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Lecture 14 APPLICATIONS IN ORGANIC SYNTHESIS Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Lecture 14 APPLICATIONS IN ORGANIC SYNTHESIS Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

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Page 1: Lecture 14 APPLICATIONS IN ORGANIC SYNTHESIS Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Lecture 14 APPLICATIONS IN ORGANIC SYNTHESIS

Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Page 2: Lecture 14 APPLICATIONS IN ORGANIC SYNTHESIS Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

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