Advanced organic

Enantiomeric excess• Optical purity - an outdated measurement of the enantiomeric excess (amount of

two enantiomers) in a solution / mixture• If a solution contains only one enantiomer, the maximum rotation is observed...

1

CO2H

H NH2

measure rotationderive [α]D = +14 100% (+) enantiomer

100% of maximum observed rotation

CO2H

H2N H

measure rotationderive [α]D = -14 100% (–) enantiomer

100% of maximum observed rotation

• The observed rotation is proportional to the amount of each enantiomer present...

Advanced organic

Enantiomeric excess II

2

90% (+) enantiomer10% (–) enantiomer

= +90% clockwise10% anti-

clockwise80% of maximum rotation observed

60% (+) enantiomer40% (–) enantiomer

60% clockwise40% anti-clockwise

= +

= +50% (+) enantiomer50% (–) enantiomer

50% clockwise50% anti-clockwise

10% of major enantiomer is ‘cancelled out’

40% of major enantiomer is ‘cancelled out’

20% of maximum rotation observed

50% of major enantiomer is ‘cancelled out’

0% of maximum rotation observed

Advanced organic

Enantiomeric excess III• Previous slide indicates that a polarimeter measures difference in the amount of

each enantiomer• Racemate (racemic mixture) - 1 to 1 mixture of enantiomers (50% of each)• Racemisation - converting 1 enantiomer to a 1:1 mixture of enantiomers

• Optical rotation very unreliable so use new methods to measure amounts and use the value enantiomeric excess

• How do we measure enantiomeric excess?• Problem - all the physical properties of enantiomers are identical (in an achiral

environment) except rotation of plane polarised light• Solution - the interaction of a chiral molecule with other chiral compounds is

different depending on the enantiomer used...• Imagine you have a mixture of left and right-handed gloves and you are asked to

separate them...suddenly there is a power cut, and you are left in a darkened room. How would you do it? Use just one hand and try the gloves on...

3

Enantiomeric excess (% ee) = [R] – [S][R] + [S]

= %R – %S

Advanced organic

Resolution of enantiomers: chiral chromatography• Resolution - the separation of enantiomers from either a racemic mixture or

enantiomerically enriched mixture• Chiral chromatography - Normally HPLC or GC• A racemic solution is passed over a chiral stationary phase• Compound has rapid and reversible diastereotopic interaction with stationary phase• Hopefully, each complex has a different stability allowing separation

4

racemic mixture in solution

‘matched’ enantiomer - more

stable (3 interactions)

‘mis-matched’ enantiomer - less

stable (1 interaction)

‘matched’ enantiomer

travels slowly

‘mis-matched’ enantiomer

readily eluted

chiral stationary phase

Advanced organic

Chiral chromatography

• Measurements of ee by HPLC or GC are quick and accurate (±0.05%)• Chiral stationary phase may only work for limited types of compounds• Columns are expensive (>£1000)• Need both enantiomers to set-up an accurate method

5

SiN

H

ONO2

NO2

SiOSi

Si OO

O

O

OSi

OSiO

O

O

O

O

MeMe

silica chiral aminechiral stationary phase

R S

R/S

RS

S

R

inject mixture on to column

chiral column prepared from a suitable chiral

stationary phase (many different types)

R

Advanced organic

NMR spectroscopy: chiral shift reagents• Chiral paramagnetic lanthanide complexes can bind reversibly to certain chiral

molecules via the metal centre• Process faster than nmr timescale and normally observe a downfield shift (higher

ppm)• Two diastereomeric complexes are formed on coordination; these may have different

nmr signals

• Problems - as complexes are paramagnetic, line broadening is observed (especially on high field machines)

• Compound must contain Lewis basic lone pair (OH, NH2, C=O, CO2H etc)• Accuracy is only ±2%

6

O EuL2O

C3F7

+ substrate

Eu(hfc)3

Eu(hfc)3•••substrate

Advanced organic

Chiral shift reagents II

• New reagents are being developed all that time that can overcome many of these problems

• 1H NMR spectra (400 MHz) of valine (0.06 M, [D]/[L] = 1/2.85) in D2O at pH 9.4

7

CO2H

NH2L-valine

αβ

γ

O

O N N O

OMeH

OO

OOSm3+

Advanced organic

MeOMe

O

OMeOMe

O

O+

2 diastereoisomers

CO2HMeOMe DCC, DMAP,

DCM, rt, 24h+

enantiomerically pure

OH

OH+=

mixture of enantiomers

OH

(±) racemate

Chiral derivatising agents

• A racemic mixture of enantiomers can be converted to a mixture of diastereoisomers by covalently attaching a second, enantiomerically pure unit

• The advantage of this over the previous methods is there is normally larger signal separation in nmr

• There is no reversibility• Diastereoisomers can often be separated by normal, achiral chromatography

8

• To understand why diastereoisomers are useful we need to do some more revision...

Advanced organic

Two chiral centres

• A molecule with one stereogenic centre exists as two stereoisomers or enantiomers• The two enantiomers differ by their absolute configuration• A molecule with two stereogenic centres can exist as four stereoisomers

9

NH2HN

N

O

OHNH2 NH

N

O

HOS R

Mirror

enantiomersdifferent absolute

configuration

OH

NH2(1R,2S)

OH

NH2(1S,2S)

OH

NH2(1R,2R)

OH

NH2(1S,2R)

each molecule has an enantiomer

each molecule has an enantiomer

other stereoisomers that are not mirror images are diastereoisomers

• A molecule can have one enantiomer but any number of diastereoisomers

Advanced organic

Diastereoisomers

• Diastereoisomers can have the same relative stereochemistry• The stereoisomers above differ only by their absolute stereochemistry• Or they can have different relative stereochemistry

• Relative stereochemistry - defines configuration with respect to any other stereogenic element within the molecule but does NOT differentiate between enantiomers

• In simple systems the two different relative stereochemistries are defined as below

10

OH

NH2

OH

NH2

same relative stereochemistry / configuration

diastereoisomers

OH

NH2

OH

NH2

different relative stereochemistry / configuration

diastereoisomers

OH

NH2

OH

NH2

synsame face

antidifferent face

• Occasionally you will see the terms erthyro & threo - depending on the convention...used, these can mean two either relative stereochemistry so I will not use them!

Advanced organic

HOCHO

OH OH

OH

(2R,3R,4R)-2,3,4,5-tetrahydroxypentanalribose

Diastereoisomers II

• If a molecule has 3 stereogenic centres then it has potentially 8 stereoisomers (4 diastereoisomers & 4 enantiomers)

• If a molecule has n stereogenic centres then it has potentially 2n stereoisomers• Problem is, the molecule will never have more than 2n stereoisomers but it might

have less...

11

HOCHO

OH OH

OH

HOCHO

OH OH

OH

HOCHO

OH OH

OH

HOCHO

OH OH

OH

HOCHO

OH OH

OH

HOCHO

OH OH

OH

HOCHO

OH OH

OH

HOCHO

OH OH

OH

(2R,3R,4R)-ribose (2R,3R,4S)-arabinose (2R,3S,4R)-xylose (2R,3S,4S)-lyxose

(2S,3S,4S)-ribose (2S,3S,4R)-arabinose (2S,3R,4S)-xylose (2S,3R,4R)-lyxose

four diastereoisomers

and their 4 enantiomers

mirror plane

Advanced organic

Meso compounds

• Tartaric acid has 2 stereogenic centres. But does it have 4 diastereoisomers?

12

HO2CCO2H

OH

OH

tartaric acid

HO2C CO2HOH

OHHO2C CO2H

OH

OH

HO2C CO2HOH

OHHO2C CO2H

OH

OH

diastereoisomersenantiomers identical

HO2C CO2HOH

OHHO2C

CO2HOH

OH

HO2C

CO2H

OH

OH

HO2C

CO2H

OH

OH

• 2 diastereoisomers with different relative stereochemistry• 2 mirror images with different relative stereochemistry• 1 is an enantiomer• The other is identical / same compound• Simple rotation shows that the two mirror images are superimposable

Advanced organic

HO2C

OH

CO2H

HO OH

CO2H

HO

HO2C

plane of symmetry

Meso compounds II• Meso compounds - an achiral member of a set of diastereoisomers that also

includes at least one chiral member• Simplistically - a molecule that contains at least one stereogenic centre but has a

plane of symmetry and is thus achiral • Meso compounds have a plane of symmetry with (R) configuration on one side and

(S) on the other

13

rotate LHS

HO2C

CO2HHO

OH

• Another example...

ClH

ClH

achiralplane of symmetrysuperimposable on

mirror image(meso)

ClH

HCl

chiralno plane of symmetrynon-superimposable

on mirror image(but it is symmetric!)

Advanced organic

Meso compounds III

• The meso compound shows two peaks for the cis and anti CH3 (wrt to CO2Et)This compound is achiral

• The chiral ester shows only one peak because it is symmetricalIt has a C2 axis of symmetryThis molecule is chiral but symmetrical

14

• One compound displays two CH3 peaks in 1H nmr; the other just one peak. Which...one is which?

Me MeCO2EtEtO2C

Me MeCO2EtEtO2C

plane of symmetrymeso

achiral

no plane of symmetry

chiral

Me MeCO2EtEtO2C

axis of symmetry

Me MeCO2EtEtO2C

plane of symmetry

Advanced organic

Enantiomers vs. diastereoisomers

• Different physical properties, such as crystallinity or polarity allow diastereoisomers to be separated

15

• Two enantiomers have identical physical properties in an achiral environment• Two diastereoisomers have different physical properties

O

CO2Me

O2N

O

CO2Me

O2N

enantiomerstrans

epoxidemp = 141°C

O

CO2Me

O2N

O

CO2Me

O2N

enantiomerscis

epoxidemp = 98°C

diastereoisomers

different mp

NH2 NH2 NH2 NH2

2HCl 2HClchiral

solubility 0.1g/100ml EtOH

NH2 NH2

2HClmeso

solubility 3.3g/100ml EtOH

diastereoisomers

different solubilityseperable

Advanced organic

R

R*

pure enantiomer

cleave diastereoisomer

S–R*

R–R*

diastereoisomers separable

pure diastereoisomer

R–R* + S–R*

mixture of diastereoisomers

R*

enantiomerically pure derivatising agent

R / Sracemic mixture

Chiral derivatising agents II

• Remember a good chiral derivatising agent should:• Be enantiomerically pure (or it is pointless)• Coupling reaction of both enantiomers must reach 100% (if you are measuring ee)• Coupling conditions should not racemise stereogenic centre• Enantiomers must contain point of attachment• Above list probably influenced depending whether you are measuring %ee or

preparatively separating enantiomers

16

• This difference allows chiral derivatising agents to resolve enantiomers

Advanced organic

Chiral derivatising agents: Mosher’s acid

• Popular derivatising agent for alcohols and amines is α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) or Mosher’s acid

• Difference in nmr signals between diastereoisomers (above): 1H nmr Δδ = 0.08 (Me)..................................................................................................19F nmr Δδ = 0.17 (CF3)

• Typical difference in chemical shifts in 1H nmr 0.15 ppm• 19F nmr gives one signal for each diastereoisomer• No α-hydrogen so configurationally stable• Diastereoisomers can frequently be separated

• In many cases use of both enantiomers of MTPA can be used to determine the absolute configuration of a stereocentre (73JACS512, 73JOC2143 & 91JACS4092)

17

OH+ CO2H

F3C OMe

R / S S

DCC, DMAP CH2Cl2, –10°C

F3C OMeO

O

MeH

R–S & S–S

DCC - dicyclohexylcarbodiimide

NC

N

Advanced organic

Chiral derivatising agents: salts

• No need to covalently attach chiral derivatising group can use diastereoisomeric ionic salts

• Benefit - normally easier to recover and reuse reagent

18

OOH

NH

R / S

HO2CCO2H

OTol

OTol

OOH

NH2O2C

CO2HOTol

OTol

S diastereoisomer is insoluble so easily removed by filtration

NaOH

OOH

NH

(–)-propranololβ-blocker

Advanced organic

Enzymatic resolution

• Enzymes are very useful for the resolution of certain compounds• Frequently they display very high selectivity• There can be limitations due to solubility, normally only one enantiomer exists and

can be too substrate specific• Below is the rationale for the selectivity observed above...

19

BuOEt

O

F

lipase PS from Pseudomonas cepacia, 0.05M phosphate buffer,

pH 7, 0.1M NaOH, 5°C

60% conversionBu

OEt

O

F

BuO

O

F

Na+

R / S R>99% ee

soluble in organic phase

S69% ee

soluble in aqueous phase

NNH

ONH

OH

OR

OEt

his

ser

OBu

FH

O

enzyme

diastereomeric interaction of enzyme lone pair with σ* orbital of C–F of (S)-enantiomer favoured over interaction

with (R)-enantiomer

Advanced organic

Stereoselective synthesis• The term ‘asymmetric synthesis’ should be used with caution. As we shall see, a

number of important chiral compounds are symmetric!!• As such this course will primarily focus on diastereoselective or enantioselective

synthesis or the synthesis of chiral molecules• Chiral compounds can be prepared in a number of ways:

20

Enantiospecific synthesis; ‘the chiral pool’

OH

O

(S)-leucine

HONOH2O

H2N HO

OH

N2 H H

O

O

OH

O

HO HHO H

(S)-(–)-ipsenol

retension inversion

inversion

H2O

• Use enantiomerically pure starting material and stereospecific reactions• Good - if a cheap, readily available source of chirality exists• Problems - often results in long, tortuous syntheses.......................suitable material not always available

Advanced organic

Stereoselective synthesis

• Chiral auxiliary - allows enantioselective synthesis via diastereoselective reaction• Add chiral unit to substrate to control stereoselective reaction• Can act as a built in resolving agent (if reaction not diastereoselective)• Problems - need point of attachment

....................adds additional steps

....................cleavage conditions must not damage product!

21

Chiral auxiliaries

substrate(achiral) +

chiral auxiliary

couple to form new chiral compound

product

chiral auxiliary

substrate(achiral) chiral

auxiliary

product(chiral)

chiral auxiliary

+cleave chiral

auxiliary

product

chiral auxiliary

resolve other diastereoisomer

diastereoselective reaction

overall reaction

Advanced organic

Stereoselective synthesis II

• Chiral reagent - stereochemistry initially resides on the reagent• Advantages - No coupling / cleavage steps required

........................Often override substrate control

........................Can be far milder than chiral auxiliaries• Disadvantages - Need a stoichiometric quantity (not atom economic)

.............................Frequently expensive

.............................Problematic work-ups

22

substrate(achiral) +

chiral reagent

product(chiral)

chiral reagent interacts with

achiral substrate

substrate(achiral)

chiral reagent

chiral complex

reaction

dead reagent

+

Chiral reagents

Advanced organic

product(chiral)

chiral catalyst

chiral catalyst

substrate(achiral) chiral

catalyst

Stereoselective synthesis III

• Chiral catalysis - ideally a reagent that accelerates a reaction (without being destroyed) in a chiral environment thus permitting one chiral molecule to generate millions of new chiral molecules...

23

substrate(achiral)

product(chiral)

Advanced organic

24

product

chiral auxiliary

chiral reagent

substrate(achiral) chiral

auxiliary