MacMillan's synthesis, highlighting the use of organocatalysis.

1. LECTURE EIGHT
callipeltoside C
gareth j rowlands ©oxmox@flickr

2. OH
MeO OH
O O
H
O
H OH
callipeltoside C MeO O O
Cl
Angew. Chem. Int. Ed., 2008, 47, 3568
©Islands in the Stream Expedition 2002. NOAA Office of Ocean Exploration

3. anti-tumor
activity
©mararie@flickr

4. retrosynthesis
OH
MeO OH
O O
H
glycosylation
remove sensitive
O sugar
H OH
MeO O O
Cl
simplification

5. retrosynthesis
Yamaguchi
OH lactonisation
form macrocycle
by esterification
O
H OH
MeO O O
Cl
allows molecule
to be split into
fragments

6. retrosynthesis
OH
CO2H
O
H OH chelation
controlled
MeO OH alkylation
Cl
divide
in ha
lf

7. retrosynthesis
OH
CO2H
O
H OH chelation
controlled
MeO OH alkylation
Cl
divide
in ha
lf

8. 3 targets
OH
MeO OH
OH
MeO
OH
OH HO O
H O O
H
O
CO2H H OH
O MeO
H OH O O
O
X Cl
OH
Cl

9. synthesis
may
change order ©YaniG@flickr

10. Horner-Wadsworth-
X Emmons
OH
Cl
organocatalysis
MeO
I MeO P
OH
Cl
O O
I
retrosynthesis
bottom half
O

11. Semmelhack
cyclisation
OH
OH OH
5
1 PGO 7 5
7 3
CO2Me 3
O
H OH
O
retrosynthesis
middle section

12. difficult
to see
seeforward
reaction
©bitterlysweet@flickr

13. OH OH
PGO
retrosynthesis
middle section

14. OH OH
PGO
pattern retrosynthesis
recognition
middle section

15. OH O
R1 R2
think
aldol
©lecates@flickr

16. alkylkation
substrate
OH OH
control OH O
PGO
PGO
aldol
organocatalysis
O O
retrosynthesis PGO
middle section

17. retrosynthesis
sugar section
OH
MeO OH
HO O
H

18. retrosynthesis
sugar section
OH
MeO OH
HO O
H
aldol

19. retrosynthesis
sugar section
OH
MeO OH
HO O
H
aldol

20. OH
OH
MeO OH FGI MeO OTIPS
C–C HO O
HO O
H H
OTIPS
aldol
chelation
control O
MeO OTIPS
retrosynthesis TESO TIPSO
sugar section OTIPS

21. O O
OTIPS C–C OTIPS
TIPSO O
OTIPS OTIPS
aldol
organocatalysis retrosynthesis
sugar section

22. the synthesis
©Time Inc

23. the synthesis
©euthman@flickr

24. synthesis I
OH
bottom half Cl
1. AlMe3,
....Cp2ZrCl2 then I2
2. (COCl)2, I
OH ....DMSO, Et3N
O

25. Negishi
carbometallation-
iodination
mechanism
complex!
©Toby Maloy@flickr

26. R H
R H
Cl
Cl Me δ– Cl
Al Me Zr Cp
Zr Al Me δ+
Cl Me Me Me Cp
R H R H
I2
Me I Me AlMe2
possible mechanis
m

27. OH
organocatalysis MeO OH
O O
H
O
H OH
MeO O O
Cl

28. synthesis I
OH
bottom half Cl
N CO2H
I H I NHPh
PhNO O
O 99%ee O
see lecture six

29. synthesis I
OH
bottom half Cl
1. NaBH4
2. Zn, AcOH
3. Bu2Sn(OMe)2, PMBCl
I NHPh I
O 4. TBSCl, imidazole OTBS
O 62% OPMB
Bu
I Bu
O Sn
O PG

30. synthesis
OH
of middle section
CO2Me
O
H OPG
PGO
PMBO O
N CO2H PMBO OH O
H
O 99%ee
12:1 syn:anti
see lecture six

31. synthesis
OH
of middle section
CO2Me
O
H OPG
PGO
Br
PMBO OH OH
PMBO OH O
Zn
98%
6:1 syn

32. PMBO OH OH
Me O Me OH
R R
HH H H
Zn
Felkin-Ahn
substrate
control

33. synthesis
OH
O
of middle section H
O
OMe
OMe
PMBO
[PdCl2(MeCN)2]
CO, MeOH
OH
PMBO OH OH
O O
O
75% O OMe
20:1dr H OMe
PMBO

34. nightmare mechansim
©New Line Cinema

35. HO OH
HO
Pd2+
O O
Pd0
HO Pd2+
O
O OMe
MeOH O
Pd+
O
O Pd+
C O
Pd2+
O O O
O OMe O OMe O OMe
Pd2+ Pd+ OMe
MeOH

36. synthesis
OTBS
of middle section
CO2Me
O
H OMe
O
1. TBSCl
OH OTBS
2. DDQ
3. SO3•pyr,
O ....DMSO, Et3N
CO2Me
O OMe 80% O
H OMe H OMe
PMBO O
NC O
Cl
NC
OMe Cl
O

37. I
OTBS OTBS
OPMB
CO2Me
O
H OMe
BrMg
OTBS O
OPMB MgBr•Et2O
OH 98%
OH
MeO 16:1dr
O
H
O
OTBS
O
H OH
O O
MeO
Cl CO2Me
O
H OMe
synthesis HO OTBS
OPMB
callipeltoside C

38. I
OTBS OTBS
OPMB
CO2Me
O
H OMe
BrMg
OTBS O
OPMB MgBr•Et2O
OH 98%
OH
MeO 16:1dr
O
H
O
OTBS
O
H OH
O O
MeO
Cl CO2Me
O
H OMe
chelation HO OTBS
OPMB
control

39. synthesis MeO
OH
OH
callipeltoside C O
H
O
O
H OH
MeO O O
Cl
OTBS OTBS
1. MeOTf, base
2. DDQ
3. SO3•pyr,
CO2Me ....DMSO, Et3N CO2Me
O O
H OMe 84% H OMe
HO OTBS MeO OTBS
OPMB O

40. synthesis MeO
OH
OH
callipeltoside C O
H
O
O
H OH
MeO O O
OTBS
Cl
OTBS
CO2Me
O 1. HWE
H OMe 2. TBAF CO2H
3. Ba(OH)2 O
MeO OTBS H OMe
O 84% MeO OH
MeO Cl
MeO P
Cl
O
Org. Lett., 2001, 3, 503

41. synthesis
aglycone
OTBS OTBS
CO2H 2,4,6-Cl3C6H2COCl,
O iPr2NEt, DMAP O
H OMe H
MeO OH 83% MeO O O
Cl Cl

42. synthesis
aglycone
OTBS OH
1. PPh3•HBr, H2O
O 2. TFA O
H H OH
MeO O O 81% MeO O O
Cl Cl

43. sugar OH
MeO OH
portion
HO O
H

44. disaster
OH
MeO OH
O O
H
O
H OH
MeO O O
Cl
©dawn m. armfield@flickr

45. real
sugar
portion
OH
MeO OH
HO O

46. synthesis of sugar MeO
OH
OH
HO O
O
N CO2H O OH
OTIPS H
O 75%
99%ee TIPSO OTIPS
OTIPS
see lecture six

47. synthesis of sugar MeO
OH
OH
HO O
OTES
OH
OMe
MgBr2•OEt2 MeO OTIPS
O OH
47%
>20:1dr HO O
TIPSO
TIPSO OTIPS
substrate
control

48. synthesis of sugar MeO
OH
OH
HO O
OTES
OH
OMe
MgBr2•OEt2 MeO OTIPS
O OH
47%
>20:1dr HO O
TIPSO
TIPSO OTIPS
substrate
control

49. TIPSO O OH
TIPSO R
R
MeO MeO H
HH H
H
TESO O
≡
OH
O OH OH
MeO OTIPS
HO O OMe OTIPSOTIPS
OTIPS

50. synthesis of sugar MeO
OH
OH
HO O
1. AcCl, BnOH
OH 2. PhOC(S)Cl
3. Bu3SnH, AIBN O
MeO OTIPS
4. DMP MeO OTIPS
HO O 47%
BnO O
TIPSO
Ac
A cO O Ac
O
I
O
O

51. synthesis of sugar
1. MeMgBr,
....MgBr2•OEt2
O OH
2. H2, Pd/C then
MeO OTIPS ....Cl3CCN MeO OTIPS
CCl3
86%
BnO O HN O O

52. endgame synthesis
callipeltoside C
OH
OH
MeO OH
MeO OTIPS
CCl3
OH
O O
HN O O
1. TMSOTf
2. TASF
O
H OH 63% O
H OH
MeO O O
MeO O O
Cl
Cl

53. 18-steps
longest linear
12%
sequence
O
PMBO H
corrected
stereochemistry