catalysis for the synthesis of bioactive...

MASTER 2

Molecular Chemistry – Medicinal Chemistry

Université de Rennes 1 – Vietnam National University, Hanoi

CATALYSIS FOR THE SYNTHESIS

OF BIOACTIVE COMPOUNDSOF BIOACTIVE COMPOUNDS

Prof. Pierre van de Weghee-mail : [email protected] 2011-2012

INTRODUCTION TO CATALYSIS

Synthesis of Losartan (marketed by Merck & Co), an angiotensin II receptor antagonist drug

used to treat high blood pressure (hypertension).

KEY STEP : A PALLADIUM-CATALYZED CROSS-COUPLING REACTION

An example

NOH

ClNN

CPh3N

NOH

Cl

Bu5 mol% Pd(PPh ) , K CO

newaryl-aryl bond

catalytic amount !

2

What is the mechanism of this reaction ?

What is the role of the palladium and the base ?

Br

NOH

Bu NNN

N

B(OH)2

N

NHN

N Nlosartan

+

5 mol% Pd(PPh3)4, K2CO3THF - H2O

then H 3O+

aryl-aryl bond


Pro memoria

A catalyst accelerates the rate of a thermodynamically feasible reaction by opening a loweractivation energy pathway. It is added to the reaction mixture in quantities that are much lowerthan stoichiometric ones and, in principle, it is found unchanged at the end of reaction. Thus itdoes not appaer in the reaction balance, and is usually written on the reaction arrow in order toemphasis this feature:

A + B[cat]

C + D

3

A + B C + D

A + B[cat]

C + D

[cat] [cat]-A

A

BC + D

activation

reaction

[cat]

1- transition metal complex

2- organic molecule

3- enzyme

slow


The catalyst does not influence the thermodynamics of a reaction. It changes the reactionpathways, i. e. the kinetics; in particular it lowers the energy of transition states.

4

Comparison of the profiles of the uncatalyzed and catalyzed reaction :- the energy levels of the starting substrates and reaction products are the same

with or without catalyst (∆G° constant), but the activation energy ∆G‡ is much lower when thereaction is catalyzed (∆G1

‡ >> ∆G2‡).

- a catalyzed reaction can eventually involve one or several reaction intermediates(for instance, one intermediate in the right figure above).


Three different modes of catalysis

� transition metal complexes as catalysts

� organic molecules as catalysts or organocatalysis

AcO

CO2H

NHAc

OMe

1 - H2, [cat]

2- deprotection HONH3

OH

CO2

H

(S)-DOPAtreatment of Parkinson's disease

[cat] =P

Rh(MeOH)2

PPh

Ph

MeO

MeO

Mosanto's approach

5

� organic molecules as catalysts or organocatalysis

� enzymes as catalysts

O ONH

MeMe

EtO2C CO2Et

Bn2NH - TFA (cat.)Lepidopteran sex pheromon

O

OEt

O reductase in yeast OH

OEt

O OH

OEt

O

S Rmajor product minor product

ethyl acetoacetate 3-hydroxy-ethylbutanoate

TRANSITION METAL COMPLEXES

AS CATALYSTS

PART 1

6

AS CATALYSTS

TRANSITION METAL COMPLEXES AS CATALYSTS

Organic versus Organometallic reactivity

7

What is a transition metal ?


A transition metal = an element with valence of d- or f-electrons.

8

Transition metal valence electron count


9

for free (gas phase)transition metals: (n+1)s isbelow (n)d in energy.

Fe4s2 3d6

= 3d8OC Fe

COCO

CO

CO

3d8

for complexed transitionmetals: the (n)d levels arebelow the (n+1)s and thusget filled first.

NN N

FeΙΙΙΙΙΙΙΙ

Cl Cl

3d6

for oxidized metals, substract theoxidation from the group “8” .


Transition metal valence orbitals

10


The 18-electron rule

Recall : first row of elements have 4 valence orbitals (1 s + 3 p) so they can accomodate up to 8valence electrons the octet rule.

Transition metals have 9 valence orbitals (1 s + 3 p + 5 d). Upon bonding to a ligand set, therewill be a totyal of 9 low lying orbitals (bonding + non-bonding molecular orbitals). Therefore, wacan expect that the low lying molecular orbitals can accommodate up to 18 valence electrons.

the 18-electron rule.

11

Organometallics complexes with 18 electrons are predicted to be a particularly stable becausethey will have a closed shell of electrons. Complexes with 18 electrons are aften referred to asbeing coordinatively saturated.

There are exceptions to this rule !


Electron counting

Two models for counting electrons: the colvalent and ionic models. Both give the same answer,but offer different advantages and disavantages.

Example: CH4

� covalent model: since C-H bond are covalent, assume that the electrons are sharedequally between carbon and hydrogen. To count the electrons, we dissect the moleculegiving each atom 1 electron of the bonding pair.

H CH

H H C

H

HH : 4x1 e = 4C : 4 e

12

� ionic model: alternatively, we can treat the bonds as being ionic. This allow us to assigna formal oxidation state to the carbon atom. This can be useful to determine whether aparticular transformation is an oxidation or a reduction. In this model, both electrons aregiven to the atom with highe electronegativity. For C-H bond, this is the carbon.

Similarly for a transition metal complex, the electron count is the sum of the metalvalence electrons + the ligand centered electrons.

H CH

H H C

H

H C : 4 eTotal = 8 electron s

H CH

HH H C

H

H

HH+ : 4x0 e = 0C (-4): 8 eTotal = 8 electron s

4


Covalent model :NVE= nb metal electrons + nb ligand electrons – complex charge

(NVE = Number of Valence Electrons)

•Metal = the number of metal electrons equals it’s row numberexamples: Ti = 4e, Fe = 8e, Pd = 10e• Ligands = in general L donates 2 electrons, X donates 1 electron.

•Formal oxidation state of the metal = nb of ligands X + complex charge(oxidation states in organometallic complexes are merely formalisms that may bear little resemblance to the actualpositive charge on the metal)

13

(oxidation states in organometallic complexes are merely formalisms that may bear little resemblance to the actualpositive charge on the metal)

Ionic model :NVE= nb metal electrons (dn) + nb ligands electrons

• Metal = you must first determine the formal oxidation state of the metal. The number ofelectrons is the row number minus the charge on the metal. The formal oxidation state issimply the charge on the complex minus the charges of the ligands.• Ligands = in general L and X are both 2 electrons donors.

In my opinion the covalent model is easier. All discussions in this class will use the covalent model, so I would encourageyou to learn that one. You should also be aware of the ionic method, since you will encounter it from time to time.


Organometallic ligands :

14

© R. H. Crabtree, The Organometallic Chemistry of the Transition Metals (fourth edition), John Wiley & Sons, 2005

Most common ligands found in classical transition metal complexes in catalysis :� ligands type L (2 electrons in CM) : PR3, CO, NR3, alkenes, NHC, ROR1 …� ligands type X (1 electron in CM) : I, Br, Cl, OR, R, Ar, H …

NC

N ArAr

NHC


Electron counting and oxidation state:

- procedure for a neutral complex MLlXx NVE = n + 2l + xoxidation state = x

n = nb electrons metal, l = nb of ligands L, x = nb of ligands X

- procedure for complex with charge [MLlXx]q NVE = n + 2l + x – qoxidation state = x + q

n = nb electrons metal, l = nb of ligands L, x = nb of ligands x, q = complex charge

covalent model

Rh : d 9 = 9 e

3 x PPh3 : 3 x L = 6 e1 x Cl : 1 x X = 1 e

oxidation state : 1 x X = + ΙΙΙΙ

ionic model

Rh+ : d 8 = 8 e

3 x PPh3 : 3 x L = 6 e1 x Cl - : 2 e

total = 16 e, + IRh

PPh3

PPh3

Cl PPh3

Rh

PPh3

PPh3

Cl PPh 3 Rh

PPh3

PPh3

Cl PPh3

(L)

(L)

(L)

(L)

(L)

(L)

(X, 1 e) (X, 2 e)

15


Electron counting and oxidation state:

Fe

di(cyclopentadienyl)iron(ferrocene)

covalent model

Fe : d8 = 8 e

2 x Cp : 2 x (L 2X) = 2 x (2 x 2 + 1) = 10 eoxidation state : 2 ligands X, 0 charge = +ΙΙΙΙΙΙΙΙ

ionic model

Fe2+ : d 6 = 6 e

2 x Cp - : 2 x 6 = 12 e total = 18 e, + ΙΙΙΙΙΙΙΙ

covalent model

Cr : d6 = 6 e

ionic model

Cr : d6 = 6 e

16

CrOCOC CO

CO

CO

H

Cr : d6 = 6 e

5 x CO : 5 x L = 10 e1 x H : 5 x X = 1 e

oxidation state : 1 x X + 1 x (-1) = 0

Cr : d6 = 6 e

5 x CO : 5 x 2 = 10 e1 x H- : 2 e

total = 18 e, 0

charge : -1 e

Pd

PPh3

PPh3

Ph3P PPh3

covalent model

Pd : d 10 = 10 e

NVE = 10 + 2 x 4 = 18 e

oxidation state : 0 x X = 0000

ionic model

Pd : d10 = 10 e

NVE = 10 + 2 x 4 = 18 e total = 18 e, 0

training = PdCl2(PPh3)2, Mn(CO)5H, Au(Me)3(PMe3).

Common geometries for transition metal complexes


Two aspects to define the geometry of the complex : sterics and electronics.- sterics : to a first approximation, geometries of complexes were determined bu

steric factors. The M-L bonds are arranged to have the maximum possible separation aroundthe metal.

- electronics : d electron count combined with the complex electron count must beconsidered when predicting geometries for complexes with non-bonding d electrons. Often thisleads to sterically less favorable geometries for electronic reasons (e.g. CN = 4, d8, 16 ecomplexes prefer a square planar geometry).

STERICSL

17

L M L

(CN = coordination number)

CN = 2 linear

L MCN = 3 trigonal planarL

L

CN = 4

L

ML L

Ltetrahedral

CN = 5 L ML

LL

L

trigonal bipyramidal

CN = 6 ML

L L

L

L

L

octahedral

ELECTRONICS

L M LL

T-shaped

MLL L

L

square planar

LL

M LL

L

square pyramidal

Main classes of reactions around the transition metal


� ligand substitution

� oxidative addition & reductrice elimination

MLl [ML l-1]- L

ML l-1L1+ L1

A B

[M][M] A

B[M]

BA

18

� insertion & elimination

NVE (M) < or = 16 e ; o.s. NVE (M) + 2 ; o.s. + 2

[M] A+ B

[M] AB

[M] B A

[M]

L

X C

H- L

NVE

[M]X C

H

NVE - 2

[M]X C

H [M]

X C

NVE

H


Ligand substitution

Two limiting mechanisms for ligand substitution- associative mechanism : bond making occurs before bond breaking.This is the most common mechanism for coordinatively unsaturated metal complexes. The d8square planar complexes are prototypical examples (Pt(II), Pd(II), Ir(I) and Rh(I)).

PtLL X

L+ Y

slowPt

LL X

L

Y

Pt YX

L

L

L

PtLL Y

LX

fastPt

LL Y

L+ X

19

-dissociative mechanism : bond breaking occurs before bond making.This is normally the preferred mechanism for coordinatively 18 e complexes. The rates ofligand substitution for ccordinatively satured complexes are usually significantatly slower thanthose for coordinatively unsaturated complexes.

L

M

L

L1 LL

L

- LL

M

L

L1L

L

L

M

L

L1 L2L

L

+ L2

LM

LL1

L

L

L2

M

L

L1 LL

L

+ L2

+ L2L

M

L2

L1 LL

L


Oxidative addition – reductive elimination

- oxidative addition : addition of A-B to a metal center resulting in an increase in coordinationnumber by 2, an increase of oxidation state by 2 units, and an increase in the electron count by2.- reductive elimination : elimination of two ligands from a metal center to gice a new A-Bbond. The metal center is reduced by 2 units and has 2 fewer coordinated ligands. The complexhas 2 less electrons (concerted reductive elimination requires cis coordination of the ligands tobe eliminated).

m+ AA

20

Oxidative addition and reductive elimination are the microscopic reverse of each other. Theyrepresent the foward and reverse reaction of an equilibrium. The position of the equilibriumdepends on the thermodynamics of the oxidative addition or reductive elimination process. Forexample many metal complexes will oxidatively add CH3I, but few will reductively eliminate thiscompound. In contrast, M(H)R usually undergo rapid reductive elimination, but oxidativeaddition of alkanes is much less common.

LnMm+ +AB

LnM (m+2)+

B

NVE NVE+2


Insertion – elimination

Features of this transformation :- there is no change in the formal oxidation state of the metal unless AB is an alkalydene or analkylidyne.- the groups undergoing migratory insertion must be cis to one another. In complexes wherethe cis coordination sites are blocked by strongly coordinated ligands, insertion or eliminationprocesses are not possible.- an open coordination site is created during migratory insertion. Therefore, for the reversereaction (elimination) to occur, an open coordination site must be generated by liganddissociation.

17

dissociation.- in the case where C is a chiral center, the reaction usually occurs with retention ofconfiguration.- cases where C migrates to AB followed by coordination of L in place of C, and where ABmigrates to C followed by coordination of L in place of AB are both known.

M A

C

B M AC

B

1,1-insertion

eliminationM

L+ L

- LA

C

B

M

C

M AB1,2-insertion

elimination

+ L

- L

A

B

C

M AB

CL


Applications : alkenes hydrogenation

The Wilkinson’s catalyst, a Rhodium complex : RhCl(PPh3)3

R + H2

[cat]R

HH

catalytic cycleRh

Ph3P

Ph3P Cl

PPh3

= ML3X

Rh = d 9

NVE (Rh) = 9 + (3 x 2) + 1 = 16 eo.s. = +ΙΙΙΙ

22

= ML3X o.s. = +ΙΙΙΙ

= R > R

R

> RR

> RR >

R

reactivity =

to have a good understanding of themechanism of the reaction, it is well todetermine the NVE and o.s. of the metal ateach stage of the catalytic cycle.


� stereoselective synthesis of (+)-biotin : an example of asymmetric hydrogenation.

� selective hydrogenation.

Me

Me

O

O

Rh(PPh3)3Cl / H2

Me

Me

O

O

Hydrogenation of olefins (and alkynes) can be carried out in the presence of functional groupssuch as RCHO, R2CO, OH, CN, NO2, Cl, ROR1, CO2R, CO2H.

23

� stereoselective synthesis of (+)-biotin : an example of asymmetric hydrogenation.

O

NHN

O

O

Ph

Me

O O

HO steps H2 / [Rh]

O

NHN

O

O

Ph

Me

HHsteps

S

NHHN

O

HHCO2H

(+)-biotin

[Rh] =Fe

PPh2

t-Bu 2P

Me

Rh(COD) COD = cyclooctadiene = ligand L 2

(Lonza industrial process)

� stereoselective synthesis of Naproxen : asymmetric hydrogenation.

Naproxen, a nonsteroidal anti-inflammatory drug


MeO

CO2H

Ru-BINAP

H2 (100 atm)

MeO

CO2H

Me

97% e.e.(1 mol%)CH2Cl2, 50 °C

Ru-BINAP =

(Noyori's catalyst, Nobel Prize 2001)

PP

RuO

O

OO

Me

MePhPh

PhPh

24

industrial synthesis (Synthex) : non catalyzedsynthesis (racemic approach)


Applications : alkenes reduction – hydride transfer

R + H2

[cat] / baseR

HH

a Ruthenium complex : RuCl2(PPh3)3

RuCl PPhPPh3

RuPh3P

Cl PPh3

Cl

PPh3

HHδδδδ−

RuPh3P

Cl PPh3

H

PPh3

+ HCl

+B:B:H+ Cl−

generation of the Ruthenium active species

25

RuPh3P

Cl PPh3

Cl+ B: + H2

HHδδδδ−

δδδδ+

RuPh3P

Cl PPh3

Cl

PPh3

HH

:B

δδδδ−

δδδδ+

RuPh3P

Cl PPh3

Cl

PPh3

H

- BH+ -Cl−

RuPh3P

Cl PPh3

H

PPh3

RuPh3P

Cl PPh3

H

PPh3

RuPh3P

Cl PPh3

H

PPh3

R

RuPh3P

Cl PPh3

PPh3

R

RuPh3P

Cl PPh3

PPh3

RHHδδδδ−

δδδδ+

R R

catalytic cycle

RuCl

Ph3P Cl

PPh3

= ML3X2

Ru = d 8

NVE (Ru) = 8 + (3 x 2) + (2 x 1) = 16 eo.s. = + ΙΙΙΙΙΙΙΙ

PPh3


� asymmetric hydrogenation transfer : the Noyori’s ruthenium catalyst.

PPhPh

RuCl Ph

H2N

O

NHMei-PrOH

catOH

NHMe

O

NHMe

F3C

fluoxetine(antidepressant agent )

cat = = ML4X2

Ru = d8

NVE (Ru) = 8 + (4 x 2)

in classical organic chemistry = Meerwein-Ponndorf-Verley / Oppenauer reaction

26

PPh Ph

RuCl PhN

H2

cat = = ML4X2 + (2 x 1) = 18 eo.s. = + ΙΙΙΙΙΙΙΙ

Me Me

OH

Me Me

O+ HCl

PP Ru

H

Cl

N

N

HH

H H

R R1

O

OH

N

RuHR1

R

R R1

OH

PP Ru

Cl

N

N

HH

H H

HClPP Ru

Cl

Cl

N

N

HH

H H

catalytic cycle


Applications : hydroboration of olefins

Hydroboration of olefins with catecholborane : the reaction catalyzed by the Wilkinson’scatalyst (Rh(PPh3)3Cl) gives the Markovnikov product.

R +[cat]

R

HB

OB

OH O

OH2O2 / OH-

R

HOH

R

BH

OO

R

OHH

+

anti-Markovnikov Markovnikov

catalytic cycle

27

catalytic cycleclassical hydroboration, recall :

hex-1-ene

9-BBN H2O2 / NaOHOH

OH

99

1

catalyzed hydroboration :

Ph +O

BO

HRhCl(PPh 3)3 H2O2 / NaOH

Ph

OH

application to asymmetric synthesis


� diastereoselective catalyzed hydroboration.

OPPh2 1- RhCl(PPh 3)3O

BHO

2- H2O2, NaOH

2-Ac2O, base

OAc

OAc

85% yield

syn > 50:1

28


Applications : the palladium catalyzed reactions

Generalities

During the last decades, palladium-catalyzed reactions have emerged as versatile tools for theformation of carbon-carbon bonds, hydrogenation and oxidation.

Pd electronic configuration = 4d 8 5s2 or 4d 10 5s0

formal oxidation number = 0, +2, (+4)

29

A

Pd

"Pd" (recycling) + B

A fundamental

C-Pdactivation

modification(s) of the Pdcomplexed organic fragments

C---Pdcleavage

Pd formal oxidation number = 0, +2, (+4)

General principlereview for fundamental transformations, see Tetrahedron 2000, 56, 5959.Pd-cat cross-coupling in total synthesis, see Angew. Chem. Int. Ed. 2005, 44, 4442.

Nobel Prize of Chemistry 2010

Richard F. Heck Ei-ichi Negishi Akira SuzukiRichard F. Heck Ei-ichi Negishi Akira Suzuki

for palladium-catalyzed cross couplings in organic synthesis

Nobel Prize 2010

The Heck cross-coupling reaction

Br

+ R1HPd(0) cat.

base

R1

(1968)


Nobel Prize 2010

The Negishi cross-coupling reaction

(1977)X

+ R1 ZnYPd(0) cat.

base

R1


The Suzuki-Miyaura cross-coupling reaction

(1979)X

+ R1 BPd(0) cat.

base

R1

R

R

Nobel Prize 2010

Heck reaction


Negishi andSuzuki reactions

Nobel Prize 2010


Palladium-catalyzed cross-coupling reactions

The cross-coupling reactions have become powerful synthetic methods because they allow C-Cand C-heteroatom bonds to be formed under very mild conditions with high fucntional grouptolerance.

30


� catalyst precursors.

metal sources : Palladium is the most widely used metal for cross-coupling reactions, althoughthere are examples of Nickel, Rhodium and Copper catalyzed cross-coupling reactions.

In general, the palladium is supported by a ligand and the catalyst can be derivedfrom a preformed palladium complex or formed in situ from combination of palladium sourcesand a ligand. Both Pd(0) and Pd(II) sources can be used although the active species is Pd(0) inall cases.

common sources of palladium

Pd/CPd(PPh ) = tetrakis(triphenylphosphine) palladium (most common complex)

31

Pd/CPd(PPh3)4 = tetrakis(triphenylphosphine) palladium (most common complex)Pd2(dba)3 or Pd(dba)2

PdCl2(PPh3)2

PdCl2(CH3CN)2

Pd(OAc)2

PdCl2

dba = dibenzylideneacetone

O

Ph Ph

training = determine NVE and formal oxidation state (except Pd/C)


� ligands.

Palladium alone can catalyze the reactions, but usually only with reactive Ar-I substratesand/or high temperature.Ligands necessary to - give more active catalyst system,

- stabilize the Pd(0) intermediate- solubilize the catalyst- increase the rate of oxidative addition.

The most ligands use in palladium chemistry = phosphine derivatives. In general arylphosphinesremain the most widely used.

32

P

3

P

3

CH3

FePPh2

PPh2

PPh2

PPh2

triphenylphosphine tri- o-tolylphosphine

dppf

1,1'-Bis(diphenylphosphino)ferrocene

BINAP

2,2'-bis(diphenylphosphino)-1,1'-binaphthyle

PMe3

P(t-Bu)3

PR2

R2 = Cy, t-Bu

PPh2Ph2P Ph2P PPh2

1,2-Bis(diphenylphosphino)ethane 1,3-Bis(diphenylpho sphino)propan e

monodentate phosphines

chelating phosphines


A new generation of ligands = the N-heterocyclic carbenes (NHC)NHC are stronger electron donors than phosphines and they tend to have stronger M-L bonds,thus they may give more stable catalysts.

N

N

H3C

CH3

CH3

CH3

H3C

..N

N

i-Pr

i-Pr

i-Pr

i-Pr

..N

N

H3C

CH3

CH3

CH3

H3C

..N

N

i-Pr

i-Pr

i-Pr

i-Pr

..

33

CH3IMes IPr

CH3sIMes sIPr

Review Pd complexes of NHC as catalysts : Angew. Chem. Int. Ed. 2007, 46, 2768.


� The Heck reaction (Nobel Prize 2010).

The Heck reaction involves coupling of alkenyl or aryl halides with alkenes in the presence ofpalladium complex and a base to furnish alkenyl- and aryl-substituted alkenes.

Catalytic cycle

Pd sources : PdCl2, Pd(OAc)2, Pd(PPh3)4. Bases : Et3N, CH3CO2Na, K2CO3, NaHCO3.

Solvents : THF, Toluène, DMF, DMA (in general under reflux).

R1-X + RPd(0)

baseR1 R

R1 = R2or

reactivity order in oxidative addition

Ar-I > Ar-OTf > Ar-Br >> Ar-Cl

34

Base : essential to capturethe formation of HX

H

HR1

Pd

RHonly syn-ββββ-H-elimination

Review : Angew. Chem. Int. Ed. 1994, 33, 2379,and Chem. Rev. 2003, 103, 2945.


Heck reaction = regioselectivity.

Br

+ AlkenePd cat. / base

Product

CO2Me

100%

CN

100% 100% 100%

Me

80%

20%

CO2Me

1%

Me

99%

100%

OMeMeO

21%

Me

79%

7%

93%

Me

35

Heck reaction = stereoselectivity.

In general, reactions of terminal olefins give a prepoderance of E product.

OTBS

Me

I

Me+

Me

OH

cat. Pd(OAc) 2, AgOAc

DMF, rt

OTBS

Me Me

Me

OH70%

100% E

Chem. Eur. J. 2003, 9, 1129.

R1 R2

PdAr X

L

syn-addition ArL(X)Pd

HR1 R2H

HL(X)Pd

HR1 Ar

R2

ββββ-H-elim

(syn) R1

R2

Ar


Heck reaction = applications.

- UV-B sunscreen

Br

MeO+ O

O

MePd/C, Na2CO3

NMP, 180 - 190 °C MeO

Me

O

O

Me

Me

pilot scale - several tons

- synthesis of Eleptritan or Relprax (Pfizer, for the treatment of migraineheadaches)

OO 1- cat. Pd(OAc) , P(o-Tol) OO

36

SOO

+Br

NH

N1- cat. Pd(OAc)2, P(o-Tol)3 Et3N, CH3CN

2- cat. Pd/C, H 2

Me

NH

NMe

SOO

- synthesis of Naproxen (anti-inflammatory)

Br

MeO

< 0.05 mol% PdCl 2, L, Et3N

30 bar pentan-3-oneH2O, 95 °C

MeO MeO

Me

CO2H

500 tons/year

pentan-3-one precursor of CH 2=CH2 L =

Me

i-PrPPh2


Heck reaction = β-H-elimination – insertion - migration, case of cyclic ethers.

O

+I 0.01 mol% Pd(OAc) 2

Et3N, 100 °C O Ph

+

O Ph

expected obtained !

Ph PdL

I

O

+δδδδ -δδδδ

syn addition

O

Ph Pd(I)L 2

HH

ββββ-H elim

only syn

O

PhPd

H

ILinsertion

O

Ph

Pd(I)L2

H

Ph Ph Ph L2Pd(I)H Ph

37

ββββ-H elimO

Ph

HPd

I

L

insertionO

Ph

Pd(I)L2H

ββββ-H elimO

Ph

H Pd LI

L2Pd(I)H

O

Ph

- synthesis of platelet activator factor antagonist

OMeOMe

I

O

2.5 mol% Pd(OAc) 2 / PPh3

AcOK, 80 °C

OMeMeO

O 2.5 mol% Pd(OAc) 2 / PPh3

AgCO3, CH3CN, 80 °C

OMeMeO

I

O

H2 / PtO2

OMeMeO

O

J. Org. Chem. 1990, 55, 407.


Heck reaction = β-H-elimination – insertion - migration, case of allylic alcohols.

Ar-I +

OHMe

2 mol% Pd(OAc)2

PPh3, baseOH

MeAr

OMe

Arversus

base = AgOAc base = NaOAc

Ar Pd

L

I

HO

Me

L Pd

L

IAr

OHMe

H Pd

L

I

HO

MeArL Pd

L

IAr

OHMe

H Pd

L

I

Me

OH

Ar

38

HO HO Me

kinetically favoredbut reversibly formed

inclusion of Ag+ prevents reversibility

- synthesis of prostaglandin E2

HO

HO

I C5H11

OTBS

5 mol% Pd(OAc) 2

Bu4NCl, DMF, rt

(Jeffery's conditions)

HO

HO

HPd(I)L2

R

HO

HOR

Pd(H)(I)L O

HOR

- L2Pd(H)(I)

O

HOC5H11

HO

CO2HPure & Appl. Chem. 1990, 62, 653.


� The Palladium-catalyzed cross-coupling with organometallic reagent.

The palladium-catalyzed cross-coupling of alkenyl or aryl halides (and triflates) withorganometallics proceeds via sequential oxidative addition, transmetallation, (trans-cis-isomerization), and reductive elimination processes.

R X + R1 M[Pd]

R R1 + M X

reactivity order in oxidative addition


39

General catalytic cycle



� the Suzuki-Miyaura reaction (Nobel Prize 2010).

The Suzuki-Miyaura reaction provides a versatile, general method for stereo- and regiospecific synthesis ofconjugated dienes, enynes, aryl substituted alkenes, and biaryl compounds. The wide use of this reactionstems from the tolerance of functional groups, and the ready availability of the starting materials.

Catalytic cycle Pd sources : Pd(PPh3)4, PdCl2(PPh3)2.

Bases : Na2CO3, EtONa, NaOH, KOH, K3PO4, Et3N.

Solvents : THF, toluene (presence of water possible).

X

+ R1 BPd(0) cat.

base

R1

orX

+ R1 BPd(0) cat.

base

R1

R

R

R

R

X = I, Br, Cl, OTf

L2Pd(0)Ar-X

40

Solvents : THF, toluene (presence of water possible).

Main sources of organoboron reagents

:B

HO

OHB

ArHO

OHB

RO

ROB

ArRO

RO

boronic acids boronic esters

Ar-X

L2PdAr

X

oxidative addition

L2PdAr

transmetallationreductiveelimination

(II)

R1

ArR1

R1BR

RNaOH

R1BR

ROH

Na

BRR

OH+ NaX

Review : Chem. Rev. 1995, 95, 2457.applications in total synthesis : Tetrahedron 2002, 58, 9633


- synthesis of Boscalid (polyvalent fongicide,BASF, > 1000 tons/years)

NO2

Cl+

Cl

B(OH)2

Pd(PPh 3)4 cat.

Bu 4NBr, K 2CO3Toluene, H 2O

NO2

Cl

NH

Cl

O

N Cl

Boscalid

- preparation of valuable intermediate(GlaxoSmithKline, 20 L scale) t-Bu

41

NH

CO2Et

Br

+

t-Bu

B(OH)2

Pd(OAc) 2 cat.

P(o-Tolyl) 3KHCO3, H2O, i-PrOH

NH

CO2Et

- kg-scale manufacture of dibenzoxapine (cascade reaction, 2 kg scale)

Br

Me

OI

NO2(HO)2B

Pd(OAc) 2 cat.

Na2CO3dioxane, H 2O

Br O

MeNO2

Br O

MeNH2.HCl


- Suzuki coupling of sp3 nucleophiles (sp2 – sp3 bonds)

Br

9-BBN

Br

9-BBN Pd(0) cat., base

OTPSTBSO

OMe

OMe 9-BBN9-BBN

OTPSTBSOCH(OMe)2

3

SN

IOAc

PdCl2(dppf) cat

application to the synthesis of epothilone A

42

PdCl2(dppf) catCsCO3, AsPh 3

H2O, DMFS

N

OAc

CH(OMe)2

OTBSOTPS

71% yield

S

N

O

OHO

OOH

epothilone A

Review Suzuki-Miyaura cross-coupling in natural product synthesis : Angew. Chem. Int. Ed. 2001, 40, 4545.


� the Stille cross-coupling reaction.

The Stille reaction involves the palladium-catalyzed cross-coupling of organostannanes with electrophiles suchas organic halides, triflates, or acid chlorides. The coupling of the two carbon moieties is stereospecific andregioselective, occurs under mild conditions, and tolerates a variety of functional groups (CHO, CO2R, CN,OH) on either coupling partner. These properties make the Stille reaction frequently the method of choice insyntheses of complex molecules. A problem of the Stille reaction is the toxicity of organotin reagents,especially the lower-molecular weight alkyl derivatives.

R1 X + R2 SnR3

[Pd]R1 R2 + R3Sn X

R1 = acyl, allyl, aryl, vinyl, benzyl

R2 = aryl, vinyl Pd sources : Pd(PPh3)4, (MeCN)2PdCl2.

43

R = aryl, vinyl

L2Pd(0)R1-X

L2PdR1

X

oxidative addition

L2PdR1

R2


(II)

R2R1

R2 SnR3

X SnR3

Catalytic cycle

Pd sources : Pd(PPh3)4, (MeCN)2PdCl2.

improved reactivity with CuI/CsF

Solvents : THF, DMF (anhydrous)

Best catalytic system : Pd2(dba)3, AsPh3, LiCl, THF

The most widely used groups in transmetalation fromtin to carbon are those with proximal π-bonds such asalkenyl-, alkynyl-, and arylstannanes.reactivity order in transmetallation (R2) :

RC≡C > RCH=CH > Ar > RCH=CHCH2 ≈ ArCH2 >> alkyl

Review : mechanisms of the Stille reaction: Angew. Chem. Int. Ed. 2004, 43, 4704.short historical note : J. organometall. Chem. 2002, 653, 50.


- short efficient synthesis of pleraplysillin-1 (isolated from a marine sponge)

TfOPd(PPh ) cat.

Bu I + CO2Et

Bu 3Sn

PdCl2(CH3CN)2 cat

DMF, rtBu

CO2Et

65% yield

IMeO2C +N

Bu3SnPdCl2(PPh3)2 cat

THF, 65 °CMeO2C

N

95% yield

44

SnBu 3

O+TfO

Me Me

Pd(PPh3)4 cat.

LiCl, THF, 70 °CMe Me

O

75% yield

- enediyne construction system for the dynemicin total synthesis

81% yield

TeocN

OTBS

O

I

H

OH

OH

Me

I

Me3Sn SnMe3

5 mol% Pd(PPh 3)4

DMF, 75 °C

TeocN

OTBS

O

H

OH

OH

Me

NH

OH

O

H

CO2H

OH

Me

OH O

OH O


- carbonylative Stille cross-coupling

When the Stille reaction is carried out under a CO atmosphere, the carbonylative coupling proceeds withcarbon monoxide insertion; namely, carbonyl insertion into the Pd–C bond of the oxidative additioncomplex.transmetalation, followed by cis-trans-isomerization and reductive elimination, generates the ketoneproduct.

L2Pd(0) R1-X

L2PdR1

X

oxidative addition

reductiveelimination

R2 R1

O

O

A similar carbonylation could be carried out inthe Suzuki-Miyaura cross-coupling reaction.

LnPdR1 + CO

L(n-1)PdR1CO

LnPd+ L

O

R1

45

L2PdX

L2PdC

Xtransmetallation (II)

CO

carbon monoxideinsertion

O

R1

R2 SnR3

X SnR3

L2PdC

R2

O

R1

MeOTf

SnMe3

Pd(PPh 3)4 cat.LiCl / CO (1 atm)

THF, 50 °C

Me

O

78% yiel d

XLnPd

XL(n-1)Pd

XLnPd

- L

I + Ph

Bu3Sn

PdCl2(CH3CN)2 cat

CO, THF, 50 °C65% yield

BuBu

O

Ph


� the Sonogashira cross-coupling reaction.

HR1 +X Pd(0) cat., CuI cat.

base

R1

The Sonogashira reaction has emerged as one of the most general, reliable, and effective methods for thesynthesis of substituted alkynes. In addition to Heck and Suzuki-Miyaura coupling reactions, Sonogashirareactions have been realized on an industrial scale as well.

L2Pd(0)Ar-X

Catalytic cyclePd sources : Pd(PPh3)4 or (PPh3)2PdCl2.Solvents : without solvent (the amine was used as reagent

46

Ar-X

L2PdAr

X

L2PdAr

H R1CuX

Cu R1

Et3N

R1

CuX

transmetallation

(II)

R1

Ar

oxidative addition

reductiveelimination

Pd sources : Pd(PPh3)4 or (PPh3)2PdCl2.Solvents : without solvent (the amine was used as reagentand as base) or THF or CH2Cl2

CuI / Et3N (or other amines) to form the copper(I) alkynide

Review : Chem. Rev., 2007, 107, 874.


- synthesis of Eniluracil (Glaxo SmithKline ; a chemotoxic agent enhancer used incombination with 5-fluorouracil, one of the most widely used drugs in cancer chemotherapy.

HN

NH

O

O

I

+ H SiMe30.5 mol% PdCl 2(PPh3)2

0.5 mol% CuIEt3N, AcOEt

HN

NH

O

O

SiMe3

93% yield

NaOH HN

NH

O

O

H

eniluracil

HN

NH

O

O

F

5-fluorouracil

- synthesis of lipoxin A4.

Me Br

OTBS

+CO2Me

OTBSTBSO

47

Me Br

1 mol% Pd(PPh 3)416 mol% CuI

PrNH2, benzene, rt

OTBS

Me

CO2MeOTBSTBSO

96%

OH

Me

CO2HOHHO

(5S, 6S, 15S)-lipoxin A 4- cascade reactions in the total synthesis of frondosin B.

OHI

OMe

+

CO2Me

Me

PdCl2(PPh3)2 cat.

CuI cat.Et3N, DMF, rt

OH

OMeCO2Me

Me

50 °C O

MeO CO2Me

Me O

HO

Me

MeMe

frondosin B


� the Negishi cross-coupling reactions (Nobel Prize 2010).

The Negishi palladium-catalyzed cross-coupling reaction of alkenyl, aryl, and alkynyl halides with unsaturatedorganozinc, organoaluminium, and organozirconium reagents provides a versatile method for preparingstereodefined arylalkenes, arylalkynes, conjugated dienes, and conjugated enynes.

R1 X + R2 M[Pd] cat.

R1 R2 + X M M = ZnCl, AlR 2, Zr(Cl)Cp 2

L2Pd(0)R1-X

R1

oxidative addition

R2

Catalytic cycle

48

L2PdR1

X

L2PdR1

R2


(II)

R2R1

R2 M

X M

Review : Bull. Chem. Soc. Jpn 2007, 80, 233.


OAcOMe

IOHC

i-Pr2Zn (0.55 equiv)

NMP, rtLi(acac) (0.1 equiv)

OAcOMe

ZnOHC 2

C6H11

O

Cl

2.5 mol% Pd 2(dba)5 mol% P(furyl) 3

OAcOMe

OHCO

75% yield

- Negishi cross-coupling reaction : applications.

IBr + BrZn SiMe3

2 mol% Pd(PPh 3)4

THF, rtSiMe3

Br

81% yield

49

O

OMeMeO

MeOCl

Me2AlMe

Me

Me

2+

2 mol% Pd(PPh 3)4

THF, 0 °C

O

OMeMeO

MeOMe

Me

Me

2

coenzyme Q s

MePh

OMe

Me

Cp2Zr(H)Cl

THF, 50 °C

PhOMe

Me

Zr(Cl)Cp 2

Me

Hhydrozirconation

Cp2Zr(H)Cl = Schwartz reagent

PhOMe

Me MeOTBS

Me

NHBocOTBSMe

NHBoc

I

Pd(PPh3)4, dry ZnCl 2

THF, rt


� Carbon-heteroatom cross-coupling reaction :

the example of the Buchwald-Hartwig coupling reaction (C-N bond formation).

X

+

R1NHR2

R1OH

R1SH

Y

Y = NR1R2, OR1, SR1

X

+ R1NHR2NR1R2

[Pd] cat.

base

50

base

X

Catalytic cycle

Best catalytic system

Pd2(dba)3 or Pd(OAc)2, Ligand, NaOt-Bu, Toluene rt to 100 °C

Ligand = dppf,

P(tBu)2 P(Cy)2

Review : Adv. Synth & Catal. 2004, 346, 1599.


- process scale synthesis of a pharmaceutical intermediate (Astra Zeneca)

NH

Ph

Me

Me

Br

+

N

HN

Me

0.5 mol% Pd 2(dba) 3

1.5 mol% BINAPNaOt-Bu, Tol, 100 °C

NH

Ph

Me

Me

N

NMe

95% yield125 kg scale

- a cholesteryl ester transfer protein inhibitor, the Torcetrapib (Pfizer)(abandoned, excessive mortality during clinical trials)

MeO2C CF3

51

Cl

F3C+

Me

CN

H2N

0.5 mol% Pd 2(dba)3

1.5 mol% BINAPNaOt-Bu, Tol, 100 °C

NH

F3C

Me

CN

NH

F3CN

Me

MeO2C

CF3

CF3

- double N-arylation : synthesis of Mukonine

MeO2C OMe

OTfOTf

2 mol% Pd 2(dba)3

10 mol% XantPhos

K3PO4, xylene, 100 °C

BocNH 2

NBoc

MeO2COMe

NH

MeO2COMe

TFA

Mukonine

O

MeMe

PPh2 PPh2XantPhos


� The Tsuji-Trost reaction : Palladium-catalyzed allylic substitution.

Allylic substrates with good leaving groups are excellent reagents for joining an allyl moiety with a nucleophile.However, these reactions suffer from loss of regioselectivity because of competition between SN2 and SN2

’

substitution reactions. Palladium-catalyzed nucleophilic substitution of allylic substrates allows the formationof new carbon-carbon or carbon-hetero bonds with control of both regio and stereochemistry.

R1 OAc + R2 M[Pd] cat.

R1 R2 + AcOM

L2Pd(0)

oxidative

R1 OAc

R1Catalytic cycle

Pd source : Pd(PPh ) .

52

L2Pd

addition

L2Pd

R2 M

AcOM

R1

AcO

(M = Na, K, Li)

R1

R2

R1 R2

Pd source : Pd(PPh3)4.Solvents : THF or DMF.Other possible leaving groups : OC(O)OR,OP(O)OR2, OPh, Cl, Br.Nucleophiles : best results with malonatetype anions, other soft nucleophiles asanions from nitromethane, enolates, andenamines.

The palladium-mediated allylation proceeds via an initial oxidative addition of an allylic substrate to Pd(0). Theresultant π-allylpalladium(II) complex is electrophilic and reacts with carbon nucleophiles generating the Pd(0)complex, which undergoes ligand exchange to release the product and restart the cycle for palladium. Withsubstituted allylic compounds, the palladium-catalyzed nucleophilic addition usually occurs at the lesssubstituted side. The reaction is usually irreversible and thus proceeds under kinetic control.


- Tsuji-Trost reaction : the stereoselectivity.

Palladium-catalyzed displacement reactions with carbon nucleophiles are not only regioselective but also highlystereoselective. In the first step, displacement of the leaving group by palladium to form the π-allylpalladiumcomplex occurs from the less hindered face with inversion. Subsequent nucleophilic substitution of theintermediate π-allylpalladium complex with soft nucleophiles such as amines, phenols, or malonate-type anionsalso proceeds with inversion of the stereochemistry. The overall process is a retention of configuration asa result of the double inversion.

CO2Me

OAc

Pd(PPh3)4 cat.

CH2(CO2Me)2 / NaH

THF

CO2Me

PdL

Nu

CO2Me

CH(CO2Me)

53

THF PdL2

The mechanism of doubleinversion operates with softstabilized nucleophiles. In thepresence of hard nucleophilesthe reaction occurs withinversion of configuration.


- Tsuji-Trost reaction : examples.

Me

Me Me

OAcgeranyl acetate

Me

Me Me

neryl acetateOAc

+ HCCO2Me

SO2Ph

Na Pd(PPh3)4 cat

THF, 65 °C

Me

Me Me

Me

Me Me

CO2Me

SO2Ph

SO2Ph

CO2Me

OAc

54

OAc

CO2Me

O Me 7 mol% Pd(PPh 3)4

NaH, THF, 65 °C

OMe

CO2Me99% yield

AcO OCO2R

EE

E = CO2Me

Pd2(dba)3 / PPh3

NaH, THF, 65 °CO

CO2R

EEH

H

H

only cis


- π-trimethylene methane cyclization.

Me CO2Me +

SiMe3

OAc

Pd(PPh3)4 / dppe

THFMe

CO2Me

SiMe3

OAc

L2Pd(0) SiMe3

PdL 2

OAc

PdL2

C6H11

O

OMe

PdL2

H11C6

OMe

OC6H11

CO2MePdL 2

55

O O+

SiMe3

OAc

Ph

Pd(PPh3)4

Toluen, reflux O O

Ph

H

H

mixture of stereoisomers


� The palladium-catalyzed oxidation reaction of terminal olefins : the Wacker reaction .

R[Pd(II)] cat, CuCl2 cat.

O2 atm, H2O, DMFMeR

O

The Wacker process consists to oxidize selectively terminal olefins in the presence of palladium +2 ascatalyst. The most common palladium source used in this reaction id PdCl2.

R

Cu(+2)

Cu(+1)O2 + HCl

PdCl2

Regioselectivity : Markonikov addition usually

56

Catalytic cycle

R

PdCl2

H2O

O

RPdCl2

H

H

HClO

RPdCl2H

Pd(H)Cl

R

OHMe

R

O

HCl nucleophilicattackββββ-H elimination

reductrice elimination

oxidation

Cu(+2)

Pd(0)

Regioselectivity : Markonikov addition usuallyobserved.

Anti-hydroxypalladation :

R R CH3 R CHO

O

no formed

R

PdCl

ClH2O

OH

H

antiPd

Cl

ClH2O

ROH


- Wacker reaction: examples.

O

PdCl2 cat, CuCl 2 cat

O2, DMF / H2OO

O

- The Wacker reaction could oxidize only the terminal olefin �� regioselective reaction.

H HO

- CuCl/O2 could replace CuCl2 to avoid chlorinated by-products.

57

OO OTBS

PdCl2 cat, CuCl cat

O2, DMF / H2OO

O OTBS

- Used also in intramolecular process.

OH O

Pd(OAc) 2

Cu(OAc) 2, O2

[Pd(II)]

H

O [Pd(II)] O O


Applications : the metathesis of olefins

CH

HCR1

CH

R4HC

R2 R3+CH

HCR1

CH

R4HC

R3 R2+M=CH2

most common catalysts in metathesis of olefins

PCy3

Ru

PCy3

PhCl

ClRu

PCy3

PhCl

Cl

N N MesMesN

MoPh

i-Pr

i-Pr

MeMe

O

O

F3C

CF3Me

F3C

58Y. Chauvin R.H. Grubbs R.R. Schrock

Nobel Prize in Chemistry 2005"for the development of the metathesis method in organic synthesis"

PCy3 PCy3

[Ru]-2[Ru]-1

first generationGrubbs catalyst

second generationGrubbs catalyst

MeMe

CF3

F3CMe

[Mo]

Schrock catalyst


( )n

( )n

( )n ( )n

[M]

RCM- C2H4

ROMP+ C2H4

ROM

ADMET- C2H4

� common metathesis olefins reactions and simplified catalytic cycle.

X M=CH2 X

RCM

M=CH2

X

X

Metathesis = « change places »

59

( )n ( )n

R1R2+ R1

R2 + C2H4CM

[M]

H2C CH2

[M]

X

[M]

RCM = Ring Closing MetathesisROM = Ring Opening MetathesisROMP = Ring Opening Metathesis PolymerizationADMET = Acyclic Diene Metathesis PolymerizationCM = Cross Metathesis

All of the above reactions are reversible, so equilibrium mixtures are obtained. To produce high yields of agiven product a suitable driving force must be present.• Cross metathesis: Mixtures of products are produced unless a volatile byproduct (ethylene) is produced thatcan be removed from the reaction mixture.• RCM is favored for the production of unstrained rings and is driven both entropically and by the eliminationof a volatile alkene.• ROM is only favored at very high olefin concentrations, or more commonly with strained olefins.


- the RCM reaction : examples.

C8H17 + C13H27[Ru]-1 cat

C8H17C13H27 + H2C CH2 + other products

commercial synthesis of house fly pheromone

N

OR

N

OR( )n ( )n

3 mol% [Ru]-1

PhH, rt, 1 hn = 0, 78%n = 1, 93%

60

O

OOH

N

SH

OH

[Ru]-1

O

OOH

N

SH

OH

desoxyepothilone A

81% yield, E / Z = 9 / 1

PhH, rt, 1 h n = 1, 93%


Metalloenzymes : examples

Metals play roles in approximately one-third of the known enzymes. Metals may be a co-factor(prosthetic group), and these are known as metalloenzymes. Amino acids in peptide linkageposses groups that can form coordinate-covalent bonds with the metal atom. The free aminoand carboxy group bind to the metal affecting the enzymes structure resulting in its activeconformation .Metals main function is to serve in electron transfer. Many enzymes can serve as electrophilesand some can serve as nucleophilic groups. This versatility explains metals frequent occurrencein enzymes. Some metalloenzymes include hemoglobins, cytochromes, phosphotransferases,alcohol dehydrogenase, arginase, ferredoxin, and cytochrome oxidase.

61

� The Methionine Aminopeptidase 2 (MetAP2).

The Methionine aminopeptidase 2 (MetAP2) is a metalloenzyme, abifunctional protein that plays a critical role in the regulation of post-translational processing and protein synthesis.The MetAP2 catalyzesrelease of N-terminal amino acids, preferentially methionine, from peptidesand arylamides. Methionine aminopeptidases (MetAPs) are the enzymesresponsible for the removal of methionine from the amino-terminus ofnewly synthesized. The removal of methionine is essential for further aminoterminal modifications (e.g., acetylation by N-alpha-acetyltransferase andmyristoylation of glycine by N-myristoyltransferase, NMT) and for proteinstability.

H2N

HN

OPept

O

R1

SMe

MetAP2

H2NH2N

OPept

O

R1

SMe

OH+


Active site with an irreversible inhibitor (fumagilline)

His 231

Asp 251

Asp 262Glu 364

Glu 459

His 331

Fumagilline

covalent bond

O

OOCH3

CH3

O

HCH3

CH3

O

CO2H3

fumagillin

The fumagillin was found to inhibit theangiogenesis process (construction of new bloodvessels). The MetAP2 was identified as biologicaltarget of the fumagillin. The formation of acovalent bond between the fumagillin and theMetAP2 was catalyzed by the presence of twocations of Manganese (Mn2+) which act as Lewisacids.

62

mechanism of inhibition of MetAP2 with fumagillin


� The Carbonic Anhydrases (CAs).

Carbonic anhydrases (CAs), a group of ubiquitouly expressed metalloenzymesare involved in numerous physiological and pathological processes, includinggluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth andvirulence of various pathogens. Furthemore, recent studies suggest that CAactivation may provide a novel therapy for Alzheimer’s disease.

CAs catalyse the following reaction : CO2 + H2O �� HCO3-

+ H+

OC

Zn2+

OH-

His94

His96

His119

Active site

63

OH

Zn2+

His94 His96

His119

CO2

O

Zn2+

His94 His96

His119

CO

O

Zn2+

His94 His96

His119

H O

O+ H2O

- HCO3OH2

Zn2+

His94 His96

His119

- BH++ B

ORGANOCATALYSIS

PART 2

64

ORGANOCATALYSIS

Definition : in organocatalysis, a purely organic and metal-free small molecule is used tocatalyze a chemical reaction.This approach has some important advantages :

- small organic molecule catalysts are generally stable and fairly easy to design andsynthesize.- often based on nontoxic compounds, such as sugars, peptides, or even amino acids,and can easily be linked to a solid support, making them useful for industrialapplications.

Organocatalysts can be broadly classified as Lewis bases, Lewis acids, Brønsted bases, andBrønsted acids.

Major reaction pathways :

65

Major reaction pathways :- via covalent activation complexes as enamine and iminium ion

- via noncovalent activation complexes as H-bonding or ion pairing

ONH

R2R1

+ H+N

R2R1- H+

NR2R1

OH A

Reviews : Angew. Chem. Int. Ed. 2004, 43, 5138 , Angew. Chem. Int. Ed. 2008, 47, 4638 and Drug Discovery Today, 2007, 12, 8.

ORGANOCATALYSIS

The most common system : Proline (and derivatives) as catalyst

Why Proline ?

NH O

O

H

L-proline

Proton deliveryAmine function toactive the carbonylgroup

Chiral center � asymmetric synthesis

Abundant end cheap material

Proline as catalyst for the aldol reaction – proposed mechanism

66

O+

H

O

R

NH

CO2H

(30 mol%)

DMSO

OH

R

O

54 - 97% yiel d60 - 96% ee

R = aryl or i-Pr

Seminal work : J. Org. Chem. 1974, 39, 1615 .

Mechanism : Science 2002, 298, 1904.

ORGANOCATALYSIS

Proline as catalyst for the aldol reaction – justification of the enantioselectivity

67

J. Am. Chem. Soc. 2000, 122, 2395.

ORGANOCATALYSIS

Proline as catalyst for the aldol reaction – comparaison with various organocatalyst

O O

O

pyrrolidine derivatives

solvent, rtOH

O

O

68

ORGANOCATALYSIS

Proline as catalyst : examples

HMe

O

"2 equiv"

10 mol% L-Proline

DMF, 4 °C H

O

Me

MeOH

80% yield

4 : 1 anti : syn99% ee (anti)

H

O+

H

O10 mol% L-Proline

DMF, 40 h, 5 °C

then TBSCl, base H

O OTBS

TBSO

OEt

BF3.OEt2, CH2Cl2

OH OTBS

EtO

O

69

Et2O/CH2Cl261% (two steps)

Me -78 °C, 65% Me

O

O

HOMe

48% HF, H2O, CH3CN4.5 h, rt, 55%

(-) Prelactone BTetrahedron Lett. 2003, 44, 7607

3 steps, 22% overall yield

O

OH

+ H

O

+

NH2

OMe

35 mol% L-Proline

DMSO, rt, 12 h

O

OH

HN

OMe

57% yiel d

ORGANOCATALYSIS

Proline and derivatives as catalysts

NH

CO2H NH

NH

BnBnAr

OTMSAr N

HCO2H

Me

NH HN N

NN

the MacMillan catalystsN

Bn

O Me

MeN

Bn

O Me

Me

70

the MacMillan catalystsNH

BnMeMe

.HCl

NH

Bn

.HClMe

Me

OO

R1

N

NH

Bn

O Me

MeMe

.HCl

(5 mol%)

THF, rt

O

R1

O

85-99% yield80-97% ee

ORGANOCATALYSIS

MacMillan as catalysts : examples

71

ORGANOCATALYSIS

H-bonding catalysis : examples of the chiral phosphoric acid

Ar

Ar

O

O

PO

OH

R1 H

NBoc 2 mol% cat

CH2Cl2, rt, 1 h+

Me Me

O O

R1

NHBoc

O Me

Me

O

> 94% yield, > 92% ee

N 10 mol% cat

Tol, -78 °C, 24 h+

NH O

OH

OEt

OTMSH

OH

72

R1 H Tol, -78 °C, 24 h R1 OEt

> 97% yield, > 88% ee

OEtR2

R2

Bull. Chem. Soc. Jpn 2010, 83, 101.

ENZYMES AS CATALYSTS

PART 3

73


Enzyme-catalyzed chemical transformations are now widely recognized as practicalalternatives to traditional organic synthesis, and as convenient solutions to certain intractablesynthetic problems.

Typical enzyme-catalyzed transformations

Enzymes commonly used in organic synthesis

74


Enzymes commonly used in organic synthesis

75


Examples of applications

- synthesis of a new [beta]-lactam.

H2N

OO CO2Me H

N

O

O

PhO HN

O

NH2

- resolution of racemic mixture of alcohols.

R1 R2

OH lipase or esterase+

O Me

O

R1 R2

OH+

R1 R2

OAc

76

NO

CO2H

Penicillin G acylaseN

OCO2H

ON

O

OCl

CO2HLoracarbef(antibiotic)

- a representative chemgenzymatic preparation of cyclic imine sugars.

MeCHO

N3

OH

+ OPO32-

OHO

1- aldolase

2- phosphataseMe

N3

OH

OH

OH

O

OH

H2, Pd/C, HCl

HO OH

OOHHCl.H2N

Me

OH NaOH NOHOH

OHHO

Me

catalysis for the synthesis of bioactive...

Documents