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1 Asymmetric synthesis • There are a number of different strategies for enantioselective or • • diastereoselective synthesis I will try to cover examples of all, but in the context of specific transformations Such an approach does not include use of the ‘chiral pool’ so here are two examples 4 HO O OH 1 5 OH Me 2 5 Me 2 HO 3 2-deoxy-D-ribose 4 3 1 Me (R)-sulcatol • In this example, one stereogenic centre is retained • All others are destroyed O HO OH 1. MeOH, H 2. MsCl HO O MsO OMe 1. KI 2. Raney Ni Me O MsO H2O Me OH Me OMe Me Ph3P Me OH Me Me Me O OH CHO Advanced organic 2 ‘Chiral pool’ II Me OH HO HO 2 4 3 3 steps OH 6 O 5 D-mannose 1 Me O Me O O N3 BnO O 1. TBAF Me 2. PCC 3. Ph3P=CHCHO CHO OTBDPS O O O O BnO O overall retention of stereochemistry OTBDPS 1. NaBH4 2. Tf2O Me stereoselective reduction Me Me O O BnO Me reduction of alkene & azide followed by reductive amination PCC NaN3 N3 OTBDPS O O O BnO OTf O OTBDPS hydrogenolysis of benzyl (Bn) group & reductive amination of resultant aldehyde Pd / C H2 Me OH OH addition of protecting groups Me Me O BnO remove stereogenic centre Me HO O O H H N 1. H2, Pd / C, H 2. TFAA 2 3 HO 4 1 two step reversal of stereogenic centre N H BnO O 6 H HO 5 swainsonine • In this example three stereogenic centres are retained • One stereogenic centre undergoes multiple inversion -- but overall it is retained Advanced organic 3 Stereoselective reactions of alkenes • Alkenes are versatile functional groups that, as we shall see, present plenty of scope • for the introduction of stereochemistry Hydroboration permits the selective introduction of boron (surprise), which itself can undergo a wide-range of stereospecific reactions Substrate control Me Me BH3 H H B H 1. TMEDA 2. BF3•OEt2 Me Me H H B H Me (+)-α-pinene Me Me Me Me (+)-IpcBH2 (–)-Ipc2BH BH3 Me H Me H B H H 1. TMEDA 2. BF3•OEt2 Me Me Me H Me BH2 H Me Me H Me Advanced organic 4 Hydroboration: reagent control Me H 1. (–)-Ipc2BH 2. H2O2 / NaOH H OH Me H H B H Me Me Me Me 98.4% ee H (–)-Ipc2BH • The two compounds formed previously, mono- & diisopinocampheylborane are • • common reagents for the stereoselective hydroboration of alkenes Ipc2BH is very effective for cis-alkenes but less effective for trans IpcBH2 gives higher enantiomeric excess with trans and trisubstituted alkenes Me H 1. (+)-IpcBH2 2. H2O2 / NaOH H HO Me H 66% ee Me Me H Me BH2 H (+)-IpcBH2 Advanced organic 5 Hydroboration: catalyst control O H + B H 1. RhL2 Cl 2. H2O2 / NaOH H OH O H H H 82% ee catecholborane H L= Me Me O O OH PAr2 PAr2 H Ar = 2-MeOC6H4 HO2C CO2H OH (2R,3R)-tartaric acid • Hydroboration can be catalysed using certain rhodium complexes • Good enantiomeric excesses can be achieved • The example above utilises an initially complicated diphosphine • But the central core of the ligand (and the stereogenic centres) is derived from the natural compound tartaric acid (cheap and readily available as both enantiomers) Advanced organic 6 Hydroboration: catalyst control II Me Me 1. [Rh(COD)2] .BF4 (R)-BINAP / catecholborane Me 2. Me Me Me Me HO OH Me Me O H B O 1. LiCHCl2 2. NaClO2 [oxidation] Me H CO2H Me Me Me 99%; 97% ee Rh [Rh(COD)2] 88%; 97% ee PPh2 PPh2 (R)-BINAP • This second example utilises BINAP and again gives very impressive ee’s • The second part of the reaction gives an example of an alternative stereospecific ...transformation of the boron species Advanced organic 7 Homogeneous hydrogenation: substrate control Me OH H2(g) [(Cy3P)Ir(COD)py] Me OH PF6 H Me Me Ir PCy3 N H2(g) [(Cy3P)Ir(COD)py] MeO i-Pr Me MeO PF6 i-Pr [(Cy3P)Ir(COD)py] H Me • Cationic iridium or rhodium complexes are very effective catalysts for substrate • • • directed hydrogenations Whilst the hydroxyl group gives a very diastereoselective reaction; it is probably not via hydrogen bonding The methoxy group also directs hydrogenation Presumably, coordination of oxygen lone pair and cationic complex causes selectivity Advanced organic 8 Substrate control in acyclic systems OH O Me H2(g) [Rh(nbd)(diphos-4)] OH BF4 X Me Me anti 93:7 O H2(g) [Rh(nbd)(diphos-4)] X Me Me X H Me Me Me OH O OH Ph P Rh Ph Ph P Ph O [Rh(nbd)(diphos-4)] BF4 Me X Me H syn 91:9 Me • Acyclic systems can undergo highly diastereoselective directed hydrogenations • Allylic alcohols give the best selectivities • Importantly - the position of the double bond changes the selectivity • This allows us to selectively form either the anti or syn diastereoisomers Advanced organic 9 Mechanism of directed hydrogenation L M S + S L coordination of the alkene OH H L L H2 M O H oxidative addition H L M L O H insertion of M–H into C=C reductive elimination (loss of M–H & formation of C–H) H L L M S + H S OH L = ligand S = solvent H H L O H M L S • This is a simplified mechanism for alkene reduction by homogeneous hydrogenation • Replace M–O bond with M–S if the reaction is not directed • This is the mechanism for dihydride reductants, monohydride reductants also exist • Note - the ligands remain attached to the metal, therefore if alkene is prochiral and the ligands are chiral we can get enantioselective catalysis • But first, what about the selectivity in these reactions... Advanced organic 10 Explanation of diastereoselectivity L L Rh OH H OH R H Me R H OH R Me H H Me anti Me H L Rh OH Me R steric interaction L • Once again, allylic strain is responsible for the diastereoselectivity • One diastereoisomeric complex suffers less steric congestion & is favoured L L Rh OH R OH R H Me Me H Me Me OH R H H R L Rh OH L Me Me Me Me syn steric interaction Advanced organic 11 Catalytic enantioselective hydrogenation H MeO CO2H H2(g) [((S)-DIPAMP)RhL2] L=solvent H H MeO CO2H P P H NHAc NHAc AcO MeO AcO OMe 95% ee (S,S)-DIPAMP • One of the most important industrial reactions; above example produces amino acids • Variety of diphosphines can be used • It is essential that there is a second coordinating group (here the amide) • On coordination, two diastereoisomeric complexes are formed • The stability / ratio of each of these is unimportant • It is their reactivity we are concerned with... Ar MeO HO2C P L OMe Rh P L N H O MeO Me P Ar P Rh O HO2C N OMe H Me MeO P O Ar Rh Me OMe N H P CO2H Advanced organic 12 Mechanism for catalytic hydrogenation Ph Ar Ar Ar Ar P Rh O Ph P HO2C N H Me HO2C Me Me oxidative addition fast complex more reactive Ph Ar P Rh O Ar N P Ar H N H Ar P Ph CO2H H2 fast oxidative addition H H N H P O Ar Rh Ar + [DIPAMPRhL2] H2 slow insertion HO2C Ph O H Ph One complex more reactive Me P O Ar Rh Ar Me Ph Ph H N CO2H P H Ar reductive elimination Ph H P Ar L Ar Ar O P Rh Ph HO2C N H H Me H H H HO2C Ar N H O O Me minor enantiomer Me Ar N H H H H CO2H major enantiomer L Ar P O Rh Ar Ph Me N H H H Ar P Ph CO2H Advanced organic 13 Organocatalytic hydrogenation Me O Me N t-Bu O Bn H H Me O N H2 Cl3CO2 H H H MeO2C NC CO2Me NC 89%; 96% ee i-Pr N H catalyst 10% hydrogen source 1eq Me HE O Me N Bn H t-Bu N H Ar δ– HE Ar Me O Me N H N Ph Me Me Me H O Me δ+ N H i-Pr Me N Bn t-Bu N Me H Ar H Me • A recent development is the use of small organic molecules to achieve hydrogenation • Inspire by nature • Based on the formation of a highly reactive iminium ion (this is the basis of many organocatalytic reactions) Advanced organic 14 Sharpless Asymmetric Epoxidation (SAE) Me Me (+)-DIPT, Ti(Oi-Pr)4, TBHP O OH must be allylic alcohol OH 92% ee Me Me (–)-DET, Ti(Oi-Pr)4, TBHP Me Me Me Me OH Me O Me >90% ee OH Me O TBHP OH i-PrO2C OH OH CO2i-Pr OH (+)-DIPT EtO2C CO2Et OH (–)-DET • Sharpless asymmetric epoxidation was the first general asymmetric catalyst • There are a large number of practical considerations that we will not discuss • Suffice to say it works for a wide range of compounds in a very predictable manner • Compounds must be allylic alcohols • Second example shows that this limitation allows highly selective reactions Advanced organic 15 Sharpless Asymmetric Epoxidation II D-(–)-DET unnatural isomer “O” Ti(Oi-Pr)4 TBHP R2 R3 O R1 R2 OH “O” D-(+)-DET natural isomer OH place alkene vertical and alcohol in bottom right corner R3 R1 if you want “O” on top its on your kNuckles so you use Negative (–)-DET Ti(Oi-Pr)4 TBHP R2 R3 O R1 using your left hand, the index finger is the alkene and your thumb the alcohol if you want “O” on top its on your Palm so you use Positive (+)-DET OH • SAE is highly predictable -- the mnemonic above is accurate for most allylic alcohols • To understand where this comes from we must look at the mechanism • A simplified version of the basic epoxidation is given below TiL4 + TBHP + t-Bu O Ot-Bu L L Ti O O L L Ti O O L L Ot-Bu Ti O O L L Ti Ot-Bu O O HO activation of peroxide Advanced organic 16 Mechanism of SAE i-Pr Ti(Oi-Pr)4 + (+)-DET O O i-Pr CO2Et i-Pr O O Ti O O CO2Et Ti OEt O O O i-Pr t-BuO2H O Ti O i-Pr O O O i-Pr CO2Et i-Pr O O CO2Et Ti CO2Et O O O O t-Bu EtO Active species thought to be 2 x Ti bridged by 2 x tartrate Reagents normally left to ‘age’ before addition of substrate thus allowing clean formation of dimer i-Pr HO i-Pr R O O CO2Et Ti E O O R i-Pr O Ti O HO CO2Et O O O EtO O O i-Pr O Ti O O CO2Et Ti E O O t-Bu EtO O O R CO2Et O O O t-Bu R EtO must deliver “O” from lower face Advanced organic 17 R2 R2 OH OH R1 R3 R3 R2 OH R1 OH good substrates high yields and ee's >90% • SAE works for a wide range of allylic alcohols • Only cis di-substituted alkenes normally good ee's >90% few examples R1 appear to be problematic problematic slow reactions moderate ee's, especially with bulky R3 R3 OH • Example below shows that SAE can over-ride the inherent selectivity of a substrate • Furthermore, it demonstrates the concept of matched & mismatched • When the catalyst & substrate reinforce each other spectacular (or matched) results are achieved Me Me Me conditions O O Me Me Me O + O OH OH O O OH O t-BuO2H, VO(acac)2 t-BuO2H, Ti(Oi-Pr)4, (+)-DET t-BuO2H, Ti(Oi-Pr)4, (–)-DET 2.3 1 99 O : : : 1 22 1 Advanced organic 18 Use of SAE in synthesis SAE (+)-DIPT Ph OH Red-Al [NaAlH2(OCH2CH2OMe)2] O Ph OH Ph OH OH H MsCl CF3 O Ph 1. NaH 2. ArCl OH Ph OH MeNH2 NHMe Ph OMs NHMe fluoxetine • Fluoxetine is a commercial anti-depressant (better known as Sarafem® or Prozac®) • Can be synthesized in a number of methods • One involves the use of the SAE reaction Advanced organic 19 Kinetic resolution R3 R R2 racemic mixture OH R1 slow steric hindrance fast (–)-DET, Ti(Oi-Pr)4, TBHP R2 R2 R3 R R1 R3 H R1 OH OH H R if reaction goes to 100% completion you get a 1:1 mixture of diastereoisomers if allylic alcohol is desired use 0.6eq TBHP if epoxy alcohol is desired use 0.45eq TBHP R3 R3 R R2 OH R1 O R2 R OH R1 • Both enantiomers should be epoxidised from same face • But rate of epoxidation is different • If sufficient rate difference then stop the reaction at 50% conversion Advanced organic 20 Kinetic resolution II Me3Si OH C5H11 (R/S) (+)-DIPT, Ti(Oi-Pr)4, TBHP Me3Si Me3Si O OH rate of epoxidation (S) : (R) ~700 : 1 C5H11 >95% ee + OH C5H11 (R) >95% ee • Kinetic resolution normally works efficiently • The problem with kinetic resolution is that is can only give a maximum yield of 50% • Desymmetrisation of a meso compound allows 100% yield • Effectively, the same as two kinetic resolutions, first desymmetrises compound • second removes unwanted enantiomer ee of desired product increases with time (84% ee 3hrs ➔ >97% 140hrs) OH FAST slow FAST O slow wanted OH OH O (–)-DIPT O slow FAST OH O meso readily removed O H OH H O Advanced organic 21 Desymmetrisation in synthesis NHPh OH OBn OH (–)-DIPT, Ti(Oi-Pr)4, TBHP OBn PhNCO pyr O OBn O OBn O O OBn OBn BF3•OEt2 HO HO2C OH O O OH O O OH OH KDO OBn HO OBn • Desymmetrisation has been used in many elegant syntheses Advanced organic 22 Jacobsen-Katsuki epoxidation • SAE is a marvelous reaction but suffers certain limitations • substrate must be an allylic alcohol cis-disubstituted alkenes are poor substrates (salen)Mn catalysts with bleach (NaOCl) are good for these substrates L (S,S)-cat (2-15%) NaOCl, pH 11 S L S Ph CO2Me O O L = larger group S = smaller group O t-Bu CN O 97% ee ≥95% ee O H O Me O O 94% ee Me H H N Cl N Mn O O t-Bu t-Bu (S,S)-Mn(salen) N t-Bu Mn O H N O manganese(IV) oxo species active oxidant Advanced organic 23 Jacobsen-Katsuki oxidation in synthesis N N OH CHBn N CONHt-Bu H N OH O Indinavir (Merck / HIV treatment) (salen)Mn cat NaOCl, R3N+–O– H2SO4 MeCN OH O 2000kg scale MeCN OH NH2 H2O OH O N Me N C Me • This example demonstrates the industrial potential of such catalytic systems Advanced organic 24 Organocatalytic epoxidations cat. oxone, K2CO3 DME / H2O, –15°C Me Ph Me Ph O 100%; 86% ee F F O O O F F cat. O R O R H R O H R H H • As with most chemical reactions, epoxidation has seen a move towards ‘greener’ chemistry and the use of catalytic systems that do not involve transition metals • A number of systems exist, notably the catalysts of Shi & Armstrong • Most are based on the in situ conversion of ketones to the active, dioxirane species, that actually performs the epoxidation • Non of these have yet to match the utility of their metal counter-parts Advanced organic 25 Sharpless Asymmetric Dihydroxylations (SAD) K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH, H2O, 0°C, (DHQD)2-PHAL CO2Et C5H11 OH C5H11 CO2Et OH 99% ee • Looks complicated but isn’t too bad... • The active, catalytic, oxidant is K2OsO2(OH)4 - OsO4 is too volatile & toxic • K3Fe(CN)6 is the stoichiometric oxidant • K2CO3 & MeSO2NH2 accelerate the reaction • Normally use a biphasic solvent system • And the two ligands are... Et N Et Et N N N O H Et O N H MeO N N (DHQD)2-PHAL O H OMe N N N O H MeO OMe N N (DHQ)2-PHAL • Ligands are pseudo-enantiomers (only blue centres are inverted; red are not) • They act if they were enantiomers (see slide 26) • Coordinate to the metal via the green nitrogen Advanced organic 26 Sharpless Asymmetric Dihydroxylation II OH Ph Ph K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH, H2O, 0°C, (DHQD)2-PHAL Ph Ph K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH, H2O, 0°C, (DHQ)2-PHAL OH Ph Ph OH 98.8% ee OH >99.5% ee • Reaction works on virtually all alkenes • Exact mechanism not known but... • It is relatively predictable (but not as predictable as the SAE) (DHQD)2PHAL OsO4 small steric barrier attractive area attracts flat, aromatic substituents or large, hydrophobic aliphatic groups S M L H large steric barrier OsO4 (DHQ)2PHAL Advanced organic 27 SAD & Sharpless aminohydroxylation reaction Me OsO4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH, H2O, 0°C, (DHQD)2-PHAL Me O OH Me Me Me HO O O O TsOH O Me O 95% ee exo-Brevicomin • The simple example above shows the power of the SAD reaction in synthesis • A variant has now been developed that permits aminohydrodroxylation • Used in the semi-synthesis of Taxol O Ph Oi-Pr AcNHBr, LiOH, K2OsO2(OH)4, (DHQ)2-PHAL AcNH O Oi-Pr Ph HCl, H2O O Ph OH O Me O Oi-Pr Ph OH regioselectivity >20:1 94% ee AcO HCl.NH2 O Me OH Me Ph N H O Me OH HO taxol OBz H AcO O Advanced organic 28 Diastereoselective conjugate additions Me Me Me Me Me NH Me Me EtMgCl N N S O O O S O O Oppolzer's camphor sultam S trans conformation disfavoured Me Me HO Me NH S O O O LiOH Et Me Me H N S O O O 90% de Et Et O Mg Cl Mg Cl O O Et cis conformation favoured chelation restricts rotation Me Me H Me Me Me N S H Et O Mg Cl Mg Cl O O Et • Possible to use chiral auxiliary to control 1,4-nucleophilic addition • Chelation of amide and sultam oxygens to Mg restricts rotation and favours cis conformation • Addition occurs from most sterically accessible side • Chiral auxiliary readily cleaved (& reused) to give enantiomerically pure compound via diastereoselective reaction Advanced organic 29 Chiral auxiliary to control two stereocentres addition as slide 28 Me Me Me Me N 1. BuMgCl 2. MeI Me Me H N S S O O O Me Bu Me H Me H N O Mg L O O L electrophile approaches from bottom face Me Bu S O O O 95% de Me I LiOH Me Me Me NH S O O + HO Me O Bu • It possible to utilise 1,4-addition to introduce two stereogenic centres • The first addition (BuMgBr) occurs as before to generate an enolate • The enolate can then be trapped by an appropriate electrophile • Once again the sultam chiral auxiliary controls the face of addition (of Me) Advanced organic 30 Alternative chiral auxiliaries I aldol-like reaction & acid catalysed elimination O Ph Ph O 1. LDA Me N OH Ph R1 R1 N H 3. CF3CO2H R1 OMe NH2 R2–Li 2. R1CHO OMe H OMe O CO2H Ph O Ph N Li OMe O Ph H2O H3O R1 H R2 95-99% ee R2 H R2 R1 N OMe H R2 N Li OMe hydrolysis • A second chiral auxiliary is the oxazoline (5-membered ring) of Meyers’ • It can be prepared from carboxylic acids (normally in 3 steps) or from condensation • of the amino alcohol and a nitrile As can be seen excellent enantiomeric excesses can be achieved via a highly diastereoselective reaction Advanced organic 31 Alternative chiral auxiliaries II L L Zn O O O O S ZnBr2 O O MeO MgBr S MeO O O S O O H MeO Ar O Raney Ni nuc O MeO O O O Ar2COCl H MeO OMe O H O Ar (–)-podorhizon 95% ee O • Sulfoxide is a good chiral auxiliary; not only does it introduce a stereocentre but it • • • • activates the alkene by addition of an extra electron-withdrawing group Lewis acid tethers groups together to give a rigid cyclic chelate Nucleophile attacks from opposite face to bulky aryl group Sulfoxide is readily removed under reductive conditions Simple substrate control of enolate chemistry instals aryl group on opposite face to substituent Advanced organic 32 Enantioselective catalytic conjugate addition O Et2Zn, Cu(OTf)2 (2%), lig. (4%), tol, 3h, –30°C O Ph O O Et Me P N Me Ph 94% >98% ee lig. • Much effort has been expended trying to develop enantioselective catalysts for • • conjugate addition Whilst many are very successful for certain substrates, few are capable of acting on a wide range of compounds The system above gives excellent enantioselectivities for cyclohexenone but... no selectivity for cyclopentenone O Et2Zn, Cu(OTf)2 (2%), lig. (4%), tol, 3h, –30°C O Et 75% 10% ee Advanced organic 33 Potential mechanism transmetallation of alkyl group (R) to copper ZnR2 L2CuX2 ZnR2 copper(II) (with 2 P ligands) reduced to copper(I) by zinc reagent XZn L2CuX + RZnX L2CuR + RZnX O O R L L Cu O R XZn alkyl transfer occurs after enone and copper bind R zinc probably activates enone Advanced organic 34 Bifunctional catalysis O O O + MeO O (R)-ALB (0.3%) t-BuOK (0.27%) MS 4Å, THF, rt, 120h CO2Me OMe CO2Me 94% 99% ee H O O Li Al O Al O O O O O O (R)-ALB O RO Li O OR • Heterobimetallic catalyst of Shibasaki works remarkably well even at low catalyst • • • loadings Aluminium acts as Lewis acid to activate enone Lithium alkoxide acts as Brønsted base to deprotonate malonate Lithium alkoxide also positions the enolate Advanced organic 35 Organocatalysis Me N O O Bn O + Ph Me BnO OBn N H CO2H cat. (10%), neat, rt, 165h CO2Bn BnO2C Ph O Me 86% 99% ee Me Me N CO2H N Me H N N BnO H O CO2Bn CO2H Me CO2Bn H CO Bn 2 • New small molecule organic catalysts are now achieving remarkable results • Enone is activated by formation of the charged iminium species • The catalyst also blocks one face of the enone allowing selective attack Advanced organic 36 Organocatalysts II O Me N X Bn NR2 O Me X Me N H•HCl Me + H O H R2N O O Me N Me H H X X H Me N Me Me Me N Me Me O Me N N 68-90% 84-92% ee Me Me N NR2 Me H X Ar H steric hindrance results in predominantly one conformation • A range of reactions can be achieved, including enantioselective Friedel-Crafts • Catalyst ensures that the enone reacts via one conformation • Must use electron rich aromatic substrates Advanced organic 37 Organocatalysts III O Me N Bn H + TMSO O Me R O Me Me N H•HCl Me O O cat. (20%) DCM / H2O –20 to –70°C, 11–30h Me O R H 77% syn:anti = 1-31:1 84-99% ee • Possible to introduce two stereogenic centres with good diastereoselectivity and • enantioselectivity An interesting reaction is the Stetter reaction - this is the conjugate addition of an acyl group onto an activated alkene and proceeds via Umpolung chemistry (the reversal of polarity of the carbonyl group) OMe cat. (20%) KHMDS (20%) 25°C, 24h O Me H O CO2Et O Me N N CO2Et O 80% 97% ee N O H BF4 Advanced organic 38 Mechanism of Stetter reaction O O Me Me Ar CO2Et H N N O O N CO2Et O N Me Ar N Ar N N base O H N CO2Et OH H N base Ar2 O Ar N N N N HO OEt N O Ar O H N OEt OH O base O Me Me • The Stetter reaction is analogous to the activity of thiamine (vitamin B1) in our bodies and the reaction is thus biomimetic Advanced organic 39 Organocatalytic bifunctional catalysis CF3 S F3C NO2 + EtO2C CO2Et N H N H Me N EtO2C CO2Et Me NO2 toluene, rt, 24h 86% 93% ee CF3 CF3 S F3C S H N H N Me H H Me O O H O N O H EtO Ph F3C N OEt N N H H O O N N H Ph Me Me H CO2Et CO2Et • The thio(urea) moiety acts as a Lewis acid via two hydrogen bonds • The amine both activates the nucleophile and positions it to allow good selectivity Advanced organic