enantioselective total synthesis of amphidinolide fccc.chem.pitt.edu/wipf/current...
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Dimas José da Paz LimaWipf group - Current Literature
August 25, 2012
Enantioselective Total Synthesis of Amphidinolide F
Mahapatra, S.; Carter, R. G. Angew. Chem. Int. Ed. 2012, 51, 7948
O
O
O O
O
O
Me
Me OHMe
OH
HHO
Me
HHH
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Amphidinolide F - Isolation, Structure and Biological Active
Amphidinolides are secondary metabolites from Amphidinium sp. collected fromOkinawa Island by Kobayashi at al.
The family of amphidinolides contains more than 30 members that possess ahighly oxigenated macrolactone core
Amphidinolide F exhibed cytotoxic activity against L1210 (IC50 = 1.5 µg/mL)and KB cell (IC50 = 3.2 µg/mL)
11 stereogenic centersTwo THF rings1,4-diketone moietyHighly substitued diene moiety
O
O
O O
O
O
Me
Me OHMe
OH
HHO
Me
HHH
Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77
Kobayashi, J. J. Antibiot. 2008, 61, 271
Dimas Paz @ Wipf Group Page 3 of 16 8/31/2012
Retrosynthesis
O
O
O O
O
O
Me
Me OHMe
OH
HHO
Me
HHH
Amphidinolide F
OEE
O
O OTES
OPiv
O
Me
Me OTBS
OTBS
HTBSO
Me
HHH
Macrolactonization
SO2Ph
OH
H
Me
OEE
O
OPiv
Me
Me OTBS
I
OTBS
TBSO H H
Me
O
OPiv
TBSO
TBSOO
H H
Common intermediate
OTES
Sulfone alkylation
Oxidative desulfurization
+
Dimas Paz @ Wipf Group Page 4 of 16 8/31/2012
Synthesis of Common intermediateO
OOPivTBSO
TBSO H H
O O
Ph
HO
1) (ClCO)2, DMSO
Et3N, DCM, !78 °C
PO
N2
(OMe)2
O
NaOMe, THF67% (2 steps)
O O
Ph
2)
1) CSA, MeOH
2) PivCl, Py, DCMthen BzCl, DMAP
61% (2 steps)
OPivOBz
TBSO I
[PdCl2(Ph3)2]CuI, Et3NTHF, 78%
OPivOBz
TBSO
AD Mix "#
t-BuOH/H2O
87%, d.r. >20:1
OPivOBz
TBSO
OH
OH
Chem. Eur. J.2003, 9, 1405
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Synthesis of Common intermediate O
OOPivTBSO
TBSO H H
O
OOPivTBSO
TBSO H H
OPivOBz
TBSO
OH
OH
AgBF4 (10 mol%)
C6H6, 80 °C65-70%
TBSO OH
CBzO
R
H
OH
Ag
O
BzOOPivTBSO
HO H H1) TBSOTf, 2,6-lutidine
DCM, 85%
2) MeLi•LiBrEt2O, !78 °C, 81%
d.r. >20:1
Dimas Paz @ Wipf Group Page 6 of 16 8/31/2012
Synthesis of the left-hand segmentO
OPiv
Me
Me OTBS
I
OTBS
TBSO H H
Me
EtO OEt
O O CHI3, NaH
reflux, Et2O65%
MeEtO OEt
O O
Me CHI2
1) KOH, EtOH-H2Oreflux, 88%
2) LiAlH4, THF0 °C - 20 °C, 71%
3) MnO2, DCM, 98%
I OMe
1) Ph3P=CHCO2Me, DMCDCM, 0 °C, 93%
2) DIBALH, DCM!78 °C - 20 °C, 92% I
Me
HO
(+)-DET, Ti(Oi-Pr)4
TBHP, DCMmol sieves, !35 °C
87%, 95% ee IMe
HOO
Mahapatra, S.; Carter, R. G. Org. Biomol. Chem. 2009, 7, 4582
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Synthesis of the left-hand segmentO
OPiv
Me
Me OTBS
I
OTBS
TBSO H H
Me
IMe
OOTBS
AlMe
MeMe
IMe
OTBS
OHMe
1) TBSOTf, 2,6-lutidineDCM, 98%
2) TMS-acetylene[PdCl2(PPh3)2]
CuI, Et3N, THF, 78%3) K2CO3, MeOH, 95%
Me
OTBS
OTBSMe
1) [PdCl2(PPh3)2]Bu3SnH, THF, 72%
2) I2, DCM, 70% Me
OTBS
OTBSMe
I
IMe
HOO
1) TBSCl, imid. DMAPDMF, 99%
2) Me3Al, DCM, !78 °C95%, >20:1 dr
Dimas Paz @ Wipf Group Page 8 of 16 8/31/2012
Synthesis of the left-hand segment O
OPiv
Me
Me OTBS
I
OTBS
TBSO H H
Me
O
OOPivTBSO
TBSO H HLDA, THF, DMPU
Me2N CH2I
71%
O
OOPivTBSO
TBSO H H [(Ph3P)3RhCl], PhMe, H2
89%, d.r.=10:1
O
OOPivTBSO
TBSO H H
Me
1) NaBH4, MeOH, 92%2)
PhMe, 100 °C, 91%
3) Bu3SnH, AIBNPhMe, 95 °C, 96%
Im2C=SO
OPivTBSO
TBSO H H
Me
Dimas Paz @ Wipf Group Page 9 of 16 8/31/2012
Synthesis of the left-hand segmentO
OPiv
Me
Me OTBS
I
OTBS
TBSO H H
Me
O
OPivO
TBSO H H
Me
Me
I
Me OTBS
OTBS
n-BuLi, THF, !78 °C62%, d.r.=3:1
2) TBSOTf, 2,6-lutidineDCM, 87%
1)
O
OPivOTBS
O H H
Me
TBSMe
Me O
OTBS
TBS1) HF•Py, THF, 81%
2) PPh3, I2, Imidazole
C6H6, 90%O
OPivOTBS
O H H
Me
TBSMe
Me O
I
TBS
O
OPivTBSO
TBSO H H
Me
1) HF•Py, THF, 83%
2) DMP, Py, DCM
Dimas Paz @ Wipf Group Page 10 of 16 8/31/2012
Synthesis of the right-hand segmentSO2Ph
OH
H
Me
OEE
OTES
O
O
H
1) NaBH4, MeOH, 95%2)
PhMe, 100 °C, 99%
3) Bu3SnH, AIBNPhMe, 90 °C, 91%
Im2C=S
OTBS
OTBSOPiv
H OH
OTBS
OTBSOPiv
H
1) LiAlH4, Et2O, 96%
2) (ClCO)2, DMSOEt3N, DCM
OBn
MeI
t-BuLi, THF, ! 78 °C
72% (2 steps)d.r.= 1.5:1 (1:2)
OH
OTBS
OTBS
H
BnO XY
Me
1 X = H, Y = OH
2 X = OH, Y = H
3) EtOCH=CH2, PPTSDCM, 94%
4) Pd/C, H2, i-PrOH
OH
OTBS
OTBSO
H
OH
OTBS
OTBS
H
HO
Me
OEE
OL 2003, 5, 1617JACS 2001, 123, 8420 1) TPA, NMO, DCM
2) L-Selectride, THF
d.r.= 15:1 (1:2)85% (2 steps)
Dimas Paz @ Wipf Group Page 11 of 16 8/31/2012
Synthesis of the right-hand segment
SO2Ph
OH
H
Me
OEE
OTES
OH
OTBS
OTBS
H
HO
Me
OEE1) Ph2S2, Bu3P
THF, 78% (2 steps)
2) TPAP, NMOMeCN, 92%
OH
OTBS
OTBS
H
SO2Ph
Me
OEE 1) HF•Py, THF
2) DMSO, (ClCO)2
Et3N, DCM
0 °C, 80%
OH
OTBS
O
H
SO2Ph
Me
OEE
PBu3
Me
Me
Br
n-BuLi, THF97% (2 steps)E/Z=11:1
OH
OTBSH
SO2Ph
Me
OEE
Me
Me
1) TBAF, THF
2) TESCl, DMAPEt3N, DCM
95% (2 steps)
OH
OTESH
SO2Ph
Me
OEE
Me
Me
Dimas Paz @ Wipf Group Page 12 of 16 8/31/2012
Completion of the Synthesis
OH
OTESH
SO2Ph
Me
OEE
Me
MeLHMDS, THF, HMPA
10 °C - r.t., 74%
O
OPivOTBS
O H H
Me
TBSMe
Me O
I
TBS
OEE
O
O OTES
OPiv
SO2Ph
Me
Me OTBS
OTBS
HTBSO
Me
HHH
LDA, DMPU, THF
NO
SO2PhPh
3 + 4: 65%(1.8:1 3:4), 94% brsm
OEE
O
O OTES
OPiv
Me
Me OTBS
OTBS
HTBSO
Me
HHH
OEE
O
O OTES
OH
Me
Me OTBS
OTBS
HTBSO
Me
HHH
+
3
O O
Dimas Paz @ Wipf Group Page 13 of 16 8/31/2012
Completion of the Synthesis
OEE
O
O OTES
OPiv
Me
Me OTBS
OTBS
HTBSO
Me
HHH
OEE
O
O OTES
OH
Me
Me OTBS
OTBS
HTBSO
Me
HHH
+
3 4
O O
1) LiAlH4, Et2O2) (ClCO)2, Et3N, DCM
83% (2 steps)
(ClCO)2, Et3N, DCM, 83%
Aldehyde
NaClO2, 2-Me-2-buteneNaH2PO4•H2O
t-BuOH/H2O, 85%
OEE
O
O OTES
CO2H
Me
Me OTBS
OTBS
HTBSO
Me
HHH
O
Dimas Paz @ Wipf Group Page 14 of 16 8/31/2012
Completion of the Synthesis
OEE
O
O OTES
CO2H
Me
Me OTBS
OTBS
HTBSO
Me
HHH
O
1) PPTS, MeOH
OH
OCl
Cl Cl
Et3N, DMAPPhMe/THF65% (2 steps)
2)
OEE
O
O O
O
O
Me
Me OTBSMe
OTBS
HTBSO
Me
HHH
1) AcOH, THF, H2O2) DMP, Pyr
62% (2 steps)
3) Et3N•HFEt3N/MeCN, 56%
O
O
O O
O
O
Me
Me OHMe
OH
HHO
Me
HHH
Amphidinolide F
Dimas Paz @ Wipf Group Page 15 of 16 8/31/2012
Summary and Outlook
*Amphidinolide F was synthesized in 34 steps (longest linearSequence)
*Key transformations include:
-Silver-catalyzed dihydrofuran formation
- Diastereoselective ring opening of vinil iodide/allylic epoxide
-Regioselective hydrostannylation of enyne
- Diastereoselective addition of 2-lithio-1,3-diene to aldehyde
- Sulfone alkylation/Oxidative desulfurization sequence
Dimas Paz @ Wipf Group Page 16 of 16 8/31/2012