1 Advanced Organic Chemistry Gareth J. Rowlands Advanced organic 2 Enantioselective synthesis Why is enantioselective synthesis important? • Nature yields an enormous variety of chiral compounds • A change in stereochemistry can have profound effects O O CO2Me O H O OHO O H O O N O O H OH AcO OH N N MeO C H Me 2 O azadiractin (S)-3-(1-methylpyrrolidin- (1R,2R,3S,5S)-2-acetyl-8-methyl-8- anti-feedant 2-yl)pyridine aza-bicyclo[3.2.1]octan-3-yl benzoate nicotine cocaine toxin / stimulant stimulant O O Me CO2H Me CO2H NH N O NH2 NH2 H O (S)-2-aminopropanoic acid (R)-2-aminopropanoic acid (S)-2-(2,6-dioxopiperidin-3- L-alanine D-alanine yl)isoindoline-1,3-dione mammalian amino acid bacterial cell wall (S)-thalidomide teratogen (birth defects) Advanced organic 3 Chirality and biology HIV protease + inhibitor Nicotinic receptor • Enzymes & receptors are invariably chiral • Chiral drugs can interact with these to give two diastereomeric complexes • Imagine the hand below is the enzyme, it can form two very different complexes depending on the chirality or “handness” of the drug it interacts with... Advanced organic 4 Chirality and biology II NH HN CO2H CO2H OH OH HS HS NH2 NH2 (R)-1-(isopropylamino)-4- (S)-1-(isopropylamino)-4- (S)-2-amino-3-mercapto-3- (R)-2-amino-3-mercapto-3- (naphthalen-1-yl)butan-2-ol (naphthalen-1-yl)butan-2-ol methylbutanoic acid methylbutanoic acid (–)-propanolol (+)-propanolol D-penicillamine L-penicillamine β-blocker for heart disease contraceptive treats chronic arthritus toxic Et OH OH Et H H N N N N H H OH Et Et OH (S,S)-2-[2-(1-Hydroxymethyl- (R,R)-2-[2-(1-Hydroxymethyl- propylamino)-ethylamino]-butan-1-ol propylamino)-ethylamino]-butan-1-ol Ethambutol causes blindness tuberculostatic (anti-TB) • As you can imagine, these two complexes can have very different effects • The three drugs above highlight the possible effects of using the “wrong” compound • As a result we must have methods to prepare the correct enantiomers Advanced organic 5 Revision: 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 • The easiest to identify are the cis-trans isomers found with sp2 systems • Alkenes should be assigned E or Z using Cahn-Ingold-Prelog rules • We are not going to look at these BUT will see their effects in enolate chemistry A C A C B D B D A & C have highest priority A & D have highest priority alkene = Z alkene = E • Imines are treated in a similar manner A C A C N N B B A has highest priority B has highest priority imine = Z or cis imine = E or trans Advanced organic 6 One stereogenic centre: chirality on an atom • Chiral compounds - 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 H OH P Ph H Ph Me Me chiral centre Advanced organic 7 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 Advanced organic 8 Enantiomers & optical rotation α light light (λ) polariser plane sample reading source polarised light cell length l (dm) • 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 • Not very useful as value is very unreliable (dependent on solvent & all factors below) • Even sign (+/–) can change depending on concentration!! t H OH HO H optical rotation [α]D = α Ph CO2H Ph CO2H l x c (R)-(-)-mandelic acid (S)-(+)-mandelic acid α = observed rotation; l = cell 131-133°C 131-134°C path (dm); c = concentration g/ [ ]23 –153 [ ]20 +154 α D α D ml (or g/100ml); t = temperature Advanced organic 9 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 Advanced organic 10 Defining absolute configuration II O1 O1 O 4 1 2 4 S O 3 P 2 P Me Me S Me Ph Me Me OMe 3 2 4 3 Me MeO Me • Define priorities according to CIP • Define priorities according to CIP • Point lowest priority (4) away from viewer • Point lowest priority (4) away from viewer • Draw line from 1 to 3 • Draw line from 1 to 3 • Line is anti-clockwise so (S) • Line is anti-clockwise so (R) 1 1 O O Me P S Ar Ph Me Tol 2 3 3 2 O O P S Me Me OMe Me (S)-(4- methoxyphenyl)methylphenyl (R)-methyl-4- phosphine oxide methylphenylsulfoxide Advanced organic 11 Central chirality at elements other than carbon Chiral Nitrogen compounds • As last two examples indicated it is not just carbon that can have central chirality • Any tetrahedral or pyramidal atom with four (three) different substituents can be chiral • Nitrogen / amines have the potential to be chiral... N Me 2 1 R R 3 R Me N 3 N N R1 R R2 Tröger's base (5S)-2,8-Dimethyl-6H,12H-5,11- methano-dibenzo[b,f][1,5]diazocine • But rapid pyramidal inversion normally prevents isolation of either enantiomer • If substituents are constrained in a ring then rigid structure prevents inversion • Quaternary ammonium salts (below) can be isolated enantiomerically pure • Racemisation has been observed, presumably via dissociation... Ph N Cl Et Me i-Pr Advanced organic 12 Central chirality at phosphorus • Trigonal pyramidal phosphorus (III) is configurationally stable below 200°C • P-chiral phosphines have a rich history as chiral ligands MeO P Me X P Me MeO (S)-cyclohexyl(4- methoxyphenyl)(methyl) phosphine • Tetrahedral phosphorus (V) is configurationally stable O P O t-Bu Ph (S)-naphthalen-1-yl tert- butyl(phenyl)phosphinate Advanced organic 13 Central chirality at sulfur • Sulfoxides are tetrahedral; remember they have a lone pair! • Configurationally stable at room temperature • Certain anions (Cl ) can cause racemisation (interconversion of the enantiomers) O O O S S S S t-Bu N 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 it is not a requirement • Furthermore, as we shall see, not all compounds with a stereogenic centre are chiral!! Advanced organic 14 Axial chirality Axial chirality - Nonplanar arrangement of four groups about an axis Spiro-compounds Mirror Mirror HO2C CO2H HO2C CO2H CO2H CO2H axis of chirality H CO2H HO2C H H H H H D-Fecht acid L-Fecht acid H H (S)-spiro[3.3]heptane-2,6- (R)-spiro[3.3]heptane-2,6- dicarboxylic acid dicarboxylic acid Viewed along axis axis of chirality Mirror 2 CH2R O O 4 3 O RH2C OR O O O OR 1 olean olean anti-clockwise (R)-1,7- (S)-1,7- = (S) dioxaspiro[5.5]undecane dioxaspiro[5.5]undecane attracts male olive flies attracts female olive flies Advanced organic 15 Axial chirality II Allenes Mirror H Cl Cl H axis of C C chirality Cl H H Cl (R)-1,3-dichloropropa- (S)-1,3-dichloropropa- 1,2-diene 1,2-diene Axial chirality and atropisomerism Atropisomers - stereoisomers resulting from restricted rotation about a single bond Mostly commonly found in hindered biaryls axis of chirality Mirror PPh2 Ph2P PPh2 Ph2P (R)-(+)-BINAP (S)-(-)-BINAP (R)-2-(diphenylphosphino)-1-(2- (S)-2-(diphenylphosphino)-1-(2- (diphenylphosphino)naphthalen (diphenylphosphino)naphthalen -1-yl)naphthalene -1-yl)naphthalene Advanced organic 16 Axial chirality III • Atropisomerism is not just found in biaryl compounds • Any molecule in which rotation is restricted sufficiently to allow isolation of each isomer can be chiral... rotation around central bond O N O N MeO MeO CHO X CHO • Atropisomerism is found in nature HO • Vancomycin is an anti-bacterial HO • Kotanin is from rice mold OH Me O Me O O Me OMe O NH2 Cl OH O O HO Cl OH O O O MeO O O H H O N N NHMe N N N MeO O O H H H HN O O O Me HO2C Me NH2 OH Me OMe HO OH kotanin Vancomycin Advanced organic 17 Helicity • Molecules that twist like a helix, propeller or screw • Right-handed helix is denoted P (clockwise as you travel away from viewer) • Interestingly, [8]helicene racemises (1:1 mixture of enantiomers) readily at 293°C! Mirror P [8]helicene M [8]helicene Advanced organic 18 Planar chirality • Planar chirality - chirality resulting from the arrangement