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
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 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=O
ASYMMETRIC HYDROGENATION OF C=O
ORGANOMET CHEM IN ORGANIC SYNTHESIS
Transfer hydrogenation (TH) Asymmetric TH ASYMMETRIC HYDROGENATION OF C=O
Assymetric Hydrogenation Using Ir(I) Catalysts
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
TSUJI – TROST REACTION Organic synthesis using allylic substrates: unpredictable stereochemistry poor control of regioselectivity possible carbon- skeleton rearrangement. Leaving groups for 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 - 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
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
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
Also know as Cross Coupling Reaction: C-C Bond Bond formation via Transmetallation Reactions
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’.
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 but similar in scope as the Stille. 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 : 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.
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