Literature ReportLiterature Report

Enantioselective Total Synthesis of Amphidinolide Fof Amphidinolide F

Reporter: Mu-Wang Chen Checker: Ran-Ning Guo

Carter, R. G. et al.Angew.Chem. Int. Ed. 2012, 51, 7948-7951

1

Structurally complex amphidinolide natural products

Retrosynthetic analysis of amphidinolide F.

OH

O

O15 18

20 macrolactonizationOTBS

O

OEE15 18

20

14

OH

OH

OH

O

O

O

O

H

HHH1

36

9

1123 25

29

OTBS

OTBSO

OTESO

H

HHH

36

9

11

20

2429

1OH O OTBS

OPivamphidinolide F (3)

SO2Ph

4 sulfone alkylation/oxidativedesulfurization

OEE

OH

15 18

25OTBSHH

OTESH 29

5

OTBS11

IOTBS

OHH

OPivO7

OTBS

OTBS

OHH

11

OPi

1

8

common intermediatefor C1-C8 and C18-C25

OPiv6

Synthesis of common intermediate

OBz OPiv

AD Mix t BuOH/H O

OBz OPiv

OH

13OTBS

AD Mix t-BuOH/H2O87%, d.r. >20:1 14

OTBS OH

AgBF4 (10 mol%)TBSO OH

OH

OHHO H

AgBF4 (10 mol%)

C6H6, 80 oC, 65-70%BzO •

H15 AgOPiv BzO

16

OPivTBSO

OHTBSO H

OHTBSO H

TBSOTf, 2,6-lutidine85%

O

BzO17

OPivTBSO

MeLi.LiBr, Et2O

-78 oC, 81%

O

O 7

OPivTBSO17 7

Synthesis of the C1-C14 subunit

I1) KOH EtOH/H2O 36 h 88%

CO2MeI

CO2Me1) KOH, EtOH/H2O, , 36 h, 88%2) LiAlH4, THF, 0 oC to 20 oC, 71%

3) MnO2, CH2Cl2, rt, 10 h, 98%I O

a b

Ph3P=CHCO2Me

CH2Cl2, 0 oC, 45 min, 93%

OMeDIBAH, CH2Cl2, -78 oC to 20 oC

I

OH

I

c

O 2 h, 92% I

d

(+)-DET, Ti(Oi-Pr)4TBHP, CH2Cl2

mol sieves,-35 oC I

OHO

,87%, 95% ee e

O 1)TBSCl imid DMAP O

OH OTBS

Al

Me

Me1)TBSCl, imid, DMAPDMF, 99%

2) Me3Al, CH2Cl2, -78 oC95%, d. r. >20:1

Me

10

Ie I

OTBS OTBS

OH

TBSOTf, 2,6-IutidineCH2Cl2, 98%

OTBS

If I24

10 10

10

Synthesis of the C15-C29 subunit

OOPiv OPiv

OTBS

O

O

HH

1) NaBH4, MeOH, 95%2) Im2C=S, PhMe, 100 oC, 99%

3) Bu3SnH, AIBN, PhMe90 oC 91%

OTBS

OH

H

1) LiAlH4, Et2O, 96%2) (ClCO)2, DMSO, Et3N, CH2Cl2

OTBSH 90 C, 91%

7 OTBSH

28

OTBS

O

+

OBnt-BuLi, THF, -78 oC

OBn

YX17

18

O

OTBSH

H

29

+I 72% d.r. = 1.5:1 (31:32) OTBS

O

OTBSH

H30

8

OTBS31 X = H, Y = OH32 X = OH, Y = H

11

OTBS

OBn

YX17

18 1) EtOCH=CH2, PPTS (5 mol%)CH2Cl2, 94%

OTBS

OBn

YX17

181) TPAP, NMO, CH2Cl2

O

OTBSH

H

31 X = H, Y = OH32 X = OH, Y = H

2) Pd/C, H2, IPAO

OTBSH

H

31 X = H, Y = OH32 X = OH, Y = H

2) L-Selectride 31:32 = 15:185%

SO2Ph

OEE

OH

OEE15

18

OTBS

O

OTBSH

H

OEE18

25

34

OTBS

O

OTBSH

H

18

25

1) Ph2S2, Bu3P, THF, 78%

TPAP, NMO, MeCN, 92%2)

33OTBS

SO2Ph

OEE

34

1) TF.Pyr, THF, 0 oC, 80%

2) DMSO, (ClCO)2, Et3N, CH2Cl2O

O

OTBSH

H

OEE

25

35

12

OTBS35

13

I

Total synthesis of amphidinolide F

SO2Ph

OEE OTBS

I14

LHMDS THF HMPA15

OH

H24

+O

TBSO H H

LHMDS, THF, HMPA

-10 oC to rt, 2.5 h, 74%

OTESH

5 6

OPivOTBS

SO2Ph

OEE1514

OTBS

TBSOO

OTESO

H

HHH

OTBS

OTESO

OPiv38

1

14

SO2Ph

OEE1514 LDA, DMPU, THF

TMSOOTMS-50 to -35 oC

PhO2SOEE

1514

O SiMe3 Nu

OTBS

TBSOO

OTESO

H

HHH

1

4+39: 65% (1.8:1 4:39)(94% brsm)

OTBS

TBSOO

OTESO

H

HHH

OTBSOPiv38

1

O

OTBSOPiv

1

OTBS

OEE

OH

1514

TBSO

OTBS

O

OTESO

H

HHH

R

4 R= CH2OPiV (42%)

39 R= CH2OH (23%)

40 R= CHODMSO, (ClCO)2

CH2Cl2, Et3N, 83%

1) LAH, Et2O2) DMSO, (ClCO)2

CH2Cl2, Et3N, 83%40 R CHO

OEE15

O

NaClO2, 2-Me-2-buteneOEE

O

OTBS

TBSOOH

HHH

2,NaH2PO4

.H2Ot-BuOH/H2O, 85% OTBS

TBSOOH

HHH

OTBS

OTESOHH

CHO1 OTBS

OPOHH

CO2H1

4041 P = TES

42 P = HPPTSMeOH

OEE

O

ArCOCl, Et3NPhMe/THFDMAP, 65%

OTBS

TBSOO

OO

H

HHH

24

1Cl Cl

OTBS

OO 1

O

43

Ar =Cl

Over 30 members of the diverse amphidinolide family of biologicallyactive macrolides have been isolated from the dinoflagellate Amphidiniumsp. From this family, amphidinolides C (1–2) and F(3) are among the mostp y p ( ) ( ) gcomplex and densely functionalized members . These natural products 1–3 contain eleven stereogenic centers embedded within a 25-memberedmacrolactone including two trans-disposed tetrahydrofuran ring systems, amacrolactone including two trans disposed tetrahydrofuran ring systems, a1,4-diketone motif, and a highly substituted diene moiety at C9–C11. Inaddition to the sizable structural challenges present in 1–3, thesemacrolides have shown significant cytotoxic activity Consequentlymacrolides have shown significant cytotoxic activity. Consequently,compounds 1–3 have attracted considerable synthetic attention fromnumerous laboratories, including our own. Despite these sizableendeavors neither amphidinolide C nor amphidinolide F have beenendeavors, neither amphidinolide C nor amphidinolide F have beensuccessfully synthesized in the more than 20 years since their isolation. Itshould be noted that the stereochemical assignment of compound 3 isb d l d 1 d i l i f h ibased on analogy to compound 1 and isolation from the same organism.Herein, we disclose the first total synthesis of amphidinolide F (3), and thusconfirm both the absolute and relative stereochemistry of the naturalproduct.

In summary, the total synthesis of amphidinolide F hasbeen accomplished in 34 steps (longest linear sequence)been accomplished in 34 steps (longest linear sequence).Highlights of the synthetic sequence include a silver-catalyzed dihydrofuran formation, use of commonintermediate 7 to access both the C1–C8 and C18–C25fragments, regioselective hydrostannylation of enyne 25,di t l ti dditi f 2 lithi 1 3 di idiasteroselective addition of a 2-lithio-1,3-diene speciesto aldehyde 22, and the sulfone alkylation/oxidativedesulfurization sequence to couple the major subunitsdesulfurization sequence to couple the major subunitsand incorporate the carbonyl moiety at C15.