Literature PresentationIevgeniia Kovalova

16. 06. 2016

TotalSynthesisandStereochemical AssignmentofCallyspongiolide

ZhouJ.,GaoB.,Xu Zh.,Ye T.J.Am.Chem.Soc., 2016, 138 (22),pp6948–6951

OOONH2

O

Br

HO

OH

2

Isolationandbiologicalactivity

[Picture]https://commons.wikimedia.org/wiki/File:Callyspongia_sp._(Tube_sponge).jpgPham,C.-D.;Hartmann,R.;Bohler,P.;Stork,B.;Wesselborg,S.;Lin,W.;Lai,D.;Proksch,P.Org.Lett.2014,16,266.

Callysongiolidewas isolated from the marine sponge Callyspongia sp. collectedin Indonesia.

OOONH2

O

Br

HO

OH

Callyspongiolide showed strong in vitro cytotoxicity against human Jurkat J16 T(IC50=70 nM) and Ramos B (IC50=60 nM) lymphocytes.

3

RetrosyntheticAnalysisofCallyspongiolide (1)

OOONH2

O

13

1

35

30

9

31

33

7

Br

HO

OH15

1721

27

25

32

Sonogashiracross-coupling

OOHO

I

1

2

+

Br

HO

OTES

3

Br

OTBS

Kiyooka Aldol reaction

Yamaguchiesterification

OH

Br

O

5

OHTBSOO

OH

I

Kociencki-Juliaolefination

Still-Gennariolefination

4

NN N

NPh

SOO

I

OPMB

+

OHTBSO

OTBS

6 7

Krischeallylation

HO OPMB TBSO O

8 9

4

SynthesisofFagment 6

Hassan,A.;Lu,Y.;Krische,M.Org.Lett.2009,11,3112

OH

OPMB OPMB

HO

Cs2CO3 (60 mol%), m-ClBzOH (10moi%),H2O (200 mol %),THF (0.4 M)100˚C, 20h

8 11

Krische olefinationDDQ, DCM

OH

HO

11-1

TBSOTf,THF

OTBS

TBSO

11-2

9-BBN, THF

OTBS

TBSO

12

OHNaClO, TEMPONaClO2, MeCN/Buffer

OTBS

TBSO

12-1

OH

O

nBuLi,THF, -78˚C

OHN

O

Bn

OTBS

TBSO

13

O

ON

O

BnOTBS

TBSO

13-1

O

ON

O

Bn

NaHMDSMeI, THF

-78˚C

LiBH4, THF

OTBS

TBSO

6

OH

O Ir

O

NO2

Cl

PPPh

Ph

OO

OO

(5 mol%)OAc

(200 mol%)

PivCl, Et3N

5

SynthesisofFragment7

OTBS

O

9

TMS+

Ti(PrO)4, (s)-BINOLEt2Zn, Et2O

80% TBSO

14

OH

TMS PMBBr, NaH, THFthen K2CO3, MeOH

TBSO

15

OPMB

Pd(PPh3)4, Bu3SnHthen I2

TBSO

16

OPMB

I

TBAF, THF

OH

16-1

OPMB

I

N NNN

SH

Ph

PPh3, DEAD, THF

16-1

OPMB

I

S

NN

NN

Ph

(NH4)2Mo7O24, H2O2EtOH

7

OPMB

I

S

NN

NN

Ph

O O

73% 77%

6

SynthesisofMacrolactone 2

OTBS

TBSO

6

OHDMP, NaHCO3

94% OTBS

TBSO

19

O7

OPMB

I

S

NN

NN

Ph

O O

LiHMDS, -78˚CHMPA/THF

OTBS

TBSO

20

OPMB

IE/Z=6:1

CSA, MeOH

OH

TBSO

21

OPMB

IE/Z=6:1

1. DMP, NaHCO3,2. KHMDS, THF

OMe

O PO OCH2CF3

OCH2CF322

OPMBTBSOO

O

IE/Z=6:1

23

DDQ, DCMOHTBSOO

O

I

24

LiOH, THF

OHTBSOO

OH

I

4

Cl

Cl Cl

Cl

O

1. 2,4,6-trichlorobenzoyl chloride Et3N, DMAP, toluene2. CSA,MeOH

OOHO

I

2

7

SynthesisofFragment3

OTMS

OMe25

O

5

Br

HO

TBSCl, DCM

O

5-1

Br

TBSO

N-Tos-D-Valine, BH3*THF, 25

OH

26

Br

TBSO

MeO2C 1. TESOTf, Et3N2. DIBALH,DCM

OTES

27

Br

TBSO

HO

OTES

28

Br

HO

1. DMP, DCM2. CrCl2, CHI3, THFthen K2CO3, MeOHI

1.Pd(PPh3)4, CuI THFthen K2CO3, MeO

TMSOTES

3

Br

TBSO2. TBSCl, imid

8

SynthesisofCallyspongiolide 1a

OOHO

I

2

OTES

3

Br

TBSO

+

Pd(PPh3)4, CuIEt3N, THF

OOHO

OTES

Br

TBSO

29

1. Cl3CC(O)NCO, DCM, K2CO3, MeOH2. TASF, THF

OOO

OH

Br

HOO

NH2Callyspongiolide 1a

9

SynthesisofCallyspongiolide 1b

OOHO

I

2

OTES

ent-3

Br

TBSO

+

OOO

OH

Br

HOO

NH2Callyspongiolide 1b

(synthetic procedure as for 3, butusing L- instead of D-valine)

10

SynthesisofCallyspongiolide 1canditsEpimer 1d

dwcdcwdvwdv

OTES

ent-3

Br

TBSO

OTES

3

Br

TBSO

OOHO

I

ent-2

OOO

OH

Br

HOO

NH2Callyspongiolide 1c

OOO

OH

Br

HOO

NH2Callyspongiolide 1d

11

Conclusion

• FirsttotalsynthesisofCallyspongiolide andthreeadditionalstereoisomershadmade.

• Establishedtherelativestereochemistryaswellastheabsoluteconfigurationofthenaturalproduct.

• Evaluationofbiologicalactivityagainstdifferenttypesofcancercellsdisplayedinhibitory activities.

Thankyouforyourattention!

12

Krische allylation

13

Krische allylation

14

Preparationoftheknownalcohol8

Fujiwara,K.;Naka,J.;Katagiri,T.;Sato,D.;Kawai,H.;Suzuki,T.Bull.Chem.Soc.Jpn.2007,80,1173

15

Preparationoftheknownaldehyde9

16

Kiyooka aldolreaction