123.702 Organic Chemistry

enantiomerscis

epoxidemp = 98°C

Two chiral centres (diastereoisomers)

• A molecule with 1 stereogenic centre exists as 2 stereoisomers or enantiomers• Enantiomers have identical physical properties in an achiral environment

1

NH2HN

N

O

OHNH2 NH

N

O

HOS R

Mirror

Two enantiomersdiffer by absolute configuration

O

CO2Me

O2N

O

CO2Me

O2N

enantiomerstrans

epoxidemp = 141°C

O

CO2Me

O2N

O

CO2Me

O2N

diastereoisomers

different mp

• A molecule with 2 stereogenic centres can exist as 4 stereoisomers• Enantiomers (mirror images) still have identical physical properties • Diastereoisomers (non-mirror images) have different properties

123.702 Organic Chemistry

Diastereoisomers

• Enantiomers differ only by their absolute stereochemistry (R or S etc)• Diastereoisomers differ by their relative stereochemistry• Relative stereochemistry - defines configuration with respect to any other

stereogeneic element within the molecule but does NOT differentiate enantiomers

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

2

NH2 NH2 NH2 NH2

2HCl 2HClchiral

solubility 0.1g/100ml EtOH

NH2 NH2

2HClmeso

solubility 3.3g/100ml EtOH

diastereoisomers

different solubilityseperable

MeOH

NH2

MeOH

NH2

synsame face

antidifferent face

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

• The different physical properties of diastereoisomers allow us to purify them• The differences between diastereoisomers will be the basis for everything we do...

123.702 Organic Chemistry

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...

3

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

123.702 Organic Chemistry

Meso compounds

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

4

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

123.702 Organic Chemistry

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

5

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!)

123.702 Organic Chemistry

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

• 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

6

• Difference in diastereomers allows chiral derivatising agents to resolve enantiomers

123.702 Organic Chemistry

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)

7

OH+ CO2H

F3C OMe

R / S S

DCC, DMAP CH2Cl2, –10°C

F3C OMeO

O

MeH

R–S & S–S

DCC - dicyclohexylcarbodiimide

NC

N

123.702 Organic Chemistry

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• Use of non-covalent interactions allows other methods of resolving enantiomers...

8

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

123.702 Organic Chemistry

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

9

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

123.702 Organic Chemistry

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

10

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

123.702 Organic Chemistry

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%

11

O EuL2O

C3F7

+ substrate

Eu(hfc)3

Eu(hfc)3•••substrate

123.702 Organic Chemistry

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

12

CO2H

NH2L-valine

αβ

γ

O

O N N O

OMeH

OO

OOSm3+

123.702 Organic Chemistry

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...

13

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