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
