Chiral Auxiliaries

• Previously on Advanced Synthesis.....

• Discussed the need for stereoselective synthesis
• Looked at the use of resolution, the chiral pool and substrate control
• But there are some potential problems with those methods
• What if the substrate does not contain an appropriate stereocentre?
• What if the target does not contain a readily exploited stereocentre?

attach auxiliary
Substrate Substrate Auxiliary

formation of single do chemistry

enantiomer

Substrate Substrate Auxiliary

remove auxiliary
Substrate Auxiliary

R R
R

• A form of substrate control in which a temporary asymmetric unit is attached

• At worst it is a built in resolving agent
• At best they are stereodirecting groups resulting in single enantiomers
Criteria for Chiral Auxiliaries
• cheap and readily available
• easily attached
• induce stereochemistry (surprise)
• chemically inert
• easily removed
Evans' Oxazolidinones
Alkylations
• Enolate chemistry very important (Strategy in Synthesis 2nd year)
• One of the commonest means of forming C–C bonds is via enolate alkylation
• If a chiral centre present can get a diastereoselective reaction
preferred
• metal fixes
O conformation by M
O O O
chelation
M O
N O O
N O NH O

• auxiliary readily
prepared from amino
acids Bottom face
blocked

O O O O O
1. NaHMDS
R 2. CH 2=CHCH2Br R R
N O N O 1. KOH OH

diastereoisomer enantiomer
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis
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 • The aldol reaction is an extremely valuable means of introducing stereochemistry
• Used extensively in the synthesis of polypropionate natural products
• Frequently used to control two new stereocentres
• geometry of enolate
determines syn or anti aldol

O O Bu 2BO O OH O O
Bu2BOSO2 CF3,
N O iPr2NEt N O RCHO R N O

• auxiliary determines
absolute stereochemistry

• bulky substituent adopts • Lewis acidic boron activates

psuedo-equatorial position • thermodynamic carbonyl by co-ordination and
enolate arranges 6-membered transition state

Bu Bu Bu
O B O O B O O B O
R R R
+ H Bu H Bu H Bu
H N H N H N
i-Pr i-Pr i-Pr
O O O
O O O

• aldehyde approaches • C–O dipoles oppose

from least hindered work-up
face (due to auxiliary)

OH O O
OH O

≡
R
R N O
H
H N
i-Pr
O
O

• There are a number of useful ways of removing the oxazolidinone unit

R CO2H

LiOH, MeOH, E
O O H 2O

R LiAlH4 R CH2 OH
N O
E E
PhCH 2OLi
O
R
OCH2Ph
E

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

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 Chiral Sulfoxides
• Chiral sulfoxides have been shown to induce good diastereoselectivities
• Remember last years course they have many useful transformations
• This combination has led to their use as chiral auxiliaries • metal used to fix
conformation by chelation

M
O O
O O
R–M S
S pTol
pTol

R–

• reductive • approach from least

cleavage sterically hindered side
(away from toluene group)

O O
Raney–Nickel
pTolS(O)

• Sulfoxide can be used to control reduction of ketones

• Depending on reaction conditions either diastereoisomer can be produced with complete
control

• preferred conformation has

dipoles opposed
Tol O
O OH
S
O R S
DIBAL-H Tol R
H
O O • hydride approaches
from opposite side to
S bulky toluene group
Tol R Ln
Zn
DIBAL-H O O O OH
ZnCl2 S S
Tol R Tol R
• conformation controlled H
by chelation

Auxiliary Removal

O OH Li / NH 3 OH
S
Tol C7H 15 C7H 15

• reduce sulfoxide

O OH H OH
1. LiAlH4 O KOH O
S 2. Me3OBF 4 S C8H 17
Tol C8H 17 Tol C8H 17

• cation formation

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

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 Miscellaneous Reactions and Auxiliaries
Diels–Alder Reaction
• A number of auxiliaries have been utilised for this extremely useful reaction
• The following was derived from camphor (a readily available chiral material)

Cl
NH N O
NaH
S O S O
O • acylation O
(SC last year)
• chiral auxiliary can be
recovered and used again
EtAlCl2 ,
• Lewis acid activates enone - 78 ˚C, 1 hr

CH2 OH
LiAlH4
+ NH N O
S O S O
O O

• The second example show the versatility of oxazolidinone auxiliaries

• Lewis acid activates enone
O O • Controls conformation by chelation Ph
Ph
O
O N ZrCl4
+ N
Ph O
Ph O
• think about regiochemistry
Radical Reactions and endo / exo selectivity
• Recently it has been found that radical reactions can occur with excellent
diastereoselectivity
• The first example utilises a camphor derivative
• readily coverted to amino acid O
O
NOBn NHOBn
N Bu3SnH, Et 3B N
SO2
+ SO2
I

• top face blocked

by oxygen
Et3 B + O2 O O
NOBn
N
S
Et• + H–SnBu3 Bu3Sn + O
I

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

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• The donor / acceptor properties can be readily reversed to give chiral radicals

O O
I initiator
N N
O SnBu3 O
S S
O O

What have we learnt?

• Chiral auxiliaries are, in essence, a form of substrate control
• They are temporarily attached, allowing diastereoselective reactions
• On removal they can produce the equivalent of an enantioselective reaction
• Two disadvantages: need point of attachment (limits structures)
• Need a stoichiometric amount of the auxiliary

Next lecture a further improvement in stereoselective synthesis......

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

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