MASTE 2 Molecular Chemistry dicinal Chemistry Université de ennes 1 Vietnam ational University, anoi CATAYSIS F TE SYTESIS F BIACTIVE CMPUDS Prof. Pierre van de Weghe e-mail : pierre.van-de-weghe@univ-rennes1.fr 2011-2012
ITDUCTI T CATAYSIS An example Synthesis of osartan (marketed by rck & Co), an angiotensin II receptor antagonist drug used to treat high blood pressure (hypertension). KEY STEP : A PAADIUM-CATAYZED CSS-CUPIG EACTI Bu Cl + Br catalytic amount! CPh 3 5 mol% Pd(PPh 3 ) 4, K 2 C 3 TF - 2 B() 2 then 3 + Bu Cl new aryl-aryl bond losartan What is the mechanism of this reaction? What is the role of the palladium and the base? 2
ITDUCTI T CATAYSIS 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 A A + B A + B slow [cat] C + D C + D [cat] activation [cat]-a reaction [cat] 1- transition metal complex 2- organic molecule 3- enzyme C + D B 3
ITDUCTI T CATAYSIS 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 ( G 1 >> G 2 ). - a catalyzed reaction can eventually involve one or several reaction intermediates (for instance, one intermediate in the right figure above). 4
ITDUCTI T CATAYSIS Three different modes of catalysis transition metal complexes as catalysts Mosanto's approach Ac C 2 Ac 1-2, [cat] 2- deprotection C 2 3 (S)-DPA treatment of Parkinson's disease [cat] = Ph P h() 2 P Ph organic molecules as catalysts or organocatalysis Et 2 C C 2 Et Bn 2 - TFA (cat.) epidopteran sex pheromon enzymes as catalysts reductase in yeast Et S Et major product Et minor product ethyl acetoacetate 3-hydroxy-ethylbutanoate 5
PAT 1 TASITI META CMPEXES AS CATAYSTS 6
TASITI META CMPEXES AS CATAYSTS rganic versus rganometallic reactivity 7
TASITI META CMPEXES AS CATAYSTS What is a transition metal? A transition metal = an element with valence of d- or f-electrons. 8
TASITI META CMPEXES AS CATAYSTS Transition metal valence electron count Fe for free (gas phase) transition metals: (n+1)s is below (n)d in energy. 4s 2 3d 6 C C Fe C = 3d 8 C C 3d 8 for complexed transition metals: the (n)d levels are below the (n+1)s and thus get filled first. Cl Fe ΙΙ Cl 3d 6 for oxidized metals, substract the oxidation from the group 8. 9
TASITI META CMPEXES AS CATAYSTS Transition metal valence orbitals 10
TASITI META CMPEXES AS CATAYSTS The 18-electron rule ecall : 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. rganometallics 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. There are exceptions to this rule! 11
TASITI META CMPEXES AS CATAYSTS Electron counting Two models for counting electrons: the colvalent and ionic models. Both give the same answer, but offer different advantages and disavantages. Example: C 4 covalent model: since C- 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. C C : 4x1 e = 4 C : 4 e Total = 8 electrons 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- bond, this is the carbon. C 4 C + : 4x0 e = 0 C (-4): 8 e Total = 8 electrons Similarly for a transition metal complex, the electron count is the sum of the metal valence electrons + the ligand centered electrons. 12
TASITI META CMPEXES AS CATAYSTS Covalent model : VE= nb metal electrons + nb ligand electrons complex charge (VE = umber of Valence Electrons) tal = the number of metal electrons equals it s row number examples: Ti = 4e, Fe = 8e, Pd = 10e igands = in general 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) Ionic model : VE= nb metal electrons (d n ) + nb ligands electrons tal = 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. igands = in general 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. 13
TASITI META CMPEXES AS CATAYSTS rganometallic ligands :.. Crabtree, The rganometallic Chemistry of the Transition tals (fourth edition), John Wiley & Sons, 2005 Most common ligands found in classical transition metal complexes in catalysis : ligands type (2 electrons in CM) : P 3, C, 3, alkenes, C, 1 ligands type X (1 electron in CM) : I, Br, Cl,,, Ar, Ar C Ar C 14
TASITI META CMPEXES AS CATAYSTS Electron counting and oxidation state: - procedure for a neutral complex M l X x VE = n + 2l + x oxidation state = x n = nb electrons metal, l = nb of ligands, x = nb of ligands X - procedure for complex with charge [M l X x ] q VE = n + 2l + x q oxidation state = x + q n = nb electrons metal, l = nb of ligands, x = nb of ligands x, q = complex charge PPh 3 Cl h PPh 3 PPh 3 covalent model h : d 9 = 9 e 3 x PPh 3 : 3 x = 6 e 1 x Cl : 1 x X = 1 e oxidation state : 1 x X = +Ι ionic model h + : d 8 = 8 e 3 x PPh 3 : 3 x = 6 e 1 x Cl - : 2 e total = 16 e, +I () PPh 3 () PPh 3 () () Cl h PPh 3 Cl h PPh 3 (X, 1 e) (X, 2 e) () PPh 3 () PPh 3 15
TASITI META CMPEXES AS CATAYSTS Electron counting and oxidation state: Fe di(cyclopentadienyl)iron (ferrocene) covalent model Fe : d 8 = 8 e 2 x Cp : 2 x ( 2 X) = 2 x (2 x 2 + 1) = 10 e oxidation state : 2 ligands X, 0 charge = +ΙΙ ionic model Fe 2+ : d 6 = 6 e 2 x Cp - : 2 x 6 = 12 e total = 18 e, +ΙΙ C C C C Cr C covalent model Cr : d 6 = 6 e 5 x C : 5 x = 10 e 1 x : 5 x X = 1 e charge : -1 e oxidation state : 1 x X + 1 x (-1) = 0 ionic model Cr : d 6 = 6 e 5 x C : 5 x 2 = 10 e 1 x - : 2 e total = 18 e, 0 PPh 3 Ph 3 P Pd PPh 3 PPh 3 covalent model Pd : d 10 = 10 e VE = 10 + 2 x 4 = 18 e oxidation state : 0 x X = 0 ionic model Pd : d 10 = 10 e VE = 10 + 2 x 4 = 18 e total = 18 e, 0 training = PdCl 2 (PPh 3 ) 2, Mn(C) 5, Au() 3 (P 3 ). 16
TASITI META CMPEXES AS CATAYSTS 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- 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. ften this leads to sterically less favorable geometries for electronic reasons (e.g. C = 4, d 8, 16 e complexes prefer a square planar geometry). STEICS C = 2 C = 3 C = 4 M M M linear trigonal planar tetrahedral C = 5 M C = 6 M trigonal bipyramidal octahedral (C = coordination number) EECTICS M M M T-shaped square planar square pyramidal 17
TASITI META CMPEXES AS CATAYSTS Main classes of reactions around the transition metal ligand substitution - M l [M l-1 ] oxidative addition & reductrice elimination + 1 M l-1 1 A B [M] [M] A B [M] A B VE (M) < or = 16 e ; o.s. VE (M) + 2 ; o.s. + 2 insertion & elimination [M] A + B B [M] A [M] B A X [M] C - X C [M] X C [M] X C [M] VE VE - 2 VE 18
TASITI META CMPEXES AS CATAYSTS igand 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 h(i)). Pt X + Y slow Y Pt X Pt Y X Pt X Y fast Pt Y + X -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. 1 M - 1 M 1 M + 2 1 M 2 + 2 + 2 1 M 2 1 2 M 19
TASITI META CMPEXES AS CATAYSTS xidative 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 n M m+ + VE B A nm (m+2)+ B VE+2 xidative 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 C 3 I, but few will reductively eliminate this compound. In contrast, M() usually undergo rapid reductive elimination, but oxidative addition of alkanes is much less common. 20
TASITI META CMPEXES AS CATAYSTS 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. - 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 in place of C, and where AB migrates to C followed by coordination of in place of AB are both known. C M A 1,1-insertion C B M A elimination B + - M A C B C M A B 1,2-insertion elimination M C A B + - M C A B 17
TASITI META CMPEXES AS CATAYSTS Applications : alkenes hydrogenation + 2 [cat] The Wilkinson s catalyst, a hodium complex : hcl(pph 3 ) 3 catalytic cycle Ph 3 P Cl h h = d 9 Ph 3 P PPh 3 VE (h) = 9 + (3 x 2) + 1 = 16 e = M 3 X o.s. = +Ι to have a good understanding of the mechanism of the reaction, it is well to determine the VE and o.s. of the metal at each stage of the catalytic cycle. reactivity = = > > > > 22
TASITI META CMPEXES AS CATAYSTS selective hydrogenation. h(pph 3 ) 3 Cl / 2 ydrogenation of olefins (and alkynes) can be carried out in the presence of functional groups such as C, 2 C,, C, 2, Cl, 1, C 2, C 2. stereoselective synthesis of (+)-biotin : an example of asymmetric hydrogenation. steps Ph 2 / [h] [h] = t-bu 2 P h(cd) P Fe Ph 2 Ph CD = cyclooctadiene = ligand 2 steps C 2 S (+)-biotin (onza industrial process) 23
TASITI META CMPEXES AS CATAYSTS stereoselective synthesis of aproxen : asymmetric hydrogenation. aproxen, a nonsteroidal anti-inflammatory drug C 2 2 (100 atm) u-biap (1 mol%) C 2 Cl 2, 50 C C 2 97% e.e. u-biap = PhPh P P u PhPh (oyori's catalyst, obel Prize 2001) industrial synthesis (Synthex) : non catalyzed synthesis (racemic approach) 24
TASITI META CMPEXES AS CATAYSTS Applications : alkenes reduction hydride transfer + 2 [cat] / base a uthenium complex : ucl 2 (PPh 3 ) 3 generation of the uthenium active species PPh 3 u Ph 3 P Cl PPh 3 u Ph 3 P Cl Cl PPh 3 Cl PPh 3 + B: + δ 2 δ + Ph 3 P PPh 3 u Cl Cl PPh 3 δ PPh 3 u Ph 3 P Cl PPh 3 + Cl +B: B: + Cl PPh - B + 3 -Cl PPh 3 Cl u PPh 3 u Ph 3 P Cl Ph 3 P Cl PPh 3 δ + :B catalytic cycle PPh 3 u Ph 3 P δ δ + Cl PPh 3 PPh 3 u Ph 3 P Cl PPh 3 PPh 3 u Ph 3 P Cl PPh 3 Ph 3 P PPh 3 u Cl PPh 3 PPh 3 Ph 3 P Cl u Cl PPh 3 = M 3 X 2 u = d 8 VE (u) = 8 + (3 x 2) + (2 x 1) = 16 e o.s. = +ΙΙ 25
TASITI META CMPEXES AS CATAYSTS asymmetric hydrogenation transfer : the oyori s ruthenium catalyst. in classical organic chemistry = erwein-ponndorf-verley / ppenauer reaction F 3 C cat i-pr Ph Ph u = d 8 P Cl 2 Ph VE (u) = 8 + (4 x 2) cat = u = M 4 X 2 + (2 x 1) = 18 e P Ph Ph Cl 2 Ph o.s. = +ΙΙ fluoxetine (antidepressant agent) catalytic cycle P P + Cl P P u Cl Cl u Cl 1 Cl 1 P P u Cl u 1 26
TASITI META CMPEXES AS CATAYSTS Applications : hydroboration of olefins + B [cat] B + anti-markovnikov B 2 2 / - Markovnikov ydroboration of olefins with catecholborane : the reaction catalyzed by the Wilkinson s catalyst (h(pph 3 ) 3 Cl) gives the Markovnikov product. classical hydroboration, recall : catalytic cycle 9-BB 2 2 / a 99 hex-1-ene 1 catalyzed hydroboration : Ph + B hcl(pph 3 ) 3 2 2 / a Ph application to asymmetric synthesis 27
TASITI META CMPEXES AS CATAYSTS diastereoselective catalyzed hydroboration. PPh 2 1- hcl(pph 3 ) 3 B 2-2 2, a 2-Ac 2, base Ac Ac 85% yield syn > 50:1 28
TASITI META CMPEXES AS CATAYSTS Applications : the palladium catalyzed reactions Generalities During the last decades, palladium-catalyzed reactions have emerged as versatile tools for the formation of carbon-carbon bonds, hydrogenation and oxidation. electronic configuration = 4d8 5s 2 or 4d 10 5s Pd 0 formal oxidation number = 0, +2, (+4) General principle review for fundamental transformations, see Tetrahedron 2000, 56, 5959. Pd-cat cross-coupling in total synthesis, see Angew. Chem. Int. Ed. 2005, 44, 4442. C-Pd activation modification(s) of the Pd complexed organic fragments C---Pd cleavage Pd A fundamental A "Pd" (recycling) + B 29
obel Prize of Chemistry 2010 ichard F. eck Ei-ichi egishi Akira Suzuki for palladium-catalyzed cross couplings in organic synthesis obel Prize 2010
obel Prize of Chemistry 2010 The eck cross-coupling reaction Br + 1 Pd(0) cat. base 1 (1968) obel Prize 2010
obel Prize of Chemistry 2010 The egishi cross-coupling reaction X + 1 ZnY Pd(0) cat. base 1 (1977) The Suzuki-Miyaura cross-coupling reaction X + 1 B Pd(0) cat. base 1 (1979) obel Prize 2010
obel Prize of Chemistry 2010 eck reaction egishi and Suzuki reactions obel Prize 2010
TASITI META CMPEXES AS CATAYSTS 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. 30
TASITI META CMPEXES AS CATAYSTS catalyst precursors. metal sources : Palladium is the most widely used metal for cross-coupling reactions, although there are examples of ickel, hodium 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 3 ) 4 = tetrakis(triphenylphosphine) palladium (most common complex) Pd 2 (dba) 3 or Pd(dba) 2 PdCl 2 (PPh 3 ) 2 PdCl 2 (C 3 C) 2 Pd(Ac) 2 Ph PdCl 2 training = determine VE and formal oxidation state (except Pd/C) dba = dibenzylideneacetone Ph 31
TASITI META CMPEXES AS CATAYSTS ligands. Palladium alone can catalyze the reactions, but usually only with reactive Ar-I substrates and/or high temperature. igands 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. C 3 P P 3 3 triphenylphosphine tri-o-tolylphosphine P 2 2 = Cy, t-bu P 3 P(t-Bu) 3 monodentate phosphines PPh 2 PPh 2 PPh 2 Ph 2 P Ph 2 P PPh 2 1,2-Bis(diphenylphosphino)ethane 1,3-Bis(diphenylphosphino)propane BIAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyle Fe PPh 2 PPh 2 dppf 1,1'-Bis(diphenylphosphino)ferrocene chelating phosphines 32
TASITI META CMPEXES AS CATAYSTS A new generation of ligands = the -heterocyclic carbenes (C) C are stronger electron donors than phosphines and they tend to have stronger M- bonds, thus they may give more stable catalysts. C 3 C 3 3 C 3 C. C 3 C 3 i-pr i-pr. i-pr i-pr 3 C 3 C. C 3 C 3 i-pr i-pr. i-pr i-pr C 3 Is IPr C 3 sis sipr eview Pd complexes of C as catalysts : Angew. Chem. Int. Ed. 2007, 46, 2768. 33
TASITI META CMPEXES AS CATAYSTS The eck reaction (obel Prize 2010). The eck 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. 1 -X + Pd(0) base 1 1 = or 2 Pd sources : PdCl 2, Pd(Ac) 2, Pd(PPh 3 ) 4. Bases : Et 3, C 3 C 2 a, K 2 C 3, ac 3. Solvents : TF, Toluène, DMF, DMA (in general under reflux). reactivity order in oxidative addition Ar-I > Ar-Tf > Ar-Br >> Ar-Cl Catalytic cycle Base : essential to capture the formation of X eview : Angew. Chem. Int. Ed. 1994, 33, 2379, and Chem. ev. 2003, 103, 2945. Pd 1 only syn-β--elimination 34
TASITI META CMPEXES AS CATAYSTS eck reaction = regioselectivity. Br + Alkene Pd cat. / base Product 100% 100% 100% 100% 80% 1% 100% 21% 7% C 2 C 20% 99% C 2 79% 93% eck reaction = stereoselectivity. In general, reactions of terminal olefins give a prepoderance of E product. TBS I + cat. Pd(Ac) 2, AgAc DMF, rt 70% TBS 100% E Chem. Eur. J. 2003, 9, 1129. Ar Pd X 1 2 syn-addition (X)Pd Ar (X)Pd β--elim 1 2 1 Ar 2 (syn) 1 2 Ar 35
TASITI META CMPEXES AS CATAYSTS eck reaction = applications. - UV-B sunscreen Br + Pd/C, a 2 C 3 MP, 180-190 C pilot scale - several tons - synthesis of Eleptritan or elprax (Pfizer, for the treatment of migraine headaches) 1- cat. Pd(Ac) S Br 2, P(o-Tol) 3 Et 3, C 3 C S + 2- cat. Pd/C, 2 - synthesis of aproxen (anti-inflammatory) Br < 0.05 mol% PdCl 2,, Et 3 C 2 30 bar pentan-3-one 2, 95 C 500 tons/year pentan-3-one precursor of C 2 =C 2 = i-pr PPh 2 36
TASITI META CMPEXES AS CATAYSTS eck reaction = β--elimination insertion - migration, case of cyclic ethers. Ph Pd +δ -δ I β- elim syn addition + I 0.01 mol% Pd(Ac) 2 Ph Pd(I) 2 Et 3, 100 C Ph only syn β- elim Ph Ph Ph Ph insertion β- elim Pd I Pd(I) 2 - synthesis of platelet activator factor antagonist + Ph expected obtained! I Pd Pd I I Ph insertion 2 Pd(I) Ph Pd(I) 2 I 2.5 mol% Pd(Ac) 2 / PPh 3 AcK, 80 C 2.5 mol% Pd(Ac) 2 / PPh 3 AgC 3, C 3 C, 80 C J. rg. Chem. 1990, 55, 407. 2 / Pt 2 37
TASITI META CMPEXES AS CATAYSTS eck reaction = β--elimination insertion - migration, case of allylic alcohols. Ar-I + 2 mol% Pd(Ac) 2 PPh 3, base Ar base = AgAc versus Ar base = aac Ar Pd I Pd I Pd I Pd I Pd I Ar Ar Ar Ar - synthesis of prostaglandin E2 kinetically favored but reversibly formed inclusion of Ag + prevents reversibility I C 5 11 TBS Pd(I)2 Pd()(I) - 2 Pd()(I) 5 mol% Pd(Ac) 2 Bu 4 Cl, DMF, rt (Jeffery's conditions) C 5 11 C 2 Pure & Appl. Chem. 1990, 62, 653. 38
TASITI META CMPEXES AS CATAYSTS 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-cisisomerization), and reductive elimination processes. X + 1 M [Pd] 1 + M X reactivity order in oxidative addition Ar-I > Ar-Tf > Ar-Br >> Ar-Cl General catalytic cycle 39
TASITI META CMPEXES AS CATAYSTS the Suzuki-Miyaura reaction (obel 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. X + 1 B Pd(0) cat. base 1 or X + 1 B Pd(0) cat. base 1 X = I, Br, Cl, Tf Catalytic cycle Ar 1 reductive elimination 2 Pd(0) oxidative addition transmetallation Ar 2 Pd (II) 1 2 Pd Ar X eview : Chem. ev. 1995, 95, 2457. applications in total synthesis : Tetrahedron 2002, 58, 9633 Ar-X a B B 1 + ax Pd sources : Pd(PPh 3 ) 4, PdCl 2 (PPh 3 ) 2. Bases : a 2 C 3, Eta, a, K, K 3 P 4, Et 3. Solvents : TF, toluene (presence of water possible). a B Main sources of organoboron reagents : B 1 B Ar boronic acids B B Ar boronic esters 40
TASITI META CMPEXES AS CATAYSTS - synthesis of Boscalid (polyvalent fongicide, BASF, > 1000 tons/years) Cl 2 Cl + B() 2 Cl Pd(PPh3)4 cat. Bu 4 Br, K 2 C 3 Toluene, 2 2 Cl Boscalid Cl - preparation of valuable intermediate (GlaxoSmithKline, 20 scale) t-bu Br t-bu C 2 Et + B() 2 Pd(Ac) 2 cat. P(o-Tolyl) 3 KC 3, 2, i-pr C 2 Et - kg-scale manufacture of dibenzoxapine (cascade reaction, 2 kg scale) () 2 B 2 Br Br Br I Pd(Ac) 2 cat. a 2 C 3 dioxane, 2 2 2.Cl 41
TASITI META CMPEXES AS CATAYSTS - Suzuki coupling of sp 3 nucleophiles (sp 2 sp 3 bonds) 9-BB 9-BB Pd(0) cat., base Br Br application to the synthesis of epothilone A S TBS TPS 9-BB 9-BB TBS 3 TPS C() 2 I Ac PdCl 2 (dppf) cat S S CsC 3, AsPh 3 2, DMF Ac C() 2 71% yield TPS TBS epothilone A eview Suzuki-Miyaura cross-coupling in natural product synthesis : Angew. Chem. Int. Ed. 2001, 40, 4545. 42
TASITI META CMPEXES AS CATAYSTS 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 (C, C2, C, ) 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. 1 X + 2 Sn 3 [Pd] 1 2 + 3 Sn X Catalytic cycle 2 1 reductive elimination 1 = acyl, allyl, aryl, vinyl, benzyl 2 = aryl, vinyl 2 Pd(0) 1 2 Pd (II) 2 oxidative addition transmetallation 2 Pd 1 1 -X X 2 Sn 3 X Sn 3 eview : mechanisms of the Stille reaction: Angew. Chem. Int. Ed. 2004, 43, 4704. short historical note : J. organometall. Chem. 2002, 653, 50. Pd sources : Pd(PPh 3 ) 4, (C) 2 PdCl 2. improved reactivity with CuI/CsF Solvents : TF, DMF (anhydrous) Best catalytic system : Pd 2 (dba) 3, AsPh 3, icl, TF 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 ( 2 ) : C C > C=C > Ar > C=CC 2 ArC 2 >> alkyl 43
TASITI META CMPEXES AS CATAYSTS Bu I + C 2 Et Bu 3 Sn PdCl 2 (C 3 C) 2 cat DMF, rt Bu C 2 Et 65% yield 2 C I + Bu 3 Sn PdCl 2 (PPh 3 ) 2 cat TF, 65 C 2 C - short efficient synthesis of pleraplysillin-1 (isolated from a marine sponge) 95% yield SnBu 3 Tf + Pd(PPh 3 ) 4 cat. icl, TF, 70 C 75% yield I I - enediyne construction system for the dynemicin total synthesis Teoc 3 Sn Sn 3 5 mol% Pd(PPh 3 ) 4 DMF, 75 C Teoc C 2 TBS TBS 81% yield 44
TASITI META CMPEXES AS CATAYSTS - carbonylative Stille cross-coupling When the Stille reaction is carried out under a C 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. 2 1 reductive elimination C 2 Pd 1 2 X Sn 3 transmetallation 2 Sn 3 2 Pd(0) 1 -X oxidative addition C 2 Pd (II) X 1 1 2 Pd X C A similar carbonylation could be carried out in the Suzuki-Miyaura cross-coupling reaction. n Pd carbon monoxide insertion 1 X + C - C (n-1) Pd 1 X + n Pd X 1 Tf Sn 3 Pd(PPh 3 ) 4 cat. icl / C (1 atm) TF, 50 C 78% yield Bu I + Ph Bu 3 Sn PdCl 2 (C 3 C) 2 cat C, TF, 50 C Bu Ph 65% yield 45
TASITI META CMPEXES AS CATAYSTS the Sonogashira cross-coupling reaction. The Sonogashira reaction has emerged as one of the most general, reliable, and effective methods for the synthesis of substituted alkynes. In addition to eck and Suzuki-Miyaura coupling reactions, Sonogashira reactions have been realized on an industrial scale as well. 1 + X Pd(0) cat., CuI cat. base 1 Ar Catalytic cycle 1 reductive elimination 2 Pd(0) Ar 2 Pd (II) oxidative addition 1 Ar 2 Pd X Ar-X Pd sources : Pd(PPh 3 ) 4 or (PPh 3 ) 2 PdCl 2. Solvents : without solvent (the amine was used as reagent and as base) or TF or C 2 Cl 2 CuX Cu 1 Et 3 transmetallation CuX 1 CuI / Et 3 (or other amines) to form the copper(i) alkynide eview : Chem. ev., 2007, 107, 874. 46
TASITI META CMPEXES AS CATAYSTS - 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. I + Si 3 0.5 mol% PdCl 2 (PPh 3 ) 2 0.5 mol% CuI Et 3, AcEt 93% yield Si 3 a eniluracil F 5-fluorouracil - synthesis of lipoxin A 4. TBS Br + TBS TBS C 2 1 mol% Pd(PPh 3 ) 4 16 mol% CuI Pr 2, benzene, rt 96% TBS TBS C 2 C 2 TBS - cascade reactions in the total synthesis of frondosin B. (5S, 6S, 15S)-lipoxin A 4 I + C 2 PdCl 2 (PPh 3 ) 2 cat. CuI cat. Et 3, DMF, rt C 2 50 C C 2 frondosin B 47
TASITI META CMPEXES AS CATAYSTS the egishi cross-coupling reactions (obel Prize 2010). The egishi 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. 1 X + 2 M [Pd] cat. 1 2 + X M M = ZnCl, Al 2, Zr(Cl)Cp 2 Catalytic cycle 2 2 1 2 Pd(0) oxidative addition 1 -X 1 2 Pd 1 X reductive elimination transmetallation 1 2 Pd (II) 2 2 M X M eview : Bull. Chem. Soc. Jpn 2007, 80, 233. 48
TASITI META CMPEXES AS CATAYSTS C - egishi cross-coupling reaction : applications. Ac I i-pr 2 Zn (0.55 equiv) i(acac) (0.1 equiv) MP, rt Ac C 2 Zn C 6 11 Cl 2.5 mol% Pd 2 (dba) 5 mol% P(furyl) 3 Ac C 75% yield I 2 mol% Pd(PPh 3 ) 4 Br + BrZn Si 3 TF, rt Br 81% yield Si 3 Cl + 2 Al 2 2 mol% Pd(PPh 3 ) 4 TF, 0 C 2 coenzyme Q s Ph Cp 2 Zr()Cl TF, 50 C Ph Zr(Cl)Cp 2 hydrozirconation Cp 2 Zr()Cl = Schwartz reagent Boc I TBS Pd(PPh 3 ) 4, dry ZnCl 2 TF, rt Ph Boc TBS 49
TASITI META CMPEXES AS CATAYSTS Carbon-heteroatom cross-coupling reaction : X + 1 2 1 Y Y = 1 2, 1, S 1 1 S the example of the Buchwald-artwig coupling reaction (C- bond formation). X + 1 2 base [Pd] cat. 1 2 Best catalytic system Pd 2 (dba) 3 or Pd(Ac) 2, igand, at-bu, Toluene rt to 100 C X igand = dppf, P(tBu) 2 P(Cy) 2 Catalytic cycle eview : Adv. Synth & Catal. 2004, 346, 1599. 50
TASITI META CMPEXES AS CATAYSTS - process scale synthesis of a pharmaceutical intermediate (Astra Zeneca) F 3 C Br Ph + 0.5 mol% Pd 2 (dba) 3 1.5 mol% BIAP at-bu, Tol, 100 C Ph 95% yield 125 kg scale - a cholesteryl ester transfer protein inhibitor, the Torcetrapib (Pfizer) (abandoned, excessive mortality during clinical trials) + Cl 2 C F 0.5 mol% Pd 2 (dba) 3 C 3 1.5 mol% BIAP at-bu, Tol, 100 C C 2 C CF 3 F 3 C CF 3 - double -arylation : synthesis of Mukonine 2 C Boc 2 2 C 2 C Tf Tf 2 mol% Pd 2 (dba) 3 10 mol% XantPhos K 3 P 4, xylene, 100 C Boc TFA Mukonine PPh 2 PPh 2 XantPhos 51
TASITI META CMPEXES AS CATAYSTS 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. owever, these reactions suffer from loss of regioselectivity because of competition between S 2 and S 2 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. 1 Ac + 2 M [Pd] cat. 1 2 + AcM 2 Pd(0) 1 Ac Catalytic cycle 1 2 2 Pd oxidative addition 1 2 2 Pd 1 2 M AcM Ac (M = a, K, i) Pd source : Pd(PPh 3 ) 4. Solvents : TF or DMF. ther possible leaving groups : C(), P() 2, Ph, Cl, Br. ucleophiles : 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 substituted allylic compounds, the palladium-catalyzed nucleophilic addition usually occurs at the less substituted side. The reaction is usually irreversible and thus proceeds under kinetic control. 52
TASITI META CMPEXES AS CATAYSTS - 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. C 2 Ac C 2 Pd(PPh 3 ) 4 cat. u C 2 (C 2 ) 2 / a TF Pd 2 C 2 C(C 2 ) The mechanism of double inversion operates with soft stabilized nucleophiles. In the presence of hard nucleophiles the reaction occurs with inversion of configuration. 53
TASITI META CMPEXES AS CATAYSTS - Tsuji-Trost reaction : examples. geranyl acetate neryl acetate Ac a + C C 2 S 2 Ph Ac Pd(PPh 3 ) 4 cat TF, 65 C C 2 S 2 Ph C 2 S 2 Ph Ac 7 mol% Pd(PPh 3 ) 4 C 2 a, TF, 65 C E E Pd 2 (dba) 3 / PPh 3 99% yield C 2 E E Ac C 2 E = C 2 a, TF, 65 C C 2 only cis 54
TASITI META CMPEXES AS CATAYSTS - π-trimethylene methane cyclization. C 2 + Si 3 Ac Pd(PPh 3 ) 4 / dppe TF C 2 11 C 6 Si 3 Ac 2 Pd(0) Si 3 Ac C 6 11 Pd 2 C 6 11 C 2 Pd 2 Pd 2 Pd 2 Ph + Si 3 Ph Ac Pd(PPh 3 ) 4 Toluen, reflux mixture of stereoisomers 55
TASITI META CMPEXES AS CATAYSTS The palladium-catalyzed oxidation reaction of terminal olefins : the Wacker reaction. 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 PdCl 2. [Pd(II)] cat, CuCl 2 cat. 2 atm, 2, DMF 2 + Cl Cu(+1) Cu(+2) oxidation PdCl 2 egioselectivity : Markonikov addition usually observed. Cl Pd()Cl Pd(0) β- elimination Catalytic cycle PdCl 2 PdCl 2 nucleophilic attack Cl 2 PdCl 2 C 3 C no formed Anti-hydroxypalladation : 2 Cl Pd Cl anti 2 Cl Pd Cl reductrice elimination 56
TASITI META CMPEXES AS CATAYSTS - Wacker reaction: examples. - The Wacker reaction could oxidize only the terminal olefin regioselective reaction. PdCl 2 cat, CuCl 2 cat 2, DMF / 2 - CuCl/ 2 could replace CuCl 2 to avoid chlorinated by-products. PdCl 2 cat, CuCl cat TBS 2, DMF / 2 TBS - Used also in intramolecular process. [Pd(II)] Pd(Ac) 2 Cu(Ac) 2, 2 [Pd(II)] 57
TASITI META CMPEXES AS CATAYSTS Applications : the metathesis of olefins 1 C C 4 C 2 + 3 C M=C 2 1 C C 4 C 3 + 2 C most common catalysts in metathesis of olefins i-pr CF 3 i-pr F 3 C Mo Ph F 3 C CF 3 [Mo] Schrock catalyst Cl PCy s s 3 Cl Cl u u Ph Cl Ph PCy 3 PCy 3 [u]-1 first generation Grubbs catalyst [u]-2 second generation Grubbs catalyst obel Prize in Chemistry 2005 "for the development of the metathesis method in organic synthesis" Y. Chauvin.. Grubbs.. Schrock 58
TASITI META CMPEXES AS CATAYSTS common metathesis olefins reactions and simplified catalytic cycle. tathesis = «change places» CM - C 2 4 M + C 2 4 ( ) n MP X M=C 2 X CM M=C 2 ( ) n ADMET - C 2 4 ( ) n ( ) n [M] X [M] X 1 CM + 2 1 2 + C 2 4 [M] CM = ing Closing tathesis M = ing pening tathesis MP = ing pening tathesis Polymerization ADMET = Acyclic Diene tathesis Polymerization CM = Cross tathesis 2 C C 2 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. CM is favored for the production of unstrained rings and is driven both entropically and by the elimination of a volatile alkene. M is only favored at very high olefin concentrations, or more commonly with strained olefins. X [M] 59
TASITI META CMPEXES AS CATAYSTS - the CM reaction : examples. C 8 17 + C 13 27 [u]-1 cat C 8 17 C 13 27 + 2 C C 2 + other products commercial synthesis of house fly pheromone ( ) 3 mol% [u]-1 n ( ) n n = 0, 78% Ph, rt, 1 h n = 1, 93% S S [u]-1 81% yield, E / Z = 9 / 1 desoxyepothilone A 60
TASITI META CMPEXES AS CATAYSTS talloenzymes : examples tals play roles in approximately one-third of the known enzymes. tals 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. tals 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. The thionine Aminopeptidase 2 (tap2). The thionine aminopeptidase 2 (tap2) is a metalloenzyme, a bifunctional protein that plays a critical role in the regulation of posttranslational processing and protein synthesis.the tap2 catalyzes release of -terminal amino acids, preferentially methionine, from peptides and arylamides. thionine aminopeptidases (taps) 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 -alpha-acetyltransferase and myristoylation of glycine by -myristoyltransferase, MT) and for protein stability. 2 S 1 Pept tap2 2 S + 2 1 Pept 61
TASITI META CMPEXES AS CATAYSTS Active site with an irreversible inhibitor (fumagilline) Glu 459 The fumagillin was found to inhibit the angiogenesis process (construction of new blood vessels). The tap2 was identified as biological target of the fumagillin. The formation of a covalent bond between the fumagillin and the tap2 was catalyzed by the presence of two cations of Manganese (Mn 2+ ) which act as ewis acids. C 3 C 3 C 3 C 3 C 2 3 fumagillin Glu 364 is 331 Asp 262 Asp 251 covalent bond Fumagilline is 231 mechanism of inhibition of tap2 with fumagillin 62
TASITI META CMPEXES AS CATAYSTS 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 : C 2 + 2 C 3 - + + is 94 Zn 2+ C 2 is 119 is96 is 94 C Zn 2+ is 119 is96 Active site - + B - B + is 94 Zn 2+ is 119 is 94 2 Zn 2+ is 119 is96 - C 3 + 2 is 94 Zn 2+ is 119 is96 is 96 63
PAT 2 GACATAYSIS 64
GACATAYSIS 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. rganocatalysts can be broadly classified as ewis bases, ewis acids, Brønsted bases, and Brønsted acids. Major reaction pathways : - via covalent activation complexes as enamine and iminium ion 1 2 + + 1 2 - + 1 2 - via noncovalent activation complexes as -bonding or ion pairing A eviews : Angew. Chem. Int. Ed. 2004, 43, 5138, Angew. Chem. Int. Ed. 2008, 47, 4638 and Drug Discovery Today, 2007, 12, 8. 65
GACATAYSIS The most common system : Proline (and derivatives) as catalyst Why Proline? Abundant end cheap material -proline Amine function to active the carbonyl group Chiral center asymmetric synthesis Proton delivery Proline as catalyst for the aldol reaction proposed mechanism + = aryl or i-pr C 2 (30 mol%) DMS 54-97% yield 60-96% ee Seminal work : J. rg. Chem. 1974, 39, 1615. chanism : Science 2002, 298, 1904. 66
GACATAYSIS Proline as catalyst for the aldol reaction justification of the enantioselectivity J. Am. Chem. Soc. 2000, 122, 2395. 67
GACATAYSIS Proline as catalyst for the aldol reaction comparaison with various organocatalyst pyrrolidine derivatives solvent, rt 68
GACATAYSIS Proline as catalyst : examples "2 equiv" 10 mol% -Proline DMF, 4 C 80% yield 4 : 1 anti : syn 99% ee (anti) + 10 mol% -Proline DMF, 40 h, 5 C then TBSCl, base Et 2 /C 2 Cl 2 61% (two steps) TBS Tetrahedron ett. 2003, 44, 7607 3 steps, 22% overall yield TBS Et BF 3.Et 2, C 2 Cl 2 Et -78 C, 65% (-) Prelactone B TBS 48% F, 2, C 3 C 4.5 h, rt, 55% + + 2 35 mol% -Proline DMS, rt, 12 h 57% yield 69
GACATAYSIS Proline and derivatives as catalysts C 2 TMS Ar Ar C 2 Bn Bn 1 the MacMillan catalysts Bn.Cl (5 mol%) TF, rt Bn 85-99% yield 80-97% ee 1.Cl Bn.Cl 70
GACATAYSIS MacMillan as catalysts : examples 71
GACATAYSIS -bonding catalysis : examples of the chiral phosphoric acid Boc 1 1 + + 2 mol% cat C 2 Cl 2, rt, 1 h Boc 1 > 94% yield, > 92% ee TMS 10 mol% cat Et Tol, -78 C, 24 h 2 1 Et 2 Ar P Ar > 97% yield, > 88% ee Bull. Chem. Soc. Jpn 2010, 83, 101. 72
PAT 3 EZYMES AS CATAYSTS 73
EZYMES AS CATAYSTS Typical enzyme-catalyzed transformations Enzyme-catalyzed chemical transformations are now widely recognized as practical alternatives to traditional organic synthesis, and as convenient solutions to certain intractable synthetic problems. Enzymes commonly used in organic synthesis 74
EZYMES AS CATAYSTS Enzymes commonly used in organic synthesis 75
EZYMES AS CATAYSTS Examples of applications - resolution of racemic mixture of alcohols. 1 2 + lipase or esterase 1 2 Ac + 1 2 - synthesis of a new [beta]-lactam. 2 C 2 Ph 2 C 2 Penicillin G acylase C 2 oracarbef (antibiotic) Cl C 2 - a representative chemgenzymatic preparation of cyclic imine sugars. 3 C + P 3 2-1- aldolase 2- phosphatase 3 2, Pd/C, Cl Cl. 2 a 76