INTRODUCTION TO CATALYSIS

Université de Rennes 1 – Vietnam National University, Hanoi

CATALYSIS FOR THE SYNTHESIS

OF BIOACTIVE COMPOUNDS

OF BIOACTIVE COMPOUNDS

Prof. Pierre van de Weghe

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

What is the mechanism of this reaction ?

What is the role of the palladium and the base ?

Br N OH Bu N N N N B(OH)₂ N N HN N N _losartan + 5 mol% Pd(PPh3)4, K2CO3 THF - H2O then H3O+ aryl-aryl bond

Pro memoria

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

A + B [cat] C + D 3 A + B C + D A + B [cat] C + D [cat] [cat]-A A B C + 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 reaction pathways, i. e. the kinetics; in particular it lowers the energy of transition states.

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 the}

reaction is catalyzed (∆G₁‡ _>> ∆_G 2‡).

- 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

[cat] = P Rh(MeOH)₂ P Ph Ph MeO MeO Mosanto's approach 5

organic molecules as catalysts or organocatalysis

enzymes as catalysts

O Me NH Me O

EtO2C CO2Et

Bn₂NH - TFA (cat.)

Lepidopteran sex pheromon

O OEt O _{reductase in yeast} OH OEt O OH OEt O S R

major product minor product

TRANSITION METAL COMPLEXES

AS CATALYSTS

Organic versus Organometallic reactivity

What is a transition metal ?

Transition metal valence electron count

9

for free (gas phase) transition metals: (n+1)s is below (n)d in energy. Fe 4s 2 _3d6 = 3d8 OC Fe CO CO CO CO 3d8

for complexed transition metals: the (n)d levels are below the (n+1)s and thus get filled first.

N

N N

FeΙΙΙΙΙΙΙΙ Cl Cl

3d6

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

The 18-electron rule

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

Transition metals have 9 valence orbitals (1 s + 3 p + 5 d). Upon bonding to a ligand set, there will be a totyal of 9 low lying orbitals (bonding + non-bonding molecular orbitals). Therefore, wa can 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 because they will have a closed shell of electrons. Complexes with 18 electrons are aften referred to as being coordinatively saturated.

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 shared equally between carbon and hydrogen. To count the electrons, we dissect the molecule giving each atom 1 electron of the bonding pair.

H C H

H H C

H

H H : 4x1 e = 4_{C : 4 e}

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

H C H H H C H H _{C : 4 e} Total = 8 electrons H C H H H H C H H H H + _{: 4x0 e = 0} C (-4): 8 e Total = 8 electrons 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 number}

examples: 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 actual positive charge on the metal)

13

(oxidation states in organometallic complexes are merely formalisms that may bear little resemblance to the actual positive 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 of}

electrons is the row number minus the charge on the metal. The formal oxidation state is simply 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 encourage you to learn that one. You should also be aware of the ionic method, since you will encounter it from time to time.

Organometallic ligands :

© 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 …

N

C N Ar Ar

Electron counting and oxidation state:

- procedure for a neutral complex ML_lX_x NVE = n + 2l + x oxidation state = x

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

- procedure for complex with charge [ML_lX_x]q _{NVE = n + 2l + x – q} oxidation state = x + q

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

covalent model Rh : d9 = 9 e 3 x PPh3 : 3 x L = 6 e 1 x Cl : 1 x X = 1 e oxidation state : 1 x X = +ΙΙΙΙ ionic model Rh+ : d8 = 8 e 3 x PPh3 : 3 x L = 6 e 1 x Cl- : 2 e total = 16 e, +I Rh PPh₃ PPh₃ Cl PPh₃ Rh PPh₃ PPh₃ Cl PPh₃ 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 (L₂X) = 2 x (2 x 2 + 1) = 10 e

oxidation state : 2 ligands X, 0 charge = +ΙΙΙΙΙΙΙΙ ionic model Fe2+ : d6 = 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 Cr OC OC CO CO CO H Cr : d6 = 6 e 5 x CO : 5 x L = 10 e 1 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 e 1 x H- : 2 e total = 18 e, 0 charge : -1 e Pd PPh₃ PPh3 Ph3P PPh3 covalent model Pd : d10 = 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

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 around the metal.

- electronics : d electron count combined with the complex electron count must be considered when predicting geometries for complexes with non-bonding d electrons. Often this leads to sterically less favorable geometries for electronic reasons (e.g. CN = 4, d8_{, 16 e}

complexes prefer a square planar geometry). STERICS L 17 L M L (CN = coordination number) CN = 2 linear L M CN = 3 trigonal planar L L CN = 4 L M L _LL tetrahedral CN = 5 L M L L L L trigonal bipyramidal CN = 6 M L L L L L L octahedral ELECTRONICS L M L L T-shaped M L L L L square planar L L M _L L L square pyramidal

Main classes of reactions around the transition metal

ligand substitution

oxidative addition & reductrice elimination

ML_l [ML_l-1] - L ML_l-1L1 + L1 A B [M] [M] A B [M] B A

insertion & elimination

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

[M] A + B [M] A B [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 d8 square planar complexes are prototypical examples (Pt(II), Pd(II), Ir(I) and Rh(I)).

Pt L L X L + Y slow Pt L L X L Y Pt Y X L L L Pt L L Y L X fast Pt L L 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 of ligand substitution for ccordinatively satured complexes are usually significantatly slower than those for coordinatively unsaturated complexes.

L M L L1 L L L - L L M L L1 L L L M L L1 L2 L L + L2 L M L L1 L L L2 M L L1 L L L + L2 + L2 L M L2 L1 L L L

Oxidative addition – reductive elimination

- oxidative addition : addition of A-B to a metal center resulting in an increase in coordination number by 2, an increase of oxidation state by 2 units, and an increase in the electron count by 2.

- reductive elimination : elimination of two ligands from a metal center to gice a new A-B bond. The metal center is reduced by 2 units and has 2 fewer coordinated ligands. The complex has 2 less electrons (concerted reductive elimination requires cis coordination of the ligands to be eliminated).

m+ A

A

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

L_nMm+ + A

B LnM

(m+2)+ B

Insertion – elimination

Features of this transformation :

- there is no change in the formal oxidation state of the metal unless AB is an alkalydene or an alkylidyne.

- the groups undergoing migratory insertion must be cis to one another. In complexes where the cis coordination sites are blocked by strongly coordinated ligands, insertion or elimination processes are not possible.

- an open coordination site is created during migratory insertion. Therefore, for the reverse reaction (elimination) to occur, an open coordination site must be generated by ligand dissociation.

17

dissociation.

- in the case where C is a chiral center, the reaction usually occurs with retention of configuration.

- cases where C migrates to AB followed by coordination of L in place of C, and where AB migrates to C followed by coordination of L in place of AB are both known.

M A C B M A C B 1,1-insertion elimination M L + L - L A C B M C M A B 1,2-insertion elimination + L - L A B C M A B C L

Applications : alkenes hydrogenation

The Wilkinson’s catalyst, a Rhodium complex : RhCl(PPh3)3 R + H2 [cat] R H H catalytic cycle Rh Ph₃P Ph₃P Cl PPh₃ = ML₃X Rh = d9 NVE (Rh) = 9 + (3 x 2) + 1 = 16 e o.s. = +ΙΙΙΙ = ML₃X o.s. = +ΙΙΙΙ = _R > _R R > _R R > _R R > R reactivity =

to have a good understanding of the mechanism of the reaction, it is well to determine the NVE and o.s. of the metal at each 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 groups such as RCHO, R₂CO, OH, CN, NO₂, Cl, ROR1_{, CO}

2R, CO2H.

23

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

O NH N O O Ph Me O O HO _{steps H2 / [Rh]} O NH N O O Ph Me H H steps S NH HN O H H CO2H (+)-biotin [Rh] = Fe PPh₂ t-Bu2 P Me

Rh(COD) COD = cyclooctadiene = ligand L₂

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) P P Ru O O O O Me Me PhPh Ph Ph

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

Applications : alkenes reduction – hydride transfer

a Ruthenium complex : RuCl2(PPh3)3

Ru Cl PPh PPh3 Ru Ph₃P Cl PPh3 Cl PPh₃ H H δδδδ− Ru Ph3P Cl PPh3 H PPh3 + HCl +B: B:H+ Cl−

generation of the Ruthenium active species

25 Ru Ph3P Cl PPh3 Cl + B: + H2 H H δδδδ− δδδδ+ Ru Ph₃P Cl PPh₃ Cl PPh₃ H H :B δδδδ− δδδδ+ Ru Ph3P Cl PPh3 Cl PPh₃ H - BH+ _-Cl− Ru Ph3P Cl PPh3 H PPh3 Ru Ph3P Cl PPh₃ H PPh3 Ru Ph₃P Cl PPh3 H PPh₃ R Ru Ph3P Cl PPh₃ PPh3 R Ru Ph3P Cl PPh₃ PPh3 R H H δδδδ− δδδδ+ R _R catalytic cycle Ru Cl Ph3P Cl PPh₃ = ML3X2 Ru = d8 NVE (Ru) = 8 + (3 x 2) + (2 x 1) = 16 e o.s. = +ΙΙΙΙΙΙΙΙ PPh3

asymmetric hydrogenation transfer : the Noyori’s ruthenium catalyst. P Ph Ph Ru Cl H_N2 _Ph O NHMe i-PrOH cat OH 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

P Ph Ph Ru Cl N Ph H₂ cat = = ML₄X₂ + (2 x 1) = 18 e o.s. = +ΙΙΙΙΙΙΙΙ Me Me OH Me Me O + HCl P P Ru H Cl N N H H H H R R1 O O H N Ru H R1 R R R1 OH H H P Cl N H H catalytic cycle

Applications : hydroboration of olefins

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

R + [cat] R H B O B O H O O H2O2 / OH -R H OH R B H O O R OH H + anti-Markovnikov Markovnikov catalytic cycle 27 catalytic cycle classical hydroboration, recall :

hex-1-ene 9-BBN H₂O₂ / NaOH OH OH 99 1 catalyzed hydroboration : Ph + O B O H RhCl(PPh₃)₃ H₂O₂ / NaOH Ph OH application to asymmetric synthesis

diastereoselective catalyzed hydroboration. OPPh2 _{1- RhCl(PPh3)3} O BH O 2- H₂O_2, NaOH 2-Ac₂O, base OAc OAc 85% yield syn > 50:1

Applications : the palladium catalyzed reactions

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

Pd

29 A Pd "Pd" (recycling) + B A fundamental C-Pd activation modification(s) of the Pd complexed organic fragments

C---Pd cleavage

Pd

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

The Heck cross-coupling reaction

The Negishi cross-coupling reaction

The Suzuki-Miyaura cross-coupling reaction

(1979) X + R1 B Pd(0) cat. base R1 R R

Heck reaction

Negishi and Suzuki reactions

Palladium-catalyzed cross-coupling reactions

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

catalyst precursors.

metal sources : Palladium is the most widely used metal for cross-coupling reactions, although there 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 derived from a preformed palladium complex or formed in situ from combination of palladium sources and a ligand. Both Pd(0) and Pd(II) sources can be used although the active species is Pd(0) in all cases.

common sources of palladium Pd/C

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

31

Pd/C

Pd(PPh₃)₄= tetrakis(triphenylphosphine) palladium (most common complex) Pd₂(dba)₃or Pd(dba)₂ PdCl₂(PPh₃)₂ PdCl₂(CH₃CN)₂ Pd(OAc)2 PdCl₂ dba = dibenzylideneacetone O Ph Ph

ligands.

Palladium alone can catalyze the reactions, but usually only with reactive Ar-I substrates and/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 arylphosphines remain the most widely used.

P 3 P 3 CH₃ Fe PPh₂ 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 PPh2 Ph₂P Ph₂P PPh₂ 1,2-Bis(diphenylphosphino)ethane 1,3-Bis(diphenylphosphino)propane monodentate 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

..

..

..

..

The Heck reaction (Nobel Prize 2010).

The Heck reaction involves coupling of alkenyl or aryl halides with alkenes in the presence of palladium 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 + _R

Pd(0)

base R

1 R _R1 _{= or R}2

reactivity order in oxidative addition Ar-I > Ar-OTf > Ar-Br >> Ar-Cl

Base : essential to capture the formation of HX

Pd

Review : Angew.Chem. Int. Ed. 1994, 33, 2379,

Heck reaction = regioselectivity. Br + Alkene Pd cat. / base Product CO2Me 100% CN 100% 100% 100% Me 80% 20% CO2Me 1% Me 99% 100% OMe MeO 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 OH 70% 100% E Chem. Eur. J.2003,9, 1129. R1 R2 Pd Ar X L syn-addition L(X)Pd Ar H R1 R2H H L(X)Pd H R1 ArR 2 ββββ-H-elim (syn) _R1 R2 Ar

Heck reaction = applications. - UV-B sunscreen Br MeO + O O Me Pd/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 migraine headaches)

O

O _{1- cat. Pd(OAc) , P(o-Tol)} O O

S O O + Br N H

N 1- cat. Pd(OAc)2, P(o-Tol)3 Et3N, CH3CN 2- cat. Pd/C, H2 Me N H N Me S O O

- synthesis of Naproxen (anti-inflammatory) Br MeO < 0.05 mol% PdCl₂, L, Et₃N 30 bar pentan-3-one H₂O, 95 °C MeO MeO Me CO2H 500 tons/year Me

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 Pd L I O +δδδδ -δδδδ syn addition O Ph Pd(I)L2 H H ββββ-H elim only syn O Ph Pd H I L insertion O Ph Pd(I)L₂ H Ph Ph Ph L2Pd(I)H _Ph 37 ββββ-H elim O Ph H Pd _I L insertion O Ph Pd(I)L₂ H ββββ-H elim O Ph H Pd L I L2Pd(I)H O Ph

- synthesis of platelet activator factor antagonist OMe OMe I O 2.5 mol% Pd(OAc)2 / PPh3 AcOK, 80 °C OMe MeO O _{2.5 mol% Pd(OAc)} 2 / PPh3 AgCO3, CH3CN, 80 °C OMe MeO I O H₂ / PtO₂ OMe MeO O J. Org. Chem.1990,55, 407.

Heck reaction = β-H-elimination – insertion - migration, case of allylic alcohols. Ar-I + OH Me 2 mol% Pd(OAc)₂ PPh₃, base OH Me Ar O Me Ar versus

base = AgOAc base = NaOAc

Ar Pd L I HO Me L Pd L I Ar OH Me H Pd L I HO Me Ar L Pd L I Ar OH Me H Pd L I Me OH Ar HO HO Me kinetically favored but 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 H Pd(I)L2 R HO HO R Pd(H)(I)L O HO R - L₂Pd(H)(I) O CO H

The Palladium-catalyzed cross-coupling with organometallic reagent.

The palladium-catalyzed cross-coupling of alkenyl or aryl halides (and triflates) with organometallics 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 Ar-I > Ar-OTf > Ar-Br >> Ar-Cl

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 of conjugated dienes, enynes, aryl substituted alkenes, and biaryl compounds. The wide use of this reaction stems from the tolerance of functional groups, and the ready availability of the starting materials.

Catalytic cycle _{Pd sources : Pd(PPh}

3)4, PdCl2(PPh3)2.

Bases : Na₂CO₃, EtONa, NaOH, KOH, K₃PO₄, Et₃N. Solvents : THF, toluene (presence of water possible).

X + R1 B Pd(0) cat. base R1 or X + _R1 B Pd(0) cat. base R1 R R R R X = I, Br, Cl, OTf L₂Pd(0) Ar-X

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

Main sources of organoboron reagents : B HO OH B Ar HO OH B RO RO B Ar RO RO boronic acids boronic esters Ar-X L₂Pd Ar X oxidative addition L2Pd Ar transmetallation reductive elimination (II) R1 Ar R1 R1 B R R NaOH R1 B R R OH Na B R R OH + NaX

- synthesis of Boscalid (polyvalent fongicide, BASF, > 1000 tons/years) NO₂ Cl + Cl B(OH)₂ Pd(PPh3)4 cat. Bu₄NBr, K₂CO₃ Toluene, H₂O NO₂ Cl NH Cl O N Cl Boscalid

- preparation of valuable intermediate

(GlaxoSmithKline, 20 L scale) t-Bu

41 N H CO2Et Br + t-Bu B(OH)₂ Pd(OAc)₂ cat. P(o-Tolyl)₃ KHCO₃, H₂O, i-PrOH N H CO2Et

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

Br Me O I NO2 (HO)2B Pd(OAc)2 cat. Na2CO3 dioxane, H₂O Br O Me NO₂ Br O Me NH₂.HCl

- Suzuki coupling of sp nucleophiles (sp – sp bonds) Br 9-BBN Br 9-BBN Pd(0) cat., base OTPS TBSO OMe OMe 9-BBN 9-BBN OTPS TBSO CH(OMe)₂ 3 S N I OAc PdCl₂(dppf) cat

application to the synthesis of epothilone A

PdCl₂(dppf) cat CsCO_3, AsPh₃ H₂O, DMF S N OAc CH(OMe)₂ OTBS OTPS 71% yield S N O OH O O OH epothilone A

the Stille cross-coupling reaction.

The Stille reaction involves the palladium-catalyzed cross-coupling of organostannanes with electrophiles such as organic halides, triflates, or acid chlorides. The coupling of the two carbon moieties is stereospecific and regioselective, 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 in syntheses 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(PPh}

3)4, (MeCN)2PdCl2. 43 R = aryl, vinyl L₂Pd(0) R1-X L₂Pd R1 X oxidative addition L2Pd R1 R2 transmetallation reductive elimination (II) R2 R1 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 from tin to carbon are those with proximal π-bonds such as alkenyl-, 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 efficient synthesis of pleraplysillin-1 (isolated from a marine sponge) TfO Pd(PPh ) cat. Bu I + CO2Et Bu3Sn PdCl₂(CH₃CN)₂ cat DMF, rt Bu CO2Et 65% yield I MeO2C + N Bu3Sn PdCl2(PPh3)2 cat THF, 65 °C MeO2C N 95% yield SnBu3 O + TfO Me Me Pd(PPh₃)₄ cat. LiCl, THF, 70 °C Me Me O 75% yield - enediyne construction system for the dynemicin total synthesis

TeocN O I H OH OH Me I Me₃Sn SnMe₃ 5 mol% Pd(PPh3)4 DMF, 75 °C TeocN O H OH OH Me NH O H CO2H OH Me OH O

- carbonylative Stille cross-coupling

When the Stille reaction is carried out under a CO atmosphere, the carbonylative coupling proceeds with carbon monoxide insertion; namely, carbonyl insertion into the Pd–C bond of the oxidative addition complex.transmetalation, followed by cis-trans-isomerization and reductive elimination, generates the ketone product. L2Pd(0) R1-X L2Pd R1 X oxidative addition reductive elimination R2 R1 O O

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

LnPd R1 + CO L(n-1)Pd R1 CO LnPd + L O R1 45 L2Pd X L₂Pd C X transmetallation _(II) CO carbon monoxide insertion O R1 R2 SnR₃ X SnR₃ L₂Pd C R2 O R1 Me OTf SnMe3 Pd(PPh3)4 cat. LiCl / CO (1 atm) THF, 50 °C Me O 78% yield X LnPd X L(n-1)Pd X LnPd - L I + Ph Bu₃Sn PdCl₂(CH₃CN)₂ cat CO, THF, 50 °C 65% yield Bu Bu O Ph

the Sonogashira cross-coupling reaction.

H

R1 +

X _{Pd(0) cat., CuI cat.} base

R1

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

L₂Pd(0)

Ar-X

Catalytic cycle

Pd sources : Pd(PPh₃)₄or (PPh₃)₂PdCl₂.

Solvents : without solvent (the amine was used as reagent

Ar-X L2Pd Ar X L2Pd Ar H R1 CuX Cu R1 Et₃N R1 CuX transmetallation (II) R1 Ar oxidative addition reductive elimination Pd sources : Pd(PPh₃)₄or (PPh₃)₂PdCl₂.

Solvents : without solvent (the amine was used as reagent and as base) or THF or CH2Cl2

CuI / Et3N (or other amines)

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

HN N H O O I + H SiMe₃ 0.5 mol% PdCl2(PPh3)2 0.5 mol% CuI Et₃N, AcOEt HN N H O O SiMe3 93% yield NaOH HN N H O O H eniluracil HN N H O O F 5-fluorouracil - synthesis of lipoxin A₄. Me Br OTBS + CO2Me OTBS TBSO 47 Me Br 1 mol% Pd(PPh3)4 16 mol% CuI PrNH₂, benzene, rt OTBS Me CO₂Me OTBS TBSO 96% OH Me CO₂H OH HO (5S, 6S, 15S)-lipoxin A₄

- cascade reactions in the total synthesis of frondosin B.

OH I OMe + CO₂Me Me PdCl₂(PPh₃)₂ cat. CuI cat. Et3N, DMF, rt _OH OMe CO₂Me Me 50 °C _O MeO CO2Me Me O HO Me Me Me frondosin B

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

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

R1 X + R2 M [Pd] cat. R1 R2 + X M M = ZnCl, AlR2, Zr(Cl)Cp2 L₂Pd(0) R1-X R1 oxidative addition R2 Catalytic cycle L₂Pd R1 X L2Pd R1 R2 transmetallation reductive elimination (II) R2 R1 R2 M X M

OAc OMe I OHC i-Pr2Zn (0.55 equiv) NMP, rt Li(acac) (0.1 equiv) OAc OMe Zn OHC ₂ C₆H₁₁ O Cl 2.5 mol% Pd₂(dba) 5 mol% P(furyl)₃ OAc OMe OHC O 75% yield

- Negishi cross-coupling reaction : applications.

I Br + BrZn SiMe3 2 mol% Pd(PPh₃)₄ THF, rt SiMe₃ Br 81% yield 49 O O Me MeO MeO Cl Me₂Al Me Me Me 2 + 2 mol% Pd(PPh₃)₄ THF, 0 °C O O Me MeO MeO Me Me Me 2 coenzyme Q_s Me Ph OMe Me Cp₂Zr(H)Cl THF, 50 °C Ph OMe Me Zr(Cl)Cp₂ Me H hydrozirconation Cp2Zr(H)Cl = Schwartz reagent Ph OMe Me Me OTBS Me NHBoc OTBS Me NHBoc I Pd(PPh₃)_4, dry ZnCl₂ 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 + R1NHR2 NR1R2 [Pd] cat. base base

X

Best catalytic system

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

Ligand = dppf,

- process scale synthesis of a pharmaceutical intermediate (Astra Zeneca) N H Ph Me Me Br + N H N Me 0.5 mol% Pd₂(dba)₃ 1.5 mol% BINAP NaOt-Bu, Tol, 100 °C N H Ph Me Me N N Me 95% yield 125 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% Pd₂(dba)₃ 1.5 mol% BINAP NaOt-Bu, Tol, 100 °C NH F3C Me CN N H F3C N Me MeO₂C CF₃ CF₃

- double N-arylation : synthesis of Mukonine

MeO2C OMe OTf OTf 2 mol% Pd₂(dba)₃ 10 mol% XantPhos K₃PO₄, xylene, 100 °C BocNH2 NBoc MeO₂C OMe NH MeO₂C OMe TFA Mukonine O Me Me PPh₂ PPh₂ XantPhos

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 formation of new carbon-carbon or carbon-hetero bonds with control of both regio and stereochemistry.

R1 OAc _{+ R}2 _M [Pd] cat. R1 R2 + AcOM L₂Pd(0) oxidative R1 OAc R1 Catalytic cycle Pd source : Pd(PPh ) . 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 malonate type anions, other soft nucleophiles as anions from nitromethane, enolates, and enamines.

The palladium-mediated allylation proceeds via an initial oxidative addition of an allylic substrate to Pd(0). The resultant 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. With

- Tsuji-Trost reaction : the stereoselectivity.

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

inversion operates with soft stabilized nucleophiles. In the presence of hard nucleophiles

the reaction occurs with

- Tsuji-Trost reaction : examples. Me Me Me OAc geranyl acetate Me Me Me neryl acetate OAc + _HC CO2Me SO₂Ph Na _{Pd(PPh3)4 cat} THF, 65 °C Me Me Me Me Me Me CO2Me SO2Ph SO₂Ph CO2Me OAc OAc CO2Me O Me _{7 mol% Pd(PPh} 3)4 NaH, THF, 65 °C O Me CO2Me 99% yield AcO O CO2R E E E = CO₂Me Pd2(dba)3 / PPh3 NaH, THF, 65 °C O CO2R E E H H H only cis

- π-trimethylene methane cyclization. Me CO2Me + SiMe3 OAc Pd(PPh3)4 / dppe THF Me CO2Me SiMe3 OAc L2Pd(0) SiMe3 PdL2 OAc PdL2 C6H11 O OMe PdL2 H11C6 OMe O C6H11 CO₂Me PdL₂ 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, DMF

Me R

O

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

R Cu(+2)

Cu(+1) O₂ + HCl

PdCl₂

Regioselectivity : Markonikov addition usually

Catalytic cycle R PdCl₂ H₂O O R PdCl₂ H H R Pd(H)Cl OH Me O HCl nucleophilic attack ββββ-H elimination oxidation Cu(+2) Pd(0)

Regioselectivity : Markonikov addition usually observed. Anti-hydroxypalladation : R R CH₃ R CHO O no formed R Pd Cl Cl H2O O H H anti Pd Cl Cl H2O R OH

- Wacker reaction: examples.

O

PdCl2 cat, CuCl2 cat O₂, DMF / H₂O

O O

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

H H O

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

57

O

O _OTBS

PdCl2 cat, CuCl cat O2, DMF / H2O

O

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

most common catalysts in metathesis of olefins

PCy3 Ru PCy₃ Ph Cl Cl Ru PCy₃ Ph Cl Cl N N _Mes Mes N Mo Ph i-Pr i-Pr Me Me O O F3C CF₃ Me F3C

Nobel Prize in Chemistry 2005

"for the development of the metathesis method in organic synthesis"

PCy₃ PCy₃ [Ru]-2 [Ru]-1 first generation Grubbs catalyst second generation Grubbs catalyst Me Me CF3 F3C Me [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 R1 R2 + R1 R2 + C2H4 CM [M] H₂C CH₂ [M] X [M]

RCM= Ring Closing Metathesis ROM= Ring Opening Metathesis

ROMP = Ring Opening Metathesis Polymerization

ADMET = Acyclic Diene Metathesis Polymerization

CM = Cross Metathesis

All of the above reactions are reversible, so equilibrium mixtures are obtained. To produce high yields of a given product a suitable driving force must be present.

• Cross metathesis: Mixtures of products are produced unless a volatile byproduct (ethylene) is produced that can be removed from the reaction mixture.

• RCM is favored for the production of unstrained rings and is driven both entropically and by the elimination of a volatile alkene.

- the RCM reaction : examples. C₈H₁₇ + C13H27

[Ru]-1 cat

C₈H₁₇ C13H27 + H₂C CH₂ + other products

commercial synthesis of house fly pheromone

N O R N O R ( )n 3 mol% [Ru]-1 ( )n PhH, rt, 1 h n = 0, 78% n = 1, 93% O O OH N S H OH [Ru]-1 O O OH N S H 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 linkage posses groups that can form coordinate-covalent bonds with the metal atom. The free amino and carboxy group bind to the metal affecting the enzymes structure resulting in its active conformation .

Metals main function is to serve in electron transfer. Many enzymes can serve as electrophiles

and some can serve as nucleophilic groups. This versatility explains metals frequent occurrence in 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, a bifunctional protein that plays a critical role in the regulation of post-translational processing and protein synthesis.The MetAP2 catalyzes release of N-terminal amino acids, preferentially methionine, from peptides and arylamides. Methionine aminopeptidases (MetAPs) are the enzymes responsible for the removal of methionine from the amino-terminus of newly synthesized. The removal of methionine is essential for further amino terminal modifications (e.g., acetylation by N-alpha-acetyltransferase and myristoylation of glycine by N-myristoyltransferase, NMT) and for protein stability. H2N H N O Pept O R1 S Me MetAP2 H2N H2N O Pept O R1 S Me OH +

Active site with an irreversible inhibitor(fumagilline) His 231 Asp 251 Asp 262 Glu 364 Glu 459 His 331 Fumagilline covalent bond O O OCH₃ CH₃ O H CH₃ CH₃ O CO₂H 3 fumagillin The fumagillin was found to inhibit the

angiogenesis process (construction of new blood vessels). The MetAP2 was identified as biological target of the fumagillin. The formation of a covalent bond between the fumagillin and the MetAP2 was catalyzed by the presence of two cations of Manganese (Mn2+_{) which act as Lewis}

The Carbonic Anhydrases (CAs).

Carbonic anhydrases (CAs), a group of ubiquitouly expressed metalloenzymes are involved in numerous physiological and pathological processes, including gluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth and virulence of various pathogens. Furthemore, recent studies suggest that CA activation may provide a novel therapy for Alzheimer’s disease.

CAs catalyse the following reaction : CO2 + H2O

Definition : in organocatalysis, a purely organic and metal-free small molecule is used to catalyze a chemical reaction.

This approach has some important advantages :

- small organic molecule catalysts are generally stable and fairly easy to design and synthesize.

- 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 industrial applications.

Organocatalysts can be broadly classified as Lewis bases, Lewis acids, Brønsted bases, and Brønsted 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 O NH R2 R1 + H+ R1_N R2 - H+ R1_N R2 O H A

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

active the carbonyl group

Chiral centerasymmetric synthesis Abundant end cheap material

Proline as catalyst for the aldol reaction – proposed mechanism

O + H O R N H CO₂H (30 mol%) DMSO OH R O 54 - 97% yield 60 - 96% ee R = aryl or i-Pr

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

67

Proline as catalyst for the aldol reaction – comparaison with various organocatalyst O O O pyrrolidine derivatives solvent, rt OH O O

Proline as catalyst : examples H Me O "2 equiv" 10 mol% L-Proline DMF, 4 °C H O Me Me OH 80% yield 4 : 1 anti : syn 99% ee (anti) H O + H O 10 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/CH₂Cl₂ 61% (two steps) Me -78 °C, 65% Me O O HO Me 48% HF, H2O, CH3CN 4.5 h, rt, 55% (-) Prelactone B Tetrahedron 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% yield

Proline and derivatives as catalysts N H CO2H _N H NH Bn Bn Ar OTMS Ar N H CO2H Me N H _{HN N} N N

the MacMillan catalysts

N Bn O Me Me N Bn O Me Me

the MacMillan catalysts

N H Bn Me Me .HCl N H Bn .HCl Me Me O O R1 N N H Bn O Me Me Me .HCl (5 mol%) THF, rt O R1 O 85-99% yield 80-97% ee

MacMillan as catalysts : examples

H-bonding catalysis : examples of the chiral phosphoric acid

Boc _{2 mol% cat}

CH2Cl2, rt, 1 h + Me Me O O R1 NH Boc O Me Me O > 94% yield, > 92% ee N 10 mol% cat Tol, -78 °C, 24 h + NH O OH OEt OTMS H OH R1 H Tol, -78 °C, 24 h R1 OEt > 97% yield, > 88% ee OEt R2 R2

ENZYMES AS CATALYSTS

Enzyme-catalyzed chemical transformations are now widely recognized as practical alternatives to traditional organic synthesis, and as convenient solutions to certain intractable synthetic problems.

Typical enzyme-catalyzed transformations

Enzymes commonly used in organic synthesis

Examples of applications

- synthesis of a new [beta]-lactam.

H₂N O O CO₂Me _H N O O PhO H_N O NH₂

- resolution of racemic mixture of alcohols.

R1 R2 OH _{lipase or esterase} + O Me O R1 R2 OH + R1 R2 OAc N O CO2H Penicillin G acylase _O N CO2H O N O O Cl CO2H Loracarbef (antibiotic)

- a representative chemgenzymatic preparation of cyclic imine sugars.

Me CHO N₃ OH + OPO3 2-O HO 1- aldolase 2- phosphatase Me N₃ OH OH OH O OH H₂, Pd/C, HCl O OH HCl.H₂N _OH NaOH N _OH OH Me