GarethRowlandsGareth J. Rowlands

Asymmetric Synthesis

123.702 Organic Chemistry

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123.702 Organic Chemistry

The importance of chirality

• Nature yields an enormous variety of chiral compounds• Each enantiomer can have very different effects as highlighted below• As a result we must have methods to control stereochemistry

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NHMeN

nicotinetoxin / stimulant

Me CO2H

NH2

L-alaninemammalian amino acid

Me CO2H

NH2

D-alaninebacterial cell wall

OHNH

Me Me

(–)-propanololβ-blocker for heart disease

(+)-propanololcontraceptive

OHHN

MeMe NH

HN

OH

Et OH

Et

Ethambutoltuberculostatic (anti-TB)

NH

HN

OH

EtOH

Et

(R,R)-enantiomercauses blindness

123.702 Organic Chemistry

The importance of chirality

• Roughly 1/3 of pharmaceuticals are chiral • 90% of the top 10 selling drugs the active ingredient is chiral• A. M. Rouhi, Chem. Eng. News. 2004, June 14, 47 & Sept. 6, 41

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NAME GLOBAL SALES2003 (BILLION $)

ACTIVE INGREDIENT

FORM OF ACTIVE INGREDIENTS

THERAPEUTIC EFFECT

LIPITOR 10.3 ATROVASTATIN Single Enantiomer Lipid-Lowering agent

ZOCOR 6.1 SIMVASTATIN Single Enantiomer Lipid-Lowering agent

ZYPREXA 4.8 OLANZAPINE Achiral Psychotropic agent

NORVASC 4.5 AMLODIPINE Racemate Calcium channel blocker

PROCRIT 4.0 EPOETIN A Protein Stimulant of blood cells production

PREVACID 4.0 LANSOPRAZOLE Racemate Inhibitor of gastric acid secretion

NEXIUM 3.8 ESOMEPRAZOLE Single Enantiomer Inhibitor of gastric acid secretion

PLAVIX 3.7 CLOPIDOGREL Single Enantiomer Inhibitor of platelet aggregation

ADVAIR 3.7 SALMETEROL Racemate β2-Adrenergic bronchodilator

FLUTICASONE Single Enantiomer Anti-inflammatory agent

ZOLOFT 3.4 SERTALINE Single Enantiomer Inhibitor of serotonin re-uptake

TOTAL 48.3

123.702 Organic Chemistry

Terminology• Stereoisomers - Isomers that differ only by the arrangement of substituents in space• Stereogenic element - the focus of stereoisomerism, be it a stereogenic centre, axis

or plane, within the molecule such that the change of two substituents about this element leads to different stereoisomers

• Chiral compound - simply a molecule (or object) that cannot be superimposed upon its mirror image

• Most obvious example is our hands...

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Mirror image Left & right hands Non-superimposable

• Chiral centre - In a tetrahedral (Xabcd) or trigonal pyramidal (Xabc) structure, the...atom X to which the four (or three, respectively) substituents abc(d) are attached

Ph Me

OHHP

Ph MeHc

Xd

baX

a bc

chiral centre

123.702 Organic Chemistry

One stereogenic centre: chirality on an atom

Chiral• Mirror images are non-superimposable• Each mirror image is an enantiomer• Only differ by their absolute...configuration or actual 3D shape• Simplistically - 4 different groups• Do not have a plane of symmetry

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Mirror plane

Mirror plane

rotaterotaterotate rotaterotate

Achiral• Mirror images are superimposable• Compound has a plane of symmetry

R4 R3chiral

R1≠R2≠R3≠R4

R2R1R4 R3achiral

R1=R1≠R3≠R4

R1R1

plane of symmetry running through central

carbon, hydrogen and OHACHIRAL

Me Me

H OH

123.702 Organic Chemistry

Me CO2H

H NH21

2Me CO2H

H NH21

Me CO2H

H NH2

Me NH2

CO2HH

1

2

3Me

H

CO2HNH2 Me NH2

HO2C H ≡

rotate around axis until lowest priority points

away from you

Me CO2H

H NH21

23

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Defining absolute configuration

• Need to be able to define the absolute configuration of a chiral centre• First assign priorities according to Cahn-Ingold-Prelog rules (highest atomic number)

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• Next rotate molecule until lowest priority (4) is pointing away from viewer• Draw a line connecting 1 to 3• If line clockwise (right) the (R)• If line anti-clockwise (left) the (S)

Me CO2H

H NH2

alanine

Me CO2H

H NH2

(S)-alanine(S)-2-aminopropanoic acid

123.702 Organic Chemistry

PAr Ph

OMe

1

2 3

PO

MePh

12

3

4

MeO

PO

OMeMe

123

4

PO

OMeMe

12P

O

OMeMe

1

Defining absolute configuration II

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• Define priorities according to CIP

• Point lowest priority (4) away from viewer

• Draw line from 1 to 3

• Line is anti-clockwise so (S)

PO

OMeMe

(S)-(4-methoxyphenyl)methylphenyl

phosphine oxide

PO

OMeMe

123.702 Organic Chemistry

Central chirality at elements other than carbon• Any tetrahedral or pyramidal atom with four (three) different substituents can be chiral• Nitrogen / amines have the potential to be chiral...• But rapid pyramidal inversion normally prevents isolation of either enantiomer• If substituents are constrained in a ring then rigid structure prevents inversion

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R1N R3R2

R1N R3R2

N

N

Me

Me

Tröger's base

• Trigonal pyramidal phosphorus(III) is configurationally stable below 200°C• Tetrahedral phosphorus (V) is configurationally stable

PMe

MeOP Me

MeO

X(S)-cyclohexyl(4-

methoxyphenyl)(methyl)phosphine

PO

O

Pht-Bu

(S)-naphthalen-1-yl tert-butyl(phenyl)phosphinate

123.702 Organic Chemistry

Central chirality at elements other than carbon II

• Sulfoxides are tetrahedral; remember they have a lone pair!• Configurationally stable at room temperature• Certain anions (Cl ) can cause racemisation (interconversion of the enantiomers)

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SMe

O

Me

(R)-1-methyl-4-(methylsulfinyl)benzene

OSS

Me

MeMe

MeMe

Me(R)-S-tert-butyl 2-methylpropane-2-

sulfinothioate

H Ph

NSO

t-Bu

(S)-N-benzylidene-2-methylpropane-2-sulfinamide

• It should be stressed that the definition of a chiral compound is that it ...cannot be superimposed upon its mirror image• A stereogenic centre (central chirality) is sufficient for the existence of ...chirality BUT it is not a requirement• Furthermore, as we shall see, a compound can have a stereogenic ...centre BUT be achiral

123.702 Organic Chemistry

Axial chiralityAxial chirality - Nonplanar arrangement of four groups about an axis

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Spiro-compoundsMirror

O

O

O

O

olean(R)-1,7-

dioxaspiro[5.5]undecaneattracts male olive flies

olean(S)-1,7-

dioxaspiro[5.5]undecaneattracts female olive flies

OO

axis of chirality

(R)-olean

Axial chirality and atropisomerismAtropisomers - stereoisomers resulting from restricted rotation about a single bond

Mirror

PPh2

PPh2

(R)-(+)-BINAP(R)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene

Ph2PPh2P

(S)-(-)-BINAP(S)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene

axis of chirality

123.702 Organic Chemistry

Other forms of chirality• Helical chirality - molecules that twist (like a cork-screw)• Right-handed helix is denoted P (clockwise as you travel away from viewer)

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• Planar chirality - chirality resulting from the arrangement of out-of-plane groups...with respect to a plane

P-[8]helicene M-[8]helicene

Mirror

Fe PPh2

PhFePh2P

Ph

(S)-2-phenyl-1-(diphenylphosphanyl)

ferrocene

(R)-2-phenyl-1-(diphenylphosphanyl)

ferrocene

Mirror

123.702 Organic Chemistry

Ph CO2H

OHH

(R)-(-)-mandelic acid131-133°C[α]23 –153D

Ph CO2H

HHO

(S)-(+)-mandelic acid131-134°C[α]20 +154D

Enantiomers & optical rotation

• Each enantiomer has identical physical & chemical properties (in an achiral environment)

• Only differ by how they rotate plane polarised light (rotate in opposite directions)

• Enantiomers are said to be optically active

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α

light source

polariser plane polarised light

samplecell length l (dm)

readinglight (λ)

[α]t = αDl x c

Optical rotation

α = observed rotationl ..= cell path (dm)c .= concentration .(g/ml [or g/100ml])t .= temperature

• Not very useful as value is very unreliable (dependent on solvent, all factors listed...above and more besides)• Even sign (+/–) can change depending on concentration!!

123.702 Organic Chemistry

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...

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CO2H

H NH2

measure rotationderive [α]D = +14

100% (+) enantiomer100% of maximum observed rotation 100% enantiomer excess

CO2H

H2N H

measure rotationderive [α]D = -14

100% (–) enantiomer100% of maximum observed rotation100% enantiomer excess

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

123.702 Organic Chemistry

Enantiomeric excess II

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90% (+) enantiomer10% (–) enantiomer

= +90% clockwise10% anti-

clockwise80% of maximum rotation observed

80% e.e.

= +

50% (+) enantiomer50% (–) enantiomer

50% clockwise50% anti-clockwise

10% of major enantiomer is ‘cancelled out’

50% of major enantiomer is ‘cancelled out’

0% of maximum rotation observed

0% e.e.

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

• Polarimeter measures difference in the amount of each enantiomer• New methods more reliable & purity measured in terms of enantiomeric excess (e.e.)

• How do we measure enantiomeric excess?

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

= %R – %S