Multifunctionalized glycolurils

Article abstract of DOI:10.1021/ol990536t

(equation presented) Synthetic approaches to a variety of substituted glycoluril compounds are presented herein. We have applied several of these compounds in the solution-phase synthesis of combinatorial libraries, and we have developed methods to differ

Full text of DOI:10.1021/ol990536t

ORGANIC
LETTERS
1999
Vol. 1, No. 1
39-42
Multifunctionalized Glycolurils
Kent E. Pryor†,‡ and Julius Rebek, Jr.*
,†
The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, and Department of Chemistry,
Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
jrebek@scripps.edu
Received March 25, 1999
ABSTRACT
Synthetic approaches to a variety of substituted glycoluril compounds are presented herein. We have applied several of these compounds in
the solution-phase synthesis of combinatorial libraries, and we have developed methods to differentiate individual reaction sites for the
stepwise synthesis of individual polyfunctionalized compounds.
Glycolurils have found application in a number of settings,
including light stabilization,1 polymer cross-linking,2 explo-
sives,3 and molecular recognition.4 Previous work in this
laboratory in the last of these applications5 and in solution-
phase combinatorial chemistry6 led us to consider the
glycoluril framework for use as a core molecule for the
synthesis of combinatorial libraries.
mixtures or individual compounds. The core molecules we
envisioned were variously substituted glycoluril polyacids
or polyacid derivatives, and three examples of such are
shown in Figure 1. In each case, the bicyclic glycoluril
We developed a series of glycoluril derivatives which
allow functionalization at various positions about the core
structure via amide linkages. Using either a one-pot reaction
or a stepwise reaction sequence, we could synthesize either
† The Scripps Research Institute.
‡ Massachusetts Institute of Technology.
(1) Krause, A.; Aumueller, A.; Korona, E.; Trauth, H. U.S. Patent 5,-
670,613, 1997.
(2) Wang, A.; Bassett, D. U.S. Patent 4,310,450, 1982.
(3) (a) Fang, Y.; Wu, G. Hanneng Cailiao 1997, 5, 9. (b) Boileau, J.;
Carail, M.; Wimmer, E.; Gallo, R.; Pierrot, M. Propellants, Explos.,
Pyrotech. 1985, 10, 118.
(4) (a) Dave, P. R.; Forohar, F.; Kaselj, M.; Gilardi, R.; Trivedi, N.
Tetrahedron Lett. 1999, 40, 447. (b) Elemans, J. A. A. W.; de Gelder, R.;
Rowan, A. E.; Nolte, R. J. M. Chem. Commun. 1998, 15, 1553. (c) Reek,
J. N. H.; Wlwmans, J. A. A. W.; Nolte, R. J. M. J. Org. Chem. 1997, 62,
2234. (d) Murray, B. A.; Whelan, G. S. Pure Appl. Chem. 1996, 68, 1561.
(e) Coolen, H. K. A. C.; van Leeuwen, P. W. N. M.; Nolte, R. J. M. J.
Org. Chem. 1996, 61, 4739. (f) Sijbesma, R. P.; Nolte, R. J. M. Top. Curr.
Chem. 1995, 175, 25.
(5) (a) Meissner, R.; Rebek, J., Jr.; de Mendoza, J. Science 1995, 270,
1485. (b) Valdez, C.; Spitz, U. P.; Toledo, L. M.; Kubik, S. W.; Rebek, J.,
Jr. J. Am. Chem. Soc. 1995, 117, 12733.
(6) Pryor, K. E.; Shipps, G. W., Jr.; Skyler, D. A.; Rebek, J., Jr.
Tetrahedron 1998, 54, 4107 and references therein.
Figure 1. Three glycoluril polyacid core molecules.
centerpiece was formed by the condensation of 2 equiv of
an appropriately substituted urea with benzil or a substituted
benzil derivative.
The first member of this class, tetraacid 1, can be
synthesized by saponification of the corresponding tetraethyl
ester. However, tetraacid 1 is so highly water soluble that
10.1021/ol990536t CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/17/1999

separation of the compound from the salt byproducts of the
reaction was impossible. By replacing the ethyl esters with
benzyl esters (compound 4) and performing a hydrogenolysis
instead of a saponification, we were able to access 1 cleanly
and in high yield. This optimized procedure is shown in
Scheme 1.
glycoluril diester 9 (Scheme 2). Saponification of the diester
with LiOH yields diacid 2, which precipitates immediately
upon pouring the reaction mixture into 1 M HCl.
Scheme 2
Scheme 1
Similarly, benzyl hydantoate 8 can be condensed with
benzil9 to yield diester 10 (Scheme 3). Diacid 3 crystallizes
upon chilling after pouring the reaction mixture into 1 M
HCl after saponification of diester 10 with LiOH.
Scheme 3
Following a published procedure, we demethylated com-
mercially available anisil 5 with pyridine‚HCl.7 The resulting
4,4′-dihydroxybenzil 6 was then alkylated with benzyl
bromoacetate to provide the requisite diketone 7 for con-
densation. The other partner in the condensation, benzyl
hydantoate 8,8 is prepared in two steps from glycine by initial
esterification with benzyl alcohol followed by conversion
of the amino functionality into a urea upon reaction with
KOCN in EtOH/H2O. The TFA-catalyzed condensation is
performed with azeotropic removal of water, and the resulting
tetraester 4 is converted in quantitative yield to tetraacid 1
by catalytic hydrogenolysis.
Mindful of the remarkable water solublity of 1, initial
syntheses of other analogues with fewer acid substituents
were originally based on the hydrogenolysis of the corre-
sponding benzyl esters, as well. However, issues of solubility
and product recovery limited yields for this step in both cases
to approximately 35-55%.
The cis-substituted product 10 is isolated in 63% yield,
while the corresponding trans-substituted product 11 is
produced in only 8% yield.10 The two isomers can be isolated
from the crude reaction mixture (after aqueous extraction)
by selective crystallization.
Once the synthesis of the polyacids was accomplished, it
became necessary to develop methodology to couple building
(9) Substituted benzils have also been used to incorporate additional
functional groups in the core molecules; see Supporting Information for an
example.
(10) This is thought to be the result of the production of intermediate
12, which, particularly under acidic conditions, reacts with a second
equivalent of benzyl hydantoate 8 to preferentially form the cis-isomer.
Fortunately, subsequent trials proved that the diacids were
also less soluble in water than the tetraacid, so saponification
of either the ethyl or benzyl esters was a viable option; yields
of the saponification reactions are routinely greater than 90%.
Condensation of substituted benzil 7 with urea yields
(7) Somin, I. N.; Kuznetsov, S. G. Khim. Nauka I Prom. 1959, 4, 801.
(8) Previously reported in Kotani, T.; Ishii, A.; Nhagaki, Y.; Toyomaki,
Y.; Yago, H.; Suehiro, S.; Okukado, N.; Okamoto, K. Chem. Pharm. Bull.
1997, 45, 297.
40
Org. Lett., Vol. 1, No. 1, 1999

blocks to them in a clean, efficient manner. Historically,6
activation of core acids as acid chlorides has been a simple,
effective way to accomplish this goal. In the case of the
glycoluril core molecules, however, the presence of the urea
functionality precludes activation as acid chlorides.
Alternatives to acid chloride activation are, happily,
numerous. One option is to make use of a coupling reagent
to directly couple the amine building blocks to the polyacid
core. Another option is to activate the acids on the core as
some functional group other than as acid chlorides and isolate
the activated core for use in a subsequent amidation step.
Exemplifying the latter route, we activated diacid 2 as the
bis(pentafluorophenyl ester) 13 by coupling the diacid and
pentafluorophenol with EDC‚MeI and catalytic DMAP in
THF (see Scheme 4).11 The resulting active ester reacts
To synthesize smaller libraries and individual compounds
with the tetrasubstituted core molecule 1, it is necessary to
incorporate different protecting groups into the molecule that
would allow orthogonal deprotection under conditions that
would not epimerize amino acid substituents. The bis(2,2,2-
trichloroethyl ester)/bis(benzyl ester) 16 provides us with this
ability. Deprotection of the trichloroethyl esters yields the
diacid/diester 17; subsequent derivatization at the acid
positions, followed by mild hydrogenolysis, yields a diacid
for further reaction.
A synthetic scheme for diester/diacid 17 is shown in
Scheme 5. The diethyl ester substituted benzil 1814 is
Scheme 5
Scheme 4
readily with a variety of amines, including relatively unre-
active anilines.12 Additionally, both unreacted excess amines
and pentafluorophenol can be removed by aqueous extraction
during workup. The glycoluril core is unaffected by the
reaction conditions used for deprotection of tert-butyl ester
derivatives of amino acids used as building blocks (neat TFA,
12 h), as demonstrated by the synthesis of bis(leucine tert-
butyl ester) derivative 14 and its subsequent TFA deprotec-
tion to yield diacid 15.
Attempts to synthesize libraries by the direct reaction
between the polyacid cores and amine building blocks using
coupling reagents have been stymied in many cases by our
inability to clean the library of byproducts sufficiently. A
number of coupling reagents have been used to test their
efficacy, including DCC, EDC‚MeI, PyBOP, PyBrOP, and
DPPA. Many of the reactions worked fairly well, but it was
impossible to purify the products completely without resort-
ing to chromatography.13
saponified to 19 in almost quantitative yield with LiOH in
aqueous THF. Conversion of this diacid to the diacid chloride
20 was accomplished using oxalyl chloride in good yield.
Esterification with 2,2,2-trichloroethanol provided the pro-
tected dione 21.
The dione was condensed with benzyl hydantoate 8 to
yield the differentially protected glycoluril 16. Deprotection
of the trichloroethyl esters was accomplished by treatment
with zinc and acetic acid to give the diacid 17. Attempts to
condense the free diacid 19 in a glycoluril-forming reaction
(13) The synthesis of bis(leucine) adduct 14 by reaction of diacid 2 with
H-Leu-OtBu‚HCl under the action of DPPA is described in the Supporting
Information. In this and a few other cases (with other cores, amines, and
coupling reagents), the reaction was sufficiently clean to allow nonchro-
matographic workup.
(14) Diethyl ester 18 is prepared in a manner similar to that of dibenzyl
ester 7, with the substitution of ethyl bromoacetate as the alkylating agent.
The dibenzyl ester should be able to be used interchangeably in this reaction.
(11) Similar methodology can be applied to other polyacid glycoluril
core molecules, as described in the Supporting Information.
(12) Mass spectroscopy of libraries formed by the reaction of the
glycoluril core with aniline and several other single amines showed that all
three masses expected for the two homo- and the heterosubstituted products
were present.
Org. Lett., Vol. 1, No. 1, 1999
41

A synthesis of the “reverse” glycoluril 22 (Scheme 6), in
which the benzyl and trichloroethyl esters are switched
relative to compound 16, also met with failure. The trichlo-
roethyl hydantoate 23 (available in three steps from N-R-
Boc-L-glycine-4-nitrophenyl ester 24) is more labile to
hydantoin formation than the benzyl analogue, and glycoluril
formation was not competetive in this case, despite the
favorable solubility properties of the reactants.
Scheme 6
In summary, we have developed methodologies for the
preparation of a variety of differently substituted glycolurils
and have applied these methods in the construction of
solution-phase combinatorial libraries. Glycoluril intermedi-
ates with orthogonal protecting groups for the synthesis of
individual compounds have also been produced. Current
progress in our laboratory is directed toward the expansion
of the linker chemistries available for the introduction of
building blocks on the glycoluril skeleton and will be
reported in due course.
Acknowledgment. We thank the Skaggs Research Foun-
dation and Novartis AG for financial support.
only met with success when unsubstituted urea was used,
yielding glycoluril diacid 2.15 In several attempts with benzyl
hydantoate, the acid-catalyzed cyclization of the hydantoate
to give hydantoin proceeded to the exclusion of the desired
condensation; it is thought that the poor solubility of diacid
19 in the reaction medium is to blame.
Supporting Information Available: Experimental pro-
cedures and analytical information for compounds 1-4,
7-11, 13-21, 23, 25, and 26 and glycolurils with other
substitutions. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) See Supporting Information.
OL990536T
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Org. Lett., Vol. 1, No. 1, 1999