1

Importance of stereochemistry• Enantiomers have identical chemical and physical properties• Differ - rotating polarised light

....... ..- interaction with other chiral molecules• Important in biology...

Me2NMe

Ph O

EtO

darvon

Darvon is a painkiller.

Its enantiomer is an anticough agent.

R R

enzyme

X

only one enantiomer matches chiral enzyme

2

Polarised light• Ordinary light has EM radiation oscillating in all possible planes (3 shown)• Polarised light is in a single plane

CO2H

H NH2

measure rotationderive [α]D = +14

CO2H

H2N H

measure rotationderive [α]D = -14

≡≡

ordinary light polarised light

• Chiral compounds rotate polarised light.• A pair of enantiomers rotate the plane of polarised light by equal amounts in opposite directions.• A 1:1 mixture of enantiomers does not rotate light and is called a racemate

3

Diastereoisomers I• Cyclic compounds can exist as diastereoisomers• Diastereoisomers differ by the spatial orientation of atoms• Can have very different physical properties• Do NOT have to be chiral (if they have a plane of symmetry)

OH

OH

OH

OH

diastereoisomersidentical identical

OH

molecule has a plane of symmetry

4

Diastereoisomers II

• 2 stereocentres can result in FOUR compounds (4 diastereoisomers)• No plane of symmetry ∴ chiral & 2 pairs of enantiomers (mirror images)• 2 enantiomeric pairs - each enantiomer has identical physcial properties• But diastereoisomers have different physical properties• Enantiomers have same relative stereochemistry but different absolute

stereochemistry

O

CO2Me

O2N

O

CO2Me

O2N

O

CO2Me

O2N

O

CO2Me

O2N

diastereoisomersenantiomersenantiomers

trans epoxide

mp = 141˚Ccis

epoxidemp = 98˚C

5

Diastereoisomers III

• If a molecule has 3 stereocentres then it has potentially 8 stereoisomers (4 diastereoisomers & their enantiomers)• If a molecule has n stereocentres then potentially 2n stereoisomers• But if a molecule has a plane of symmetry it wil be less...

HOCHO

OH

OH OH

(2S,3S,4S)-ribose

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

(2S,3S,4R)-arabinose

(2R,3S,4R)-xylose

(2S,3R,4S)-xylose

(2R,3S,4S)-lyxose

(2S,3R,4R)-lyxose

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

ribose(2R,3R,4R)-2,3,4,5-tetrahydroxypentanal

fourdiastereomers

and their 4 enantiomers

6

HO2CCO2H

OH

OH

tartaric acid

Meso compounds I

• 2 stereocentres so 4 stereoisomers?• There are 2 diastereoisomers - one has an enantiomer

...................................na......... - the other does NOT

HO2C CO2HOH

OHHO2C CO2H

OH

OH

HO2C CO2HOH

OHHO2C CO2H

OH

OH

diastereoisomersenantiomers identical

7

Meso compounds II

• Meso compounds - compounds containing stereocentres but are still achiral• Meso compounds have a plane of symmetry with (R) configuration

on one side and (S) on the other

Two compound on previous slide identical as rotation below shows...

HO2C CO2HOH

OHHO2C CO2H

OH

OH

≡ HO2CCO2H

OH

OH

HO2C

CO2H

OHHO

CO2HHO2C

OH

OHrotate around central axis

HO2C

CO2HHO

OH

rotate LHS

• Even though compound has TWO stereocentres it is ACHIRAL• It is achiral because it has a plane of symmtery...

HO2C

OH

CO2H

HO

mirror plane

8

H OH

(±) or (R) / (S)racemate

Resolution

• Enantiomers physically the same - diastereoisomers are not!

+HO2C Ph

OMe

HO

O

OMe

Ph + O

O

OMe

Ph

2 diastereoisomers (hopefully separable)

• React 2 chiral compounds to form diastereoisomers• Separate these (if possible)

NaOHH2O

NaOHH2O

OH OH

pure (S) pure (R)

• Regenerate required compound

• Separation of enantiomers is ..called resolution

• If you can't synthesise it pure ..how do you purify enantiomers?

• We need enantiomerically pure ..compounds

9

Chirality in nature I

• Insulin is made of 2 peptide chains - 1x30 amino acids & 1x21 amino acids• Potentially 2.25 x 1015 diastereoisomers• A relatively small protein is ribonuclease at 124 amino acids or• Potentially 2.13 x 1037 diastereoisomers

Natural amino acids are enantiomerically pureThese are the building blocks of proteins and enzymes

HO2C Me

NH2

HO2C

NH2

HO2C

NH2 N

HN

alanine phenylalanine histidine

Why this enantiomer? Who knows...But why just one enantiomer is more obvious...

10

Chirality in nature II

• Enantiomers are identical except their interaction with polarised light and other chiral molecules (like our bodies)• This can have trivial effects...like smell / taste

HO OH

ON

OP

OP

OP

HO

N

N

N

NH2

OHOOHOOHO

adenosine triphosphate ATP

O

HO

N

NH

O

OHO

thymine derivative of deoxyribonucleic acid

(DNA)

O

HO OH

NHO

N

N

NH

O

NH2

guanine derivative of ribonucleic acid (RNA)

Nucleosides are enantiomerically pureThese are the basis of all life via DNA and / or RNA

Also ATP which is the main sourse of energy in our cells

O

H

(R)-carvonespearmint

(R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enone

O

H

(S)-carvonecaraway

(S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enone

H

(S)-limonenelemons

(S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene

H

(R)-limoneneoranges

(R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene

11

Chirality in nature III

• Drugs frequently need to be optically pure• (R)-Thalidomide is a sedative - (S) isomer cause birth defects• Dextromethorphan is a cough suppresant• Levomethorphan (its enantiomer) is a narcotic• Top two drugs were Lipitor and Zucor and are single enantiomers• They generated $14 billion in 2002• Single enantiomer drugs worth $159 billion in 2002• Big buisiness!

N

S

O

HNR

O

H H

CO2H

penicillin skeleton

O

N

N

NH

O

OHO

NN

AZTazidothymidine

NH

O O

HN

O

O

(R)-thalidomideOMe

HN

dextromethorphan

12

Other forms of chirality

• It is not necessary for a compound to have a tetrahedral stereocentre to be a chiral compound!!

(Rp)-4-amino[2.2]para-

cyclophane

(Sp)-4-amino[2.2]para-

cyclophanemirror plane

NH2 H2N

PPh2

PPh2

(S)-BINAP2-(diphenylphosphino)-1-((S)-2-

(diphenylphosphino)naphthalen-1-yl)naphthalene

Ph2PPh2P

(R)-BINAP2-(diphenylphosphino)-1-((R)-2-

(diphenylphosphino)naphthalen-1-yl)naphthalene

mirror plane

full rotation impossible

axial chirality

planar chirality