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.

1. LECTURE THREE
chiral auxiliaries
gareth j rowlands

2. MeO
OMe OR
O
O
MeO NH
O
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

3. 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

4. substrate
control ?
©Oberazzi@flickr

5. auxiliary
control
overall product
substrate
reaction (chiral)
(achiral)
add remove
auxiliary auxiliary
substrate product
substrate
control (chiral)
(achiral)
chiral chiral
auxiliary auxiliary

6. at worst
substrate product
substrate
control (chiral)
(achiral)
chiral chiral
auxiliary auxiliary
chiral chiral
product auxiliary
in
built
resolution

7. O
O
(–)-frontalin not the right beetle!
©BugMan50@flickr

8. O
O Ph OH
O RMgBr O
Ph
O
LiAlH4
O
HO OH
O3
O
100% ee

9. chiral
auxiliary
control O
O
O

10. oxazolidinones
O
R
O N
R2
common
auxiliary

11. oxazolidinones
H H
H O N
O R 2 made from
amino acids

12. 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

13. 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

14. 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

15. 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

16. 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

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

18. auxiliary
easily removed
O O
O
N O LiOOH
OH
Ph
Ph
as
but not
as
easy
people claim!

19. auxiliary
easily removed
O O
H H
N O LiAlH4
OH
Ph
Ph

20. 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

21. 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

22. the
aldol
reaction

23. the
aldol
M
O
reaction
M O OH
O O
R1
R2 R1 R3 R1 R3
O
R2 R2
R3

24. 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

25. 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

26. 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)

27. warning
©GraemeNicol@Flickr

28. Bu Bu
O O B
Bu2BOTf O O
N O iPrNEt2
N O
O
chiral Ph H
Ph Bu
auxiliary
Bu
B
in the aldol
H O O
N
O
O

29. 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

30. 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

31. 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

32. 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

33. 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

34. the
Diels-Alder
reaction
©Anchor Bay Entertainment

35. Diels-Alder reaction
R 1 R1
R 3 R3
heat
R 4 R4
R 2 R2

36. Diels-Alder reaction
R1 R 1
R 3 R 3
heat
4 R 4
R
R2 R 2
2 new
bonds

37. Diels-Alder reaction
R 1 R1
R3 R3
heat
R 4 R4
R 2 R2
4 new
stereocentres

38. Diels-Alder reaction
R 1 R1
R 3 R3
heat
R 4 R4
R 2 R2
control
excellent

39. achiral example
O
O OBn
OBn
O OBn
0%ee

40. 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

41. 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

42. 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

43. 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

44. (–)-stenine
Angew. Chem. Int. Ed., 1996, 35, 904
O Me
H
O H
H
Et N
H
©Christian Puff

45. 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

46. 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.

47. 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

48. 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

49. 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

50. 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

51. 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

52. other
many
chiral
auxiliaries
©Jared Zimmerman@flickr

53. other
many
chiral
auxiliaries
©Gaetan Lee@flickr