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Carbon-Carbon Bond Forming Reactions I. Substitution Reaction II. Addition Reaction
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Carbon-Carbon Bond Forming Reactions II. Addition Reaction : Condensation Reaction Aldol condensation : base catalyzed acid catalyzed Directed Aldol condensation : usually kinetic control
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Base Catalyzed aldol condensation
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Acid Catalyzed aldol condensation
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Mixed aldol condensation Classical : with non-enolizable carbonyls trans : major
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Base catalyzed v.s. Acid catalyzed Under base catalysis
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Under acid catalysis
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Control of regio- and stereochemistry in aldol condensation Directed aldol : regioselective, stereoselective 100% single enolate, generally non-equilibirum
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Stereocontrol in Aldol Condensation Syn aldolanti aldol
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Erythro vs. Threo syn vs. anti started from sugar chem. Extension (generalization) : following the priority rule for (R, S) configuraiton If priority eclipses --- erythro If priority does not eclipse --- threo Proposed by Masamune : ACIE 1980, 19, 557
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Aldol condensation of enolates For syn, anti selectivity i) Enolate geometry is important – usually syn is dominant E,Z-selectivity of enolates depends on substitution, base & additives R= Et 3.3 : 1 R= i-Pr 1.7 : 1 R= t-Bu 1 : >50
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Aldol condensation of enolates Z-enolate E-enolate
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Aldol condensation of enolates For syn, anti selectivity i)Enolate geometry is important – usually syn is dominant ii)Cyclic ketones --- anti aldol is major E-enolate 84 : 16
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Aldol condensation of enolates For syn, anti selectivity i)Enolate geometry is important – usually syn is dominant ii)Cyclic ketones --- anti aldol is major iii)Kinetically Z-enolate is preferred iv)Metal plays an important role – size, ligands v)In reality, aggregation state is important -- effect of additives enolates can equilibrate fast – thermodynamic mixture
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Aldol condensation of enolates i)Can be easily generated with LDA from ketone, ester, amide, etc. ii)Can chelate to other functional groups a. Li enolates iii)Regioselective addition
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Aldol condensation of enolates b. Boron enolate i)Cyclic transition state ii)Transition state is compact – amplify steric factor :better selectivity iii)Two extra ligand can influence the outcome iv)Z-enolate dominant v)With bulky ligand on boron, E-enolate dominates (n-Bu) 2 BOTf 97 : 3 (2-BCO) 2 BOTf 3 : 97
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Aldol condensation of enolates i)Somewhere between B, and Li enolate ii)Extra chelation available, could have extra ligands c. Ti, Sn, Zr enolate Mostly syn selective !!! Acyclic T.S.
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Mukaiyama aldol : acid catalyzed aldol Silyl enol ether + lewis acids + carbonyl (or acetal)
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Mukaiyama aldol : acid catalyzed aldol i)Usually acyclic transition state Silyl enol ether + lewis acids + carbonyl (or acetal)
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ii) Catalytic aldol condensation !!!
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Anti – selective aldol condensation Selective formation of E- enolate With 9-BBN-- >97:3 -- syn selective Lewis acid catalyzed aldol 32 : 1 JACS, 2002, 124, 392
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Evans Chiral Aldol condensation LDA R 2 BOTf; R 3 N TiCl 4 ; R 3 N i) LDA ii) ClTi(Oi-Pr) 3
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Evans Chiral Aldol condensation LDA R 2 BOTf; R 3 N TiCl 4 ; R 3 N
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Evans Chiral Aldol condensation i) LDA ii) ClTi(Oi-Pr) 3
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Evans Chiral Aldol condensation MgCl 2 ; R 3 N
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Evans Chiral Aldol condensation MgCl 2 ; R 3 N Boat-like T.S.
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Evans Chiral Aldol condensation MgCl 2 ; R 3 N Boat-like T.S.
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Enantio-selective aldol condensation i)Chiral center in enolate ii)Chiral center in aldehyde iii)Chiral auxiliary iv)Chiral metal v)Chiral Lewis acid
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Enantio-selective aldol condensation i)Chiral center in enolate TL 21, 4678(1980) Through extra chelation
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Enantio-selective aldol condensation ii) Chiral center in aldehyde Anti aldol products are very minor ** Chiral centers in both aldehyde and enolate ** 85% Kinetic resolution or Double stereodifferentiation JOC 46, 2290 (1981) Mutual kinetic resolution
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Matched v.s. Mismatched
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Mutual kinetic resolution Product ratio??
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(n-Bu) 2 BOTf 97 : 3 9-BBNOTf 97 : 3 (2-BCO) 2 BOTf 3 : 97 9-BBNOTf (2-BCO) 2 BOTf
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Enantio-selective aldol condensation iii) Chiral auxiliary D.A. Evans Reliable, can predict stereochemistry stoichiometric, not economic W. Oppolzer
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vi) Chiral Metal E.J. Corey, JACS 5493(1989) 1 eq. E.J. Corey, JACS 4977(1990)
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v) Chiral Lewis acid S. Masamune E.J. Corey M. Shibasaki E. Carreira Catalyst!!
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Intramolecular Aldol condensation Dieckman condensation Scheme 2.9
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Robinson annulation Too reactive Enolate control needed
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Robinson annulation Stable Vinylketone Enamines for annulation
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Robinson annulation Asymmetric synthesis
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Proline catalyzed Asymmetric aldol reaction JACS, 123, 5260(2001) OL, 3305 (2004)
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Proline catalyzed Asymmetric aldol reaction JACS, 123, 5260(2001) OL, 3305 (2004) JACS, 124, 6798(2002) anti:syn=3:1
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Application to organic synthesis : “biogenetic type synthesis” Science, 305, 1754(2004) anti:syn=4:1 MgBr 2 Et 2 O MgBr 2 CH 2 Cl 2 TiCl 4 CH 2 Cl 2 glucose mannose allose
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Modificaiton of the reaction Mannich reaction Electrophile : reactivity
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Mannich Reaction
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Synthesis of tropinone : biogenetic type synthesis Sir. Robinson Decarboxylation
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Tropinone Roboinson “Mannich reaction” Willstatter
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Synthesis of tropinone : biogenetic type synthesis Sir. Robinson
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Amine catalyzed reaction Knoevenagel reaction
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81% 80%
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Amine catalyzed reaction Baylis-Hillman reaction Org. Rxn. 51, 201 (1997) Chem. Rev. 103, 811 (2003)
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The Baylis-Hillman Reaction
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Asymmetric Baylis Hillman Reactions: Chiral Auxiliary Leahy, JACS. 1997, 119, 4317
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Asymmetric Baylis Hillman Reactions: Chiral Catalyst Hatakeyama : JACS 1999, 121, 10219 R = Alkyl, Aryl Yield: 31-58% ee: R (>91%) Yield: 82-96% ee: (S) 79-92% Shi : Chem. Commun. 2003, 1310
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Application of the Baylis-Hillman reaction M. Krische, JACS, 2003, 124, 2404 H. Tae, Ph.D.Thesis, KAIST
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Claisen condensation Michael addition
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Acylation Forming the enolate Drives equilibrium. Electrophile Mg enolate prevents O-acylation
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Acylation Weinreb amide Stile’s reagent
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Homework Chapter 2 : 1, 2, 13, 15 Due : April, 27
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