Axial Chirality Axial Chirality - Nonplanar Arrangement of Four Groups About an Axis Spiro-Compounds

Home , Axial chirality, Chirality (chemistry), Chirality (mathematics), Planar chirality, Stereoisomerism

Asymmetric Synthesis

Gareth Rowlands Gareth J. Rowlands 123.702 Organic Chemistry 2 The importance of chirality

Me CO2H Me CO2H N H Me NH2 NH2 N nicotine L-alanine D-alanine toxin / stimulant mammalian amino acid bacterial cell wall

• 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

NH HN Et OH OH Et H H OH OH N N Me Me Me Me N N H H OH Et Et OH

(–)-propanolol (+)-propanolol Ethambutol (R,R)-enantiomer β-blocker for heart disease contraceptive tuberculostatic (anti-TB) causes blindness

123.702 Organic Chemistry 3 The importance of chirality

GLOBAL SALES ACTIVE FORM OF ACTIVE NAME THERAPEUTIC EFFECT 2003 (BILLION $) INGREDIENT INGREDIENTS

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 • 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, 41 123.702 Organic Chemistry 4 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...

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

a b H OH X X P a c Ph H c d b Ph Me Me chiral centre 123.702 Organic Chemistry 5 One stereogenic centre: chirality on an atom

Mirror Mirror plane plane

rotate rotate

Chiral Achiral • Mirror images are non-superimposable • Mirror images are superimposable • Each mirror image is an enantiomer • Compound has a plane of symmetry • Only differ by their absolute ...conﬁguration or actual 3D shape • Simplistically - 4 different groups • Do not have a plane of symmetry H OH R1 R1

R4 R3 Me Me R1 R2 achiral 1 1 3 4 4 3 R =R ≠R ≠R plane of symmetry R R running through central chiral carbon, hydrogen and OH R1≠R2≠R3≠R4 ACHIRAL

123.702 Organic Chemistry 6 Deﬁning absolute conﬁguration

H NH2

Me CO2H alanine

• 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) rotate around axis until lowest priority points away from you 2 4 1 H H NH CO2H H NH2 HO2C H H NH2 ≡ Me CO2H Me Me NH2 Me NH2 3 2 CO2H 3 1 • 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)

H NH2

Me CO2H (S)-alanine (S)-2-aminopropanoic acid 123.702 Organic Chemistry 7 Deﬁning absolute conﬁguration II

O1 O1 2 4 3 P 2 P Me Me OMe Ph 4 3 MeO • Deﬁne priorities according to CIP • Point lowest priority (4) away from viewer • Draw line from 1 to 3 • Line is anti-clockwise so (S) 1

O Me P 2 Ar Ph 3

O P Me OMe

(S)-(4- methoxyphenyl)methylphenyl phosphine oxide 123.702 Organic Chemistry 8 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

N Me 2 1 R R R3 N 3 N R1 R Me N R2 Tröger's base

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

MeO O P P O t-Bu Me X P Me Ph MeO (S)-cyclohexyl(4- (S)-naphthalen-1-yl tert- methoxyphenyl)(methyl) butyl(phenyl)phosphinate phosphine

123.702 Organic Chemistry 9 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)

Me O O Me O Me S S S S t-Bu N Me Me Me Me Me H Ph (R)-1-methyl-4- (R)-S-tert-butyl 2- (S)-N-benzylidene-2- (methylsulfinyl)benzene methylpropane-2- methylpropane-2-sulfinamide sulfinothioate

• 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 10 Axial chirality Axial chirality - Nonplanar arrangement of four groups about an axis Spiro-compounds

axis of Mirror chirality O O O O O O

(R)-olean olean olean (R)-1,7- (S)-1,7- dioxaspiro[5.5]undecane dioxaspiro[5.5]undecane attracts male olive flies attracts female olive flies

Axial chirality and atropisomerism Atropisomers - stereoisomers resulting from restricted rotation about a single bond axis of chirality Mirror

PPh2 Ph2P

(R)-(+)-BINAP (S)-(-)-BINAP (R)-2-(diphenylphosphino)-1-(2-(diphenyl (S)-2-(diphenylphosphino)-1-(2-(diphenyl phosphino)naphthalen-1-yl)naphthalene phosphino)naphthalen-1-yl)naphthalene 123.702 Organic Chemistry 11 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)

Mirror

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

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

Mirror

Ph Ph

Fe PPh2 Ph2P Fe

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

123.702 Organic Chemistry 12 Enantiomers & optical rotation

H OH HO H • Each enantiomer has identical physical & Ph CO2H Ph CO2H chemical properties (in an achiral environment) (R)-(-)-mandelic acid (S)-(+)-mandelic acid • Only differ by how they rotate plane polarised light 131-133°C 131-134°C (rotate in opposite directions) 23 20 [α]D –153 [α]D +154 • Enantiomers are said to be optically active

α Optical rotation t [α]D = α l x c light light (λ) polariser plane sample reading α = observed rotation source polarised light cell length l (dm) l ..= 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 13 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...

H NH2

CO2H

measure rotation 100% (+) enantiomer 100% of maximum derive [α]D = +14 observed rotation 100% enantiomer excess

H2N H

CO2H

measure rotation 100% (–) enantiomer 100% of maximum derive [α]D = -14 observed rotation 100% enantiomer excess • The observed rotation is proportional to the amount of each enantiomer present... 123.702 Organic Chemistry 14 Enantiomeric excess II

= +

90% (+) enantiomer 10% anti- 90% clockwise 10% of major 80% of maximum 10% (–) enantiomer clockwise enantiomer is rotation observed ‘cancelled out’ 80% e.e.

= +

50% (+) enantiomer 50% anti- 50% clockwise 50% of major 0% of maximum 50% (–) enantiomer clockwise enantiomer is rotation observed ‘cancelled out’ 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.) Enantiomeric excess (% ee) = [R] – [S] = %R – %S [R] + [S]

• How do we measure enantiomeric excess? 123.702 Organic Chemistry