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
CO2):
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: LnM+ (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 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 :
-
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 triterpenoid 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