Total Synthesis of Isokindamycin
B. Michael O´Keefe, Douglas M. Mans, David E. Kaelin, Jr, Stephan F. Martin J. Am. Chem. Soc. ASAP
M. M. Baag
O O
O O
O OH Me
HO Me
2N
H
OH
NMe
2R
Kidamycin (1): R = H Isokindamycin (2): R = H
2.11.2010
AcO O AcO
OAc
O AcO
N3
H O j) BnBr, NaH, DMF k) LiAlH4, Et2O l) Boc2O, CH2Cl2 m) MeI, NaH, DMF 90% (4 steps)
s-BuLi, THF, -78 - -50 oC chlorodimethylvinylsilane
-78 oC, 82%
9-BBN, THF, H2O2 NaOH, 84%
O BnO
H O
NMeBoc Si
OH a) NaOMe, MeOH
b) TsCl, Et3N, DMAP c) Ac2O
d) NaI e) Bu3SnH 51% (5 steps)
f) H2O, 80 oC then
NaN3, AcOH, 24 h 93%
g) Ac2O, py, CH2Cl2 95%
3
6
9 h)
i)
4 5
7
8
Si O O
O Br
Br
OBn
NMeBoc OMe BnO
OH H O Si
O Br
Br
OBn
NMeBoc OMe BnO
H OH
+ OTMS
O
O +
rt, 18 h CH2Cl2
O
O
OH PCC, CH2Cl2 rt, 8 h 30-50%
from diene 10
10 11 12 13
OH
OMe OBn
Br d) Na2S2O4, CH2Cl2
Et3N, H2O; Me3OBF4 proton sponge
Br
4 A molecular sieves CH2Cl2, 90%
o
c) PyHBr3, CH2Cl2 0 oC, 90%
14 15 16
9 16 17
a)
b)
OBn O
O OMe H
OBn
NMeBoc Si
O
TBAF-
3H
2O, DMF, 70
oC MeI, NaH, 0
oC, 85%
OBn OMe
O OMe H
OBn
NHMe
a) formalin, NaBH(OAc)
3, DCE, 95%
b) TIPSOTf, 2,6-lutidine, CH
2Cl
2, 80%
c) H
2, Pd(OH)
2/C (20 mol %), pyridine MeOH, EtOAc, 90%
d) NBS, CH
2Cl
2, -78
oC - rt, 77%
e) MOMCl, NaH, THF, 89%
OH
OMOM OMe
O OMe H
OBn
NMe
2TIPSO O
17
18
20
23
19
21
f)
g)
a) Cbz-O-Succinimide, NaHCO
3dioxane, H
2O
b) HCl, MeOH, 89%
O AcO
NHCbz OAc Vancomycin (24)
25
26 c)
d)
a) Et2NH, EtOH, > 99%
b) LiBF4, 5% aq. MeCN 82 oC, µµµW, 15 min;µ TBAF, THF, 0 oC, 50%
OMe
O OMe H
OBn
NMe2
OAc O
O AcO O
NHCbz H
O
O O H
OH
NMe2
OH O
O HO O
Me2N
H 23
27
28
2 c)
d)
e)
f) g)
