Biomedical Engineering Reference
In-Depth Information
TBSO
OTES
N
CO
2
Et
3 steps
7
N
OTf
MeO
6
MeO
1.
n
-BuLi
O
O-F-TIPS
O
O-F-TIPS
2. (
S,S
)-Noyori cat.
M
-103
M
-104
-PrOH
94%
i
F-TIPS = Si (
i
-Pr)
2
CH
2
CH
2
Rf
a
(6
R
,7
S
), Rf = C
3
F
7
b
(6
S
,7
R
), Rf = C
4
F
9
c
(6
S
,7
S
), Rf = C
6
F
13
d
(6
R
,7
R
), Rf = C
3
F
17
1. Dess-Martin
2. Ba(OH)
2
MeO
O
P
O
OTES
MeO
OH
107
1. H
2
, Lindlar (99%)
2. TBSOTf, 2,6-lutidine (96%
)
3. Cl
2
CHCO
2
H (90%)
TBSO
TBSO
OPMB
82%, 2 steps
3. [PPh
3
CuH]
6
(96%)
4. LiAl(O
OTf
OTf
i
-Bu)
3
H
OH O-F-TIPS
O-F-TIPS
TBSO
M
-105
M
-106
TBS
1. DDQ (91%)
2. KOH
3. Yamaguchi
(59%, 2 steps)
4. demix
5. 3 N HCl
MeOH, THF
OH
O
1. TBSOTf, Et
3
N
(100%)
2. ZnBr
2
(93%)
3. Dess-Martin
4. Still-Gennari
(80%, 2 steps)
TBSO
TBSO
OPMB
PMBO
CO
2
Me
OTf
TBSO
O-F-TIPS
O-F-TIPS
TBSO
M
-108
( -OH, 10%)
( -OH, 45%)
M
-109
OH
)-
110
, Dictyostain (40%)
Ts
(6
R
,7
S
HO
Ph
N
)-
111
, 6,7-
bis-epi-
Dictyostain (8%)
(6
S
,7
R
Ru
O
O
N
Ph
)-
112
, 6-
epi
-Dictyostain (22%)
(6
S
,7
S
Ts
)-
113
, 7-
epi
-Dictyostain (29%)
(6
R
,7
R
(
S,
S)-Noyori cat.
OH
OH
GI
50
of 4 diastereomers in 1A9/Ptx22 human ovarian carcinoma cells
Compounds
GI
50
(nM)
)-
110
(Dictyostain)
(6
R
,7
S
3.4 ± 0.7
123 ± 25
0.81 ± 0.17
4.7 ± 0.6
(6
S
,7
R
)-
111
(6
S
,7
S
)-
112
(6
R
,7
R
)-
113
SCHEME 10.23
FMS of (
)-dictyostatin and three stereoisomers [1].
with Stryker's reagent followed by the reduction of C19 ketone with LiAl(O
t
-Bu)
3
H
gave
-alcohol M-
108
as the major product, which was isolated by silica gel
chromatography conducted on the mixture. TBS protection of the C19 hydroxy
group, removal of the trityl group with ZnBr
2
, oxidation of the allylic alcohol with
the Dess-Martin reagent, and then Still-Gennari reaction provided (
E
,
Z
)-diene M-
109
. The removal of the PMB group with DDQ and basic hydrolysis of the
conjugated ester followed by macrolactonization under Yamaguchi conditions gave
a mixture of major (2
Z
,4
E
)- andminor (2
E
,4
E
)-macrolactones. Demixing of the final
mixture was accomplished by a preparative F-HPLC to provide the four individual
components that were desilylated with 3N HCl in MeOH to afford, after HPLC
purification, dictyostatin (6
R
,7
S
)-
110
and the other three C6,C7-
epi
-dictyostatin
diastereomers.
b
Search WWH ::
Custom Search