Biomedical Engineering Reference
In-Depth Information
C
8
F
17
-PMBO
R
1
F-PMBO
1. BzCl (90%)
2. TBAF (86-94%)
3. H
2
, Pd/CaCO
3
(90-96%)
4. PPh
3
, I
2
(70-93%)
F-PMBO
R
1
n-
BuLi
C
4
F
9
-PMBO
TBDPSO
I
( )
1-2
3 parallel
rxns with
89a-89c
80%
( )
1-2
OBz
OH
C
6
F
13
-PMBO
OO
O
O
OEOM
90a-90c
91a-91c
3 sets of 3 compounds
88a-88c
Set of 3 compounds
3 sets of 3 compounds
C
6
F
13
-PMBO
C
6
F
13
-PMBO
1. BzCl (90%)
2. TBAF (86-
9
4%)
3. PPh
3
, I
2
(70-93%)
TBDPSO
I
( )
1-2
t-
BuLi
( )
1-2
C
6
F
13
-PMBO
OH
OBz
I
3 parallel
rxns with
89a-89c
>80%
OO
OO
89d
90d-90f
3 sets of compounds
91d-91f
3 sets of compounds
NH
CCl
3
CHO
CHO
CHO
TBDPSO
TBDPSO
TBDPSO
O
O
O
O
O
O
O
EOMO
C
n
F
2n+1
O
87
89a
89b
89c
F-PMB-trichloroacetimidate
SCHEME 10.21
Synthesis of four F-PMB attached compounds
91a-91f
.
alcohols was attached to a different
p
-methoxybenzyl linker by reacting with F-PMB-
trichloroacetimidates
87
to form
88a-88c
(Scheme 10.21). The equimolar mixture of
88a-88c
was split into three portions and each reacted with one of the three aldehydes
89a-89c
to afford three mixtures of
90a-90c
. After sequential hydroxyl group
protection, TBDPS deprotection, and iodination, compounds
90a-90c
were con-
verted into three mixtures of
91a-91c,
each containing three components. Through
a similar pathway, compound
88d
reacted with aldehydes
89a-89c
to afford
compounds
91d-91f
.
The second stage of FMS involved the reaction of three compounds of
92a-92c
with each of the six compounds of
91a-91f
to afford compounds
93
(Scheme 10.22).
Among the 18 pools of
93
, nine are three-component mixtures generated from
91a-91c
and nine are single compounds generated from
91d-91f.
At this point, those
nine three-component mixtures were demixed on HPLC with a fluorous column to
afford 27 individual compounds of
93
. These 27 compounds and another nine
compounds of
93
generated from
91e-91f
were treated with DDQ and TBAF to
remove both the fluorous linker and the TMSE group. The macrocyclization reactions
were promoted by the Mitsunobu reactions using fluorous PPh
3
and DIAD. The
fluorous derivatives were easily removed from the reaction mixture by F-SPE.
Treatment with NaOH removed the Bz group to afford a total of 36 macrocyclic
compounds
94
. Among them, 24 (X
CH or CH
2
) were treated with DMP to form
95,
and then by HF to afford compounds
96
. Another 12 of
94
were treated with PS-SO
3
H
and PS-IBX to afford products
97
. Compounds
96
and
97
were converted to
98-102
through simple transformations to afford a total of 51 macrocyclic compounds.
(
ΒΌ
)-Dictyostatin is a marine macrolactone that has potent anticancer activity.
While this compound has been known for over a decade, its absolute configuration
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