A Concise and Flexible Total Synthesis of (-)- Diazonamide A
Burgett, A.W.G., Li, Q., Wei, Q., Harran, P.G., Angew.Chem. Int.Ed.Eng., 2003, 115, 5111-5116
H2N
HCl
CO2Me
O
N
NH
HO
O
R
N
a
Cl
Br
1) N-Z-[L]-Val-OH,
1-3
then a, pyr
N
H2N
N
Ghosez reagent is a very
mild/ pH neutral method
to form acid chlorides
Cl
2) DDQ
3) HBr, AcOH
CO2Me
O
Cl
R
DDQ oxidation forms intermediate (Yonemistu
oxidation)
COOMe
O
O
HBr
R
O
Cl
NH
N
H
Br
A
4
oNBS
HN
4) TBTU, (iPr)2NEt,
O
OH
N
which forms oxazole after subsequent DDQ
oxidation
How does TBTU look like?
oNBS
HN
N
O
N
H
CO2Me
HO
O
NH
HO
N
Br
NO2
oNBS
S
O O
N
N
N
O
BF4
N
5
5) PhI(OAc)2, LiOAc
What other possible products do you expect?
cationic species in para-position to phenol,
5 membered spiroring formation
Mechanism for desired cyclization:
oNBS
HN
HN
N
O
O
CO2Me
N
H
O
Br
NH
O
B
6) PhSH, Na2CO3
7) Teoc-Cl, K2CO3
8) LiOH, aq. MeOH
9) TBTU, (iPr)2NEt,
6-10
NH2
OAc
NH
OH
H
Teoc N
N
H
O
HCl
10) Ac2O, pyr
HN
N
O
N
H
H
NH
O
O
O
N
H
O
O
11,12
NH
Br
Teoc
11) DDQ, H2O
12) PPh3, (CCl3)2, Et3N
O
TMS
NHTeoc
HN
N
N
O
O
Yonemistu oxidation in water:
H2O
COOMe
O
N
H
O
N
NH
NH
O
and subsequent
oxidation to ketone
Br
OAc
N
N
O
C
O
NH -LiBr
13
H
13) hυ, MeCN/aq. LiOH
O
Br
NH
NH
O
NH
NHTeoc
HN
N
O
N
O
O
O
NH
NH
OH
14-15
14) 4-nitrophenyltriflate, K2CO3
15) Pd(OH)2/C, H2
14-15) 2 step sequence takes of the phenolic -OH
HN
NHTeoc
N
N
O
O
O
NH
NH
O
D
16) diallyldicarbonate, Et3N
then Teoc-Cl
then Pd(PPh3)4, morpholine
17) 2,3,4,5,6,6-hexachloro2,4-cyclohexadien-1-one
18) (Me2N)3SSiMe3F2
19) (S)-α-hydroxy isovaleric acid,
(EtO)2P(O)CN,
N-methylmorpholine
16-19
H
N
HO
O
HN
N
O
N
O
16) selective Alloc protection of indoline,
Teoc protection of indole,
Alloc deprotection of indoline
O
Cl
17) selective chlorination with
Cl
18) TASF is a mild fluoride
source for silyl deprotection
Cl
N
S
N H N
O
Cl
O
NH
NH
Cl
Cl
Me
F
Me Si
F
Me
19) Yamada coupling
O
(-)-Diazonamide A
Cl
Cl
OH
O
P
EtO
CN
OEt
O
O
P
O
OEt
OEt
activated acid can
be attacked