Synthesis of N-Acyl Sulfamates from Fluorosulfonates and Potassium Trimethylsilyloxyl Imidates

Article abstract of DOI:10.1021/acs.joc.9b02394

An efficient and operationally simple method for the synthesis of N-acyl sulfamates from fluorosulfonates and potassium trimethylsilyloxyl imidates as amide precursor is reported. This approach showed broad substrate scope, mild and base-free reaction conditions, short reaction time, and high to excellent yields. Notably, we demonstrated the power of this reaction in the rapid late-stage functionalization of three complex phenol-containing bioactive molecules. Given the prevalence of phenol-containing drugs and building blocks, this method is applicable toward a diversity-oriented drug discovery.

Full text of DOI:10.1021/acs.joc.9b02394

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Article
Synthesis of N-acyl sulfamates from fluorosulfonates
and potassium trimethylsilyloxyl imidates
zhang shuning, Huan Xiong, Fengping Lu, Fei Ma, Yuang Gu, Peixiang Ma, Hongtao Xu, and Guang Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02394 • Publication Date (Web): 31 Oct 2019
Downloaded from pubs.acs.org on November 3, 2019
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Synthesis of N-acyl sulfamates from fluorosulfonates and
potassium trimethylsilyloxyl imidates
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Shuning Zhang a,b, Huan Xiong a, Fengping Lu a, Fei Ma a, Yuang Gu a,b, Peixiang Ma a,*, Hongtao Xu a,*, and
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Guang Yang a,*
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a Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 201210 Shanghai, China
b School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China
O
O
N
K
O
O
O
R1
S
R1
S
Volatile
b.p. 16 o
+
+
TMS
F
R2 OTMS
R2
X
F
C
X
N
H
X = C, N, O
Short reaction time
Operational simplicity
Broad substrate scope
Mild conditions
Volatile TMSF as the only byproduct
Late-stage modification of NPs or drugs
ABSTRACT
An efficient and operationally simple method for the synthesis of N-acyl sulfamates from
fluorosulfonates and potassium trimethylsilyloxyl imidates as amide precursor is reported. This
approach showed broad substrate scope, mild and base free reaction conditions, short reaction time,
and high to excellent yields. Notably, we demonstrated the power of this reaction in the rapid late-
stage functionalization of three complex phenol-containing bioactive molecules. Given the
prevalence of phenol-containing drugs and building blocks, this method is applicable toward a
diversity-oriented drug discovery.
INTRODUCTION
Sulfur (S), one of the top-five elements in FDA-approved drugs, is just behind the mainstays of
conventional synthetic organic chemistry: carbon (C), hydrogen (H), oxygen (O) andnitrogen (N).1,2
Sulfonamides and sulfur-containing functional groups play a key role in medicinal chemistry and
drug design. Since the discovery of the first sulfonamide containing antibacterial agent prontosil in
1930s,3-6 sulfonamides and related sulfur-containing agents have gained significant attention in
medicinal chemistry, and there are more than 150 FDA approved drugs bearing sulfur (S) up to
now. In view of the prevalence of sulfur-containing therapeutic agents, methods that enable efficient
access to sulfonamides, sulfamates and related sulfur-containing functionalities, and especially the
late-stage decoration of common sulfur functionalities in the context of complex molecules are of
great value in drug discovery.7,8
Among various sulfur-containing functional groups, N-acyl sulfamate is present in a diverse
array of biological active compounds covering not only in medicinal chemistry but also in food
industry.9,10 For example, Avasimibe is an acyl-coenzyme A: cholesterol acyltransferase (ACAT)
inhibitor that have reached phase III clinic for the treatment of atherosclerosis and hyperlipidemia
(Figure 1); Ascamycin is a natural antibiotic that exerts its antibiotic activity via inhibition of
aminoacyl-tRNA synthetases (aaRSs);11 Acesulfam-K, an artificial sweetener, is widely used in
food industry.12 Oestrone 3-O-(N-acetylated)-sulphamate (N-Acetylated-EMATE) is an irreversible
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inhibitor of oestrogen sulphatase (E1-STS), and it can be used as a molecular probe for the active
site of E1-STS in drug discovery.13 In addition, N-acyl sulfamate could also serve as a valuable
bioisoster of phosphate in drug design.10,14
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O
O
O
N
O
O
Me
O
O
NH2
H2N
S
N
S
N
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N
O
H
K
Me
N
N
HO OH
O
Cl
Acesulfam-K
Artifical sweetener
Ascamycin
aaRS inhibitor
O
Me
H
Me
iPr
O
iPr
O
iPr
H
O
O
NH
S
S
H
N
O
O
H
O
iPr
iPr
O
Avasimibe
ACAT inhibitor
E1-STS inhibitor
Figure 1. N-Acyl sulfamates containing bioactive molecules.
Despite the importance of N-acyl sulfamates, their chemistry is relatively unexplored, and
currently there are only limited synthetic routes available for their synthesis (Scheme 1). Classical
methods rely on the use of reactive and toxic chlorosulfonyl isocyanate (Scheme 1, route i) or its
unstable derivative, sulfamoyl chloride (Scheme 1, route ii).15,16 More recently, the De Borggraeve’s
group reported a novel route that involves direct coupling of aryl fluorosulfonates with amides in
the presence of sodium hydride to afford N-acyl sulfamates (Scheme 1, route iii).17 However, this
method remain suffers from several major drawbacks: (a) more than two equivalents of strong base
(sodium hydride) was needed, (b) lack of N-heterocycles containing substrates, and (c) low yields
of some substrates. As a consequence, the development of a mild, efficient and practical synthesis
toward N-acyl sulfamates is of great interest.
(1) Established pathways
(i) R1 = aryl or alkyl
ClSO2NCO
O
O
R2COOH
or
R1
R1
R1
S
O
NH2
R2COCl
O
O
O
(ii) R1 = aryl or alkyl
ClSO2NCO
R2COOH
or
NCO
O O
S
R1 OH
R1
S
O
N
R2
O
H
R2MgBr
O
O
(iii) R1 = aryl
SO2F2
R2CONH2
NaH
S
O
F
(2) Present pathway
N
K
R2 OTMS
F
Me Si Me
Me
O
O
O
O
O
R1
S
R1
S
X
N
R2
X
F
H
X = C, N, O
Volatile
b.p. 16 oC (lit.)
Scheme 1. Strategies for the synthesis of N-Acyl Sulfamates
Fluorosulfate was first reported in 1990s,18-23 It’s chemistry, however, was relatively unexplored
until the Sharpless group reported the robust synthesis of (hetero)aryl fluorosulfonates in 2014,24
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which sparked a surge in investigation of the chemistry of fluorosulfonate for medicinal, biological,
and material applications.25-36 Currently, as an emerging class of electrophiles, fluorosulfonate have
already showed great versatility in various chemical transformation ranging from conventional
organic synthesis to biocompatible click chemistry, i.e. cross-coupling reactions,37-42
C-H
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activation reactions,43,44 late-stage drug functionalization,45-51 sulfur(VI) fluoride exchange (SuFEx)
based click chemistry.52-57
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To achieve the goal of facile synthesis of N-Acyl sulfamates, the key is to employ a reactive,
and easy-to-handle equivalent of amide in the reaction with fluorosulfonate. In 2000, Merchant and
coworkers reported that heating of a nitrile with potssium trimethylsilanolate (TMSOK) in
tetrahydrofuran or toluene could generate a trimethylsilyloxyl iminium salt.58 Due to its insolubility
in most aprotic solvents, it can be purified by simply washing to remove all impurities. Thus,
potassium trimethylsilyloxyl imidate represents a useful precursor for the synthesis of amide. Since
it is in the form of potassium, we envisioned that the N-acylation of sulfamates could be achieved
under base free conditions. In view of the electronic properties of fluorosulfonates (electrophilic)
and potassium trimethylsilyloxyl imidates (nucleophilic), we hypothesized that the negative charge
residing on the nitrogen of 2a1 was strong enough to allow the reaction to proceed. Nucleophilic
attack of iminium ion 2a1 at the activated electrophilic sulfur center of 1a1 to yield intermediate
3ai (Scheme 2), and simultaneously release a charged fluoride ion that could further react with
intermediate 3ai to afford intermediate 3aii and the volatile fluorotrimethylsilane (TMSF) whose
o
boiling point is 16 C at 1 atm, and the release of TMSF would be another driving force of the
reaction. Finally, protonation of intermediate 3aii to give N-acyl sulfamate 3a1.
O
O
O
O
OTMS
2a1
S
S
O
F
N
O
N
O
F
Me Si Me
Me
Bond energy
522 kJ/mol
Ph
Ph
3ai
F
1a1
F
Me Si Me
Me
O
O
O
O
O
O
S
S
O
N
O
N
H
H2O
Ph
3a1
Ph
3aii
Scheme 2. Proposed reaction mechanism.
RESULTS AND DISSCUSION
To test our hypothesis, we commenced our investigation using 1a1 and 2a1 as the model
substrates (Table 1). To our gratification, when we added 1a1 into a stirring solution of 2a1 in
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anhydrous tetrahydrofuran at room temperature, the desired N-acyl sulfamates 3a1 was obtained in
a surprisingly excellent yield of 92%. We next evaluated the influences of various solvent on the
conversation. Delightfully, all the tested solvents showed little influence on the transformation and
offered excellent >90% yields in general, except for dichloromethane, which afforded a moderated
yield of 52 % (45% unreacted 1a1). We speculate that this is probably due to the poor solubility of
the 2a1 in dichloromethane. Finally, we investigated the effect of reaction time and found 20 min
to be the optimal.
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Table 1. Optimization of reaction conditionsa
Ph
N
K
O
O
O
Ph
O
O
S
OTMS
O
N
S
H
O
F
3a1
1a1
2a1
entry
reaction conditions
yieldsb (%)
1
2
3
4
5
6
7
8
1.4-Dioxane, r.t., 30 min
DCM, r.t., 30 min
DMSO, r.t., 30 min
CH3CN, r.t., 30 min
THF, r.t., 30 min
71
52
95
90
92
DMF, r.t., 30 min
DMF, r.t., 20 min
DMF, r.t., 10 min
93
95 (86)c
92
aReactions performed using 1a1 (1 mmol) 2a1 (1.2 mmol). Yield
b
1
determined by H NMR analysis of the crude reaction mixture with
1,3,5-trimethylbenzene as the internal standard. cYield determined by
the purified 3a1.
With the optimized reaction conditions in hand, we examined the scope and generality in terms
of functional groups on aryl fluorosulfonates. Results are summarized in Scheme 3. Generally, aryl
fluorosulfonates with a broad scope of functional groups at various position could be accommodated
and showed high to excellent yields. Both electron donating (3a1, 3a2, 3a3, 3b1, and 3c1) and
withdrawing (3a4, 3a5, 3a6, 3b2 and 3c2) substituents on the aromatic ring gave the expected N-
acylation products in excellent yields with short reaction time (20 min). Gratifyingly, the sensitive
nitrile groups (3a6, 3b2 and 3c2) were also well tolerated under the optimized reaction conditions.
Moreover, ortho-substituents (3c1-3c3 and 3d) did not dramatically hamper the reaction, even for
the highly sterically hindered tertiary butyl (3c1, 85%). What’s more, hetero aromatic
fluorosulfonates containing pyridine (3e) and quinoline (3f) moiety were all worked well in the
reaction to give the corresponding N-acylation products with satisfactory yields.
We also investigated the scope of potassium trimethylsilyloxyl imidates. Both electron donating
(3g) and withdrawing (3h and 3i) substituents on the aromatic ring gave the expected N-acylation
products in excellent yields with short reaction time (20 min). In addition, the hetero aromatic (3j
and 3k) and alkyl (3l) substituted imidates also works well under the optimized reaction conditions.
Notably, fluorosulfonyl analogs containing either −NSO2F (3m and 3n) or -CSO2F (3o and 3p)
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could also produce the corresponding N-acyl sulfonylacetamide in high to excellent yields (79-89%)
suggesting a compatible reactivity to fluorosulfates (−OSO2F).
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Scheme 3. Synthesis of N-Acyl Sulfamates from Fluorosulfonates and
trimethylsilyloxyl imidates a
O
O
S
O
3
O
R
K
N
H
N
R
X
S
F
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R X
DMF
rt, 20 min
R
OTMS
O
1
2
CH
O
O
O
O
O
O
O
O
3O
O
O
O
S
S
S
S
O
N
R1
O
N
O
N
O
N
H
H
H
H
R2
R3
CH3
3c1: R3 = tBu (85%)
3c2: R3 = CN (91%)
3c3: R3 = Br (85%)
3a1: R1 = Ph (86%)
3a2: R1 = Me (91%)
3a3: R1 = OMe (92%)
3b1: R2 = OMe (88%)
3b2: R2 = CN (82%)
3a4: R1 = Cl (89%)
3a5: R1 = I (85%)
3a6: R1 = CN (90%)
3d (86%)
O
O O
O
O
O O
O
O
O
O
O
S
S
S
S
H3C
O
N
O
N
H3C
O
N
O
N
H
H
H
H
N
Br
OMe
N
3h (89%)
3f (87%)
3g (91%)
3e (78%)
O
O
O
O O
O
O
O
O
O
O
O
S
S
CH3
11
S
S
S
H3C
O
N
H3C
O
N
H3C
O
N
H3C
O
N
H
H
H
H
N
CF3
3l (80%)
3k (83%)
3j (81%)
3i (85%)
O
O
O
O
O O
O
S
O
O
O
O
O
S
S
S
N
N
N
N
N
N
H
H3CO
H
H
H
N
O2N
N
MeO
3o (79%)
3n (89%)
3p (84%)
3m (82%)
aReaction conditions: 0.5 mmol of 1, 0.6 mmol of 2, 1 mL DMF (dry) at room temperature.
To demonstrate the practicality of this method, we sought to investigate whether the established
methodology could efficiently decorate N-acyl sulfamates on complex molecules such as natural
products (NPs) and approved drugs in a late-stage functionalization. First, 17-β-estrone, fulvestrant,
and (-)-arcitigenin were converted to their corresponding fluorosulfates 2q, 2r, and 2s in good to
excellent yields (see supporting information). Subsequently, under the established reaction
conditions, we were pleased to obtain the desired N-acyl sulfamates 3q, 3r, and 3s in good yields
(70-85%, Scheme 4). These results further emphasized the application of this novel methodology
on the late-stage functionalization of bioactive molecules. The evaluation of biological activities of
these new N-acyl sulfamates derivatives are ongoing, and will be disclosed in due course.
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Scheme 4. Late-stage functionalization of natural products and / or approved drugs.
a)
OH
OH
OH
7
8
9
b
H
H
H
a
O
O O
O
O
H
H
H
H
H
H
S
S
HO
F
O
Ph
N
O
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H
17 Estradiol
β -
1q
3q (85%)
b)
OH
OH
H
H
O
S
O
S
O
O
a
H
H
H
F
F
F
H
F
F
F
F
S
F
F
HO
F
O
F
1r
Fulvestrant
OH
H
b
O
O
S
O
O
H
H
F
F
F
S
F
F
Ph
N
H
O
3r (70%)
c)
O
O
O
O
O
O
O
O
O
a
O
b
O
S
S
OH
O
F
O
N
Ph
H
O
O
O
O
O
O
O
O
O
(-)-Arctigenin
1s
3s (75%)
Reaction conditions: a) SO2F2, TEA (2 equiv), r.t.; b) trimethylsilyloxyl imidates 2a1 (1.2 equiv),
r.t., 20 min.
Encouraged by the wide substrate scope and high efficiency of N-acyl sulfamates from
fluorosulfonates and potassium trimethylsilyloxyl imidates, we next evaluated the feasibility of one-
pot synthesis of N-acyl sulfamates from phenols via arylsulfonates generated in the presence of
sulfuryl fluoride (SO2F2) and triethyl amine. As shown in Scheme 5, reaction of phenol s1 with
sulfuryl fluoride (SO2F2) in anhydrous N,N-Dimethylformamide (DMF) in the presence of triethyl
amine for 3h produced 1a1 in nearly quantitative yield (determined by LC-MS). Without further
purification, 1a1 was reacted with 2a1 at room temperature for 20 min to generate 3a1 in excellent
yield (90 %).
Scheme 5. One-pot phenol fluorosulfation/ N-acylationa
H
1) SO2F2, Et3N (2.0 eq.)
DMF, r.t., 3 h
OH
O
N
Ph
S
O O
O
Ph
2) 2a1 (1.2 eq.)
r.t., 20 min
Ph
s1
3a1
aReaction conditions: a mixture of phenol (s1, 1 mmol), Et3N (2 mmol, 2.0 eq.) and DMF (1 mL)
charged with a SO2F2 balloon was stirred at room temperature for 3 hours before 2a1 (1.2 mmol,
1.2 eq.) were added and then the mixture reacted at room temperature for an additional 20 min.
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CONCLUSION
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In summary, we describe an operationally simple methodology for the synthesis of N-acyl
sulfamates from fluorosulfonates and potassium trimethylsilyloxyl imidates. Notable merits of this
method include high yields, mild reaction conditions, short reaction times, and broad substrate scope,
which make it an attractive alternative to existing methods. Under the optimized reaction conditions,
various fluorosulfates converted well providing the N-acyl sulfamates in good yields, and especially
in the context of steric and spatial complex molecules. Overall, such method provides a powerful
tool in the late-stage functionalization (LSF) tool-box of natural products and/or other bioactive
molecules.
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EXPERIMENT SECTION
General Information. All commercially available organic compounds were purchased from Sigma-
Aldrich and adamas-beta in China. Unless otherwise noted, all commercial reagents and solvents
were used without additional purification. NMR spectrums were recorded on Bruker AM-500
instruments and / or Bruker AM-600 instruments. Chemical shifts are reported in δ (ppm) referenced
to TMS as an internal standard for 1H NMR and CDCl3 (δ 77.0) for 13C NMR. High-resolution mass
spectra (HRMS-ESI) were obtained on an Agilent Technologies 6230 Accurate Mass TOF LC/MS
instrument or an AB Sciex 4600 QTOF MS instrument or Finnigan MAT-95 mass spectrometer.
General procedure for the synthesis of fluorosulfonates:
A 100 mL flask equipped with a magnetic stir bar was charged with the relative phenol or amine (1
mmol, 1 equiv.). DCM (5 mL) was added, followed by triethylamine (0.28 mL, 2 mmol, 2 equiv.).
Sealed with a rubber septum, the flask was evacuated to low vacuum, and backfilled with sulfuryl
fluoride gas by a balloon. The resulting mixture was stirred at room temperature for 12 h. Upon
completion, volatiles were removed in vacuo. The crude product was purified by flash
chromatography on silica gel (Reverse phase silica gel; Mobile phase (gradient elution): 10 to 90%
solvent B (Acetonitrile) in solvent A (Water) over 20 minutes) to give the desired fluorosulfonates.
1
[1,1'-Biphenyl]-4-yl sulfurofluoridate (1a1), white solid, (227 mg, 90%), H NMR (400
MHz, CDCl ) δ 7.67 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.41 (t,
3
J = 7.6 Hz, 3H). These data are in agreement with literature data.45
1
p-Tolyl sulfurofluoridate (1a2) colorless oil (175 mg, 85%), H NMR (500 MHz, CDCl ) δ
3
7.33 – 7.17 (m, 4H), 2.40 (s,3H). These data are in agreement with literature data.40
4-Methoxyphenyl sulfurofluoridate (1a3), colorless oil (190 mg, 92%), 1H NMR (500 MHz,
CDCl ) δ 7.26 (dd, J = 9.3, 1.1 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 3.82 (s, 2H). These data are in
3
agreement with literature data.43
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4-Chlorophenyl sulfurofluoridate (1a4), colorless oil (177 mg, 84%), H NMR (500 MHz,
CDCl ) δ 7.47 – 7.42 (m, 1H), 7.33 – 7.27 (m, 1H). These data are in agreement with literature
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CDCl ) δ 7.80 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H). These data are in agreement with
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4-Cyanophenyl sulfurofluoridate (1a6), colorless oil (185 mg, 92%), H NMR (500 MHz,
CDCl ) δ 7.82 (d, J = 8.9 Hz, 1H), 7.50 (dd, J = 9.0, 0.9 Hz, 1H). These data are in agreement with
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3-Methoxyphenyl sulfurofluoridate (1b1), colorless oil (184 mg, 89%), 1H NMR (500 MHz,
CDCl ) δ 7.14 (t, J = 8.1 Hz, 1H), 6.52 (ddd, J = 8.2, 2.3, 0.9 Hz, 1H), 6.48 – 6.42 (m, 2H), 3.78 (s,
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3H). These data are in agreement with literature data.45
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3-Cyanophenyl sulfurofluoridate (1b2), colorless oil (161 mg, 80%), H NMR (500 MHz,
CDCl ) δ 7.75 (dt, J = 7.2, 1.5 Hz, 1H), 7.68 – 7.60 (m, 3H). These data are in agreement with
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literature data.26
2-(tert-Butyl)phenyl sulfurofluoridate (1c1), Following the general procedure, 1c1 was
obtained as a colorless oil (200 mg, 86% yield), 1H NMR (500 MHz, CDCl ) δ 7.38 – 7.29 (m, 1H),
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7.23 (d, J = 7.2 Hz, 1H), 7.12 (dt, J = 11.6, 5.7 Hz, 2H), 1.29 (d, J = 9.6 Hz, 9H); 13C{1H} NMR
(126 MHz, CDCl3) δ 150.1, 141.0, 128.7, 128.1, 128.0, 120.2, 34.8, 30.3; HRMS (ESI) calcd for
[M+H]+ [C10H14FO3S]+ 233.0648, found 233.0663.
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2-Cyanophenyl sulfurofluoridate (1c2), colorless oil (181 mg, 90%), H NMR (500 MHz,
CDCl ) δ 7.87 – 7.73 (m, 2H), 7.63 – 7.53 (m, 2H). These data are in agreement with literature
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2-Bromophenyl sulfurofluoridate (1c3), colorless oil (224 mg, 88%), H NMR (500 MHz,
CDCl ) δ 7.47 (dd, J = 8.0, 1.6 Hz, 1H), 7.23 (ddd, J = 8.1, 7.3, 1.5 Hz, 1H), 7.04 (dd, J = 8.2, 1.5
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Hz, 1H), 6.82 (ddd, J = 8.0, 7.3, 1.5 Hz, 1H). These data are in agreement with literature data.17
2,6-Dimethylphenyl sulfurofluoridate (1d), colorless oil (165 mg, 81%), 1H NMR (500 MHz,
CDCl ) δ 7.18 (dd, J = 8.6, 6.2 Hz, 1H), 7.16 – 7.10 (m, 2H), 2.39 (s, 6H). These data are in
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agreement with literature data.17
Pyridin-3-yl sulfurofluoridate (1e), colorless oil (138 mg, 78%), 1H NMR (500 MHz, CDCl )
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δ 8.71 – 8.64 (m, 1H), 7.75 – 7.64 (m, 1H), 7.51 – 7.41 (m, 1H). These data are in agreement with
literature data.44
1
Quinolin-8-yl sulfurofluoridate (1f), colorless oil (216 mg, 95%), H NMR (500 MHz,
Chloroform-d) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1H), 8.24 (dd, J = 8.3, 1.7 Hz, 1H), 7.90 (dd, J = 8.3, 1.3
Hz, 1H), 7.75 (dt, J = 7.7, 1.2 Hz, 1H), 7.61 – 7.57 (m, 1H), 7.55 (dd, J = 8.3, 4.2 Hz, 1H). These
data are in agreement with literature data.44
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4-(4-methoxyphenyl)piperazine-1-sulfonyl fluoride (1m) Following the general procedure,
1m was obtained as a white solid (263 mg, 96% yield), 1H NMR (500 MHz, CDCl ) δ 7.00 – 6.80
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(m, 4H), 3.77 (d, J = 1.7 Hz, 3H), 3.59 (t, J = 5.1 Hz, 4H), 3.14 (t, J = 5.1 Hz, 4H); 13C{1H} (126
MHz, CDCl3) δ 154.9, 144.6, 119.5, 114.6, 55.6, 50.2, 47.2; HRMS (ESI) calcd for [M+H]+
[C11H16FN2O3S]+ 275.0866, found 275.0881.
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5-Methoxy-1H-indole-1-sulfonyl fluoride (1n) Following the general procedure, 1n was
obtained as a white solid (218 mg, 95% yield), 1H NMR (500 MHz, CDCl ) δ 7.75 (dd, J = 9.0, 1.8
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Hz, 1H), 7.41 – 7.33 (m, 1H), 7.09 – 6.97 (m, 2H), 6.74 – 6.68 (m, 1H), 3.84 (d, J = 2.0 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 157.42, 131.46, 129.31, 126.75, 114.58, 114.30, 111.14, 104.42,
55.71; HRMS (ESI) calcd for [M+H]+ [C9H9FNO3S]+ 230.0287, found 230.0298.
(8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-
cyclopenta[a]phenanthren-3-yl sulfurofluoridate (1q), white solid, (298 mg, 84%), 1H NMR (500
MHz, CDCl ) δ 7.36 (dd, J = 8.7, 1.1 Hz, 1H), 7.09 (dd, J = 8.6, 2.6 Hz, 1H), 7.03 (dd, J = 2.6, 1.1
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Hz, 1H), 3.75 (dd, J = 9.0, 8.1 Hz, 1H), 2.95 – 2.87 (m, 2H), 2.33 (dtd, J = 13.4, 4.3, 2.8 Hz, 1H),
2.27 – 2.19 (m, 1H), 2.13 (dtd, J = 13.2, 9.3, 5.7 Hz, 1H), 2.02 – 1.95 (m, 1H), 1.95 – 1.89 (m, 1H),
1.76 – 1.67 (m, 1H), 1.60 – 1.44 (m, 3H), 1.44 – 1.26 (m, 3H), 1.21 (ddd, J = 12.2, 10.9, 7.3 Hz,
1H), 0.79 (s, 3H). These data are in agreement with literature data.27
(7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-
pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-
cyclopenta[a]phenanthren-3-yl sulfurofluoridate (1r), white solid, (496 mg, 72%), 1H NMR (400
MHz, CDCl ) 7.39 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 7.05 (s, 1H), 3.79 (t, J = 12.4 Hz,
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1H), 2.95 (dd, J =16.2, 8.5 Hz, 1H), 2.85-2.62 (m, 5H), 2.42 - 2.12 (m, 7H), 1.98 (d, J = 12.3 Hz,
1H), 1.84-1.73 (m, 3H), 1.64-1.58 (m, 4H), 1.57-1.21 (m, 17H), 0.99 (brs, 1H), 0.79 (s, 3H); These
data are in agreement with literature data.48
4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-
methoxyphenyl sulfurofluoridate (1s) Following the general procedure, 1s was obtained as a white
solid (409 mg, 90% yield), 1H NMR (500 MHz, CDCl ) δ 7.20 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 1.9
3
Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.69 (dd, J = 8.2, 2.1 Hz, 1H), 6.58 – 6.49 (m, 2H), 4.22 (t, J =
8.4 Hz, 1H), 3.91 (t, J = 8.7 Hz, 1H), 3.87 – 3.79 (m, 9H), 3.01 – 2.92 (m, 2H), 2.64 (h, J = 6.6 Hz,
3H), 2.47 (p, J = 7.8 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 178.3, 151.1, 149.1, 148.0, 140.0,
137.8, 130.1, 122.1, 121.6, 120.6, 114.4, 111.9, 111.4, 71.2, 56.2, 55.9, 55.9, 46.3, 41.1, 38.0, 34.4;
HRMS (ESI) calcd for [M+H]+ [C21H24FO8S]+ 455.1176, found 455.1187.
General procedure for the synthesis of N-acyl sulfamates:
A 100 mL flask equipped with a magnetic stir bar was charged with potassium
trimethylsilanolate (513 mg, 4 mmol, 2 equiv.). Then anhydrous tetrahydrofuran (THF) or
benzotrifluoride (10 mL) was added, followed by aromatic nitrile (using THF as solvent) or aliphatic
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nitrile (using benzotrifluoride as solvent) (2 mmol, 1 equiv.). Then the reaction mixture was heated
to reflux until the nitrile was consumed and the solid was filtered, and washed with anhydrous
solvent (THF or benzotrifluoride), dried under reduced pressured to give the desired
trimethylsilyloxyl imidate,58,59 which without purification was used for the next step reaction.
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A 10 mL flask equipped with a magnetic stir bar was charged with trimethylsilyloxyl imidate,
(0.6 mmol, 1.2 equiv.). Then anhydrous DMF (1 mL) was added, followed by fluorosulfate (0.5
mmol, 1 equiv.) at room temperature. After stirring at room temperature for 10 to 20 min, the solvent
was removed under reduced pressure and the crude product was purified by flash chromatography
on silica gel (Reverse phase silica gel; Mobile phase (gradient elution): 10% to 90% solvent B
(Acetonitrile) in solvent A (Water) over 20 minutes) to give the desired N-acyl sulfamate.
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[1,1'-Biphenyl]-4-yl benzoylsulfamate (3a1) Following the general procedure, 3a1 was
obtained as a white solid (152 mg, 86% yield), 1H NMR (500 MHz, CDCl ) δ 7.87 – 7.79 (m, 2H),
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7.60 (t, J = 7.5 Hz, 1H), 7.48 (dtd, J = 13.0, 7.9, 7.3, 3.0 Hz, 6H), 7.40 (t, J = 7.6 Hz, 2H), 7.37 –
7.30 (m, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 164.1, 149.2, 141.1, 139.6, 134.1, 130.6, 129.2,
128.9, 128.7, 128.1, 127.9, 127.1, 122.2; HRMS (ESI) calcd for [M+H]+ [C19H16NO4S]+ 354.0800,
found 354.0804.
p-Tolyl benzoylsulfamate (3a2) Following the general procedure, 3a2 was obtained as a white
solid (133 mg, 91% yield), 1H NMR (500 MHz, CD3OD) δ 7.82 (dd, J = 8.4, 1.4 Hz, 2H), 7.66 –
7.59 (m, 1H), 7.53 – 7.45 (m, 2H), 7.25 – 7.13 (m, 4H), 2.31 (s, 3H); 13C{1H} NMR (126 MHz,
CD3OD) δ 166.3, 148.1, 137.6, 133.3, 131.6, 130.1, 128.5, 128.0, 121.3, 19.5; HRMS (ESI) calcd
for [M+H]+ [C14H14NO4S]+ 292.0644, found 292.0651.
4-Methoxyphenyl benzoylsulfamate (3a3):Following the general procedure, 3a3 was obtained
as a white solid (141 mg, 92% yield), 1H NMR (500 MHz, CD3OD) δ 7.86 – 7.78 (m, 2H), 7.62 (t,
J = 7.4 Hz, 1H), 7.52 – 7.45 (m, 2H), 7.26 – 7.19 (m, 2H), 6.96 – 6.88 (m, 2H), 3.75 (s, 3H); 13C{1H}
NMR (126 MHz, CD3OD) δ 166.3, 158.9, 143.5, 133.3, 131.6, 128.6, 128.1, 122.6, 114.5, 54.8;
HRMS (ESI) calcd for [M+H]+ [C14H14NO5S]+ 308.0593, found 308.0580.
4-Chlorophenyl benzoylsulfamate (3a4) Following the general procedure, 3a4 was obtained
as a white solid (139 mg, 89% yield), 1H NMR (500 MHz, CD3OD) δ 7.86 – 7.82 (m, 2H), 7.66 –
7.62 (m, 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.46 – 7.41 (m, 2H), 7.35 – 7.30 (m, 2H); 13C{1H} NMR
(126 MHz, CD3OD) δ 166.3, 148.7, 133.4, 132.9, 131.5, 129.7, 128.6, 128.1, 123.3; HRMS (ESI)
calcd for [M+H]+ [C13H11ClNO4S]+ 312.0097, found 312.0099.
4-Iodophenyl benzoylsulfamate (3a5) Following the general procedure, 3a5 was obtained as
a white solid (171 mg, 85% yield), 1H NMR (500 MHz, CD3OD) δ 8.97 (s, 1H), 7.82 (dd, J = 8.0,
1.5 Hz, 2H), 7.72 – 7.58 (m, 3H), 7.50 (t, J = 7.8 Hz, 2H), 7.12 – 6.99 (m, 2H); 13C{1H} NMR (126
MHz, CDCl3) δ 164.0, 149.7, 139.2, 134.2, 130.4, 129.2, 128.0, 124.0, 92.7; HRMS (ESI) calcd for
[M+H]+ [C13H11INO4S]+ 403.9453, found 403.9455 .
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4-Cyanophenyl benzoylsulfamate (3a6) Following the general procedure, 3a6 was obtained as
a white solid (136 mg, 90% yield), 1H NMR (500 MHz, CD3OD) δ 7.88 – 7.81 (m, 4H), 7.66 – 7.62
(m, 1H), 7.55 – 7.48 (m, 4H); 13C{1H} NMR (126 MHz, CD3OD) δ 166.3, 153.1, 134.1, 133.4,
131.5, 128.6, 128.2, 123.0, 117.3, 111.2; HRMS (ESI) calcd for [M+H]+ [C14H11N2O4S]+ 303.0440,
found 303.0445.
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3-Methoxyphenyl benzoylsulfamate (3b1) Following the general procedure, 3b1 was obtained
as a white solid (135 mg, 88% yield), 1H NMR (500 MHz, CD3OD) δ 7.85 – 7.80 (m, 2H), 7.67 –
7.60 (m, 1H), 7.53 – 7.46 (m, 2H), 7.31 (t, J = 8.2 Hz, 1H), 6.93 – 6.85 (m, 3H), 3.73 (s, 3H); 13C{1H}
NMR (126 MHz, CD3OD) δ 166.4, 160.9, 151.0, 133.3, 131.6, 130.0, 128.5, 128.0, 113.5, 113.2,
107.4, 54.6; HRMS (ESI) calcd for [M+H]+ [C14H14NO5S]+ 308.0593, found 308.0599.
3-Cyanophenyl benzoylsulfamate (3b2)Following the general procedure, 3b2 was obtained as
a white solid (124 mg, 82% yield), 1H NMR (500 MHz, CD3OD) δ 7.87 – 7.83 (m, 2H), 7.76 – 7.71
(m, 2H), 7.68 – 7.61 (m, 3H), 7.51 (t, J = 7.7 Hz, 2H); 13C{1H} NMR (126 MHz, CD3OD) δ 166.1,
150.1, 133.5, 131.3, 131.2, 131.2, 128.6, 128.1, 126.8, 125.6, 116.9, 113.6; HRMS (ESI) calcd for
[M+H]+ [C14H11N2O4S]+ 303.0440, found 303.0438.
2-(tert-Butyl)phenyl benzoylsulfamate (3c1) Following the general procedure, 3c1 was
obtained as a white solid (142 mg, 85% yield), 1H NMR (500 MHz, CD3OD) δ 7.90 (dd, J = 8.4, 1.4
Hz, 2H), 7.64 (d, J = 7.5 Hz, 1H), 7.56 – 7.49 (m, 3H), 7.49 – 7.43 (m, 1H), 7.22 (ddd, J = 9.0, 7.5,
1.8 Hz, 2H), 1.43 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 150.1, 141.0, 128.7, 128.1, 128.0, 120.2,
34.8, 30.3; HRMS (ESI) calcd for [M+H]+ [C17H20NO4S]+ 334.1113, found 334.1103.
2-Cyanophenyl benzoylsulfamate (3c2) Following the general procedure, 3c2 was obtained as
a white solid (138 mg, 91% yield), 1H NMR (500 MHz, CD3OD) δ 7.90 – 7.86 (m, 2H), 7.81 (dd, J
= 7.8, 1.7 Hz, 1H), 7.76 (ddd, J = 9.1, 7.5, 1.7 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.60 (dd, J = 8.5, 1.1
Hz, 1H), 7.54 – 7.49 (m, 3H); 13C{1H} NMR (126 MHz, CD3OD) δ 166.1, 151.0, 134.6, 133.9,
133.4, 131.6, 128.6, 128.3, 127.8, 123.2, 114.3, 107.2; HRMS (ESI) calcd for [M+H]+
[C14H11N2O4S]+ 303.0440, found 303.0438.
2-Bromophenyl benzoylsulfamate (3c3) Following the general procedure, 3c3 was obtained
as a yellow solid (151 mg, 85% yield), 1H NMR (500 MHz, DMSO-d6) δ 7.97 – 7.93 (m, 2H), 7.60
(ddd, J = 8.2, 3.8, 1.6 Hz, 2H), 7.45 – 7.41 (m, 1H), 7.39 – 7.34 (m, 2H), 7.31 (ddd, J = 8.3, 7.4, 1.6
Hz, 1H), 7.08 – 7.02 (m, 1H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 170.7, 150.0, 138.8, 133.4,
130.9, 128.9, 128.8, 128.1, 126.1, 123.0, 115.5; HRMS (ESI) calcd for [M+H]+ [C13H11BrNO4S]+
355.9592, found 355.9600.
2,6-Dimethylphenyl benzoylsulfamate (3d) Following the general procedure, 3d was
obtained as a white solid (131 mg, 86% yield), 1H NMR (500 MHz, CDCl3) δ 7.83 (dt, J = 7.3, 1.3
Hz, 2H), 7.68 – 7.61 (m, 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.12 – 7.01 (m, 3H), 7.08 (dd, J = 8.6, 6.0 Hz,
1H), 7.04 (d, J = 8.6, 2H). 2.37 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 163.8, 148.0, 133.9,
131.9, 130.9, 129.5, 129.3, 127.9, 127.3, 17.2; HRMS (ESI) calcd for [M+H]+ [C15H16NO4S]+
306.0800, found 306.0809.
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Pyridin-3-yl benzoylsulfamate (3e) Following the general procedure, 3e was obtained as a
white solid (109 mg, 78% yield), 1H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J = 2.6 Hz, 1H), 8.65
(dd, J = 5.3, 1.3 Hz, 1H), 8.20 (ddd, J = 8.6, 2.7, 1.3 Hz, 1H), 7.95 – 7.89 (m, 2H), 7.85 (dd, J =
8.6, 5.2 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.46 – 7.40 (m, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ
169.1, 149.9, 142.7, 139.3, 135.7, 135.2, 132.4, 129.0, 128.6, 127.1; HRMS (ESI) calcd for [M+H]+
[C12H11N2O4S]+ 279.0440, found 279.0445.
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Quinolin-8-yl benzoylsulfamate (3f) Following the general procedure, 3f was obtained as a
white solid (143 mg, 87% yield), 1H NMR (500 MHz, DMSO-d6) δ 9.43 (dd, J = 5.2, 1.5 Hz, 1H),
9.18 (dd, J = 8.4, 1.4 Hz, 1H), 8.26 (dd, J = 8.2, 1.3 Hz, 1H), 8.16 – 8.09 (m, 3H), 8.00 (dd, J = 7.7,
1.3 Hz, 1H), 7.95 (t, J = 7.9 Hz, 1H), 7.63 – 7.56 (m, 1H), 7.50 (dd, J = 8.3, 7.0 Hz, 2H); 13C{1H}
NMR (126 MHz, DMSO-d6) δ 172.7, 147.2, 145.4, 142.7, 136.1, 134.9, 132.6, 130.3, 129.9, 129.3,
128.7, 127.1, 126.4, 123.4; HRMS (ESI) calcd for [M+H]+ [C16H13N2O4S]+ 329.0596, found
329.0591.
p-Tolyl (4-methoxybenzoyl)sulfamate (3g) Following the general procedure, 3g was obtained
as a white solid (146 mg, 91% yield), 1H NMR (500 MHz, DMSO-d6) δ 7.87 – 7.82 (m, 2H), 7.07
(s, 4H), 6.88 – 6.83 (m, 2H), 3.77 (s, 3H), 2.23 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ
170.1, 161.4, 150.5, 133.8, 131.7, 130.6, 129.7, 122.1, 113.2, 55.6, 20.8; HRMS (ESI) calcd for
[M+H]+ [C15H16NO5S]+ 322.0749, found 322.0735.
p-Tolyl (4-bromobenzoyl)sulfamate (3h) Following the general procedure, 3h was obtained as
a yellow solid (165 mg, 89% yield), 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 8.3 Hz, 2H), 7.62
(d, J = 8.3 Hz, 2H), 7.14 (s, 4H), 2.32 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 163.5, 147.7,
138.0, 132.4, 130.5, 129.6, 129.5, 129.2, 121.5, 20.9; HRMS (ESI) calcd for [M+H]+
[C14H13BrNO4S]+ 369.9749, found 369.9743.
p-Tolyl (4-(trifluoromethyl)benzoyl)sulfamate (3i) Following the general procedure, 3i was
obtained as a white solid (153 mg, 85% yield), 1H NMR (500 MHz, DMSO-d6) δ 8.09 (d, J = 8.1
Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.22 – 7.14 (m, 2H), 2.29 (s, 3H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 165.6, 148.2, 137.4, 136.5, 133.02 (q, JC-F = 32.1 Hz), 130.9,
129.9, 125.99 (q, JC-F = 3.8 Hz), 124.15 (q, JC-F = 272.6 Hz); 121.9, 20.8; HRMS (ESI) calcd for
[M+H]+ [C15H13F3NO4S]+ 360.0517, found 360.0513.
p-Tolyl benzoylsulfamate (3j) Following the general procedure, 3j was obtained as a white
solid (118 mg, 81% yield), 1H NMR (500 MHz, DMSO-d6) δ 8.63 – 8.58 (m, 2H), 7.77 – 7.74 (m,
2H), 7.11 (s, 4H), 2.25 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 168.9, 150.2, 150.1, 146.1,
134.4, 129.9, 122.8, 122.1, 20.8; HRMS (ESI) calcd for [M+H]+ [C13H13N2O4S]+ 293.0596, found
293.0607.
p-Tolyl (thiophene-2-carbonyl)sulfamate (3k) Following the general procedure, 3k was
obtained as a white solid (123 mg, 83% yield), 1H NMR (500 MHz, DMSO-d6) δ 7.53 (d, J = 5.0
Hz, 1H), 7.45 (dd, J = 3.6, 1.3 Hz, 1H), 7.10 (d, J = 1.6 Hz, 4H), 7.01 (ddd, J = 5.0, 3.6, 1.1 Hz,
1H), 2.25 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 166.1, 150.2, 145.2, 134.3, 130.0, 129.8,
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298.0198.
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p-Tolyl tridecanoylsulfamate (3l) Following the general procedure, 3l was obtained as a white
solid (153 mg, 80% yield), 1H NMR (500 MHz, CD3OD) δ 7.24 (d, J = 8.2 Hz, 2H), 7.15 (d, J =
8.1 Hz, 2H), 2.35 (s, 3H), 2.25 (t, J = 7.3 Hz, 2H), 1.60 – 1.54 (m, 2H), 1.29 (s, 18H), 0.90 (t, J =
6.8 Hz, 3H); 13C{1H} NMR (126 MHz, CD3OD) δ 172.2, 148.1, 137.5, 130.0, 121.1, 35.5, 31.7,
29.4, 29.4, 29.3, 29.2, 29.1, 29.0, 28.6, 24.3, 22.3, 19.5, 13.0; HRMS (ESI) calcd for [M+H]+
[C20H34NO4S]+384.2209, found 384.2208.
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N-((4-(4-methoxyphenyl)piperazin-1-yl)sulfonyl)benzamide (3m) Following the general
procedure, 3m was obtained as a white solid (154 mg, 82% yield), 1H NMR (500 MHz, CD3OD) δ
7.93 – 7.87 (m, 2H), 7.68 – 7.60 (m, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.24 (dd, J = 9.3, 3.5 Hz, 2H),
7.00 – 6.94 (m, 2H), 3.78 (s, 3H), 3.76 – 3.71 (m, 4H), 3.42 (q, J = 4.3 Hz, 4H); 13C{1H} NMR (126
MHz, CD3OD) δ 167.0, 133.0, 132.0, 130.87, 130.85, 128.5, 127.9, 120.4, 114.6, 54.7, 52.8, 45.5;
HRMS (ESI) calcd for [M+H]+ [C18H22N3O4S]+ 376.1331, found 376.1342.
N-((5-methoxy-1H-indol-1-yl)sulfonyl)benzamide (3n) Following the general procedure, 3n
was obtained as a white solid (147 mg, 89% yield), 1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J =
7.7 Hz, 2H), 7.78 (d, J = 9.0 Hz, 1H), 7.68 (dd, J = 3.7, 1.3 Hz, 1H), 7.63 – 7.57 (m, 1H), 7.47 (t, J
= 7.6 Hz, 2H), 7.15 (d, J = 2.5 Hz, 1H), 6.95 (dt, J = 9.1, 1.9 Hz, 1H), 6.69 – 6.63 (m, 1H), 3.77 (s,
3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 166.3, 156.2, 133.7, 132.1, 131.4, 129.9, 129.1, 129.0,
128.9, 114.1, 113.4, 106.5, 104.2, 55.9; HRMS (ESI) calcd for [M+H]+ [C16H15N2O4S]+ 331.0753,
found 331.0744.
N-((4-nitrophenyl)sulfonyl)benzamide (3o)Following the general procedure, 3o was obtained
as a white solid (121 mg, 79% yield), 1H NMR (500 MHz, DMSO-d6) δ 8.47 – 8.42 (m, 2H), 8.28
– 8.21 (m, 2H), 7.91 – 7.85 (m, 2H), 7.62 (d, J = 7.4 Hz, 1H), 7.53 – 7.46 (m, 2H); 13C{1H} NMR
(126 MHz, DMSO-d6) δ 166.5, 150.6, 145.7, 133.8, 132.1, 129.8, 129.1, 129.0, 124.9; HRMS (ESI)
calcd for [M+H]+ [C13H11N2O5S]+ 307.0389, found 307.0376.
N-((5-(dimethylamino)naphthalen-1-yl)sulfonyl)benzamide (3p) Following the general
procedure, 3p was obtained as a yellow solid (149 mg, 84% yield), 1H NMR (500 MHz, DMSO-d6)
δ 8.55 (d, J = 8.5 Hz, 1H), 8.39 (dd, J = 19.9, 8.0 Hz, 2H), 7.84 (d, J = 7.7 Hz, 2H), 7.77 – 7.69 (m,
1H), 7.62 (dt, J = 14.0, 7.9 Hz, 2H), 7.52 – 7.44 (m, 2H), 7.27 (d, J = 7.6 Hz, 1H), 2.84 (d, J = 2.7
Hz, 6H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 165.7, 151.7, 134.8, 133.7, 131.9, 131.8, 131.2,
129.3, 129.2, 129.1, 128.95, 128.78, 124.2, 118.7, 115.8, 45.6; HRMS (ESI) calcd for [M+H]+
[C19H19N2O3S]+ 355.1116, found 355.1103.
(8R,9S,13S,14S,17S)-17-Hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-
cyclopenta[a]phenanthren-3-yl benzoylsulfamate (3q) Following the general procedure, 3q was
obtained as a white solid (194 mg, 85% yield), 1H NMR (500 MHz, CD3OD) δ 7.81 (d, J = 7.7 Hz,
2H), 7.63 (s, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.99
(s, 1H), 3.65 (t, J = 8.6 Hz, 1H), 2.79 (dd, J = 8.9, 4.2 Hz, 2H), 2.31 (dd, J = 13.7, 3.9 Hz, 1H), 2.23
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– 2.15 (m, 1H), 2.07 – 1.92 (m, 2H), 1.87 (dd, J = 11.2, 5.0 Hz, 1H), 1.73 – 1.63 (m, 1H), 1.55 –
1.22 (m, 7H), 1.18 (td, J = 11.5, 7.3 Hz, 1H), 0.75 (s, 3H); 13C{1H} NMR (126 MHz, CD3OD) δ
166.5, 148.0, 140.0, 138.8, 133.3, 131.8, 128.5, 128.0, 126.6, 121.4, 118.5, 81.0, 49.8, 44.1, 42.9,
38.5, 36.5, 29.3, 29.1, 26.6, 26.0, 22.6, 10.2; HRMS (ESI) calcd for [M+H]+ [C25H30NO5S]+
456.1845, found 456.1820.
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(7R,9S,13S,14S,17S)-17-Hydroxy-13-methyl-7-(9-((4,4,5,5,5-
pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-
cyclopenta[a]phenanthren-3-yl benzoylsulfamate (3r) Following the general procedure, 3r was
obtained as a white solid (276 mg, 70% yield), 1H NMR (600 MHz, DMSO-d6) δ 7.87 (d, J = 7.5
Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 8.7 Hz, 1H), 6.99 (dd, J = 8.6,
2.6 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 2.89 – 2.57 (m, 7H), 2.45 – 2.22 (m, 5H), 1.90 (p, J = 7.5 Hz,
3H), 1.78 (dt, J = 12.5, 3.2 Hz, 1H), 1.70 – 1.43 (m, 6H), 1.12 – 1.39 (m, 17H), 0.89 – 0.77 (m, 1H),
0.65 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 166.5, 166.4, 166.4, 147.9, 138.3, 137.1, 132.7,
131.2, 129.6, 128.4, 128.4, 128.2, 127.4, 127.4, 122.4, 120.0, 118.8, 116.0, 115.7, 115.5, 112.8,
80.0, 51.0, 49.2, 45.9, 42.8, 41.2, 38.0, 36.7, 33.9, 32.4, 29.8, 29.2, 29.0, 28.8, 28.7, 28.6, 28.5, 28.4,
28.1, 27.3, 26.8, 25.0, 22.2, 22.0, 14.0, 11.3, 11.2; HRMS (ESI) calcd for [M+H]+ [C39H53F5NO6S2]+
790.3234, found 790.3233.
4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenyl
benzoylsulfamate (3s) Following the general procedure, 3s was obtained as a yellow solid (208 mg,
75% yield), 1H NMR (500 MHz, DMSO-d6) δ 7.90 (d, J = 7.4 Hz, 2H), 7.59 (d, J = 7.6 Hz, 1H),
7.48 (d, J = 7.7 Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 6.80 (dd, J = 15.0, 8.0 Hz, 2H), 6.68
(s, 1H), 6.60 (d, J = 7.9 Hz, 1H), 4.11 (t, J = 7.9 Hz, 1H), 3.90 (s, 1H), 3.69 (d, J = 10.1 Hz, 6H),
3.61 (s, 4H), 2.96 – 2.73 (m, 4H), 1.24 (s, 1H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 178.8, 178.8,
151.6, 149.1, 147.8, 133.0, 132.9, 131.6, 129.3, 128.9, 128.8, 123.7, 123.4, 121.7, 120.9, 114.8,
112.9, 112.3, 71.2, 56.3, 55.9, 55.8, 45.8, 41.5, 37.2, 34.3; HRMS (ESI) calcd for [M+H]+
[C28H30NO9S]+ 556.1641, found 556.1622.
ASSOCIATED CONTENT
1
Supporting information: H and 13C NMR of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yangguang@shanghaitech.edu.cn (G. Yang), xuht@shanghaitech.edu.cn (H. Xu),
mapx@shanghaitech.edu.cn (P. Ma)
ORCID: Hongtao Xu: 0000-0001-5174-9079; Peixiang Ma: 0000-0001-6794-1663
Notes: The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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This work is supported by the National Natural Science Foundation of China (21977070, and
31500632), and the Science and Technology Commission of Shanghai Municipality (Grant
16DZ1910200).
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