FLUOROUS LINKER-FACILITATED SYNTHESIS OF BIOLOGICALLY INTERESTING MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 351

R 2

CO 2 Et

H

H

O * *

O

*
*

O

N

O H

O O

N

H N

N

R 1

H

O NH

Me

N

Me

Br

H

OMe

O

114 115

116

FIGURE 10.4 Hydanto-infusedhexahydrochromeno[4,3- b ]pyrrole 114 and related biologi-
cal active compounds.

These four compounds were assayed against human ovarian carcinoma cells in
order to evaluate their antiproliferative activity. The bis- epi diastereomer (6 S ,7 R )- 111
was found to be less active than the other isomers, while the monoepimer (6 R ,7 R )- 112
was equipotent to dictyostatin and another monoepimer (6 S ,7 S )- 113 was found to be
four times more potent.
In medicinal chemistry programs involving QSAR studies, preparation of
diastereomers of hit or lead compounds is equally important as generating structural
analogues. Unfortunately, diastereomers are usually prepared in parallel and
handled individually from start to finish. Mixture synthesis of diastereomeric
products is possible in principle because the final isomers can often be separated
by prep-LC; however, it is unclear how to purify diastereomeric intermediates
without separating them from each other during the synthesis of intermediates.
Zhang and coworkers introduced fluorous diasteoremeric mixture synthesis
(FDMS) to address this problem. Diastereomers bearing the same fluorous linker
could be collected in a single fraction by fluorous F-SPE. The fluorousmixture could
then be treated as a single component inmultistep sequences and purifications. After
the fluorous linker cleavage, the final products are separated by prep-LC to provide
individual isomers.
The principle of FDMS has been demonstrated in the synthesis of hydantoin-
fused hexahydrochromeno[4,3- b ]pyrrole 114 (Figure 10.4) [61]. This compound has
four stereogenic centers on the central pyrrolidine ring that might lead to the
formation of many diastereoisomers. The hexahydrochromeno[4,3- b ]pyrrole moiety
of 114 is related to hexahydrochromeno[4,3- b ]pyrrole 115 , which is as potent as
physostigmine against human acetylcholinesterase and butyrylcholinesterase for the
potential treatment of Alzheimer diseases [62]. Compound 114 is also related to
tricyclic thrombin inhibitors 116 [40].
The synthetic route for hydantoin-fused hexahydrochromeno[4,3- b ]pyrrole
114 is highlighted in Scheme 10.24. The first step was an intramolecular [3 2]

cycloadition of 117 with fluorous L -alanine ester 118 . Hence, by heating at 150 C for
20min under microwave irradiationwithout using silver salts, the cycloaddition led to
the formation of diasteromers 119a-119d . Since all the diastereomers bore the same
fluorous linker, they were easily isolated by F-SPE as a mixture of diastereomers.
The purified mixture was then reacted with an isocyanate to form a diastereomeric
mixture of ureas 120a-120d . The last step involved a one-pot two-step sequence that
included the linker cleavage and the cyclization. A total of eight diasteromers were
detected by HPLC. Six of them were successfully isolated by C18 reverse-phased
prep-LC (Figure 10.5). Their structures were assigned by 2DNMR analysis andX-ray
crystal structure of 114a .

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