lecture3: 123.702
DESCRIPTION
Self explanatory really, this lecture looks at chiral auxiliaries. We will concentrate on oxazolidinones in alkylations, aldol reaction and the Diels-Alder reaction. There will be a couple examples of other auxiliaries.TRANSCRIPT
LECTURE THREE
chiral auxiliaries
gareth j rowlands
©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
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
©Oberazzi@flickr
controlsubstrate
?
substrate(achiral)
product(chiral)
overall reaction
chiral auxiliary
substrate(achiral)
chiral auxiliary
product(chiral)
substrate control
add auxiliary
remove auxiliary
controlauxiliary
at worst
chiral auxiliary
substrate(achiral)
chiral auxiliary
product(chiral)
substrate control
chiral auxiliary
chiral product
built in
resolution
not the right beetle!©BugMan50@flickr
(–)-frontalin
O
O
PhO
OO RMgBr
PhO
O
OH
LiAlH4
HO OHO3
O
O
100% ee
controlauxiliarychiral
O
OO
auxiliary
oxazolidinones
common
NO
O
R
R2
amino acids
oxazolidinones
made from
NOH
R2
H
O
H
OHN
O1. n-BuLi2. EtCOCl
ON
OO
ON
O
O
LDA
LDA ON
O
OLi
ON
OOLi
enolate chemistry
ON
OOLi
PhCH2I ON
OO
Ph
NOO
OLiH N
OOOH
Bn
H
I
Phdiastereoselectivity
good
chemistry works enolate most
ON
O
Ph
O
LDAON
O
Ph
OLi
BrON
O
Ph
O
H
96% de
chemistry works enolate most
NO
Ph
H
SO2Ph
ON
O
Ph
O
HHO
>90% de
ON
O
Ph
Oi. NaHMDS
ii.
chemistry works enolate most
ON
O
Ph
O
SO2N3
i-Pr
i-Pr
i-PrON
O
Ph
O
HN3
>90% de
i. KHMDS
ii.
auxiliaryeasily removed
ON
OO
PhO
O
Ph
Bn OHN
O
LiOBn
auxiliaryeasily removed
OH
O
Ph
LiOOHON
OO
Ph
but
people claim!
not as
easy as
auxiliaryeasily removed
OH
Ph
LiAlH4H H
ON
OO
Ph
©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
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
aldol the
reaction
R1
OM
R2O
R3
O OM
R1
R2R3
O
R1 R3
R2
OH
aldol the
reaction
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
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
in the aldol
ON
OO
ON
OO
Ph
OH
500 : 1 dr(opposite syn isomer)
Bu2BOTfiPrNEt2
Ph H
O
chiral auxiliary
©GraemeNicol@Flickr
warning
in the aldol
chiralauxiliary
ON
OOB
ON
OOBu Bu
Ph H
O
N
OB
OH
Ph
OO
BuBu
Bu2BOTfiPrNEt2
B
Bu
O O
NH
Ph
Bu
H
O
O
B
Bu
OO
N H
Ph
Bu
H
O
O
disfavoured
transitionfavouredstate
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
©http://w
ww.ic
m.uu.se
/micro/group
Res
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
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
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
Diels-Alder the
reaction ©Anchor Bay Entertainment
reaction
R1
R2
R3
R4
heat
R1
R2
R3
R4
Diels-Alder
R1
R2
R3
R4
heat
R1
R2
R3
R4
reaction Diels-Alder
new 2 bonds
R1
R2
R3
R4
heat
R1
R2
R3
R4
reaction Diels-Alder
new 4 stereocentres
reaction
R1
R2
R3
R4
heat
R1
R2
R3
R4
Diels-Alder
control excellent
exampleachiral
OBn
O
O OBn
O OBn0%ee
chiral controlauxiliary
ON
OO
O N O
O
single enantiomer
Et2AlClR R
R = H 86% deR = Me 90% de>98% endo
chiral controlauxiliary
ON
OO
O N O
O
single enantiomer
Et2AlClR R
R = H 86% deR = Me 90% de>98% endo
NO Al O
OH
NO
Et2Al O
OH
NO
Et2Al O
OH
Et2AlCl2Et Et
controlauxiliary
chiral
NO Al O
OH
NO
Et2Al O
OH
NO
Et2Al O
OH
Et2AlCl2Et Et
controlauxiliary
chiral
©Christian Puff
N
O
H
H
MeO
HEt
H
Angew. Chem. Int. Ed., 1996, 35, 904
(–)-stenine
S S
PMBO
N
O
OO
Me
Ph
Me2AlCl
S S
HO
NR2*
H
PMBO
N
O
H
H
MeO
HEt
Hchiralcontrol
auxiliary
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.
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
other chiral auxiliaries
BnO
Me
O
O MeMe AlCl3
Me
O
O MeMe
BnO
CO2R
H
BnO
≡Me
O
O MeMe
HH
OBn ≡
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
NS O
OO
NS O
OO
Et
H
NHS
OO
HO
O Et
90% de
EtMgCl
LiOH
other chiral auxiliaries
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
auxiliarieschiral
many other
©Jared Zimmerman@flickr
auxiliarieschiral
many other
©Gaetan Lee@flickr