The sulfamate functional group as a new anchor for solid-phase organic synthesis

Article abstract of DOI:10.1021/ol990381p

(Formula presented) Sulfamate derivatives were loaded on trityl chloride resin, and two variants of cleavage were developed for this sulfamate anchor: an acid treatment to easily restore the free sulfamate and a nucleophilic treatment to generate the corresponding phenol. In addition to loading/ cleavage assays and stability experiments, a model sequence of reactions was performed with the new sulfamate anchor to show its applicability in further combinatorial solid-phase synthesis of libraries of biologically relevant sulfamate derivatives.

Full text of DOI:10.1021/ol990381p

ORGANIC
LETTERS
2000
Vol. 2, No. 4
445-448
The Sulfamate Functional Group as a
New Anchor for Solid-Phase Organic
Synthesis
Liviu C. Ciobanu, Rene´ Maltais, and Donald Poirier*
Laboratory of Molecular Endocrinology (DiVision of Medicinal Chemistry),
LaVal UniVersity Medical Research Center, CHUQ (PaVillon CHUL),
Que´bec G1V 4G2, Canada
donald.poirier@crchul.ulaVal.ca
Received November 30, 1999
ABSTRACT
Sulfamate derivatives were loaded on trityl chloride resin, and two variants of cleavage were developed for this sulfamate anchor: an acid
treatment to easily restore the free sulfamate and a nucleophilic treatment to generate the corresponding phenol. In addition to loading/
cleavage assays and stability experiments, a model sequence of reactions was performed with the new sulfamate anchor to show its applicability
in further combinatorial solid-phase synthesis of libraries of biologically relevant sulfamate derivatives.
Combinatorial chemistry has recently emerged as a powerful
tool that can generate large and diversified molecular
libraries.1 Further development of solid-phase organic syn-
thesis will certainly enhance the use of combinatorial
chemistry. The discovery of new linkers and anchoring
groups that accommodate various synthetic sequences of
reactions will be instrumental to the preparation of new types
of libraries. Some of the currently available anchors that have
been used to develop libraries of biologically active com-
pounds include phosphonates,2 carbamates,3 and sulfona-
mides,4 but to date the use of a sulfamate functional group
as an anchor for solid-phase organic synthesis has not been
implemented.
The sulfamate derivatives, which can be obtained from
phenols or alcohols, possess numerous interesting biological
properties, such as antibacterial,5 antitumoral,6 cytotoxic,7 and
anticonvulsive.8 Moreover, steroidal and nonsteroidal sulfa-
mates have been recently identified as potent inhibitors of
steroid sulfatase.9 The linkage of sulfamates to a solid
* Tel: (418) 654-2296. Fax: (418) 654-2761.
(1) (a) Gallop, M. A.; Barret, R. W.; Dower, W. J.; Fodor, S. P. A.;
Gordon, E. M. J. Med. Chem. 1994, 37, 1233. (b) Gordon, E. M.; Barret,
R. W.; Dower, W. J.; Fodor, S. P. A.; M.; Gallop, M. A. J. Med. Chem.
1994, 37, 1385. (c) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki,
R. J.; Steele, J. Tetrahedron 1995, 51, 8135. (d) Wilson, S. R.; Czarnik, A.
W. Combinatorial Chemistry: Synthesis and Application; John Wiley and
Sons: New York, 1997. (e) Obrecht, D.; Villalgordo, J. M. Solid-Supported
Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound
Libraries; Tetrahedron Organic Chemistry Series (Volume 17); Pergamon:
Oxford, U.K., 1998. (f) Diversity information pages (http://www.5z.com/
divinfo/).
(4) Beaver, K. A.; Siegmund, A. C.; Spear, K. L. Tetrahedron Lett. 1996,
37, 1145.
(5) Takahashi, E.; Beppu, T. J. Antibiot. (Tokyo) 1982, 35, 939.
(6) Bloch, A.; Coutsogeorgopoulos, C. Biochemistry 1971, 10, 4395.
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3991.
(2) (a) Zhang, C.; Mjalli, A. M. M. Tetrahedron Lett. 1996, 37, 5457.
(b) Cao, X.; Mjalli, A. M. M. Tetrahedron Lett. 1996, 37, 6073.
(3) (a) Paikoff, S. J.; Wilson, T. E.; Cho, C. Y.; Schultz, P. G.
Tetrahedron Lett. 1996, 37, 5653. (b) Cho, C. Y.; Youngquist, R. S.; Paikoff,
S. J.; Beresini, M. H.; Hebert, A. R.; Berleau, L. T.; Liu, C. W.; Wemmer,
D. E.; Keough, T.; Schultz, P. G. J. Am. Chem. Soc. 1998, 120, 7706.
(8) Maryanoff, B. E.; Costanzo, M. J.; Nortey, S. O.; Greco, M. N.;
Shank, R. P.; Schupsky, J. J.; Ortegon, M. P.; Vaught, J. L. J. Med. Chem.
1998, 41, 1315.
(9) (a) Poirier, D.; Ciobanu, L. C.; Maltais, R. Expert Opin. Ther. Pat.
1999, 9, 1083. (b) Reed, M. J.; Purohit, A.; Woo, L. V. L.; Potter, B. V. L.
Endocr. Relat. Cancer 1996, 3, 9.
10.1021/ol990381p CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/22/2000

polymer support and further introduction of molecular
diversity will accelerate the discovery of new biologically
active compounds through creation of sulfamate libraries.
In this paper, we describe for the first time the loading of a
sulfamate group to a trityl chloride polystyrene solid support
and its use as an anchor or a linker for the solid-phase
synthesis of sulfamates or phenols (Figure 1). The question
(TFA) in dichloromethane. Under these conditions, the
relative chemical stability of the recovered sulfamates was
found to be phenolic > primary alcohol > secondary alcohol
(phenolic and primary alcohol sulfamates being stable for
several hours). As expected, the sulfamates 1, 2, and 4 were
completely recovered within 1 h after acidic cleavage, while
the sulfamate 3 was isolated in the form of a trifluoroacetate
derivative 3A of the corresponding primary alcohol 3B.
Sulfamate derivatives 1-4 were then loaded onto trityl
chloride resin (Novabiochem, 0.95 mmol/g) before being
cleaved from the solid support by procedures similar to those
used for the model reaction assays in solution described
above.12,13 The 13C NMR spectra of the resin that reacted
with estrone-3-O-sulfamate (1) clearly revealed the presence
of the C-17 carbonyl group of the estrone derivative along
with additional evidence of the steroid backbone (Figure 2).
Figure 1. Loading of sulfamate on trityl chloride resin and both
variants (A and B) for the cleavage of the new sulfamate anchor
after introducing or not introducing molecular diversity (R′).
of the sulfamate anchor stability under conditions commonly
used in solid-phase organic reactions is also addressed.
Finally, a sequence of reactions is reported that illustrates
the viability of sulfamate anchoring.
Figure 2. 13C NMR spectra of trityl chloride resin (A) and estrone-
3-O-sulfamate (1) loaded to trityl resin (B). The spectra were
recorded at 75.5 MHz using 100 mg of resin swelled in 0.6 mL of
CDCl3, within a total experiment time of 12 h with the following
conditions: d1 - 1.0 s, p1 ) 30° (3.0 µs), aq ) 430 ms, RG 800,
SI ) 32 K.
The triphenylmethyl (trityl) group was previously used to
protect sulfamates of primary alcohols in the synthesis of
nucleocidin.10 Acidic deprotection recovers the initial sulfa-
mates without producing side products. Because these
protection-deprotection reactions were almost quantitative
in solution, it prompted the investigation of the efficiency
of coupling-decoupling sulfamate molecules with com-
mercially available trityl chloride polystyrene resin. Before
attempting the solid-phase experiments (Table 1), preliminary
liquid-phase tests were first performed with sulfamates 1-4,
which were derived from corresponding phenols or alcohols
by known methodology.11 These sulfamates were treated with
trityl chloride (1.2 equiv) in the presence of diisopropyl-
ethylamine (DIPEA) (1.5 mL/mmol) and dichloromethane
to yield the N-trityl sulfamate derivatives. These yields varied
between 75% and 96% for the trityl sulfamate model
compounds and were found to be particularly high for
phenolic sulfamates 1 and 4. The free sulfamate compounds
1-4 were then regenerated by reacting the corresponding
trityl sulfamates with a solution of 1% trifluoroacetic acid
Furthermore, a characteristic shift of the tertiary carbon signal
of the triphenylmethyl group signaled the formation of a
C-N covalent bond and, correspondingly, the loading of the
compound 1 on the resin. The results summarized in Table
1 (part A) show high overall yields (80-96%) for coupling
and cleavage of both alkyl and aryl sulfamates. The lower
yield of compound 3B (64%) could be explained by the
additional reaction step (1.2 equiv of NaOH from a 4 N
(12) General Procedure for Loading Sulfamate Derivatives on Trityl
Chloride Resin. A solution of sulfamate derivative (3 equiv) and diiso-
propylethylamine (1.5 mL/mmol) were added successively to the trityl
chloride resin (Novabiochem, 0.95 mmol/g) previously swelled in the
corresponding volume of CH2Cl2, and the mixture was agitated for 3-12
h. The resin was filtered and washed with CH2Cl2 (3×) and methanol (3×).
(13) General Procedure for the Acidic Cleavage of Sulfamate
Derivatives from Trityl Resin. To the loaded resin (Table 1) swelled in
CH2Cl2 was added sufficient trifluoroacetic acid (TFA) to obtain a 1%
solution of TFA in CH2Cl2. After 1 h, the resin was filtered and washed
with CH2Cl2 (3×). The solution containing the recovered sulfamate
derivative was washed with water (2 ×) and evaporated to dryness.
(10) Shuman, D. A.; Robins, M. J.; Robins, R. K. J. Am. Chem. Soc.
1970, 92, 3434.
(11) Schwarz, S.; Thieme, I.; Richter, M.; Undeutsch, B.; Henkel, H.;
Elger, W. Steroids 1996, 61, 710.
446
Org. Lett., Vol. 2, No. 4, 2000

Table 1. Cleavage Studies of Sulfamate Anchor to Generate Sulfamates 1-4 (A) or Phenols 5 and 7 (B)
aqueous solution, THF) needed to hydrolyze the trifluoro-
acetate intermediate 3A.
Treatment with 1% TFA in dichloromethane easily recovers
the free sulfamates, while a convenient treatment with
nucleophiles (DEA or piperidine) can be used to obtain the
corresponding phenols.
An interesting feature of the sulfamate anchor is its
stability with regard to nucleophiles. In a liquid-phase model
study, the N-trityl derivative of sulfamate 1 was found to be
resistant to nucleophilic cleavage for 3-5 h when treated
with 20% piperidine in dichloromethane at room temperature.
This proves that the sulfamate anchor can withstand condi-
tions that are currently used in peptide synthesis when
removing Fmoc amine protecting groups. Alkyl sulfamates
are even more resistant to nucleophilic attack than aryl
sulfamates. After several days of heating with 20% diethyl-
amine in dichloromethane, the N-trityl derivatives of alkyl
sulfamates 2 and 4 were practically unchanged. In contrast,
the N-trityl derivatives of aryl sulfamates 1 and 3 liberated
the corresponding phenols in high yields when heated with
either 20% piperidine in dichloromethane or with 20%
diethylamine (DEA) in ethanol at 50-60 °C for 1 day.
Compounds 1 and 3 were then loaded onto trityl chloride
resin, and the sulfamate anchor was cleaved by 20% DEA
in ethanol.14 The coupling-cleavage yields and the purity of
the resulting phenols 5 and 7 are presented in Table 1 (part
B). Thus, two variants may be used for the cleavage of
phenolic trityl sulfamates from solid support (Figure 1).
The N-trityl derivatives of sulfamates 1-4 were tested in
liquid phase for their stability under basic, oxidative, and
reductive reaction conditions. The N-trityl derivative of
estrone-3-O-sulfamate (1) was reacted with tetrabutylam-
monium fluoride (3-9 equiv) in THF and with 4 N sodium
hydroxide (20 equiv) in water-dioxane (1:1). In both assays,
after 1 day at room temperature, followed by another day in
refluxing solvents, no reaction occurred. N-Trityl derivatives
of sulfamates 2-4 were also tested in these conditions, and
the anchoring group remained stable. Reduction of the C17-
ketone of the N-trityl derivative of estrone (or epiandroster-
one)-3-O-sulfamates 1 (or 2) with LiAlH4 in THF and
oxidation (TPAP, 4-Me-NMO, CH2Cl2) of their correspond-
ing 17â-OH derivatives were completed without affecting
the sulfamate anchor.
To show the viability of the sulfamate anchor for solid-
phase organic synthesis, a sequence of reactions was
performed (Figure 3). The oxirane 9 was synthesized from
epiandrosterone-3-O-sulfamate (2) and linked to a trityl
chloride resin following standard procedure. The opening
of the oxirane 10 with an excess of piperazine in ethanol at
55-60 °C was completed in 2 days to yield the secondary
amine 11. This later was then converted to amides 12 or 13
by reacting with hexanoyl chloride or N-Fmoc phenylalanine.
Finally, the treatment of resins 12 or 13 with 1% TFA in
(14) General Procedure for Nucleophilic Cleavage of Phenolic Sulfa-
mates from Trityl Resin. The loaded resin (Table 1) was swelled in CH2-
Cl2, and a corresponding amount of diethylamine (DEA) was added to obtain
a 20% v/v solution of DEA in CH2Cl2. The mixture was heated overnight
at 55-60 °C, filtered, and washed with CH2Cl2 (2×). The resulted solution
was washed with water (2×) and evaporated to dryness.
Org. Lett., Vol. 2, No. 4, 2000
447

and 97%, respectively). Compounds 14 and 15 were char-
1
acterized by IR, MS, and H and 13C NMR analysis.
In summary, we have shown that sulfamates of phenols
and alcohols can be easily loaded onto and cleaved from a
trityl resin solid support. The sensitivity of the anchor to
nucleophiles limits the use of phenolic sulfamates in solid-
phase organic synthesis, but careful planning of the synthetic
strategies may overcome this problem. In fact, this sensitivity
provides the means to produce biologically active sulfamates
and phenols through either acidic or nucleophilic cleavage,
respectively. The newly developed sulfamate anchor is also
resistant to basic, oxidative, and reductive conditions. Fol-
lowing the successful solid-phase synthesis of model com-
pounds 14 and 15, work is in progress to extend the use of
the sulfamate anchor to the preparation of combinatorial
libraries of steroid sulfatase inhibitors.15,16
Acknowledgment. We are grateful to the Medical
Research Council of Canada (MRC) and Le Fonds de la
Recherche en Sante´ du Que´bec (FRSQ) for their financial
support and to the Division of Medicinal Chemistry of the
Laboratory of Molecular Endocrinology (CHUQ, Pavillon
CHUL) for providing the chemical facilities. We would also
like to mention our appreciation of the discussions we had
with Dr. Martin Tremblay.
Figure 3. Solid-phase synthesis of sulfamate derivatives 14 and
15. (a) H2NSO2Cl, 2,6-di-tert-butyl-4-methylpyridine (1.5 equiv),
CH2Cl2, rt, 1 h; (b) (CH3)3S+I-, NaH (12 equiv), DMSO, rt, 12 h;
(c) trityl chloride resin, DIPEA (6 equiv), CH2Cl2, rt, 12 h; (d)
piperazine (R ) H) (200 equiv), EtOH, 55-60 °C, 48 h; (e)
CH3(CH2)4COCl, pyridine (6 equiv), rt, 2 h; (f) (1) N-R-Fmoc-L-
phenylalanine, PyBrOP, HOBt, DIPEA, DMF, rt, 2 h; (2) piperidine
(20%), CH2Cl2, rt, 1 h; (g) 1% TFA in CH2Cl2, rt, 1 h.
Supporting Information Available: HPLC chromato-
grams of compounds 1, 3-5, 7, 14, and 15 and spectroscopic
data of compounds 14 and 15. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL990381P
(15) Poirier, D.; Boivin, R. P. Bioorg. Med. Chem. Lett. 1998, 8, 1891.
(16) Ciobanu, L. C.; Boivin, R. P.; Luu-The, V.; Labrie, F.; Poirier, D.
J. Med. Chem. 1999, 42, 2280.
dichloromethane yielded the sulfamate derivatives 14 or 15
after washing with K2CO3/MeOH (HPLC purities of 93%
448
Org. Lett., Vol. 2, No. 4, 2000