This document summarizes the synthesis of the anti-cancer compound epothilone A. It discusses the retrosynthesis of epothilone C and the synthesis of the required fragments - C1-C6, C7-C12, and C13-C21. These fragments were coupled and the ring was formed using ring-closing metathesis. Finally, epothilone C was converted to the target compound epothilone A through oxidation and reduction reactions. The synthesis utilized substrate-controlled aldol reactions, Sharpless asymmetric dihydroxylation, and ring-closing metathesis to construct the molecule with high stereoselectivity.

1. LECTURE FOUR
epothilone A
1

2. ©NASA
epothilone A
Angew. Chem. Int. Ed. Engl., 1997, 36, 523
O OH O
O
N
S
HO
O
2

3. © Katja Röper@Department of Physiology, Development,
and Neuroscience, University of Cambridge
anti-cancer
interacts with
microtubules
3

4. O OH O
O
N
S
HO
O
epoxidation
O OH O
O
N
S
HO
epothilone Aretrosynthesisof
epothilone C!
4

5. O OH O
O
N
S
HO
O OH O
O
N
S
HO
ring-closing
metathesis
retrosynthesisof epothilone C
5

6. O OH O
O
N
S
HO
aldol
esterification
OHC
O O O
OH
N
S
C12
C13
C7
C6
C1
C15
C12
C13
C7
C6
C1
C15
retrosynthesis
6

7. O O O
OH OH
R2B
O OH
carbonyl
addition
C–C
FGI
asymmetric
allylation
C–C
retrosynthesisof
C1-C6 fragment
7

8. C7-C12 fragmentretrosynthesisof
OHC
C–C
FGI
O
aux*
FGI
O
O
auxiliary-
controlled
alkylation
8

9. OH
N
S FGI
C=C
N
S
P
O
EtO
EtO
PGO
OH
O
PGO
OH
PGO
O
Horner-
Wadsworth-
Emmons
Sharpless
kinetic resolution
&
Grignard
FGI
C13-C21 fragmentretrosynthesisof
9

10. ©Status Frustration@Flickr
the
synthesis
10

11. OH OH
1. NaH, TBSCl
2. DMSO, (COCl)2
....then Et3N
3.
36%; 95%ee
B(ipc)2
OH OTBS
C1-C6 fragmentsynthesisof
see lecture four
11

12. B
O
H
OTBS
(ipc)2B
O
H
OTBS
allylation
Brown
12

13. O O O
1. acetone,
....CuSO4, H+
2. OsO4, NaIO4
62%OH OTBS
C1-C6 fragmentsynthesisof
13

14. C1-C6 fragmentsynthesisof
O O O
1. EtMgBr
2. TPAP, NMO
69% O O O
C6
C1
14

15. C7-C12 fragment
synthesisof
O
O
1. NaOH
2. TBSCl, imidazole
3. K2CO3, MeOH
4. SOCl2
5. aux, n-BuLi
46%
NO
O O
OTBS
15

16. C7-C12 fragmentsynthesisof
NO
O O
OTBS
NaHMDS NO
O O
OTBS
Na
I
Me
NO
O O
OTBS
MeI
1. LiAlH4
2. DMSO, (COCl)2
....then Et3N
60%
O
OTBS
16

17. missing
alkene
formation
©mugley@Flickr
17

18. O OTBS
MgBr
TBSO
OH
88%
C13-C21 fragment
synthesisof
see slide 11
18

19. TBSO
OH
(–)-DIPT, 4Å MS,
Ti(OiPr)4, TBHP
46%
80%ee
TBSO
OH
C13-C21 fragment
synthesisof
Sharpless kinetic resolution
19

20. Sharpless kinetic resolution
H
R3
R1
R2
OH
"O" (–)-DIPT
R
R
R3
R1
R2
OH
H
R2 OH
RR3
R1
slow fast
R2 OH
RR3
R1
R2 OH
RR3
R1
O
see lecture 5
0.6eq TBHP 0.45eq TBHP
20

21. C13-C21 fragmentsynthesisof
TBSO
OH
1. TBSCl,
....imdazole
2. O3, PPh3
69%
TBSO
OTBS
O
N
S
P
O
MeO
MeO BuLi
75%
OTBS
OTBS
N
S
1. HF / glass
2. DMP
3. Ph3P=CH2
4. TBAF
56%
OH
N
S
O
I
O
OAc
AcO
OAc
21

22. ©EJP Photo@Flickr
put the
now
together
blocks
22

23. fragments
couplingthe
O O O
C6
C1
O
C7
C12
LDA
70%
>98%de
O O O
HO
C12
C7
C6
C1
23

24. O
≡
R
H
O
H
R
H
O
H
nucleophile
H
R
OH
Hnuc
≡
OH
nuc
wrong
Felkin-Anh
24

25. N
iPr
H
O
Li
H
iPrR
O
O
O
Li
formation
enolate
25

26. aldol
substrate
control
Li
O
O
H
H
R
H
R2
O Li O
H
R
H
H
R2
vs.
Felkin-Anh
syn-pentane
anti-Felkin-Anh
no syn-pentane
26

27. aldol
substrate
control
H
Li
O
O
O
O
H
H
O
Li
O
H
H
O
O
H
H
R R
H
vs.
disfavoured
27

28. fragments
couplingthe
O O O
HO
1. pPTS, MeOH
2. TBSOTf
3. CSA, MeOH
4. PDC
55%
O OTBSO
TBSO
OH
28

29. fragments
couplingthe
OH
N
S
O OTBSO
TBSO
OH
N
C
N
Cy CyNN
80%
O OTBSO
O
N
S
TBSO
C12
C13
C7
C6
C1
C15
29

30. alkene metathesis
© Nobel Web AB
© Nobel Foundation
30

31. © Nobel Foundation 2005
31

32. R2 R1
[M]
R1
R2
[M]
[M]
R1
[M]
R1
[M]
R1
R2
R2
H
H H
H
32

33. [M]
[M]
[M]
H
H H
H
[M]
[M]
H
H H
H
ring-closing
metathesis
RCM
33

34. N
Mo
iPr iPr
(F3C)2MeCO
(F3C)2MeCO
Ph
PCy3
Ru
PhPCy3
Cl
Cl
Schrock Grubbs's
'1st generation'
(but he had many before)
Ru
PhPCy3
Cl
Cl
NN
Grubbs's
'2nd generation'
catalysts
34

35. O OTBSO
O
N
S
TBSO
C12
C13
C7
C6
C1
C15
PCy3
Ru
PhPCy3
Cl
Cl
O OTBSO
O
N
S
TBSO
C12
C13
C7
C6
C1
C15
O
O
N
S
OOTBS
TBSO
1 : 1
94%
epothilone C
synthesisof
HF gives product
35

36. ©Little Blue Penguin@Flickr
two stereoisomers
non-selective
36

37. ©Little Blue Penguin@Flickr
pure stereoisomer
want
37

38. metathesis
alkyne
O OTBSO
O
N
S
TBSO
O OTBSO
O
N
S
TBSO
catalyst
80%
N Mo
N
N
Fürstner Chem. Commun., 2001, 1057
38

39. O OH O
O
N
S
HO
1. H2, Lindlar cat.
2. HF
79%
O OTBSO
O
N
S
TBSO
epothilone C
synthesisof
Fürstner’s
39

40. ©gregoryjameswalsh@Flickr
original
backto
synthesis
40

41. epothilone A
synthesisof
O OTBSO
O
N
S
TBSO
C12
C13
C7
C6
C1
C15
1. HF
2. DMDO
31%
O OH O
O
N
S
HO
C12
C13
C7
C6
C1
C15
O
OO
41