User:Benjah-bmm27/degree/3/APD

=Asymmetric synthesis, APD=

Chirality

 * Can have chiral centres at many different atoms:
 * C: sp3 carbon with four different substituents
 * N: ammonium ion with four different substituents on nitrogen
 * P: phosphines with three different substituents on phosphorus (P lone pair is configurationally stable)
 * S: sulfoxides with two different substituents on sulfur (S lone pair is also configurationally stable)
 * Can also have axial chirality, as seen in certain allenes, 1-ethylidene-4-methylcyclohexane, BINAP, and various other molecules

Asymmetric synthesis

 * 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


 * Enantiopure drugs are now standard
 * Only the R enantiomer of prozac is effective as an antidepressant
 * The S enantiomer of propranolol is a beta-blocker, whereas the R enantiomer has recently been discovered to act as a contraceptive (although not used as such)
 * Thalidomide has a useful R enantiomer, whereas the S enantiomer is a teratogen - but racemises in vivo so enantiopurity is no solution


 * 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

 * 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
 * Cyclic starch (based on a cyclodextrin) for chiral GC
 * Cellulose or starch with free OH groups converted to aryl carbamates, for chiral HPLC

Resolution of enantiomers

 * 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
 * Can often form enantiopure crystals by salt formation with a chiral acid or base
 * In the synthesis of indinavir, the racemic product of a Ritter reaction is hydrolysed to an amino alcohol, then reacted with tartaric acid
 * One enantiomer forms a crystalline tartrate salt, whereas the other one is soluble
 * Separate by filtration, then regenerate enantiopure amino alcohol from its tartrate with NaOH
 * Benefit is simplicity - widely used industrially
 * Many enantiopure acids and bases available from nature:
 * Tartaric acid
 * Camphorsulfonic acid
 * (−)-Cinchonidine
 * (−)-Quinine
 * Brucine (very toxic!)
 * α-Methylbenzylamine

Chiral pool

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

Chiral auxiliaries

 * 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

Asymmetric reduction of ketones

 * Alpine borane from α-pinene and 9-BBN
 * Ipc2BCl
 * CBS reduction, first asymmetric catalytic reduction
 * Corey's oxazaborolidine catalyst synthesised from proline

Homogeneous catalytic hydrogenation of ketones and alkenes

 * Noyori asymmetric hydrogenation of ketones &mdash; R. Noyori (Nobel Prize 2001)
 * Method for functionalised ketones uses 0.01-1 mol% square planar BINAP-RuX2 (usually, X = Cl or Br) and 40-100 atm H2
 * Method for simple ketones uses 0.01 mol% octahedral trans-S-XylBINAP-S-daipen-RuCl2, 10 atm H2, tBuOK, iPrOH (daipen is a diamine ligand)


 * Asymmetric catalytic hydrogenation of alkenes for the synthesis of L-DOPA at Monsanto &mdash; W. S. Knowles (Nobel Prize 2001)

Asymmetric oxidation

 * Asymmetric oxidation &mdash; K. B. Sharpless (Nobel Prize 2001)
 * The Nobel Prize in Chemistry 2001
 * Press release
 * Summary for the public
 * Advanced information
 * Further reading

Sharpless asymmetric dihydroxylation

 * Sharpless asymmetric dihydroxylation

Sharpless epoxidation

 * Sharpless epoxidation
 * tert-butyl hydroperoxide, tBuOOH
 * titanium isopropoxide, Ti(OiPr)4
 * diethyl tartrate, (+)-DET
 * molecular sieve catalyst

Jacobsen epoxidation

 * Jacobsen epoxidation
 * Jacobsen's catalyst is synthesised from trans-1,2-diaminocyclohexane (either the S,S or R,R enantiomer) and 3,5-di-tert-butyl-2-hydroxybenzaldehyde (which together form a salen-type ligand), manganese(II) acetate and lithium chloride in the presence of air
 * Jacobsen's catalyst is oxidised from Mn(III) to Mn(IV) by sodium hypochlorite: L2(RO)2Mn-Cl + NaOCl → L2(RO)2Mn=O
 * Oxidised catalyst converts cis-alkenes to their epoxides
 * Example: cis-β-methylstyrene is converted to (2R,3S)-2-methyl-3-phenyloxirane with (S,S)-Jacobsen's catalyst
 * (R,R)-Jacobsen's catalyst gives the (2S,3R) epoxide

Miscellaneous

 * Asymmetric reduction
 * Alpine borane from α-pinene and 9-BBN
 * Ipc2BCl
 * Asymmetric catalytic reduction
 * Asymmetric catalytic hydrogenation for the synthesis of L-DOPA at Monsanto &mdash; W. S. Knowles (Nobel Prize 2001)
 * Noyori asymmetric hydrogenation &mdash; R. Noyori (Nobel Prize 2001)
 * Asymmetric oxidation &mdash; K. B. Sharpless (Nobel Prize 2001)
 * Sharpless oxyamination
 * Sharpless asymmetric dihydroxylation
 * Sharpless epoxidation
 * tert-butyl hydroperoxide, tBuOOH
 * titanium isopropoxide, Ti(OiPr)4
 * diethyl tartrate, (+)-DET
 * molecular sieve catalyst
 * The Nobel Prize in Chemistry 2001
 * Press release
 * Summary for the public
 * Advanced information
 * Further reading


 * Jacobsen epoxidation
 * Oxaziridines

Enzymatic transformations

 * 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

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

Lactate dehydrogenase

 * Lactate dehydrogenase works best isolated, so need to supply your own catalytic NADH and regenerate it with sacrificial isopropanol:
 * α-keto acid + NADH --[lactate dehydrogenase]--> α-hydroxy acid + NAD+
 * NAD+ + isopropanol --[dehydrogenase]--> NADH + acetone
 * Example: achiral pyruvic acid → chiral (S)-lactic acid

Hydrolases

 * Hydrolases catalyse reactions with water, so don't need a cofactor
 * Common hydrolases
 * Pig liver esterase (PLE)
 * Aspergillus niger epoxide hydrolase (AnEH)
 * Great for kinetic resolution, but as with any resolution method, usually limited to 50% yield
 * However, with meso-substrates, get up to 100% yield by internal kinetic resolution
 * Asymmetric ester hydrolysis with pig liver esterase
 * PLE enantiospecifically hydrolyses one of the two methyl ester groups in a meso compound, which one depends on the size of the ring



Lipases

 * 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