ch3e4_stereoselective_synthesis_mw_handout_reorganised_021111.pdf

Year 3 CH3E4 notes: Asymmetric Catalysis, Prof Martin Wills Reorganised to highlight key areas to learn and understand. You are aware of the importance of chirality. This section will focus on asymmetric catalysis, i.e. the use of a catalyst to create new enantiomerically pure molecules. This can be...

Year 3 CH3E4 notes: Asymmetric Catalysis, Prof Martin Wills Reorganised to highlight key areas to learn and understand. You are aware of the importance of chirality. This section will focus on asymmetric catalysis, i.e. the use of a catalyst to create new enantiomerically pure molecules. This can be achieved in several ways: Introductory, no need to revise, but understand concepts. O O H t-butyl peroxide (oxygen source) Ti(OiPr)4 (metal for complex formation) OH Ti O O OH O 70-90% yield, >90% e.e. O HO CO2Et HO CO2Et O CO2Et Ti The oxygen atom is directed to the alkene. The alkene is above the peroxide. Ti O CO2Et CO2Et O O CO2Et Ti O O O O O (+)-diethyl tartrate (source of chirality) 2) A covalent intermediate may be formed: Proline catalyses the asymmetric cyclisation of a diketone (known as the Robinson annelation reaction). this is not a chiral centre O O Now this IS a chiral centreS configuration L-proline 10 mol%: N H CO2H O O Major product O Mechanism is via: O M Wills CH3E4 notes N O HO2C 1 Introductory, no need to revise, but understand concepts. 3) The reaction may take place within an asymmetric environment controlled by an external source: The chiral counterion controls the asymmetry of the reaction. E R Chiral Acid H E N H R R R N The asymmetric environment promotes reduction on one face of cation H O O P O OH R R N R O P H O O O N H R The key features of these approaches will be described and examples from the literature will be described. Some examples of enantiomerically pure drugs: F3C NH2 N NC F HN N Aprepitant (antiemetic) NHtBu Bn N CO2Et F N O O F HN H N N N NH CF3 O OH F F H N O CF3 Ly2497282 (Eli Lilly, diabetes) MeN AZ960 (AZ, anticancer) O N NHtBoc O Rivastigmine (Novartis, Alzheimer's) F M Wills CH3E4 notes F Takada (Renin inhibitor for hydpertension) 2 Oxidation reactions of alkenes. R1 R1 2 2 R1 O This represents a good way to create chiral centres. R OH R R3 Dihydroxylation 2 3 R R3 R1 OH R epoxidation 2 R OH NH2 3 R1 OH NH2 2 R3 R R aminohydroxylation Understand how each enantiomer of ligand gives a different product enantiomer. No need to memorise which way round it goes. The Sharpless dihydroxylation reaction employs ligand-acceleration to turn the known dihydroxyation reaction into an asymmetric version. This process depends on the use of an amine to accelerate a reaction: Dihydroxylation m R OsO4 RS RL Sharpless et al realised that enantiomericallyenriched amines could change this to an asymmetric reaction: OMe Rm OH RS RL OH use of the amine below speeds the reaction up: N ADmix-a contains a dimer of quinine '(DHQ)2PHAL' ADmix-b contains a dimer of quinidine '(DHQD)2PHAL)' (also a small amount of osmium salt + stoichiometric K3Fe(CN)6 OMe N N OH HO N AD-mix a contains DHQ (note both amine groups are of the same OMe absolute configuration): OMe N Dihydroquinine (DHQ) Dihydroquinidine (DHQD) 'psuedo enantiomers' N N N M Wills CH3E4 notes N N O O N 3 Understand how each enantiomer of ligand gives a different product enantiomer. No need to memorise which way round it goes. RL=large group, RM=medium group, RS=small group. Rm OH DHQD gives: L R HO R HO Ph 2 x 'OH' added to lower face. RS RL OH Rm How to remember:: OH OH DHQ gives: S Ph Rm ADmix-a (DHQ) Ph Ph RL ADmix-b Ph OH (DHQD) HO Ph in this orientation M Wills CH3E4 notes 2 x 'OH' added to upper face. 4 Oxidation reactions of alkenes. Learn the two possible mechanisms. No need to memorise examples. The mechanism may be one of a number of possibilities: AD-mix a (DHQ) A chiral complex may be formed, directing the reaction to one face in [3+2] cycloaddition: OMe N N HO O Os O O Ph O amine structure abbreviated OMe N N O O Os HO Ph O N N O O Os O Ph Ph O O O O or it could be a [2+2] cycloaddition, then ring-expansion. Os O Ph Ph O Ph Ph Ph HO OH Ph Hydrolysis and reoxidation. See if you can work out the mechanism. Most recent evidence favours the [3+2] addition mechanism: K. B. Sharpless et al, J. Am. Chem. Soc. 1997, 119, 9907. M Wills CH3E4 notes 5 Oxidation reactions of alkenes. No need to memorise the examples, but understand what the dihydroxylation achieves, and how versatile it can be. OH CO2Et 1 eq. MeSO2NH2 CO2Et CO2Et AD-mix-b, 0oC tBuOH/H2O OH (DHQD)2PHAL CO2Et (AD-mix-b) OH 92% ee OH 97% ee OH Cl OH 1 eq. MeSO2NH2 AD-mix-b, rt tBuOH/H2O Cl OH 98% ee nC6H13 (DHQD)2PHAL Me3Si SPh OH AD-mix-b, 0oC tBuOH/H2O M Wills CH3E4 notes OH AD-mix-b, 0oC tBuOH/H2O SPh OH 88% ee up to 96% ee with alternative ligand. OH 98% ee OH 1 eq. MeSO2NH2 AD-mix-b, 0oC tBuOH/H2O OH 97% ee Me3Si OH 1 eq. MeSO2NH2 nC6H13 (AD-mix-b) OH OH 93% ee Ph 1 eq. MeSO2NH2 AD-mix-b, 0oC tBuOH/H2O Ph 97% ee HO HO 6 Understand the concepts, no need to memorise examples on this slide. O C5H11 1 eq. MeSO2NH2 O O Diastereoselective reactions: O OH AD-mix-b, 0oC tBuOH/H2O O Si(tBu)Me2 1 mol% OsO4 Ph 3 eq. K3Fe(CN)6 O O 94% ee EtO2C (CH2)2N3 OsO4 + oxidant A:B with no ligand: 2:1 (DHQD)2PHAL: >20:1 (DHQ)2PHAL: 1:10 OH Ph (DHQD)2PHAL, 0oC, tBuOH/H2O Asymmetric dihydroxylation OH O OH OH A O (CH2)2N3 EtO2C OH 93% ee Sharpless aminodihydroxylation is a closely-related process (CH2)2N3 EtO2C B O O HN CO2Et TsN BnO OBn NClNa 4 mol% K2Os2(OH)4 5 mol% (DHQ)2PHAL, rt, tBuOH/H2O, 45% CO2Et OH TsN catalyst 5 mol% Jacobsen epoxidation of alkenes: H H N The iodine reagent transfers its oxygen atom to Mn, then the Mn tranfers in to the alkene in a second step. The chirality of the catalyst controls the absolute configuration. Advantage? You are not limited to allylic alcohols >15:1 regioselectivity, 93% ee But O tBu N Mn O O But I M Wills CH3E4 notes tBu O (hypervalnet iodine reagent) Source of oxygen. 7 Reduction reactions of Double bonds (C=C, C=N, C=O). This is a major area of asymmetric catalysis - atom efficient, low waste, low energy. H R4 H source R1 R1 R4 H source O H catalyst catalyst 2 3 2 3 2 R 3 R R R R R H source might be H2 gas, hydride, or an organic molecle (transfer hydrogenation) OH H R2 H source NR R3 R2 R3 NHR H catalyst R2 R3 Learn how a chiral environment is created around Rh(I) and how the enamine substrate co-ordinates. H PPh2 H PPh2 PPh2 PPh2 R P face edge O P PPh2 face O H Rh P P edge Chiral environment: R R DuPHOS (R=Me, Et etc) Chiraphos/Rh(I) H S-BINAP (often used with Ru(II) Rh/Diphosphine complex- ligands create a chiral environment at the metal R R P R BPE R R R P Rh R P P PPh2 R R DIOP/Rh(I) M Wills CH3E4 notes 8 Reduction reactions of Double bonds (C=C, C=N, C=O). Learn how a chiral environment is created around Rh(I) and how the enamine substrate co-ordinates. Understand that there is a difference in energy between the diastereoisomers which leads to enantioselectivity. Examples of generalised applications (specific examples to follow). MeOCHN CO2Me R3 MeOCHN H2 catalyst H H H2N CO2Me deprotect 2 R P Rh H R P H N + O R H H N P O Rh H CO2Me P R CO2Me R R or MeO2C P R3 R 2 R3 R R R CO2Me catalyst deprotect H2N H H CO2Me 2 R CO2H The acyl group co-ordinates to Rh, reducing flexibility in transition state. R H Two diastereoisomers may be formed, energy difference influences stereochemistry MeOCHN H2 MeOCHN R3 amino acid R3 R This isomer leads to product, with hydrogen transferred to back face as drawn. CO2H R3 R M Wills CH3E4 notes H H N Rh H P O The difference in reactivity may be due to extra stability of one diastereoisomer or increased activity of one of them. R 9 Reduction reactions of C=C Double bonds using Rh(I) complexes– representative examples. No need to memorise examples but understand that the sense of reduction in each case is relative to the directing group X. co-ordinating group MeOCHN CO2Me H MeOCHN 6.5 a tm H2 CO2Me MeOCHN (NHCOMe, OH, OCOMe etc) H X A X A 99.2% ee H 6.5 a tm H2 B C 0.2 mol % [Rh(A)]+ 25oC, benzene. CO2Me R3SiO CO2Me 1 atm H2 MeOCHN H 1 mol % [Rh(B]+ 20oC, ClCH2CH2Cl. R3SiO H NHCOMe Fe MeOCHN H 6.5 a tm H2 H CO2Me Single diastereoisomer 98.2% ee CO2Me Single diastereoisomer 95% ee H NHCOMe 25 at m H2 2 mol % [Rh(C)2]+ 20oC, ClCH2CH2Cl. Ph2P B 0.2 mol % [Rh(A)]+ 25oC, benzene. 97.2% ee MeOCHN Fe CO2Me MeOCHN P A PPh2 B H Addiition of hydrogen is relative to the co-ordinating group C 0.2 mol % [Rh(SS-DuPHOS)]+ (R=Et), 2h, MeOH. MeOCHN CO2Me P M Wills CH3E4 notes O N P O C P(C6H11)2 P(C6H11)2 D 10 Reduction reactions of C=C Double bonds using Rh(I) complexes– representative examples. No need to memorise examples but understand that the sense of reduction in each case is relative to the directing group X. O Directing O co-ordinating group (NHCOMe, OH, OCOMe etc) H X A X A B EtO2C C F3C P(C6H11)2 D Ph CF3 PPh2 P 99.8% ee H O CO2Me EtO2C 99 % ee O O 4 atm H2 P OMe OMe 0.8 mol % Ph [Rh(SS-DuPHOS)]+ (R=Et), rt MeOH. O O H O P OMe OMe 96% ee CF3 Fe E CO2Me 1.1 mol% [Rh(D)]+ EtOH. Directing P(C6H11)2 CO2Me 5 atm H2 H O 0.4 mol % [Rh(SS-DuPHOS)]+ (R=Et), 12h, DCM. Directing B H Addiition of hydrogen is relative to the co-ordinating group C O CO2Me 4 atm H2 CF3 Directing ButO2C O B O ButO2C 35 at m H2 5 mol% [Rh(E)]+ -5oC, toluene. M Wills CH3E4 notes H O B O 94 % ee 11 Reduction reactions of Double bonds using catalysts derived from Ru(II) (C=C). Learn that Ru(II) complexes of diphosphine ligands can also direct hydrogenations. No need to memorise examples. 1 atm H2 H3C CO2H 0.5 mol% [(R-BINAP)Ru(OAc)2] MeOH/DCM (5:1) MeO directing group MeO Directing groups on the substrate help to improve rates and enantioselectivity: (BINAP or similar biaryl ligands are generally favoured) H CO2H >97% ee H3C H 100 a tm H2 N O MeO 135 a tm H2 N MeO Ar H O 0.5 mol% [(S-BINAP)Ru(OAc)2] MeOH directing group O 1 mol% [(R-BINAP)Ru complex] MeOH, 50oC. O MeO MeO O H Ar >99.5% ee C2H5 F 5 atm H2 CO2H directing group 1 mol% [(R-BINAP)Ru complex] MeOH, 50oC. O H O C3H7 O O directing group N 100 a tm H2 F N H C3H7 O 0.2 mol% [(R-BINAP)Ru complex] DCM, 50oC. directing group H O C2H5 O 95% ee CO2H 90% ee M Wills CH3E4 notes 12 Reduction reactions of Double bonds using catalysts derived from Ru(II) (C=C). Learn that Ru(II) complexes of diphosphine ligands can also direct hydrogenations. No need to memorise examples. Allyliic alcohols provide a good example of how the directing group works. alcohol is directing group OH OH OH 0.2 mol% Ru(S-BINAP) 0.2 mol% Ru(S-BINAP) H2 Hydrogen on front face relative to OH H2 H H3C OH H3C H Hydrogen on front face relative to OH OH OH H CH3 M Wills CH3E4 notes 13 Reduction reactions of isolated C=C double bonds can be achieved with variants of Crabtree’s catalyst. Crabtree's catalyst works well on isolated (i.e. no nearby co-ordinating group) C=C, bonds: + N + PCy3 PF6- 4 R R PCy3 N Ir 1 Ir 2 R3 R H2 catalyst P(oTol)2 Ir(COD) O CH3 97% ee H CH3 N B((3,5-C6H3(CF3)2)4(BARF-) H CH3 CH3 B((3,5-C6H3(CF3)2)4(BARF-) 1 mol% catalyst C + CH3 MeO 89% ee 50 at m H2 rt, CH2Cl2 MeO CH3 S N C CH3 rt, CH2Cl2 A PPh2 Ir(COD) 92% ee 50 at m H2 CH3 Ir(COD) tBu + iPr H 0.1 mol% catalyst A CH3 PPh2 B N R3 R 1 mol% catalyst B B((3,5-C6H3(CF3)2)4- O H 2 The catalyst is prepared with a cycloactadiene (COD) ligand but this is hydrogenated at the start of the catalytic cycle. The 'parent' Crabtree catalyst is, of course, non-chiral. 50 at m H2 rt, CH2Cl2 + O O R4 CH3 + Ph H No need to memorise examples.No directing group required Asymmetric versions of the Crabtree catalyst (prepared as COD complexes, but with the COD left off for clarity): N R1 Ph PPh2 Ir(COD) D B((3,5-C6H3(CF3)2)4- OH CH3 M Wills CH3E4 notes 0.5 mol% catalyst D 50 at m H2 rt, CH2Cl2 OH H CH3 99% ee Steric control - not OH group. 14 Reduction reactions of isolated C=C double bonds can be achieved with variants of Crabtree’s catalyst. Understand that Ir(I) complexes with P and N donors can reduce double bonds without a directing group in substrate. No need to memorise examples. + O N Ph Particularly challenging application: P(oTol)2 Ir(COD) B B((3,5-C6H3(CF3)2)41 mol% catalyst B AcO R O Vitamin E precursor AcO 50 at m H2 rt, CH2Cl2 R R R O >98% RRR enantiomer. Each reduction is controlled by the catalyst i.e. it is not diastereocontrol. M Wills CH3E4 notes 15 Reduction reactions of C=O Double bonds using organometallic complexes. Understand that a C=O group can be reduced by a Ru or Rh complex as well. No need to memorise examples. The same principle regarding directing groups also applies to C=O reduction, Ru and Rh are most commonly used: O O H3C H OH 0.1 m ol% [(R-BINAP)Ru(OAc)2] OMe 86 atm H2 51h, 20oC, EtOH,100% O H3C OMe 99% ee directing group directing group O H3C O P 4 atm H2 OMe 72h, 25oC, MeOH,99% OMe H OH H3C O P OMe OMe >95% ee bromine is directing group O H3C Br 0.1 m ol% [(R-BINAP)Ru(OAc)2] 86 atm H2 H OH Br H3C o 62h, 20 C, EtOH,97% >92% ee M Wills CH3E4 notes 16 Reduction reactions of C=O Double bonds using organometallic complexes. Understand that a C=O group can be reduced by a Ru or Rh complex as well. No need to memorise examples. The same principle regarding directing groups also applies to C=O reduction, Ru and Rh are most commonly used: PPh2 RuBr2 O PPh2 1-2 m ol% H3C SPh H OH 30 atm H2 30h, rt, 100% H3C SPh 94% ee directing group 0.25m ol% N (C5H9)2P O H3C NMe2.HCl OP(C5H9)2 Rh(OCOCF3) 50 atm H2 18h, 20oC, PhMe, 100% 2 H OH H3C NMe2.HCl 99% ee 0.5mol% directing group H O NHMe.HCl H P Rh(I). P tBu But 10 atm H2 complex 18h, 50oC, MeOH, 92% H OH NHMe.HCl 99% ee directing group M Wills CH3E4 notes 17 Reduction reactions of C=O Double bonds using organometallic complexes. Dynamic kinetic resolution can result in formation of two chiral centres: Understand that a beta-keto ester can epimerise rapidly and that one enantiomer is more quickly reduced. Be able to draw the mechanism of this. No need to memorise examples. O Racemic! O R2 OMe 1 R H2 catalyst O O O R2 OMe R1 R2 H reduced very slowly O O OMe R1 enol O R2 OMe 1 R fast H OH O 2 R OMe Principle: The substrate is rapidly racemising and one enantiomer is selectively reduced: 1 H R Enantiomerically Pure M Wills CH3E4 notes 18 Reduction reactions of C=O Double bonds using organometallic complexes. Dynamic kinetic resolution can result in formation of two chiral centres: No need to memorise examples. O H OH O 4 atm H2 P OMe P OMe H3C 0.17 mol% OMe Ru/R-BINAP OMe H NHAc 65h, 25oC, MeOH 94% de >98% ee O H3C AcHN 88% de, 98% ee e.g. O O H3C Cl 90 at m H2 H OH 0.5 mol% H C OMe Ru/R-BINAP 3 5h, 80oC, DCM O OMe Cl H 98% de 99% ee O 100 a tm H2 O H3C OMe NHCO2Ph 1 mol% Ru/R-BINAP 20h, 50oC, DCM H OH H3C O OMe H NHCO2Ph 88% de 98% ee M Wills CH3E4 notes 19 Ketone reduction by pressure hydrogenation (i.e. hydrogen gas) can be achieved using a modified catalyst containing a diamine, which changes the mechanism. Understand that the mechanism changes when a diamine is added to a Ru(II)/diphosphine complex, and this allows C=O bonds to be reduced without a nearby directing group present. Be able to draw the mechanism of this. Ph2 P H Ru P Ph2 O H H2 N Ph N H2 Ph HO H Very high e.e. from very low catalyst loadings H2 , solvent Mechanism Ph O Me Ph2 P P Ph2 H Ru H H H N N H2 Ph OH Me H Ph Ph2 P P Ph2 Ph Ru H N N H2 H Ph Ph H2 M Wills CH3E4 notes 20 Ketone reduction by pressure hydrogenation (i.e. hydrogen gas) can be achieved using a modified catalyst containing a diamine, which changes the mechanism. No need to memorise the examples. O 0.2 mol% catalyst 2.5 mol% KOH 5 atm H2, EtOH, 5h, 100% H OH 97% e.e. M Wills CH3E4 notes OH O 0.2 mol% catalyst 0.24 mol% KOH 5 atm H2, iPrOH, 3.5h, 100% cis:trans 100:1 21 The use of hydride type reagents. H source O R2 R3 R R2 H source NR 2 catalyst OH H 3 R catalyst R3 Oxazaborolidines require a relatively high catalyst loading of 10%, But are effective in several applications. NHR H R2 H R3 N O Ph Ph Ph O B i) Borane (BH3), Me oxazaborolidine catalyst ii) hydrolysis (work up) How it works: HO H H Ph N O B Me O B H Concave molecule H H hydride directed to one face. Understand that hydride reagents can also be used in reductions. Understand how the mechanism of hydride transfer relates to the previous slide. Be able to draw the mechanism of the hydride transfer step. M Wills CH3E4 notes 22 The use of hydride type reagents. Understand that hydride reagents can also be used in reductions. Understand how the mechanism of hydride transfer relates to the previous slide. Be able to draw the mechanism of the hydride transfer step. More contemporary focus is on asymmetric transfer hydrogenation and on organocatalysis. Transfer hydrogenation – Ru catalysts. O edge/face interaction R activation Ru TsN Cl N Ph H substrate HCO2H, Et3N H Ru TsN Ph H Ph H N H Ru TsN N Ph H H O H N Ph Ph Ph Ru TsN H O H H R Ph HCO2H, (-CO2) Product R ee >96% full conversion Catalyst prepared by combining: Cl Ph NHTs and Ph NH2 Ru Cl Cl Ru Cl in iPrOH/KOH or HCO2H/Et3N Rh TsN H N Ph H Ph M Wills CH3E4 notes H Ir TsN H N Ph H Ph H Rhodium and iridium complexes are isoeletronic with Cp' on metal in place of arene. 23 Examples of reductions using transfer hydrogenation with metal complexes: add C=O and C=N reductions. These are examples to provide an appreciation of the scope, No need to memorise examples. O X H OH 0.5 mol% SS-Ru catalyst X=H, 98% ee X=Cl, 95% ee X=OMe 96% ee HCO2H/TEA 28oC, TsN X A wide range of substituents can be tolerated, except for orthogroups, which result in reduced selectivities. O Ph O Cl 99% ee HCO2H/TEA 28oC, 0 or 1 0 or 1 N Improved catalyst with a link between amine and arene ring. Following reactions are with this catalyst. Cl H Ph H OH 0.5 mol% SS-Ru catalyst Ru 0.1 mol% RR-Ru catalyst above HCO2H/TEA 28oC, X X=H, Cl, OMe typically 96% ee 0.1 mol% RR-Ru catalyst above O S S O2 Cl H OH 0.5 mol% SS-Ru catalyst HCO2H/TEA 28oC, N HCO2H/TEA 28oC, 98% ee S S O2 Precursor to jknown drug C4H9 0.5 mol% SS-Ru catalyst 0.6 mol% KOH, iPrOH 28oC, C4H9 H OH >99% ee X OH 98% ee X=O 97% ee X=S M Wills CH3E4 notes H OH Cl N up to 97% ee Other reduction products: H O Cl X (i.e. fused five or six-membered ring) O H OH H OH N H OH OPh 97% ee N 97% ee 24 These are examples to provide an appreciation of the scope, No need to memorise examples. TsN Ph MeO MeO N Ru N Some imines can also be reduced by asymmetric transfer hydrogenation: Cl H Ph 0.5 mol% RR-Ru catalyst HCO2H/TEA 28oC, Typically >96% ee MeO N NH MeO H Ar N H H Ph Typically >98% ee O Other ligands can be used with ruthenium(II) in asymmetric catalysis (and also with Rh and Ir), e.g. NH Ph N H Ar as above BocHN OH NH2 NH H2N Ph N H OH NH HN PPh2 Ph2P NHTs OH Challenging substrates: Excellent ligand for transfer hydrogenation. O H OH 0.5 mol% [RuCl2(arene)]2 1.25 mol% ligand O P O O P O 5 mol% NaOH, iPROH 28oC, 16h, 96% O O 0.5 mol% [RuCl2(arene)]2 90% ee H OH 1.25 mol% ligand 5 mol% NaOH, iPROH 28oC, 22h, 99% M Wills CH3E4 notes 99% ee 25 O Asymmetric transfer hydrogenation by organocatalysis. H H Inspired by Nature's NADH; a coenzyme which transfers hydride H H H CONH2 CONR2 CONR2 R2NOC OH H N R N N R Me Understand that Hantzsch esters are used as reagents for reduction of C=N bond in organocatalysis reactions. Be able to draw the mechanism of the hydride transfer step and the imine formation. No need to memorise examples. Use combination of a chiral acid with a hydride source: R H H O Homochiral acid (directs reaction) R=aryl ring, trialkylsilyl etc., usually a bulky group. Catalytic amount needed. O O O OH *OP P O + OH Mechanism: *O H R1 O R2 + N H O O R3 P H H R2NOC + OH condensation H 1 R N O *O P R3 O O Source of hydride - stoichiometric amount needed. Similar to NADH used in biological transformations. Known as 'Hantzsch ester'. H CONR2 R2NOC N H R (Either use a preformed imine or via reductive amination) CONR2 R2NOC CONR2 H 1 R N H H H R2NOC R2 close ion pair formed M Wills CH3E4 notes N R2 CONR2 O O *O P O 3 R Proton can be reused N H H N R1 H N H 26 R2 R3 Asymmetric transfer hydrogenation by organocatalysis. No need to memorise examples, but understand the concept. fully heteroaromatic rings can be reduced: Some examples of reductions: OMe OMe N 1 mol% cat where R=H HN 1.4 eq. Hantzsch ester Toluene, 35oC, 71h, 91% N H 93% ee OMe N 1 mol% cat where R=H 1.4 eq. Hantzsch ester Toluene, 35oC, 60h, 80% HN MeO 90% ee 90% ee MeO Ts N Asymmetric reductive amination: Ts N O H N H 2.4eq. Hantzsch ester toluene, 60oC, 12h MeO 95% MeO OMe H 1 mol% cat where R=bulky aryl + H2N M Wills CH3E4 notes 10 mol% cat where R= SiR3 HN H 1.2 eq. Hantzsch ester Toluene, 40oC, 48h, 90% + molecular seives 27 93% ee Formation of chiral centres by nucleophilic additions to unsaturated bonds. This slide is for information only and does not need to be memorised EtO C for the exam. EtO C Nu NHR Nu Nu OH NR O 2 2 R2 R2 R3 Diethylzinc additions NMe2 O Nu HO OH R3 Results: Et Et2Zn, toluene (solvent) H R2 R2 R3 H (-)-DAIB (see below) R2 R3 Nu mol% DAIB used (relative to Et2Zn Yield E.e. 0 (i.e. none) 0% - 2 (0.02 eq.) 97% 98 100 (1.0 eq.) 0% - Et2Zn NMe2 -EtH OH O H Zn O With excess Et2Zn, a dimer is formed. the dimer splits and enters the catalytic cycle: Me2 N Et2Zn Me2 N O PhCHO Zn Zn O O N Me2 N O Me2 N Zn Zn O O Zn Et2Zn PhCHO 2 DAIB of 15% ee will give a Another interesting Me fact: product of 95% ee! This is because the dimer made from one of each enantiomer is more stable, and does not split up to enter the catalytic cycle. O H Me2 N O Zn O M Wills CH3E4 notes + Zn reduction product! H Zn Ph H Ph H Ph H Ph H O H Zn O H H acid workup - CH2=CH2 R3 How come a little bit of amino alcohol catalyses the reaction, but a lot of it doesn't? Answers - the stoichiometric (100% ligand) reaction forms the wrong reactive species: Me2 N R2 Nu R3 Ph Ph Ph H Ph H acid workup H HO 28 Ph H Ph More applications of organocatalysis. Examples of common organocatalysts: Understand that the combination of a chiral amine and a ketone or aldehyde forms an enamine which directs a subsequent aldol reaction. Be able to draw the mechanism of the enamine formation, the reaction with a ketone or aldehyde and the subsequent hydrolysis step. No need to memorise examples. Some time ago, it was found that proline catalyses the asymmetric cyclisation of a diketone (known as the Robinson annelation reaction). this is not a chiral centre O O 10 mol%: N H O or pyrrolidines: Ph N H Ph Ph N H or other N-heterocycles: O NMe Ph Major product CO2H N H Now this IS a chiral centreS configuration L-proline CO2H L-proline N H CO2H O The enantiomeric compound is: O O O Mechanism is via: N O O HO2C M Wills CH3E4 notes 29 More applications of organocatalysis. No need to memorise examples. This is now the basis for many other reactions e.g.: O L-proline Aldols: O O 10 mol%: N H H H Me Me O CO2H 90% yield OH 4:1 anti:syn H Me DMF O N Me anti product e.e.: 99% O H H Me Me OtBu and even more complex ones: O O H2N H TBSO OTBS 20 mol% O CO2H O O OH 3 mol% water, rt 2 days. 68%, major product: D-fructose precursor O TBSO OTBS O These reactions take place via formation of an enamine which then reacts with the other reagent e.g. M Wills CH3E4 notes 30 More applications of organocatalysis which proceed via formation of an enamine – bonds to C atoms. These are examples to provide an appreciation of the scope, No need to memorise examples. C-N bond formation: L-proline CO2Bn O CO2H i) 10 mol%: N o H MeCN, 0 C N + H via: N CO2Bn nBu CO2Bn N H nBu 97% ee N ii) NaBH4, EtOH, 94% Ar= 3,5-(CF3)2C6H3 CO2Et i) 10 mol%: N DCM, rt. O + H N CO2Et N H Ar Ar O CO2Bn OH HO N NH2 H nBu amino acids. 97% ee O NH OTMS O via: O Cl Cl + H C5H11 5 mol% MeN Cl Cl Cl DCM, -24oC, 71% N N H Ph H + H ii) 20 mol%: tBu tBu Br Br C5H11 Cl N DCM, -24oCH Ar Ar OTMS ii) NaBH4, MeOH OH Cl Cl 95% ee Z-enamine, O orientated away MeN from dimethyls phenyl ring N blocks lower face H2O Cl C5H11 O O etc Cl Cl 1.2 eq. O But 92% ee O Cl O MeN O 1.2 eq. O N N nBu CO2Bn O ii) NaBH4, EtOH, 83% C-Halide bond formation: CO2H CO2Bn Cl Cl C5H11 Br tBu M Wills CH3E4 notes 31 Ph Cl C5H11 C=C reduction by organocatalysis. Understand that a chiral amine can direct a conjugate reduction reaction. Be able to draw the mechanism of the hydride transfer step and the imine formation and hydrolysis. No need to memorise examples. Asymmetric catalysis of C=C bonds can be catalysed by organocatalysts, if they are conjugated to a C=O: H General mechanism: R1 O 2 R N R1 H H N + H R H H 2 H R CONR2 R2NOC R + H CONR2 R2NOC NR2 R2 N N H R1 H H H2O R N H R1 O H R2 H H H H H R2NOC Source of hydride. CONR2 N H 20 C=C reduction by organocatalysis. No need to memorise examples. Examples: O H Ph O O H 10 mol% Bn Me N H H H 1.02 eq. EtO2C O O NMe H tBu Ph CO2Et H Me 90% ee H t-Bu O NMe H 5 mol% Me H H EtO2C 1.2 eq. H tBu N H t-Bu CO2Et Me H 90% ee N H N H O NMe 20 mol% O Bn N H H H tBu ButO2C 1.1 eq. O O CO2tBu tBu N H 20 Additions to C=O – aldol reactions are a very important class of synthetic reaction. Catalytic asymmetric aldol reactions can be directed by a chiral Lewis acid (ML*n), which initially binds to the electrophilic component the silyl enol ether is required as nucleophile (known as the 'Mukaiyama aldol' reaction: Me3 SIMe3 Si SiMe 3 O OH SiMe3 ML*n ML*n O O O O hydrolysis O O O R2 R3 3 R2 R H 2 R2 3 R2 R H H R R3 R1 1 H 1 R 1 1 R R ML*n R Silyl enol ether These slides are for information only and do not need to be memorised for the exam. However you should understand that addition of a silyl enol ether to an aldehyde can by catalysed by a Lewis acid. 22 mol% O BnO SiMe3 OBn + H N NMe H O H SiMe3 20 mol% Sn(OTf)2 20 mol% SnO MeCN, -78oC Open transitions states operate in this case, rather than chair-like cyclic ones: LnM Favoured approach leading to major BnO O product. H O HO Me3Si O OBn SiMe3 MLn MeO BnO O SiMe3 BnO Disfavoured by H steric clash. 97:3 syn:anti, 91% ee. Me3Si OBn O SiMe3 M Wills CH3E4 notes 34 Additions to C=O – aldol reactions are a very important class of synthetic reaction. This slide is for information only and do not need to be memorised for the exam. However you should understand that addition of a silyl enol ether to an aldehyde can by catalysed by a Lewis acid. 22 mol% O SiMe3 + EtS Me N Me O H R N H 20 mol% Sn(OTf)2 MeCN, -78oC O OSiMe3 EtS R Me Open transitions states operates again in this case and ligand determines overall face selectivity: LnM R=Ph, 93:7 syn:anti, O Favoured approach BnO 90% ee (syn) leading to major H R product. R=nC7H15, 100:0 syn:anti Me3Si O OBn >98% ee M Wills CH3E4 notes 35 Other examples of metal/ligand-catalysed asymmetric aldol reactions. This slide is for information only and do not need to be memorised for the exam. However you should understand that addition of a silyl enol ether to an aldehyde can by catalysed by a Lewis acid. O O N BBu Ts 20 mol% O SiMe3 + Ph N H O H R O MeCN, 14h, -78oC OSiMe3 Ph R R=Ph, 89% ee R=nC6H13, 93% ee No relative stereocontrol in this case, just absoluteby the catalyst. O 20 mol% OiPr O O t-Bu O SiMe3 + HO2C OiPr O H R EtO O O O B 3,5-(CF3)2C6H3 MeCN, -78oC O t-Bu SiMe3 + 20 mol% O N BBu Ts O H O R MeCN, 1h, -78oC O OSiMe3 EtO R 91-99% ee OSiMe3 R 93:7 syn:anti, 94% ee Although in some cases, the relative stereochemistry can be changed by a different combination of reagents: H OMe H Bn O N Si(tBu)Me2 MLn OMe OMe O O HO NMe O MeO O + OMe H OMe MeO OMe MeO O [(nBu)2Sn(OAc)2] BnO Favoured approach OBn Me3Si Sn(OTf)2 leading to major major product, 87% ee. CH2Cl2, -23oC product. Mukaiyama, Chem. Eur. J. 1999, 5, 121-161 Cycloaddition reactions can be catalysed by Lewis acid/chiral ligands. The ligand and metal choice can have a dramatic effect: Understand how a copper complex of the bis(oxazolidine) ligand can control the Diels-Alder reaction. Be able to draw the complex of Cu and Mg and illustrate which face the cyclic diene adds from. Be able to draw the product, which is of endo stereochemistry. Do not memorise examples. Cu complex is square planar tBu blocks lower face, Cp adds from other side 10 mol% O O X O O + N TfO O X N N X=CH2 98:2 endo:exo >98% ee Cu o OTf 18h, -78 C, CH2Cl2 O O Cu O O N X=O, 80:20 endo:exo 97% ee (endo) M Wills CH3E4 notes N N O O O O N X 37 Cycloaddition reactions can be catalysed by Lewis acid/chiral ligands. The ligand and metal choice can have a dramatic effect: No need to memorise examples, but understand how the selectivity is controlled. M Wills CH3E4 notes 38 There are many other similar catalysts for Lewis-acid catalysed Diels-Alder reactions. Be able to draw the Cu complex and how it controls the reaction. No need to memorise examples. Organocatalysts can be applied to Diels-Alder reactions, by forming a cationic intermediate: Intramolecular versions also work: O 5 mol% O N O TBDMSO O O O O O TBDMSO N N Cu H SbF6 O N Me H N 4 4 24h, rt, CH2Cl2 81% >99:1 endo:exo 96% ee H (-)-Isopulo'upone (natural product) H 24 There are many other similar catalysts for Lewis-acid catalysed Diels-Alder reactions. For the organocatalysis part you should be able to draw a mechanism for imine formation, for the cycloaddition (understanding that it is endo and with addition from the unhindered face) and the product, as well as the hydrolysis step. No need to memorise examples. O O 1 R Ph N H Ph Ph H NMe 20 mol% N H Ph + Et Ph R O H Product = R1 H NMe CbzHN N H N H Ph 2 N H 20:1, 90% ee 20 mol% NMe H + R1 R1 O tBu O NHCbz O H O O O Ph H R1 R1 R2 O + 2N R + R2 N R2 + N NMe NMe NMe NMe H + O O O Ar O Et O >100:1, 98% ee 10 mol% + O O NH O O O Bn NH2 CHO H 92% ee 24 Allylic substitution reactions are powerful methods for forming C-C bonds. Understand that a flat allyl complex is formed and that the ligand directs a nucleophile to one end by a combination of steric and electronic factors. No need to memorise examples. PdLn Ph Nucleophile adds trans to PdLn group Ph Nu AcO Attack at the other end of allylic system gives alternative enantiomer: Nu Pd(0), Nu Ph Ph Chiral ligand Ph Ph Ph PdLn Ph Ph Ph PdLn Nu Nu PdLn Ph Ph The Pd is behind the allylic group. PdLn Nu AcO Nu Ph PdLn LnPd LnPd Ph Ph Ph Ph Ph 41 M Wills CH3E4 notes Nu Allylic substitution reactions are powerful methods for forming C-C bonds. Understand that a flat allyl complex is formed and that the ligand directs a nucleophile to one end by a combination of steric and electronic factors. No need to memorise examples. PdLn Example ligand: 0 Ph Nucleophile adds trans to PdLn group O Ph2P Ph N Pd Nu R Favoured conformation: the allyl group is in front of the Pd complex. H O Ph2P N Pd Ph R Ph or OAc (racemic) Ph Ph 0 O Ph2P N Pd Ph -AcO O Ph2P Ph N Pd OAc R Ph Ph Ph2P R Ph Pd N H O Ph disfavoured by steric clash with equatorial H or slower to react. Nu Ph2P N Pd Ph Ph Trans effect favours addition to end opposite the P atom. H Nu R Ph Ph (enantiomerically enriched) and catalyst is released to re-enter cycle. 42 M Wills CH3E4 notes Allylic substitution reactions – examples of ligands and reactions. These are examples to provide an appreciation of the scope, No need to memorise examples. Just understand that a Pd/chiral ligand combination is required. 5 mol% Ph2P O Other ligands commonly used: AcO Ph Ph 2.5 mol% [Pd(allyl)Cl]2 NaCH(CO2Et)2 Ph EtO2C Ph Ph CO2Et O N 97% ee Ph O N O O NH PPh2 HN and many more... M Wills CH3E4 notes PPh2 Ph Ph N PCy2 PPh2 Ph2P Trost Ligand N Ph2PO Me (t-Bu)S iPr Fe 43 Allylic substitution reactions – examples of ligands and reactions. These are examples to provide an appreciation of the scope, No need to memorise examples. Just understand that a Pd/chiral ligand combination is required. Trost ligand creates a chiral environment through the phenyl rings on the phosphines. OAc O O NH HN PPh2 CO2Et Trost ligand (7.5 mol%) CO2Et NaCH(CO2Et)2 Ph2P Pd AcO >98% ee AcO 2.5 mol% [Pd(allyl)Cl]2 O In this example (below) the catalyst displaces one OAc selectively, and also controls the regio and stereochemistry of the reaction. O AcO Trost ligand and palladium OAc Ph Trost ligand (7.5 mol%) O N AcO iPr O O P Pd P O 98% ee O AcO Ph Trost ligand (7.5 mol%) 2.5 mol% [Pd(allyl)Cl]2 NaCMe(CO2Et)2 AcO EtO2C M Wills CH3E4 notes >95% ee Pri Ph 2.5 mol% [Pd(allyl)Cl]2 Ph N O AcO Ph AcO Ph 90% ee CO2Et 44 Allylic substitution reactions – examples of ligands and reactions. These are examples to provide an appreciation of the scope, No need to memorise examples. Other transformations which can be achieved by allylic substitution - soft nucleophiles generally favoured, otherwise the only limits are your own imagination... Ph Ph Ph Ph O Pd(0) + chiral ligand AcO O K N O Pd(0) + chiral ligand O OAc N O N K O N O O Ph Ph Ph Ph Ph Pd(0) + chiral ligand AcO HN H2N Pd(0) + chiral ligand Ph Pd(0) + chiral ligand O O O O NHTs TsHN N HN Pd(0) + chiral ligand O OAc O N HTs H2N MeO2CO OCO2Me Ph N Ph Uses of enzymes in asymmetric synthesis. this can Invert an alcohol overall. Understand that asymmetric reactions can be done by an enzyme. By racemising the substrate, the reaction can give 100% of a chiral product (see analogy with slide 11). O OH R2 R1 OH Enzyme Acylating agent e.g. AcOCH=CH2 O + R1 R2 Dynamic kinetic resolution can produce 100% yield. O OH R1 2 R R1 one enantiomer formed selectively 50% max yield. OH R2 1 R Enzyme 2 R Acylating agent e.g. AcOCH=CH2 O R1 R2 one enantiomer formed selectively 100% max yield. M Wills CH3E4 notes 46 Uses of enzymes in asymmetric synthesis. Understand that asymmetric reactions can be done by an enzyme. By racemising the substrate, the reaction can give 100% of a chiral product (see analogy with slide 11). No need to memorise mechanism of racemisation. R1 O 2 R R1 R2 Ph Ph Ph OC OC Ru Ph Ph Ph OC OC Ru Enzyme N O ROH OR O O rotate O Ru H O R2 Ph Ph Ph Ru OC O OC H R1 Ph Ph R2 R1 Ph Ph Ph Ph Ph Ph Ph Ru OC O OC H R2 M Wills CH3E4 notes Ph Ph Ph Ru OC OC H Cl H N R OC OC Ph Ph Ph Ph O Ph Ph R R R OH Ph R2 R1 Cl 2 Selective ring opening of a heterocycle: R R1 O O N N OH O H Ph 1 Ph Ph R2 R1 Ph Ph Ph OH Mecahnism of inversion by oganometallic complex: Ph Racemisation may be achieved via oxidation/reduction: OH this can Invert an alcohol overall. OC Ru OC H OH R1 + R2 R1 enantiomer 47 Uses of dehydrogenase enzymes in synthesis. These are examples to provide an appreciation of the scope, No need to memorise examples. Amine 'deracemisation' using an enzyme. O OH Enzyme Dehydrogenase 1 2 R 2 1 R R R NH Enzymes can be 'evolved towards particular substrates - Reetz etc. N R NH R H R Over several cycles, all in situ, almost complete conversion to product is achieved. NaBH4 Enzyme catalysis: amine oxidation. Chem. Commun. 2010, 7918-7920. H H + Step 2: multicomponent coupling. N H step 1: monoamine oxidase M (enzyme) 37oC, OH O N N H O O N O N H H N 94% ee AcO C H N N O H H H N N H N N H H N AcO H N N O O O O Step 3: remove OAc to give OH, then oxidise to b-keto amide) Telepravir (Hepatitis CNS3 protease inhibitor) For a nice example of use of an enzyme in dynamic kinetic resolution to make side chain of taxol see: D. B. Berkowitz et al. Chem. Commun. 2011, 2420-2422. M Wills CH3E4 notes 48 These are examples to provide an appreciation of the scope, No need to memorise examples. Review on directed evolution by Reetz: M. T. Reetz, Angew. Chem. Int. Ed. 2011, 50, 138-174. By undertaking cycles of directed evolution, highly selective enzymes can be prepared, as shown by the example of desymmetrisation (Baeyer-Villiger reaction) shown below: O H O H Optimised mutant enzyme O Optimised mutant enzyme O O >99% ee O H H 94% ee O O H H Optimised mutant enzyme Cl O Optimised mutant enzyme O Cl O >99% ee O H H 99% ee O O H H Optimised mutant enzyme Optimised mutant enzyme O O O >99% ee O H H 91% ee Optimised mutant R enzyme R HO HO O O Optimised mutant enzyme O O O R= nBu 97% ee R=CH2Ph 78% ee R=Ph 96% ee O 99% ee Me OH M Wills CH3E4 notes Me OH 49 Concluding material, non examinable. Other asymmetric reactions – for interest. Asymmetric hydroboration: L= L= O H OH BH N Ph2P O Asymmetric hydroformylation: Ph2P Ph2P 1 mol%[Rh(COD)L]BF4 MeO 20oC, THF, then H2O2, NaOH MeO Product formed in 88% ee. Ligand = O H H2, CO, 0.1-0.2 mol% ligand 0.05 mol% Rh(acac)(CO)2, H PPh2 O 88:12 O P H + 60oC, >99% conversion Product formed in 96% ee. O 94% ee Asymmetric catalysis – Isomerisation. Ph2 P Rh PPh2 NMe2 H H NMe2 [Rh/S-BINAP] Isomerisation (not a reduction!) R-citronellal, 96-99% e.e. M Wills CH3E4 notes H H O ZnBr2 then H2, Ni cat (to reduce alkene) OH (-)-menthol 50 There are many other reactions which have been converted into asymmetric processes. Catalytic Strecker synthesis: R NH2 + O R2 Concluding material, non examinable. Nu NR R3 R2 3 R NHR R2 NC H+/H2O R3 R2 HO2C R3 N Other reactions: Hetero Diels-Alders Hydrosilylation 1,3-dipolar cycloadditions. [2+2] cycloadditions Hydroacylation Cyclopropanation Hydrocyanation Epoxidation using iminium salts Asymmetric allylation NHR Cross coupling reactions Conjugate addition reactions Etc. etc. M Wills CH3E4 notes 51