asymmetric synthesisgjrowlan/stereo/lecture5.pdf · sharpless asymmetric epoxidation ii • sae is...

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Advanced organic 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 1 O HO OH HO 2-deoxy-D-ribose Me Me Me OH (R)-sulcatol 1 2 3 4 5 1 2 3 4 5 In this example, one stereogenic centre is retained All others are destroyed O HO OH HO Me Me Me OH Ph 3 P Me Me 1. MeOH, H 2. MsCl O MsO OMe MsO 1. KI 2. Raney Ni O Me OMe H 2 O O Me OH Me CHO OH

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Advanced organic

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

1

OHO

OH

HO2-deoxy-D-ribose

Me Me

MeOH

(R)-sulcatol

1

23

4

5

1

2

34

5

• In this example, one stereogenic centre is retained • All others are destroyed

OHO

OH

HO

Me Me

MeOH Ph3P Me

Me

1. MeOH, H2. MsCl

OMsO

OMe

MsO

1. KI2. Raney Ni OMe OMe

H2O

OMe OH

Me CHO

OH

Advanced organic

OHO

HOOH

OH

OH

D-mannose

N

HOH

HO

HO

swainsonine

51

23

4

12

34

56

6

‘Chiral pool’ II

• In this example three stereogenic centres are retained• One stereogenic centre undergoes multiple inversion -- but overall it is retained

2

Pd / CH2

OBnO

OO

MeMe

HN

H

H

1. H2, Pd / C, H2. TFAA

OBnO

N3

OO

MeMe

CHO

1. TBAF2. PCC3. Ph3P=CHCHO

OBnO

N3

OTBDPS

OO

MeMe

NaN3

OBnO

O

OTBDPS

OO

MeMe

PCC

OBnO

OTf

OTBDPS

OO

MeMe

1. NaBH42. Tf2O

OBnO

OH

OTBDPS

3 steps OO

MeMe remove

stereogenic centre

stereoselective reduction

two step reversal of stereogenic centre

overall retention of stereochemistry

addition of protecting groups

reduction of alkene &

azide followed by reductive amination

hydrogenolysis of benzyl (Bn) group & reductive amination of resultant

aldehyde

Advanced organic

BHMe

H

H

HBH2

HMeMe Me

1. TMEDA2. BF3•OEt2

Me

1. TMEDA2. BF3•OEt2

Me

(+)-IpcBH2

H

BHMe

HH Me

B

HMeMe Me

H

H

Me

Me MeH

BH3

BH3

(–)-Ipc2BH

Me

MeMeMe

(+)-α-pinene

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 reactionsSubstrate control

3

Advanced organic

Hydroboration: reagent control

• 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

4

Me

Me

1. (–)-Ipc2BH2. H2O2 / NaOH

MeMe

OHHH

H 98.4% ee

BHMe

HH Me

(–)-Ipc2BH

Me

H

1. (+)-IpcBH22. H2O2 / NaOH

H

HOH

Me

66% eeH

BH2

HMeMe Me

(+)-IpcBH2

Advanced organic

O

O PAr2

PAr2

H

H

MeMe

Ar = 2-MeOC6H4

L =

Hydroboration: catalyst control

• 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)

5

+O

BO

H

catecholborane

1. RhL22. H2O2 / NaOH

Cl

H

H HH

HOH

82% ee

O

O PAr2

PAr2

H

H

MeMe

Ar = 2-MeOC6H4

L = HO2CCO2H

OH

OH(2R,3R)-tartaric acid

Advanced organic

1. LiCHCl22. NaClO2[oxidation] Me

Me

H CO2H

88%; 97% ee

Me

1. [Rh(COD)2] .BF4(R)-BINAP / catechol-borane

2.

HO OH

MeMe

MeMe Me

Me

H B OO

Me

Me

MeMe

99%; 97% ee

Hydroboration: catalyst control II

• This second example utilises BINAP and again gives very impressive ee’s

6

Rh

[Rh(COD)2]

PPh2PPh2

(R)-BINAP

• The second part of the reaction gives an example of an alternative stereospecific...transformation of the boron species

Advanced organic

Homogeneous hydrogenation: substrate control

• 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

7

Me

Me OH H2(g)[(Cy3P)Ir(COD)py] PF6

Me OH

H

Me

Me

MeO

i-Pr

H2(g)[(Cy3P)Ir(COD)py] PF6

MeO

i-PrH

Me

IrPCy3N

[(Cy3P)Ir(COD)py]

Advanced organic

Substrate control in acyclic systems

• 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

8

anti 93:7

Me X

OOH

Me

H2(g)[Rh(nbd)(diphos-4)] BF4

Me X

OOH

MeH Me

syn 91:9

Me X

OOH

MeMe

H2(g)[Rh(nbd)(diphos-4)] BF4

Me X

OOH

MeMe H

P

Ph

[Rh(nbd)(diphos-4)]

RhP

Ph

Ph

Ph

Advanced organic

Mechanism of directed hydrogenation

• 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...

9

LM

S

L S+

OH

coordination of the alkene L

ML O

H

HM

L OH

H

L

H2

oxidative addition

HM

L S

O

L

HH

insertion of M–H into C=C

reductive elimination (loss of M–H & formation of

C–H)LM

S

L S+

OH

HH

L = ligandS = solvent

Advanced organic

Explanation of diastereoselectivity

• Once again, allylic strain is responsible for the diastereoselectivity• One diastereoisomeric complex suffers less steric congestion & is favoured

10

R MeMe

OH

anti

R

HH

OH

Me H

RhLL

R

HH

OH

H Me

RhLL

R Me

OH

steric interaction

R MeMe

OH

syn

R MeMe

OHMe

HR

OH

Me H

RhLL

MeHR

OH

H Me

RhLL

steric interaction

Advanced organic

P P

OMe

MeO

RhO

Me NH

CO2H

ArP P

OMe

MeO

Rh O

MeNH

HO2C

Ar

Catalytic enantioselective hydrogenation

• 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...

11

HCO2H

NHAc

MeO

AcO

H2(g)[((S)-DIPAMP)RhL2]

L=solvent MeO

AcO

CO2H

H NHAc

H H

95% ee(S,S)-DIPAMP

P P

OMe

MeO

P P

OMe

MeOO

MeNH

HO2C

Ar

RhL L

Advanced organic

ArPHPh

Rh

H

PAr Ph

O

MeNH

HO2C

Ar

Mechanism for catalytic hydrogenation

12

L

PhPP

Ar

Ph Ar

Rh O

MeNH

HO2C

ArH

H

ArP P

Ph

ArPh

Rh O

MeNH

HO2C

Ar

H2slow

L

ArP P

Ph

ArPh

RhO

Me NH

CO2H

ArH

H

ArP H

Ph

Rh

H

PArPh

O

Me NH

CO2H

Ar

ArP P

Ph

ArPh

RhO

Me NH

CO2H

Ar

H2fast

O

MeNH

HO2C

ArHHH

minor enantiomer

O

Me NH

CO2H

ArHHH

major enantiomer

O

MeNH

HO2C

Ar

+ [DIPAMPRhL2]

oxidative addition fastcomplex more

reactive

oxidative addition

insertion

reductive elimination

One complex more reactive

Advanced organic

N

Ar

H

N

t-BuBn

O Me

HMe

N NH

ArMe

H

PhMe

OH

Me MeMe

NMe

i-PrE

EH

H

Hδ–

δ+

N

Ar Me

H

N

t-BuBn

O Me

Me

H

O

NC

NH2

N

Bnt-Bu

OMe

Cl3CO2

NH

MeO2C

Me i-Pr

CO2MeH H

H

O

NC

H Me

89%; 96% ee

catalyst 10%hydrogen source 1eq

Organocatalytic hydrogenation

• 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)

13

Advanced organic

Me

Me

MeOH

Me

OH

(–)-DET, Ti(Oi-Pr)4, TBHPMe

Me

MeOH

O

>90% ee

(+)-DIPT, Ti(Oi-Pr)4, TBHP Me

OHO

92% ee

Me

Me

MeOH

Me

OH

Sharpless Asymmetric Epoxidation (SAE)

• 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

14

EtO2CCO2Et

OH

OH(–)-DET

i-PrO2CCO2i-Pr

OH

OH(+)-DIPT

Me O

MeMe

OH

TBHP

• Compounds must be allylic alcohols• Second example shows that this limitation allows highly selective reactions

must be allylic alcohol

Advanced organic

OTi

Ot-BuLL

OO

Ot-Bu

OTi

LL

O

t-BuO

OTi

LL

OTi

OLL

Ot-BuTiL4

TBHP+

+

HO

Sharpless Asymmetric Epoxidation II

• 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

15

if you want “O” on top its on your kNuckles so you

use Negative (–)-DET

if you want “O” on top its on your Palm so you use

Positive (+)-DET

using your left hand, the index finger is

the alkene and your thumb the alcohol

R1

R2 R3

OHO

Ti(Oi-Pr)4TBHP

R1

R2 R3

OHO

Ti(Oi-Pr)4TBHP

R3

R1

R2

OH

D-(–)-DET unnatural isomer

“O”

“O”D-(+)-DET

natural isomer

place alkene vertical and

alcohol in bottom right corner

activation of peroxide

Advanced organic

E

OO

O

TiO

O O

O

O

TiO

O

CO2Et

CO2Et

i-Pr

i-Pr

EtOt-Bu

R

HO

RO E

OO

O

TiO

O O

O

O

TiO

O

CO2Et

CO2Et

i-Pr

i-Pr

EtOt-Bu

R

HO

R

t-BuO2H CO2Et

OO

O

TiO

O O

O

O

TiO

O

CO2Et

CO2Et

i-Pri-Pr

i-Pr

EtOt-Bu

OO

O

TiO

O O

O

O

TiO

O

CO2Et

CO2Et

i-Pri-Pr

i-Pr

i-Pr

OEt

EtO

Ti(Oi-Pr)4 +(+)-DET

Mechanism of SAE

16

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

must deliver “O” from lower face

Advanced organic

• SAE works for a wide range of allylic alcohols

• Only cis di-substituted alkenes appear to be problematic

17

R2 OHR2 OH

R1good substrates

high yields and ee's >90%

OHR1

R3

R2 OHR1

R3normally good

ee's >90%few examples

OH

R3 problematicslow reactionsmoderate ee's,

especially with bulky R3

OHO

O

MeMe

OHO

O

MeMe

OHO

O

MeMe

O O

conditions

t-BuO2H, VO(acac)2t-BuO2H, Ti(Oi-Pr)4, (+)-DETt-BuO2H, Ti(Oi-Pr)4, (–)-DET

+

2.3199

:::

1221

• 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

Advanced organic

MeNH2

Ph NHMe

OH1. NaH2. ArCl

Red-Al[NaAlH2(OCH2CH2OMe)2]

Ph OHH

OHSAE(+)-DIPT

Ph OHO

Ph OH

Ph NHMe

O

CF3

fluoxetine

Use of SAE in synthesis

• 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

18

MsCl

Ph OMs

OH

Advanced organic

R2 OHR1

R3 RO

R

R3

R1

R2

OHH

H

R3

R1

R2

OHR

R2 OHR1

R3 R

(–)-DET, Ti(Oi-Pr)4, TBHP

Kinetic resolution

• 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

19

R2 OHR1

R3 R

if allylic alcohol is desired use 0.6eq TBHPif epoxy alcohol is desired use 0.45eq TBHP

slowsteric hindrance fast

racemic mixture

if reaction goes to 100% completion you

get a 1:1 mixture of diastereoisomers

Advanced organic

H

OH

Kinetic resolution II

• 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)

20

Me3Si

C5H11

OH

(+)-DIPT, Ti(Oi-Pr)4, TBHP

Me3Si

C5H11

OH

Me3Si

C5H11

OH+O

>95% ee (R) >95% ee(R/S)

rate of epoxidation (S) : (R) ~700 : 1

OH

O

OH(–)-DIPT

FAST

FASTslow

slow

OH

O wanted

OH

O Omesoreadily

removed

OHH

H

OH

O

slow

OHH

O

FASTslowFAST

Advanced organic

Desymmetrisation in synthesis

• Desymmetrisation has been used in many elegant syntheses

21

OH

OBnOBn

(–)-DIPT, Ti(Oi-Pr)4, TBHP

OH

OBnOBnO

O

OBnOBnO

O

NHPhPhNCO

pyr

BF3•OEt2

HOOBn

OO

O

OBn

O

OH

OHOH

OH

HO2C

HO

KDO

Advanced organic

Jacobsen-Katsuki epoxidation• SAE is a marvelous reaction but suffers certain limitations

substrate must be an allylic alcoholcis-disubstituted alkenes are poor substrates

• (salen)Mn catalysts with bleach (NaOCl) are good for these substrates

22

NNMn

OOt-Bu

t-Bu t-Bu

t-Bu

HHCl

(S,S)-Mn(salen)

H

H

NN

O OMn

O

manganese(IV) oxo species active oxidant

L S

L = larger groupS = smaller group

(S,S)-cat (2-15%) NaOCl, pH 11 L S

O

O

OO

Ph CO2Me

O

O CNMe

MeO

94% ee ≥95% ee 97% ee

Advanced organic

Jacobsen-Katsuki oxidation in synthesis

• This example demonstrates the industrial potential of such catalytic systems

23

N

NN

HN

OH CHBn

CONHt-Bu

OH

O

Indinavir(Merck / HIV treatment)

(salen)Mn catNaOCl, R3N+–O–

O2000kg scale

H2SO4MeCN OH

OH

N CMe

N

O

Me

OH

NH2

H2O

MeCN

Advanced organic

Organocatalytic epoxidations

• 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

24

PhMe

cat.oxone, K2CO3

DME / H2O, –15°CPh

MeO

100%; 86% ee

O

F

F

cat.F

F

OO

RH

H

OO

RR

H

HO

R

Advanced organic

Sharpless Asymmetric Dihydroxylations (SAD)

• 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...

25

C5H11CO2Et

K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH,

H2O, 0°C, (DHQD)2-PHALC5H11

CO2EtOH

OH99% ee

• 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

N

HO

N

MeO

EtN

HO

N

OMe

EtNN

(DHQD)2-PHAL

N

HO

N

OMe

N

HO

N

MeO

N NEt Et

(DHQ)2-PHAL

Advanced organic

Sharpless Asymmetric Dihydroxylation II

• Reaction works on virtually all alkenes• Exact mechanism not known but...• It is relatively predictable (but not as predictable as the SAE)

26

PhPh

PhPh

OH

OHPh

PhOH

OH98.8% ee >99.5% ee

K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH,

H2O, 0°C, (DHQ)2-PHAL

K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH,

H2O, 0°C, (DHQD)2-PHAL

small steric barrier

large steric barrier

attractive area - attracts flat, aromatic substituents or large, hydrophobic aliphatic

groups

H

MS

L

OsO4

(DHQD)2PHAL

OsO4(DHQ)2PHAL

Advanced organic

SAD & Sharpless aminohydroxylation reaction

• 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

27

Me

OO

Me OsO4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH, H2O,

0°C, (DHQD)2-PHAL Me

OO

Me

HO

OH

95% ee

TsOH

O

O

Me

Me

exo-Brevicomin

Ph Oi-Pr

O

Ph Oi-Pr

OAcNH

OHregioselectivity >20:1

94% ee

Ph Oi-Pr

OHCl.NH2

OH

HCl, H2O

AcNHBr, LiOH, K2OsO2(OH)4, (DHQ)2-PHAL

ONH

Ph

O OPh

OH

Me

OBz

Me

Me

AcO OHMe

H OAcO

O

HOtaxol

Advanced organic

Me Me

NHSO

O

HO Me

O Et

LiOH

Me Me

NS O

OO

Et

MeH

90% de

Me Me

NSO O

OMg

HMe

MgEt

ClEt

Cl

Me Me

NSO O

OMg

MgEt

ClEt

Cl

HMe

EtMgCl

Me Me

NS O

Me

OO

Me Me

NHS

OO

Oppolzer's camphor sultam

Diastereoselective conjugate additions

• 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

28

trans conformation disfavoured

cis conformation

favouredchelation restricts rotation

Advanced organic

Me Me

NHSO

O

HO Me

O Bu

Me

+

Me Me

NS O

OO

Bu

MeH

95% de

MeH

Me Me

NSO O

OMg LL

Bu

MeH

MeI

Me Me

NS O

Me

OO

1. BuMgCl2. MeI

Chiral auxiliary to control two stereocentres

• 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)

29

addition as slide 28

electrophile approaches from

bottom face

LiOH

Advanced organic

O

N

Ph

OMe

R1

LiR2

H

O

N

Ph

OMe

R1

LiHR2

O

N

Ph

OMe

R1R2

H

H2O

R2–Li1. LDA2. R1CHO3. CF3CO2H

O

N

Ph

OMe

R1

H

O

N

PhMe

OMe

Alternative chiral auxiliaries I

• 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

30

aldol-like reaction & acid catalysed elimination

hydrolysis

R1CO2H

R2HPh

OH

OMeNH2

H3O

95-99% ee

Advanced organic

Raney Ni

O

O

H

Ar

O

OS

O

MeO H

Ar

O

O

MgBr

ZnBr2

O

O

SOZn

MeO

L L

O

OS

O

MeO

Alternative chiral auxiliaries II

• 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

31

nuc

O

O

H

O

O

OOMe

MeO

MeO

(–)-podorhizon95% ee

Ar2COCl

Advanced organic

Enantioselective catalytic conjugate addition

• 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

32

O

75%10% ee

O

Et

Et2Zn, Cu(OTf)2 (2%), lig. (4%), tol, 3h, –30°C

O Et2Zn, Cu(OTf)2 (2%), lig. (4%), tol, 3h, –30°C

O

Et94%

>98% ee

OO

P NMe

Ph

MePh

lig.

Advanced organic

OCuR

LL

XZnR

Potential mechanism

33

copper(II) (with 2 P ligands) reduced to

copper(I) by zinc reagent

transmetallation of alkyl group (R) to copper

alkyl transfer occurs after enone and copper bind

zinc probably activates enone

L2CuR + RZnX

ZnR2

OO

XZn

R

L2CuX2

L2CuX+

RZnX

ZnR2

Advanced organic

Li

OAl

O O

OO

O O

RO OR

H

Li

OAl

O O

OO

Li

OAl

O O

O

Bifunctional catalysis

• 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

34

O(R)-ALB (0.3%)t-BuOK (0.27%)

MS 4Å, THF, rt, 120hO

MeO

O

OMe

O

CO2Me

CO2Me

94%99% ee

+

OOAl

OO

Li

(R)-ALB

Advanced organic

N

N CO2H

Me

Me

H

CO2Bn

CO2Bn

N

N CO2H

Me

Me

H

CO2Bn

BnOOH

Ph Me

O

BnO OBn

O O

N

NH

CO2HBn

Me

cat. (10%), neat, rt, 165h Ph

Me

CO2BnBnO2C

O

86%99% ee

+

Organocatalysis

• 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

35

Advanced organic

N

N

MeO

Me

MeMe

H

X ArH

N

N

MeO

Me

MeMe

H

X

N

N

MeO

Me

MeMe

H

X

NR2

H

X O

H

NR2

N

NH•HCl

Bn

MeO

Me

MeMe

R2N

O

HX

68-90%84-92% ee

+

Organocatalysts II

• 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

36

steric hindrance results in predominantly one

conformation

Advanced organic

Organocatalysts III

• 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)

37

OTMSO Me R O

HO

HR

OO

Me

N

NH•HCl

Bn

MeO

Me

MeMe

cat. (20%)DCM / H2O

–20 to –70°C, 11–30h77%

syn:anti = 1-31:184-99% ee

+

MeH

O

O CO2Et O

O

CO2EtMe

cat. (20%)KHMDS (20%)

25°C, 24h

80%97% ee

NN

NO

OMe

HBF4

Advanced organic

Mechanism of Stetter reaction

38

NN

NO

Ar

NN

N

Ar

Ar2

OHH

NN

N

Ar

HO

OMe

H base

OEt

O

base

O

CO2EtMe

O HN

N

N

Ar

NN

N

Ar

OH

O

Me

O

OEt

MeH

O

O CO2Et

base

O

O

CO2EtMe

• The Stetter reaction is analogous to the activity of thiamine (vitamin B1) in our bodies and the reaction is thus biomimetic

Advanced organic

N N

S

F3C

CF3

NH HO O

N

Ph

H

CO2Et

CO2EtH

MeMe

N N

S

F3C

CF3

H HO O

N

Ph

H

N MeMe

HO

O

OEtEtO

H

H

NO2NO2

EtO2C CO2EtNH

NH

S

F3C

CF3

NMeMe

EtO2C CO2Ettoluene, rt, 24h

86%93% ee

+

Organocatalytic bifunctional catalysis

• 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

39