The document summarizes the retrosynthetic analysis and total synthesis of the natural product callipeltoside C. The retrosynthesis breaks the molecule down into 3 main fragments - the sugar portion, middle section, and bottom half. The synthesis proceeds by synthesizing each fragment separately and coupling them together, with the sugar portion requiring the most steps due to protecting group manipulation and diastereoselective transformations. The total synthesis takes 18 linear steps to assemble all the fragments and achieve the target natural product.

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