Fluorous diastereomeric mixture synthesis (FDMS) of hydantoin-fused hexahydrochromeno[4,3-b]pyrroles

Article abstract of DOI:10.1039/c0cc01967d

Fluorous diastereomeric mixture synthesis (FDMS) is introduced and demonstrated in the synthesis of six diastereomers of hydantoin-fused hexahydrochromeno[4,3-b]pyrroles.

Full text of DOI:10.1039/c0cc01967d

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Fluorous diastereomeric mixture synthesis (FDMS) of hydantoin-fused
hexahydrochromeno[4,3-b]pyrroleswz
Yimin Lu,a Steven J. Geib,b Krishnan Damodaran,b Bin Sui,b Zijuan Zhang,c
Dennis P. Curranb and Wei Zhang*c
Received 19th June 2010, Accepted 1st September 2010
DOI: 10.1039/c0cc01967d
Fluorous diastereomeric mixture synthesis (FDMS) is intro-
duced and demonstrated in the synthesis of six diastereomers
of hydantoin-fused hexahydrochromeno[4,3-b]pyrroles.
experiment of FDMS. This compound has four stereogenic
centres on the central pyrrolidine ring which could have many
diastereomers. The hexahydrochromeno[4,3-b]pyrrole moiety
in 1 can be found in compound 2 which is as potent as
physostigmine against human acetylcholinesterase and butyryl-
cholinesterase for potential treatment of Alzheimer’s disease.12
Compound 1 is also related to tricyclic thrombin inhibitor 3.13
Since it was introduced by the Curran group in 2001, fluorous
mixture synthesis (FMS)1 has become a powerful tool
for solution-phase synthesis of natural product analogs,2
diastereomers,3 enantiomers4 as well as drug-like compound
libraries,5 glycosides,6 oligomers,7 and dendrimers.8 FMS
requires a set of different length fluorous tags to be attached
to a set of analogous reactants and relies on fluorous liquid
chromatography (LC) to separate the mixture. In the fluorous
racemic mixture synthesis (FRMS) developed by the Mikami
group, two enantiomers are attached to a single fluorous tag
and chiral LC is used to separate the racemic mixture.9
Introduced in this paper is fluorous diastereomeric mixture
synthesis (FDMS) which employs a single fluorous tag to
attach to diastereomers. The diastereomeric intermediates
are isolated from the reaction mixture by fluorous solid-phase
extraction (F-SPE). The tag-cleaved diastereomeric products
are separated by reverse-phase LC instead of fluorous or
chiral LC.
A stereoselective solution-phase synthesis of hydantoin-
fused hexahydrochromeno[4,3-b]pyrrole 8 has been developed
by the Kurth group (Scheme 2).14 It has the following three
steps: (1) AgOAc-promoted intramolecular 1,3-dipolar cyclo-
addition of 4 with 5 to form hexahydrochromeno[4,3-b]pyrrole
6 as a single trans-fused compound;15 (2) reaction of 6 with an
isocyanate to form urea 7; and (3) cyclization of 7 to form 8 as
a single diastereomer or a pair of epimers.
In diversity-oriented synthesis, generation of stereoisomers
is equally important to skeleton and substitution variations.10
Preparation of diastereomers for QSAR studies is one of
the major tasks in medicinal and agricultural chemistries.
Traditionally, diastereomers are prepared in parallel and
handled individually from start to finish. Mixture synthesis of
diastereomeric products is possible in principle since the final
product isomers can often be separated by prep-LC; however, it
is unclear how to purify diastereomeric intermediates without
separating them from each other. FDMS addresses this problem
by collecting all the fluorous intermediates in a single F-SPE
fraction.11 The diastereomeric mixture can be treated as a single
component in the multistep synthesis (Scheme 1).
In order to generate more stereoisomers, we made the
following two modifications to Kurth’s route: (1) The 1,3-dipolar
cycloaddition of 9 and fluorous L-alanine ester 10 was carried
out under microwave heating without using a metal salt. It is
known in the literature that both metal-free and microwave
heating generate cis- and trans-fused cycloaddition products.16,17
(2) We used alanine ester 10 to afford cycloaddition products
with an additional steric variation at the pyrrolidine 2-position
(Scheme 3). The LC-MS analysis of the reaction mixture gave
four major peaks in a ratio of 9 : 4 : 59 : 28 together with a
minor peak (less than 1%) which could be an epimer of one of
the four major components. The reaction mixture was loaded
directly onto an F-SPE cartridge and eluted with 80 : 20
MeOH–H2O to remove all the non-fluorous components and
then eluted with MeOH to collect the mixture of 11a–d in a
single fraction.11,18
Hydantoin-fused hexahydrochromeno[4,3-b]pyrrole 1 was
selected as the target molecule for the proof-of-principle
a Fluorous Technologies, Inc., UPARC, 970 William Pitt Way,
Pittsburgh, Pennsylvania 15238, USA
b Department of Chemistry, University of Pittsburgh, Pittsburgh,
Pennsylvania 15260, USA
c Department of Chemistry, University of Massachusetts Boston,
100 Morrissey Boulevard, Boston, MA 02125, USA.
E-mail: wei2.zhang@umb.edu
w This publication is part of the web themed issue on fluorine
chemistry.
z Electronic supplementary information (ESI) available: Experimental
details. CCDC 781897. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0cc01967d
Scheme 1 FDMS (diastereomers are shown in different colours).
c
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Scheme 2 Kurth’s route for diastereoselective synthesis.
Scheme 3 Formation of four diastereomers of 11.
The mixture of compounds 11a–d was reacted with an
isocyanate to form ureas 12a–d (Scheme 4). No new diastereomers
were generated at this step. After F-SPE purification, the
mixture of 12a–d was subjected to K2CO3-promoted cyclization
to cleave the fluorous tag and form the hydantoin ring. A total of
eight diastereomers were detected by LC-MS. Among them, six
diastereomers (1a : 1b : 1c : 1d : 1a0 : 1d0 = 24 : 39 : 19 : 4 : 4 : 10)
were separated by prep-scale reverse-phase LC in a combined
yield of 53%. Compounds 1b0 and 1c0 were present in trace
amounts and could not be isolated.
Scheme 4 Formation of eight diastereomers of 1.
The structures of six isolated diastereomers were established
by analysis of a battery of 1H NMR spectra. From the 1D
spectra, the compounds were classed into two groups of three
with either a cis (J2,7 = 6–8 Hz) or trans (J2,7 = 12 Hz)
hexahydrochromeno[4,3-b]pyrrole ring fusion. From there,
analysis of the 2D-NOE spectra provided the assignments of
the remaining stereocenters. To support this spectroscopic
analysis, a single crystal of 1a was obtained for X-ray crystal
structure analysis to confirm that it is the cis–anti–trans isomer
(Fig. 1). Diastereomers 1a–d are the expected products.
Diastereomers 1a0 and 1d0 in small amounts (4% and 10%)
were generated by the epimerization of the ester group at the
1
Fig. 1 X-ray structure and H NMR (NOESY) of 1a.19
3-position of the pyrrolidine. Compound 1a0 is the epimer of
1a and compound 1d0 is the epimer of 1d. Another two
c
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Notes and references
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Fig. 2 TLC of crude compounds 11 and 13. Left, on normal silica gel
developed with 2 : 1 hexanes-EtOAc; right, on fluorous silica gel
developed with 4 : 1 MeOH–H2O. aCrude sample containing unreacted
compound 9.
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due to the very small amount could be 1b0 and 1c0 which are
the epimers of 1b and 1c, respectively.
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hydantoin formation step, a major 1,3-dipolar cycloaddition
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urea compound 12a was formed, but two hydantoin-fused
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a non-fluorous
diastereomeric mixture 13 prepared by the reaction of 9 and
L-alanine methyl ester was tested side-by-side with fluorous
diastereomeric mixture 11 on normal and fluorous TLC plates,
respectively (Fig. 2). On the normal silica gel, crude reaction
mixtures 11 and 13 both gave tailed spots because the
diastereomers in each mixture have slightly different polarities.
Compounds 11 and 13 could not be separated from unreacted
compound 9. However, on the fluorous TLC, crude sample 11
gave a spot at the baseline and it was well-separated from 9.
Because it is a fluorous tag-based separation, diastereomers
bearing the same tag should have the same retention on
fluorous TLC. On the other hand, crude sample 13 had almost
no retention on fluorous TLC and gave a mixture spot close
to the solvent front. This TLC experiment explains why
fluorous-tagged diastereomeric mixture 11 can be collected
as a single fraction and separated from non-fluorous component
9 by F-SPE.
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In summary, FDMS is developed as a new solution-phase
method for the synthesis of diastereomeric products. The
mixture of fluorous-tagged diastereomeric intermediates could
be easily isolated by F-SPE without separation from each
other, which overcomes the major separation issue and
increases the efficiency of mixture synthesis of diastereomers.
In this project, eight possible diastereomers of hydantoin-fused
hexahydrochromeno[4,3-b]pyrroles were synthesized by FDMS
and six of them were isolated for structure characterizations.
Use of FDMS to prepare compound libraries with substitution,
skeleton, and stereochemistry diversities is in progress and will
be reported in due course.
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18 (a) Fluorous media available from Fluorous Technologies, Inc;
(b) WZ and DPC hold an equity interest in this company.
19 Crystal data for compound 1a: C24H23BrN2O6, M = 515.35,
monoclinic, a = 13.396(2), b = 6.8114(12), c = 24.048(4) A,
b = 90.825(4)1, V = 2194.1(7) A3, T = 173 K, space group P21/c
This work was supported by the National Institutes
of General Medical Sciences P41GM081269 (WZ) and
P50GM067082 (DPC).
(no. 14), Z = 4, 26 044 reflections measured, 7225 unique (Rint
=
0.054) which were used in all calculations. The final wR(F2) was
0.1345 (using all data).
c
7580 Chem. Commun., 2010, 46, 7578–7580
This journal is The Royal Society of Chemistry 2010