Lecture 14 APPLICATIONS IN ORGANIC SYNTHESIS

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I. Enantioselective functional group interconversions

ORGANOMET CHEM IN ORGANIC SYNTHESIS

II. Carbon-carbon bond formation via nucleophilic attack on a



ligand.

ORGANOMET CHEM IN ORGANIC SYNTHESIS

III. Carbon-carbon bond formation via carbonyl or alkene insertion.

ORGANOMET CHEM IN ORGANIC SYNTHESIS

IV. Carbon-carbon bond formation via transmetallation reactions.

ORGANOMET CHEM IN ORGANIC SYNTHESIS

V. Carbon-carbon bond formation through cyclization reactions.

ORGANOMET CHEM IN ORGANIC SYNTHESIS

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

Methods of producing an enantiomer of a chiral compound: Chemical resolution of a racemate Chiral chromatography Use of a chiral natural products as starting material Stoichiometric use of chiral auxilliaries Asymmetric catalysis

Asymmetric Hydrogenations

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

Synthesis of biotin (involved in enzymatic transfer of CO 2 ):

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Use of chiral auxiliaries:

ORGANOMET CHEM IN ORGANIC SYNTHESIS

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

Wilkinson’s catalyst: L n M + (M = Rh or Ir)

Assymetric Hydrogenations

Chiral Diphosphine Ligands:

Asymetric Hydrogenation using Rh Catalysts

Mechanism:

Assymetric Hydrogenation using Rh-CHIRAPHOS

Assymetric Hydrogenation

Assymetric Hydrogenation

Assymetric Hydrogenation

Assymetric Hydrogenation of C=C bonds using Ru(II)

Noyori pioneered the development of Ru(II) catalysts showing enantioselective hydrogenation.

ASYMMETRIC HYDROGENATION OF C=C BONDS

ASYMMETRIC HYDROGENATION OF C=C BONDS

ASYMMETRIC HYDROGENATION OF C=C BONDS

Asymmetric Hydrogenation of C=O

ASYMMETRIC HYDROGENATION OF C=O

ASYMMETRIC HYDROGENATION OF C=O

ORGANOMET CHEM IN ORGANIC SYNTHESIS

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Transfer hydrogenation (TH) Asymmetric TH

ASYMMETRIC HYDROGENATION OF C=O

ASYMMETRIC HYDROGENATION OF C=O

Assymetric Hydrogenation Using Ir(I) Catalysts

ORGANOMET CHEM IN ORGANIC SYNTHESIS

ORGANOMET CHEM IN ORGANIC SYNTHESIS

ASYMMETRIC OXIDATION

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Pd-Catalyzed Oxidation of Secondary Alcohols

OXIDATION OF SECONDARY ALCOHOLS

ORGANOMET CHEM IN ORGANIC SYNTHESIS

CARBON – CARBON BOND FORMATION VIA NUCLEOPHILIC ATTACK ON AN



3 -



ligand: THE TSUJI-TROST REACTION

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Organic synthesis using allylic substrates: unpredictable stereochemistry poor control of regioselectivity possible carbon- skeleton rearrangement.

Leaving groups for Tsuji-Trost Reaction

TSUJI – TROST REACTION

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.

TSUJI – TROST REACTION

TSUJI – TROST REACTION

TSUJI – TROST REACTION - EXAMPLE

TSUJI – TROST REACTION

Several points in catalytic cycle where asymmetric reaction could occur: a) enantiomeric faces of the alkene b) enantiomeric leaving groups c) enantioface exchange in the  3 allyl complex d) attack at enantiotopic termini of the  3 ally ligand e) Attack by different enantifaces of prochiral nucleophiles.

ASSYMETRIC TSUJI – TROST REACTION

TSUJI-TROST REACTION

TSUJI_TROST REACTION Assymetric Quat center

Tsuji-Trost Reaction – Quat Center

EXAMPLE:

Tsuji-Trost Reaction

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Tsuji Trost Reaction:

C-C Bond formation via CO and alkene insertion

CARBONYLATION INSERTIONS

CARBONYL INSERTIONS EXAMPLE

CARBONYL INSERTIONS

C-C Double bond Insertion: The Heck Reaction

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

Heck Reaction – migratory C=C insertion

Rate of reaction and regioselectivity are sensitive to steric hindrance about the C=C bond.

Rate of reaction varies according to:

Heck Reaction:

Example:

Heck Reaction

Heck Reaction

Also know as Cross Coupling Reaction:

C-C Bond Bond formation via Transmetallation Reactions

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’.

Transmetallation Reaction

TRANSMETALLATION REACTIONS

Via a concerted



-bond metathesis --------transfer of R to M with retention of configuration.

TRANSMETALLATION REACTION MECHANISM

TRANSMETALLATION REACTIONS 4-TYPES

GENERAL REACTION MECHANISM

CROSS-COUPLING REACTION - GENERAL

CROSS-COUPLING REACTION

The use of organotin compound have the advantage that one group will preferentially transfer over the other:

CROSS-COUPLING REACTION

Example: Propose a catalytic cycle for the cross coupling plus carbonylation reaction below

CROSS-COUPLING REACTION

Mechanism:

CROSS-COUPLING REACTION - STILLE

Synthesis Application Example:

CROSS-COUPLING REACTION - STILLE

Sample Problem:

CROSS-COUPLING REACTION - STILLE

Transmetalating Agent is R-B(R’) 2 as the Stille.

but similar in scope

CROSS-COUPLING REACTION - SUZUKI

Reaction Pathway:

CROSS-COUPLING REACTION - SUZUKI

Synthesis Application: The chemo-, regio-, and stereoselectivity similar to those with Stille. Suzuki more widely used for aryl-aryl coupling.

CROSS-COUPLING REACTION - SUZUKI

Cross coupling between alkynyl and aryl :

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.

CROSS-COUPLING REACTION - Sonogashira

Mechanism:

CROSS-COUPLING REACTION -

Mechanism:

CROSS-COUPLING REACTION - Sonogashira

Synthesis Applications:

CROSS-COUPLING REACTION - Sonogashira

Method of choice for syhthesis of acrylic, di- and tri terpenoid systems. Organozinc are often used.

CROSS-COUPLING REACTION - Negishi

Reaction mechanism:

CROSS-COUPLING REACTION - Negishi

Synthesis Applications:

CROSS-COUPLING REACTION – Negishi

Mechanism: Dotz Arene Synthesis

C-C Bond formation: Cyclizations

Cyclization involving Palladium

Mechanism:

CYCLIZATION Pd

Cyclization – Oppolzer’s

Cyclization – Pauson - Kand

CROSS-COUPLING REACTION