Synthesis of allophanate-derived branched glycoforms from alcohols and p-nitrophenyl carbamates.

Article abstract of DOI:10.1021/ol0060127

[reaction: see text] The formation of saccharide-derived carbamates and alkyl 2, 4-dialkylallophanates from alcohols and p-nitrophenyl carbamates is described. Optimization of allophanate formation has led to the synthesis of branched glycoforms with inte

Full text of DOI:10.1021/ol0060127

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2113-2116
Synthesis of Allophanate-Derived
Branched Glycoforms from Alcohols
and p-Nitrophenyl Carbamates
Pek Y. Chong and Peter A. Petillo*
Department of Chemistry, UniVersity of Illinois at UrbanasChampaign,
600 S. Mathews AVenue, Urbana, Illinois 61801
alchmist@alchmist.scs.uiuc.edu
Received May 3, 2000
ABSTRACT
+
The formation of saccharide-derived carbamates and alkyl 2,4-dialkylallophanates from alcohols and p-nitrophenyl carbamates is described.
Optimization of allophanate formation has led to the synthesis of branched glycoforms with inter-saccharide allophanate linkages that are
rigidified by intramolecular hydrogen bonds.
The generation of glycoforms that display multiple copies
of a saccharide ligand at their periphery has been the subject
of much investigation due to their potential as high-affinity
inhibitors of carbohydrate-binding proteins involved in
biologically relevant recognition processes.1 Although a
structurally diverse range of scaffolds can and has been used
to assemble synthetic glycoclusters, a more rigid or ordered
scaffold would allow for a greater degree of control over
the spatial arrangement of the saccharide ligands and
minimize the entropic penalty of binding.2 Such a design
should allow multivalent glycoforms to be “tailored” to
complement the arrangement of the specific target receptors.
We now report the generation of saccharide-derived alkyl
2,4-dialkylallophanates as secondary products of base-
induced carbamoylations and their optimization for the
generation of branched glycoforms with inter-saccharide
allophanate linkages. These allophanates are intramolecularly
hydrogen bonded branched glycoforms that can be incorpo-
rated into the design of glycoclusters with multivalent
saccharide ligands. In these allophanate systems, the rigidity
imparted by the hydrogen bond may be an important design
element for glycoclusters with a more ordered or well-defined
ligand arrangement.
The synthesis of allophanates3 is generally achieved by
two routes. The first utilizes the treatment of a carbamate
with an isocyanate or isocyanate equivalent4 while the second
relies on reaction between a urea and a chloroformate or
chloroformate equivalent.5 It is known that organic iso-
(1) Representative references regarding the design and use of multivalent
glycoforms for enhancing carbohydrate-protein binding: (a) Kiessling, L.
L.; Pohl, N. L. Chem., Biol. 1996, 3, 71-77. (b) Roy, R. Curr. Opin. Struct.
Biol. 1996, 6, 692-702. (c) Jayaraman, N.; Nepogodiev, S. A.; Stoddart,
J. F. Chem. Eur. J. 1997, 3, 1193-1199. (d) Mammen, M.; Choi, S.-K.;
Whitesides, G. M. Angew. Chem., Int. Ed. 1998, 37, 2754-2794. (e) Fulton,
D. A.; Stoddart, J. F. Org. Lett. 2000, 2, 1113-1116 and references therein.
(f) Roy, R. Recent Developments in the Rational Design of Multivalent
Glycoconjugates. In Glycoscience; Driguez, H., Thiem, J., Eds.; Springer-
Verlag: Berlin, 1999; p 241-274.
(2) (a) Kitov, P. I.; Sadowska, J. M.; Mulvey, G.; Armstrong, G. D.;
Ling, H.; Pannu, N. S.; Read, R. J.; Bundle, D. R. Nature 2000, 403, 669-
672. (b) See ref 1a.
(3) The majority of the allophanates reported are endocyclic.
10.1021/ol0060127 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/16/2000

cyanates react with alcohols in a sequence of reactions to
give carbamates, allophanates, and isocyanurates (Scheme
1).6 The rate constants have been found to depend strongly
of this methodology for generating saccharide-derived allo-
phanates.
We previously described the base-catalyzed conversion of
the activated carbamate 1 to its isocyanate.9 “Transcarbam-
oylations” of 1 with alcohols derived from saccharides may
be achieved in high yields with the use of NaH and Et3N at
40 °C.10 During the course of further investigations into this
reaction, we found that the carbamates were capable of
undergoing further reaction with the isocyanate to generate
allophanates when excess isocyanate and higher reaction
temperatures were employed. Thus, treatment of the glycosyl
azide 2 with 1.3 equiv of p-nitrophenyl carbamate 1 at 50
°C for 1 h afforded the carbamate 3 in 80% yield (Table 1)
and the allophanate 4 in 9% yield.
Scheme 1. Reaction of Alcohols with Isocyanates
The identity of allophanate 4 was established by NMR
spectroscopic, mass spectral, and IR spectral analyses.11 The
NMR spectra clearly showed incorporation of two saccharide
units of 1 for each unit of 2. The anomeric azide remained
intact12 during the reaction as judged by the presence of the
NdNdN IR stretch at 2117.16 cm-1 of 4. The distinctive
triplet corresponding to the NH proton of 4 appears at 8.7
ppm, significantly downfield shifted with respect to the
carbamate NH signal at 5.2 ppm for 3.13 The magnitude of
this downfield shift is a strong indicator that the allophanate
is largely or wholly hydrogen-bonded.14 Both the chemical
shift range and the magnitude of the shift in CDCl3 are very
similar to those observed for hydrogen bonded NH protons
in other systems including Nowick’s oligourea scaffolds and
artificial â-sheets.15 Mass spectral analyses confirmed the
molecular composition of 4. To maximize allophanate
formation, the reaction temperature was elevated to 60 °C
and a greater excess of 1 was used (3.9 equiv). Under these
conditions, allophanate 4 was isolated in 94% yield after 6
h (Table 1).16
on the tertiary amine base and substrates. While the synthesis
of 2,4-diarylallophanates may be achieved by the consecutive
reaction of two aryl isocyanates with an alcohol,7 a mixture
of carbamate, allophanate, and isocyanurate is typically
afforded by the base-catalyzed reactions of alkyl isocyanates
with alkyl alcohols, making optimization of the allophanate
difficult.8
In a recent report on the cyclooligomerization of a
saccharide-based isocyanato alcohol to produce carbamate-
containing cyclodextrin analogues,9 we demonstrated the
high-yielding formation of inter-saccharide carbamate link-
ages from saccharide-derived p-nitrophenyl carbamates. This
“transcarbamoylation”, which occurs by in situ activation
of the p-nitrophenyl carbamate to the isocyanate, proceeded
in good yields for several model systems. Continued studies
on this transformation led to the discovery of the potential
(4) For examples see: (a) Dyer, E.; Reed, R. E. J. Org. Chem. 1959,
24, 1788-1789. (b) Krieg, B.; Lautenschla¨ger, H. Liebigs Ann. Chem. 1976,
208-220. (c) Shimasaki, C.; Murai, A.; Sakai, Y.; Tsukurimichi, E. Chem.
Lett. 1988, 1009-1012. (d) Shimasaki, C.; Hayase, S.; Murai, A.; Takai, J.
Bull. Chem. Soc. Jpn. 1990, 63, 1074-1079. (e) Botella, J.-M.; Klaebe,
A.; Perie, J.; Monnier, E. Tetrahedron 1992, 48, 5111-5122. (f) Pirkle,
W. H.; Simmons, K. A. J. Org. Chem. 1983, 48, 2520-2527. Isocyanate
generated from amide by Hoffman rearrangement: (g) Mu¨ller, J. H.; Donin,
M. N.; Behnke, W. E.; Hofman, K. J. Am. Chem. Soc. 1951, 73, 2487-
2491. Isocyanate generated from acyl azide by Curtius rearrangement: (h)
Misiti, D.; Santaniello, M.; Zappia, G. Synth. Commun. 1992, 22, 883-
891. Phosgene followed by amine: (i) see ref 4f. Trichloromethyl
chloroformate followed by amine: (j) Turconi, M.; Nicola, M.; Quintero,
M. G.; Maiocchi, L.; Micheletti, R.; Giraldo, E.; Donetti, A. J. Med. Chem.
1990, 33, 2101-2108.
The rates of formation of the carbamate and in turn the
allophanate vary with the nature of the substrate, presumably
due to differences in the reactivity of the pyranose alcohol
(10) The use of NaH and Et3N was found to be optimal for carbamate
formation. NaH plays an important role in driving the reaction to completion
by precipitating the p-nitrophenol out of solution as the phenolate salt (see
ref 9).
(11) The allophanate was formed by reaction of the carbamate with the
isocyanate at the carbamate N as expected based on existing literature. The
appearance of a second CdO stretch (at 1721-1728 cm-1) in the IR spectra
supports the formation of the allophanates. The alternative structure, resulting
from reaction at the carbamate CdO, is discounted based on the absence
of a CdN stretch (at 1690-1645 cm-1). In support of this, we observe the
appearance of isocyanurate 11 upon disappearance of the allophanate.
(12) Under these conditions, the azides remained intact although azides
have been shown to undergo reduction under NaH/refluxing THF condi-
tions: Lee, J.-Y.; Closson, W. D. Tetrahedron Lett. 1974, 4, 381-384.
(13) The NH resonance for the symmetrical urea is also at 5.2 ppm.
(5) For examples see: (a) Kamata, S.; Haga, N.; Matsui, T.; Nagata, W.
Chem. Pharm. Bull. 1985, 33, 3160-3175. (b) Yamashita, J.; Yamakawi,
I.; Ueda, S.; Yasumoto, M.; Unemi, N.; Hashimoto, S. Chem. Pharm. Bull.
1982, 30, 4258-4267. (c) Kondo, H.; Miura, K.; Seki, E.; Sunamoto, J.
Bull. Chem. Soc. Jpn. 1985, 58, 2801-2804. (d) Sundberg, S. A.; Barrett,
R. W.; Pirrung, M.; Lu, A. L.; Kiangsoontra, B.; Holmes, C. P. J. Am.
Chem. Soc. 1995, 117, 12050-12057. Phosgene followed by alcohol: (e)
Ulrich, H.; Tilley, J. N.; Sayigh, A. A. R. J. Org. Chem. 1964, 29, 2401-
2404. Trichloromethyl chloroformate followed by alcohol: (f) see ref 4b
and (g) Kuroda, T.; Hisamura, K.; Matsukuma, I.; Nishikawa, H.; Nakamizo,
N. Bull. Chem. Soc. Jpn. 1989, 62, 674-681.
(6) Schwetlick, K.; Noack, R. J. Chem. Soc., Perkin Trans. 2 1995, 395-
402.
(14) The presence of intramolecular hydrogen bonding in allophanates
is supported by existing literature: (a) Kogon, I. C. J. Am. Chem. Soc.
1957, 79, 2253. (b) Bloodworth, A. J.; Davies, A. G. J. Chem. Soc., B
1966, 125-127. (c) See ref 4b.
(15) (a) Nowick, J. S. Acc. Chem. Res. 1999, 32, 287-296 and references
therein. (b) Kim, K.; Germanas, J. P. J. Org. Chem. 1997, 62, 2847-2852.
(c) Liang, G. B.; Rito, C. J.; Gellman, S. H. J. Am. Chem. Soc. 1992, 114,
4440-4442.
(7) With aryl isocyanates: (a) Kogon. I. C. J. Am. Chem. Soc. 1956, 78,
4911-4914. (b) Ellzay, S. E.; Mack, C. H. J. Org. Chem. 1962, 27, 7,
2655-2656.
(8) (a) Ulrich, H.; Tucker, B.; Sayigh, A. A. R. J. Org. Chem. 1967, 32,
3938-3941. (b) Farkas, E.; Swallow, J. A. J. Med. Chem. 1964, 7, 739-
741.
(9) Chong, P. Y.; Petillo, P. A. Org. Lett. 2000, 2, 1093-1096.
2114
Org. Lett., Vol. 2, No. 14, 2000

Table 1. Synthesis of Carbamates and Allophanates from Alcohols and p-Nitrophenyl Carbamate 1
a
1H NMR chemical shifts in CDCl3 at 25 °C.
groups. While the reaction between 1 and 5 led to carbamate
6 in 92% yield after 1 h at 40 °C, the corresponding reaction
with 8 led to carbamate 9 in 85% yield after 3 h at 50 °C
(Table 1).
Using the observed optimal conditions for the synthesis
of 4, the corresponding allophanates 7 (73%) and 10 (75%)
were obtained from alcohols 5 and 8, respectively. The NH
protons in allophanates 7 and 10 show downfield shifts
similar to 4 (Table 1). These saccharide-derived allophanates
(like the activated carbamate 1) are white foams when dried
in vacuo and have shown no signs of decomposition in air.
They are also stable under mildly basic conditions such as
(16) The appearance of the allophanate as well as the disappearance of
the carbamate was monitored by TLC during the course of the reaction.
When 3.1 equiv of 1 was used, allophanate 4 was isolated in 76% yield
after 1 h at 60 °C.
Org. Lett., Vol. 2, No. 14, 2000
2115

Et3N in THF, however, when resubjected to the reaction
conditions used for its formation (NaH, Et3N, heat), they
partially revert back to the carbamate and alcohol, verifying
the reversibility of this transformation.17
For all of these reactions, we found that at longer reaction
times (> 6 h) at 60 °C, both the corresponding carbamates
and allophanates gradually become consumed, and the
formation of isocyanurate 11 is observed (Scheme 2).18 The
mixture of unidentified compounds is probably a series of
partially deacetylated forms of isocyanurate 11.
As mentioned previously, the presence of NaH was found
to be essential for the progress of these reactions, due to its
ability to intercept p-nitrophenol thereby allowing for the
stoichiometric generation of the isocyanate. The use of the
tertiary amine base alone with the reactants leads only to a
mixture of the alcohol and the carbamate and no allophanate
formation is detected. As expected, we found the relative
rates of formation of the carbamate, allophanate, and
eventually the acetylated alcohol to be dependent on the
tertiary amine base. For example, the use of DBU/NaH for
the reaction of 1 (3.1 equiv) with alcohol 2 led quickly to
acetylated alcohol after 1 h at 60 °C while the same reaction
(2 equiv of 1) using DABCO/NaH afforded carbamate 3 in
82% yield after 2 h at 60 °C with no allophanate formation
detected.
Scheme 2. Further Reaction of Allophanate 4, Affording
Isocyanurate 11 and Regenerating Alcohol 2, Which Is
Eventually Recovered in Its Acetylated Form
We note that these saccharide-derived allophanates are
branched glycoforms that are not only structurally interesting
but can be incorporated into the design of glycoclusters as
multivalent saccharide ligands, where the rigidity imparted
by the intramolecularly hydrogen bonded allophanate linkage
should lead to a more ordered and well-defined ligand
arrangement.20 In conclusion, we have described the forma-
tion of saccharide-derived alkyl 2,4-dialkylallophanates from
alcohols and p-nitrophenyl carbamates. Optimization of this
process has led to the synthesis of branched glycoforms with
inter-saccharide allophanate linkages.
Acknowledgment. We gratefully acknowledge NIH,
PRF, American Heart Association, UIUC Research Board,
and Critical Research Initiatives Program for financial
support. We also extend special gratitude to Professor David
Y. Gin for useful suggestions. All mass spectra were obtained
by the UIUC Mass Spectrometry Lab.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is free of charge via the Internet at http://pubs.acs.org.
highly symmetrical isocyanurate shows one set of pyranose
1
signals by H and 13C NMR while HRFAB-MS confirmed
OL0060127
the expected molecular composition.19 In all three cases, if
heating is continued in excess of 12 h, a mixture of
unidentified compounds and the corresponding acetylated
alcohol is recovered. We presume that our recovery of the
acetylated alcohols is the result of transacetylation of the
regenerated alcohols (Scheme 2) and that the observed
(18) We have been unable to prepare 11 by (a) TBAF-catalyzed
trimerization of isocyanates: Nambu, Y.; Endo, T. J. Org. Chem. 1993,
58, 1932-1934; and (b) N-alkylation of cyanuric acid: Ghosh, M.; Miller,
M. J. J. Org. Chem. 1994, 59, 1020-1026.
(19) The observed δ (13C) for the isocyanurate CdO at 148.8 ppm is
within the reported range for isocyanurates prepared by Miller and co-
workers (see ref 18b).
(20) The issue of whether the intramolecular hydrogen bond persists in
aqueous solution was raised by the referees and is an important one. Studies
that address this are currently in progess.
(17) When this mixture is heated for an extended period of time, the
acetylated alcohol is recovered. See following paragraph.
2116
Org. Lett., Vol. 2, No. 14, 2000