LECTURE THREE

iral auxiliaries
ch

gareth j rowlands
 MeO
OMe OR

O
O
MeO NH

macbecin I
J. Chem. Soc., Perkin Trans 1, 1989, 190 & 1990, 47 &
J. Chem. Soc., Chem, Commun., 1989, 378 ©Lisa Pickard@Institute of Cancer Research
 OMe OMe O O
N
N O

OMe
i. NaHMDS
ii. O
N
PhO2S Ph

OMe OMe O O
MeO
N
N O OMe OR

O
OH MeO O
NH

OMe
O
substrate
control ?
©Oberazzi@flickr
auxiliary
control
overall product
substrate
reaction (chiral)
(achiral)

add remove
auxiliary auxiliary
substrate product
substrate
control (chiral)
(achiral)
chiral chiral
auxiliary auxiliary
at worst

substrate product
substrate
control (chiral)
(achiral)
chiral chiral
auxiliary auxiliary

chiral chiral
product auxiliary

in
built
resolution
 O

(–)-frontalin not the right beetle!

©BugMan50@flickr
 O
O Ph OH
O RMgBr O
Ph
O

LiAlH4

O
HO OH
O3

100% ee
chiral
auxiliary
control O
O
O
oxazolidinones
O
R
O N

R2
common
auxiliary
oxazolidinones

H H
H O N

O R 2 made from

amino acids
 enolate
Li
chemistry O O O O

N O LDA N O

O
1. n-BuLi
HN O 2. EtCOCl

O O
Li
O N O LDA O N O
 Li O
O O O

PhCH2I N O
N O

Ph

good
I
diastereoselectivity
Ph
Li O Bn O
O O O O
N H N H
H
most enolate chemistry works

O Li O
O O O O
Br
LDA
N O N O N O
H
Ph Ph Ph
96% de
most enolate chemistry works

O O O O
i. NaHMDS
N O N O
ii. H O HO H
N
Ph Ph
Ph SO2Ph >90% de
most enolate chemistry works

O O O O
i. KHMDS
N O N O
i-Pr ii. i-Pr N3 H
Ph Ph
>90% de
SO2N3
i-Pr
 auxiliary
easily removed

O O O
O
N O LiOBn Bn HN O
O
Ph
Ph
 auxiliary
easily removed

O O
O
N O LiOOH
OH
Ph
Ph

as
but not
as
easy
people claim!
 auxiliary
easily removed

O O
H H
N O LiAlH4
OH
Ph
Ph
Bistramide A
J. Am. Chem. Soc., 2006, 128, 4936

Me Me
O O Me
H
N
Me O N O
H H H H O
OH O Me Me
H
Me

OH
©Nemo's great uncle@Flickr
chiral auxiliary
Me Me
O O Me
H
N
Me O N O
H H H H O

control
OH O Me Me
H
Me

OH

iPr
NaHMDS,
THF, –78°C H
N O
N O I BnO
BnO
81% O O
O O 96%de
i. LiBH4
ii. DMSO,
(COCl)2, Et3N

H
H
BnO
O
 the
aldol
reaction
 the
aldol
M
O
reaction
M O OH
O O
R1
R2 R1 R3 R1 R3
O
R2 R2

R3
 O
O OH
OLi
H R
Me X R
X
Me
cis-enolate
enolate syn aldol

geometry
X X
H M H M
O O
H O H O
R R
Me Me
 O
OLi O OH
H R
X X R
Me Me
trans-enolate enolate anti aldol

geometry
H H

Me O Me O
R O R O
M M
X X
H H
chiral auxiliary in the aldol

O O OH O O
Bu2BOTf
N O iPrNEt2 Ph N O
O

Ph H
500 : 1 dr
(opposite syn isomer)
warning

©GraemeNicol@Flickr
 Bu Bu
O O B
Bu2BOTf O O
N O iPrNEt2
N O

chiral Ph H

Ph Bu
auxiliary
Bu
B
in the aldol
H O O

N
O
O
favoured transition
state
Bu Bu
O O O O
B B
Ph Ph
H Bu Bu H
H O N N H
O

O O

disfavoured
 Bu
O O OH O O
O O
Bu2BOTf B
Ph
N O iPrNEt2 Ph N O
H Bu
O H O N

Ph H
O 500 : 1 dr
(opposite syn isomer)

chiral
auxiliary
in the aldol
cytovaricin
J. Am. Chem. Soc., 1990, 112, 7001

©http://www.icm.uu.se/micro/groupResearch.php?G=ProkaryoticDevelopment
Me
H
O OH
Me O
OH H Me
H O O
H Me Me
H OH
Me O H
HO
OH H
OH MeO
Me O O Me
OH
OH
H
 Me

chiral auxiliary Me
H
O
O
OH

in the aldol
OH H Me
H O O
H Me Me
H OH
Me O H
HO
OH H
OH MeO
Me O O Me
OH
OH
H

1. Bu2BOTf, Et3N
O O 2. O
Me O OH

O N Et
N Et
Ph
Ph O
Ph O
O
92%
100%de
O Bu
HN
B Bu
Et O
H O
 Me

chiral auxiliary Me
H
O
O
OH

in the aldol
OH H Me
H O O
H Me Me
H OH
Me O H
HO
OH H
OH MeO
Me O O Me
OH
OH
H

1. Bu2BOTf, Et3N
2. O
O O O OH
OPMB
O N N
87% Ph
100%de O O OPMB
Ph
 the
Diels-Alder
reaction
©Anchor Bay Entertainment
Diels-Alder reaction

R 1 R1

R 3 R3
heat

R 4 R4

R 2 R2
Diels-Alder reaction

R1 R 1

R 3 R 3
heat

4 R 4
R
R2 R 2

2 new
bonds
Diels-Alder reaction

R 1 R1

R3 R3
heat

R 4 R4

R 2 R2

4 new
stereocentres
Diels-Alder reaction

R 1 R1

R 3 R3
heat

R 4 R4

R 2 R2

control
excellent
achiral example
O
O OBn
OBn

O OBn
0%ee
chiral auxiliary control

O O

R N O O
R
Et2AlCl
O N O

single enantiomer
R = H 86% de
R = Me 90% de
>98% endo
chiral auxiliary control

O O

R N O O
R
Et2AlCl
O N O

single enantiomer
R = H 86% de
R = Me 90% de
>98% endo
Et Et Et2AlCl2 Et2
O Al O O Al O
H H
N O N O

Et2
O Al O
H
N O chiral
auxiliary
control
Et Et Et2AlCl2 Et2
O Al O O Al O
H H
N O N O

Et2
O Al O
H
N O chiral
auxiliary
control
(–)-stenine
Angew. Chem. Int. Ed., 1996, 35, 904

O Me
H
O H

H
Et N
H

©Christian Puff
 O

chiral auxiliary
Me
H
O H

control H
N
Et
H

S S
S S

Me2AlCl H

PMBO O H
PMBO O
Me N
O NR2*
Ph O
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 auxiliary in conjugate
addition
O O O O R2
Yb(OTf)3, R2–X,
O N R1 Bu3SnH, Et3B, O2 O N R1

81-94%
Ph Ph
76-96%de
Ph Ph
Ln
Yb
O O R2

O N R1

Ph
Ph
other chiral auxiliaries

Me
O Me
H
H O
BnO Me BnO
AlCl3
O
Me
Me
OBn ≡ H

≡
Me
O O Me CO2R

Me O

BnO Me
other chiral auxiliaries
Me Me R
O
H
TiCl4
N R
R = H 99% de O N
S O R = Me >97% de
O >98% endo O2S
Me Me

Me Me
R Me Me
R
N
S O N
SO2 O
O O Ti
Ln
other chiral auxiliaries

H
EtMgCl
N N Et
S O O S O O
O O
90% de

LiOH

HO
NH
S O O Et
O
 other chiral auxiliaries
O O
O O
ZnBr2 S
S O
O
O MgBr H
MeO
MeO
O Ar

O O
MeO
O

MeO H

OMe
O

(–)-podorhizon O
95% ee
 other
many
chiral
auxiliaries

©Jared Zimmerman@flickr
 other
many
chiral
auxiliaries
©Gaetan Lee@flickr