1

The Diels-Alder reaction Me CO2Me +

Me

Me

Δ

CO2Me

+ CO2Me

major Me

CHO +

minor

Me

Δ

Me

CHO

+ CHO

toluene, 120°C, no catalyst benzene, 25°C, SnCl4

59 96

: :

41 4

Lewis acid improves selectivity

• 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 NMe2

NMe2 CO2Me

CO2Me

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

HOMO

LUMO

NMe2 CO2Me

Advanced organic

2

Endo vs. exo selectivity A

secondary orbital overlap

H

H

A

A

endo B

A

B

D

C

H C D

A

D B

C

H

C

B D

favoured

D B endo

H

A

A C

H H

≡

H

exo B

C

C

≡

D

D B exo

• 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

Advanced organic

3

Diels-Alder reaction A

A

A H

A

H B draw a cube

add the diene

D

C B

D

add dienophile (endo product has substituents directly under diene)

C B

H H

D

remember other substituents present

C B

D

do reaction (make new bonds)

C B

A H H H H

A

H

B

H

H C D H

should be able to see relative stereochemistry

• 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

MeO

OMe

H

+

MeO H

NO2

O2N

H

H NO2

Advanced organic

4

Chiral auxiliaries on the dienophile O

O

BnOH

+

+

Cl

OBn achiral dienophile

O

+

OBn

O OBn 1 : 1 mixture of enantiomers

achiral diene

• 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 O R O HN

R O

O

O

Cl

N

O

Et2AlCl

+

Me (S)-valine derivative

O

N

O O

Me Me

Me

Me

R

chiral dienophile

achiral diene

Me single(ish) diastereoisomer R = H 86% de R = Me 90% de >98% endo

BnOH R O

OBn

single enantiomer

Advanced organic

5

Explanation of diastereoselectivity s-cis favoured

Et2 O Al O H N O Me

O

O

Me N

Et2AlCl2 Et Et Al O O

O N

Me Me

s-trans disfavoured

Et2 O Al O H N O Me Me

O

Et2 O Al O H N O Me

Me Me

Me

lower face blocked

• 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 Advanced organic

6

Camphor-derived auxiliary Me

Me

R

O N

R

+

TiCl4 –78°C

H

S O O

Me

O

N O2S

Me Me R = H 99% de R = Me >97% de >98% endo

Me

R

Me

Me

R

N S

O

O O Ti Ln

N SO2

O

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

7

Chiral auxiliaries II phenyl group blocks lower face

H Me

O

O BnO

Me

Me

AlCl3

OBn

O

BnO

H

Me

Me

≡

≡

+

Me

O

Me

O

diene approaches from the top

H CO2R

Me

O Me

BnO

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

O

OH

MeO

O

OMe H Ph

B(OAc)3

+ O

H Ph

H

O

OH

H

O >95% de endo

Advanced organic

8

Chiral catalysis and the Diels-Alder reaction O Me MeO +

N

MeO

cat.

Br

H

O Me N

Br

H

O

O >97% ee

Me Me Me

F3CO2S

Me

N

Al

N

SO2CF3

Me

• 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

Advanced organic

9

Chiral catalysis and the Diels-Alder reaction II O

O +

N

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

H O

O O

N

Cl

N

N

Cl

Cl

Cl

O

92% ee

• 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 O

O BH3 / HOAc

+ OH

O

Ph

H

OMe

OH OH

O

H

>98% ee

OH OMe Ph

Advanced organic

10

Organocatalysis and the Diels-Alder reaction OMe

cat. (20%) HClO4

O +

COEt

Et

OMe 96% ee endo / exo >200 : 1 Me

O Ph

O

Me

N N H

O

Me

Ar N Me

O

N

N

N

OMe

O Et

Et Me

• 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 Advanced organic

11

Organocatalysis and the Diels-Alder reaction II OMe

O +

Ph

H

O

1. cat. (10%) 2. TFA

Ph

O O

TBSO

Ph Tf

Ph

N

N

O 87% ee Tf

H H Ph

TFA H

Ph

O

Me

Tf

N N MeO H O O H Ph TBSO

Tf

O TBS

Ph

O

H

O

• 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 Advanced organic

12

Organocatalysis III TBSO H

1. cat. (10%) 2. AcCl

Ph

+ Me

N

Ph

Me

Me

O

Ph

>98% ee

OH OH

O Ph

O

Ph O

O

Me

H

O

AcCl

Ph TBSO

O O H O H O H

Ph

H O Ph Me

N

Me

• 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 Advanced organic

13

[3,3]-Sigmatropic rearrangements R2

R2

R2

heat X R1

X R3

R1

X R3

R1

R3

• A class of pericyclic reactions whose stereochemical outcome is governed by • • •

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 R

c

X a

c b

d

R2 d

c

a R

X b R2

R

a

X

d

R

X b

H

the

R2

H

a b

R2 c

d

Advanced organic

14

Cope rearrangement Ph

H

Me Me

Ph

Ph

Me

H Me 91%

Me

Me

H

Me

Ph Me

Me Ph

1,3-diaxial interactions disfavoured

Me H 9%

• 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’

Advanced organic

15

Claisen rearrangements Claisen rearrangement OEt

OH +

Hg+

O

O

heat

H

Johnson-Claisen rearrangement

OH +

MeO OMe Me

O

H+

OMe

O

heat

OMe

OMe

Eschenmoser-Claisen rearrangement

OH +

MeO OMe Me

O

H+

NMe2

O

heat

NMe2

NMe2

Ireland-Claisen rearrangement O

OH + Me

O O

Et3N Me

R3SiCl base

O Me

O

O

heat OSiR3

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

O OSiR3

rearrangement Advanced organic

16

‘Enantioconvergent’ synthesis SET reduction gives most stable alkene

OH

Na NH3

Me Me

OH

Me

Me

NMe2

MeO OMe

O

NMe2

Me

O

Me

H

Me

Me

Me

Me

NMe2

Me

Me Me

≡

H

NMe2

H

NMe2 H

H

i-Pr

i-Pr

O

Me

i-Pr

H H

Me

O

i-Pr

O

Me

O Me2N

H

Me

H

Me2N

Me

Me

NMe2 Me

≡

same configuration

H2 Lindlar cat.

OH Me

OH

Me

NMe2

MeO OMe Me

Me

O

NMe2

Me

Me

Me

O

Me

NMe2 O Me

H

Me Me

Me

Me

heterogeneous hydrogenation leads to syn addition of H2

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

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

Advanced organic

17

Ireland-Claisen reaction

H 1. LDA, THF 2. R3SiCl

O

OSiR3 Me

Me Me

O

O

OSiR3 Me

H

OSiR3

O Me

H

H

O

Me

Me

OSiR3 Me

Me

O Me

H

1. LDA, THF/HMPA 2. R3SiCl

H

O Me

OSiR3

OSiR3 Me

Me Me

O H

O

OSiR3 Me Me

O H

Me

OSiR3 Me

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

Advanced organic

18

Substrate control in Ireland-Claisen rearrangement methyl group is pseudo-equatorial

Me

Me O O 91% ee

OH

1. LHMDS 2. TMSCl

Me O

Me O

H

H

Me H OTMS OTMS

OTMS Me

H OTMS OTMS

Me

HO2C Me 98% syn 91% ee

• 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

Advanced organic

19

Auxiliary control in the Ireland-Claisen rearrangement N

Ar* Me

O N O

Ar* Me

Me LDA

Me

O

O Me

Me

Li

Me

N

Ar*

Me Li

N

anti / syn 98:2 94% de for anti

Ar*

Me NHAr* Me

Ar*NH2 =

O

OMe NH2

• 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... Advanced organic

20

Chiral reagent control in the Ireland-Claisen rearrangement

i-Pr2NEt CH2Cl2 –78°C

R*2B

OH

O Me

O Ph

O O

Me Me

+

ArO2S

N

Ph

B

N

warm

Me >97% ee

Me

SO2Ar

R*2B

Br

OH

O warm

Et3N Tol / hexane –78°C

Me

O

O

O

Me

Me Me

Me 96% ee

• 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

Advanced organic

21

Chiral catalyst control in the Ireland-Claisen rearrangement Ph MeAl(OR*)2 O

Si Me

Me

Ph

Ph

SiMe3

O

O H

Me

SiMe3

SiMe2t-Bu

MeAl(OR*)2 =

O O

Al Me

SiMe2t-Bu

• 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

Advanced organic

22

The Heck reaction R1

X

+

cat. PdX2 R2 R3N [R33P]

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

R1

R2

• 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 Br

R3NH Br L Pd L

oxidative addition

R3N H

L

L Pd Br L +L H

L Pd Br

Pd Br

Pd(0) (14e) Pd(II) (16e)

L Pd(II) (16e)

–L L

Pd(II) (16e)

Pd Br

H

syn addition

β-hydride elimination Br

Pd

L

Advanced organic

23

Alkene isomerisation 0.01% Pd(OAc)2 R3N

+ O

I

L Pd I δ+

O

δ–

O

100°C

syn addition

Pd(I)Ln H

H

O

β-hydride elimination

Ph O

L hydroI palladation Pd H

Ph O

Pd(I)Ln H

H

Ph O O H Pd L I

Ph

Ph

O

O

H

Pd(I)Ln

L Pd I H

• 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 Advanced organic

24

Enantioselective Heck reaction Pd[(R)-BINAP]2 proton sponge

OTf + O

CO2Et

NMe2 NMe2

O EtO2C 62% >96% ee

PPh2 PPh2 proton sponge (R)-BINAP

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

+ O

TfO

O O

PPh2 N 92% >99% ee

t-Bu lig amino acid derivative

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

25

Enantioselective Heck reaction II TBSO

TBSO

Pd[(R)-BINAP]Cl2 AgPO4, CaCO3

I

N Me

O

H 78% 82% ee

PPh2 PPh2

O N O

Pd2(dba)3 (R)-BINAP

Me I

O

O

Ag3PO4 N,N-dimethylaniline

Me N

(R)-BINAP

O O 71% ee

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

26

Suzuki-Miyuara reaction L Pd0 L –L R2

reductive elimination

L Pd0

oxidative addition

X R2

R1

L Pd

X R1 L

Pd

R2

R2 transmetallation

R1

B(OH)2

• 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...

Advanced organic

27

Enantioselective biaryl formation Me O

B

(PdClC3H5)2 lig1 CsF

+

Me

Me

O

Me

I

PPh2 NMe2 Fe H Me lig1

60% 85% ee

Br P(O)(OMe)2

+

Pd2(dba)3 (0.2%) lig2 Me

Me

NMe2

P(O)(OMe)2

PCy2

B(OH)2 95% 86% ee

lig2

• 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 Advanced organic

28

Other catalytic enantioselective reactions Br

O Ph

Me

N

+

O

Pd2(dba)3 (1%) lig1

Ph

NaOt-Bu

Me

Me O

N

i-Pr2P

Me 80% 93% ee

lig1

• 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

O

O L2 (10mol%), PhH, 22°C, 48h

N Me

N

i-Pr

i-Pr

Ar Me

Me

Me 91% 98% ee

N

O Mo THF Me O Ar Ph Me L2

Advanced organic

29

Enantioselective Negishi reactions NiCl2•glyme (10mol%), L1 (13mol%), DMI:THF (7:1), 0°C

O Bn

Et

N Ph

+

hex

ZnBr

O Bn

Et

N

Ph hex 90% 95% ee

Br

NiBr2•diglyme (10mol%), L1 (13mol%), DMA, 0°C

Br O + BrZn

O O

O

Cl

Cl 82% 91% ee

O N

i-Pr

O

N N L1

i-Pr

• 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!!! Advanced organic

30

Summary of methods for stereoselective synthesis Method

Advantages

Disadvantages

resolution

both enantiomers available maximum 50% yield

synthesis of (–)-propranolol

chiral pool

100% ee guaranteed

synthesis of (R)-sulcatol

often only 1 enantiomer available

Examples

chiral auxiliary often excellent ee’s; built in extra steps to introduce resolving agent and remove auxiliary

oxazolidinones

chiral reagent

alpine-borane®, Brown allylation reagents

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

chiral catalyst economical; only small amounts of recyclable material used

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

only a few reactions are asymmetric hydrogenation; really successful; frequently Sharpless epoxidation a lack of substrate generality

• 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... Advanced organic