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 ‘’ 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- (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


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 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 Me HO two step reversal of Me O 2 1 stereogenic centre reduction 1. H2, Pd / C, H of & 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 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


(+)-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: 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 for the stereoselective hydroboration of alkenes • Ipc2BH is very effective for cis-alkenes but less effective for trans • IpcBH2 gives higher 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)-

• 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 (and the stereogenic centres) is derived from the natural compound tartaric acid (cheap and readily available as both )

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 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 = • 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 • But first, what about the selectivity in these reactions...

Advanced organic 10 Explanation of diastereoselectivity


R Me R Me Me H Me H anti H R L Rh OH steric L interaction • Once again, allylic 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 ) • 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 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 to achieve hydrogenation • Inspire by nature • Based on the formation of a highly reactive iminium (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 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 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 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. NaH OH OH 2. ArCl MeNH2 O Ph NHMe Ph OMs Ph NHMe

• 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

R3 R R2 OH R1

slow steric hindrance fast (–)-DET, Ti(Oi-Pr)4, TBHP

R2 R2 R3 R3 R H R1 R1 OH OH

H R if reaction goes to if allylic alcohol is desired use 0.6eq TBHP 100% completion you if epoxy alcohol is desired use 0.45eq TBHP get a 1:1 mixture of diastereoisomers R3 R R3 R O R2 OH R2 OH R1 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 Me3Si Me3Si (+)-DIPT, Ti(Oi-Pr)4, TBHP O OH OH + OH rate of epoxidation C5H11 (S) : (R) ~700 : 1 C5H11 C5H11 (R/S) >95% ee (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 allows 100% yield • Effectively, the same as two kinetic resolutions, first desymmetrises compound second removes unwanted enantiomer • ee of desired increases with time (84% ee 3hrs ➔ >97% 140hrs)

OH FslowAST O FAST wanted slow OH OH O (–)-DIPT H O O meso OH slow readily OH FAST removed H O O Advanced organic 21 Desymmetrisation in synthesis


OH (–)-DIPT, Ti(Oi-Pr)4, OH PhNCO TBHP pyr O O





• 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

(S,S)-cat (2-15%) O L S Ph CO2Me Me O CN L S NaOCl, pH 11 O O O Me L = larger group O S = smaller group O 94% ee ≥95% ee 97% ee

H O H H N Cl N Mn N N Mn t-Bu O O t-Bu O H O t-Bu t-Bu manganese(IV) oxo species active oxidant (S,S)-Mn(salen)

Advanced organic 23 Jacobsen-Katsuki oxidation in synthesis

N OH CHBn OH H N N N CONHt-Bu O Indinavir (Merck / HIV treatment)

(salen)Mn cat H2SO4 NaOCl, R N+–O– MeCN 3 OH O 2000kg scale MeCN

OH H O OH 2 O Me N N NH2 Me C

• This example demonstrates the industrial potential of such catalytic systems

Advanced organic 24 Organocatalytic epoxidations

cat. oxone, K2CO3 DME / H2O, –15°C Me Me Ph Ph O 100%; 86% ee


O O O F F cat.

O O O R R H H R 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 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, OH H2O, 0°C, (DHQD)2-PHAL CO2Et CO2Et C5H11 C5H11 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 Et Et Et N N N N N N N N O O O O H H H H MeO OMe MeO OMe


• 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 Advanced organic 26 Sharpless Asymmetric Dihydroxylation II

K2OsO2(OH)4, K3Fe(CN)6, K2OsO2(OH)4, K3Fe(CN)6, OH K2CO3, MeSO2NH2, t-BuOH, K2CO3, MeSO2NH2, t-BuOH, OH H O, 0°C, (DHQD) -PHAL H O, 0°C, (DHQ) -PHAL Ph 2 2 Ph 2 2 Ph Ph Ph Ph OH OH 98.8% ee >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)



small steric barrier S M attractive area - attracts flat, aromatic substituents or large, L H large steric hydrophobic aliphatic barrier groups



Advanced organic 27 SAD & Sharpless aminohydroxylation reaction

OsO , K Fe(CN) , K CO , OH Me 4 3 6 2 3 MeSO NH , t-BuOH, H O, Me Me Me 2 2 2 Me 0°C, (DHQD)2-PHAL TsOH O HO O O O O O Me

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 AcNHBr, LiOH, O AcNH O K2OsO2(OH)4, HCl.NH O (DHQ) -PHAL 2 2 HCl, H2O Ph Oi-Pr Ph Oi-Pr Ph Oi-Pr OH OH regioselectivity >20:1 94% ee

AcO O OH O Ph O Me Me Me Ph N O H OH Me H O HO AcO taxol OBz Advanced organic 28 Diastereoselective conjugate additions

Me Me Me Me Me Me Me Me H EtMgCl Et NH N N O O Mg Cl S O S O S trans conformation Mg Cl O O O O disfavoured Et Oppolzer's cis camphor sultam conformation favoured chelation restricts rotation

Me Me Me Me Me Me Me Me H H HO Me LiOH Et N NH N Et O Mg Cl O Et O S S O S O Mg Cl O O O O Et 90% de • Possible to use to control 1,4- • 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 Me Me Me Me H Me Me 1. BuMgCl H H 2. MeI N Bu N O N Bu O S Me O S O Mg L S O O O O L I O 95% de

LiOH approaches from bottom face Me Me Me HO Me NH +

S O O Bu O

• 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 O Ph O Ph Me 1. LDA R2–Li 1 N 2. R1CHO R N R1 N R2 H H OMe 3. CF3CO2H OMe Li OMe

OH O Ph O Ph 1 R H3O H2O CO2H Ph OMe R1 N R1 N H R2 R2 R2 NH 2 95-99% ee H OMe H Li OMe


• A second chiral auxiliary is the (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 O O O O Zn ZnBr S S 2 O O O O S H O MgBr O MeO MeO MeO O Ar

Raney Ni nuc O O MeO O O Ar2COCl O MeO H OMe H O Ar O (–)-podorhizon 95% ee • 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 • 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 O Ph Et2Zn, Cu(OTf)2 (2%), Me lig. (4%), tol, 3h, –30°C O P N O Me Et 94% Ph >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 O Et2Zn, Cu(OTf)2 (2%), lig. (4%), tol, 3h, –30°C

Et 75% 10% ee

Advanced organic 33 Potential mechanism

transmetallation of alkyl group (R) to copper


ZnR2 L2CuX2 copper(II) (with 2 P ligands) reduced to copper(I) by zinc L2CuX L2CuR + RZnX reagent + RZnX O XZn O

R L L Cu R O XZn R alkyl transfer occurs after zinc probably enone and copper bind activates enone

Advanced organic 34 catalysis

(R)-ALB (0.3%) O O t-BuOK (0.27%) O O MS 4Å, THF, rt, 120h + CO Me MeO OMe 2

CO2Me 94% 99% ee

H O O Li Al O O Al O O O O O LLii O O


• 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

Me N CO Bn Bn CO H 2 N 2 BnO C O O O H 2 + cat. (10%), Ph Me BnO OBn Ph O neat, rt, 165h Me 86% 99% ee

Me Me N N CO H N 2 N CO2H

Me BnO H Me CO2Bn H O H CO2Bn CO2Bn

• New small 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 Me Bn X H NR2 N Me X O H•HCl Me + O H R2N 68-90% 84-92% ee

O Me O Me O Me N N N Me Me Me N Me N Me N Me Me Me Me H H NR2 H

X Ar X X H 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 Me O Bn N Me H O H•HCl Me Me + O TMSO O Me R O cat. (20%) DCM / H2O –20 to –70°C, 11–30h 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

O cat. (20%) O KHMDS (20%) Me Me 25°C, 24h N N H CO2Et H O CO2Et O N 80% O BF4 97% ee

Advanced organic 38 Mechanism of Stetter reaction

O O Me Ar Me CO Et H 2 N N O O CO Et N 2 O

N Ar N Ar N O H base N N Me OH CO2Et N H base Ar2 O

O O Ar Ar N N OEt N N OH HO OEt N N O H 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



F3C N N H H EtO C CO Et N 2 2 NO2 Me Me + EtO2C CO2Et NO2 toluene, rt, 24h

86% 93% ee



F3C N N F3C N N H Me H H N Me H H N Me Me O O H O O O H N O N CO Et H 2 H OEt

EtO CO2Et Ph Ph • 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