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Total Synthesis of Amphidinolide F �Galle Valot, Christopher S. Regens, Daniel P. OMalley, Edouard Godineau, Hiroshi
Takikawa, and Alois Frstner*
Angew. Chem. Int. Ed. 2013, 52, 9534-‐9538 �
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Feng Zhang Wipf Group Current Literature
Sep. 21, 2013 �
OH
OH
OO
OHO O
O
H HOH
H
amphidinolide F
Feng Zhang @ Wipf Group Page 1 of 12 10/2/2013
Marine dinoflagellates Okinawan marine organisms
Marine dinoflagellates have proved to be a subject of considerable aWenXon as a new valuable source of bioacXve compounds. More than thirty macrolides have been isolated from different strains, which are collecXvely called amphidinolides. Most of them exhibiXng a potent cytotoxicity against human cancer cell lines in micromolar, nanomolar, or even subpicomolar concentraXons in vitro.
IntroducXon
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Feng Zhang @ Wipf Group Page 2 of 12 10/2/2013
OH
OH
OO
OHO O
O
H HOH
H
amphidinolide C: X = OH, Y = Hamphidinolide C2: X = OAc, Y = Hamphidinolide C3: X , Y = O
X Y
OH
OH
OO
OHO O
O
H HOH
H
amphidinolide F
In 1991, a new natural product Amphidinolide F was isolated from a dinoflagellate of the genus Amphidinium which was associated with the Okinawan flatworm Amphiscolops magniviridis and a different species from those reported previously.
cytotoxic acXvity (IC50)
murine lymphoma LI210 cells
human epidermoid carcinoma KB cells
Amphidinolide F 0.0006 1.5 µg/mL 3.2 µg/mL
Amphidinolide C 0.0015 5.8 ng/mL 4.6 ng/mL
Amphidinolide C 2 0.00015 0.8 µg/mL 3.0 µg/mL
Amphidinolide C 3 0.00006 7.6 µg/mL 10.0 µg/mL
IsolaXon yield (%)
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Due to their impressive potenXal bioacXvity, unique structure, and low natural accessibility, total synthesis therefore becomes an important potenXal source. 20 years passed since Amphidinolide F was isolated, no total synthesis was reported unXl 2012 (totally 34 steps).
Angew. Chem. Int. Ed. 2012, 51, 7948 – 7951.
OH
OH
OO
OHO O
O
H HOH
H
amphidinolide F
O O
Ph
OH
O
BzOOPivTBSO
TBSO H HOTES
OH
H
OTBS
OTBS
OTBSO
OPiv
H H
I
OEESO2Ph
OTBS
OTBS
O
TBSOO OTES
OPiv
H HOH
H
OEE
sulfone alkylation
oxidative desulfurization
macrolactonization
common intermediate
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RetrosyntheXc analysis
Feng Zhang @ Wipf Group Page 5 of 12 09/21/2013�
OH
OH
OO
OHO O
O
H HOH
H
amphidinolide F
OR
OR
ORO O
O
H HOH
H
O
A
OR
OR
ORO O
O
H HOH
H
B
OH
OR
OR
ORO O
O
H HOH
H
C
OH
X
OR
OH
1518
15
D
+
OR
O OH
O
H H
E
ORY+
OH
OH
H
18
F
M
Feng Zhang @ Wipf Group Page 5 of 12 10/2/2013
The syntheXc method for the fragment D
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X
OR
OH15
D
HO OHa. TBSCl, TEA, 86%
b, TEMPO, KBr, NaOCl, 86%TBSO
O
TMS
OMs
Pd(OAc)2, PPh3, Et2Zn, 87% OH TMS
HClEtOH
OH TMS
TBSO
OH91% OTES TMSTESO
TESOTf, 2,6-lutidinequant
PPTS, MeOHDCM, 80% OTES TMSOH
SO3.pyridine, iPr2NEt
93% OTES TMSO
OMs
Inl, PdCl2(dppf), THF/HMPA73%
OTES TMSOH
TBSOTf, 2,6-lutidine91%
OTES TMSTBSO
PhMe2SiLi, CuCN, MeI
90% OTES TMSTBSOPhMe2Si
K2CO3, MeOH 88%
OTESTBSOPhMe2Si
OTESTBSOI
a.
b. nBuLi, MeI, 97%
NIS, MeCN, benzene
88%
1 2 3
4 5 6
7 8
9 10
11 12
Feng Zhang @ Wipf Group Page 6 of 12 10/2/2013
OR
O OH
O
H H
E
ORY
O OHO
TrClpyridine
91%
O OTrO
LDA, MeI
THF
OHTrO
OEtO
O OTrO
a. Dibal-H, DCM
b. Ph3P=CHCOOEt, 85%
TBAF.3H2O
87%
OTrO
OEtOH H
a. TFA/EtOH, 86% OO
OEtOH H
b. SO3.pyridine, iPr2NEt
OTBSO
L-proline, DMF, 66%
OH HOHO
TBSO
OEt
O
TBSOTf
pyridine, 91%
OH HO
TBSO
OEt
O
OTBSKHMDS, PhNTf2, THF
73%
OH HTfO
TBSO
OEt
O
OTBS
Pd2(dba)3, P(2-furyl)3
Me6Sn2, LiCl, 81%
OH HMe3Sn
TBSO
Et
O
OTBSKOH
EtOH, THF, H2O, 98%
OH HMe3Sn
TBSO
OH
O
OTBS
13 14 15 16
17 18
19 20 21
22 23
The syntheXc method for the fragment E
Feng Zhang @ Wipf Group Page 7 of 12 09/21/2013�
Feng Zhang @ Wipf Group Page 7 of 12 10/2/2013
The syntheXc method for the fragment F
Feng Zhang @ Wipf Group Page 8 of 12 09/21/2013�
O Propyne, nBuLi, BF3.Et2O87%
OH OOH
H H(nmp)2Co, tBuOOH
O2, iPrOH, 84%
SO3.pyridine, iPr2NEt86%
OO
H HBra. , tBuLi, ZnBr2
b.N
O OH
O
N , tBuLi
OH
OH
H
18
F
OH H OH
24 25 26
27 28
85%
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Fragment Coupling and CompleXon of the Total Synthesis
Feng Zhang @ Wipf Group Page 9 of 12 09/21/2013�
OH H OH
28
OH HMe3Sn
TBSO
OH
O
OTBS
23
+
OTESTBSOI
122,4,6-Trichlorobenzoyl chloride, TEA
DMAP, toluene, 80%
OH HMe3Sn
TBSO
O
O
OTBS
29
OH
H
Pd(PPh3)4, Ph2PO2NBu4, CuTC, 56%
OH H
TBSO
O
O
OTBS
30
OH
H
OTBS
OTES
OH H
TBSO
O
O
OTBS
31
OH
H
OTBS
OTES
OH H
TBSO
O
O
OTBS
32
OH
H
OTBS
OH
OH H
TBSO
O
O
OTBS
33
OH
H
OTBS
OH
a. [(C2H4)PtCl2]2, Et2O, 97%
b. PPTS, benzene, 98%
OH H
TBSO
O
O
OTBS
34
OH
H
OTBS
OHO
a. TPAP, DCM, 70%
b. HF.NEt3, TEA, MeCN, 60%
OH
OH
OO
OHO O
O
H HOH
H
amphidinolide F
A
B
B
C
A: 35, toluene, DCM, 73%
B: PPTS, MeOH, DCM, 87% (33), 95% (32)C: 36, toluene, 70%
35
36
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Conclusions
• No more than 21 steps and therefore compares favorably with the only other completed approach known in the literature.
• A late-‐stage interplay of ring-‐closing alkyne metathesis (RCAM) and π-‐acid
catalysis nicely solved the selecRvity issue arising from the unusual 1,4-‐dioxygenaRon paUern decoraRng the targets polyfuncRonal backbone.
• The success of this strategy showcases the maturity of these methods and augurs well for future applicaRons.
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Thanks! �
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