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 O 1 OH OH Me HO 5 5 2 3 2 Me 4 Me HO 3 1 2-deoxy-D-ribose (R)-sulcatol • In this example, one stereogenic centre is retained • All others are destroyed O OH 1. MeOH, H O OMe 1. KI HO 2. MsCl MsO 2. Raney Ni Me O OMe HO MsO H2O Me OH Me OH Ph3P Me Me O OH Me Me Me CHO Advanced organic 2 ‘Chiral pool’ II Me Me remove OH Me Me stereogenic 3 steps O O centre HO 2 4 OH PCC 3 O OH O O 6 OH HO 1 O 5 OTBDPS OTBDPS D-mannose BnO O BnO O addition of 1. NaBH protecting groups overall retention of 4 stereochemistry 2. Tf2O stereoselective Me 1. TBAF Me Me reduction Me 2. PCC Me Me O O O 3. Ph P=CHCHO NaN O 3 O 3 O N3 N3 OTf OTBDPS OTBDPS BnO O CHO BnO O BnO O Pd / C hydrogenolysis of benzyl (Bn) group & H reductive amination of resultant 2 aldehyde Me HO two step reversal of Me O 2 1 stereogenic centre reduction 1. H2, Pd / C, H of alkene & H H 3 O N 2. TFAA azide HO 4 N followed by reductive H 6 amination BnO O 5 H HO 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 H H Me H H Me 1. TMEDA Me H BH3 B 2. BF3•OEt2 B H Me (+)-α-pinene (–)-Ipc2BH (+)-IpcBH2 Me Me H Me H 1. TMEDA Me Me Me Me Me H BH3 Me 2. BF3•OEt2 Me B BH2 H H H H Me Me Me Advanced organic 4 Hydroboration: reagent control H Me H 1. (–)-Ipc2BH Me H H Me H OH B 2. H2O2 / NaOH Me Me Me H 98.4% ee (–)-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 Me Me 1. (+)-IpcBH2 H Me H 2. H2O2 / NaOH Me BH2 H HO H H 66% ee (+)-IpcBH2 Advanced organic 5 Hydroboration: catalyst control 1. RhL Cl O 2 H 2. H2O2 / NaOH H + B H OH H O H H catecholborane 82% ee H OH O Me PAr 2 CO2H L = HO C Me PAr 2 O 2 OH H Ar = 2-MeOC6H4 (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 Me 1. LiCHCl2 H CO2H (R)-BINAP / catechol- O Me 2. NaClO2 borane [oxidation] H B O Me 2. Me Me Me Me Me Me Me HO OH Me 99%; 97% ee 88%; 97% ee PPh Rh 2 PPh2 [Rh(COD)2] (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 Me OH H2(g) [(Cy3P)Ir(COD)py] PF6 H Me Me PCy3 Ir N MeO MeO H2(g) [(Cy P)Ir(COD)py] PF 3 6 i-Pr [(Cy3P)Ir(COD)py] i-Pr H Me 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 H2(g) OH O [Rh(nbd)(diphos-4)] BF4 Me X Me X Me H Me Me anti 93:7 Ph P Rh Ph Ph P Ph OH O H OH O 2(g) [Rh(nbd)(diphos-4)] [Rh(nbd)(diphos-4)] BF4 Me X Me X Me Me Me H Me syn 91:9 • 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 coordination H L S of the alkene L H2 H M + M M L S OH L O oxidative L O H addition L H insertion of M–H into C=C reductive elimination (loss of H H M–H & formation of O H L S C–H) M + H H M L S L S OH L L = ligand S = solvent • 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 R H H Me H OH OH R Me R Me Me H Me H anti H R L Rh OH steric L interaction • Once again, allylic strain is responsible for the diastereoselectivity • One diastereoisomeric complex suffers less steric congestion & is favoured L L Rh OH R Me H Me H OH OH R Me R Me Me Me H Me H syn Me R L Rh OH steric interaction L Advanced organic 11 Catalytic enantioselective hydrogenation MeO H H 2(g) H H [((S)-DIPAMP)RhL2] MeO CO2H L=solvent MeO CO2H P P NHAc H NHAc AcO 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 O MeO MeO MeO HO2C N Me H Ar Ar P P P O P P P Rh Rh O Rh L L HO2C N Me Me N CO2H OMe OMe H OMe H Advanced organic 12 Mechanism for catalytic hydrogenation Ar Ph Ar O Ph Ar P Ar P P Ar P Ar Rh O Ph Ar O Rh Ph HO2C N Me H HO2C N Me Me N CO2H H H + [DIPAMPRhL2] H2 H2 slow oxidative fast addition oxidative addition fast complex more insertion H reactive H Ph Ph H Ar P P Ar H Rh O O Rh Ar One complex more reactive Ar HO2C NP Me Me NP CO2H Ar H H Ar Ph Ph reductive elimination H L L H Ph Ar Ar H Ar Ar H Ph Ar Ar P O P H O O H P O P Ar Rh Ph H H Ar Rh Ph HO2C N Me HO2C N Me Me N CO2H Me N CO2H H H H H H minor enantiomer major enantiomer H Advanced organic 13 Organocatalytic hydrogenation Me O N t-Bu Me O H Me O Bn N H2 Cl3CO2 H H H H NC MeO2C CO2Me NC 89%; 96% ee Me N i-Pr H catalyst 10% hydrogen source 1eq H E Meδ+ O Me O Me N H N δ– i-Pr N H H E Bn t-Bu O Ar N Bn N t-Bu H N Me N H H Me Ph H Ar H Me Me Me Ar Me 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 OH must be 92% ee allylic alcohol Me Me (–)-DET, Ti(Oi-Pr)4, TBHP Me Me O OH OH Me Me >90% ee Me OH OH Me OH CO2i-Pr CO2Et Me O i-PrO2C EtO2C OH OH TBHP (+)-DIPT (–)-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 2 3 D-(–)-DET Ti(Oi-Pr)4 R R TBHP if you want “O” on top its unnatural isomer O on your kNuckles so you “O” OH use Negative (–)-DET R1 R2 R3 place alkene using your left hand, vertical and the index finger is R1 alcohol in bottom the alkene and your OH right corner thumb the alcohol 2 3 Ti(Oi-Pr)4 R R “O” TBHP if you want “O” on top its D-(+)-DET O on your Palm so you use OH Positive (+)-DET natural isomer R1 • 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 TiL t-Bu 4 Ot-Bu Ot-Bu L + L O Ot-Bu O L L L TBHP L Ti Ti Ti Ti O L O + L O O O O O HO activation of peroxide Advanced organic 16 Mechanism of SAE CO Et CO Et 2 i-Pr 2 i-Pr i-Pr O i-Pr O O O O O O O O O i-Pr i-Pr t-BuO H Ti(Oi-Pr) + Ti CO Et Ti 2 Ti CO Et Ti CO2Et 4 2 OEt 2 (+)-DET O O O O O O i-Pr O O O O t-Bu EtO EtO Active species thought to be 2 x Ti bridged by 2 x tartrate HO Reagents normally left to ‘age’ before addition of substrate thus allowing clean formation of dimer R CO2Et CO2Et i-Pr O i-Pr O O O O O O O O O i-Pr i-Pr HO Ti Ti E Ti Ti E O CO2Et CO2Et O O O O O O R O O O O R R t-Bu t-Bu EtO EtO must deliver “O” from lower face Advanced organic 17 R2 OH good substrates R2 OH high yields and ee's >90% R1 R3 R3 normally good • SAE works for a wide range of 2 ee's >90% allylic alcohols OH R OH few examples 1 1 • Only cis di-substituted alkenes R R appear to be problematic R3 problematic slow reactions moderate ee's, OH especially with bulky R3 • 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 Me Me Me conditions O O O + O O O OH OH OH O O t-BuO2H, VO(acac)2 2.3 : 1 t-BuO2H, Ti(Oi-Pr)4, (+)-DET 1 : 22 t-BuO2H, Ti(Oi-Pr)4, (–)-DET 99 : 1 Advanced organic 18 Use of SAE in synthesis SAE Red-Al OH (+)-DIPT O [NaAlH2(OCH2CH2OMe)2] Ph OH Ph OH Ph OH H MsCl CF3 1.