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Asymmetric synthesis, APD

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Chirality

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Asymmetric synthesis

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  • Asymmetric synthesis
  • Natural molecules are chiral and enantiopure, so enantiomers have different biological effects
    • Limonene's R enantiomer smells of orange, whereas the S enantiomer smells of lemon
    • Aspartame is very sweet, but its enantiomer and all its diastereomers are bitter
  • Unsymmetrical ketones (e.g. acetophenone) have Re and Si enantiotopic faces, so reduction with NaBH4 leads to a racemic mixture of S and R alcohols, respectively (due to enantiomeric transition states, which must have equal energy)
    • Can make one enantiomer at a greater rate but using a chiral analogue of BH4 (transition states now diastereomeric, thus not equal in energy)
    • Often an unsuitable solution, as the chiral reagent can be large and expensive, and possibly only slightly enantioselective

Enantiomeric excess

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  • Simplest measure of enantiopurity is enantiomeric ratio (e.r.): the ratio of major to minor enantiomers.
  • However, almost universally used in enantiomeric excess (e.e.): the percentage of one enantiomer minus the percentage of the other
    • If the e.r. is 9:1, the e.e. is 90% − 10% = 80%
    • if the e.r. is 99:1, the e.e. is 99% − 1% = 98%
  • Analogously, mixtures of diastereomers are characterised by diastereomeric ratio (d.r.) and diastereomeric excess (d.e.)
  • Can determine e.e. by derivatisation
  • A chiral derivatizing agent converts enantiomers to diastereomers, which have different physical properties
  • The diastereomeric derivatives can then be separated by HPLC or GC, or quantified by integration of 1H or 19F NMR spectra
  • Mosher's acid chloride is a common, but expensive, derivatising reagent for NMR - makes Mosher esters from alcohols
    • Its chiral carbon is quaternary, so cannot epimerise
    • Its methoxy group gives a singlet in 1H, while its trifluoromethyl group gives a singlet in 19F NMR
    • Can get misleading results if derivatisation reaction goes faster for one enantiomer
  • Can also use chiral NMR shift reagents, which form hydrogen bonds with analyte molecules, generating diastereomeric complexes
  • Chiral stationary phases for chromatography are available

Resolution of enantiomers

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  • Chiral resolution
  • From a racemic mixture, convert the enantiomers to diastereomers, separate them, then discard the unwanted diastereomer
  • Simple but wasteful, 50% of the racemic product is discarded
  • Commonly convert to diastereomers with a mandelic acid derivative, (R)-2-methoxy-2-phenylacetyl chloride
  • Crystallization is the most convenient resolution method

Chiral pool

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  • Dipping into the chiral pool means starting from an enantiopure chiral compound from nature
    • Effective but may involve many steps

Chiral auxiliaries

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  • Chiral auxiliary – a chiral molecule temporarily added to a substrate. With the auxiliary attached, the substrate undergoes a diastereoselective reaction to form mostly one of two possible diastereomers. Subsequent removal of the auxiliary leaves enantiomeric products, hopefully with one enantiomer in great excess.
  • Evans' chiral auxiliary
    • Control conformation of Evans-derivatized substrate in Diels-Alder reaction with Et2AlCl, forming a chelate with the two carbonyl groups
  • 8-Phenylmenthol
    • Used by Corey in enantioselective prostaglandin synthesis
    • Synthesised from the (S) enantiomer of the natural product pulegone
    • Its OH group reacts with acyl chlorides to form 8-phenylmenthyl esters
    • 8-Phenylmenthyl acrylate esters can undergo asymmetric Diels-Alder reactions with achiral cyclopentadienes in the initial stages of the syntheses of several prostaglandins

Chiral reagents and catalysts

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Asymmetric reduction

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Asymmetric reduction of ketones

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Homogeneous catalytic hydrogenation of ketones and alkenes

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Asymmetric oxidation

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Sharpless asymmetric dihydroxylation

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Sharpless epoxidation

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Jacobsen epoxidation

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Miscellaneous

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Enzymatic transformations

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  • Enzymes are highly efficient chiral catalysts that generate enantiopure products. However...
    • Enzymes have evolved to use substrates found in biological systems, so won't operate on most organic molecules
    • Enzymes often require stoichiometric reagents (co-factors) such as NADH
    • Enzymes have evolved in aqueous biological systems, often limiting us to using them in water (but lipases work well in nonpolar solvents)
    • These problems can often be overcome, so certain enzymes are very useful for certain transformations in asymmetric synthesis

Dehydrogenases

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  • Dehydrogenases need a cofactor, so just use the whole organism: yeast
    • Converts ketones to secondary alcohols

Lactate dehydrogenase

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Hydrolases

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Lipases

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  • Esterases that act on lipids are termed lipases
  • Lipases work well in nonpolar solvents
  • Can use lipases to effect transesterification, acetylating an alcohol with vinyl acetate, a high energy acyl donor
  • Candida lipase with vinyl acetate will enantiospecifically acetylate one of the two OH groups in the meso compound cis-4-cyclopentene-1,3-diol (CAS # 29783-26-4)
  • The other enantiomer of the product can be made by acetylating both OH groups with acetic anhydride, then enantiospecifically hydrolysing one of them with Candida lipase and water