W20 Chirality PDF

WEEK 19 MPharm Programme Chirality Dr Matt Smith Slide 1 MPharm PHA114 Chirality 1 WEEK 19 Constitutional isomerism Constitutional isomerism (also called structural isomerism) Molecu...

WEEK 19 MPharm Programme Chirality Dr Matt Smith Slide 1 MPharm PHA114 Chirality 1 WEEK 19 Constitutional isomerism Constitutional isomerism (also called structural isomerism) Molecules with same formulae but different connectivity of C skeleton are constitutional isomers Isomers have different physical properties (e.g. m.p., b.p., solubility, density) Isomers have different chemical and pharmaceutical properties The atoms and groups are often arranged differently Different connectivity of atoms can result in diverse functional groups in isomers, even although they have same formulae Constitutional isomers cannot interconvert Slide 2 MPharm PHA114 Chirality 1  Example: 3 constitutional isomers WEEK 19 of C9H8O4 ane Aspirin Caffeic acid 4-Hydroxyphenyl- Plant origin/synthetic Plant origin pyruvic acid Analgesic, Key intermediate in Animal origin antipyretic, biosynthesis of Intermediate in tyrosine antiplatelet, NSAID lignin metabolism; if not metabolised efficiently, (non-steroidal anti- Anti-cancer and excess is converted into inflammatory drug) antioxidant activity toxic metabolite CO2H O O O CH3 HO OH OH O O HO HO Slide 3 MPharm PHA114 Chirality 1  Geometric isomerism - cis and trans WEEK 19 Geometric isomerism – may have covered cis and trans alkenes previously Same formulae, but different spatial arrangement of substituents around alkene Two substituents on opposite ends of π-bond – On same face: cis – On opposite faces: trans No interconversion between cis and trans forms at ambient or body temperatures Slide 4 MPharm PHA114 Chirality 1  Examples of C4H4O4 WEEK 19 ↑ von der Wods F ↑ melting point Maleic acid Fumaric acid Cis-form Trans-form Often used as salt for basic Often used as salt for basic medicines in pharmaceutical medicines in pharmaceutical manufacture manufacture Melting point: 139 – 140oC F Melting point: 287oC H H H CO2H HO2C CO2H HO2C H Slide 5 MPharm PHA114 Chirality 1 WEEK 19 IUPAC nomenclature for alkenes: Cahn-Ingold-Prelog (CIP) Rules If the priority 1 groups are on the same face of the alkene, use the prefix Z (from the German zusammen, meaning = iS ‘together’) X X C C If the priority 1 groups are on opposite faces, use the prefix E = trans (from the German entgegen, meaning ‘across’) X C C X Slide 6 MPharm PHA114 Chirality 1 WEEK 19 Example H 1 CO2H 1 relative priority 2 check some/opposite HO2C H 2 2(is)/Eltrans ( 1 We have already met maleic and fumaric acids Let’s look at fumaric acid: Consider the two ends of the alkene separately On the LHS, there is a C and an H atom attached to the alkene overall atomic number ↑ atomic number ↑ priority The C atom takes priority 1 as the atomic number is 6; H atomic number is 1 The same exercise with the RHS gives the C priority 1 Overall, the priority 1 groups are on opposite faces, so fumaric acid has E geometry = trans Slide 7 MPharm PHA114 Chirality 1 WEEK 19 Example exercises Me Me No geometry – 2 identical groups N on 1 end H 1 1 COOH H E HO Z 1 E 1 N CO2H Me H O Me H3C H Me O Acrivastine HO H Histamine H1-receptor antagonist Fusidic Acid Me Antibiotic Assign the geometry of the alkene groups in both molecules Slide 8 MPharm PHA114 Chirality 1 WEEK 19 Why is Geometry Important? · related to the shape & 'molecula = 3D' makes a big difference in how this drug going to work The Z (trans) geometry of tamoxifen gives it the correct shape to bind tightly to the estrogen receptor causing inhibition of the signalling that would result in cell growth In this way, breast cancer cell growth can be inhibited Slide 9 MPharm PHA114 Chirality 1 WEEK 19 * EXAM Key Messages: Alkene Geometry Z and E allow unambiguous naming of any alkene Consider ends of alkene separately and prioritise the 2 substituents Do Not apply alkene geometry in benzene # – If priority 1 groups on same face: Z Cromatic ↓ practice system · examples ! – If priority 1 groups on opposite faces: E Use Z and E for pharmaceuticals (not cis and trans) Alkene geometry essential for binding to targets Correct geometry for binding correlates to greater potency of drugs Slide 10 MPharm PHA114 Chirality 1 WEEK 19 Conformational Isomerism As the name suggests, this type of isomerism arises because a single compound can adopt a number of different conformations Is the only form of isomerism in which the isomers can interconvert from one conformation to another Interconversion occurs by rotation around C-C bonds (acyclic molecules) or ‘ring flip’ (cyclic molecules) Energy in a stable molecule influenced by internal strain Molecules usually prefer conformations that minimise strain and result in lowest energy Conformation (and geometry) have big impact on SHAPE Molecules with complementary shape to that of target usually display greatest potency – vital for medicinal effect Slide 11 MPharm PHA114 Chirality 1 WEEK 19 Sources of Strain Within Molecules There are 3 forms of strain commonly experienced by covalently bonded molecules: Steric strain – Resulting from repulsion between atoms that are positioned too close in space Torsional strain – Resulting from repulsion between electrons (both bonding and non-bonding) in orbitals that are positioned too close in space Angle strain – Resulting from the bond angles around an atom being larger or smaller than the preferred angles for the hybridisation state of that atom Slide 12 MPharm PHA114 Chirality 1 WEEK 19 Acyclic Molecules Consider the simple medicine cysteamine, NH2CH2CH2SH, used to treat the rare disease cystinosis If we look along the C-C bond using Newman projections, we can see the relative arrangement of the substituents on each C NH 2 HS The substituents on the front C can be eclipsed H with the substituents on the rear C HH H – Synperiplanar with steric and torsional strain synperiplanar H2N The substituents on each C can occupy different H H planes in a staggered conformation H H SH – Antiperiplanar - strain minimised antiperiplanar In aqueous solution, the antiperiplanar conformation of cysteamine has lowest energy (ignoring possible H-bonding) Slide 13 MPharm PHA114 Chirality 1 WEEK 19 Conformations of Cysteamine X  Y Notes A A 1. Eclipsed conformations C E at energy maxima (ACE) E 2. Staggered conformations n at energy minima (BDF) e r 3. Synperiplanar highest g B F energy conformation y D 4. Antiperiplanar lowest energy conformation 0 90 120 180 240 300 360 WHY? Dihedral angle  NH2 H2N NH2 H2N NH2 H2N HS H SH H H H H HS H H H H SH H H H H H HH H H HH H SH H SH H H A B C D E F eclipsed staggered eclipsed staggered eclipsed staggered Synperiplanar Gauche or Syncinical Anticlinical Antiperiplanar Anticlinical Gauche or Synclinical Slide 14 MPharm PHA114 Chirality 1 WEEK 19 Example of Exceptions - Sulpiride H H In aqueous solution at H3CH2C N H physiological pH (7.2), only H NH the 3o amine of sulpiride is A hydrogen bond O protonated between the ionised OCH3 3o amine and the H3CO SO2NH2 carbonyl group promotes the stability of H2NO2S HN the eclipsed form H3CH2C O H O NHN OCH3 N Sulpiride H CH2CH3 H H 3o amine group in sulpiride is protonated at pH 7.2 H2NO2S Slide 15 MPharm PHA114 Chirality 1 WEEK 19 Conformations of Cyclic Molecules Saturated cyclic rings are relatively common in pharmaceuticals and mammalian biochemicals – Cyclohexane rings, e.g. steroids, tranexamic acid – Piperazine and piperidine rings, e.g. cetrizine, ropivacaine – Pyranose rings, e.g. galactose, streptidine Preferred conformation usually most stable form Preferred conformations minimise strain – Angle, steric and torsional strain Affects shape and therefore binding to target receptor or enzyme Slide 16 MPharm PHA114 Chirality 1 WEEK 19 Cyclohexanes Chair and boat forms provide correct bond angles for sp3 carbonsin cyclohexane (angles 109.5o) – Chair conformation generally preferred: all staggered bonds, steric and torsional strain minimised – Boat has eclipsed bonds with high torsional strain and steric strain from ‘flagpole’ atoms Flagpole groups close in space cause steric strain Cyclohexane Cyclohexane chair form boat form H H H H H H ‘Endview’ of boat H H Chair conformation: all bonds on adjacent conformation shows H eclipsing and torsional strain H carbons are H H staggered Slide 17 MPharm PHA114 Chirality 1 WEEK 19 Chair Form: Drawing the Bonds Axial substituents are on vertical bonds HH H H H equatorial substituents circle the equator of the ring XH Y H HH H Notice each equatorial bond is parallel to ring C-C bonds two carbon atoms away: structures A, B and C HH H HH H HH H H H H H H H XH Y XH Y XH Y H H H HH HH HH H H H A B C Slide 18 MPharm PHA114 Chirality 1 WEEK 19 Ring Flip During ring flip, all axial bonds become equatorial and all equatorial bonds become axial Ability to swap equatorial and axial allows most stable conformations to be adopted Important for molecular shape and binding to receptors The chair passes through the boat form during the ring flip H Y Right end H Y Left end X Y X H H H flips up flips down H X X Y Right end X Y Left end H Y H H X H flips up flips down H H Slide 19 MPharm PHA114 Chirality 1 WEEK 19 Tranexamic Acid: Preferred Chair Form Tranexamic acid is an antifibrinolytic: it is used to prevent heavy bleeding Tranexamic acid: one substituent on upper face and one on lower face Two possible conformations: either both substituents axial or both equatorial To minimise steric strain, substituents preferred in equatorial position – Equatorial substituents point away from the ring and from each other CO2H H2N H H2N H CO2H H CO2H H H2N RH structure is more stable as both substituents in equatorial position which is preferred. Slide 20 MPharm PHA114 Chirality 1 WEEK 19 Numerous Pharamceutical Examples Cl Me Me H H N Cetirizine Ropivacaine N H O H H Me Piperidine N H2N O CO2H N NH H Piperazine HN Streptidine OH O H HO N NH2 O OH CHO HO NH OH OH OH O OH Me O HO O OH HO O HO Streptomycin OH O Galactose HO NHMe HO Lactuclose - L Glucosamine Cetirizine: histamine H1-receptor antagonist; Ropivacaine: local anaesthetic; Lactulose: Laxative; Streptomycin: antibiotic Slide 21 MPharm PHA114 Chirality 1 WEEK 19 Five-Membered Ring Systems There are many examples of pharmaceuticals with 5- membered rings systems; some examples… – Sugars: ribose, streptose, fructofuranose – Pyrrolidines: e.g. in sulpiride, – Tetrahydrofurans: e.g. in furethidine (an opioid analgesic) 5 membered rings can adopt a twist or envelope shape to minimise strain – But still some eclipsing and torsional / steric strain CO2Et O O N H Envelope conformation Conformation of furethidine (in aqueous solution) Slide 22 MPharm PHA114 Chirality 1 WEEK 19 Four-Membered Ring Systems Saturated cyclic systems with 4 atoms are less common Due to their restricted options, strain is difficult to minimise – Steric, angle and torsional strain Commonly adopt a V-shape H3N Me Me Sibutramine in aqueous solution V-shaped cyclobutane 3-Membered ring systems - carbons are 120° with adjacent carbon atoms Slide 23 MPharm PHA114 Chirality 1 WEEK 19 Key Messages: Cyclic Conformations Saturated cyclic systems are not planar They adopt conformations that minimise strain – Angle strain: bond angles of 109.5o preferred for sp3 atoms – Steric strain: minimised by distant positioning of atoms – Torsional strain: minimised by staggering of bonds For 6 membered rings, chair conformations preferred, with large substituents in equatorial rather than axial positions (if possible) Envelope conformation common in 5 membered rings 4 membered rings most often adopt V-shape – Angle, steric and torsional strain remain relatively high Slide 24 MPharm PHA114 Chirality 1 WEEK 19 MPharm Programme Chirality 2 Dr Matt Smith Slide 25 MPharm PHA114 Chirality 2 WEEK 19 Stereoisomerism Tetrahedral-carbonylQ intermediate Stereoisomerism (also called optical or configurational isomerism, or chirality) Stereoisomers are not interconvertible Stereoisomerism usually arises due to asymmetry around a saturated carbon atom Stereoisomerism is a very important aspect of the pharmaceutical industry and of medicinal use Adverse effects have been seen in patients due to stereoisomerism and caused major changes to registration and licensing of new medicines ex) thalidomide treat including - - sickness morning zisomers Slide 26 MPharm PHA114 Chirality 2 WEEK 19 Terminology Many terms are used interchangeably and are considered analogous – Stereoisomerism = chirality – Chiral carbon (atom) = stereocentre = stereogenic carbon (atom) = chird centre – Chirality = stereochemistry = configuration – Racemic mixture = racemate = 1 : 1 mixture of enantiomers – Optically inactive suggests something is achiral = not chiral (or a racemic mixture) – Enantiomers = non-superimposable mirror images - – Diastereoisomers = non-superimposable non-mirror images (Chirality 3, slide 3) o / - Xinteract Interact w. receptor Slide 27 MPharm PHA114 Chirality 2 WEEK 19 What is a Chiral Carbon? Usually, a chiral carbon atom is sp3 hybridised and has four different atoms or groups attached to it = if you rotate > cannot get - superimposable structure One test for a chiral carbon in a compound is whether or not its mirror image is superimposable – If superimposable, it is achiral (not chiral) – If non-superimposable, it is chiral The non-superimposable mirror image forms are called enantiomers Slide 28 MPharm PHA114 Chirality 2 WEEK 19 Practice: Identify the Chiral Carbons HO OH COOH NH2 HO O H2N O O NH2 HO OH HO HO O OH OH HO N Latanoprost O H NH2 treat glaucoma H Amikacin H2N antibiotic (streptomycin class) CO2H N H CH2CH2CH3 H N Perindopril O CO2CH2CH3 ACE inhibitor (anti- H CH3 hypertensive) S CH3 O ① H HO Me NMe 2 HO H H N N OH - H HO H H ② chird ② NH2 O NH Nelfinavir OH HIV protease OH O OH O O inhibitor Tetracycline antibiotic Slide 29 MPharm PHA114 Chirality 2 WEEK 19 Practice: Identify the Chiral Carbons more chird moreisomers (potential we can get HO OH * * COOH O * NH2 HO * H2N * * * * * O NH2 * * O * OH HO HO HO * O * * OH * OH * * * Latanoprost HO N O * * H NH2 treat glaucoma H Amikacin H2N antibiotic (streptomycin class) * CO2H * * N CH2CH2CH3 H H N * Perindopril * O CO2CH2CH3 ACE inhibitor (anti- H CH3 hypertensive) S CH3 O * * * H HO Me NMe 2 HO * H H N N H * OH HO H H * * * * * NH2 O NH Nelfinavir OH HIV protease OH O OH O O inhibitor Tetracycline antibiotic Slide 30 MPharm PHA114 Chirality 2 WEEK 19 Nomenclature IUPAC adopted the Cahn-Ingold-Prelog (CIP) rules to provide unambiguous naming system * not for alkene carbon Prioritise atoms / groups around chiral carbon – If clockwise order: R (from Latin Rectus) I Two enantiomers – If anticlockwise order: S (from Latin Sinister) left-handed sinister - in church = S Slide 31 MPharm PHA114 Chirality 2 WEEK 19 Steps to Classify Chirality 1. Ensure chiral C drawn in 3D with wedge bonds 2. Prioritise atoms directly attached to chiral C using atomic number (not atomic mass) – If atoms attached to chiral C are same, look at next atoms attached until find difference 3. Make sure priority 4 atom at back on dashed normally H = wedge bond. going C 4. Add priority numbers to remaining atoms behind me towards – me If order 1→ 2→ 3 (not 4) clockwise, classify as R – If order 1→ 2→ 3 anticlockwise, classify as S * practice with examples ! Slide 32 MPharm PHA114 Chirality 2 WEEK 19 Worked Example: Acebutolol The active enantiomer of acebutolol is shown below Identify the chiral carbon and ensure it is drawn in 3D Prioritise the atoms attached directly to it by atomic number O has highest priority (Z = 8), then C (Z = 6), then H O has priority 1 and H priority 4; to differentiate the two C atoms, we need to look at the atoms attached directly to them The CH2 on the LHS is attached to O, while the CH2 on the RHS is attached to N – O has a higher atomic number than N (Z = 7), so CH2O takes priority 2 and CH2N priority 3 Make sure the priority 4 atom 4 S 1 is at the back, then look at the I H OH H Me direction of 1→ 2→ 3 O O Is N 1/ It is anticlockwise, so the active 6 6 7 Int21 2 3 2I! Me Me enantiomer of acebutolol Me N S has S stereochemistry H anticlockwise O Acebutolol Slide 33 MPharm PHA114 Chirality 2 WEEK 19 Worked Example: Rivastigmine EXAM ALERT ! centre ① redraw chird ③ drow a clockwisel attclockwise arrow Identify chiral C ② express 1- * prorities ⑦ label R/s configuration Prioritise atoms directly attached Make sure priority 4 at back Direction 1→ 2→ 3 anticlockwise, so S 3 4 Me Me H 1 O N Me Me2N 2 S O Rivastigmine Slide 34 MPharm PHA114 Chirality 2 WEEK 19 What do we do if Priority 4 Atom not at back? 11. ? If priority 4 atom is at front instead….. We are viewing the molecule from the opposite side Anything that looks clockwise is really anticlockwise, and vice versa Assign chirality as usual, then reverse answer Consider cetirizine’s active enantiomer – Assign as usual – Anticlockwise direction of 1→ 2→ 3 – Looks like S chirality, but H at front, so reverse….. It has R chirality O CO2H HO 2C O 4 N N Cl H 1 4 N H Cl N 2 1 2 3 Cetirizine 3 Cetirizine R Check by rotating in space Slide 35 MPharm PHA114 Chirality 2 WEEK 19 What do we do if Priority 4 Atom not at back? If priority 4 atom in plane, cannot assign chirality confidently (usually wrong!) Must rotate molecule to get priority 4 atom either at back (preferable) or at front To rotate: – Keep one bond to chiral C (Ar-C in this example) stationary in the plane – Rotate rest of molecule around that one bond, like turning steering wheel CF3 H3C NH O Rotation Hj CF3 around 1 O H4 & 2 CH3 Ar-C bond 2 S 3 N H Fluoxetine 2713H the plane #11 ! # priority on > - cannot find (S)-Fluoexetine configuration Slide 36 MPharm PHA114 Chirality 2 WEEK 19 OH Serine vs Cysteine SH * H IS THE LOWEST PRIORITY GROUP AND IS * H H IN THE BACK OF THE PAGE FOR BOTH H3N α * O H3N α * O S R O O Atom bonded to Atomic No. of Priority (1-4) of Atom bonded to Atomic No. of Priority (1-4) of α atom atoms α atom atoms C 6 C 6 C 6 C 6 N 7 1 N 7 1 H 1 4 H 1 4 Have to prioritise the two carbons Have to prioritise the two carbons Look at atoms directly bonded to next carbons Look at atoms directly bonded to next carbons Atom bonded Atomic No. of Priority (1-4) of Atom bonded Atomic No. of Priority (1-4) of carbon * atom, which atoms carbon * atom, which atoms atom has largest atom has largest atomic No. atomic No. OHH 8/ 1 / 1 3 SHH 16/ 1 / 1 2 OOO 8/8/8 2 OOO 8/8/8 3 Slide 37 MPharm PHA114 Chirality 2 WEEK 19 - Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) for relieving pain. - It is often administered as a racemic mixture, but only the S-enantiomer is active. - In vivo, the non-active R-enantiomer can epimerise to the active S-configuration. - Draw the R and S isomers of ibuprofen. CH3 3 CH3 2 OH OH CH 3 CH 3 S R O1 O H 3C H 3C Atom bonded to α Atoms and atomic Priority (1-4) of Same rules apply but……… Lowest no. atoms C 6C priority group (H) is facing towards us. C 6C 6C STILL GET R BUT……LOWEST PRIORITY C 1H GROUP IS FACING TOWARDS US SO H 4 THEREFORE IS S (swap rule) Have to prioritise the THREE carbons Look at atoms directly bonded to next carbons Atom bonded to next Atoms and atomic Priority (1-4) of C no. atoms CCC 6C 6C 6C 2 HHH 1H 1H 1H 3 OOO 8O 8O 8O 1 Slide 38 MPharm PHA114 Chirality 2 WEEK 19 Methamphetamine is a highly active central nervous system stimulant and is chiral. 2 H # H R N CH 4 * N 1 CH 3 S 3 H #CH3 CH3 3 Atom bonded to Atomic No. of Priority (1-4) of Same rules apply but………………………. Lowest * atom atoms priority group (H) is facing towards us. N 7 1 (highest) C 6 Same IF LOWEST GROUP IS POINTING TOWARDS US THEN DO THE SAME………..GIVES S C 6 Same BUT………….LOWEST PRIORITY GROUP IS FACING H 1 4 (lowest) TOWARDS US SO THEREFORE IS R. Have to prioritise the two carbons For instance: Look at atoms directly bonded to next carbons (#) If we follow the same rules for a different compound where the lowest group is pointing Atom bonded Atomic No. of Priority (1-4) of carbon # atom, which atoms towards us but we assigned is as R, this will in atom has largest fact be S. atomic No. CHH 8+1+1 Carbon (2) We do not need to apply the swap (R to S) if HHH 1+1+1 H (3) the lowest priority group is facing away from us. Slide 39 MPharm PHA114 Chirality 2 WEEK 19 Properties of Enantiomers Now we can assign enantiomers correctly, we can discuss their similarities and differences R and S isomers of a molecule have identical physical and chemical properties – E.g. m.p., b.p., solubility, pKa (acidity) – Not surprising, as have same functional groups and same skeleton 2 exceptions: 1. Rotation of plane polarised light (PPL) 2. Interaction with other chiral molecules Slide 40 MPharm PHA114 Chirality 2 WEEK 19 Plane Polarised Light (PPL) PPL is produced by passing light through a polarising filter Compound in cell Polarised Polarised Analyser (α) Unpolarised (C and L) filter light light rotated light Lamp by interacting with compound Rotation of plane polarised light is measured in degrees and represented by [D], using light corresponding to the D line of a sodium lamp [D] =   = measured rotation CxL C = conc of solution (g/100mL) = % w/v L = path length (of cell) in dm It is usual to give the temp, conc and solvent used Slide 41 MPharm PHA114 Chirality 2 WEEK 19 Rotation of PPL by Enantiomers Enantiomers rotate PPL in opposite directions by equal amounts Use + for clockwise (dextrorotatory) and – for anticlockwise (levorotatory) O O antibacterial F COOH F COOH N N N N CH3 N O H N O H3C H3C CH3 (S)-Ofloxacin α[D] -96o ~ It does not tell RIS you (R)-Ofloxacin α[D] +96o configuration potentia of [ optical rotation value The specific rotation (+) or (-) does not tell you if the compound has R or S configuration Slide 42 MPharm PHA114 Chirality 2 WEEK 19 Interactions with other Enantiomers The 3 point model of binding is often used to explain differences in enantiomer interactions with another chiral species, as receptors and enzymes are also chiral because formed from amino acids (chiral). Numerous examples of enantiomers having different activities: – Note that not all pairs of enantiomers have different activities – Important to distinguish undesirable activity in enantiomer from no adverse activity In this example shown….. will not bind to the receptor - no drug actulty – Active (R)-enantiomer binds correctly to receptor to trigger response – (S)-enantiomer cannot bind correctly, does not trigger response Slide 43 MPharm PHA114 Chirality 2 WEEK 19 Carvone spearmint caraway CH3 CH3 O O 2 3 1 C C H3C CH2 H3C CH2 (R)-Carvone α[D] -62.5o (S)-Carvone α[D] +61o Slide 44 MPharm PHA114 Chirality 2 WEEK 19 Vigabatrin (Sabril®) Used in treatment of epilepsy and other seizures Seizures thought to be caused by low -aminobtyric acid (GABA) levels in brain (S)-enantiomer active as anti-convulsant Inhibits inactivation of GABA by GABA transaminase Increases levels of GABA and reduces incidence of seizures Marketed as the racemate: (R)-enantiomer has no adverse effects + + NH3 NH3 x Pharmacologically active 1 2 - - 3 O2C CO2 IRI-enonHomer GABA transaminase inhibitor anti-convulsant Slide 45 MPharm PHA114 Chirality 2 WEEK 19 Fluoxetine (Prozac®) Marketed as the racemate for treatment of depression Activity as serotonin selective reuptake inhibitor in both ex citalopram enantiomers. (R)-enantiomer most rapidly eliminated (S)-fluoxetine considered pharmacological form, as present at highest concentration F F O O 1 2 3 NHCH3 H3CHN Slide 46 MPharm PHA114 Chirality 2 WEEK 19 Warfarin O O 1 3 CH3 2 OH O Administered as the racemate Commonly used to reduce risk of unwanted blood clots Both forms active in inhibiting vitamin K epoxide reductase (VKORC1) (S)-form about 4x more active than (R) in practice (R)-form rapidly metabolised and excreted Overall, (S)-form responsible for anti-coagulant activity Slide 47 MPharm PHA114 Chirality 2 WEEK 19 Why are Amines Rarely Chiral? ??? practice 2 reasons: problems in wzo 1. If the amine can protonate / deprotonate, then it can invert to opposite stereochemistry H R2 Inversion R2 +H + R1 - H+ N R1 R3 R3 R3 N N R1 N R3 R2 R1 R2 H 2. If amine can resonate lone pair with adjacent group, adopts partial double bond – No chirality with sp2 centre: if N is not tetrahedral, it can not be chiral Br O H H O N Me N S Br H OH O OH H OH Acamprosate Dembrexine Used in the treatment of alcohol dependence Veterinary mucolytic agent Slide 48 MPharm PHA114 Chirality 2 WEEK 19 L and D: Fischer Notation You will sometimes see chiral molecules assigned as having D or L stereochemistry – L-alanine (L-amino acids), D-glucose, D-ribose (D-sugars) – Note upper case D and L This notation was devised by Emil Fischer in late 1800s Based on D-glyceraldehyde Still applied in particular to amino acids and sugars – Simplifies and standardises the names of these more complex molecules Note: D / L notation different to d / l (in lower case) d = dextrorotatory (clockwise rotation of PPL), now use + l = levorotatory (anticlockwise rotation of PPL), now use – Slide 49 MPharm PHA114 Chirality 2 WEEK 19 Fischer Projections Fischer arranged the carbon atoms of the sugar or amino acid vertically on the page, with the most 1 2 CHO oxidized C at the top 4 H 2 1 OH 3 3 HO H The substituents on each vertical C then stick up 4 H OH from the page (like a ‘bow-tie’ on each C) 5 H OH D Fischer used the penultimate C (C5 of glucose or C2 6 CH2OH of alanine) to decide D or L: Glucose – If the OH (on a sugar) or NH2(on an amino acid) was on the LHS, the molecule was given L notation 1 2 CO2H – If the OH or NH2 was on the RHS, it was given the 1 2 4 L H2N H notation D 3 CH 3 3 D-Glucose IUPAC name = (2R, 3S, 4R, 5R)-2,3,4,5,6-pentahydroxyhexanal Al ine an L-Alanine IUPAC name = (2S)-2-aminopropanoic acid Slide 50 MPharm PHA114 Chirality 2 WEEK 19 Example Exercise 1. Assign the form of glyceraldehyde shown below as D or L 2. Draw it in 3D, rather than its 2D shadow form, and assign the stereochemistry at C2 as R or S 3. Name this form of glyceraldehyde using the IUPAC system CHO CHO 1 CHO H OH H OH 2 3 OH HOH2C CH2OH CH2OH H Glyceraldehyde D-Glyceraldehyde (2R)-2,3-dihydroxypropanal Slide 51 MPharm PHA114 Chirality 2 WEEK 19 Key Messages: Many pharmaceuticals have one or more chiral carbon The mirror image forms are non-superimposable The non-superimposable mirror image forms are called enantiomers Chiral centres are assigned using Cahn-Ingold-Prelog rules with R or S stereochemistry Enantiomers have identical chemical and physical properties, except for the interaction with PPL and other chiral species Enantiomers rotate PPL by equal amounts in opposite directions The effect of an inactive enantiomer can be undesirable Rotation of PPL (+) or (-) has no link with if a compound is R or S configuration Slide 52 MPharm PHA114 Chirality 2 WEEK 19 MPharm Programme Chirality 3 Dr Matt Smith Slide 53 MPharm PHA114 Chirality 3 WEEK 19 OH 1 2 3 Multi-Chiral Centres OH HN CHCl2 O 2N O Chloramphenicol - The more asymmetric carbons present, the more stereoisomers are possible - For a compound with n asymmetric carbon atoms, there are 2n (2 to the power n) possible stereoisomers To draw the possible stereosiomers, draw C-C bond between chiral C atoms vertically – Add the biggest groups in the plane on the LHS – Add the H behind the plane (makes it easier to assign) – Add the last group in front of the plane (solid wedge bond) – Use an imaginary mirror to draw the enantiomer – Make sure you draw each chiral C with both R and S possibilities O2N H OH (1R) (2R) 1R, 2R Cl2HCCONH H OH Slide 54 MPharm PHA114 Chirality 3 WEEK 19 Diastereoisomers O2N H H NO2 OH HO Enantiomers (1S) 1R, 2R 1S, 2S (1R) (2R) (2S) Cl2HCCONH NHCOCHCl2 H H OH HO Inactive Active form Diastereoisomers Diastereoisomers Diastereoisomers O2N OH OH NO2 H H (1R) 1S, 2R 1R, 2S (1S) (2R) (2S) Cl2HCCONH Enantiomers NHCOCHCl2 H H Inactive OH HO Inactive Chloramphenicol = antibiotic isolated from the bacterium Streptomyces venezuelae and first launched on the pharmaceutical market in 1949 Slide 55 MPharm PHA114 Chirality 3 WEEK 19 Enantiomeric Excess - Example A sample of Methamphetamine (MA) obtained by police was found to be a mixture of 60% (+)-MA and 40% (-)-MA and has an *α+20D = +2° Enantiomeric excess (ee) = (x-y)/(x+y) = (60-40)/100 = 0.2 x 100 = 20% ee of (+)-MA What is the *α+20D of a mixture comprising 100% (+) MA and 100% (-) MA: What is the *α+20D of a mixture comprising 25% (+) MA and 75% (-) MA: -5° 0° [α]20 D -8° -4° -2° Racemic +2° +4° +6° +8° +10° -10° -6° 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 0% % of the (+) enantiomer 25% We want to know the *α+20 D at 25% (+)MA ee = 75-25 = 50% 25/ee = 25/50 =0.5 There is 50% more (-)MA 0.5 x *α+20D at 100% -(MA) (as (-)MA is in excess) = 0.5 x -10° = -5° Slide 56 MPharm PHA114 Chirality 3 WEEK 19 Molecules with 2 Identical Chiral Carbons Two asymmetric carbon atoms both with identical groups attached Still have 22 theoretically possible stereoisomers but only 3 actual different stereoisomers Why? To answer this, we need to draw all of the possible stereoisomers Use same method as used for HS SH chloramphenicol H C C H HO2C CO2H Dimercaptosuccinic acid (DMSA) Slide 57 MPharm PHA114 Chirality 3 WEEK 19 DMSA What is the relationship between the (2R, 3S) and (2S, 3R) forms? SH 1 SH H CO2H HO2C H C2 Enantiomers C 2R, 3R 2S, 3S C3 C HS CO2H HO2C SH 4 H H Diastereoisomers Diastereoisomers Diastereoisomers H H HO2C SH HS CO2H C Identical, C 2R, 3S 2S, 3R C superimposable C HO2C SH HS CO2H H H Slide 58 MPharm PHA114 Chirality 3 WEEK 19 How are the 2nd Pair Identical? 4 3 H 1 H HO2C SH HS CO2H C C 2 2 C 1 C 3 HO2C SH HS CO2H H H 4 This (R,S or S,R) stereoisomer is called: the meso form Meso compounds have two or more asymmetric carbons and a plane of symmetry Chiral compounds cannot have a plane of symmetry Therefore, meso compounds are achiral Slide 59 MPharm PHA114 Chirality 3 WEEK 19 Importance of meso-DMSA Used medically to chelate toxic metals in cases of metal poisoning Particularly in children, as more sensitive – Pb (in children, 20-25 mg Pb / 100 mL blood leads to irreversible CNS damage) – Hg, As, Cd [http://www.thorne.com/media/dmsa_monograph.pdf] Hg HS SH S S Hg2+ H C C H H C C H HO2C CO2H HO2C CO2H Meso-DMSA Meso form essential to chelate metal SH groups must be on same side Slide 60 MPharm PHA114 Chirality 3 WEEK 19 Identifying Stereoisomers with 2 Chiral Carbons Look for non-superimposable mirror images – Enantiomers Non-superimposable, non-mirror images of same structural formula – Diastereoisomers Superimposable, has internal mirror plane – Meso compound Slide 61 MPharm PHA114 Chirality 3 WEEK 19 Properties of Diasteroisomers S,S R,R R,S (meso) H H H HO2C OH HO CO2H HO2C OH C C C C C C HO2C H H CO2H HO2C OH OH OH H m.p. (oC) [a]D (25oC) Solubility (g/100g H2O at 15oC) (2R,3R)-(+)-Tartaric acid 170 +11.98o 139 (2S,3S)-(-)-Tartaric acid 170 -11.98o 139 (2R,3S)-Tartaric acid 140 0o 125 (±)-Tartaric acid 206 0o 139 Slide 62 MPharm PHA114 Chirality 3 WEEK 19 Separation of Diastereoisomers The different physical characteristics of diastereoisomers enables their separation Relatively simple methodology The different solubility in solvents can be used to separate the diastereoisomers: – Use a solvent in which one diastereoisomer is very soluble, the other is less soluble – Both diastereoisomers dissolve – The less soluble one crystallises out and is filtered – Evaporate the solvent to get the other pure diastereoisomer Slide 63 MPharm PHA114 Chirality 3 WEEK 19 Classical Resolution Example (S)-base (R,S)-salt + (S,S)-salt (R)-acid / (S)-acid mixture enantiomers diastereoisomers The (R,S)-salt has different Crystallise and separate solubility to its (S,S)-salt diastereoisomer (R,S)-salt (S,S)-salt One diastereoisomer crystallises HCl HCl and can be filtered off leaving the other in solution to be evaporated (S)-baseH+ (S)-baseH+ + + The enantiomers are recovered by acidifying the separated (R)-acid (S)-acid diastereoisomeric salts Slide 64 MPharm PHA114 Chirality 3 WEEK 19 Resolution by Esterification (S)-alcohol (R)-acid / (S)-acid mixture (R,S)-ester + (S,S)-ester Catalytic enantiomers diastereoisomers acid separate Use similar approach to separate diastereoisomers of ester (R,S)-ester (S,S)-ester Form covalent bond between Ester chiral enantiomers of carboxylic HCl/ hydrolysis HCl/ acid and alcohol Separate diastereoisomers by (S)-alcohol (S)-alcohol crystallisation then recover the + + separate enantiomers by ester (R)-acid (S)-acid hydrolysis Slide 65 MPharm PHA114 Chirality 3 WEEK 19 Example Racemic Ibuprofen H3C H H CH3 CH3 CO2H HO2C CH3 CH3 CH3 H CH3 Catalytic acid / OH dry solvent / heat (R)-alcohol H3C H + (S)-ibuprofen-(R)-ester O CH3 C O H CH3 CH3 (R)-ibuprofen-(R)-ester Separate diastereoisomers due to differential solubilities Slide 66 MPharm PHA114 Chirality 3 WEEK 19 Consequences of Chirality Pharmacological effects Appropriate recognition by targets Strong binding to targets Correct pharmacological activity If only 1 enantiomer active, consider effects of inactive forms – No adverse effects – Adverse effects / toxicity Slide 67 MPharm PHA114 Chirality 3 WEEK 19 Key Messages: 2 or more Chiral Centres Many pharmaceuticals have 2 or more chiral centres For n chiral centres, there are 2n possible stereoisomers Besides the non-superimposable mirror image enantiomers, there are non-superimposable non-mirror image forms called diastereoisomers If 2 identical chiral centres, internal mirror plane in one form produces the achiral meso-form (and only 3 stereoisomers) Diastereoisomers have different physical properties (many chemical properties very similar as same functional groups in same relative C skeleton) Can use diastereoisomer formation to separate enantiomers – Must be reversible and preferably economically viable Slide 68 MPharm PHA114 Chirality 3 WEEK 19 Selectivity in Reactions Stereoselectivity possible in reactions due to mechanism If chiral reactant and / or product, mechanisms: – Can show no stereoselectivity Result in racemisation – Or can show stereoselectivity Invert stereochemistry, or Conserve stereochemistry, or Preferentially react or form particular stereoisomers Stereochemical outcomes important in, e.g. – Metabolism of drugs to active (or inactive) forms – Drug action at receptors – Toxicity through undesirable activity of stereoisomers Mechanism of reaction affects stereochemistry Slide 69 MPharm PHA114 Chirality 3 WEEK 19 Concerted vs Non-concerted Reactions In a non-concerted reaction, the bond breaking and making occurs in different steps Intermediates are formed: C+, C or C- (depending on reactant) Intermediates allow changes to stereochemistry, e.g. SN1, E1, some electrophilic/radical additions to alkenes Racemisation usually results if intermediate formed In a concerted reaction, all bond making and breaking happens in the same step Stereochemistry is usually defined, e.g. SN2, E2 reaction Stereochemistry either inverted or conserved in concerted reactions Biological systems, such as enzymes, generally prefer reactions to produce defined products Slide 70 MPharm PHA114 Chirality 3 WEEK 19 Non-concerted Reaction: SN1 These reactions occur at sp3 hybridised carbons Always more than one step 1st step: polarised bond between C and heteroatom (Br) breaks Intermediate carbocation formed: planar – Stereochemical definition lost Reactant forms new bond to C – Can attack planar intermediate from above or below plane equally easily – 3D tetrahedral carbon re-formed with 1:1 mix of enantiomers uc N No stereoselectivity CH3 C Br CH3CH3 CH3 C CH3 CH3CH 3 - Br Nuc C 1:1 bond cleavage CH2CH3 bond formation CH3CH3 1 enantiomer Planar intermediate C CH 3 Nuc Slide 71 MPharm PHA114 Chirality 3 WEEK 19 Concerted Reaction: SN2 These reactions also occur at sp3 hybridised carbons Polarised bond between C and heteroatom (Br) causes slight positive charge (+) on C making it electrophilic Nucleophile attacks electrophilic C+, breaks existing polarised C-Br bond as new bond is made – one step reaction No intermediate formed Only one product, with stereochemistry defined by attack of nucleophile horizontally opposed to leaving group Br CH3 C CH2CH3 - Br [If nucleophile is part of protein CH2CH 3 C or DNA, can see why molecules Nuc CH3 with good leaving groups are Nuc usually toxic] Slide 72 MPharm PHA114 Chirality 3 WEEK 19 Reduction of Carbonyl Compound H- attack from behind C=O H B H Trigonal planar O H O Tetrahedral H Na OBH3 OH sp2