lecture10: 123.702
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LECTURE TEN
epothilone A
gareth j rowlands
©NASA
epothilone AAngew. Chem. Int. Ed. Engl., 1997, 36, 523
O OH O
O
N
S
HO
O
© Katja Röper@Department of Physiology, Development, and Neuroscience, University of Cambridge
anti-cancerinteracts with microtubules
O OH O
O
N
S
HO
Oepoxidation
O OH O
O
N
S
HO
epothilone Aretrosynthesis of
epothilone C!
O OH O
O
N
S
HO
O OH O
O
N
S
HO
ring-closing metathesis
retrosynthesis of epothilone C
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
retrosynthesis
O O OOH OH
R2B
O OH
carbonyl addition
C–CFGI
asymmetric allylation
C–C
retrosynthesis of
C1-C6 fragment
C7-C12 fragmentretrosynthesis of
OHC
C–CFGI
O
aux*
FGI
O
O
auxiliary-controlled alkylation
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
©Status Frustration@Flickr
the synthesis
OH OH
1. NaH, TBSCl2. DMSO, (COCl)2 ....then Et3N3.
36%; 95%ee
B(ipc)2
OH OTBS
C1-C6 fragmentsynthesis of
see lecture four
B
O
H
OTBS
(ipc)2B
O
H
OTBS
allylationBrown
see lecture four
O O O
1. acetone, ....CuSO4, H+
2. OsO4, NaIO4
62%OH OTBS
C1-C6 fragmentsynthesis of
C1-C6 fragmentsynthesis of
O O O
1. EtMgBr2. TPAP, NMO
69% O O O
C6C1
C7-C12 fragmentsynthesis of
O
O
1. NaOH2. TBSCl, imidazole3. K2CO3, MeOH4. SOCl25. aux, n-BuLi
46%
NO
O O
OTBS
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
OTBS
missingalkene
formation
©mugley@Flickr
CHO OTBS
MgBrTBSO
OH88%
C13-C21 fragmentsynthesis of
see slide 11
TBSO
OH
(–)-DIPT, 4Å MS, Ti(OiPr)4, TBHP
46%80%ee
TBSO
OH
C13-C21 fragmentsynthesis of
Sharpless kinetic resolution
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
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
©EJP Photo@Flickr
put the
now
together blocks
fragmentscoupling the
O O O
C6C1
OC7
C12
LDA
70%>98%de
O O O
HO
C12
C7C6
C1
N
iPr
H
O
LiH
iPrR
O
O
O
Li
formationenolate
OO
LiH
H
RR
OHOH
H
RR
O O O
HO
C12
C7C6
C1
aldol
substratecontrol
fragmentscoupling the
O O O
HO
1. pPTS, MeOH2. TBSOTf3. CSA, MeOH4. PDC
55%
O OTBS O
TBSO
OH
fragmentscoupling the
OH
N
S
O OTBSO
TBSO
OH
NC
NCy CyNN
80%
O OTBSO
O
N
S
TBSO
C12
C13
C7C6
C1
C15
alkene metathesis
© Nobel Web AB© Nobel Foundation
© Nobel Foundation 2005
R2 R1[M]
R1R2
[M]
[M]R1
[M]R1
[M]R1
R2
R2
H
H H
H
[M]
[M]
[M]
H
H H
H
[M]
[M]
H
H H
H
ring-closingmetathesis
RCM
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
©manu_le_manu@Flickr
RuCy3PCl NHC
Cl
Ph
ON
N
NO
MeO OMe
O
HH
PCy3Ru
PhPCy3ClCl
N
MeO OMe
HH
O
67%
N
N
MeO OMe
HH
O
OHN
N
H OH
H
H
PCy3Ru
PhPCy3ClCl
26%
O
HCl
synthesis of
manzamine A
NNH
N
N
H OH
H
H
O
TsN
SiPCy3
RuPhPCy3
ClCl
OSi
TsN
TBAF78% 2 steps
NTs H
OH
NH H
OH
(–)-halosalin
ROM-RCM cascade
OTBDPSPCy3Ru
PhPCy3ClCl
OTBDPS
[Ru]
OTBDPS
[Ru]
repeat
70%
OTBDPS
enynemetathesis
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 product
©Little Blue Penguin@Flickr
two stereoisomersnon-selective
©Little Blue Penguin@Flickr
pure stereoisomerwant
metathesisalkyne
O OTBSO
O
N
S
TBSO
O OTBSO
O
N
S
TBSO
catalyst80%
N MoN
N
Fürstner Chem. Commun., 2001, 1057
O OH O
O
N
S
HO
1. H2, Lindlar cat.2. HF79%
O OTBS O
O
N
S
TBSOepothilone Csynthesis of
Fürstner’s
©gregoryjameswalsh@Flickr
originalback to
synthesis
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
2ndepothilone Asynthesis of
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