahedron, 1999, 55,12431-12477
oncatalytic alogenation eagent-controlled alogenation: Chiral Fluorinating eagents Pioneering work: Differding, E. and Lang,. W. Tetrahehron Lett. 1988, 29, 6087-6090 Moderate yields and low to moderate enantioselectivities Syntheses of these reagents require several steps Wong, C.-., Angew. Chem. Int. Ed., 2005, 44, 192 Taylor, S. D.; Kotoris, C. C. and um, G. Tetrahedron, 1999, 55,12431-12477
oncatalytic alogenation eagent-controlled alogenation: Cinchona Alkaloids Fluorinating eagents [F + ] F X - [F + ] = 2BF - 4 F PhS 2 PhS 2 F Selectfluor, -fluorobenzenesulfonimide or F-TEDA or FSI 10 11 12 13 Cinchona alkaloids (CA) are readily available in both pseudo-enantiomeric forms Easily prepare, more reactive Can be generated and used in situ Can be reloaded by F-TEDA or FSI and reused without loss in selectivity Can such CA be used catalytically in these reactions? Ibrahim,.; Togni, A. Chem. Commun. 2004, 1147 1155
Catalytic Asymmetric Fluorination rgano-catalytic Enantioselective Fluorination by Phase-Transfer Catalysts Kim, D. Y. and Park, E. J. rg. Lett., 2002, 4, 545 547.
Catalytic Asymmetric Fluorination rgano-catalytic Enantioselective Fluorination by L-Proline Derevatives + F + Source * F! ab 4 F! Challenges: -fluorination of catatlyst Fluorination of substrate should be faster acemization and difluorination Both SM and product can form enamine species a-proton of product is more acidic F atom is not big enough to contribute to an added steric shielding Products are not stable to survive silica gel Screen catalysts and solvents Lower the catalyst loading Screen fluorinating reagents Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2005, 44, 2 5
Catalytic Asymmetric Fluorination rgano-catalytic Enantioselective Fluorination by L-Proline Derevatives Ph Ph X 14a, X= 14b, X= 2 15 16, TMS Ar Ar Ar= CF 3 CF 3 MTBE= FSI, 16(1mol%) MTBE, T F ab 4 Me, T F! PhS 2 PhS 2 FSI F = Pr (96%ee), Bu(91%ee), ex (96%ee), Bn(C 2 ) 3 (91%ee), Yield: 55-95% Bn (93%ee), Cy (96%ee), tbu(97%ee), 1-Ad (96%ee) In the solvents other than MTBE, catalyst 16 decomposes Products were reduced to alcohol in situ Dr. MacMillan s Work: Enantioselective rganocatalytic Direct a-fluorination: Beeson, T. D. and MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, in press True nucleophiles toward electrophilic fluorine: enols, enolates or enamines Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2005, 44, 2 5
Catalytic Asymmetric Fluorination Chiral Lewis Acid Catalyzed Asymmetric Fluorination Addition of sub-stoichiometric amount of Lewis acid significantly accelerates formation of fluorination product 12 17 18 Ti-based Lewis acids are the most potent catalysts Umemoto, T et al J. Am. Chem. Soc., 1990, 112, 8563 8575 intermann, L. ; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359 4362
Catalytic Asymmetric Fluorination Ti 2 [,-(TADDLLato)] Catalyzed Asymmetric Fluorination 12 intermann, L. ; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359 4362 Ibrahim,.; Togni, A. Chem. Commun. 2004, 1147 1155
Catalytic Asymmetric Fluorination Mechanism of Ti Catalyzed Asymmetric Fluorination 12 The bidentate nature of substrates is beneficial for high facial selectivity Piana, S.; Togni, A. et al Angew. Chem., Int. Ed., 2002, 41, 979 982 Ibrahim,.; Togni, A. Chem. Commun. 2004, 1147 1155
Catalytic Asymmetric Fluorination Asymmetric Fluorination Catalyzed by ther Lewis Acids 13 Alcoholic solvents can work well ot sensitive to water Catalyst can be recycled and re-used without loss of any slectivity amashima, Y.; Sodeoka, M. et al J. Am. Chem. Soc., 2002, 124, 14530 14531.
Catalytic Asymmetric Fluorination Asymmetric Fluorination Catalyzed by ther Lewis Acids FIP= F 3 C CF 3 13 Ph M Ph X - 62 M= Cu, X - = Tf 63 M= i, X - = 4 Ibrahim,.; Togni, A. Chem. Commun. 2004, 1147 1155 Ma, J.-A. and Cahard, D. Tetrahedron: Asymmetry, 2004, 15, 1007 Shibata,.; Ishimaru, T.; agai, T., Kohno, J. and T. Toru Synlett 2004, 1703 1706
Catalytic Asymmetric Chlorination & Bromination Chiral Lewis Acid Catalyzed Asymmetric Chlorination & Bromination 1 2 Me + X 5mol% 38 or 39 MeC, rt 1 2 X Me X=, up to 88%ee X= Br, up to 23%ee intermann, L. and Togni, A. elv, Chim. Acta, 2000, 83, 2425 2435 Me I + Bn Me 64 65 5mol% 38 1.2eq py toluene, 50 o C Me Bn Me (S)-66, 67%, 71%ee With 2, (S)-66, 62%, 30%ee intermann, L. and Togni, A. elv, Chim. Acta, 2004, 87, 605 610 1 3 2 + X 10mol% 67 Et 2 1 2 2 X X=, up to 77%ee X= Br, up to 82%ee Marigo, M.; Kumaragurubaran,.; Jørgensen, K. A. Chem. Eur. J. 2004,10, 2133 2137 t-bu 2 Tf - Cu t-bu (S, S)-67 estreich, M. Angew. Chem. Int. Ed., 2005, 44, 2324-2327
Catalytic Asymmetric Chlorination & Bromination rgano-catalyzed Asymmetric Chlorination & Bromination Acyl alides Tadem halogenation/esterification process of acyl halides 67 Base TF -78 o C C 68 (2.0eq) 69(10mol%) 70 or 71 (1.0eq) TF, -78 o C Ar X 72 LG X 72 u C 68 Base 67 Ph LG - 69 Me u 69 + u Br Br Br Br LG X 74 X LG - LG + u X - 73 70 71 70 or 71 The choice of chlorinating agents is pivotal for the reaction to turn over France, S.; Lectka, T. et al J. Am. Chem. Soc. 2004, 126, 4245 4255
rgano-catalytic Asymmetric Chlorination & Bromination ptimization of eaction Conditions The choice of chlorinating agents: the window is very narrow X Unreactive: Too reactive:, 2 The choice of base: reactive, cheap, easy to handle Me 2 Me 2 Me 2 Me 2 70 C 6 5 Me 2 Me 2 C 5 C 6 69 70 71 67 68 75 76 France, S.; Lectka, T. et al J. Am. Chem. Soc. 2004, 126, 4245 4255
rgano-catalytic Asymmetric Chlorination & Bromination Choice of Base and Summary a, 15-crown-5 69(10mol%), 70(1.0eq) TF, -78 o 5 C 6 C to rt, 4h 67 75 = Ph, PhC 2, 1-p, p- 2 Ph, Et, o-ph Yield: 43-79%, ee: 90-99% ac 3, 15-crown-5 69(10mol%), 70(1.0eq) Ph, -35 o 5 C 6 C to rt, 5h 67 75 = Ph, PhC 2, 1-p, p-meph Yield: 56-68%, ee: 88-91% Moderate yields, high enantioselectivity Inexpensive reagents Can be scaled up Ketenes from other sources (Wolff rearrangement) can be used as well France, S.; Lectka, T. et al J. Am. Chem. Soc. 2004, 126, 4245 4255
rgano-catalytic Asymmetric Chlorination Asymmetric Chlorination of Aldehydes Catalyzed by Chiral Amines 76 77 79 8 examples Yield: 60-88% ee: 97-99% 78 Such cyclic transition state might enforce activation of 70 in the asymmetric environment of an e-rich enamine mediated by proton 70 80 70 Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 4109
rgano-catalytic Asymmetric Chlorination of Aldehydes Asymmetric Chlorination of Aldehydes: Catalysts and Chlorinating eagents CS 82 83 82 83 70 70 70 70 70 81 82 83 L-Proline doesn t work well CS doesn t work well Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 4109
rgano-catalytic Asymmetric Chlorination of Aldehydes Asymmetric Chlorination of Aldehydes: the Solvent Effects 82 82 Inert to halogenation reagent ptimal selectivity, reaction rate, and chemical yield Product epimerization, formation of,-dichlorooctanal, or octanal aldol dimerization were comprehensively suppressed using these conditions Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 4109
rgano-catalytic Asymmetric Chlorination of Aldehydes Asymmetric Chlorination of Aldehydes: The Scope Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 4109
rgano-catalytic Asymmetric Chlorination of Aldehydes Asymmetric Chlorination of Aldehydes: b-chiral Aldehydes - 82 70 82 Internal asymmetric induction is almost completely over-compensated Selectivity is sterically and chemically good Substrate scope is broad All the reagents (70, 82 and - 82) are bench stable and commercially available Products are stable Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 4109
rgano-catalytic Asymmetric Chlorination of Aldehydes Asymmetric Chlorination of Aldehydes: Jørgensen s Work Catalyst! ipr ipr CS CS 2 3c Ph 3i Ph alland,. ; Jørgensen, K. A. et al J. Am.Chem. Soc. 2004, 126, 4790 4791
rgano-catalytic Asymmetric Chlorination of Aldehydes Asymmetric Chlorination of Aldehydes: The Scope CS (1.3eq) 3c or 3i (10mol%)! C 2 2, rt, 1-10h 1 2 CS 2 3c Asymmetric Bromination & Iodination of Aldehydes 1d 1a BS 3i (10mol%) C 2 2, rt IS 3i (10mol%) C 2 2, rt! I! Br 80%ee 24%ee Ph 3i Ph alland,. ; Jørgensen, K. A. et al J. Am.Chem. Soc. 2004, 126, 4790 4791
rgano-catalytic Asymmetric Chlorination of Ketones rgano-catalyzed Asymmetric Chlorination of Ketones CS Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2004, 43, 5507 5510
rgano-catalytic Asymmetric Chlorination of Ketones Asymmetric Chlorination of Ketones: Effects of Additives & Solvent CS Ph Ph 3i C 3 C is the best solvent Significant improvement by adding acids: Promotion of enamine formation Suppression of catalyst chlorination Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2004, 43, 5507 5510
rgano-catalytic Asymmetric Chlorination of Ketones Asymmetric Chlorination of Ketones: The Scope 3i (20mol%) 2-2 -PhC 2 (50mol%) CS (2eq), MeC, 20h 1 2! Ph Ph 3i CS igh e.e. Moderate yields: poly-chlorination occurs Broad substrate scope Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2004, 43, 5507 5510
Asymmetric Chlorination of Ketones Back to eagent Controlled Asymmetric Chlorination of Ketones eagent-controlled process can sometimes be competitive alternative! 1 Si 2 3 + X X 1 Lewis acid! X= or 1 3 2 Chirality of auxiliary (X) could be transferred to silicon enolates Lewis acids are necessary to activate 1 Chlorinating reagents 1 can be prepared easily Zhang, Y. ; Shibatomi, K.; Yamamoto,. J. Am. Chem. Soc. 2004, 126, 15038 15039
Asymmetric Chlorination of Ketones Asymmetric Chlorination of Ketones: Effects of X group & Si Group Zr 4 is uniquely reactive The size of X group The size of si group Yields are high (>90%) Zhang, Y. ; Shibatomi, K.; Yamamoto,. J. Am. Chem. Soc. 2004, 126, 15038 15039
Asymmetric Chlorination of Ketones Asymmetric Chlorination of Ketones: Scope
Asymmetric Chlorination of Ketones Asymmetric Chlorination of Ketones: Potential to be Catalytic Si Zr 4 ( ) ( ) n n 1-p 1c 1-p 1-p 2c 1-p CF 3 S 2 CF 3 S 2 2c can be easily recovered and chlorinated back to 1c ecovered 1c can be re-used for the reaction This novel process might be extended to catalytic asymmetric variants! Zhang, Y. ; Shibatomi, K.; Yamamoto,. J. Am. Chem. Soc. 2004, 126, 15038 15039
Catalytic Asymmetric alogenation of Carbonyl Compounds Conclusions Enantioselective electrophilic a-halogenation of carbonyl compounds: a topical area of current asymmetric catalysis A new tool has presented itself to synthetic organic chemistry More applications are expected
To What They Should Thank? 2BF - 4 F PhS 2 PhS 2 F Dr. Togni ET Selectfluor, -fluorobenzenesulfonimide or F-TEDA or FSI 12 13 Br X Br Br Br 70 71 Wong, C.-., Angew. Chem. Int. Ed., 2005, 44, 192 X=, CS X= Br, BS X= I, IS Taylor, S. D.; Kotoris, C. C. and um, G. Tetrahedron, 1999, 55,12431-12477 Dr. Lectka Johns opkins U. Dr. MacMillan Caltech Dr. Jørgensen Aarhus U. Dr. Yamamoto U. of Chicago