The Baylis –Hillman Reaction and Related Modifications

1. The Baylis–Hillman Reaction and Related Modifications Literature meeting Presented by Josée Philippe Prof André B. Charette October 4th, 2005

2. 2 Content • What is the Baylis–Hillman Reaction? • Activation of the Reaction • Enantioselective Reaction • Intramolecular Reaction • Aza–Baylis–Hillman Reaction • Application of Baylis–Hillman Reaction in the Synthesis of Natural Products such as Salinosporamide A.

3. 3 About Baylis–Hillman Reaction • In 1968, Morita reported the reaction between acetaldehyde and ethyl acrylate in the presence of a tertiary phosphine. • Four years later, Baylis and Hillman developed the same transformation, but in the presence of a tertiary amine, DABCO, which is less toxic and cheaper. • Reaction works with aliphatic as well as aromatic aldehydes. • Carbon-carbon bond formation involving Michael-type addition. Morita, K. et al. Bull. Chem. Soc. Jpn. 1968, 41, 2815 Basavaiah, D. et al. Chem. Rev.2003, 103, 811-891

4. 4 What Kind of Substrates Are Used in BH Reaction? • Activated alkenes • Electrophile • Catalyst • Amine (BH Rxn) • Phosphine (MBH Rxn) Basavaiah, D. et al. Chem. Rev.2003, 103, 811-891

5. 5 General Mechanism of BH Reaction Basavaiah, D. et al. Chem. Rev.2003, 103, 811-891

6. 6 New Interpretation of the Mechanism • RDS is the elimination product and not the 1,2-Addition • The rate law is second order in aldehyde and first order in catalyst and in methyl acrylate Aprotic Solvent Byproduct observed McQuade, D.T. et al. Org. Lett.2005, 7, 147-150

7. 7 New Interpretation of the Mechanism Protic Solvent Aggarwal, V.K. et al. Angew. Chem. Int. Ed. 2005, 44, 1706-1708

8. 8 Tertiary Amines and PhosphinesUsed in the BH or MBH Reaction Drawback of reaction: very slow process: can take many days, weeks or even months to complete the reaction!!!

9. 9 What Can Be Used to Activate the Reaction? • Different methods have been used so far to enhance the rate of the reaction. • Use of DBU as catalyst or DMAP • Mixture of water and organic solvent has been shown to increase the rate of reaction • Solvent dependant: Dioxane and methanol are also used • Use of stoichiometric amount of catalyst • Use of co-catalyst in the reaction: LiClO4 with DABCO, proline with imidazole, DABCO with CaH2 • These modifications are often substrate dependant and vary in yield and in time: usually between 0.5 h and 6 days or more!!! • Question: Are there more efficient conditions for the BH-reaction? Basavaiah, D et al. Chem. Rev.2003, 103, 811-891

10. 10 Activation of the BH Reaction • Catalysis by Ionic Liquid Immobilized Quinuclidine • Reaction time between 30 minutes and 12 hours • Works well when EWG = CO2Alkyl and CN (yields > 62%) • Good yield obtained with R = alkyl, aromatic subtituted either by EDG or EWG and hetero aromatic ring • The catalyst can be reused after extraction with ether up to 6 time without losing significant activity Cheng, J.–P. et al. J. Org. Chem.2005, 70, 2338-2341

11. 11 Activation of the BH Reaction • Use of TiCl4 in combination with proazaphosphatranes Verkade J. G. et al. Angew. Chem. Int. Ed, 2003, 42, 5054-5056

12. 12 Activation of the BH Reaction catalyst

13. 13 Activation of the BH Reaction catalyst

14. 14 Activation of the BH Reaction catalyst

15. Intramolecular Morita–BH Reaction 15 • Few work has been done on the intramolecular MBH reaction compared to the acyclic one • Can lead to interesting multifunctionalized cycles

16. Intramolecular Morita–BH Reaction 16 When an excess of piperidine is used, the reaction stops at the intramolecular aldol reaction to give mainly product 2. Murphy, P. J. et al. Tetrahedron, 2001, 57, 7771-7784

17. Vinylogous Intramolecular Morita–BH Reaction 17 Roush, W. R et al. J. Am. Chem. Soc. 2002, 124, 2404-2405

18. Vinylogous Intramolecular Morita–BH Reaction 18 Conclusion: 5 membered cycloalkenes are easier to synthesise by a vinologous intramolecular MBH reaction. Lower concentration reduces the yield due to self-condensation. Roush, W. R et al. J. Am. Chem. Soc. 2002, 124, 2404-2405

19. Explanation of Regioselectivity 19 The most electrophilic carbon will react first: aldehyde>ketone>ester Roush, W. R et al. J. Am. Chem. Soc. 2002, 124, 2404-2405

20. 20 Combination of MBH Reaction and Trost–Tsuji Reaction Krische M.J. et al. J. Am. Chem. Soc. 2003, 125, 7758-7759

21. Combination of MBH Reaction and Trost–Tsuji Reaction 21

22. 22 New MBH Cyclization Reactions Krafft, M. E. et al. J. Am. Chem. Soc. 2005, 127, 10168-10169

23. 23 Enantioselective MBH Reactions • Have been a challenge in organic synthesis • Enantioselectivity can come from: • Chiral Lewis acid • Chiral amine • Bifunctional organocatalyst • Kinetic Resolution

24. 24 Enantioselective MBH Reactions Proposed Intermediate Miller, S. J. et al. Org. Lett. 2003, 5, 3741-3743

25. 25 Enantioselective MBH Reactions Acylation Kinetic Resolution Conditions: THF/H2O 3:1, 0.6M, 48 h at r.t. Miller, S. J. et al. Org. Lett. 2005, 7, 3849-3851

26. Enantioselective MBH Reactions 26 B-H = Chiral Bronsted Acid Mechanism Schaus, S. E. et al. J. Am. Chem. Soc. 2003, 125, 12095-12096

27. Enantioselective MBH Reactions 27 Catalyst : Schaus, S. E. et al. J. Am. Chem. Soc. 2003, 125, 12095-12096

28. Enantioselective MBH Reactions Via a Bifunctional Organocatalyst 28 Catalyst and Transition State: Wang, W. et al. Org. Lett. 2005, 7, 4293-4296

29. 29 Aza-BH Reaction: General • Use of imines instead of aldehydes • General reaction:

30. 30 Enantioselective Aza-BH Reaction Proposed Transition State Shi, M. et al. Angew. Chem. Int. Ed. 2002, 69, 4507-4510

31. Enantioselective Aza-BH Reaction 31 ORTEP of 4 • Only works when directly attached to Ph ring • With aliphatic imines, no product obtained • Best results obtained with EDG • Configuration is R Shi, M. et al. Angew. Chem. Int. Ed. 2002, 69, 4507-4510

32. Enantioselective Aza-BH Reaction 32 Catalyst ORTEP of 3 Shi, M. et al. Chem. Eur. J. 2005, 11, 1794-1802

33. Change of Configuration: Explanation 33 Shi, M. et al. Chem. Eur. J. 2005, 11, 1794-1802

34. Enantioselective Aza-BH Reaction 34 • The use of phenyl acrylate or acrolein worked • well, but showed a decrease in enantioselectivity • Reaction time between 18 and 36 h • By changing CH3 by H or OPh, the same configuration was obtained! Shi, M. et al. J. Am. Chem. Soc. 2005, 127, 3790

35. Enantioselective Aza-BH Reaction: Proposed TS 35 S R

36. Enantioselective Aza-BH Reaction 36 Lewis Base Lewis Acid Sasai, H. et al. J. Am. Chem. Soc. 2005, 127, 3680-3681

37. Application of BH Reaction in Total Synthesis 37 Salinosporamide A 1 Retrosynthetic Analysis Corey, E.J. et al. J. Am. Chem. Soc. 2004, 126, 6230-6231

38. Application of BH Reaction in Total Synthesis 38 Corey, E.J. et al. J. Am. Chem. Soc. 2004, 126, 6230-6231

39. BH Reaction as Key Step 39 Explanation

40. BH Reaction as Key Step 40 Explanation Less interaction because the methyl is more far from the quinuclidine moiety

41. Why One is Silylated and Not the Other One? 41 Big interaction between the chain and benzyl group The methyl groups on the silicon are more far from the methyl of the ester

42. End of the Synthesis of Salinosporamide A 42

43. Conclusion 43 • Activation of BH reaction by reusable Ionic Liquid Immobilized Quinuclidine and use of TiCl4 in combination with proazaphosphatranes can provide adduct in less than 10 minutes! • Development of new methods of intramolecular cyclization • Enantioselective MBH reaction providing ee up to 99% • Synthesis of aromatic α-substituted chiral tosyl amines by Aza-BH reaction. Very few BH adducts with alkyl imines • Total synthesis of Salinosporamide A by Corey using BH reaction as a key step with a 10% overall yield for 18 steps