Two chiral centres (diastereoisomers)

1 Two chiral centres (diastereoisomers) Mirror N S N Two enantiomers differ by absolute configuration N N 2 N 2 N A molecule with 1 stereogenic centre exists as 2 stereoisomers or enantiomers Enantiomers have identical physical properties in an achiral environment A molecule with 2 stereogenic centres can exist as 4 stereoisomers Enantiomers (mirror images) still have identical physical properties Diastereoisomers (non-mirror images) have different properties 2 N 2 N C 2 Me C 2 Me enantiomers trans epoxide mp = 141 C diastereoisomers different mp enantiomers cis epoxide mp = 98 C 2 N 2 N C 2 Me C 2 Me 123.702 rganic Chemistry

2 Diastereoisomers N 2 N 2 N 2 N 2 2Cl 2Cl chiral solubility 0.1g/100ml Et diastereoisomers different solubility seperable N 2 N 2 2Cl meso solubility 3.3g/100ml Et Enantiomers differ only by their absolute stereochemistry ( or S etc) Diastereoisomers differ by their relative stereochemistry elative stereochemistry - defines configuration with respect to any other stereogeneic element within the molecule but does NT differentiate enantiomers In simple systems the two different relative stereochemistries are defined as below: Me Me N 2 syn same face N 2 anti different face A molecule can only have one enantiomer but any number of diastereoisomers The different physical properties of diastereoisomers allow us to purify them The differences between diastereoisomers will be the basis for everything we do... 123.702 rganic Chemistry

3 Diastereoisomers II C (2,3,4)-2,3,4,5-tetrahydroxypentanal ribose C C C C (2,3,4)-ribose (2,3,4S)-arabinose (2,3S,4)-xylose (2,3S,4S)-lyxose C C C C (2S,3S,4S)-ribose (2S,3S,4)-arabinose (2S,3,4S)-xylose (2S,3,4)-lyxose four diastereoisomers mirror plane and their 4 enantiomers If a molecule has 3 stereogenic centres then it has potentially 8 stereoisomers (4 diastereoisomers & 4 enantiomers) If a molecule has n stereogenic centres then it has potentially 2 n stereoisomers Problem is, the molecule will never have more than 2 n stereoisomers but it might have less... 123.702 rganic Chemistry

4 Meso compounds 2 C C 2 tartaric acid 2 C C 2 2 C C 2 2 C C 2 enantiomers diastereoisomers identical C2 2 C 2C C 2 2 C C 2 2 C C 2 C2 2C Tartaric acid has 2 stereogenic centres. But does it have 4 diastereoisomers? 2 diastereoisomers with different relative stereochemistry 2 mirror images with different relative stereochemistry 1 is an enantiomer The other is identical / same compound Simple rotation shows that the two mirror images are superimposable 123.702 rganic Chemistry

5 Meso compounds II Meso compounds - an achiral member of a set of diastereoisomers that also includes at least one chiral member Simplistically - a molecule that contains at least one stereogenic centre but has a plane of symmetry and is thus achiral Meso compounds have a plane of symmetry with () configuration on one side and (S) on the other 2 C C 2 rotate LS 2 C C 2 plane of symmetry Another example... Cl Cl Cl Cl chiral no plane of symmetry non-superimposable on mirror image (but it is symmetric!) achiral plane of symmetry superimposable on mirror image (meso) 123.702 rganic Chemistry

6 Chiral derivatising agents Difference in diastereomers allows chiral derivatising agents to resolve enantiomers / S racemic mixture pure enantiomer enantiomerically pure derivatising agent * * cleave diastereoisomer * + S * diastereoisomers separable mixture of diastereoisomers * pure diastereoisomer S * emember a good chiral derivatising agent should: Be enantiomerically pure (or it is pointless) Coupling reaction of both enantiomers must reach 100% (if you are measuring ee) Coupling conditions should not racemise stereogenic centre Enantiomers must contain point of attachment Above list probably influenced depending whether you are measuring %ee or preparatively separating enantiomers 123.702 rganic Chemistry

7 Chiral derivatising agents: Mosher s acid F 3 C Me + C 2 DCC, DMAP C 2 Cl 2, 10 C F 3 C Me Me / S S N C N S & S S DCC - dicyclohexylcarbodiimide Popular derivatising agent for alcohols and amines is α-methoxy-αtrifluoromethylphenylacetic acid (MTPA) or Mosher s acid Difference in nmr signals between diastereoisomers (above): 1 nmr Δδ = 0.08 (Me)... 19 F nmr Δδ = 0.17 (CF3) Typical difference in chemical shifts in 1 nmr 0.15 ppm 19 F nmr gives one signal for each diastereoisomer No α-hydrogen so configurationally stable Diastereoisomers can frequently be separated In many cases use of both enantiomers of MTPA can be used to determine the absolute configuration of a stereocentre (73JACS512, 73JC2143 & 91JACS4092) 123.702 rganic Chemistry

8 Chiral derivatising agents: salts Tol N 2 C Tol C 2 N 2 2 C Tol C 2 Tol / S S diastereoisomer is insoluble so easily removed by filtration Na N ( )-propranolol β-blocker No need to covalently attach chiral derivatising group can use diastereoisomeric ionic salts Benefit - normally easier to recover and reuse reagent Use of non-covalent interactions allows other methods of resolving enantiomers... 123.702 rganic Chemistry

9 esolution of enantiomers: chiral chromatography esolution - the separation of enantiomers from either a racemic mixture or enantiomerically enriched mixture Chiral chromatography - Normally PLC or GC A racemic solution is passed over a chiral stationary phase Compound has rapid and reversible diastereotopic interaction with stationary phase opefully, each complex has a different stability allowing separation matched enantiomer - more stable (3 interactions) matched enantiomer travels slowly mis-matched enantiomer - less stable (1 interaction) mis-matched enantiomer readily eluted racemic mixture in solution chiral stationary phase 123.702 rganic Chemistry

10 Chiral chromatography inject mixture on to column /S S S chiral column prepared from a suitable chiral stationary phase (many different types) Si Si Si Si Si Me Si Me N N 2 S silica N 2 chiral amine chiral stationary phase Measurements of ee by PLC or GC are quick and accurate (±0.05%) Chiral stationary phase may only work for limited types of compounds Columns are expensive (> 1000) Need both enantiomers to set-up an accurate method 123.702 rganic Chemistry

11 NM spectroscopy: chiral shift reagents Chiral paramagnetic lanthanide complexes can bind reversibly to certain chiral molecules via the metal centre Process faster than nmr timescale and normally observe a downfield shift (higher ppm) Two diastereomeric complexes are formed on coordination; these may have different nmr signals C 3 F 7 EuL 2 + substrate Eu(hfc) 3 substrate Eu(hfc) 3 Problems - as complexes are paramagnetic, line broadening is observed (especially on high field machines) Compound must contain Lewis basic lone pair (, N2, C=, C2 etc) Accuracy is only ±2% 123.702 rganic Chemistry

12 Chiral shift reagents II N N Me Sm 3+ γ β α N 2 L-valine C 2 New reagents are being developed all that time that can overcome many of these problems 1 NM spectra (400 Mz) of valine (0.06 M, [D]/[L] = 1/2.85) in D2 at p 9.4 123.702 rganic Chemistry

13 Enzymatic resolution Bu F Et lipase PS from Pseudomonas cepacia, 0.05M phosphate buffer, p 7, 0.1M Na, 5 C 60% conversion Bu F Et + Bu F Na / S >99% ee soluble in organic phase S 69% ee soluble in aqueous phase Enzymes are very useful for the resolution of certain compounds Frequently they display very high selectivity There can be limitations due to solubility, normally only one enantiomer exists and can be too substrate specific Below is the rationale for the selectivity observed above... diastereomeric interaction of enzyme lone pair with σ* orbital of C F of (S)- enantiomer favoured over interaction with ()-enantiomer enzyme Bu F N his N ser N Et 123.702 rganic Chemistry