Advanced organic

The Diels-Alder reaction

• Diels-Alder (DA) reaction is incredibly valuable method for the synthesis of 6-rings• It is not within the remit of this course to go into detail about this reaction • We are interested in the stereochemical outcome but need a bit of revision...• Normally DA is highly regioselective (as seen above)• It is controlled by the ‘relative sizes’ of the p orbitals in the LUMO & HOMO involved• More accurately referred to as the orbital coefficients • In the presence of a Lewis acid dienophile is polarised giving higher regioselectivity

and a faster reaction

1

NMe2

+CO2Me

NMe2CO2Me

NMe2CO2Me

HOMO LUMO

Me

+CO2Me

Δ +

MeCO2Me

Me

CO2Memajor minor

Me+

CHOΔ

Me

CHO+

Me CHO

toluene, 120°C, no catalystbenzene, 25°C, SnCl4

5996

::

414 Lewis acid

improves selectivity

regioselectivity often follows simple electronic argument (consider which C is δ+ve or δ–ve)

Advanced organic

B

A

D

C B

AH

HDHC

H AC

DB

≡exo

exo

B

AH

DHCH

H AC

DB

≡

endo

B

A

D

Cendo

B

AC

D

Endo vs. exo selectivity

• Endo transition state & adduct is more sterically congested thus thermodynamically less stable

• But it is normally the predominant product• The reason is endo transition state is stabilised by π orbital overlap of the group on

C or D with the diene HOMO; an effect called ‘secondary orbital overlap’

• The reaction is suprafacial and we observe that the geometry of the diene & dienophile is preserved

2

favoured

secondary orbital overlap

Advanced organic

Diels-Alder reaction

• The ‘cube’ method is a nice way to visualise the relative stereochemistry

• Finally, remember that the dienophile invariably reacts from the less hindered face• If you are a little rusty on the Diels-Alder reaction either re-read your lecture notes or

any standard organic text book

3

draw a cube

add the diene

add dienophile (endo product has

substituents directly under diene)

remember other substituents

present

do reaction (make new

bonds)

A

B CD B

A

CD B

AH

H

HH C

D

A

B

should be able to see relative stereochemistry

CD

A

B

H

HH

H CD

HH

HHB

A

≡

OMe

NO2

+

HMeO

H

O2N NO2

H

HMeO

Advanced organic

+ O N O

O

MeMe

single(ish) diastereoisomer

Et2AlClR

R = H 86% deR = Me 90% de>98% endo

achiral diene

ON

O

MeMe

O

R

chiral dienophile

Cl

O

OHN

O

MeMe

(S)-valine derivative

R

1 : 1 mixture of enantiomers

O OBn

+

O OBnCl

O BnOH

OBn

O

achiral diene

+

achiral dienophile +

Chiral auxiliaries on the dienophile

• One diastereoisomer is formed - the endo product• But mixture of enantiomers • If we add a chiral auxiliary then there are two possible endo diastereoisomers• But one predominates - thus we can prepare a single enantiomer

4

O OBn

BnOH

single enantiomer

R

Advanced organic

ON

O

MeMe

OAl

Et Et

NO

Et2Al O

OH

MeMe

Et2AlCl2

ON

O

MeMe

O

NO

Et2Al O

OH

MeMe

NO

Et2Al O

OH

MeMe

Explanation of diastereoselectivity

• Coordination to the Lewis acid activates dienophile• The rigid chelate governs reactive conformation (s-cis) as s-trans disfavoured• iso-Propyl group blocks bottom face• Diene’s approach maximises secondary orbital overlap and favours endo product

5

lower face blocked

s-cis favoured

s-trans disfavoured

Advanced organic

Me Me

NS O

R

O O TiLn

Me Me

NS

OO

O

R +TiCl4–78°C

RH

NOO2S

MeMeR = H 99% deR = Me >97% de>98% endo

Camphor-derived auxiliary

• A range of auxiliaries can be utilised• Most give good diastereoselectivities

6

Me Me

NSO2 O

R

Advanced organic

Me

O

O MeMe

BnO

CO2R

H

BnO

≡Me

O

O MeMe

HH

OBn ≡

BnOMe

O

O MeMe

AlCl3+

Chiral auxiliaries II

• It is possible to attach the chiral auxiliary to the diene as well

7

O

O OH

O

OOMe

H Ph +B(OAc)3

O

O

OHO

O

H

H

MeO

H Ph

>95% deendo

phenyl group blocks lower face

diene approaches from the top

Advanced organic

Chiral catalysis and the Diels-Alder reaction

• The fact the Diels-Alder reaction is mediated or catalysed by Lewis acids means enantioselective variants are readily carried out

• The aluminium catalyst above has been utilised in enolate chemistry (aldol) reaction and is very effective in this Diels-Alder reaction

8

MeON

O

O

Me

Br+cat.

N

O

O

Me

Br

H

H

MeO

>97% ee

NAl

N

Me

SO2CF3F3CO2S

Me

Me Me

Me

Advanced organic

Chiral catalysis and the Diels-Alder reaction II

• The oxazolidinone substituent on the dienophile is important• Good selectivities are only achieved when there are two binding points on the

dienophile• The two carbonyl groups allow a rigid chelate to be formed & maximise the

commincation of chirality

9

N NCl

Cl Cl

Cl+

N O

O O lig. (10%)Cu(OTf)2 (9%) H

O N O

O

92% ee

OH O

O

+

OMe

BH3 / HOAc

O

OOHH

H

OMe>98% ee

OH

Ph

OH

Ph

Advanced organic

OMeN

N

Et

ArO Me

N

NMeO

OMeEt

96% eeendo / exo >200 : 1

cat. (20%)HClO4

OMe

+Et

O COEt

OMe

Organocatalysis and the Diels-Alder reaction

• Organic secondary amines can catalyse certain Diels-Alder reactions• The reaction proceeds via the formation of an iminium species• This charged species lowers the energy of the LUMO thus catalysing the reaction• In addition one face of dienophile is blocked thus allowing the high selectivity

10

NH

NMe

Ph

O

O Me

Advanced organic

TFA

OPh

OO

O

TBS

Me

OH

O

HPh

H

N N

PhPh

TfTf

TBSO

MeO

TBSO

OMe O

HO

Ph+1. cat. (10%)2. TFA

O

OPh

O87% ee

Organocatalysis and the Diels-Alder reaction II

• This is an example of a hetero-Diels-Alder reaction• The aldehyde is the dienophile• We have to use a very electron rich diene• The amine catalyst acts as a Lewis acid via two hydrogen bonds

11

OPh

OO

O

TBS

MeH

NH H

N

Ph Ph

Tf Tf

Advanced organic

O

Ph

NMeMe

TBSOO

HO H O H O

H

Ph

HO

TBSO

NO

H Ph

MeMe

+1. cat. (10%)2. AcCl

O

PhO

>98% ee

Organocatalysis III

• Another hetero-Diels-Alder reaction• It looks very similar to the previous reaction but...• It is believed that only one hydrogen bond activates the aldehyde• The other is used to form a rigid chiral environment for the reaction

12

AcClOHOHO

O

Ph Ph

Ph Ph

MeMe

Advanced organic

bX

c

HR2

dR

a

bX

c

HR2

dR

aX

R

R2

da b

c

heatX

R2

R3R1

X

R1 R3

R2

[3,3]-Sigmatropic rearrangements

• A class of pericyclic reactions whose stereochemical outcome is governed by the geometric requirements of the cyclic transition state

• Reactions generally proceed via a chair-like transition state in which 1,3-diaxial interactions are minimised

• General relationship is outlined below...• Indicates that geometry of double bonds important to controlling relative

stereochemistry

13

X

R1 R3

R2

X

R2

R

dcb

a

Advanced organic

H

Me

MePh

H Me

PhMe

91%

H

Ph

MeMe

Me H

MePh

9%

Me

Me

Ph

Cope rearrangement

• A very simple example of a substrate controlled [3,3]-sigmatropic rearrangement is the Cope rearrangement

• To minimise 1,3-diaxial interactions phenyl group is pseudo-equatorial • Note: the original stereocentre is destroyed as the new centre is formed• This process is often called ‘chirality transfer’

14

1,3-diaxial interactions disfavoured

Advanced organic

Claisen rearrangements

• One of the most useful sigmatropic rearrangements is the Claisen rearrangement and all it’s variants

15

Claisen rearrangement

Johnson-Claisen rearrangement

Eschenmoser-Claisen rearrangement

Ireland-Claisen rearrangement

OH +OEt Hg+ O O

H

heat

OH +Me OMe

MeO OMe H+ O

OMe

O

OMe

heat

OH +Me NMe2

MeO OMe H+ O

NMe2

O

NMe2

heat

OH +Me O Me

O O Et3N

Me

O

O

O

OSiR3

O

OSiR3

heatR3SiClbase

Advanced organic

Me

Me

OMe

NMe2

Me NMe2

MeO OMe

Me

Me

OH MeH2

Lindlar cat.

MeNMe2

Me

Me O

≡

MeMe

Me

NMe2

O HMe

Me

O

Me

NMe2

Me NMe2

MeO OMeNaNH3 Me

Me

OH

MeMe

Me

Me

OH

Me

Me

Me

OH

‘Enantioconvergent’ synthesis

• Both enantiomers of initial alcohol can be converted into the same enantiomer of product

• This process (Eschenmoser-Claisen) shows the importance of alkene geometry

16

SET reduction gives most stable alkene

heterogeneous hydrogenation leads to syn addition of H2

O

H NMe2

i-Pr

Me

O

H NMe2

i-Pr

Me

HH

Me2N

O

H Me

Hi-PrMe2N

O

H Me

Hi-Pr

same configuration

MeH

Me

NMe2

O Me

≡

Advanced organic

O

H

H

OSiR3MeMe O

H

H

OSiR3MeMe

O

OSiR3Me

Me

1. LDA, THF/HMPA2. R3SiCl

O

MeMe

OSiR3

O

H

Me

OSiR3Me

H

O

OSiR3Me

MeO

H

Me

OSiR3Me

H

1. LDA, THF2. R3SiCl

O

MeOSiR3

Me

O

MeMe

O

Ireland-Claisen reaction

• Enolate geometry controls relative stereochemistry• Therefore, the enolisation step controls the stereochemistry of the final product

17

Advanced organic

Substrate control in Ireland-Claisen rearrangement

• In a similar fashion to the Cope rearrangement we saw earlier, the Ireland-Claisen rearrangement occurs with ‘chirality transfer’

• Initial stereogenic centre governs the conformation of the chair-like transition state• Largest substituent will adopt the pseudo-equatorial position

• Once again, the relative stereochemistry is governed by the geometry of the enolate

18

O

Me Me

OHO

91% ee

1. LHMDS2. TMSCl

H

O

OTMS

H

Me

OTMS

Me

H

O

OTMS

H

Me

OTMS

Me

HO2CMe

OTMS

Me98% syn91% ee

methyl group is pseudo-equatorial

Advanced organic

O

NAr*

Me

MeN

O

Me

Me

Li Ar*N

O

Me

Me

Li Ar*

O

NAr*

Me

Me

anti / syn 98:294% de for anti

Me

Me

O

NHAr*

LDA

Auxiliary control in the Ireland-Claisen rearrangement

• Use of chiral auxiliaries allows the control of absolute stereochemistry• Good news is that it is hard to predict and so will not be examined...

19

OMeNH2

Ar*NH2 =

Advanced organic

O

OHMe

Me96% ee

warmO

O

Me

R*2B

MeEt3NTol / hexane

–78°C

O

OHMe

Me>97% ee

warmO

OMe

Me

R*2Bi-Pr2NEtCH2Cl2–78°C

O

OMe

Me

+ NBN

Ph Ph

ArO2S SO2Ar

Br

Chiral reagent control in the Ireland-Claisen rearrangement

• Funnily enough, it is possible to carry the reaction out under “reagent” control • Although, it could be argued that this is just a form of temporary auxiliary control!• Enolate formation (enolate geometry) governs relative stereochemistry

20

Advanced organic

Chiral catalyst control in the Ireland-Claisen rearrangement

• It is also possible to perform the reactions under chiral catalyst control• Presumably, the Lewis acid coordinates to the oxygen & influences the reactive

conformation thus controlling enantioselectivity

21

O

Ph

SiMe

MeMe

HO

SiMe3

Ph

O

Ph

SiMe3

MeAl(OR*)2

OO

Al Me

SiMe2t-Bu

SiMe2t-Bu

MeAl(OR*)2 =

Advanced organic

The Heck reaction

• The Heck reaction is a versatile method for the coupling sp2 hybridised centres• Again it is not the purpose of this course to teach organometallics etc

22

R1 X + R2cat. PdX2

R3N[R3

3P]

R2 R1

R1 = Ar, ArCH2,X = Br, I, OTf

Br

PdL

LBr

oxidative addition

PdL

Br

syn addition

R3N

R3NH Br

Pd(0)(14e)

L Pd L

L Pd BrH

L

Pd

H

PdLH

Br

LBr

–L

+L Pd(II)(16e)

Pd(II)(16e)

Pd(II)(16e)

β-hydride elimination

Advanced organic

O

Ph

PdI

L

H

O

Ph

Pd(I)Ln

H

hydro-palladation

β-hydride elimination

O

PhPd

IL

HO

Pd IL

δ+ δ–

syn addition

O

Pd(I)LnH

HH

Alkene isomerisation

• β-Hydride elimination is reversible• This alkenes can ‘walk’ or migrate to give the most stable alkene• Only restriction is every step must be syn

23

O+

I

O

0.01% Pd(OAc)2R3N

100°C

O

Ph

Pd(I)LnH

O

Ph

PdHI

LO

Advanced organic

Enantioselective Heck reaction

• With the use of chiral ligands the Heck reaction can be enantioselective• Remember that we often see alkene migration

24

OTf

CO2Et+

O

Pd[(R)-BINAP]2proton sponge

O

EtO2C62%

>96% ee

NMe2 NMe2

proton sponge

PPh2PPh2

(R)-BINAP

O TfO+

Pd(dba)2 (3%), lig (6%)i-Pr2NEt

O

92%>99% ee

N

O

PPh2

t-Buligamino acid derivative

Advanced organic

Enantioselective Heck reaction II

• Intramolecular variant allows the construction of ring systems• The silver salt accelerates the reaction and prevents alkene isomerisation

25

I

TBSO Pd[(R)-BINAP]Cl2AgPO4, CaCO3

NMe

O H

TBSO

78%82% ee

O

O

N

O

I

Me Pd2(dba)3(R)-BINAP

Ag3PO4N,N-dimethylaniline

O

O

NO

Me

71% ee

PPh2PPh2

(R)-BINAP

Advanced organic

Suzuki-Miyuara reaction

• The Suzuki-Miyuara reaction is (normally) the palladium catalysed coupling of an alkenyl or aryl halide with an alkenyl or aryl boronic acid

• Normally the components should be sp2 hybridised to avoid β-eliminations• Mechanism etc is (surprise surprise) outside the scope of this course but the

wonderful enantioselective examples are not...

26

Pd0L L

Pd0L

–Loxidative addition

transmetallation

reductive elimination

PdL

X

B(OH)2

X

PdL

R1

R2

R1

R2

R2

R1R2

Advanced organic

Enantioselective biaryl formation

• Virtually every (if not every...) reaction we have covered in this course has formed a stereogenic centre (central chirality)

• These two examples form axially chiral compounds• Please note: both ligands are thought to be mono-dentate (in the active species at

least, although they may be bidentate in ‘resting state’) via the phosphine

27

BrP(O)(OMe)2 +

B(OH)2

Me P(O)(OMe)2

Me

95%86% ee

Pd2(dba)3 (0.2%)lig2

PCy2

NMe2

lig2

MeB

O O

+Me

I

(PdClC3H5)2lig1

CsF MeMe

60%85% ee

FePPh2

lig1Me

NMe2H

Advanced organic

Other catalytic enantioselective reactions

• Pd(0) chemitry has been utilised in the enantioselective arylation of enolates• The reaction is related to much of Pd chemistry you have covered• Below is an example of a chiral variant of the Schrock metathesis catalyst• The reaction involves desymmetrisation by selective reaction if one disubstituted

alkene

28

O

NMePh

Me

+

Br Pd2(dba)3 (1%)lig1

NaOt-Bu

O

NPh

Me

Me

80%93% ee

i-Pr2PO

lig1

N

O

Me

Me

N

O

MeMe

L2 (10mol%), PhH, 22°C, 48h

91%98% ee

NMo THF

OOAr

Ar

i-Pri-Pr

Me

Me

Ph

L2

Advanced organic

Enantioselective Negishi reactions

• Last year (2005) saw the first examples of catalytic enantioselective Negishi couplings• The system still has some limitations but is an exciting development• On a practical note, many of the reactions above were run in air!!!

29

BnN

EtO

Ph Br

hex ZnBr+

NiCl2•glyme (10mol%), L1 (13mol%), DMI:THF

(7:1), 0°C BnN

EtO

Ph hex90%

95% ee

Cl

Br

+BrZn O

O

NiBr2•diglyme (10mol%), L1

(13mol%), DMA, 0°C

Cl

OO

82%91% ee

NN

OO

N

i-Pr i-PrL1

Advanced organic

Summary of methods for stereoselective synthesis

30

Method Advantages Disadvantages Examples

resolution both enantiomers available maximum 50% yield synthesis of (–)-propranolol

chiral pool 100% ee guaranteed often only 1 enantiomer available

synthesis of (R)-sulcatol

chiral auxiliary often excellent ee’s; built in resolving agent

extra steps to introduce and remove auxiliary

oxazolidinones

chiral reagent often excellent ee’s; stereoselectivity can be independent of substrate control

only a few reagents are successful and often only for a few substrates

alpine-borane®, Brown allylation reagents

chiral catalyst economical; only small amounts of recyclable material used

only a few reactions are really successful; frequently a lack of substrate generality

asymmetric hydrogenation; Sharpless epoxidation

• Hopefully this course has shown that the area of stereoselective synthesis (or more particularly, methodology for stereoselective synthesis) is a vast & fascinating topic

• There are many reactions we have not covered (there is already far too much material in the course)

• I hope you found the course as interesting as I did...