Total&Synthesis&of& AmphidinolideFccc.chem.pitt.edu/wipf/Current Literature/Feng_3.pdf · 2013. 10. 2. · PhMe2SiLi, CuCN, MeI 90% TBSO OTES TMS PhMe 2Si K 2CO 3, MeOH 88% TBSO OTES

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 �

Feng Zhang @ Wipf Group Page 1 of 12 09/21/2013�

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



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 (%)



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



RetrosyntheXc analysis


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


The syntheXc method for the fragment D


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


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



The syntheXc method for the fragment F


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%


Fragment Coupling and CompleXon of the Total Synthesis


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




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.



Thanks! �



Total&Synthesis&of& AmphidinolideFccc.chem.pitt.edu/wipf/Current Literature/Feng_3.pdf · 2013. 10. 2. · PhMe2SiLi, CuCN, MeI 90% TBSO OTES TMS PhMe 2Si K 2CO 3, MeOH 88% TBSO OTES

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