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

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. 2

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 3

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 4

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

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 McQuade, D.T. et al. Org. Lett. 2005, 7, 147-150 Aprotic Solvent Byproduct observed 6

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

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

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: LiClO 4 with DABCO, proline with imidazole, DABCO with CaH 2 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 9

10. Activation of the BH Reaction Catalysis by Ionic Liquid Immobilized Quinuclidine  Reaction time between 30 minutes and 12 hours  Works well when EWG = CO 2 Alkyl 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 10

11. Activation of the BH Reaction Use of TiCl 4 in combination with proazaphosphatranes Verkade J. G. et al. Angew. Chem. Int. Ed, 2003, 42, 5054-5056 11

12. Activation of the BH Reaction catalyst 12

13. Activation of the BH Reaction catalyst 13

14. Activation of the BH Reaction EntryREWGt (min)Yield (%) 1NO 2 COCH 3 592 2HCOCH 3 585 3NO 2 CO 2 Et1092 4NO 2 CO 2 CH 3 1092 5ClCO 2 CH 3 1092 6HCO 2 CH 3 1088 7OCH 3 CO 2 CH 3 1087 8HCN2095 9NO 2 CN1088 catalyst 14

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

16. Intramolecular Morita – BH Reaction Murphy, P. J. et al. Tetrahedron, 2001, 57, 7771-7784 EntryRnMethodYield (%) 1Ph10.3 equiv. piperidine, CDCl 3, 144 h50 2OEt10.4 equiv. n-Bu 3 P, CDCl 3, 28 days40 3Ph2 0.3 equiv. piperidine, CDCl 3, 14 to 28 days 24-30 4Ph20.2 equiv. n-Bu 3 P, CDCl 3, 2 h75 5OEt20.2 equiv. n-Bu 3 P, CDCl 3, 24 h50 When an excess of piperidine is used, the reaction stops at the intramolecular aldol reaction to give mainly product 2. 16

17. Vinylogous Intramolecular Morita – BH Reaction Roush, W. R et al. J. Am. Chem. Soc. 2002, 124, 2404-2405 EntryRR’Cat (%)Solvent[M]t (h)Yield (%) Ratio (A/B) 1MeOMePBu 3 (10)CH 3 CN0.05248095:5 2MeOMePBu 3 (10)CH 3 CN0.1086195:5 3MeOMePBu 3 (10)t-amyl-OH0.10118896:4 4MeOMePMe 3 (10)t-amyl-OH0.0539197:3 5MeOMePMe 3 (10)t-amyl-OH1.000.758196:4 6HOMePMe 3 (20)t-amyl-OH0.100.2543100:0 7HOMePMe 3 (20)t-amyl-OH0.01490100:0 17

18. Vinylogous Intramolecular Morita – BH Reaction Roush, W. R et al. J. Am. Chem. Soc. 2002, 124, 2404-2405 EntryRR’Cat (%)Solvent[M]t (h)Yield (%) Ratio (A/B) 8MeOMePMe 3 (25)t-amyl-OH0.1088392:8 9HMePBu 3 (50)CH 3 CN0.060.55590:10 10HMePMe 3 (50)t-amyl-OH0.010.754595:5 Conclusion: 5 membered cycloalkenes are easier to synthesise by a vinologous intramolecular MBH reaction. Lower concentration reduces the yield due to self-condensation. 18

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

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

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

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

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

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

25. Enantioselective MBH Reactions Miller, S. J. et al. Org. Lett. 2005, 7, 3849-3851 Conditions: THF/H 2 O 3:1, 0.6M, 48 h at r.t. Acylation Kinetic Resolution 25

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

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

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

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

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

31. Enantioselective Aza-BH Reaction EntryArYield (%)ee (%) 1C6H5C6H5 8097 2p-MeC 6 H 4 7696 3p-MeOC 6 H 4 6499 4p-ClC 6 H 4 6893 5p-NO 2 C 6 H 4 6074 6C 6 H 5 -CH=CH5446 Shi, M. et al. Angew. Chem. Int. Ed. 2002, 69, 4507-4510 Only works when directly attached to Ph ring With aliphatic imines, no product obtained Best results obtained with EDG Configuration is R ORTEP of 4 31

32. EntryArRConditionsYield (%)ee (%) 1C6H5C6H5 HTHF, -25 o C8085 2C6H5C6H5 OMeDCM, 0 o C7683 3p-MeOC 6 H 5 OMeDCM, 0 o C6470 4C6H5C6H5 OPhCH 3 CN, -20 o C6474 5p-MeC 6 H 4 HTHF, -25 o C6883 6p-MeC 6 H 4 OMeDCM, 0 o C6080 7p-MeC 6 H 4 OPhCH 3 CN, -20 o C5469 Shi, M. et al. Chem. Eur. J. 2005, 11, 1794-1802 Enantioselective Aza-BH Reaction ORTEP of 3 Catalyst 32

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

34. Enantioselective Aza-BH Reaction Shi, M. et al. J. Am. Chem. Soc. 2005, 127, 3790 EntryArYield (%)ee (%) 1C6H5C6H5 83 2p-MeC 6 H 5 8281 3p-FC 6 H 5 8481 4m-FC 6 H 5 9685 5p-BrC 6 H 5 8583 6p-ClC 6 H 5 9087 7m-ClC 6 H 5 88 8o-ClC 6 H 5 8561 9p-NO 2 C 6 H 5 8692 10o-NO 2 C 6 H 5 8884 11C 6 H 5 CH=CH9495  The use of phenyl acrylate or acrolein worked well, but showed a decrease in enantioselectivity  Reaction time between 18 and 36 h  By changing CH 3 by H or OPh, the same configuration was obtained! 34

35. Enantioselective Aza-BH Reaction: Proposed TS 35 RS

36. EntryArRYield (%)ee (%) 1C6H5C6H5 Me9387 2p-ClC 6 H 4 Me9695 3m-ClC 6 H 4 Me93 4p-BrC 6 H 4 Me9394 5p-MeOC 6 H 4 Me9394 62-furylMe10088 72-naphtylMe9491 8p-NO 2 C 6 H 4 Me91 9p-NO 2 C 6 H 4 Et88 10p-NO 2 C 6 H 4 H9594 Enantioselective Aza-BH Reaction Lewis Base Lewis Acid Sasai, H. et al. J. Am. Chem. Soc. 2005, 127, 3680-3681 36

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

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

39. BH Reaction as Key Step Explanation 39

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

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

42. End of the Synthesis of Salinosporamide A 42

43. Activation of BH reaction by reusable Ionic Liquid Immobilized Quinuclidine and use of TiCl 4 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 Conclusion 43