Fluorous mixture synthesis of fused-tricyclic hydantoins. Use of a redundant tagging strategy on fluorinated substrates

Article abstract of DOI:10.1021/jo0502596

Simple HPLC experiments were used to identify a redundant tagging scheme wherein six different amino acids were tagged with only four fluorous tags. The tagged amino acids were converted to regiosiomeric mixtures of tricyclic hydantoins. Despite the lack of selectivity, the mixtures were demixed and detagged to give 11 individual pure products in just 25 steps.

Full text of DOI:10.1021/jo0502596

Fluorous Mixture Synthesis of Fused-Tricyclic Hydantoins. Use of
a Redundant Tagging Strategy on Fluorinated Substrates
Sukhdev Manku and Dennis P. Curran*
Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue,
Pittsburgh, Pennsylvania 15260
curran@pitt.edu
Received February 8, 2005
Simple HPLC experiments were used to identify a redundant tagging scheme wherein six different
amino acids were tagged with only four fluorous tags. The tagged amino acids were converted to
regiosiomeric mixtures of tricyclic hydantoins. Despite the lack of selectivity, the mixtures were
demixed and detagged to give 11 individual pure products in just 25 steps.
Introduction
small molecules bearing fluorine atoms typically have a
stronger affinity toward perfluoroalkyl stationary phases
than those lacking fluorine.2,4
We have recently introduced the technique of fluorous
mixture synthesis and highlighted its usefulness in the
simultaneous synthesis of multiple analogues of natural
products and other small organic molecules.1 Briefly, each
member of a series of precursors is coded with a member
of a homologous series of fluorous tags. The tagged
compounds are mixed, taken through a series of steps,
and then demixed prior to detagging to provide the final
set of analogues in individual, pure form. Demixing
entails HPLC separation on fluorous silica gel,2 a process
that resolves the mixture in an orchestrated fashion on
the basis of the fluorine content of the tags. The technique
captures the inherent efficiency of solution-phase mixture
synthesis by overcoming its traditional separation li-
abilities.
Combining the medicinal and analytical features of the
element fluorine, we envisioned that fluorous mixture
synthesis would be ideal in preparing focused libraries
containing fluorine atoms and that we could leverage the
separation properties of the fluorinated library members
by the use of “redundant tags”, that is, by having more
components in a mixture synthesis than there are tags.
In all past fluorous mixture syntheses, the number of
tagged components and the number of tags were the
same (typically 2-7).1 Here we tag six components with
four tags (two pairs of redundant tags) and capitalize on
the separation features of the fluorinated components to
allow demixing despite the redundancies.
The incorporation of fluorine atoms is a popular tactic
in medicinal chemistry for modulating polarity, solubility,
metabolism, hydrogen bonding capabilities, and other
features of druglike small molecules.3 Accordingly, the
design of analogue libraries in medicinal chemistry often
incorporates fluorinated members. On the analytical side,
Results and Discussion
Pairing Tags and Amino Acids. In a recent mixture
synthesis of the 4-alkylidene cyclopentenones,5 we se-
lected favorable pairings of fluorous tags with amino acid
side chains by tagging individual amino acids 1 with
(1) For other examples of fluorous mixture syntheses, see: (a) Luo,
Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766-
1769. (b) Zhang, W.; Luo, Z.; Hiu-Tung Chen, C.; Curran, D. P. J. Am.
Chem. Soc. 2002, 124, 10443-10450. (c) Zhang, Q.; Lu, H.; Richard,
C.; Curran, D. P. J. Am. Chem. Soc., 2004, 126, 36-37. (d) Dandapani,
S.; Jeske, M.; Curran, D. P. Proc. Nat. Acad. Sci. U.S.A. 2004, 101,
12008-12012. (e) Short review: Zhang, W. Arkivoc 2004, 101-109.
(2) (a) Curran, D. P. Synlett 2001, 1488-1496. (b) Curran, D. P. In
Handbook of Fluorous Chemistry; Gladysz, J. A., Curran, D. P.,
Horvath, I., Eds.; Wiley-VCH: Weinheim, 2004; pp 101-128.
(3) (a) Bo¨hm, H.-J.; Banner, D.; Bendals, S.; Kansey, M.; Kuhn, K.;
Mu¨ller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637-
643. (b) Biffinger, J. C.; Kim. H. W.; DiMagno, S. G. ChemBioChem
2004, 5, 622-627. (c) Ojima, I. ChemBioChem 2004, 5, 628-635. This
issue of ChemBioChem also contains other articles and reviews
regarding fluorine in the life sciences.
(4) Curran, D. P.; Oderaotoshi, Y. Tetrahedron 2001, 57, 5243-5253.
(5) Manku, S.; Curran, D. P. J. Comb. Chem. 2005, 7, 63-68. In
this work, secondary propargyl esters [RCOOCH(Me)CtCTMS] were
studied.
10.1021/jo0502596 CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/04/2005
4470
J. Org. Chem. 2005, 70, 4470-4473

Fluorous Mixture Synthesis of Fused-Tricyclic Hydantoins
SCHEME 1. Tagging Four Mixtures of Eight
Compounds
different fluorous Cbz (FCBz) tags6 followed by conver-
sion to propargyl esters such as 35 and measurement of
retention times on fluorous HPLC. To more quickly
identify suitable redundant tag pairings, we first treated
each of four identical mixtures of eight amino acids 1
(alanine, leucine, norvaline, phenylalanine, 4-fluorophe-
nylalanine, 3,4-difluorophenyl-alanine, 4-CF3-phenyl-
alanine, and 3-CF3-phenyl-alanine) with one of four
different fluorous carbobenzyloxy succidinyl esters 2
(FCBzOSu, Rfn ) C4F9, C6F13, C8F17, and C9F19) (Scheme
1).
The tagged acids were then esterified with 3-trimeth-
ylsilylpropargyl alcohol, giving four mixtures of esters 3,
each mixture containing eight different amino acids
bearing the same FCBz tag. These propargyl mixtures
were analyzed by LCMS with a fluorous column, and the
resulting four chromatograms are shown in Figure 1.
The retention of each of the 32 fluorous esters 3 can
be influenced by many features,2 but the chromatograms
show the expected importance of the fluorine content of
tag. For example, all eight C4F9-tagged esters elute before
the first C6F13-tagged ester. In turn, all eight of the C6F13-
tagged esters elute before the first C8F17-tagged ester.
However, there is some overlap between the late eluting
members bearing the C8F17 tag and the early eluting ones
bearing the C9F19 tag. This is expected because these tags
differ only by one CF2 group and because some of the
component members are fluorinated amino acids.
Within each series of derivatives bearing the same tag,
there was a secondary separation wherein members
bearing different amino acid side chains eluted in the
same order (Me < Bn < 4-F-Bn < i-Bu ≈ Pr < 3,4-diF-
Bn < 3-CF3-Bn ≈ 4-CF3-Bn). As expected, the ana-
logues with the polyfluorinated side chains eluted at the
end of each tag series.
FIGURE 1. Chromatograms of the 4 eight-compound mix-
tures of 3. Conditions: FluoroFlash PF-C8 (4.6 × 150 mm)
column using a gradient from 80/20 acetonitrile in water to
100% acetonitrile in 30 min at 1 mL/min. UV signal at 254
nm is shown.
C9F19 group. The HPLC retention times of the six tagged
compounds are listed at the bottom of Figure 1. A
comfortable separation of 3-4 min between each pair of
peaks was observed.
Fluorous Mixture Synthesis of Tricyclic Hydan-
toins. Will the separation based on redundant tags
reliably translate through a series of different substrates
in a multistep synthesis? To address this question, we
conducted a six-compound mixture synthesis of tricyclic
hydantoins that is summarized in Schemes 2 and 3.7 The
synthesis is related to a previous fluorous mixture
synthesis of sixteen 4-alkylidene cyclopentenones via a
[2 + 2 + 1] cycloaddition of an alkynyl allene. In that
case, a Rh(I) catalyst in the presence of a CO atmosphere
was used to give the exclusively the 4-alkylidene cyclo-
pentenone scaffold.5,8 Here, we effect the cycloaddition
with Mo(CO)6 to give regioisomeric 4- and R-alkylidene
cyclopentenones.8,9
These simple experiments (four reactions and four
HPLC injections) provide much information for selecting
tag/side pairings. From among many possibilities, we
matched norvaline to the C4F9 group and alanine to the
C8F17 group. In the redundant taggings, both phenyl-
alanine and 4-trifluoromethylphenylalanine were paired
with the C6F13 group and both 4-fluorophenylalanine and
3-trifluoromethylphenylalanine were paired with the
The six fluorous carbobenzyloxy amino acids were
prepared individually and mixed to give acids 4{1-6}
(7) For another example of fluorous synthesis of hydantoins, see:
Zhang, W.; Lu, Y. Org. Lett. 2003, 5, 2555-2558. For a review on the
use of fluorous reagents for the synthesis of heterocycles, see: Zhang,
W. Chem. Rev. 2004, 104, 2531-2556.
(8) For the use of Rh(I) catalysts on alkynyl allenes, see: (a)
Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245-2248. (b)
Brummond, K. M.; Chen, H.; Fisher, K. D.; Kerekes, A. D.; Rickards,
B.; Sill, P. C.; Gein, S. J. Org. Lett. 2002, 4, 1931-1934. (c) Brummond,
K. M.; Chen, H.; Sill, P.; You, L. J. Am. Chem. Soc. 2002, 124, 15186-
15187.
(6) (a) Curran, D. P.; Amatore, M.; Guthrie, D.; Campbell, M.; Go,
E.; Luo, Z. J. Org. Chem., 2003, 68, 4643-4647. (b) The fluorous
reagents and columns were purchased from Fluorous Technologies, Inc.
(www.fluorous.com). (c) DPC holds an equity interest in this company.
(9) Brummond, K. M.; Wan, H.; Kent, J. L. J. Org. Chem. 1998, 63,
6535-6545.
J. Org. Chem, Vol. 70, No. 11, 2005 4471

Manku and Curran
SCHEME 2. Fluorous Mixture Synthesis
fluorous HPLC chromatograms of mixtures 6-9 each
exhibited six clean peaks (see Supporting Information),
and the components were characterized by LCMS.
The allenic Pauson-Khand reaction was performed by
heating 9{1-6} with Mo(CO)6 (2 equiv) and catalytic
DMSO in toluene to 150 °C under microwave conditions.
A relatively complex 24-component mixture resulted;
however, analytical demixing showed that each compo-
nent precursor had been partially converted to three new
products. The conversions were about 67% for each
component, and three products, R-alkylidenecyclopen-
tenone stereoisomers 10-syn and 10-anti along with
4-alkylidenecyclopentanone regioisomer 11, were formed.
Due to overlapping of HPLC peaks, we could only make
crude estimates of product ratios at this stage. Ratios of
10-syn/10-anti/11 were about 1/0.5/1 for the components
with larger R substituents, while the methyl analogue
showed only a trace amount of 11{4} and gave a higher
ratio of 10{4}-syn/10{4}-anti.12
This complex mixture showed only three main spots
in standard silica TLC analysis, and it was purified by
flash chromatography over regular silica gel eluting with
10% EtOAc/hexane. The least polar spot containing the
starting materials 9{1-6} was separated, and the other
two overlapping fractions containing the cyclized prod-
ucts were collected and combined. The resulting mixture
contained all but one of the 18 cyclized products by LCMS
analysis. The minor diastereomer of 10{4}-anti (R ) Me)
was missing, and we believe that this is more polar and
was retained on the column.
SCHEME 3. Formation of Hydantoins
Moving ahead with the single 17-compound mixture
of 10{1-6}-syn, 10{1-6}-anti, and 11{1-3,5,6}, we
cleaved the tert-butyl ester with TFA, and the resulting
acid mixture was coupled with phenethylamine (Scheme
3). At this stage, three main spots were observed on silica
TLC, and the mixture was preparatively separated to
give three submixtures containing predominately 12{1-
6}-syn, 12{1-6}-anti, and 13{1-3,5,6}. These submix-
tures were then demixed by fluorous HPLC to give 17
crude individual products 12 and 13. These crude prod-
ucts were not cross contaminated with compounds bear-
ing other fluorous tags, yet they were still not isomeri-
cally pure in most cases. Combined yields of the products
were n-Pr {1}, 67%; Bn {2}, 66%; 4-CF3-Bn {3}, 68%;
Me {4}, 61%; 4-F-Bn {5}, 61%; and 3-CF3-Bn {6}, 94%.
Removal of the fluorous tag with concomitant hydan-
toin formation was achieved by exposing the individual
amides 12-syn/anti and 13 to diisopropylethylamine
(DIPEA) in the microwave at 140 °C for 40 min (Scheme
3). The crude hydantoins 14{1-6} and 15{1-6} were
then purified by fluorous solid-phase extraction (F-SPE)2a
to remove the fluorous benzyl alcohol. The DIPEA could
be removed either by adding a layer of Amberlite CG-50
ion-exchange resin to the top of the F-SPE cartridge13 or
by an aqueous acid-base extraction after the F-SPE.
With the C4F9-tagged substrates, 14{1} and 15{1}, the
relatively low fluorine content (C4F9) of the tag made
(Scheme 2). These acids were converted to allenes by
esterification with alcohol 510 to the propargyl esters 6-
{1-6}, followed by a zinc-chelated ester enolate Claisen
rearrangement.11 The carboxylic acid on the resulting
allene was converted to the tert-butyl ester with tert-butyl
2,2,2-trichloroacetimidate, and the trimethylsilyl group
was removed to give mixture 7{1-6} in 52% yield from
the propargyl esters 6. The alkynyl allenes 9{1-6} were
then obtained by N-propargylation with bromide 8. The
(12) This estimate was aided by a study of cyclization of two
nonfluorous analogues. The standard CBz analogue of 9{2} (R1 ) Bn)
provided a 0.9/0.5/1 ratio of the corresponding products 10-syn/10-
anti/11, while the CBz analogue of 9{4} (R1 ) Me) gave a 4/1 mixture
of 10-syn/10-anti with little or no 11. Full details can be found in
Supporting Information.
(10) Trimethylsilylpropargyl alcohol, which was used in the initial
tag assignments, failed to undergo the ester-enolate Claisen rear-
rangement cleanly.
(11) Kazmaier, U.; Go¨rbitz, C. H. Synthesis 1996, 1489-1493.
(13) Zhang, W. Org. Lett. 2003, 5, 1011-1013.
4472 J. Org. Chem., Vol. 70, No. 11, 2005

Fluorous Mixture Synthesis of Fused-Tricyclic Hydantoins
TABLE 1. Yields and Purities of Hydantoins from
that survived the flash chromatography of the amide
mixtures 12{1-6} and 13{1-6} was removed. For the
5-6-5 hydantoin tricycles, good purities were obtained
simply after F-SPE.
Detagging Either Crude or after Semipreparative HPLC
14
15
R
yield (%)a purity (%)a,b yield (%) purity (%)b
nPr {1}
e
e
44a
90c
38a
d
99a
86c
94a
d
Conclusion
Bn {2}
74
59
40
57
25
99
91
99
91
90
4-CF3-Bn {3}
Me {4}
4-F-Bn {5}
3-CF3-Bn {6}
After only 25 chemical steps, including the 6 tagging
reactions and the 11 detaggings, 11 complex hydantoins
were obtained by using fluorous mixture synthesis with
two pairs of redundant tags. In addition, we also devel-
oped a rapid method for coding fluorous tags to building
blocks prior to the fluorous mixture synthesis. The
redundant tagging strategy and methods for tagging
introduced herein should be applicable not only to
fluorinated substrates but to other substrates that exhibit
reliable secondary separations on fluorous HPLC.
99c
86c
85c
87c
a After normal-phase semipreparative HPLC. b Purity deter-
mined by C18-HPLC at 254 nm. c Yield and purity after F-SPE.
d Not obtained. e Isolated but difficult to remove fluorous benzyl
alcohol.
removal of the fluorous byproduct difficult by F-SPE.
However, with compound 15{1}, the byproduct could be
removed by preparative TLC.
The cyclative cleavage reactions of 12-syn and 12-anti
provided not different products but the same ones.
Crystal structures of 14{2} and 14{4} showed that these
were anti isomers, and we assigned all the others as anti
by analogy. Evidently, the syn isomers isomerized to the
more stable anti isomers during the base-promoted
reaction.
Acknowledgment. Financial support has been pro-
vided by the National Institutes of Health and the
Natural Sciences and Engineering Research Council of
Canada (postdoctoral fellowship to S.M.). The authors
also thank Prof. Kay M. Brummond and Mr. Branko
Mitasev for helpful discussions and Dr. Steven Geib for
X-ray crystallography.
This “reconvergence” of two pairs of products then left
11 total products, whose yields and purities are shown
in Table 1. All of the 5-5-5-fused ringed hydantoins 14-
{1-6} were purified by normal phase semipreparative
HPLC to increase their purities above 90%. During this
chromatography, any remaining 4-alkylidene product
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0502596
J. Org. Chem, Vol. 70, No. 11, 2005 4473