Morita Baylis Hillman Reaction. Aaron C. Smith 11/10/04

Transcription

1 Morita Baylis Hillman Reaction Aaron C. Smith 11/10/04

2 Outline 1. Background 2. Development of Asymmetric Variants 3. Aza-Baylis Hillman Reaction 4. Applications of Baylis Hillman Adducts

3 Outline 1. Background 1. Mechanism, Scope of Reaction 2. Advancements in Rate 2. Development of Asymmetric Variants 3. Aza-Baylis Hillman Reaction 4. Applications of Baylis Hillman Adducts

4 Basic Baylis Hillman Reaction

5 Background Reported by Morita and coworkers in 1968 used PCy 3 as nucleophilic catalyst Mortia, K., Suzuki, Z., Hirose, H. Bull. Chem. Soc. Jap. 1968, 41, Baylis and Hillman in 1972 used tertiary amines (DABCO) as nucleophilic catalyst. Baylis, A. B., Hillman, M. E. D. German Patent , 1972, Chem. Abstr. 1972, 77, 34147q. Applications in complex systems limited by low rates of conversion and substrate dependence of reaction Led to underdevelopment of reaction until 1980 s when 3 o amine variant was further studied Majority of reactions require days-weeks for reasonable conversions Basavaiah, D. et al. Chem. Rev. 2003, 103, 811.

6 Basavaiah, D. et al. Chem. Rev. 2003, 103, 811. Versatility of Nucleophiles

7 Basavaiah, D. et al. Chem. Rev. 2003, 103, 811. Versatility of Electrophiles

8 Basavaiah, D. et al. Chem. Rev. 2003, 103, 811. Mechanism

9 Temperature Dependence on Rate at rt, reactions takes many days for a variety of different aldehydes in this system at 0 o C, reactions complete in hours proposed explanation: at 0 o C, a greater population of one enolate is formed, leading to more rapid reaction with aldehyde Leahy, J. W. et al. JOC 1997, 62, Leahy, J. W. et al. Tetrahedron 1997, 53,

10 Other Examples of Rate Acceleration Aggarwal, V. K., et al. Chem. Comm. 1996, Aggarwal, V. K., et al. JOC 1998, 63, Yu, C. et al. JOC, 2001, 66, Aggarwal, V. K., et al. Chem. Comm. 1999, 2311.

11 Rate vs pk a more acidic the catalyst, the slower the rate Aggarwal, V. K., et al. JOC, 2003, 68, 692.

12 Ikegami, S., et al. TL 2000, 41, Use of Bronsted Acids

13 Efficient Catalyst with Titanium Activation Verkade, J. G., et al. ACIEE 2003, 42, 5054.

14 Conjugate Acids of Phosphines Problems with trialkylphosphines regarding air stability, solved through protection as phosphonium salts: Baylis Hillman reaction proceeds smoothly with the salt Fu, G. et al. Org. Lett. 2001, 3, 4295.

15 Outline 1. Background 2. Development of Asymmetric Variants 1. Use of Chiral Auxiliaries 2. Chiral Bronsted Acids 3. Chiral Amines 3. Aza-Baylis Hillman Reaction 4. Applications of Baylis Hillman Adducts

16 Early Examples Gilbert, et. al. Tet: Asymm. 1991, 2, 969. Leahy, et al. Tet. 1997, 53,

17 Use of Chiral Sultam Auxiliary yields 33-98%, ee's >99%, reaction times <1 day Works only for aliphatic aldehydes Sultam is expelled from the reaction upon formation of dioxinone leading to recoverable auxiliary. ~ 15 eq. aldehyde are required, however Leahy, J.W. JACS 1997, 119, 4317

18 Leahy, J.W. JACS 1997, 119, 4317 Proposed Mechanism

19 Use of Chiral Lewis Acids

20 Use of Chiral Bronsted Acids

21 Use of Proline Derivatives in Catalysis

22 Nagasawa, K., et al. TL 2004, 45, Use of Bis-thiourea in Catalysis

23 Use of Chiral Amines

24 Proposed Mechanism

25 Outline 1. Background 2. Development of Asymmetric Variants 3. Asymmetric Aza-Baylis Hillman Reaction 4. Applications of Baylis Hillman Adducts

26 Asymmetric Aza-Baylis Hillman * with methyl acrylate: yields <72%, ee's <83% yields <78 %, ee's < 93% proposed mechanism: proposed H-bonding providing rigid T. S. Shi, M., Xu, Y-M. ACIEE 2002, 41, 4507.

27 Hatakeyama, S. et al. Org. Lett. 2003, 5, Asymmetric Aza-Baylis Hillman

28 Hatakeyama, S. et al. Org. Lett. 2003, 5, Proposed Mechanism

29 Asymmetric Aza Baylis Hillman proposed that phosphine utilized as lewis base with phenolic proton utilized as bronsted acid

30 Outline 1. Background 2. Development of Asymmetric Variants 3. Aza-Baylis Hillman Reaction 4. Applications of Baylis Hillman Adducts

31 Applications of Baylis Hillman Adducts Leahy, J. W., et al. JACS 1997, 119, Leahy, J. W. et al. Tetrahedron 1997, 53,

32 Application to Total Synthesis Krishna, P. R., et al. TL, 2004, 45, 4773.

33 Application to Total Synthesis

34 Application to Total Synthesis Furaquinocin E Trost, B. M., et al. JACS 2002, 124,

35 Summary Achievements made in reducing the time of reaction Changing solvents, temperature, use of Bronsted acids, Several approaches to achieving enantioselective Baylis Hillman: Use of chiral auxiliaries Use of chiral Bronsted acids Use of chiral amines Development of Aza Baylis Hillman Reaction use of chiral bases to provide induction in the reaction Reaction applied to several total syntheses

36 References For Reviews see: Baylis Hillman: Basavaiah, D. et al. Tetrahydron 1996, 52, Basavaiah, D. et al. Chem. Rev. 2003, 103, 811. Nucleophilic Phosphine Organocatalysis: Roush, W. R. et al. Adv. Synth. Catal. 2004, 346, 1035.