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Transcript of Lecture 14 APPLICATIONS IN ORGANIC SYNTHESIS Copyright ©The McGraw-Hill Companies, Inc. Permission...
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Lecture 14 APPLICATIONS IN ORGANIC SYNTHESIS
Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
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I. Enantioselective functional group interconversions
ORGANOMET CHEM IN ORGANIC SYNTHESIS
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II. Carbon-carbon bond formation via nucleophilic attack on a ligand.
ORGANOMET CHEM IN ORGANIC SYNTHESIS
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III. Carbon-carbon bond formation via carbonyl or alkene insertion.
ORGANOMET CHEM IN ORGANIC SYNTHESIS
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IV. Carbon-carbon bond formation via transmetallation reactions.
ORGANOMET CHEM IN ORGANIC SYNTHESIS
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V. Carbon-carbon bond formation through cyclization reactions.
ORGANOMET CHEM IN ORGANIC SYNTHESIS
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The C=C and C=O undergoes transformations to variety of organic compounds (alcohols, alkyl halides, alkanes).
The C=C and C=O are planar and achiral but in their reactions creates one or more stereogenic centers in the reaction product.
Assymetric Hydrogenations
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Methods of producing an enantiomer of a chiral compound:
Chemical resolution of a racemateChiral chromatographyUse of a chiral natural products as starting materialStoichiometric use of chiral auxilliariesAsymmetric catalysis
Asymmetric Hydrogenations
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Chiral chromatography:
Use of chiral, enantioenriched groups to the solid support
In the chiral environment, the two enantiomers will have diastereomerically different interactions with the columns
ORGANOMET CHEM IN ORGANIC SYNTHESIS
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Synthesis of biotin (involved in enzymatic transfer of CO2):
ORGANOMET CHEM IN ORGANIC SYNTHESIS
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Use of chiral auxiliaries:
ORGANOMET CHEM IN ORGANIC SYNTHESIS
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Asymmetric Catalysis: same approach as the use of chiral auxilliary except that the selectivity occurs catalytically
The most environmentally benign approach to enantioselectivity.
ORGANOMET CHEM IN ORGANIC SYNTHESIS
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Wilkinson’s catalyst: LnM+ (M = Rh or Ir)
Assymetric Hydrogenations
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Chiral Diphosphine Ligands:
Asymetric Hydrogenation using Rh Catalysts
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Mechanism:
Assymetric Hydrogenation using Rh-CHIRAPHOS
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Assymetric Hydrogenation
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Assymetric Hydrogenation
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Assymetric Hydrogenation
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Assymetric Hydrogenation of C=C bonds using Ru(II)
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Noyori pioneered the development of Ru(II) catalysts showing enantioselective hydrogenation.
ASYMMETRIC HYDROGENATION OF C=C BONDS
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ASYMMETRIC HYDROGENATION OF C=C BONDS
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ASYMMETRIC HYDROGENATION OF C=C BONDS
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Asymmetric Hydrogenation of C=O
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ASYMMETRIC HYDROGENATION OF C=O
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ASYMMETRIC HYDROGENATION OF C=O
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ORGANOMET CHEM IN ORGANIC SYNTHESIS
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ORGANOMET CHEM IN ORGANIC SYNTHESIS
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Transfer hydrogenation (TH) Asymmetric TH
ASYMMETRIC HYDROGENATION OF C=O
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ASYMMETRIC HYDROGENATION OF C=O
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Assymetric Hydrogenation Using Ir(I) Catalysts
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ORGANOMET CHEM IN ORGANIC SYNTHESIS
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ORGANOMET CHEM IN ORGANIC SYNTHESIS
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ASYMMETRIC OXIDATION
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ORGANOMET CHEM IN ORGANIC SYNTHESIS
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Pd-Catalyzed Oxidation of Secondary Alcohols
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OXIDATION OF SECONDARY ALCOHOLS
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ORGANOMET CHEM IN ORGANIC SYNTHESIS
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CARBON – CARBON BOND FORMATION VIA NUCLEOPHILIC ATTACK ON AN 3 - ligand:
THE TSUJI-TROST REACTION
ORGANOMET CHEM IN ORGANIC SYNTHESIS
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TSUJI – TROST REACTION
Organic synthesis using allylic substrates:unpredictable stereochemistrypoor control of regioselectivitypossible carbon- skeleton rearrangement.
Leaving groups for Tsuji-Trost Reaction
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Tsuji-Trost Reaction:
With hard nucleophiles (pKa of conjugate acid >25) results in an overall inversion of configuration at the allylic site.
With soft nucleophile (pKa of conjugate acid < 25) react to give retention of configuaration.
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TSUJI – TROST REACTION
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TSUJI – TROST REACTION
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TSUJI – TROST REACTION - EXAMPLE
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TSUJI – TROST REACTION
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Several points in catalytic cycle where asymmetric reaction could occur:
a) enantiomeric faces of the alkeneb) enantiomeric leaving groupsc) enantioface exchange in the 3 allyl complexd) attack at enantiotopic termini of the 3 ally ligande) Attack by different enantifaces of prochiral
nucleophiles.
ASSYMETRIC TSUJI – TROST REACTION
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TSUJI-TROST REACTION
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TSUJI_TROST REACTION Assymetric Quat center
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Tsuji-Trost Reaction – Quat Center
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EXAMPLE:
Tsuji-Trost Reaction
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ORGANOMET CHEM IN ORGANIC SYNTHESIS
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Tsuji Trost Reaction:
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C-C Bond formation via CO and alkene
insertion
CARBONYLATIONINSERTIONS
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CARBONYL INSERTIONS EXAMPLE
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CARBONYL INSERTIONS
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C-C Double bond Insertion: The Heck Reaction
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Heck Reaction – migratory C=C insertion
Step a ) OA b) alkene coordination c) migratory insertion of C=C d) -elimination
Insertion is key step
R = aryl, alkyl, benzyl or allyl
X = Cl, Br, I, OTf
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Rate of reaction and regioselectivity are sensitive to steric hindrance about the C=C bond.
Rate of reaction varies according to:
Heck Reaction:
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Example:
Heck Reaction
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Heck Reaction
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Also know as Cross Coupling Reaction:
C-C Bond Bond formation via Transmetallation Reactions
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Transmetallation Reaction
Transmetallation Reaction – a method for introducing a -bonded hydrocarbon ligands Into the coordination sphere transition metals.
The equilibrium is thermodynamically favorable from left to right if the electronegativity of M is greater than that of M’.
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TRANSMETALLATION REACTIONS
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Via a concerted -bond metathesis
--------transfer of R to M with retention of configuration.
TRANSMETALLATION REACTION MECHANISM
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TRANSMETALLATION REACTIONS 4-TYPES
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GENERAL REACTION MECHANISM
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CROSS-COUPLING REACTION - GENERAL
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CROSS-COUPLING REACTION
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The use of organotin compound have the advantage that one group will preferentially transfer over the other:
CROSS-COUPLING REACTION
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Example:Propose a catalytic cycle for the cross coupling plus carbonylation reaction below
CROSS-COUPLING REACTION
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Mechanism:
CROSS-COUPLING REACTION - STILLE
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Synthesis Application Example:
CROSS-COUPLING REACTION - STILLE
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Sample Problem:
CROSS-COUPLING REACTION - STILLE
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Transmetalating Agent is R-B(R’)2 but similar in scope as the Stille.
CROSS-COUPLING REACTION - SUZUKI
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Reaction Pathway:
CROSS-COUPLING REACTION - SUZUKI
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Synthesis Application: The chemo-, regio-, and stereoselectivity similar to those with Stille. Suzuki more widely used for aryl-aryl coupling.
CROSS-COUPLING REACTION - SUZUKI
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Cross coupling between alkynyl and aryl :
CROSS-COUPLING REACTION - Sonogashira
- Requires high loadings of Cu and Pd catalysts, relativelly hight temperatures
- Cu-alkynes are formed in situ and then the alkyne is transferred to Pd.
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Mechanism:
CROSS-COUPLING REACTION -
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Mechanism:
CROSS-COUPLING REACTION - Sonogashira
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Synthesis Applications:
CROSS-COUPLING REACTION - Sonogashira
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Method of choice for syhthesis of acrylic, di- and tri- terpenoid systems. Organozinc are often used.
CROSS-COUPLING REACTION - Negishi
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Reaction mechanism:
CROSS-COUPLING REACTION - Negishi
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Synthesis Applications:
CROSS-COUPLING REACTION – Negishi
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Mechanism:Dotz Arene Synthesis
C-C Bond formation: Cyclizations
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Cyclization involving Palladium
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Mechanism:
CYCLIZATION Pd
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Cyclization – Oppolzer’s
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Cyclization – Pauson - Kand
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CROSS-COUPLING REACTION