O-(Aminosulfonylation) of phenols and an example of slow hydrolytic release

Article abstract of DOI:10.1016/j.tetlet.2014.10.065

Sequential replacement of imidazole from sulfonyldiimidazole by phenols and then amines leads to O-arylsulfamate esters. Application of this coupling method to 19 phenols and 6 amines generates a library of 114 sulfamate esters, Ar-OSO₂-NR₂. A sulfamate based conjugate of ethinyl estradiol was prepared by using the steroid 3-hydroxyl as the phenol component, and an amino amide derived from linoleic acid as the amine. Hydrolysis of this conjugate was studied in aqueous buffer at pH values 2, 5, and 7.4, and (essentially identical) respective half-lives of 6.8, 6.6, and 6.7 days were observed.

Full text of DOI:10.1016/j.tetlet.2014.10.065

Tetrahedron Letters 55 (2014) 6658–6661
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
O-(Aminosulfonylation) of phenols and an example of slow
hydrolytic release
Baocheng Yang a, Zhexun Sun b, Changzhi Liu a, Yan Cui a, Zhilei Guo a, Yuwei Ren a, Zhijian Lu a,
Spencer Knapp b,
⇑
a Center for Drug Discovery, Huanghe Science & Technology College, 666 Zijinshan South Road, Zhengzhou, China
b Department of Chemistry and Chemical Biology, Rutgers—The State University of New Jersey, 610 Taylor Rd., Piscataway, NJ 08854, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Sequential replacement of imidazole from sulfonyldiimidazole by phenols and then amines leads to O-
arylsulfamate esters. Application of this coupling method to 19 phenols and 6 amines generates a library
of 114 sulfamate esters, Ar-OSO2-NR2. A sulfamate based conjugate of ethinyl estradiol was prepared by
using the steroid 3-hydroxyl as the phenol component, and an amino amide derived from linoleic acid as
the amine. Hydrolysis of this conjugate was studied in aqueous buffer at pH values 2, 5, and 7.4, and
(essentially identical) respective half-lives of 6.8, 6.6, and 6.7 days were observed.
Received 30 September 2014
Revised 7 October 2014
Accepted 9 October 2014
Available online 16 October 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Sulfonyldiimidazole
Drug conjugate
Sulfamate ester
N-methylation
Sulfatase
Introduction
derivatives under convenient, scalable conditions led to the appli-
cation of these derivatives as O-triflate equivalents in coupling
For chemically linked drug conjugate systems, where one
component is the drug itself, enzyme mediated cleavage can be a
desirable property or not, depending on the application.1–3 In
constructing potential slow release drug conjugates, we became
interested in the O-arylsulfamate ester4 as a linkage that would
be enzyme resistant under most circumstances, but otherwise
would undergo chemical hydrolysis at a slow, predictable rate.
Here we show the construction of a drug conjugate system using
ethinyl estradiol as the drug5,6 and linoleic acid as the ‘carrier’,
linked together by a sulfamate ester assembly (Fig. 1), and demon-
strate its passive cleavage at neutral and acidic pH. We have also
used the same linking chemistry to prepare a library of 114 O-aryl-
sulfamate esters wherein both the phenol and amine components
are varied systematically.
reactions.8–18 Unlike triflate, however, the 1-imidazolylsulfonyl
group can be coaxed to undergo a second displacement reaction
with amines,19,20 resulting in a sulfamate ester linkage between
the original phenol and amine components (Scheme 1).
As an example, 4-tert-butylphenol (2, Scheme 1) was converted
to its 1-imidazl-1ylsulfonyl derivative (3) by treatment with 1,10-
sulfonyldiimidazole, and 3 was N0-methylated19,20 and combined
with benzylamine to produce the sulfamate 5 in good overall yield.
The intermediate N-methylimidazolium salt 4 was simply taken on
the product in the same flask after concentration of the reaction
mixture. The product sulfamate ester 5 is stable to aqueous extrac-
tion and chromatography, and shows no tendency to revert to phe-
nol or amine upon storage.
Preparation of a library of O-arylsulfamate esters
Results and discussion
By using the reactions of Scheme 1, but systematically varying
the phenol and amine components, the library of 114 sulfamate
esters shown in Table 1 was prepared. Yields are shown for the
preparation of O-(imidazol-1-ylsulfonyl) intermediates (11a–s,
second column), and then for the coupled sulfamate esters
themselves (12–17, columns 3–8). A few of the O-arylsulfamate
esters, including those derived formally from diethylamine, ani-
line, and benzylamine, are known in the literature, and six of the
Synthesis of sulfamate esters by sequential coupling
The demonstration7 in 2008 by Albaneze-Walker et al. that phe-
nols can be efficiently converted to their O-(imidazol-1-ylsulfonyl)
⇑
Corresponding author. Tel.: +1 848 445 2627; fax: +1 732 445 5312.
E-mail address: spencer.knapp@rutgers.edu (S. Knapp).
http://dx.doi.org/10.1016/j.tetlet.2014.10.065
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

B. Yang et al. / Tetrahedron Letters 55 (2014) 6658–6661
6659
Figure 1. A drug conjugate based on a sulfamate linker.
Preparation of a sulfamate ester based drug conjugate
There is extensive literature on steroidal ring-A O-arylsulfamate
esters: their synthesis, biological activity, and chemical hydrolysis
to the phenol.21–26 Certain (usually N-unsubstituted) steroidal sul-
famate esters have found application as irreversible inhibitors of
steroid sulfatase; in situ generation of the electrophile HN@S(@O)2
by an elimination reaction is suggested to account for this activ-
ity.27 For this study, the estrogen ethinyl estradiol (9) was desig-
nated as a representative phenolic drug, and linoleic acid as a
carrier molecule. Their interconnection into a highly lipophilic sul-
famate ester based drug conjugate is shown in Scheme 2. 4-(N-Boc-
amino)piperidine (6) 28 was coupled with linoleic acid to afford N-
(Boc)amino amide 7, which in turn was deprotected to give the
amino amide, 8. Ethinyl estradiol was converted to its O(3)-[(imi-
dazol-1-yl)sulfonyl] derivative (10). For the coupling reaction, the
imidazoyl N-3 of 10 was methylated with methyl triflate as
described above, and this salt was combined with amino amide 8
to provide the drug conjugate, 1 (Scheme 2).
The ethinyl estradiol–linoleic acid conjugate (1) was character-
ized by 1H and 13C NMR spectroscopy, as well as high-resolution
mass spectrometry. In particular, the signals for the upfield aro-
matic ring H’s of 1 are observed in the 1H NMR spectrum at 7.02
(dd, J = 8.4 and 2.4 Hz, H-2) and 6.98 (d, J = 2.4 Hz, H-4) ppm, and
these are clearly distinguishable from the corresponding signals
of ethinyl estradiol 9 at 6.63 and 6.56 ppm, respectively.
Scheme 1. Preparation of
replacement.
a sulfamate O-aryl ester by sequential imidazole
O-[1-imidazol-1-yl)sulfonyl]phenols have been described before.
References are given in the Supplementary material. The coupling
yields averaged 64%, with 4-hydroxypiperidine giving the highest
average yield (83%) and glycine tert-butyl ester the lowest (49%).
Two diamines, N1,N1-dimethylpropane-1,3-diamine and 4-amino-
1-benzylpiperidine, failed to give isolable product, most likely
due to the presence of a basic nitrogen in those sulfamate esters
(see below for discussion of base promoted degradation of sulfa-
mates). Two series of sulfamate esters, namely those derived from
glycine tert-butyl ester (16a–s) and 4-hydroxypiperidine (17a–s),
are di-functional, and could be further modified to produce addi-
tional analogues.
Hydrolysis of the sulfamate-based drug conjugate
O-Arylsulfamates (that also bear an NH) hydrolyze non-enzy-
matically by two mechanisms: (1) a base promoted process at high
pH (typically >9) that features deprotonation of NH, and fragmen-
tation with loss of the phenolate anion; and (2) water-assisted
Table 1
Synthesis and yields of O-arylsulfamate esters (Ar-OSO2-NR2) from 19 phenols (Ar-OH) and 6 amines (R2NH)
Ar-OH
Ar-OSO2-Im
Et2NH
PhNH2
PhCH2NH2
n-PrNH2
H2NCH2CO2t-Bu
4-Hydroxypiperidine
Ph-OH
2-F-C6H4-OH
11a, 98%
11b, 90%
11c, 88%
11d, 90%
11e, 99%
11f, 82%
11g, 84%
11h, 98%
11i, 60%
11j, 95%
11k, 73%
11l, 97%
11m, 100%
11n, 95%
11o, 82%
11p, 100%
11q, 53%
11r, 77%
11s, 52%
12a, 77%
12b, 50%
12c, 57%
12d, 51%
12e, 57%
12f, 56%
12g, 69%
12h, 80%
12i, 53%
12j, 69%
12k, 18%
12l, 75%
12m, 37%
12n, 31%
12o, 74%
12p, 91%
12q, 50%
12r, 61%
12s, 48%
13a, 69%
13b, 75%
13c, 47%
13d, 79%
13e, 60%
13f, 78%
13g, 64%
13h, 75%
13i, 66%
13j, 87%
13k, 85%
13l, 90%
13m, 87%
13n, 73%
13o, 63%
13p, 92%
13q, 77%
13r, 76%
13s, 51%
14a, 75%
14b, 65%
14c, 67%
14d, 69%
14e, 56%
14f, 73%
14g, 52%
14h, 70%
14i, 73%
14j, 70%
14k, 82%
14l, 78%
14m, 83%
14n, 68%
14o, 55%
14p, 73%
14q, 59%
14r, 67%
14s, 67%
15a, 66%
15b, 46%
15c, 76%
15d, 65%
15e, 71%
15f, 47%
15g, 52%
15h, 57%
15i, 64%
15j, 48%
15k, 27%
15l, 52%
15m, 19%
15n, 20%
15o, 61%
15p, 53%
15q, 80%
15r, 42%
15s, 75%
16a, 38%
16b, 50%
16c, 48%
16d, 60%
16e, 49%
16f, 49%
16g, 54%
16h, 40%
16i, 50%
16j, 46%
16k, 44%
16l, 51%
16m, 45%
16n, 63%
16o, 53%
16p, 38%
16q, 40%
16r, 43%
16s, 79%
17a, 78%
17b, 76%
17c, 83%
17d, 73%
17e, 95%
17f, 98%
17g, 79%
17h, 74%
17i, 81%
17j, 98%
17k, 80%
17l, 83%
17m, 96%
17n, 63%
17o, 70%
17p, 88%
17q, 76%
17r, 96%
17s, 96%
2-Cl-C6H4-OH
2-OMe-C6H4-OH
2-Ph-C6H4-OH
3-F-C6H4-OH
3-Cl-C6H4-OH
3-OMe-C6H4-OH
3-NO2-C6H4-OH
4-F-C6H4-OH
4-Cl-C6H4-OH
4-Br-C6H4-OH
4-I-C6H4-OH
4-Me-C6H4-OH
4-i-Pr-C6H4-OH
4-OMe-C6H4-OH
4-NO2-C6H4-OH
2,4-F2-C6H4-OH
2,5-F2-C6H4-OH

6660
B. Yang et al. / Tetrahedron Letters 55 (2014) 6658–6661
O
linoleic acid
HN
O
EDCI
N
O
H11C5
N
Ot-Bu
HOBt, Et3N
CH3CN, 14 h
H
N
Ot-Bu
H
7 (78%)
6
O
TFA, CH2Cl2
N
H11C5
NH2
8 (crude)
OH
H3C
OH
H3C
1,1-sulfonyldiimidazole
Cs2CO3, THF, 18 h
H
H
H
O O
H
H
H
S
3
HO
N
O
N
9
10 (91%)
H3C
OH
1. CH3-OTf
CH2Cl2
O
H
N
H11C5
O O
S
2. 8, CH3CN
H
H
N
O
H
1 (52% from 8 and 10)
Scheme 2. Synthesis of a sulfamate ester based drug conjugate from ethinyl estradiol and linoleic acid.
OH
H3C
O
H
H
2
N
H11C5
O O
S
H
N
O
4
H
1
OH
H3C
half-life of 1:
EtOH, aq buffer
37 °C
H
6.8 days, pH = 2
6.6 days, pH = 5
6.7 days, pH = 7.4
2
H
H
HO
4
9
Scheme 3. Aqueous hydrolysis of the ethinyl estradiol based sulfamate ester, 1, at three pH values.
hydrolysis at low to neutral pH that features addition of H2O at the
sulfuryl sulfur atom and/or assistance by solvent in protonating the
departing phenolic oxygen atom.29–34 The rate of the latter process
correlates with the pKa’s of the phenol and the sulfamate ester.34
The hydrolysis of ethinyl estradiol conjugate 1 at 37 °C was
studied in three buffer systems: pH = 2 (aqueous hydrochloric
acid), pH = 5 (aqueous acetic acid), and pH = 7.4 (aqueous phos-
phate), with ethanol as the co-solvent in each case (Scheme 3). Ali-
quots taken at intervals over 22 days were analyzed by 1H NMR
spectroscopy, and the extent of disappearance of 1 and appearance
of ethinyl estradiol (9) was estimated by integration relative to an
internal standard, 1,4-dinitrobenzene. Plots of ln[fraction of 9] ver-
sus time enabled the calculation of approximate half-lives for 9 at
37 °C: 6.8 days at pH = 2, 6.6 days at pH = 5, and 6.7 days at
pH = 7.4.
Conclusion
A wide variety of O-arylsulfamate esters are readily available
from respective phenol and amine components by a double cou-
pling protocol based on 1,10-sulfonyldiimidazole. Phenolic drug
based sulfamate ester conjugates such as 1 are accessible through
this chemistry, and the sulfamate group hydrolyzes slowly at acidic
to neutral pH (half life ꢀ6.7 days) to regenerate the drug.
Acknowledgments
We thank Huanghe Science & Technology College and Samos
Pharmaceuticals for financial assistance, and Jian Guo, Yanchun
Li, and Xibin Liao for organizing and supporting activities.
Supplementary data
The roughly invariant values for the half-life of 9 in three differ-
ent buffer systems are consistent with determinations made for
other sulfamate esters. In terms of possible biological or medicinal
applications, the results with 9 would predict a comparably long
half-life under mild aqueous conditions at low to neutral pH.
Experimental and spectral details including scanned NMR spec-
tra for the reactions in Schemes 1–3, and general experimental
procedures and spectral characterization including scanned NMR

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