Advanced organic

Stereoselective reactions of alkenes

• Earlier, we saw that stereospecific reactions can produce single diastereoisomers• If there is a pre-existing stereogenic centre reactions can be stereoselective• In other words, the faces of the alkene are diastereotopic

• Following two examples show highly diastereoselective iodolactonisations

1

OOHMe

I2I

Me O O

OOH

MeI2

O

IMe

O82% de

O

Me

OH

I2

OI

Me

O88% de

• These cyclisations are probably under thermodynamic control • This means the reactions are reversible and equilibrate• Therefore the product is the most stable compound

• If the reactions are under kinetic control we have to look at other factors and need to...look at conformation again...

Advanced organic

Stereoselective reactions of alkenes II

• Two diastereoisomers formed as a result of attack from the two diastereotopic faces• Look at possible conformations...• Arguably the lowest energy conformations have greatest separation of substituents

2

Me SiMe2Ph

Me

Me SiMe2Ph

MeO

Me SiMe2Ph

MeO

m-CPBA +

>95% <5%

• The control of conformation by the interaction of methyl group and stereocentre is...called allylic strain or A(1,3) strain

Me

MeH

if no cis substituent then only small

energy difference

HH H

MeMe

H

HH H

HMe

Melowest energy: H

eclipses plane of alkeneslightly higher energy: Me eclipses plane of alkene

rotate bond

Me

MeMeH

cis substituent present then only

ONE conformation

MeH H

MeMe

HMeH H

HMe

Melowest energy: H

eclipses plane of alkenehigh energy: Me–Me

interaction disfavours conformation

HH H

HMe

Me

HH H

MeMe

H

H HMe

HH

Me

MeMe

HMe

Me

HX

Advanced organic

Stereoselective reactions of alkenes III• Apply this knowledge to the real system...

3

m-CPBA

>95%Me

Me

H SiMe2Ph

O

MeH H

HSi

Me

MeMe

Ph

OMeH H

HSi

Me

MeMe

Ph

Me

Me m-CPBA

H SiMe2Ph

m-CPBAX

lowest energy conformation

silyl group blocks approach

X

m-CPBA approaches from unhindered face

<5%Me

Me

H SiMe2Ph

O

HMe

HMe

H

Si MePh Me

m-CPBA

formation of minor diastereoisomer results

from m-CPBA approaching alkene in above conformation or

approaching passed the silyl group

Advanced organic

m-CPBA

m-CPBA

HMe H

MeH

SiPh

MeMe

O

39%

Me

H SiMe2Ph

OMe

HMe H

HSi

Me

MePh Me

O61%

Me

H SiMe2Ph

OMe

Me

H SiMe2Ph

Me

HMe H

HSi

Me

MePh Me

HMe H

MeH

SiPh

MeMe

Importance of A(1,3) strain

• The importance of a cis-substituent is made clear by the reduced stereoselectivity• This is explained as follows...

4

Me m-CPBA+

61% 39%

H SiMe2Ph

Me

H SiMe2Ph

OMe

H SiMe2Ph

OMe Me Me

X

m-CPBA attacks form least hindered

face

X

lowest energy conformation

gives major product HMe H

HSi

Me

MePh Me

HMe H

MeH

SiPh

MeMe

both conformations low energy -- so mixture of

products

Advanced organic

H2B HH2B

H CH2OBnMeH

Me

OH CH2OBn

MeHMe

O

H

H2O2NaOH

OBn

H Me

O

H Me

OH74% de

Me

OBn

H Me

O

BH3

OBn

H Me

O

H Me

H2B

Other reactions...• Epoxidation is not the only stereoselective reaction of alkenes• Below is an example of hydroboration, a useful reaction that you should be familiar

with...

5

R

R1

HS

LL R1

RS H

S = smaller groupL = larger group

R

R1

SL

HR

R1

LH

S

favoured destabilised by repulsion between C-1 & C-3 substituents or A(1,3) strain

13

13

preferred approach Selectivity in addition to cis alkenes

Attack from the least sterically demanding face of the alkene as it resides in the most favoured conformation. Followed by stereospecific oxidation

Advanced organic

Directed epoxidation

• A hydroxyl group can reverse normal selectivity and direct epoxidation• Epoxidation with a peracid, such as m-CPBA, is directed by hydrogen bonding and

favours attack from the same face as hydroxyl group• The reaction with a vanadyl reagent results in higher stereoselectivity as it bonds /

chelates to the oxygen

6

OHreagent

OH

O

reagent:m-CPBAt-BuO2H, VO(acac)2

OH

O+

syn9298

t::

anti82

H

OO

HO

OH

Ar hydrogen bond O

VO OO O MeMe

Me Mevanadyl acetylacetonate

O

H

OV

t-BuO O

Advanced organic

MeMe H

HO

Me

HOO

OH

Ar

Me Me

Me OHHm-CPBA Me Me

Me OHH

OMe Me

Me OHH

O+

95 5

Directed epoxidation in acyclic systems

• Hydroxyl group can direct epoxidation in acyclic compounds as well• Once again, major product formed from the most stable conformation• Thus the cis methyl group is very important

7

• The minor product is formed either via non-directed attack or via the less favoured...conformation

hydrogen bond

favoured conformation

O

MeMe H H

OH

HO

O

Me

Ardisfavoured

conformation

MeMe H

HOH

Me

O

Advanced organic

Directed epoxidation: effect of C-2 substituent

• The presence of a substituent in the C-2 position (Me) facilitates a highly diastereoselective reaction

• The preferred conformation minimises the interaction between the two Me (& Me) groups

8

• With C-2 substituent (H) there is little energy difference between conformations• Therefore, get low selectivity

H O Me

H

O

OV

t-Bu

H Me

LL

MeMe

OHH

t-BuO2HVO(acac)2 Me

MeMe

Me

O OOH OH19 1

+

:

disfavoured conformation as Me & Me eclipse

steric interaction

favoured conformation as

only Me & H eclipse

H O H

Me

O

OV

t-Bu

H Me

LL

Me Me

H OH

t-BuO2HVO(acac)2 Me Me

O OOH OH

2.5 1

+

:

Me Me H O H

Me

O

OV

t-Bu

H H

LL

H too small to differentiate

conformations

Advanced organic

Directed reactions

• It is possible to form the desired allylic epoxide in a highly selective manner by utilising a temporary blocking group

• The silyl group causes one conformation to predominate & can be removed at end• As silyl group bigger than methyl reaction more selective

• Other diastereoselective reactions of alkenes can be controlled by a directing group• Below is an example of cyclopropanation by the Simmons-Smith reagent

9

Me Me

H OH

t-BuO2HVO(acac)2 Me

Me

OO

OHOH

25:1

MeMe

SiMe3 SiMe3TBAF

Zn

carbenoid

+

OH OZn

CH2

I

H

CI

OZnH

HOH

>98% de

CH2I2

ZnI

H2C

I

Advanced organic

Stereoselective reactions of enolates

• The stereoselectivity of reactions of enolates is dependent on:• Presence of stereogenic centres on R1, R2 or E (obviously!)• Frequently on the geometry of the enolate (but not always)

10

R1

OR2

H HR1

OR2

H

M

R1

OR2

H E

E

• Use terms cis and trans with relation to O–M to avoid confusion

R1

OH

R2

M

(E)-enolate(trans)

R2

HMO

R1

αα

C-α re face

C-α si face

R1

OR2

H

M

(Z)-enolate(cis)

H

R2MO

R1

αα

C-α re face

C-α si face

Advanced organic

R1 O

H

H R2≡

H

R2O

R1

H

R1

R2O

H

H

Enolate formation and geometry• Enolate normally formed by deprotonation • This is favoured when the C–H bond is perpendicular to C=O bond as this allows σ

orbital to overlap π orbital• σ C–H orbital ultimately becomes p orbital at C-α of the enolate p bond

11

C=O π orbital

C–H σ orbital

enolate π orbital

R1

R2O

H

base + H base

• Two possible conformations which allow this• First is given below and results in the formation of cis enolate • Initial conformation (Newman projection) similar to transition state• Little steric interaction between R1 and R2

transition state

base base

H

R2O

R1

Hbase

H

R2O

R1

baseH

(Z)-enolate(cis)

Advanced organic

Enolate formation and geometry II

• Second conformation that places C–H perpendicular to C=O gives trans-enolate• Only differs by relative position of R1 and R2

• The steric interaction of R1 and R2 results in the cis-enolate normally predominating• As results below demonstrate stereoselectivity is influenced by the size of R1

12

R1 O

H

R2 H≡

R2

HO

R1

H

base base

R2

HO

R1

Hbase

R2

HO

R1

baseH

(E)-enolate(trans)

RMe

OLDATHF

–78°C R

OLi

MeR

OLi

Me+

R = Eti-Prt-BuOMeNEt2

3060

>985

>97

cis:::::

7040<295<3

trans

Advanced organic

Enolate formation and geometry III• Previous table shows that stereoselectivity of enolate formation not always obvious• In ketones trans-enolate favoured if R1 is small but cis-enolate if R1 is large • Can explain this with transition state (again...)

13

O

H

NLiH

Me

i-Pr

i-Pr

R

O

H

NLiMe

H

i-Pr

i-Pr

R

RMe

OLDA

if R is small, 1,3-diaxial interaction is important as it destabilises this

TS‡ and trans predominates

if R is large, this TS‡ is destabilised by R–Me interaction

and cis predominates R

OLi

Metrans

R = small

RMe

OLi

cis

R = large

• With esters the R vs OMe interaction is alleviated and 1,3-diaxial interaction controls...geometry - hence trans-enolate predominates

MeOMe

O

O

H

NLiH

Me

i-Pr

i-Pr

O

O

H

NLiMe

H

i-Pr

i-Pr

OMeO

MeOLi

MeO

OLi

Metrans

cis

Me

Me

LDA

predominates

Advanced organic

Enolate formation and geometry IV

• Amides invariably give the cis-enolate; remember restricted rotation of C–N bond

• The previous arguments are good generalisations, many factors effect geometry• Use of the additive HMPA (hexamethylphosphoric triamide) reduces coordination and

favours the thermodynamically more stable enolate

14

Et2NMe

O

O

H

NLiH

Me

i-Pr

i-Pr

N

O

H

NLiMe

H

i-Pr

i-Pr

REt2N

MeOLi

Et2N

OLi

Metrans

cis

Et

Et

LDA

predominates

EtOMe

O 1. LDA2. TBSCl

EtOMe

OTBS+ EtO

OTBS

Me

THFTHF / HMPA

cis682

trans9418

Advanced organic

H

R2O

R1

H RH

H

R2O

R1

X

H HR

≡H

R2O

R1

X

H HR

Addition of an electrophile to an enolate

• Finally, need to know the trajectory of approach of the enolate and electrophile• Reaction is the overlap of the enolate HOMO and electrophile LUMO • Therefore, new bond is formed more or less perpendicular to carbonyl group• Above is simple SN2 with X = leaving group

15

X = leaving group

σ* orbital (LUMO electrophile)

π orbital (HOMO nucleophile)

Advanced organic

Enolate alkylation

• Simple alkylation of a chiral enolate can be very diastereoselective• As we have a cis-enolate diastereoselectivity can be explained in an analogous

fashion to simple alkenes via A(1,3) strain• Larger the substituent, R, greater the selectivity

16

R OEt

Me O

LDA[Li–N(i-Pr)2]

R OEt

Me OLi

Me I R OEt

Me O

R OEt

Me O

+

Me Me

syn778395

anti23275

::::

RR = PhR = BuR = SiMe2Ph

HOOEt

HMe

R

Me

≡ R OEt

Me O

MeMeI

OOEtH

HMe

R Li

most stable conformation; C–H

parallel to C=C

alkylation on face opposite to R

• Note: minor diastereoisomer probably arises from electrophile passing by R group• Therefore, size does matter...

Advanced organic

EL OEt

OS H

E H

OEt

OLi

HS

LOLi

OEt

HS

L

≡ ≡

L OEt

OS H LDA

L OLi

OEtS H

L OEt

OLiS H

(E)-enolatetrans

(Z)-enolatecis

Enolate alkylation II

• In this example enolate geometry is not important - both are cis-alkenes• Therefore, selectivity the same in both cases• If we want to reverse selectivity, change the electrophile to H • This route far less selective as H is small so less interaction with substituents

17

MeOOEtMe

HMe

R Li

H

OOEt

HMe

R

H

≡R OEt

Me O

MeLDA R OEt

Me O

H Me

preferred approach

preferred approach

Advanced organic

Nomenclature (again!!)

• You may have noticed some annoying changes nomenclature!• With ester enolates the E / Z nomenclature changes depending on the nature of M (if

we use the Cahn-Ingold-Prelog rules)

• As a result we will classify enolates as cis or trans with respect to O–MR1 = cis R2 = trans

18

R

OM

R1

R2

O

R1 R2

X

Y O

R1 R2

X

Y

syn anti

• Syn and anti in the aldol reaction refer to relative stereochemistry of enolate...substituent X and hydroxyl group (or equivalent) Y

Advanced organic

H Ph

O

t-Bu

O

Ph

OH

Mesyn aldol

t-BuMe

O LDA

t-BuMe

OLi

cis-enolate

H Ph

OO

Ph

OH

Hanti aldol

OLDA

OLi

trans-enolate

The aldol reaction

• The aldol reaction is a valuable C–C forming reaction • In addition it can form two new stereogenic centres in a diastereoselective manner• Most aldol reactions take place via a highly order transition state know as the

Zimmerman–Traxler transition state• It will not come as much surprise that this is a 6-membered, chair-like transition state

19

O

R1 R3

R2

OHO OM

R1

R2R3

Zimmerman–Traxler

R1

OM

R2

+O

R3

• Interestingly, enolate geometry effects diastereoselectivityonly possible

enolate

Advanced organic

level

level

The aldol reaction II

• Generally speaking the above guideline sums up aldol chemistry!• To understand why this happens we need to examine Zimmerman-Traxler TS‡

• So need to be able to draw a chair-like TS‡

20

XMe

OLi H R

O

X

O

R

OH

Me

trans-enolate anti aldol

cis-enolate syn aldol

X

OLiH R

O

X

O

R

OH

MeMe

start at one end of 6-ring

draw two parallel lines

bottom should be level with initial

lines

new line parallel to first

tops should all be level

draw final line parallel to first

should have 3 pairs of parallel lines

H

H HH

HH

add axial groups so that they are vertical and alternate up & down. Each carbon should

be tetrahedral

H

H

add equatorial substituents so that they are parallel to

two C–C bonds

HH

add equatorial substituents so that they are parallel to

two C–C bondsadd equatorial substituents so that they are parallel to

two C–C bonds

HH

Advanced organic

X

O

R

OH

Mesyn aldol

OO

MX

H

Me

HR

OO

MXH

Me

HR

XMe

OLi H R

O

cis-enolate

Zimmerman-Traxler transition state

• We only have one choice in the aldol reaction - the orientation of the aldehyde• Enolate substituents are fixed due to the double bond• Aldehyde substituent is pseudo-equatorial to avoid 1,3-diaxial interactions

21

OO

MX

H

Me

HR

cis-enolate

R pseudo-equatorial

OO

MX

R

Me

HH

cis-enolate

R pseudo-axialdisfavoured

1,3-diaxial interaction

OO

MXH

Me

HR

to ‘see’ relative stereochemistry

consider S as plane and see which groups are above and which

belowre face of enolate attacks

si face of aldehyde

Advanced organic

Zimmerman-Traxler transition state II

• Attack via the enantiomeric transition state (re face of aldehyde) gives the enantiomeric aldol product

• This differs only by the absolute stereochemistry - the relative stereochemistry is the same

22

XMe

OLi H R

O

X

O

R

OH

Mecis-enolate syn aldol

X

O

MO

Me

H

RH

si face of enolate attacks re face of aldehyde

X

O

MO

Me

H

RH

X

O

MO

Me

H

RH

visualising relative stereochemistry

Advanced organic

Zimmerman-Traxler transition state III

• The opposite stereochemistry of enolate gives opposite relative stereochemistry• Once again the enolate has no choice where the methyl group is placed

23

trans-enolate anti aldol

X

OLiH R

O

X

O

R

OH

MeMe

X

O

MO

H

H

RMe

re face of enolate attacks re face of aldehyde

X

O

MO

H

H

RMe visualising relative

stereochemistry

X

O

MO

H

H

RMe

Advanced organic

Enolisation and the aldol reaction• Hopefully, all the previous discussion highlights that selective enolisation is essential

for diastereoselective aldol reaction• Each geometry of enolate gives a different relative stereochemistry• With the lithium enolates of ketones the size of the non-enolised substituent, R, is

important

24

RMe

O LDA

RMe

OLi+ R

OLi

MeR = t-BuR = Et

98%30%

2%70%

• With boron enolates we can select the geometry by altering the boron reagent used

Ph

O

Me

B

trans-enolate

PhMe

O+

BCl

Et3N H Ph

O

Ph Ph

O

Me

OH

anti aldol (>90% de)bulky

substituents

forces enolate to adopt trans geometry

Advanced organic

Enolisation and the aldol reaction II

• 9-BBN (9-borabicyclononane) looks bulky• But most of it is ‘tied-back’ behind boron thus allowing formation of the cis-enolate

25

PhMe

O+

Et3N H Ph

O

Ph Ph

O

Me

OH

syn aldol (96% de)

BTfO

Ph

O

cis-enolate

B

Me