Lecture 14 APPLICATIONS IN ORGANIC SYNTHESIS - PowerPoint Presentation

Slide1

Lecture 14

APPLICATIONS IN ORGANIC SYNTHESIS

Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display.Slide2

I. Enantioselective functional group interconversions

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide3

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

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide4

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

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide5

IV. Carbon-carbon bond formation via transmetallation reactions.

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide6

V. Carbon-carbon bond formation through cyclization reactions.

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide7

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 HydrogenationsSlide8

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 HydrogenationsSlide9

Chiral chromatography:Use of chiral,

enantioenriched groups to the solid supportIn the chiral environment, the two enantiomers will have diastereomerically different interactions with the columns

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide10

Synthesis of biotin (involved in enzymatic transfer of CO2):

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide11

Use of chiral auxiliaries:

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide12

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 SYNTHESISSlide13

Wilkinson’s catalyst: LnM

+ (M = Rh or Ir)

Assymetric HydrogenationsSlide14

Chiral Diphosphine Ligands:

Asymetric

Hydrogenation using Rh CatalystsSlide15

Mechanism:

Assymetric Hydrogenation using Rh-CHIRAPHOSSlide16

Assymetric

HydrogenationSlide17

Assymetric

HydrogenationSlide18

Assymetric

HydrogenationSlide19

Assymetric

Hydrogenation of C=C bonds using

Ru(II)Slide20

Noyori pioneered the development of Ru(II) catalysts showing

enantioselective hydrogenation.

ASYMMETRIC HYDROGENATION OF C=C BONDSSlide21

ASYMMETRIC HYDROGENATION OF C=C BONDSSlide22

ASYMMETRIC HYDROGENATION OF C=C BONDSSlide23

Asymmetric Hydrogenation of C=OSlide24

ASYMMETRIC HYDROGENATION OF C=O Slide25

ASYMMETRIC HYDROGENATION OF C=OSlide26

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide27

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide28

Transfer hydrogenation (TH) Asymmetric TH

ASYMMETRIC HYDROGENATION OF C=OSlide29

ASYMMETRIC HYDROGENATION OF C=OSlide30

Assymetric

Hydrogenation Using

Ir(I) CatalystsSlide31

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide32

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide33

ASYMMETRIC OXIDATIONSlide34

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide35

Pd

-Catalyzed Oxidation of Secondary AlcoholsSlide36

OXIDATION OF SECONDARY ALCOHOLSSlide37

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide38

CARBON – CARBON BOND FORMATION VIA NUCLEOPHILIC ATTACK ON AN 3

- ligand:THE TSUJI-TROST REACTION

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide39
Slide40

TSUJI – TROST REACTION

Organic synthesis using

allylic

substrates:

unpredictable stereochemistry

poor control of

regioselectivity

possible carbon- skeleton rearrangement.

Leaving groups for Tsuji-

Trost

ReactionSlide41

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.Slide42

TSUJI – TROST REACTIONSlide43

TSUJI – TROST REACTIONSlide44

TSUJI – TROST REACTION - EXAMPLESlide45

TSUJI – TROST REACTIONSlide46

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 REACTIONSlide47

TSUJI-TROST REACTIONSlide48

TSUJI_TROST REACTION

Assymetric Quat

centerSlide49

Tsuji-

Trost

Reaction – Quat CenterSlide50

EXAMPLE:

Tsuji-

Trost ReactionSlide51

ORGANOMET CHEM IN ORGANIC SYNTHESISSlide52

Tsuji

Trost

Reaction:Slide53

C-C Bond formation via CO and alkene insertion

CARBONYLATION

INSERTIONSSlide54

CARBONYL INSERTIONS EXAMPLESlide55

CARBONYL INSERTIONSSlide56

C-C Double bond Insertion: The Heck ReactionSlide57

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,

OTfSlide58

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

Rate of reaction varies according to:

Heck Reaction:Slide59

Example:

Heck ReactionSlide60

Heck ReactionSlide61
Slide62

Also know as Cross Coupling Reaction:

C-C Bond

Bond formation via Transmetallation ReactionsSlide63

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’.Slide64

TRANSMETALLATION REACTIONSSlide65

Via a concerted -bond metathesis

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

TRANSMETALLATION REACTION MECHANISMSlide66

TRANSMETALLATION REACTIONS 4-TYPESSlide67

GENERAL REACTION MECHANISMSlide68

CROSS-COUPLING REACTION - GENERALSlide69

CROSS-COUPLING REACTIONSlide70

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

CROSS-COUPLING REACTIONSlide71

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

reaction below

CROSS-COUPLING REACTIONSlide72

Mechanism:

CROSS-COUPLING REACTION - STILLESlide73

Synthesis Application Example:

CROSS-COUPLING REACTION - STILLESlide74

Sample Problem:

CROSS-COUPLING REACTION - STILLESlide75

Transmetalating Agent is R-B(R’)2 but similar in scope as the

Stille.

CROSS-COUPLING REACTION - SUZUKISlide76

Reaction Pathway:

CROSS-COUPLING REACTION - SUZUKISlide77

Synthesis Application: The chemo-, regio

-, and stereoselectivity similar to those with Stille. Suzuki more widely used for aryl-aryl coupling.

CROSS-COUPLING REACTION - SUZUKISlide78

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.Slide79

Mechanism:

CROSS-COUPLING REACTION - Slide80

Mechanism:

CROSS-COUPLING REACTION -

SonogashiraSlide81

Synthesis Applications:

CROSS-COUPLING REACTION -

SonogashiraSlide82

Method of choice for syhthesis of acrylic, di- and tri- terpenoid

systems. Organozinc are often used.

CROSS-COUPLING REACTION - NegishiSlide83

Reaction mechanism:

CROSS-COUPLING REACTION -

NegishiSlide84

Synthesis Applications:

CROSS-COUPLING REACTION –

NegishiSlide85

Mechanism:Dotz Arene

Synthesis

C-C Bond formation: CyclizationsSlide86

Cyclization involving PalladiumSlide87

Mechanism:

CYCLIZATION PdSlide88

Cyclization –

Oppolzer’sSlide89

Cyclization –

Pauson

- KandSlide90

CROSS-COUPLING REACTION