batzelladine
13
E n a n i o s e l e c t i v e T o t a l S y n t h s i s o f B a t z e l l a d i n e A N N H N H H H O (CH 2 ) 8 Me Me O N NH O O N H NH 2 NH 2 NH 2 1 6 9 13 23 30 32 Shim okaw a,J.;Shirai,K.;Tanatani,A.;H ashim oto Y.;N agasaw a,K. Angew. Chem. Int. Ed. 2004 , 43,1559
-
Upload
broccolikim -
Category
Documents
-
view
30 -
download
0
Transcript of batzelladine
Enanioselective Total Synthsis of Batzelladine A
N
NH
NH
H H
O
(CH2)8MeMe
O
N NH
O ONH
NH2
NH2
NH2
1
69 13
2330
32
Shimokawa, J.; Shirai, K.; Tanatani, A.; Hashimoto Y.; Nagasawa, K. Angew. Chem. Int. Ed. 2004, 43, 1559
Natural Guanidine Derivatives
O CO2HHO
HHO
HN
Me OHN
NH
NH2
HO
4-guanidino-Neu5Ac2en (GG167)
The most potent influenza virus sialidase inhibitors
New Methods of guanidine synthesis continue to be developed.
For review: Berlinck, R. G. S. Nat. Prod. Rep., 1999, 16, 339
Natural Guanidine from Marine Sponges
N
NH
NH
H H
O
(CH2)8MeMe
O
N NH
O ONH
NH2
NH2
NH2
N
NH
NH
H H
O
(CH2)8MeMe
OHNH2N
NH2
N
NH
NH
H H
O
OHNH2N
NH2
3X
2X
Me
Me
Batzelladine A-E:
A
2X
D
E
Polyguanidine alkaloids isolated fromCaribbean sponge Batzella sp.
Inhibit the binding of the HIV glycoprotein gp120 to the Human CD4 receptor
Natural Guanidine from Marine Sponges
Batzelladine F-I: Polyguanidine alkaloids isolated fromCaribbean sponge Batzella sp.
N
NH
NH
H H
O
(CH2)6MeMe
O
3X
F
N
NH
NH
H H
N
NH
NH
H H
O
(CH2)6MeMe
O
3X
G
N
NH
N
H H
OH
Induce dissociation of proten tyrosine kinase p561ck from CD4
N
NH
NH
H H
O
(CH2)8MeMe
OHNH2N
NH2
2X
Total Synthesis of Batzelladine D
N
NH
NH-Cbz
H H
O
Me
OHNH2N
NH2
R
OH
N
NH
NH-Cbz
H H
HO
Me
O
R
OH
N
O R
CO2R'
Me
N
NH
NH
H H
HO
(CH2)8MeMe
O
2X
OH
HNH2N
NH2
Ngasawa, K. and coworkers Org. Lett. 2002, 4, 2921
N
O
N
O
H
(CH2)8Me
C9H19
Tol., 100°C95%
N
H
O (CH2)8MeHO
mCPBA
N
H
(CH2)8MeHO
O
HEtO2C
Me
MeCO2Me tol. 100 °C
62% (two steps)
NH
H
(CH2)8MeTBSO
H
Me
TBSO
HO
1. LAH, 0 °C2. TBSCl3. H2, Pd/C, rt
SMe
CbzN NHCbz
N
H
(CH2)8Me
H
Me
TBSO
HOOTBS
HN N
Cbz Cbz
HgCl2, Et3NDMF, 0 °C, 84%
N
H
(CH2)8Me
HHO2C
OTBS
N N
CbzCbz
Me
1. DEAD, PPh32. TBAF, 0 °C
3, Jones reagent
Synthesis of of Bicyclic Guanidinecarboxylic acid
N
H
(CH2)8Me
HHO2C
OTBS
N N
CbzCbz
Me
NBoc
BocHNHN
OH
EDCl, DMAP
N
H
(CH2)8Me
H
OTBS
N N
CbzCbz
Me
O
OHNBocHN
NBoc
N
NH
NH
H H
O
(CH2)8MeMe
OHNH2N
NH2
2X
4 steps
Formation of Esters Linkage and Completion
Enantioselective Total Synthesis of Batzelladine A
N
NH
NH
H H
O
(CH2)8MeMe
O
N NH
O ONH
NH2
NH2
NH2
1
69 13
2330
32
N
H
(CH2)8Me
H
OTBS
N N
CbzCbz
Me
O
HOOH
N NBoc
O ONH
NHBoc
NHBoc
NHBoc
7
OMPM
N NBoc
O OMe
NHBoc
7OMPM
N NBoc
NHBoc
7
H
OH
N
O
OTIPS
N O
PriO2C
PriO2C
TIPSO CO2iPR
CO2iPr N
TIPSO CO2iPR
OH
O
H
OH N O
TIPSO
H
H
OH N
HTIPSOOH
Goti, A.; Cacciarini, M.; Cardona, F.; Brandi, A. Tetrahedron Lett. 1999, 40, 2853
Mo(CO)6CH3CN, H20reflux, 18 h
; SiO2
1. MsCl2. H2, Pd/C
C6H6, rt
C6H6, rt
Synthesis of the Optically ActiveBicyclic Guanidinecarboxylic acid
N
O
N
O
H
H(CH2)8Me
C9H19
N
H
(CH2)8MeHO
O
HEtO2C
Me
N
H
(CH2)8Me
HHO2C
OTBS
N N
CbzCbz
Me
OTIPSOH
1.
2. CsF, EtOH 74%
1. ClC(S)OPh2. nBuSnH AIBN
51%N
O
H
H(CH2)8Me
N
H
O (CH2)8MeHO
mCPBA
MeCO2Me
tol. 100 °C62% (two steps)
steps
Synthesis of the Left Bicyclic Fragment OMPM
N NBoc
O OMe
NHBoc
7
N
TIPSO
O
EtO2C OMPM7
+ N O
HTIPSO CO2EtH
OMPM
tol. 90 °C
N O
HHOH
OMPM
OH1. LAH, 0 °C2. CsF, 90 °
59% (three steps) 1. TBSCl2. ClC(S)OPh3. nBu3SnH AIBN
44%
N O
HH
OMPM
OTBS
N
HOTBS
OMPM
NBoc
NHBoc
OH
7
1. H2, Pd/C2. SMe
BocN NBoc
HgCl2, NEt371%
OMPM
N NBoc
NHBoc
7
H
OH
1. PPh3, DEAD tol.2. TBAF
81%
OPMB
N NBoc
NHBoc
7
H
OH
Synthesis of the Left Bicyclic Fragment
OPMB
N NBoc
NHBoc
7
OH
TPAP, MNO
N NBoc
NHBoc
O
OPMB
N NBoc
NHBoc
7
OMeO
1. NaClO22TMSCHN2
58%
NBoc
BocHN NH
OH
OPMB
N NBoc
NHBoc
7
OHO
nPrSLi
OH
N NBoc
NHBoc
7
OONH
BocHN
NBoc
1. BOPCl2. DDQ
N
H
(CH2)8Me
HHO2C
OTBS
N N
CbzCbz
MeOH
N NBoc
NHBoc
7
OONH
BocHN
NBoc
N
N N
H H
O
(CH2)8MeMe
O
N NH
O ONH
NHBoc
NHBoc
NHBoc CbzCbz
OH
+
1. ECCl, DMAP2. HF, Py
N
NH
NH
H H
O
(CH2)8MeMe
O
N NH
O ONH
NH2
NH2
NH2
1. H2, Pd/C2. PPh3, DEAD3. TFA
24%
48%
Formation of Esters Linkage and Completion
![Diastereoselective [4 + 2] Annulation of Vinyl Carbodiimides with N-Alkyl Imines. Asymmetric Synthetic Access to the Batzelladine Alkaloids.](https://static.fdocuments.us/doc/165x107/575003ab1a28ab11489a7273/diastereoselective-4-2-annulation-of-vinyl-carbodiimides-with-n-alkyl-imines.jpg)
![Corrigendum to “Stereoselective construction of the azabicyclic core applicable to the biologically important polyguanidinium alkaloids batzelladine A and D using a free radical cyclization”: [Tetrahedron Lett. 42 (2001) 6637]](https://static.fdocuments.us/doc/165x107/575020731a28ab877e9ad498/corrigendum-to-stereoselective-construction-of-the-azabicyclic-core-applicable.jpg)
