Lecture3: 123.702
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LECTURE THREE
chiral auxiliaries
gareth j rowlands
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©Lisa Pickard@Institute of Cancer Research
O
O
OR
O
NH
OMeMeO
MeO
macbecin IJ. Chem. Soc., Perkin Trans 1, 1989, 190 & 1990, 47 &
J. Chem. Soc., Chem, Commun., 1989, 378
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NOMe
OMe
OMe
N
O
O
O
NOMe
OMe
OMe
N
O
O
O
OH
i. NaHMDSii.
NO
PhO2S Ph
O
O
OR
O
NH
OMe
MeO
MeO
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©Oberazzi@flickr
controlsubstrate
?
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substrate(achiral)
product(chiral)
overall reaction
chiral auxiliary
substrate(achiral)
chiral auxiliary
product(chiral)
substrate control
add auxiliary
remove auxiliary
controlauxiliary
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at worst
chiral auxiliary
substrate(achiral)
chiral auxiliary
product(chiral)
substrate control
chiral auxiliary
chiral product
built in
resolution
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not the right beetle!©BugMan50@flickr
(–)-frontalin
O
O
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PhO
OO RMgBr
PhO
O
OH
LiAlH4
HO OHO3
O
O
100% ee
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controlauxiliarychiral
O
OO
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auxiliary
oxazolidinones
common
NO
O
R
R2
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amino acids
oxazolidinones
made from
NOH
R2
H
O
H
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OHN
O1. n-BuLi2. EtCOCl
ON
OO
ON
O
O
LDA
LDA ON
O
OLi
ON
OOLi
enolate chemistry
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ON
OOLi
PhCH2I ON
OO
Ph
NOO
OLiH N
OOOH
Bn
H
I
Phdiastereoselectivity
good
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chemistry works enolate most
ON
O
Ph
O
LDAON
O
Ph
OLi
BrON
O
Ph
O
H
96% de
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chemistry works enolate most
NO
Ph
H
SO2Ph
ON
O
Ph
O
HHO
>90% de
ON
O
Ph
Oi. NaHMDS
ii.
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chemistry works enolate most
ON
O
Ph
O
SO2N3
i-Pr
i-Pr
i-PrON
O
Ph
O
HN3
>90% de
i. KHMDS
ii.
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auxiliaryeasily removed
ON
OO
PhO
O
Ph
Bn OHN
O
LiOBn
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auxiliaryeasily removed
OH
O
Ph
LiOOHON
OO
Ph
but
people claim!
not as
easy as
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auxiliaryeasily removed
OH
Ph
LiAlH4H H
ON
OO
Ph
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©Nemo's great uncle@Flickr
NH
HN
OO
MeMeMe
OH
H
Me
HO
Me
OHOMe
OMe
HH
O
Bistramide AJ. Am. Chem. Soc., 2006, 128, 4936
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NH
HN
OO
MeMeMe
OH
H
Me
HO
Me
OHOMe
OMe
HH
O
controlchiral auxiliary
ON
O
BnOO
ON
O
iPr
BnOO
H
I
NaHMDS, THF, –78°C
81%96%de
BnOH
O
H
i. LiBH4ii. DMSO,
(COCl)2, Et3N
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aldol the
reaction
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R1
OM
R2O
R3
O OM
R1
R2R3
O
R1 R3
R2
OH
aldol the
reaction
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geometry enolate
XMe
OLi H R
O
X
O
R
OH
Mecis-enolate syn aldol
OO
MX
H
Me
HR
OO
MX
H
Me
HR
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geometry enolate trans-enolate anti aldol
X
OLiH R
O
X
O
R
OH
MeMe
X
O
MO
H
H
RMe
X
O
MO
H
H
RMe
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in the aldol
ON
OO
ON
OO
Ph
OH
500 : 1 dr(opposite syn isomer)
Bu2BOTfiPrNEt2
Ph H
O
chiral auxiliary
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©GraemeNicol@Flickr
warning
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in the aldol
chiralauxiliary
ON
OOB
ON
OOBu Bu
Ph H
O
N
OB
OH
Ph
OO
BuBu
Bu2BOTfiPrNEt2
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B
Bu
O O
NH
Ph
Bu
H
O
O
B
Bu
OO
N H
Ph
Bu
H
O
O
disfavoured
transitionfavouredstate
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B
Bu
O O
NH
Ph
Bu
H
O
O
ON
OO
ON
OO
Ph
OH
500 : 1 dr(opposite syn isomer)
Bu2BOTfiPrNEt2
Ph H
O
in the aldol
chiralauxiliary
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©http://w
ww.ic
m.uu.se
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earch.php
?G=Proka
ryoticDev
elop
men
t
OH
OH
MeH
O
OMeOH H
H
Me
HMe
H
OMe
OH
MeOH
HO
O O
OH
MeOH
H
MeOH
H
MeO
O
cytovaricinJ. Am. Chem. Soc., 1990, 112, 7001
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NO
O O
Ph
Et
O
N
O
Et
O OH
O
Me
Ph
1. Bu2BOTf, Et3N2.
92%100%de
in the aldolchiral auxiliary
OOB
NH
H
O
O
Ph
Bu
BuEt
OH
OH
MeH
O
OMeOH H
H
Me
HMe
H
OMe
OH
MeOH
HO
O O
OH
MeOH
H
MeOH
H
MeO
O
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OH
OH
MeH
O
OMeOH H
H
Me
HMe
H
OMe
OH
MeOH
HO
O O
OH
MeOH
H
MeOH
H
MeO
Oin the aldolchiral auxiliary
NO
O O
Ph
1. Bu2BOTf, Et3N2.
N
O
O OH
O
Ph
O
OPMB
87%100%de OPMB
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Diels-Alder the
reaction ©Anchor Bay Entertainment
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reaction
R1
R2
R3
R4
heat
R1
R2
R3
R4
Diels-Alder
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R1
R2
R3
R4
heat
R1
R2
R3
R4
reaction Diels-Alder
new 2 bonds
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R1
R2
R3
R4
heat
R1
R2
R3
R4
reaction Diels-Alder
new 4 stereocentres
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reaction
R1
R2
R3
R4
heat
R1
R2
R3
R4
Diels-Alder
control excellent
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exampleachiral
OBn
O
O OBn
O OBn0%ee
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chiral controlauxiliary
ON
OO
O N O
O
single enantiomer
Et2AlClR R
R = H 86% deR = Me 90% de>98% endo
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chiral controlauxiliary
ON
OO
O N O
O
single enantiomer
Et2AlClR R
R = H 86% deR = Me 90% de>98% endo
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NO Al O
OH
NO
Et2Al O
OH
NO
Et2Al O
OH
Et2AlCl2Et Et
controlauxiliary
chiral
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NO Al O
OH
NO
Et2Al O
OH
NO
Et2Al O
OH
Et2AlCl2Et Et
controlauxiliary
chiral
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©Christian Puff
N
O
H
H
MeO
HEt
H
Angew. Chem. Int. Ed., 1996, 35, 904
(–)-stenine
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S S
PMBO
N
O
OO
Me
Ph
Me2AlCl
S S
HO
NR2*
H
PMBO
N
O
H
H
MeO
HEt
Hchiralcontrol
auxiliary
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Bond: "Free radicals," sir?M: Yes. They're toxins that destroy the body and the brain, caused by eating too much red meat and white bread and too many dry martinis!Bond: Then I shall cut out the white bread, sir.
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chiral in conjugateauxiliaryaddition
NO
O
PhPh
R1
O
NO
O
PhPh
R1
O R2Yb(OTf)3, R2–X,
Bu3SnH, Et3B, O2
81-94%76-96%de
NO
O
PhPh
R1
OYbLn
R2
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other chiral auxiliaries
BnO
Me
O
O MeMe AlCl3
Me
O
O MeMe
BnO
CO2R
H
BnO
≡Me
O
O MeMe
HH
OBn ≡
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Me Me
NS
OO
O
RTiCl4
RH
NOO2S
MeMe
R = H 99% deR = Me >97% de>98% endo
Me Me
NS O
R
O O TiLn
Me Me
NSO2 O
R
other chiral auxiliaries
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NS O
OO
NS O
OO
Et
H
NHS
OO
HO
O Et
90% de
EtMgCl
LiOH
other chiral auxiliaries
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O
O
SO
MeO
ZnBr2
O
O
MgBr
O
O
SO
MeO H
Ar
O
O
H
O
O
OOMe
MeO
MeO
(–)-podorhizon95% ee
other chiral auxiliaries
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auxiliarieschiral
many other
©Jared Zimmerman@flickr
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auxiliarieschiral
many other
©Gaetan Lee@flickr