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Raffaele Colombo 12/06/2014
Catalytic Z‑Selective Cross-Metathesis
in Complex Molecule Synthesis:
A Convergent Stereoselective Route to
Disorazole C1
A.W. H. Speed, T. J. Mann, R. V. O’Brien, R.
R. Schrock, Amir H. Hoveyda
J. Am. Chem. Soc. 2014, 136, 16136－16139
Raffalele Colombo @ Wipf Group Page 1 of 27 12/6/2014
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• Disorazoles are a relative new class of microtubule disrupting cytotoxic macrodiolides
• They are isolated in 1994 from the fermentation broth of the myxobacterium Sorangium cellulosum So ce12
• Disorazole A1 was identified as the major component between the 28 disorazoles isolated
• Minor members could be artifacts derived from side reactions during the isolation processes
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N
O
O O OH
O
N
O OO
OH
RO
Disorazole A1 (R = Me)
N
O
O O OH
O
N
O OOH
RO
Disorazole F1 (R = Me)
N
O
O O OH
O
N
O OOH
MeO
Disorazole C1
OMe
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• Disorazole C1 promotes depolymerization of the microtubules binding to or near the vinca domain, resulting in cell cycle arrest at the G2/M checkpoint and apoptotic cell death cascade
• Disorazole C1 is an effective cytotoxic agent with IC50 values < 10 nM in various human cancer cell lines
• The absence of the epoxide in the disorazole C1 reduced its cytotoxicity by 50–100 fold compare to disorazole A1
• It has a C2-symmetry
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N
O
O O OH
O
N
O OO
OH
RO
Disorazole A1 (R = Me)
N
O
O O OH
O
N
O OOH
RO
Disorazole F1 (R = Me)
N
O
O O OH
O
N
O OOH
MeO
Disorazole C1
OMe
N
O
O O OH
O
N
O OOH
MeO
OMe
Disorazole C1
Raffalele Colombo @ Wipf Group Page 3 of 27 12/6/2014
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• Truncations or alterations of the backbone reduce the activity
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N
O
O
OOH
MeO
O linear esters are inactive
unstable if lacking the methoxy group
alkyne analog is 1000 less active
cyclic structure required
cyclopropane isostere is inactive
Allylic alcohol required
C. D. Hopkins, P. Wipf Natural Product Reports 2009, 26, 585 Raffalele Colombo @ Wipf Group Page 4 of 27 12/6/2014
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N
O
O
OHO
MeO
OMe
N
O
O O OH
O
N
O OOH
MeO
Disorazole C1
OMe
esterification
macrolactonization
Stille couplingSEM
N
O
O
OHO
MeO
OMe
SEM
SnMe3
IWittig
MeO2C OO
N
O
O
MeOO
O
N
O
O
MeO OHI
H
O OTBDMS
OEt
OH OTBDMS
OEtBH3.THF
Ts-L-Val-OH
SEMO
OH
SEMO
OH
OH SEMO
O
OPMBasymmetric epoxidation
then reduction SEMO OH
SnMe3
NO
O
OH
O
OMe
OMe
SEM
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unstable M. C. Hillier, D. H. Park, A. T. Price, R. Ng, A. I. Meyers, Tetrahedron Lett., 2000, 41, 2821–2824
Z
Z
E
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NO O
OHO MeO
OMe
TBDPS 1) LiOH
2) DPTC,DMAP
N
O
OO
OMe
TBDPSO
1) TESOTf2) LiOH
NO O
OO MeO
OH
TBDPS
TES
A
A, DPTC, DMAP
N
OO O OMeO
MeOTBDPS
NO
O
OO MeOTBDPS
TES
NO
O
O OMeO
TBDPS
NO
O
OO MeOTBDPS
1) TFA2) LiOH
3) Yamaguchi
OOS
NNDPTC =
Unsuccessful desilylation
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M. C. Hillier, A. T. Price and A. I. Meyers, J. Org. Chem., 2001, 66, 6037–6045 Raffalele Colombo @ Wipf Group Page 6 of 27 12/6/2014
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N
O
O
OTBDMSO
MeO
MeO
N
O
O O OH
O
N
O OOH
MeO
Disorazole C1
OMe
esterification
macrolactonization
Sonogashiracross-couplingSEM
N
O
O
OTBDMSO
MeO
OMe
SEM
Wittig
I
reduction
• The position of the alkyne was chosen to increase the strain of the 15-membered cycle in order to suppress the intramacrocyclization
N
O
O
MeO
OMe2.5 : 1 E/Z mixture (not separable)
poor overall yield
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OPMBOTBDMS
EtO MeO
O OHBH3.THF, DCM
Ts-Val-OH, -78 °C, 96%
SEMO
O
OTBDMS
O OPMB O OTBDMS
OPMB
SEMO OTBDMS
I
I-Ph3P+CH2I, NaHMDS
HMPA, THF, -78 °C, 82%
SEMO OH
78%
HOOMe
O
NCO2Me
OMe
O
NCO2Me
75%
PdCl2(PPh3)2, CuI,
Et3N, DMF 89%
n-BuSnH, Pd(PPh3)4,
THF, then I2, 88%
OMe
O
NCO2Me
I
Ohira-Bestmann
N
O
O
OTESO
MeO
MeO
N
O
O O OH
O
N
O OOH
MeO
Disorazole C1
OMe
esterification
macrolactonization
Sonogashiracross-coupling
SEM
N
O
O
OTBDMSO
MeO
OMe
SEM
reductionI
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Raffalele Colombo @ Wipf Group Page 8 of 27 12/6/2014
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Almost a formal synthesis (different PGs)
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Barbara Niess, Ingo V. Hartung, Lars O. HaustedtH. Martin R. Hoffmann EurJOC, 2006, 1132-1143
A
OMe
O
NCO2Me
OHSEMO
OMe
O
NCO2H
OTESSEMO
A, TEA, toluene, DMAP2,4,6-trichlorobenzoyl chloride
88%
N O
O
O OSEM
OMe
OMe NO
O
OSEMO
OMe
TES
1) TBAF2) Ba(OH)2
3) YamaguchiN O
O
O OSEM
OMe
NO
O
OSEMO
OMe
27%
69%
1) TESOTf2) LiOH
LiOH OMe
O
NCO2H
OHSEMO
Shiina (dipyridyl-2-thiocarbonate)
Yamaguchi (2,4,6-trichlorobenzoyl chloride)
Mukayama (2-chloro-1-methylpyridinium iodide)
Wipf-Graham
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Hoffmann’s (unsuccessful) approach
O
OSEM
NO
O
OMe
I
N O
O
O
OSEM
OMe
NO
O
O
SEMO
OMe
double Sonogashira
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Barbara Niess, Ingo V. Hartung, Lars O. HaustedtH. Martin R. Hoffmann EurJOC, 2006, 1132-1143 Raffalele Colombo @ Wipf Group Page 10 of 27 12/6/2014
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N
O
O
OHO
MeO
MeO
N
O
O O OH
O
N
O OOH
MeO
Disorazole C1
OMe
esterification
macrolactonization
Sonogashiracross-coupling
PMB
N
O
O
OHO
MeO
OMe
PMB
reductionI
Petersonolefination
HO CN
78%TIPSO
O
64%TIPSO
OMe
30%
OMeN
OMeO2C
Br
89%
OMeN
OHO2C I
O
O OH
70%
OH O O
41%
OH O O
70%
PMBO OH OH
55%
PMBO OH
TIPS
PMBO OH
94%
PMBO OTES
55% O
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P. Wipf, T. H. Graham, J. Am. Chem. Soc. 2004, 126, 15346-15347 Raffalele Colombo @ Wipf Group Page 11 of 27 12/6/2014
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OMe
N
OMeO2C
I
PMBO OH
PMBO OH
MeO N
OCO2Me
OMeN
OHO2C I
PMBO O
MeO
N
O
CO2Me
OMe
NO
I
O
PMBO OH
NO
O
OPMBO
OMe
N O
O
O OPMB
OMe
PMBO O
MeO
N
O
CO2Me
OMe
NO
O OPMBOH
1) LiOH
2) Yamaguchi
1) DDQ2) H2, Lindlar35% over 2 steps
Disorazole C1
PdCl2(PPh3)2
CuI, CH3CN94%
DCC, DMAP, CH2Cl2
80%
PdCl2(PPh3)2CuI, CH3CN
94%78%
+
12
20 steps, 1.5% for the longest sequence
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N
O
OO
RO
MeON
O
O O OH
O
N
O OOH
MeO
Disorazole C1
OMe
N
O
O
OH OR
MeO
OH
I
(pin)B
intramolecular cross-coupling
intermolecular cross-coupling
B(pin)
I
esterification
2x
OTBSCHO
5 mol % Sc(OTf)3CH2Cl2, -10 °C, 3 h98%, 91:9 dr
NSi
N
Cl
BrBr
TBSO OH1) 1.5 eq TMSCl iPr2NEt, DMAP, CH2Cl2 0 °C, 3h, 92%
TBSO OTMS
B(pin)2) 3 eq vinyl-B(pin), MoLn C6H6, 100 torr, rt, 20 h
72%, >98:2 Z:E
MoN
CF3
PhN
O Br
TBSOBr
2 eq I2aq NaOH, THF,rt, 10 h
TBSO OTMS
I
MoLn
+
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Cross-Metathesis
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Cross-Metathesis
Cross-Metathesis
tBuO2COH 1) Me3OBF4, proton sponge
DCM, rt, 3 h, 79%
2) HCO2H, rt, 25 h, 79%HO2C
OMeTFFH, iPr2NEt, THF, rt, 2 h, then
Ser-OMe.HCl
OMe
NH
O
MeO2C
OH
1) DAST, CH2Cl2, -78°C, 3 hK2CO3 45 min
2) BrCCl3, DBU, CH2Cl2, 0 °C, 16 h, 58% (over 2 steps)
OMe
N
OMeO2C
5 mol % H.-G. 2nd gen.5 eq Brtoluene, 70°C, 18 h81%, 95:5 E:Z
1)
2) DBU, EtOAc, rt, 7h 81%, 95:5 E:Z
OMe
N
OMeO2C
5 eq vinyl-B(pin), 10 mol % MoLn C6H6, 100 torr, rt, 18 h
76%, 92:8 Z:E
MoN
CF3
PhN
O Br
TBSOBr
= MoLn
OiPr
RuCl
ClNMesMesN
= H.-G. 2nd gen.NF
N+ PF6- = TFFH
OMe
N
OMeO2C
B(pin)
NSF3
= DAST
Raffalele Colombo @ Wipf Group Page 14 of 27 12/6/2014
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OMe
N
OMeO2C
B(pin)
TBSO OH
I1) 10 mol % Pd(PPh3)4, 1.1 eq. Ag2O, THF, rt, 16 h (69%)
2) BaOH, H2O/THF, rt, 1.5 h, then KHSO4 (conv. > 98%)
OMe
N
O
CO2H
TBSO OH
various conditions
unstable
< 2% ester/dimer+
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Raffalele Colombo @ Wipf Group Page 15 of 27 12/6/2014
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OMe
N
OMeO2C
B(pin) 1) BaOH, H2O/THF, rt, 1.5 h, then NHSO4
2) DCC, DMAP, DMAP.HCl, CDCl3 rt, 7 days
OTBSO
I
OMeN
O
B(pin)O
TBSO OH
I
(30% over 2 steps)
OMe
N
OMeO2C
1) BaOH, H2O/THF, rt, 1.5 h, then NHSO4
2) DCC, DMAP, DMAP.HCl, CDCl3rt, 18 h
OTBSO
I
OMeN
O
O
(83% over 2 steps)
TBSO OH
I 7 eq vinyl-B(pin), 10 mol % MoLn C6H6, 100 torr, rt, 4 h
91%, 98:2 Z:E
MoN
PhN
O Br
TBSOBr
= MoLn OTBSO
I
OMeN
O
B(pin)O
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Cross-Metathesis
Raffalele Colombo @ Wipf Group Page 16 of 27 12/6/2014
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OTBSO
I
OMeN
O
B(pin)O
5 mol % Pd[(o-tol)3P]2, 1.0 eq CsCO3,
MeOH (4 mM), rt, 12h
N
O
O O O
O
N
O OO
MeO
OMe
TBS
TBS
60%
N
O
OO
OMe
TBSO
2%
120 eq H2SiF6 (aq)MeOH, 4 °C, 72 h
68%
N
O
O O OH
O
N
O OOH
MeO
OMe
Disorazole C1
2x
17
12 steps, 8% for the longest sequence
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Raffalele Colombo @ Wipf Group Page 18 of 27 12/6/2014
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Thanks!
Prof. Wipf Wipf group past & present
Eli Lilly – LIFA (Lilly innovation fellowship award)
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Raffalele Colombo @ Wipf Group Page 20 of 27 12/6/2014
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Raffalele Colombo @ Wipf Group Page 21 of 27 12/6/2014
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Raffalele Colombo @ Wipf Group Page 22 of 27 12/6/2014
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Raffalele Colombo @ Wipf Group Page 23 of 27 12/6/2014
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Raffalele Colombo @ Wipf Group Page 24 of 27 12/6/2014
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Raffalele Colombo @ Wipf Group Page 25 of 27 12/6/2014
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Hoveyda et al., J. Am. Chem. Soc. 2013, 135, 6026－6029 Raffalele Colombo @ Wipf Group Page 26 of 27 12/6/2014
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Hoveyda et al., J. Am. Chem. Soc. 2013, 135, 6026－6029 Raffalele Colombo @ Wipf Group Page 27 of 27 12/6/2014
