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 NH 2 HN N O OH NH 2 NH N O HO S R

Mirror

Two enantiomers

differ by absolute configuration O CO 2 Me O 2 N O CO 2 Me O 2 N enantiomerstrans epoxide mp = 141°C O CO 2 Me O 2 N O CO 2 Me O 2 N diastereoisomersdifferent 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 NH 2 NH 2 NH 2 NH 2

2HCl2HCl

chiral solubility 0.1g/100ml EtOH NH 2 NH 2 2HCl meso solubility 3.3g/100ml EtOH diastereoisomersdifferent solubility seperable Me OH NH 2 Me OH NH 2 syn same face anti different 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

HO CHO OHOH OH (2R,3R,4R)-2,3,4,5-tetrahydroxypentanal ribose

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 2 n stereoisomers Problem is, the molecule will never have more than 2 n stereoisomers but it might have less... 3 HO CHO OHOH OH HO CHO OHOH OH HO CHO OHOH OH HO CHO OHOH OH HO CHO OHOH OH HO CHO OHOH OH HO CHO OHOH OH HO CHO OHOH OH 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 HO 2 C CO 2 H OH OH tartaric acid HO 2 C CO 2 H OH OH HO 2 C CO 2 H OH OH HO 2 C CO 2 H OH OH HO 2 C CO 2 H OH OH diastereoisomersenantiomersidentical HO 2 C CO 2 H OH OH HO 2 C CO 2 H OH OH HO 2 C CO 2 H OH OH HO 2 C CO 2 H 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

HO 2 C OH CO 2 H HO OH CO 2 H HO HO 2 C 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 HO 2 C CO 2 HHO OH • Another example... Cl H Cl H achiral plane of symmetry superimposable on mirror image (meso) Cl H H Cl chiral no plane of symmetry non-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 / S racemic 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): 1

H nmr Δδ = 0.08 (Me)

F nmr Δδ = 0.17 (CF

Typical difference in chemical shifts in

H nmr 0.15 ppm

F 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 CO 2 H F 3 COMe

R / SS

DCC, DMAP

CH 2 Cl 2 , -10°C F 3 COMe O O Me H

R-S & S-S

DCC - dicyclohexylcarbodiimide

N C 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 O OH NH R / S HO 2 C CO 2 H OTol OTol O OH NH 2 O 2 C CO 2 Hquotesdbs_dbs21.pdfusesText_27

[PDF] Two chiral centres (diastereoisomers)

123.702 Organic Chemistry