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1、Literature meeting Presented byJose PhilippeProf Andr B.CharetteOctober 4th,2005,The BaylisHillman Reaction and Related Modifications,Content,What is the BaylisHillman Reaction?Activation of the ReactionEnantioselective ReactionIntramolecular ReactionAzaBaylisHillman ReactionApplication of BaylisHil
2、lman Reaction in the Synthesis of Natural Products such as Salinosporamide A.,2,About BaylisHillman 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
3、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.1968,41,2815Basavaiah,D.et al.Chem.Rev.2003,103,811-891,3,What Kind of
4、Substrates Are Used in BH Reaction?,Activated alkenesElectrophileCatalystAmine(BH Rxn)Phosphine(MBH Rxn),Basavaiah,D.et al.Chem.Rev.2003,103,811-891,4,General Mechanism of BH Reaction,Basavaiah,D.et al.Chem.Rev.2003,103,811-891,5,New Interpretation of the Mechanism,RDS is the elimination product and
5、 not the 1,2-AdditionThe 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,Protic Solvent,New Interpretation of the Mechanism,7,Aggarwal,V.K.et al.Angew.Chem.Int.Ed.2005,44,1706-1708,
6、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!,8,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
7、 catalyst or DMAPMixture of water and organic solvent has been shown to increase the rate of reactionSolvent dependant:Dioxane and methanol are also usedUse of stoichiometric amount of catalystUse of co-catalyst in the reaction:LiClO4 with DABCO,proline with imidazole,DABCO with CaH2These modificati
8、ons 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,Activation of the BH Reaction,Catalysis by Ionic Liquid Immobilized Quinuclidine,Re
9、action time between 30 minutes and 12 hoursWorks well when EWG=CO2Alkyl and CN(yields 62%)Good yield obtained with R=alkyl,aromatic subtituted either by EDG or EWG and hetero aromatic ringThe catalyst can be reused after extraction with ether up to 6 time without losing significant activity,Cheng,J.
10、P.et al.J.Org.Chem.2005,70,2338-2341,10,Activation of the BH Reaction,Use of TiCl4 in combination with proazaphosphatranes,Verkade J.G.et al.Angew.Chem.Int.Ed,2003,42,5054-5056,11,Activation of the BH Reaction,catalyst,12,Activation of the BH Reaction,catalyst,13,Activation of the BH Reaction,cataly
11、st,14,Few work has been done on the intramolecular MBH reaction compared to the acyclic oneCan lead to interesting multifunctionalized cycles,Intramolecular MoritaBH Reaction,15,Intramolecular MoritaBH Reaction,Murphy,P.J.et al.Tetrahedron,2001,57,7771-7784,When an excessof piperidine is used,the re
12、action stops at the intramolecular aldol reaction to give mainly product 2.,16,Vinylogous Intramolecular MoritaBH Reaction,Roush,W.R et al.J.Am.Chem.Soc.2002,124,2404-2405,17,Vinylogous Intramolecular MoritaBH Reaction,Roush,W.R et al.J.Am.Chem.Soc.2002,124,2404-2405,Conclusion:5 membered cycloalken
13、es are easier to synthesise by a vinologous intramolecular MBH reaction.Lower concentration reduces the yield due to self-condensation.,18,Explanation of Regioselectivity,Roush,W.R et al.J.Am.Chem.Soc.2002,124,2404-2405,The most electrophilic carbon will react first:aldehydeketoneester,19,Combinatio
14、n of MBH Reaction and TrostTsuji Reaction,Krische M.J.et al.J.Am.Chem.Soc.2003,125,7758-7759,20,Combination of MBH Reaction and TrostTsuji Reaction,21,New MBH Cyclization Reactions,Krafft,M.E.et al.J.Am.Chem.Soc.2005,127,10168-10169,22,Have been a challenge in organic synthesis Enantioselectivity ca
15、n come from:Chiral Lewis acidChiral amineBifunctional organocatalystKinetic Resolution,23,Enantioselective MBH Reactions,Enantioselective MBH Reactions,Miller,S.J.et al.Org.Lett.2003,5,3741-3743,Proposed Intermediate,24,Enantioselective MBH Reactions,Miller,S.J.et al.Org.Lett.2005,7,3849-3851,Condit
16、ions:THF/H2O 3:1,0.6M,48 h at r.t.,Acylation Kinetic Resolution,25,Enantioselective MBH Reactions,Mechanism,Schaus,S.E.et al.J.Am.Chem.Soc.2003,125,12095-12096,B-H=Chiral Bronsted Acid,26,Enantioselective MBH Reactions,Schaus,S.E.et al.J.Am.Chem.Soc.2003,125,12095-12096,Catalyst:,27,Enantioselective
17、 MBH Reactions Via a Bifunctional Organocatalyst,Wang,W.et al.Org.Lett.2005,7,4293-4296,Catalyst and Transition State:,28,Aza-BH Reaction:General,Use of imines instead of aldehydesGeneral reaction:,29,Enantioselective Aza-BH Reaction,Shi,M.et al.Angew.Chem.Int.Ed.2002,69,4507-4510,Proposed Transitio
18、n State,30,Enantioselective Aza-BH Reaction,Shi,M.et al.Angew.Chem.Int.Ed.2002,69,4507-4510,Only works when directly attached to Ph ringWith aliphatic imines,no product obtainedBest results obtained with EDGConfiguration is R,ORTEP of 4,31,Shi,M.et al.Chem.Eur.J.2005,11,1794-1802,Enantioselective Az
19、a-BH Reaction,ORTEP of 3,Catalyst,32,Change of Configuration:Explanation,Shi,M.et al.Chem.Eur.J.2005,11,1794-1802,33,Enantioselective Aza-BH Reaction,Shi,M.et al.J.Am.Chem.Soc.2005,127,3790,The use of phenyl acrylate or acrolein worked well,but showed a decrease in enantioselectivity Reaction time b
20、etween 18 and 36 h By changing CH3 by H or OPh,the same configuration was obtained!,34,Enantioselective Aza-BH Reaction:Proposed TS,35,R,S,Enantioselective Aza-BH Reaction,Lewis Base,Lewis Acid,Sasai,H.et al.J.Am.Chem.Soc.2005,127,3680-3681,36,Application of BH Reaction in Total Synthesis,Salinospor
21、amide A,Corey,E.J.et al.J.Am.Chem.Soc.2004,126,6230-6231,1,Retrosynthetic Analysis,37,Corey,E.J.et al.J.Am.Chem.Soc.2004,126,6230-6231,Application of BH Reaction in Total Synthesis,38,BH Reaction as Key Step,Explanation,39,BH Reaction as Key Step,Explanation,Less interaction because the methyl is mo
22、re far from the quinuclidine moiety,40,Why One is Silylated and Not the Other One?,Big interaction between the chain and benzyl group,The methyl groups on the silicon aremore far from the methyl of the ester,41,End of the Synthesis of Salinosporamide A,42,Activation of BH reaction by reusable Ionic
23、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 cyclizationEnantioselective MBH reaction providing ee up to 99%Synthesis of aromatic-substituted chiral tosyl amines by Aza-BH reaction.Very few BH adducts with alkyl iminesTotal synthesis of Salinosporamide A by Corey using BH reaction as a key step with a 10%overall yield for 18 steps,Conclusion,43,
