Biomedical Engineering Reference
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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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