Biomedical Engineering Reference
In-Depth Information
1. F-HPLC demix
2. DDQ (85-96%)
3. TBAF (100%)
4. F-PPh
3
,
F-DIAD
(85-96%)
5. NaOH, MeOH
(80-90%)
OPMB-F
EOMO
EOMO
OTMSE
O
R
1
18 parallel rxns
with
91a-91f
OTMSE
O
92a
, LDA,
91
(60%)
92b
, LDA,
91
, H
2
O
2
(64-85%)
92c
, K
2
CO
3
,
91
(94-100%)
( )
1-2
OMOE
X
OBz
X
OMOE
O
O
92a
(X = Me)
92b
(X = CH
2
SePh)
92c
(X = OH)
93
nine sets of three from
91a-91c
nine singles from
91e-91f
24 compounds
(X = CH or CH
2
)
DMP
O
O
O
EOMO
EOMO
OH
R
1
R
1
R
1
HF
O
O
O
50-70%
( )
1-2
( )
1-2
O
( )
1-2
HO
OMOE
X
OH
OMOE
O
HO
O
80-90%
O
OH
O
O
94
(36 compounds)
95
(24 compounds)
96
(24 compounds)
12 compounds
(X = O)
1. PS-SO
3
H (>90%)
2. PS-IBX (50%)
O
O
OH
OH
R
1
R
1
O
O
HO
O
HO
( )
1-2
HO
OH
N
O
OH
O
R
1
HO
OH
OR
3
O
98
O
OH
101
(R
3
= Me)
102
(R
3
= Bn)
R
1
( )
1-2
HO
OH
HO
O
O
O
97
(12 compounds)
( )
1-2
HO
MeO
X
OH
99
(X = O)
100
(X = OH)
SCHEME 10.22
Synthesis of RAL analogues.
was not confirmed until its total synthesis was accomplished by the Paterson and
Curran groups in 2004 [59]. Further biological testing on the synthetic sample showed
that dictyostatin had equal or better activity against the paclitaxel-resistant cell line
than its open-chain analogue discodermolide, radiolabeled paclitaxel, and epothilone
B. Curran and coworkers modified their total synthesis route (over 20 steps) and
designed a FMS tomake (
)-dictyostatin and three C6 and C7 diastereomers for SAR
studies (Scheme 10.23) [60]. Instead of making those diastereomers in four parallel
multistep syntheses, FMS was able to produce those compounds in a single set. This
is a good example of FMS making complex molecules and analogues without a
proportional increase in work. Hence, at the premix stage, a set of four enantiopure
alcohols with chiral centers at C6 and C7 were individually tagged with a set of four
fluorous TIPS-type silanes containing C
3
F
7
,C
4
F
9
,C
6
F
13
, and C
8
F
17
tags, respec-
tively. The coded alcohols were then converted to fluorous esters
103a-103d
. These
four esters were blended in a ratio of 1.5:1:1:1.5 and then the resulting mixture
M-
103a-
M-
103d
was converted to M-
104
in three steps of FMS. The products from
these reaction mixtures were purified by standard flash chromatography without
demixing. M-
104
was coupled with alkynyllithium and then reduced by the
(
S
,
S
)-Noyori catalyst to afford M-
105
. The alkyne group of M-
105
was then reduced
to the
cis
-alkene by Lindlar hydrogenation and the resulting secondary hydroxy group
was protected with a TBS group. The cleavage of the TES group with dichloroacetic
acid gave M-
106
. Dess-Martin oxidation of the primary alcohol followed by HWE
coupling with
107
gave the
a
,
b
-unsaturated ketone. The reduction of C17-C18 alkene
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