Advanced Organic Chemistry

Transcription

1 1 Advanced rganic Chemistry Gareth J. Rowlands

2 2 Enantioselective synthesis Why is enantioselective synthesis important? ature yields an enormous variety of chiral compounds A change in stereochemistry can have profound effects Ac 2 C C 2 azadiractin anti-feedant (S)-3-(1-methylpyrrolidin- 2-yl)pyridine nicotine toxin / stimulant (1R,2R,3S,5S)-2-acetyl-8-methyl-8- aza-bicyclo[3.2.1]octan-3-yl benzoate cocaine stimulant 2 C 2 (S)-2-aminopropanoic acid L-alanine mammalian amino acid 2 C 2 (R)-2-aminopropanoic acid D-alanine bacterial cell wall (S)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (S)-thalidomide teratogen (birth defects)

3 3 Chirality and biology IV protease + inhibitor icotinic 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...

4 4 Chirality and biology II S C 2 S C (R)-1-(isopropylamino)-4- (naphthalen-1-yl)butan-2-ol ( )-propanolol β-blocker for heart disease (S)-1-(isopropylamino)-4- (naphthalen-1-yl)butan-2-ol (+)-propanolol contraceptive (S)-2-amino-3-mercapto-3- methylbutanoic acid D-penicillamine treats chronic arthritus (R)-2-amino-3-mercapto-3- methylbutanoic acid L-penicillamine toxic Et Et (S,S)-2-[2-(1-ydroxymethylpropylamino)-ethylamino]-butan-1-ol Ethambutol tuberculostatic (anti-tb) Et Et (R,R)-2-[2-(1-ydroxymethylpropylamino)-ethylamino]-butan-1-ol causes blindness 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

5 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 sp 2 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 A & C have highest priority alkene = Z B D A & D have highest priority alkene = E Imines are treated in a similar manner A B C A has highest priority imine = Z or cis A B C B has highest priority imine = E or trans

6 6 ne 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... image Left & right hands on-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 Ph P chiral centre

7 7 ne stereogenic centre: chirality on an atom plane plane rotate rotate Chiral images are non-superimposable Each mirror image is an enantiomer nly differ by their absolute...configuration or actual 3D shape Simplistically - 4 different groups Do not have a plane of symmetry R 4 R 3 R 1 R 2 achiral R 4 R 3 R 1 =R 1 R 3 R 4 chiral R 1 R 2 R 3 R 4 Achiral images are superimposable Compound has a plane of symmetry R 1 R 1 plane of symmetry running through central carbon, hydrogen and ACIRAL

8 8 Enantiomers & optical rotation α light source light (λ) polariser plane polarised light sample cell length l (dm) reading Each enantiomer has identical physical & chemical properties (in an achiral environment) nly differ by how they rotate plane polarised light (rotate in opposite directions Enantiomers are said to be optically active ot very useful as value is very unreliable (dependent on solvent & all factors below) Even sign (+/ ) can change depending on concentration!! Ph C 2 (R)-(-)-mandelic acid C [α] D Ph C 2 (S)-(+)-mandelic acid C [α] D optical rotation [α] t = D α l x c α = observed rotation; l = cell path (dm); c = concentration g/ ml (or g/100ml); t = temperature

9 9 Defining absolute configuration 2 C 2 alanine eed to be able to define the absolute configuration of a chiral centre First assign priorities according to Cahn-Ingold-Prelog rules (highest atomic number) C 2 2 rotate around axis until lowest priority points away from you 2 C 2 2 C C 2 2 ext 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) 1 2 C 2 (S)-alanine (S)-2-aminopropanoic acid

10 10 Defining absolute configuration II P 2 P Ph 4 3 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 P 2 Ar Ph S S 3 2 Define priorities according to CIP Point lowest priority (4) away from viewer Draw line from 1 to 3 Line is anti-clockwise so (R) 1 S Tol 3 2 P (S)-(4- methoxyphenyl)methylphenyl phosphine oxide S (R)-methyl-4- methylphenylsulfoxide

11 11 Central chirality at elements other than carbon Chiral itrogen 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 itrogen / amines have the potential to be chiral... R 1 R 3 R 2 R 1 R 2 R3 Tröger's base (5S)-2,8-Dimethyl-6,12-5,11- 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 Et i-pr Cl

12 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 P (S)-cyclohexyl(4- methoxyphenyl)(methyl) phosphine X P Tetrahedral phosphorus (V) is configurationally stable P t-bu Ph (S)-naphthalen-1-yl tertbutyl(phenyl)phosphinate

13 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) S (R)-1-methyl-4- (methylsulfinyl)benzene S S (R)-S-tert-butyl 2- methylpropane-2- sulfinothioate t-bu S Ph (S)--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 it is not a requirement Furthermore, as we shall see, not all compounds with a stereogenic centre are chiral!!

14 14 Axial chirality Axial chirality - onplanar arrangement of four groups about an axis Spiro-compounds axis of chirality 2 C C 2 D-Fecht acid (S)-spiro[3.3]heptane-2,6- dicarboxylic acid 2 C C 2 L-Fecht acid (R)-spiro[3.3]heptane-2,6- dicarboxylic acid C 2 C 2 2 C C 2 Viewed along axis axis of chirality olean (R)-1,7- dioxaspiro[5.5]undecane attracts male olive flies olean (S)-1,7- dioxaspiro[5.5]undecane attracts female olive flies 4 R 2 C 2 C 2 R 3 R R 1 anti-clockwise = (S)

15 15 Axial chirality II axis of chirality Cl C Cl (R)-1,3-dichloropropa- 1,2-diene Allenes Cl C Cl (S)-1,3-dichloropropa- 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 PPh 2 PPh 2 Ph 2 P Ph 2 P (R)-(+)-BIAP (R)-2-(diphenylphosphino)-1-(2- (diphenylphosphino)naphthalen -1-yl)naphthalene (S)-(-)-BIAP (S)-2-(diphenylphosphino)-1-(2- (diphenylphosphino)naphthalen -1-yl)naphthalene

16 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 C X C Atropisomerism is found in nature Vancomycin is an anti-bacterial Kotanin is from rice mold 2 Cl 2 C Cl 2 kotanin Vancomycin

17 17 elicity 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! P [8]helicene M [8]helicene

18 18 Planar chirality Planar chirality - chirality resulting from the arrangement of out-of-plane groups with respect to a plane, called the chiral plane In [2.2]paracyclophane the more substituted benzene ring is considered the chiral plane 2 2 (R)-4-amino[2.2]paracyclophane (S)-4-amino[2.2]paracyclophane 2 plane of chirality

19 19 Planar chirality II Probably the most important planar chiral compounds are ferrocene derivatives These have found considerable use in enantioselective catalysis Ph Fe PPh 2 Ph Ph 2 P Fe (S)-2-phenyl-1- (diphenylphosphanyl) ferrocene (R)-2-phenyl-1- (diphenylphosphanyl) ferrocene An interesting example of planar chirality is found in some (E)-cycloalkenes (R)-(E)-cyclooctene (S)-(E)-cyclooctene