Strategies for Catalytic Asymmetric Electrophilic a Halogenation of Carbonyl Compounds

Transcription

1 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, amashima, Y.; Sodeoka, M. et al J. Am. Chem. Soc. 2002, 124, France, S.; Lectka, T. et al J. Am. Chem. Soc. 2004, 126, Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, alland,. ; Jørgensen, K. A. et al J. Am.Chem. Soc. 2004, 126, Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2004, 43, Zhang, Y. ; Shibatomi, K.; Yamamoto,. J. Am. Chem. Soc. 2004, 126, 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

2 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 MaxiPost Currently being assessed worldwide in phase III clinical trials for treatment of acute ischemic stoke estreich, M. Angew. Chem. Int. Ed., 2005, 44, Ibrahim,.; Togni, A. Chem. Commun. 2004,

3 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, Taylor, S. D.; Kotoris, C. C. and um, G. Tetrahedron, 1999, 55,

4 oncatalytic alogenation Substrate-controlled alogenation: Use of Chiral Auxiliaries estreich, M. Angew. Chem. Int. Ed., 2005, 44, Taylor, S. D.; Kotoris, C. C. and um, G. Tetrahedron, 1999, 55,

5 oncatalytic alogenation eagent-controlled alogenation: Chiral Fluorinating eagents Pioneering work: Differding, E. and Lang,. W. Tetrahehron Lett. 1988, 29, 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,

6 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 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,

7 Catalytic Asymmetric Fluorination rgano-catalytic Enantioselective Fluorination by Phase-Transfer Catalysts Kim, D. Y. and Park, E. J. rg. Lett., 2002, 4,

8 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

9 Catalytic Asymmetric Fluorination rgano-catalytic Enantioselective Fluorination by L-Proline Derevatives Ph Ph X 14a, X= 14b, X= , 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

10 Catalytic Asymmetric Fluorination Chiral Lewis Acid Catalyzed Asymmetric Fluorination Addition of sub-stoichiometric amount of Lewis acid significantly accelerates formation of fluorination product Ti-based Lewis acids are the most potent catalysts Umemoto, T et al J. Am. Chem. Soc., 1990, 112, intermann, L. ; Togni, A. Angew. Chem. Int. Ed. 2000, 39,

11 Catalytic Asymmetric Fluorination Ti 2 [,-(TADDLLato)] Catalyzed Asymmetric Fluorination 12 intermann, L. ; Togni, A. Angew. Chem. Int. Ed. 2000, 39, Ibrahim,.; Togni, A. Chem. Commun. 2004,

12 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, Ibrahim,.; Togni, A. Chem. Commun. 2004,

13 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,

14 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, Ma, J.-A. and Cahard, D. Tetrahedron: Asymmetry, 2004, 15, 1007 Shibata,.; Ishimaru, T.; agai, T., Kohno, J. and T. Toru Synlett 2004,

15 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, Me I + Bn Me mol% eq 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, X 10mol% 67 Et X X=, up to 77%ee X= Br, up to 82%ee Marigo, M.; Kumaragurubaran,.; Jørgensen, K. A. Chem. Eur. J. 2004,10, t-bu 2 Tf - Cu t-bu (S, S)-67 estreich, M. Angew. Chem. Int. Ed., 2005, 44,

16 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 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,

17 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 France, S.; Lectka, T. et al J. Am. Chem. Soc. 2004, 126,

18 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 = 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 = 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,

19 rgano-catalytic Asymmetric Chlorination Asymmetric Chlorination of Aldehydes Catalyzed by Chiral Amines 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 Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126,

20 rgano-catalytic Asymmetric Chlorination of Aldehydes Asymmetric Chlorination of Aldehydes: Catalysts and Chlorinating eagents CS 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,

21 rgano-catalytic Asymmetric Chlorination of Aldehydes Asymmetric Chlorination of Aldehydes: the Solvent Effects 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,

22 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,

23 rgano-catalytic Asymmetric Chlorination of Aldehydes Asymmetric Chlorination of Aldehydes: b-chiral Aldehydes 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,

24 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,

25 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,

26 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,

27 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,

28 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,

29 Asymmetric Chlorination of Ketones Back to eagent Controlled Asymmetric Chlorination of Ketones eagent-controlled process can sometimes be competitive alternative! 1 Si X X 1 Lewis acid! X= or 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,

30 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,

31 Asymmetric Chlorination of Ketones Asymmetric Chlorination of Ketones: Scope

32 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,

33 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

34 To What They Should Thank? 2BF - 4 F PhS 2 PhS 2 F Dr. Togni ET Selectfluor, -fluorobenzenesulfonimide or F-TEDA or FSI Br X Br Br Br 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, Dr. Lectka Johns opkins U. Dr. MacMillan Caltech Dr. Jørgensen Aarhus U. Dr. Yamamoto U. of Chicago