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aa Topics in organic chemistry 1 > Chiral Auxiliaries > Flashcards

Chiral Auxiliaries Flashcards

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1
Q

What is a chiral auxiliary

A
  1. A prochiral substrate attached to a chiral non-racemic group
  2. Chiral auxiliary is the chiral non-racemic group
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2
Q

How are chiral auxiliaries used

A
  1. A reaction is conducted which results in diastereomeric products which may be readily separated
  2. Cleavage of the auxiliary from the purified reaction mixture yields the chiral, non racemic products
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3
Q

What are the requirements of a good chiral auxiliary

A
  1. Enantiomerically pure and available in both enantiomers
  2. Cheap and available in quantity
  3. Easy to introduce into the substrate
  4. Gives high and predictable diastereocontrol
  5. Easy to purify the major diastereomer
  6. Easy to remove the chiral auxiliary from product.
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4
Q

What are used in diastereoselective enolate alkylations

A
  1. Generally ise amides as substrates- they give complete control over enolate geometry
  2. Oxazolidinone auxiliaries of Evans are widely used for asymmetric alkylation
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5
Q

Describe how diastereoselective enolate alkylations work -Evans

A
  1. First chiral auxiliary is attached to ketone- forms imide
  2. LDA (or NaHDMS) , THF, -78 degrees forms z-enolate
  3. Z-enolate formed due to avoidance of steric clashing and chelation with Li (Na) to ketones of oxazolidinone and ketone
  4. Then electrophile added and one face is blocked by R-group of oxazolidinone
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6
Q

What are the three oxazolidinone

A
  1. Valine derived
  2. Ephedrine-derived
  3. Phenylalanine-derived
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7
Q

What do oxazolidinone enolates react readily with

A
  1. Variety of reactive electrophiles
  2. MeI
  3. BnBr
  4. AllylBr
  5. NBS
  6. trysl azide
  7. oxaziridines
  8. Azodicarboxylates
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8
Q

What are the different auxiliary cleavage methods

A
  1. LiBH4- produces alcohol form of substrate separated from chiral auxiliary
  2. LiOOH, H2O produces carboxylic acid form of substrate
  3. MeONHMe.HCl, Me3Al- forms Weinreb amide- some of chiral auxiliary still attached
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9
Q

What is Weinreb amide useful for

A
  1. Useful as treatment with bulky reducing agents
  2. Produce aldehyde
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10
Q

How is an oxazolidinone produced

A
  1. From amino acid
  2. Add NaBH4/H2SO4 (used to make BH3 in reaction) and reduces acid to amino-alcohol
  3. Add C1 carbonyl equivalent- ethylchloroformate + K2CO3
  4. Amino group reacts with carbonyl displacing the chloride
  5. under action of base hydroxyl group undergoes second attack to displace the ethoxy group- forms ring system
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11
Q

How can you get an aldehyde from a Weinreb amide

A
  1. Add DIBAL-H (bulky-reducing agent)
  2. Al Coordinates with both O- stabilises transition state - 5 Membered
  3. H is added to C=O
  4. Reaction is worked up with H+/H2O
  5. Excess DIBAL-H is destroyed to form aluminium hydroxide species- fast reaction
  6. Aluminium in 5-membered transition state is replaced by H giving hemiaminal species- slow
  7. Hemiaminal species is unstable so generates aldehyde and parent amine
  8. Aldehyde is never exposed to reducing agent as is destroyed quick
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12
Q

Why is it hard to reach aldehyde OS from ester

A
  1. If add reducing agent to ester can’t stop at aldehyde
  2. As aldehyde is more reactive than the ester- as soon as formed is reduced further to alcohol
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13
Q

What is the aldol reaction important for

A
  1. Exceptionally important in organic synthesis
  2. Particularly for synthesis of biologically active polypropionate natural product
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14
Q

Describe Evans aldol reaction

A
  1. Very effective stereocontrol
  2. Forms z-enolate exclusively due to Boron coordination of both C=O
  3. Very high syn selectivity with addition of OH to R
  4. 6-membered Zimmerman-Traxler TS
  5. Aldehyde R group goes equatorial
  6. Aldehyde approaches away from large alkyl group on auxiliary
  7. The dipoles of the carbonyl of the auxiliary and aldehyde are opposed
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15
Q

Describe the diastereoselective enolate alkylation Myers method

A
  1. Based upon pseudoephedrine amides - Cheap and available in both enantiomeric forms
  2. Amide enolates much more reactive than imide enolates (have a higher pKa) and hence unactivated alkyl halides may be used
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16
Q

Describe process of Diastereoselecive enolate alkylation Myers method

A
  1. Add acid chloride to pseudoephedrine forms pseudoephedrine amide
  2. Add LDA, LiCL, R’X
  3. Solvent forms OLi with Alcohol and C=O which blocks one face of the enolate
  4. Less hindered approach used - highly diastereoselective
17
Q

What can be produced from the product of Myers enolate alkylation

A
  1. Carboxylic acid
  2. Ketone
  3. Aldehyde
  4. Alcohol
18
Q

How is a carboxylic acid produced from the product of Myers enolate alkylation

A
  1. H2SO4, dixane reflux
  2. Or Bu4NOH, tBuOH, water reflux
19
Q

How is an aldehyde produced from the product of Myers enolate alkylation

A
  1. LiAlH(OEt)3, 0 degrees
20
Q

How is an alcohol produced from the product of Myers enolate alkylation

A
  1. LiH2N
21
Q

How is a ketone produced from the product of Myers enolate alkylation

A
  1. MeLi, 0 Degrees
22
Q

What is used to carry out the asymmetric synthesis of alpha-amino acids

A
  1. Schollkopf’s auxiliary
  2. Diastereo enolate alkylation reaction
23
Q

Describe how Schollkopf’s auxiliary is produced

A
  1. Take amino acid valine - has sterically demanding isopropyl unit
  2. Protect NH2 using Boc2O, NaHCO3 and Base THF, H2O
  3. Acid group of valine couples with amino group of Glycine methyl ester-
  4. Then heat to 180 degrees which removes boc groups freeing NH2 group allowing cyclisation
  5. Add Me3O+ BF4- - electrophilic alkylating agent - both C=O change to OMe
24
Q

Describe Schollkopf’s auxilliary reaction to produce an alpha amino acid

A
  1. Add strong base e.g. BuLi which deprotonates Schollkopf’s auxiliary to produce anion
  2. Add BnBr which approaches from the less hindered face- opposite to large iPr group
  3. 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
25
Q

How can you create chiral amines

A
  1. Using Ellmans’ chiral sulfinamide
26
Q

Describe Ellmans’ chiral sulfinamide

A
  1. Sulfinamide is tetrahedral at sulfur due to presence of a lone pair of electrons and hence is chiral
  2. Sulfinamide reacts readily with a wide variety of aldehydes and ketones to give the corresponding aldimines and ketimines
27
Q

Describe Ellman’s sulfinamide reaction to produce a chiral amine

A
  1. Add ketone/aldehyde to sulfinamide
  2. Add NuH to form 6 membered transition state
  3. Large tbutyl group is pseudoequatorial
  4. Small lone pair is axial
  5. Imine substituent equatorial
  6. Organometallic chelated by R group and sulfinamide oxygen
  7. Add HCl, MeOH
  8. Produces chiral amine and racemic sulfonyl chloride - problem
28
Q

How is racemic t-butylsulfinamide formed

A
  1. Take dithiane and carry out oxidation reaction
  2. Add H2O2, AcOH then Cl2
  3. Forms sulfonyl chloride
  4. Then add NH4OH- displaces Cl with NH2
29
Q

How can you produce enantiomerically pure t-butylsulfinamide using quinidine

A
  1. Take racemic t-butyl sulfonyl chloride
  2. It is rapidly interconverting due to lone pair on S which is prone to racemisation
  3. Treat with quinidine (catalyst) and EtOH- ethanol nucleophile to displace chloride forms ester
  4. Quinidine ensures stereochemistry
  5. Add NaNH2 via SN2 mechanism to form pure t-butylsulfinamide - replaces OEt with NH2
  6. Hard to do on large industrial scale
30
Q

How does quinidine ensure an enantioselective reaction

A
  1. Quinidine only reacts with one enantiomer of racemic sulfonyl chloride to produce sulfonyl ester
  2. As it reacts the reactive enantiomer becomes deficient so racemisation that interconverts between enantiomers replenishes the reactive enantiomer
  3. Eventually ends up with all racemic sulfonyl chloride reacting to produce enantiopure ester
31
Q

What is a method of producing enantiomerically pure t-butylsulfinamide on a large scale

A
  1. Take dithiane and carry out enantioselective oxidation
  2. H2O2, acetone, vanadium complex, chiral ligand
  3. chiral ligand and achiral vanadium complex (form a chiral complex which enantioselectivity oxidise with H2O2 )
  4. Then displace thiol unit with amino group- LiNH2, NH3, -78 degrees then ice, ClCH2CO2H
  5. Recrystallise to get high ee.
32
Q

Describe how t-butylsulfinamides (Ellmans chiral sufinamide) is used to reduce ketones selectively

A
  1. Addition to a ketone forms a ketimine
  2. This can then be reduced with NaBH4 or L-selectride to give different major diastereomers of the resulting sulfinimine
  3. Then add MeOH, HCl to form primary amine
33
Q

Describe reduction of ketimine with NaBH4

A
  1. Along with THF and water
  2. 6- membered transition state
  3. Large tbutyl group pseudoequatorial
  4. Small lone pair axial
  5. Larger substituent of ketone equatorial
  6. Organometallic chelated by R2 and sulfinamide oxygen
  7. Results in NH3 opposite side to tbutyl
34
Q

Describe reduction of ketimine with L-selectride

A
  1. Can’t proceed by chair-like transition state as too bulky
  2. Minimise dipoles- opposing direction - carbonyl presented upwards
  3. Deliver hydride from least hindered end - So NH3 is same side as tbutyl
35
Q

How can you synthesise enantiopure beta amino acids

A
  1. Chiral auxiliary produced from enantiopure alpha methyl benzylamine
  2. Add RNLi, THF, -78 degrees then HN4Cl
  3. Chiral auxiliary undergoes an conjugate addition and new bond form between Nitrogen and beta carbon of double bond
  4. 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
36
Q

Why are beta amino acids useful

A
  1. Nice chiral building blocks for constructing heterocycles with stereocentres
  2. Useful for making beta-peptides

aa Topics in organic chemistry 1 (11 decks)

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