Chiral Auxiliaries Flashcards
What is a chiral auxiliary
- A prochiral substrate attached to a chiral non-racemic group
- Chiral auxiliary is the chiral non-racemic group
How are chiral auxiliaries used
- A reaction is conducted which results in diastereomeric products which may be readily separated
- Cleavage of the auxiliary from the purified reaction mixture yields the chiral, non racemic products
What are the requirements of a good chiral auxiliary
- Enantiomerically pure and available in both enantiomers
- Cheap and available in quantity
- Easy to introduce into the substrate
- Gives high and predictable diastereocontrol
- Easy to purify the major diastereomer
- Easy to remove the chiral auxiliary from product.
What are used in diastereoselective enolate alkylations
- Generally ise amides as substrates- they give complete control over enolate geometry
- Oxazolidinone auxiliaries of Evans are widely used for asymmetric alkylation
Describe how diastereoselective enolate alkylations work -Evans
- First chiral auxiliary is attached to ketone- forms imide
- LDA (or NaHDMS) , THF, -78 degrees forms z-enolate
- Z-enolate formed due to avoidance of steric clashing and chelation with Li (Na) to ketones of oxazolidinone and ketone
- Then electrophile added and one face is blocked by R-group of oxazolidinone
What are the three oxazolidinone
- Valine derived
- Ephedrine-derived
- Phenylalanine-derived
What do oxazolidinone enolates react readily with
- Variety of reactive electrophiles
- MeI
- BnBr
- AllylBr
- NBS
- trysl azide
- oxaziridines
- Azodicarboxylates
What are the different auxiliary cleavage methods
- LiBH4- produces alcohol form of substrate separated from chiral auxiliary
- LiOOH, H2O produces carboxylic acid form of substrate
- MeONHMe.HCl, Me3Al- forms Weinreb amide- some of chiral auxiliary still attached
What is Weinreb amide useful for
- Useful as treatment with bulky reducing agents
- Produce aldehyde
How is an oxazolidinone produced
- From amino acid
- Add NaBH4/H2SO4 (used to make BH3 in reaction) and reduces acid to amino-alcohol
- Add C1 carbonyl equivalent- ethylchloroformate + K2CO3
- Amino group reacts with carbonyl displacing the chloride
- under action of base hydroxyl group undergoes second attack to displace the ethoxy group- forms ring system
How can you get an aldehyde from a Weinreb amide
- Add DIBAL-H (bulky-reducing agent)
- Al Coordinates with both O- stabilises transition state - 5 Membered
- H is added to C=O
- Reaction is worked up with H+/H2O
- Excess DIBAL-H is destroyed to form aluminium hydroxide species- fast reaction
- Aluminium in 5-membered transition state is replaced by H giving hemiaminal species- slow
- Hemiaminal species is unstable so generates aldehyde and parent amine
- Aldehyde is never exposed to reducing agent as is destroyed quick
Why is it hard to reach aldehyde OS from ester
- If add reducing agent to ester can’t stop at aldehyde
- As aldehyde is more reactive than the ester- as soon as formed is reduced further to alcohol
What is the aldol reaction important for
- Exceptionally important in organic synthesis
- Particularly for synthesis of biologically active polypropionate natural product
Describe Evans aldol reaction
- Very effective stereocontrol
- Forms z-enolate exclusively due to Boron coordination of both C=O
- Very high syn selectivity with addition of OH to R
- 6-membered Zimmerman-Traxler TS
- Aldehyde R group goes equatorial
- Aldehyde approaches away from large alkyl group on auxiliary
- The dipoles of the carbonyl of the auxiliary and aldehyde are opposed
Describe the diastereoselective enolate alkylation Myers method
- Based upon pseudoephedrine amides - Cheap and available in both enantiomeric forms
- Amide enolates much more reactive than imide enolates (have a higher pKa) and hence unactivated alkyl halides may be used
Describe process of Diastereoselecive enolate alkylation Myers method
- Add acid chloride to pseudoephedrine forms pseudoephedrine amide
- Add LDA, LiCL, R’X
- Solvent forms OLi with Alcohol and C=O which blocks one face of the enolate
- Less hindered approach used - highly diastereoselective
What can be produced from the product of Myers enolate alkylation
- Carboxylic acid
- Ketone
- Aldehyde
- Alcohol
How is a carboxylic acid produced from the product of Myers enolate alkylation
- H2SO4, dixane reflux
- Or Bu4NOH, tBuOH, water reflux
How is an aldehyde produced from the product of Myers enolate alkylation
- LiAlH(OEt)3, 0 degrees
How is an alcohol produced from the product of Myers enolate alkylation
- LiH2N
How is a ketone produced from the product of Myers enolate alkylation
- MeLi, 0 Degrees
What is used to carry out the asymmetric synthesis of alpha-amino acids
- Schollkopf’s auxiliary
- Diastereo enolate alkylation reaction
Describe how Schollkopf’s auxiliary is produced
- Take amino acid valine - has sterically demanding isopropyl unit
- Protect NH2 using Boc2O, NaHCO3 and Base THF, H2O
- Acid group of valine couples with amino group of Glycine methyl ester-
- Then heat to 180 degrees which removes boc groups freeing NH2 group allowing cyclisation
- Add Me3O+ BF4- - electrophilic alkylating agent - both C=O change to OMe
Describe Schollkopf’s auxilliary reaction to produce an alpha amino acid
- Add strong base e.g. BuLi which deprotonates Schollkopf’s auxiliary to produce anion
- Add BnBr which approaches from the less hindered face- opposite to large iPr group
- Add H3O+ (mild acid) to hydrolyse the two N=C bonds which results in cleavage of heterocycle leaving 2 amino acid units- one is valine- recycle other is new one with Bn side chain
How can you create chiral amines
- Using Ellmans’ chiral sulfinamide
Describe Ellmans’ chiral sulfinamide
- Sulfinamide is tetrahedral at sulfur due to presence of a lone pair of electrons and hence is chiral
- Sulfinamide reacts readily with a wide variety of aldehydes and ketones to give the corresponding aldimines and ketimines
Describe Ellman’s sulfinamide reaction to produce a chiral amine
- Add ketone/aldehyde to sulfinamide
- Add NuH to form 6 membered transition state
- Large tbutyl group is pseudoequatorial
- Small lone pair is axial
- Imine substituent equatorial
- Organometallic chelated by R group and sulfinamide oxygen
- Add HCl, MeOH
- Produces chiral amine and racemic sulfonyl chloride - problem
How is racemic t-butylsulfinamide formed
- Take dithiane and carry out oxidation reaction
- Add H2O2, AcOH then Cl2
- Forms sulfonyl chloride
- Then add NH4OH- displaces Cl with NH2
How can you produce enantiomerically pure t-butylsulfinamide using quinidine
- Take racemic t-butyl sulfonyl chloride
- It is rapidly interconverting due to lone pair on S which is prone to racemisation
- Treat with quinidine (catalyst) and EtOH- ethanol nucleophile to displace chloride forms ester
- Quinidine ensures stereochemistry
- Add NaNH2 via SN2 mechanism to form pure t-butylsulfinamide - replaces OEt with NH2
- Hard to do on large industrial scale
How does quinidine ensure an enantioselective reaction
- Quinidine only reacts with one enantiomer of racemic sulfonyl chloride to produce sulfonyl ester
- As it reacts the reactive enantiomer becomes deficient so racemisation that interconverts between enantiomers replenishes the reactive enantiomer
- Eventually ends up with all racemic sulfonyl chloride reacting to produce enantiopure ester
What is a method of producing enantiomerically pure t-butylsulfinamide on a large scale
- Take dithiane and carry out enantioselective oxidation
- H2O2, acetone, vanadium complex, chiral ligand
- chiral ligand and achiral vanadium complex (form a chiral complex which enantioselectivity oxidise with H2O2 )
- Then displace thiol unit with amino group- LiNH2, NH3, -78 degrees then ice, ClCH2CO2H
- Recrystallise to get high ee.
Describe how t-butylsulfinamides (Ellmans chiral sufinamide) is used to reduce ketones selectively
- Addition to a ketone forms a ketimine
- This can then be reduced with NaBH4 or L-selectride to give different major diastereomers of the resulting sulfinimine
- Then add MeOH, HCl to form primary amine
Describe reduction of ketimine with NaBH4
- Along with THF and water
- 6- membered transition state
- Large tbutyl group pseudoequatorial
- Small lone pair axial
- Larger substituent of ketone equatorial
- Organometallic chelated by R2 and sulfinamide oxygen
- Results in NH3 opposite side to tbutyl
Describe reduction of ketimine with L-selectride
- Can’t proceed by chair-like transition state as too bulky
- Minimise dipoles- opposing direction - carbonyl presented upwards
- Deliver hydride from least hindered end - So NH3 is same side as tbutyl
How can you synthesise enantiopure beta amino acids
- Chiral auxiliary produced from enantiopure alpha methyl benzylamine
- Add RNLi, THF, -78 degrees then HN4Cl
- Chiral auxiliary undergoes an conjugate addition and new bond form between Nitrogen and beta carbon of double bond
- Then add H2, Pd(OH)2, MeOH to deprotect benzyl groups on nitrogen to produce beta amino acid - results in destruction of stereocentre of chiral auxiliary
Why are beta amino acids useful
- Nice chiral building blocks for constructing heterocycles with stereocentres
- Useful for making beta-peptides
