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LECTURE FOURepothilone A
1
©NASA
epothilone AAngew. Chem. Int. Ed. Engl., 1997, 36, 523
O OH O
O
N
S
HO
O
2
© Katja Röper@Department of Physiology, Development, and Neuroscience, University of Cambridge
anti-cancerinteracts with microtubules
3
O OH O
O
N
S
HO
Oepoxidation
O OH O
O
N
S
HO
epothilone Aretrosynthesis of
epothilone C!4
O OH O
O
N
S
HO
O OH O
O
N
S
HO
ring-closing metathesis
retrosynthesis of epothilone C
5
O OH O
O
N
S
HO
aldol
esterification
OHC
O O O
OH
N
S
C12
C13
C7C6
C1
C15
C12 C13
C7 C6C1
C15
retrosynthesis6
O O OOH OH
R2B
O OH
carbonyl addition
C–CFGI
asymmetric allylation
C–C
retrosynthesis of
C1-C6 fragment
7
C7-C12 fragmentretrosynthesis of
OHC
C–CFGI
O
aux*
FGI
O
O
auxiliary-controlled alkylation
8
OH
N
S FGIC=C
N
S
PO
EtOEtOPGO
OHO
PGO
OH
PGO
O
Horner-Wadsworth-
EmmonsSharpless
kinetic resolution&
Grignard
FGI
C13-C21 fragmentretrosynthesis of
9
©Status Frustration@Flickr
the synthesis
10
OH OH
1. NaH, TBSCl2. DMSO, (COCl)2 ....then Et3N3.
36%; 95%ee
B(ipc)2
OH OTBS
C1-C6 fragmentsynthesis of
see lecture four11
B
O
H
OTBS
(ipc)2B
O
H
OTBS
allylationBrown
12
O O O
1. acetone, ....CuSO4, H+
2. OsO4, NaIO4
62%OH OTBS
C1-C6 fragmentsynthesis of
13
C1-C6 fragmentsynthesis of
O O O
1. EtMgBr2. TPAP, NMO
69% O O O
C6C1
14
C7-C12 fragmentsynthesis of
O
O
1. NaOH2. TBSCl, imidazole3. K2CO3, MeOH4. SOCl25. aux, n-BuLi
46%
NO
O O
OTBS
15
C7-C12 fragmentsynthesis of
NO
O O
OTBS
NaHMDS NO
O O
OTBS
Na
IMe
NO
O O
OTBS
MeI
1. LiAlH42. DMSO, (COCl)2....then Et3N
60%
O
OTBS16
missingalkene
formation
©mugley@Flickr
17
O OTBS
MgBrTBSO
OH88%
C13-C21 fragmentsynthesis of
see slide 1118
TBSO
OH
(–)-DIPT, 4Å MS, Ti(OiPr)4, TBHP
46%80%ee
TBSO
OH
C13-C21 fragmentsynthesis of
Sharpless kinetic resolution19
Sharpless kinetic resolution
H
R3
R1
R2
OH
"O" (–)-DIPT
R
R
R3
R1
R2
OHH
R2 OH
RR3
R1
slow fast
R2 OH
RR3
R1R2 OH
RR3
R1
O
see lecture 5
0.6eq TBHP 0.45eq TBHP
20
C13-C21 fragmentsynthesis of
TBSO
OH
1. TBSCl, ....imdazole2. O3, PPh3
69%
TBSO
OTBSO
N
S
PO
MeOMeO BuLi
75%
OTBS
OTBS
N
S
1. HF / glass2. DMP3. Ph3P=CH24. TBAF
56%OH
N
S
OI
O
OAcAcO OAc
21
©EJP Photo@Flickr
put the
now
together blocks
22
fragmentscoupling the
O O O
C6C1
OC7
C12
LDA
70%>98%de
O O O
HO
C12
C7C6
C1
23
O
≡R
H
O
H
R
H
O
Hnucleophile
H
ROH
Hnuc≡
OH
nuc
wrongFelkin-Anh
24
N
iPr
H
O
LiH
iPrR
O
O
O
Li
formationenolate
25
aldol
substratecontrol
LiO
O
HH
R
H
R2
O Li O
HR
H
H
R2
vs.
Felkin-Anhsyn-pentane
anti-Felkin-Anhno syn-pentane
26
aldol
substratecontrol
HLi
OO
O
O
H
H
O Li O
HH
OOH
HR R
H
vs.
disfavoured
27
fragmentscoupling the
O O O
HO
1. pPTS, MeOH2. TBSOTf3. CSA, MeOH4. PDC
55%
O OTBS O
TBSO
OH
28
fragmentscoupling the
OH
N
S
O OTBSO
TBSO
OH
NC
NCy CyNN
80%
O OTBSO
O
N
S
TBSO
C12
C13
C7C6
C1
C15
29
alkene metathesis
© Nobel Web AB© Nobel Foundation
30
© Nobel Foundation 200531
R2 R1[M]
R1R2
[M]
[M]R1
[M]R1
[M]R1
R2
R2
H
H H
H32
[M]
[M]
[M]
H
H H
H
[M]
[M]
H
H H
H
ring-closingmetathesisRCM
33
NMo
iPr iPr
(F3C)2MeCO(F3C)2MeCO
Ph
PCy3
RuPhPCy3
ClCl
Schrock Grubbs's'1st generation'
(but he had many before)
RuPhPCy3
ClCl
NN
Grubbs's'2nd generation'
catalysts
34
O OTBS O
O
N
S
TBSO
C12
C13
C7C6
C1
C15
PCy3
RuPhPCy3
ClCl
O OTBS O
O
N
S
TBSO
C12
C13
C7C6
C1
C15O
O
N
S
OOTBS
TBSO
1 : 194%
epothilone Csynthesis of
HF gives product35
©Little Blue Penguin@Flickr
two stereoisomersnon-selective
36
©Little Blue Penguin@Flickr
pure stereoisomerwant
37
metathesisalkyne
O OTBSO
O
N
S
TBSO
O OTBSO
O
N
S
TBSO
catalyst80%
N MoN
N
Fürstner Chem. Commun., 2001, 105738
O OH O
O
N
S
HO
1. H2, Lindlar cat.2. HF79%
O OTBS O
O
N
S
TBSOepothilone Csynthesis ofFürstner’s
39
©gregoryjameswalsh@Flickr
originalback to
synthesis
40
epothilone Asynthesis of
O OTBS O
O
N
S
TBSO
C12
C13
C7C6
C1
C15
1. HF2. DMDO31%
O OH O
O
N
S
HO
C12
C13
C7C6
C1
C15
O
OO
41
