Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives

Article abstract of DOI:10.1021/jm970790w

We have explored the structure-activity relationship (SAR) surrounding the clinically efficacious antiepileptic drug topiramate (1), a unique sugar sulfamate anticonvulsant that was discovered in our laboratories. Systematic structural modification of the parent compound was directed to identifying potent anticonvulsants with a long duration of action and a favorable neurotoxicity index. In this context, we have probed the pharmacological importance of several molecular features: (1) the sulfamate group (6-8, 22- 25, 27, 84), (2) the linker between the sulfamate group and the pyran ring (9, 10, 21a,b), (3) the substituents on the 2,3- (58-60, 85, 86) and 4,5- fused (30-38, 43, 45-47, 52, 53) 1,3-dioxolane rings, (4) the constitution of the 4,5-fused 1,3-dioxolane ring (2, 54, 55, 63-68, 76, 77, 80, 83a-r, 84- 87, 90a, 91a, 93a), (5) the ring oxygen atoms (95, 96, 100-102, 104, 105), and (6) the absolute stereochemistry (106 and 107). We established the C1 configuration as R for the predominant alcohol diastereomer from the highly selective addition of methylmagnesium bromide to aldehyde 15 (16:1 ratio) by single-crystal X-ray analysis of the major diastereomer of sulfamate 21a. Details for the stereoselective syntheses of the hydrindane carbocyclic analogues 95, 96, 100, and 104 are presented. We also report the synthesis of cyclic imidosulfites 90a and 93a, and imidosulfate 91a, which are rare examples in the class of such five-membered-ring sulfur species. Imidosulfite 93a required the preparation and use of the novel sulfur dichloride reagent, BocN=SCl₂. Our SAR investigation led to the impressive 4,5-cyclic sulfate analogue 2 (RWJ37947), which exhibits potent anticonvulsant activity in the maximal electroshock seizure (MES) test (ca. 8 times greater than 1 in mice at 4 h, ED₅₀ = 6.3 mg/kg; ca. 15 times greater than 1 in rats at 8 h, ED₅₀ = 1.0 mg/kg) with a long duration of action (>24 h in mice and rats, po) and very low neurotoxicity (TD₅₀ value of > 1000 mg/kg at 2 h, po in mice). Cyclic sulfate 2, like topiramate and phenytoin, did not interfere with seizures induced by pentylenetetrazole, bicucculine, picrotoxin, and strychnine; also, 2 was not active in diverse in vitro receptor binding and uptake assays. However, 2 turned out to be a potent inhibitor of carbonic anhydrase from different rat tissue sources (e.g., IC₅₀ of 84 nM for the blood enzyme and 21 nM for the brain enzyme). An examination of several analogues of 2 (83a-r, 85-87, 90a, 91a, 93a) indicated that potent anticonvulsant activity is associated with relatively small alkyl substituents on nitrogen (Me/H, 83a; Me/Me, 83m; Et/H, 83b; allyl/H, 83e; c- Pr/H, 83j; c-Bu/H, 83k) and with limited changes in the cyclic sulfate group, such as 4,5-cyclic sulfite 87a/b. The potent anticonvulsants 83a and 83j had greatly diminished carbonic anhydrase inhibitory activity; thus, inhibition of this enzyme may not be a significant factor in the anticonvulsant activity. The α-L-sorbopyranoses 67, 68, and 80, which mainly possess a skew conformation (ref 29), were nearly twice as potent as topiramate (1). The L- fructose enantiomers of 1 (106) and 2 (107), synthesized from L-sorbose, were found to have moderate anticonvulsant activity, with eudysmic ratios (MES ED₅₀ in mice at 4 h, po) of 1:106 = 1.5 and 2:107 = 3.5. The log P values for 1 and 2 were determined experimentally to be 0.53 and 0.42, respectively, which are less than the optimal 2.0 for CNS active agents. However, analogues with more favorable calculated log P (clogP) values, in conjunction with just minor steric perturbation according to the developed SAR profile, such as 47 (clogP = 2.09), 83m (1.93), and 86 (1.50), did not display improved potency: 47 is less potent than 1, 83m is equipotent with 2, and 86 is less potent than 2. Although the measured log P value for diethyl analogue 31 is 1.52, this did not translate into enhanced potency relative to 1. The 400-MHz ¹H NMR studies of 1 and 2 indicated that the skew ³S₀ conformer predominates at ambient temperature in nonaqueous and aqueous media; 95 strongly populates a skew ³S₀ conformer in benzene and (as reported in ref 29) 67 mainly adopts this skew conformation in various solvents. X-ray crystal structures for 1, 2, and 95 (as well as 67) depict the skew ³S₀ conformer in the solid state. Solution IR studies with 1, 2, and 83b showed an absence of intramolecular hydrogen bonding, in contrast to what has been observed for alcohol 4 (ref 73).

Full text of DOI:10.1021/jm970790w

J . Med. Chem. 1998, 41, 1315-1343
1315
Str u ctu r e-Activity Stu d ies on An ticon vu lsa n t Su ga r Su lfa m a tes Rela ted to
Top ir a m a te. En h a n ced P oten cy w ith Cyclic Su lfa te Der iva tives
Bruce E. Maryanoff,* Michael J . Costanzo, Samuel O. Nortey, Michael N. Greco, Richard P. Shank,
J ames J . Schupsky, Marta P. Ortegon, and J effry L. Vaught
Drug Discovery, The R. W. J ohnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477
Received November 20, 1997
We have explored the structure-activity relationship (SAR) surrounding the clinically
efficacious antiepileptic drug topiramate (1), a unique sugar sulfamate anticonvulsant that
was discovered in our laboratories. Systematic structural modification of the parent compound
was directed to identifying potent anticonvulsants with a long duration of action and a favorable
neurotoxicity index. In this context, we have probed the pharmacological importance of several
molecular features: (1) the sulfamate group (6-8, 22-25, 27, 84), (2) the linker between the
sulfamate group and the pyran ring (9, 10, 21a ,b), (3) the substituents on the 2,3- (58-60, 85,
86) and 4,5-fused (30-38, 43, 45-47, 52, 53) 1,3-dioxolane rings, (4) the constitution of the
4,5-fused 1,3-dioxolane ring (2, 54, 55, 63-68, 76, 77, 80, 83a -r , 84-87, 90a , 91a , 93a ), (5)
the ring oxygen atoms (95, 96, 100-102, 104, 105), and (6) the absolute stereochemistry (106
and 107). We established the C1 configuration as R for the predominant alcohol diastereomer
from the highly selective addition of methylmagnesium bromide to aldehyde 15 (16:1 ratio) by
single-crystal X-ray analysis of the major diastereomer of sulfamate 21a . Details for the
stereoselective syntheses of the hydrindane carbocyclic analogues 95, 96, 100, and 104 are
presented. We also report the synthesis of cyclic imidosulfites 90a and 93a , and imidosulfate
91a , which are rare examples in the class of such five-membered-ring sulfur species.
Imidosulfite 93a required the preparation and use of the novel sulfur dichloride reagent,
BocNdSCl2. Our SAR investigation led to the impressive 4,5-cyclic sulfate analogue 2 (RWJ -
37947), which exhibits potent anticonvulsant activity in the maximal electroshock seizure (MES)
test (ca. 8 times greater than 1 in mice at 4 h, ED50 ) 6.3 mg/kg; ca. 15 times greater than 1
in rats at 8 h, ED50 ) 1.0 mg/kg) with a long duration of action (>24 h in mice and rats, po)
and very low neurotoxicity (TD50 value of >1000 mg/kg at 2 h, po in mice). Cyclic sulfate 2,
like topiramate and phenytoin, did not interfere with seizures induced by pentylenetetrazole,
bicucculine, picrotoxin, and strychnine; also, 2 was not active in diverse in vitro receptor binding
and uptake assays. However, 2 turned out to be a potent inhibitor of carbonic anhydrase from
different rat tissue sources (e.g., IC50 of 84 nM for the blood enzyme and 21 nM for the brain
enzyme). An examination of several analogues of 2 (83a -r , 85-87, 90a , 91a , 93a ) indicated
that potent anticonvulsant activity is associated with relatively small alkyl substituents on
nitrogen (Me/H, 83a ; Me/Me, 83m ; Et/H, 83b; allyl/H, 83e; c-Pr/H, 83j; c-Bu/H, 83k ) and with
limited changes in the cyclic sulfate group, such as 4,5-cyclic sulfite 87a /b. The potent
anticonvulsants 83a and 83j had greatly diminished carbonic anhydrase inhibitory activity;
thus, inhibition of this enzyme may not be a significant factor in the anticonvulsant activity.
The R-L-sorbopyranoses 67, 68, and 80, which mainly possess a skew conformation (ref 29),
were nearly twice as potent as topiramate (1). The L-fructose enantiomers of 1 (106) and 2
(107), synthesized from L-sorbose, were found to have moderate anticonvulsant activity, with
eudysmic ratios (MES ED50 in mice at 4 h, po) of 1:106 ) 1.5 and 2:107 ) 3.5. The log P
values for 1 and 2 were determined experimentally to be 0.53 and 0.42, respectively, which
are less than the optimal 2.0 for CNS active agents. However, analogues with more favorable
calculated log P (clogP) values, in conjunction with just minor steric perturbation according to
the developed SAR profile, such as 47 (clogP ) 2.09), 83m (1.93), and 86 (1.50), did not display
improved potency: 47 is less potent than 1, 83m is equipotent with 2, and 86 is less potent
than 2. Although the measured log P value for diethyl analogue 31 is 1.52, this did not translate
1
into enhanced potency relative to 1. The 400-MHz H NMR studies of 1 and 2 indicated that
3
the skew S0 conformer predominates at ambient temperature in nonaqueous and aqueous
3
media; 95 strongly populates a skew S0 conformer in benzene and (as reported in ref 29) 67
mainly adopts this skew conformation in various solvents. X-ray crystal structures for 1, 2,
3
and 95 (as well as 67) depict the skew S0 conformer in the solid state. Solution IR studies
with 1, 2, and 83b showed an absence of intramolecular hydrogen bonding, in contrast to what
has been observed for alcohol 4 (ref 73).
S0022-2623(97)00790-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/19/1998

1316 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
Epilepsy is a chronic neurological disorder character-
ized by seizures that result from the sudden, disorderly
depolarization of neurons in the brain.1 The constella-
tion of seizure disorders that comprise “epilepsy” ranges
from brief cessation of responsiveness (absence seizures)
to severe tonic-clonic muscle spasms with a loss of
consciousness (generalized seizures). Anticonvulsant
drugs, which probably function by inhibiting initiation
and/or propagation of the paroxysmal neuronal dis-
charges, are employed to control epileptic symptoms.
However, as far as therapeutic applications are con-
cerned, the available drugs are limited in number, kind,
and side-effect profile. This has inspired a broad-based
search, including that spearheaded by the National
Institute of Neurological Disorders and Stroke (NINDS),
to find new, more effective, less toxic anticonvulsant
agents.
Because of the multiple etiologies of epilepsy, and our
general lack of understanding about the responsible
physiological mechanisms, the discovery of novel anti-
epileptic drugs is often an empirical exercise. Indeed,
we discovered topiramate (1; TOPAMAX®) in our labo-
ratories around 1980 by means of a standard in vivo
screening protocol: the maximal electroshock seizure
(MES) test.2 Topiramate is orally active with rapid
absorption, high bioavailability, and a long duration of
action. Now, the antiepileptic efficacy of topiramate has
been confirmed through clinical trials in patients refrac-
tory to commonly used drugs,3 such as phenytoin and
carbamazepine, and the drug development program has
reached a very advanced stage, with several worldwide
marketing approvals.
Although topiramate was one of the more interesting
O-alkyl sulfamate anticonvulsants in our earlier paper,2a
we did not explore the structure-activity characteristics
of the sugar sulfamate pharmacophore in substantial
detail. With respect to analogues of topiramate with a
modified sulfamate group, monomethyl, monophenyl, or
dimethyl substitution on nitrogen caused a significant
attenuation in potency in the MES test in mice, while
replacement of sulfamate with carbamate abolished
activity. Additionally, linkage of the two methyl groups
on the 4,5-ketal ring into a cyclohexane ring, or removal
of the 4,5-ketal, abolished MES activity. Given our
favorable clinical experience with topiramate, we con-
tinued to investigate this novel sugar sulfamate class,
intent on identifying other potent, long-lived anticon-
vulsants devoid of neurological side effects and on
defining the structure-activity relationship (SAR) for
this series more thoroughly. In our follow-up work, we
sought to determine the pharmacological importance of
(1) the sulfamate group, (2) the linker between the
sulfamate group and the pyran ring, (3) the substituents
on the 2,3- and 4,5-fused 1,3-dioxolane rings, (4) the
constitution of the 4,5-fused 1,3-dioxolane ring, (5) the
ring oxygen atoms, and (6) the absolute stereochemistry.
We now describe the systematic structural modification
of parent compound 1, which ultimately led to a cyclic
sulfate analogue, RWJ -37947 (2), with potent anticon-
vulsant activity, a long duration of action, and an
excellent neurotoxicity index.4
Str u ctu r a l Alter a tion s a n d Syn th etic Ch em istr y
Th e Su lfa m a te Gr ou p in 1 a n d Its Lin k er . Our
previous report2a indicated that replacement of the
OSO2NH2 group in topiramate (1) with OC(O)NH2 (3)
or OH (4) resulted in a loss of anticonvulsant activity,
while the SO2N3 (5) group resulted in moderate activity.
We have further examined isosteric analogues with
NHSO2NH2 (6), NMeSO2NH2 (7), and CH2SO2NH2 (8)
groups, as well as homologues with an elongated linker
by virtue of CH2OSO2NH2 (9) and CH2CH2OSO2NH2
(10) groups (Table 1).
Topiramate is especially interesting from a structural
standpoint because it is derived from a monosaccharide
and bears an unusual sulfamate functional group. By
contrast, many well-known antiepileptic drugs, such as
phenytoin, carbamazepine, and phenobarbital, contain
a urea-type functionality accompanied by a benzenoid
group, while other drugs contain an aryl-substituted
benzodiazepine nucleus (e.g., diazepam), a backbone
derived from γ-aminobutyric acid (e.g., vigabatrin and
progabide), an amino- and aryl-substituted polyaza-
aromatic unit (e.g., lamotrigine), and carbamate groups
(e.g., felbamate). The antiepileptic agent zonisamide
(shown), a heterocyclic methanesulfonamide, is some-
what structurally related to topiramate. Topiramate’s
clinical success aptly supports a strategy of discovering
new antiepileptic drugs predicated on structural unique-
ness.
Aminodeoxyfructose 115 was reacted with sulfamoyl
chloride and NaH to give 6 in 20% yield. To obtain 7,
fructose bis-acetonide (4)2a,6 was readily converted to
iodide 12 (iodine, Ph3P, and imidazole) in 80% yield7
and then treated with N-methylbenzylamine for 2 days
in the presence of sodium carbonate to give 13 in 98%
yield. Hydrogenolysis of 13 (H2, 10% Pd/C) afforded
amine 14 (74% yield), which was reacted with sulfamoyl
chloride and NaH to give 7 in 7% yield.
* Address correspondence to this author. Fax: 215-628-4985. E-
mail: bmaryano@prius.jnj.com.

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1317
Ta ble 1. Chemical Properties and Biological Data
dosage po,
mg/kg
MES test, 4 h % block
e
compda
% yieldb
mp (purifcn)c
[R]D (c)d
(ED50)
2
6
80
20
7
150-151 dec (E/W)f
50-52 (foam, LC)
foam (LC)
142-143 (LC)
syrup (LC)
syrup (LC)
syrup (LC)
syrup (LC)
syrup (LC)
-28.8 (1.17)
-25.9 (0.08)
-18.2 (0.63)
-29.5 (1.00)
-18.7 (1.01)
-19.6 (0.98)
-27.2 (0.97)
-24.2 (1.09)
-29.2 (1.06)
-11.7 (1.18)
-27.5 (1.04)
-44.7 (1.06)j
-35.1 (1.00)
-33.9 (1.00)
-25.6 (1.00)
-18.9 (1.00)
-29.3 (1.20)
-18.1 (1.00)
-25.9 (1.00)
-25.3 (1.00)
-19.3 (1.00)
-19.5 (1.00)
-29.3 (1.00)
+1.3 (0.74)
10, 35
75
75
75
75
75
75
75
35, 75
10, 75
75
75
75
75
75, 300
75
80, 100% (6.3 mg/kg)
0%
0%
7g
8
9
10
21a
21b
22i
23
24
25
27
30
31
32
33a
33b
34
25
41
53
43
45
59
67
76
98
76
42
34
79
32
6
34
79
45
55
50
55
42
44
81
0%
0%h
0%
0%
0%
0, 90%
0, 80%
0%
30%
0%
0%
0, 80%
0%
0%
48-50 (LC)
glass (LC)
152-154 (EA/M)
125-127 (E)k
142-144 (LC)
127-130 (LC)
131-133 (EA/H)
foam (LC)
syrup (LC)
131-132 (EA/H)
97-99 (LC)
164-165 (LC)
130-133 (LC)
foam (LC)
122-124 (LC)
glass (LC)
syrup (LC)
109-112 (foam, LC)
75
10, 75
35, 75
75
75
75
35, 75
75
75
75
75
75, 300
75
75, 300
75
75
75, 300
75
0, 100%
10, 90%l
35
90%
0%
36
37m
38
0%
0, 20%n
43
45
46
0%
0%
0%
40%
0, 70%
12.5%
0, 50%
0%
0%
0, 70%
0%
0%
0, 40%
0, 100%
0%
-10.6 (1.11)j
-26.8 (1.00)
-23.8 (1.00)
-45.5 (0.48)j
-75.1 (1.75)j
-6.1 (1.03)j
-9.7 (1.03)j
-31.7 (1.00)
-19.7 (1.00)
-38.6 (1.00)
+27.0 (1.00)
+28.4 (1.20)
+27.1 (1.02)
-0.9 (1.13)
47
52o
53o
54
50
92
73
79
72
58
54
88
88-89 (B/H)
151-152 (B)
foam (LC)
55
58
59
60
63
64
65
syrup (LC)
156-158 (AE/W)
135-138 (LC)
syrup (LC)
75
75, 300
75, 300
300
10, 75
10, 75
75
75-76 (B/H)
66o
67o
68o
76
+39.4 (1.00)
+20.1 (1.00)
-39.8 (1.26)
-22.3 (1.00)
+7.7 (1.00)
0, 90% (30 mg/kg)
0, 100% (21 mg/kg)
50
53
syrup (LC)
115-116 (I)
0%
77
75
30%h
80o
83a
83b
83c
83d
83e
83f
83g
83h
83i
83j
83k
83l
83m
83n
83o
83p
83q
83r
84
18.75, 37.5
10
50, 90% (24 mg/kg)
100% (7.4 mg/kg)
0, 100% (14.4 mg/kg)
40, 90%
30, 100%
0, 70%
0, 100%
0%
0%
0, 100%
0, 90% (7.3 mg/kg)
0, 90%
0, 30%
70, 100% (6.9 mg/kg)
10, 100%
0%
0%
0, 100%
0, 100%
0%
0, 10%
0, 100%
70% (5.7 mg/kg)
70% (6.3 mg/kg)
90
89
79
74
55
48
33
68
70
94
87
57
55
44
93
69
81
87
71
44
34
57
40
18
56
23
27
24
40
55
41
68
151-153 (EA/H)
glass (LC)
125-127 (LC)
111-113 (AE/W)
75-77 (AE/W)
syrup (LC)
foam (LC)
56-62 (foam, LC)
foam (LC)
foam (LC)
foam (LC)
foam (LC)
109-111 (AE/W)
foam (LC)
foam (LC)
foam (LC)
-25.3 (1.00)
-23.6 (1.00)
-24.3 (1.00)
-25.1 (1.00)
-31.1 (1.00)
-17.1 (1.00)
-30.4 (0.96)
-28.4 (1.00)
-22.8 (1.00)
-24.3 (1.00)
-29.2 (1.00)
-23.5 (1.00)
-25.3 (1.00)
-26.3 (1.00)
-22.0 (1.00)p
-20.0 (0.82)
-20.8 (1.00)
-21.0 (1.00)
-35.5 (0.95)
-31.5 (1.00)
-23.1 (1.00)
-19.8 (0.88)n
-14.9 (1.00)
-43.5 (1.00)
+23.3 (1.00)
+4.1 (1.00)
3, 35
10, 75
10, 35
1, 10
10, 75
300
75
10, 75
1, 10
1, 10
10, 75
10, 35
10, 75
75
75
foam (LC)
foam (LC)
10, 75
10, 35
75
75, 300
10, 75
10
10
10
75, 300
300
300
powder (LC)
139-141 (E/W)
130-133 (EE/H)
148-151 (E)
151-153 (E)
197-199 dec (E)
68-73 (foam, LC)
77-101 (foam, LC)
175-176 (E)
168-170 (EA/H)
152-154 (EA/H)
70 dec (CC)
85
86
87a /b
87a
87b
90a
91a
93a
95
70% (6.5 mg/kg)
0, 75%
80%
40%
0%
0%
0%
+19.5 (1.00)
75
75
75
75
96
100
101
102
wax (CC)
50-52 (CC)
0%
0%
75

1318 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Ta ble 1. (Continued)
Maryanoff et al.
dosage po,
mg/kg
MES test, 4 h % block
e
compda
% yieldb
72
mp (purifcn)c
[R]D (c)d
(ED50)
104
64-66 (EE/H)
75
0%
105q
+1.2 (0.50)
+30.1 (1.85)
+27.1 (1.18)
5, 35
40, 80
15, 30
60
30, 80% (16.6 mg/kg)
20, 50% (82 mg/kg)
30, 80% (22 mg/kg)
60% (53 mg/kg)
106
107
72
51
125-126 (AE/W)
128-129 dec (AE/W)
topiramater
phenytoinr
(6.4 mg/kg)
a
All compounds were isolated and purified in unadducted form (i.e., no addition salts) unless indicated otherwise. They are represented
by standard molecular formulas except for the following solvates: 6 (0.1 molar equiv of toluene), 7 (0.1 EtOAc, 0.1 DMF), 9 (0.3 H2O), 10
(0.7 H2O), 22 (0.15 EtOAc), 25 (1.0 imidazole), 33b (0.1 EtOAc), 34 (0.1 EtOAc), 45 (0.1 H2O), 64 (0.1 H2O), 66 (0.15 CHCl3), 83b (0.25
EtOAc), 83f (0.1 EtOAc), 91a (0.2 CH2Cl2, 0.1 hexanes). Compounds are crystalline solids unless noted otherwise in the mp column.
Microanalytical data (C, H, N; sometimes S; water where necessary) were within the accepted range ((0.4%) unless indicated otherwise.
b
All new target compounds were characterized by high-field NMR and mass spectrometry. The yields given are for the final synthetic
step, as referred to in the text; they are for the product prior to final purification. c Mp values (in °C) are corrected to a set of standards.
The purification method is indicated in parentheses: for compounds purified by recrystallization, a solvent is given in parentheses (AE
) 95% EtOH, B ) benzene, E ) EtOH, EA ) ethyl acetate, EE ) ethyl ether, H ) hexanes, I ) 2-propanol, M ) MeOH, W ) water); “LC”
or “CC” is given in parentheses for compounds purified by preparative HPLC or flash column chromatography; for noncrystalline compounds,
d
a descriptor of physical form is indicated. Optical rotations (in units of degrees) were measured at 25 °C in methanol, unless otherwise
noted. The concentration, in g/100 mL, is given in parentheses. e Maximal electroshock seizure test in mice. Activity was measured at 4
h following administration of the oral dose, unless noted otherwise, and is reported as percent block at the given dose(s). ED50 values are
given in parentheses for selected compounds. The 95% confidence limits for the ED50 values are contained in Supporting Information (see
paragraph at the end of this paper). f For three batches, the mp varied from 150 to 151 (dec), 139-141 (dec), and 147-148 (dec) °C.
g
h
i
j
Recrystallized from ethanol-water, 1:1. %C: 44.65/45.30. Activity of 70% at 75 mg/kg at 1 h. %C: 46.07/46.54. Determined at 20
°C. Lit. mp 126-127 °C (ref 15). Activity of 60% at 35 mg/kg at 1 h. %C: 47.23/47.87. Activity of 80% at 75 mg/kg at 1 h. o Reported
in ref 29. Determined in chloroform. Reported in ref 58. Reference compound.
k
l
m
n
p
q
r
ration-oxidation to give alcohol 198b in 37% yield (eq
2). Reaction with NaH and sulfamoyl chloride provided
homologue 9 in 41% yield. For homologue 10, aldehyde
15 was converted with Ph3PdCHCO2Me to the corre-
sponding enoate (E:Z ) 13:1; 95% yield),11 which was
hydrogenated (H2, PtO2), reduced with LiAlH4 to alcohol
2012 (91%), and reacted with NaH and sulfamoyl
chloride (53%).
We also substituted the C1 methylene of 1 with
methyl (21a ) and ethyl (21b). Hence, aldehyde 15 was
reacted with methyl- or ethylmagnesium bromide in
ether to give the intermediate alcohols, each as a
strongly biased mixture of two diastereomers, with
respective isomer ratios of ca. 10:1 and 5:1, presumably
in the same direction (R configuration; vide infra).8c,13
Reaction of each alcohol with NaH and sulfamoyl
chloride provided 21a as virtually a single isomer and
21b as a 5:1 mixture (ca. 45% yield for each). Because
of the quaternary stereogenic center at C2, adjacent to
the newly created stereogenic center at C1, it was not
possible to assign the configuration at C1 from 1H or
13C NMR data. Thus, the direction of this highly
diastereoselective addition to aldehyde 15 would have
remained unknown.8d However, we were fortunately
able to obtain a single crystal of the major diastereomer
of 21a and establish the configuration at C1 as R by
X-ray analysis. By analogy with 21a , we assign the R
configuration at C1 in the major isomer of 21b.
The synthesis of sulfonamide 8 began with a Wads-
worth-Emmons olefination reaction between aldehyde
158,9 and the phosphonate reagent depicted in eq 1,
which was prepared by treating ethyl methanesulfonate
with butyllithium (THF, -70 °C) followed by diphenyl
phosphorochloridate.10 Alkene 16, which was obtained
in 67% yield exclusively in the E configuration, was
hydrogenated, hydrolyzed, and acidified to furnish 17
(48%), which was converted to 8 with thionyl chloride
and ammonia (25%).
Our previous report2a indicated that substitution of
the nitrogen of 1 resulted in attentuated anticonvulsant
activity. The N-methyl analogue showed reasonable
activity, being 50% less potent than 1; however, the
N-phenyl and N,N-dimethyl analogues were virtually
Wittig methylenation of aldehyde 15 afforded 188b
(14% yield), which was subjected to standard hydrobo-

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1319
F igu r e 1. Compound 36 shown in the twist-boat (or skew)
conformation.
inactive. We synthesized four additional N-substituted
compounds, 22-25, to further define the SAR of 1.14
Treatment of alcohol 4 with sulfuryl chloride in the
presence of pyridine (toluene, 0-10 °C) afforded a
reasonably stable chlorosulfate2a (26) in 95% yield.
Reaction of 26 with excess ethylamine, butylamine, or
benzylamine provided 22-24 (yields: 59, 67, and 76%).
Reaction of 1 with 1-acetylimidazole provided 25, which
was isolated and purified as a crystalline imidazole salt
(78% yield). Mesylate 27,15 which is isosteric with 1 but
lacks the acidic, hydrogen-bond donor group, was ob-
tained by reacting 4 with methanesulfonyl chloride in
the presence of triethylamine (76% yield).
Th e 4,5-Rin g in 1. We were interested in modifying
the 4,5-ketal of 1 by changing the ring substituents, size,
and composition, as well as breaking the ring open and
removing the ring. Data for the various target com-
pounds are presented in Table 1. Earlier, we reported2a
on 4,5-diol 28 and cyclohexylidene compound 29, both
of which are devoid of anticonvulsant activity. We have
followed up on 29 with cyclopentylidene analogue 30,
which was prepared from 28 and the trimethylsilyl enol
ether of cyclopentanone in 42% yield. A series of related
ring-substituted analogues, 31-38, were also synthe-
sized from 28. Ketone adduct 31 was produced via the
silyl enol ether method (34% yield), while 35 and 37
were produced by using the relevant ketone in the
presence of triethyl orthoformate (yields: 79 and 55%).
We obtained 35 as an 85:15 mixture of diastereomers
in favor of the R form, as shown, and 37 exclusively as
the R isomer. Analogues 33, 34, 36, and 38 were
obtained via condensation of 28 with the relevant
aldehyde diethyl acetal, generated in situ from the
aldehyde and triethyl orthoformate (yields: 39, 34, 45,
and 50%). We obtained 33 and 34 as a 90:10 mixture
of diastereomers in favor of the R form, and 33a and
33b were separated by HPLC for independent biological
testing; by contrast, we obtained 36 and 37 exclusively
as the R isomer, and 38 as a 3:1 R:S mixture (which
could not be readily separated by HPLC). It is interest-
ing to note that there is a strong preference for the bulky
substituent to occupy an endo position on the five-
membered dioxolane ring of the cis-fused 5,6-ring
system. Given a twist-boat conformation for the pyran
ring,2a,4 this suggests that the dioxolane ring fused to
the 4,5-position of the sugar pyran ring is folded
outward from the pyran ring with the large group
favored in a pseudoequatorial orientation (endo), as
opposed to a pseudoaxial orientation (exo). This struc-
tural disposition is illustrated for 36 in Figure 1.
To synthesize 32, we resorted to a different approach,
involving dibromomethane alkylation under phase-
transfer conditions (eq 3),16 because reactions of 28 with
37% formaldehyde17a (HCl, heat) or paraformaldehyde17b
(H2SO4, heat) were unsuccessful.18 Thus, 4 was ben-
zylated in 87% yield to give 39, which was carefully
hydrolyzed to furnish diol 40 in 23% yield.19 Phase-
transfer alkylation at 60 °C yielded 41 (60%), which was
subjected to hydrogen in the presence of Pearlman’s
catalyst to give 42 (99%).20 Reaction of 42 with NaH
and sulfamoyl chloride provided 32 in 79% yield. By
the same token, fused 1,4-dioxane analogue 43 was
synthesized by alkylating diol 40 with 1,2-dibromoeth-
ane in the presence of 50% NaOH (34% yield) and
deprotecting the intermediate with hydrogen and Pearl-
man’s catalyst to give 44 (98% yield). Reaction of 44
with sulfamoyl chloride and triethylamine supplied 43
in 55% yield.
Reaction of diol 28 with tetramethyl orthocarbonate21
or triethyl orthoformate (p-TsOH catalyst) afforded 45

1320 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
in 42% yield or 46 in 44% yield; the latter reaction also
contained the ethyl imidate of 46 as a significant
byproduct. Compound 46 was a 90:10 mixture of
diastereomers with the major form being the S isomer,
that is, having the ethoxy group in the exo position. This
is the opposite stereochemical preference relative to the
alkyl-substituted compounds and is probably reflective
of a strong anomeric effect,22 which would favor an ether
group in the pseudoaxial position of a 1,3-dioxolane (see
Figure 1).
attempted silica gel chromatography. Reaction of 28
with dimethyldichlorosilane (Et3N, THF) led to decom-
position products instead of 57. A more chemically
propitious result was realized in the reaction of 28 with
sulfuryl chloride,26 which afforded cyclic sulfate 2 in ca.
75% yield over two steps (eq 5).4 The chemistry for
obtaining diverse 4,5-cyclic sulfur compounds akin to 2
is discussed in the next section.
Some analogues of 1 with the 2,3-ring modified, along
with the 4,5-ring, were prepared (viz. 58-60). Thus,
reaction of D-fructose with cyclohexanone in the pres-
ence of sulfuric acid, under conditions favoring the
thermodynamic diketal, yielded a mixture of 61 and 62
in a 10:1 ratio, contaminated with oligomeric material
from self-condensation of cyclohexanone. Alcohol 61,
isolated by Kugelrohr distillation followed by HPLC,
was reacted with sulfuryl chloride and pyridine (toluene,
5 °C) to give the chlorosulfate (100% yield), which was
reacted with anhydrous ammonia to give target 58 in
98% yield. The procedure for forming the sulfamate
from an alcohol is generally superior to sulfamoyl
chloride and base. In a similar manner, D-fructose was
reacted with 3-pentanone to obtain the thermodynamic
bis-ketal (ca. 10% yield), which was subjected to sulfuryl
chloride/pyridine, then ammonia, to supply 59 in 96%
yield.32 Reaction of D-fructose with benzaldehyde and
anhydrous zinc(II) chloride provided a mixture of at
least three bis-acetal isomers,33 from which one isomeric
alcohol was isolated after chromatography and recrys-
tallization in ca. 5% yield.34 Reaction of the alcohol with
sulfamoyl chloride and triethylamine (DMF, 5 °C)
provided 60 in 72% yield.
We wanted to synthesize bis-trifluoromethyl analogue
47 because it has a very favorable clogP value of 2.09
for effective transport across the blood-brain barrier,
relative to a measured log P of 0.53 for 1 (vide infra);23
additionally, the trifluoromethyl groups would impart
little steric perturbation relative to the structure of 1.
Reaction of diol 28 with trifluoroacetaldehyde ethyl
hemiacetal or chloral diethyl acetal under acidic condi-
tions (sulfuric acid, triethyl orthoformate) led only to
the formation of 1 (30% yield), presumably via dispro-
portionation. Hexafluoroacetone was reacted with 28
to generate a 1:1 adduct that was subjected to dehydra-
tion with dicyclohexylcarbodiimide (DCC) at 90 °C;
however, target 47 was not formed.24 Cyclic carbonate
52 (vide infra) also failed to react with hexafluoroac-
etone ethyl hemiacetal at 100 °C for 18 h.25 The
successful synthesis started with diol 40, which was
converted26 to chlorohydrin 48 in 47% yield (eq 4).
Formation of epoxide 49 occurred in 100% yield, and
condensation with hexafluoroacetone in the presence of
iodide in a sealed vessel for 38 h provided ketal 50 in
89% yield.27,28 Presumably, the reaction involves an
intermediate iodohydrin that reacts with hexafluoroac-
etone to give an oxyanion adduct, which cyclizes to the
desired product. Removal of the benzyl group (100%
yield) and reaction of 51 with sulfamoyl chloride and
triethylamine (DMF, 5 °C) supplied 47 in 81% yield.
We explored the introduction of other alterations into
the 4,5-ring of 1 involving sp2 carbons and noncarbon
atom centers. Reaction of 28 with 1,1′-carbonyldi-
imidazole (Im2CdO) or 1,1′-thiocarbonyldiimidazole
(Im2CdS) provided 52 (27%) or 53 (40%),29 and with
30
MeB(OH)2 (in MeOH) or PhB(OH)2 (in MeOH/water)
provided 54 (50%) or 55 (92%). Although 28 with
dibutyltin oxide31 (refluxing MeOH) successfully gener-
ated 56, the product was hydrolyzed back to 28 on
Although ring-opened diol 28 lacks anticonvulsant
activity,2a its higher polarity than 1 detracts from a fair

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1321
comparison of structure-activity for 4,5-ring cleavage.
Thus, we studied other analogues of 1 missing the 4,5-
ring, such as ethers 63 and 64 and dideoxy compounds
65 and 66. Alkylation of 28 with dimsylsodium and MeI
failed to provide 63, the major product being the N,N-
dimethyl derivative of 28. However, diol 40 was alky-
lated with MeI or EtI (NaH, DMF) to furnish the
corresponding bis-ethers, which were deprotected (H2,
10% Pd/C) and treated with NaH and sulfamoyl chloride
to yield 63 (58%) or 64 (54%). Proton NMR data for 63
and 64 indicate that these compounds prefer the chair
conformation (vide infra).
alternative, we decided to examine dihalocarbene ad-
dition reactions. When 71 or 73 was heated with excess
PhHgCBr3 in DME at 150 °C,43 no dibromocyclopropane
adduct was detected among the numerous products;
negative results were also found for reactions of 66 with
PhHgCBr3 and 71 with PhHgCBrCl2.43 Fortunately,
reaction of 71 with PhHgCCl3 at 150 °C for 4 days
generated dichlorocyclopropane 74 in 25% yield; how-
ever, on a 6-g scale only a 10% yield of 74 was realized
after extensive HPLC purification. Most favorably,
reaction of 71 with chloroform and KOH under phase-
transfer conditions (BnNEt3+Cl- catalyst) provided 74
in 44% yield.44 Debenzylation of 74 was accomplished
by free-radical bromination followed by hydrolysis (N-
bromosuccinimide, CH2Cl2/water, hν; 21% yield),45 and
intermediate 75 was converted to target 76 with sulfam-
oyl chloride and triethylamine (50% yield). Since 76
was found to be devoid of anticonvulsant activity (vide
infra), we discontinued the pursuit of 69. Nevertheless,
we were able to prepare isosteric epoxide 77, as a related
three-membered-ring analogue of 1. Hence, sorbopy-
ranose chlorohydrin 7826,29 was cleanly transformed by
K2CO3 in methanol to epoxide 79 (99% yield), which was
reacted with NaH and sulfamoyl chloride to give 77
(58% yield). We also converted 78 into sulfamate 80,
as disclosed previously.29
The Corey-Winter reaction35 of cyclic thiocarbonate
53 in refluxing trimethyl or triethyl phosphite provided
the N-methyl or N-ethyl version of alkene 66,36 while
N,N′-dimethyl-2-phenyl-1,3,2-diazaphospholidine37 was
not satisfactory because of extensive decomposition. We
were able to execute the elimination reaction by using
distilled triisopropyl phosphite; however, the yield of 66
was poor. Reaction of 53 with Fe(CO)5 in refluxing
xylenes38 or Ni(COD)2 in refluxing THF39 also failed to
generate any 66. By contrast, reaction of 53 with MeI40
(DME, 90 °C, sealed tube) produced a mixture of iodo
thiocarbonate 67 (74%) and cyclic carbonate 52 (23%),29
and reduction of 67 with Zn powder in refluxing 95%
ethanol supplied alkene 66 in 67% yield.29 Catalytic
hydrogenation of 66 with PtO2 as catalyst furnished 65
in 88% yield. Addition of bromine to 66 furnished
dibromosorbopyranose 68, along with ca. 20% of the
related â-D-tagatopyranose isomer (not shown), as re-
ported earlier.29
4,5-Cyclic Su lfu r Der iva tives Rela ted to 2. Cyclic
sulfate 2 was prepared from 28 by bis-chlorosulfate
formation followed by base-induced 4,5-ring closure (eq
5; vide supra).4 Owing to the exceptional biological
activity found with 2 (vide infra),4 we concentrated
synthetic efforts on related compounds in order to define
the SAR surrounding this series (Table 1). A collection
of N-substituted analogues was generated from chloro-
sulfate 82,46 which was synthesized from bis-acetonide
4 or diol 28, via alcohol 81, according to the chemistry
in eq 6.4 Conversion of the tris-chlorosulfate to 81 with
sodium bicarbonate, according to the literature,26 re-
sulted in a much lower yield (24%) than that obtained
with potassium carbonate (75%); also, the reaction time
for dechlorosulfation was shorter and formation of
byproduct 78 was minimized. Reaction of 82 with
diverse primary and secondary amines provided target
sulfamates 83a -p (see Table 2 for structural definition)
in 40-90% yield.4,47 Azido sulfate 83r was obtained in
82% yield by reacting 82 with sodium azide (pyridine,
MeCN). The carbamate analogue of 2, 84, was prepared
Alkene 66 failed to undergo Simmons-Smith cyclo-
propanation with diiodomethane to yield 69, in the
presence of zinc-copper couple, diethylzinc, or Zn/CuCl
(all in ether).41 A small amount of the alcohol 70 could
be isolated from the assorted byproducts in the dieth-
ylzinc reaction. Presuming that the sulfamate group
interfered with the cyclopropanation, we prepared alk-
ene 71 for study by converting diol 40 to a cyclic
thiocarbonate (Im2CdS, THF; 93% yield) and heating
that with trimethyl phosphite (83% yield). Simmons-
Smith cyclopropanation of 71 with CH2I2/Et2Zn gave a
5% yield of 72, whereas the yield with CH2I2/Zn-Cu was
somewhat better. Alcohol 73, from hydrolysis of 66 with
KOH in ethanol (15% yield), gave a cleaner reaction
with CH2I2/Zn-Cu in a shorter amount of time, al-
though the 7% yield of 70 was still quite poor.42 As an

1322 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Ta ble 2. Structures for 4,5-Cyclic Sulfate Derivatives 83
Maryanoff et al.
compd
R
R′
compd
R
R′
83a
83b
83c
83d
83e
83f
83g
83h
83i
H
H
H
H
H
H
H
H
H
Me
Et
CH2CF3
Bu
allyl
octyl
Ph
4-anisyl
benzyl
83j
83k
83l
H
H
H
Me
Et
c-Pr
c-Bu
c-Oc
Me
83m
83n
Et
83oa
83p b
83qc
83r d
-(CH2)5-
-(CH2)2NBn(CH2)2-
-CHdNCHdCH-
-N2-
a
b
NRR′ ) piperidide. NRR′) 4-(benzyl)piperazide. c NRR′ )
d
imidazolide. NRR′ ) azide.
in 71% yield from alcohol 81 by treatment with Cl3CC-
(O)Cl (1 equiv) and pyridine, isolation of the intermedi-
ate chloroformate, and reaction of it with anhydrous
ammonia.
recovered starting material.48b Reaction of diol 28 with
excess TsNdSCl2 furnished imidosulfite 90a (56%
yield; stereochemistry tentatively assigned50), along
49
with a some 87a /b, which were difficult to separate
51
away. Oxidation with sodium periodate and RuCl3
gave imidosulfate 91a (23% yield; presumably with
retention of configuration50), along with 2 and p-TsNH2
as byproducts. Attempted detosylation of 91a with
sodium naphthalenide in 1,2-dimethoxyethane (DME)
at 5 °C48c,52 afforded alkene 66 instead of 92a , and under
the same conditions, 90a afforded diol 28. N-Boc
imidosulfite 93a (stereochemistry tentatively assigned50)
53
was synthesized from diol 28 and BocNdSCl2 (pyri-
dine, THF, 5 °C) in 27% yield, but oxidation of 93a with
sodium periodate and RuCl3 only produced 2. However,
attempts to remove the Boc group of 93a to obtain 94a
under acidic conditions was not successful. Treatment
with trifluoroacetic acid generated target 94a , but it
appeared to be too hydrolytically unstable for isolation,
while 3 N HCl (in ethyl acetate) provided diol 28 and
trimethylsilyl iodide (CH2Cl2, 30 min) caused decompo-
sition. It should be noted that 90a , 91a , and 93a
constitute rare examples of five-membered cyclic imido-
sulfur species.
Cyclic sulfates 85 and 86, with a modified 2,3-ketal
group, were synthesized from bis-ketals 58 and 59.
Thus, bis-cyclohexylidene sulfamate 58 was hydrolyzed
under acidic conditions (6 N HCl, 50 °C) to the 4,5-diol
(17% yield), which was reacted with sulfuryl chloride
and pyridine, followed by methanolic NaHCO3, to give
85 in 44% yield. Tetraethyl sulfamate 59 was hydro-
lyzed to the 4,5-diol (23%), which was converted to 86
in the same fashion (34%).
We sought to alter the cyclic sulfate moiety in 2 in
terms of substitution on sulfur. Cyclic sulfite 87 was
an obvious entity and we were interested in obtaining
the S (87a , exo) and R (87b, endo) isomers indepen-
dently for biological evaluation. Reaction of diol 28 with
thionyl chloride produced a 5.3:1 mixture of 87a :87b
(THF at 23 °C).4 The individual diastereomers were
obtained starting with diol 40 according to the route
that we described previously in our preliminary com-
munication4 (see the Experimental Section for details).
This entailed the formation of benzyl cyclic sulfites 88a
and 88b with thionyl chloride (12:1 in THF at 5 °C; 2:1
in 1,4-dioxane at 100 °C), separation of the 2:1 mixture,
photodebenzylation of each isomer with N-bromosuc-
cinimide, and sulfamoylation.4
Th e En d ocyclic Oxygen Atom s in 1 a n d 2. We
were interested in assessing the relevance of various
sugar-associated oxygen atoms, on C1-C6 of 1, to
achieving anticonvulsant activity. Some structures
already mentioned (vide supra) serve to test this point:
for 8, O1 was replaced by CH2; for 65 and 66, O4 and
O5 were removed; for 67 and 80, O5 was replaced by
halogen; for 68, O4 and O5 were replaced by bromine;
for 76, O4 and O5 were replaced by a strained car-
bocycle; and for 77, O4 and O5 were combined into a
strained ring. In addition to the unsubtle changes
wherein the 4,5-ring was either destroyed or severely
strained (except for 8), we endeavored to replace O2,
O3, and O6 specifically with methylene groups and keep
the tricyclic ring system intact. We have already
communicated the stereoselective, multistep syntheses
of hydrindan derivatives 95 and 96, in which O2, O3,
and O6 are replaced by CH2.54,55 We have also used
intermediate alcohol 9754 to prepare 4,5-cyclic sulfate
analogue 100, according to the chemistry in eq 7. Crude
97 was benzylated, and the resulting ether was oxidized
stereoselectively to diol 98 with catalytic OsO4 and
N-methylmorpholine N-oxide (NMO).56 Sequential treat-
ment with NaH and sulfuryl diimidazole57 afforded the
cyclic sulfate, which was debenzylated to give 99.
Benzyl cyclic sulfite 884 was reacted with p-tosyl azide
and copper(0) (refluxing MeOH) in the hope of forming
imidosulfate 89,48a but no reaction was detected; reac-
tion with (BocN)OsO3 or Se(NTs)2 also resulted in

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1323
quinic acid via a lengthy, multistep protocol that has
been published in detail.58
Treatment of 99 with NaH and sulfamoyl chloride
resulted in a complex product mixture, from which 100
could not be isolated cleanly; reaction of 99 with sulfuryl
chloride followed by ammonia also failed. The cyclic
sulfate in this series, because of the absence of two
neighboring, electron-attracting oxygen atoms, is more
chemically reactive. Target 100 was ultimately ob-
tained in 90% yield by reacting 99 with sulfamoyl
chloride and triethylamine.
L-F r u ctose Isom er s of 1 a n d 2. The L-enantiomers
of topiramate (1) and RWJ -37947 (2) were sought for
biological evaluation (106 and 107). Consequently, we
prepared L-fructose from L-sorbose via the four-step
process developed by Chen and Whistler,59 with one
proviso. The single-pot conversion of 108 to 109 was
problematic, with yields of L-fructose under 10%. As a
remedy, we isolated diol 109 prior to treatment with
hydroxide and thereby garnered a 60% yield of L-
fructose. Following our established methodology, 106
was produced by bis-acetonide formation (56% yield) and
sulfamoylation (72%),2a and 107 was produced, in anal-
ogy to 2 (eq 5),4 by controlled hydrolysis of 106 (37%),
bis-chlorosulfate formation (48%), and 4,5-ring closure
(50%).
Biologica l Activity
Anticonvulsant activity for topiramate (1) and its
analogues was generally evaluated by using the stan-
dard maximal electroshock seizure (MES) test.60 Activ-
ity is indicated by a block of the hind-limb tonic-extensor
seizure caused by application of an electric shock via
corneal electrodes (percent of total animals dosed).
From experience over many years, this assay is noted
for being highly predictive of clinical efficacy for new
anticonvulsant compounds in patients with partial-onset
or generalized seizures. Data for the diverse topiramate
analogues, tested 4 h after oral administration, are
presented in Table 1.
Alcohol 97 was converted into sulfamate 101 with
NaH and sulfamoyl chloride (15% yield) and into
saturated sulfamate 102 (76% yield) by hydrogenation
(10% Pd/C) followed by NaH and sulfamoyl chloride.
Simmons-Smith cyclopropanation of alcohol 97 with
diiodomethane and diethylzinc worked well, in com-
parison to cyclopropanation of 73 (vide supra), to provide
103 in 67% yield; reaction with NaH and sulfamoyl
chloride gave target 104 in 72% yield.
Compound 105 was synthesized as an analogue of 1
with the O6 replaced by a methylene group. This
derivative of pseudo-â-D-fructose was obtained from (-)-
An t icon vu lsa n t St r u ct u r e-Act ivit y R ela t ion -
sh ip s. In our earlier work on analogues of topiramate,

1324 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
monomethyl, monophenyl, or dimethyl substitution on
nitrogen of the sulfamate group caused a significant
attenuation in potency in the MES test in mice, while
replacement of the sulfamate with a carbamate abol-
ished activity. Additionally, linkage of the two methyl
groups on the 4,5-ketal ring into a cyclohexane ring, or
removal of the 4,5-ketal to give a 4,5-diol, abolished
MES activity. Further modifications of the sulfamate
group were investigated.
(vide infra).29 The cyclopropane (76) and epoxide (77)
analogues showed attenuated potency.
The high potency of 4,5-cyclic sulfate 2 is a noteworthy
finding (ED50 ) 6.3 mg/kg). Consequently, several
analogues (83a -r , 85-87, 90a , 91a , 93a ) were prepared
and investigated (Table 1). To summarize, very potent
anticonvulsant activity is associated with relatively
small alkyl substituents on the nitrogen, i.e., Me/H, Me/
Me, Et/H, allyl/H, c-Pr/H, c-Bu/H) and with limited
changes in the sulfate group, such as cyclic sulfite 87a /
b. Compound 2 is approximately 8 times more potent
than topiramate and the N,N-dimethyl analogue in the
cyclic sulfate series, 83m (70% at 10 mg/kg, ED50 ) 6.9
mg/kg), is nearly 20 times more potent than the N,N-
dimethyl analogue in the topiramate series (0% at 75
mg/kg and 80% at 200 mg/kg).2a,4 The least potent
compounds in this N-substituted series were phenyl
(83g), 4-anisyl (83h ), cyclooctyl (83l), piperidide (83o),
and 4-(benzyl)piperazide (83p ). The cyclic sulfite iso-
mers 87a and 87b were potent anticonvulsants with no
significant stereochemistry-based difference in activity.
N-Tosylimido sulfate 90a exhibited modest potency
(75% block at 300 mg/kg), as did the other imidosulfur
compounds, 91a and 93a (80% and 40% block at 300
mg/kg).
The nitrogen and carbon isosteric analogues of OSO2-
NH2, 6, 7, and 8, were devoid of activity, as were
homologues with an elongated linker, 9 and 10, and
mesylate 27 (Table 1). Methyl and ethyl substitution
of the side chain, 21a and 21b, also resulted in a total
loss of activity. Substitution of the nitrogen of topira-
mate (1) with one methyl, ethyl, or butyl group did not
have a major effect on potency (1, 60% block at 60 mg/
kg;4 N-Me 1, 60% at 75 mg/kg;4 22, 90% at 75 mg/kg;
23, 80% at 75 mg/kg); however, phenyl (0% at 200 mg/
kg2a) or benzyl substitution (24, 0% at 75 mg/kg) did.
Substitution with acetyl (25, 30% at 75 mg/kg) and
dimethyl (N,N-Me2 1, 0% at 75 mg/kg and 80% at 200
mg/kg)2a,4 groups caused a significant drop in potency.
The 4,5-ring turned out to be very sensitive to
substitution. Although we already knew that a cyclo-
hexylidene group is undesirable (29, 20% at 200 mg/
kg),2a we looked at this area in some detail. The
homologous cyclopentylidene analogue 30 was also
found to be inactive. Removal of the two 4,5-ring methyl
groups of topiramate drastically reduced potency (32,
0% at 75 mg/kg). Removal of one methyl from 1 was
less critical if it is the endo methyl, which results in
the S isomer (33b, 100% at 75 mg/kg), as the R isomer
(exo methyl removed) was inactive (33a , 0% at 75 mg/
kg). On the contrary, the monoethyl R isomer 34 had
reasonable potency (90% at 75 mg/kg). Addition to the
structure of 1 of one methyl group hardly affected
potency (35, 90% at 75 mg/kg); however, addition of two
methyl groups did (31, 0% at 75 mg/kg and 80% at 300
mg/kg). Bulkier compounds 36 and 37 were devoid of
activity at 75 mg/kg, and phenyl analogue 38 was weak
(20% at 75 mg/kg). The dimethoxy (45) and monoethoxy
(46) analogues were inactive at 75 mg/kg. The bis-
trifluoromethyl analogue showed moderate potency
(40% at 75 mg/kg). Potency for the cyclic carbonate (52),
thiocarbonate (53), methylboronate (54), phenylboronate
(55), bis-cyclohexylidene (58), tetraethyl (59), and di-
phenyl (60) analogues was significantly attenuated.
However, the 4,5-cyclic sulfate derivative 2 had remark-
able potency, as discussed below.
Exploration of the ring oxygen atoms was an interest-
ing endeavor that required considerable synthetic chem-
istry. Replacement of O2, O3, and O6 of topiramate via
95 and 96 resulted in a loss of potency, which was not
helped by introducing a cyclic sulfate group (100).
Carbocyclic sulfamates 101, 102, and 103 were also
lacking in potency. One bright spot was 105, in which
only O6 was replaced by CH2; this analogue has a 4-h
ED50 value of 17 mg/kg, making it 3 times more potent
than topiramate.
The biological results with the L-fructose enantiomers
of 1 and 2, 106 and 107, are surprising in that the
anticonvulsant activity for each pair, 1 vs 106 and 2 vs
107, is not dramatically different. The eudysmic ratios
based on the ED50 values in Table 1 are 1:106 ) 1.5
and 2:107 ) 3.5. At 1 h in mice, orally, 1 had an ED50
of 44 (30-61) mg/kg and 106 had an ED50 of 160 (140-
189) mg/kg for a eudysmic ratio of 3.5.
The structure-activity relationships for the topira-
mate analogues studied to date, for the attainment of
reasonably good anticonvulsant activity, can be sum-
marized as follows. It is necessary that the sulfamate
nitrogen be unsubstituted or bear fairly small alkyl
groups. In the cyclic sulfate series, a larger variety of
nitrogen substituents is acceptable, including cyclobutyl
(83k ) and dimethyl (83m ). The sulfamate group cannot
be replaced by carbamate and the linker between the
sulfamate group and the sugar unit (-CH2O-) cannot
be altered in terms of its constitution, length, or
substitution. The fused 4,5-ring is important, with a
five-membered-ring being preferred. This ring can have
a tetrahedral carbon (ketal) or tetrahedral sulfur (cyclic
sulfate or sulfite) group with very limited substitution;
but a planar group, such as CdO or MeB, appears to
be highly disfavored. In the case of the 4,5-ketal, the
two carbon substituents have to be larger than hydrogen
and smaller than ethyl, which certainly applies a great
constraint on the SAR. Additionally, the two substit-
uents on the carbon of the 2,3-ketal should not be larger
Compounds 63 and 64 were inactive in the MES test
at 75 mg/kg, although weak activity was observed for
64 at 300 mg/kg (40% block); fused six-membered-ring
analogue 43 (a homologue of 32) was also inactive (0%
at 75 mg/kg); and analogues 65 (0% at 75 mg/kg and
100% at 300 mg/kg) and 66 (0% at 300 mg/kg) had
attenuated potency. However, 67 gave a 90% block at
75 mg/kg with an ED50 of 30.1 mg/kg, which compares
quite favorably with topiramate (1) (60% block at 60 mg/
kg; ED50 ) 53.5 mg/kg). The ED50 values for 80 and 68
were also a respectable 21 and 24 mg/kg. The good
potency for the L-sorbopyranose analogues, 67, 68, and
80, is believed to be connected with their preference for
a skew conformation, which is the case for topiramate

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1325
Ta ble 3. Physicochemical Data for 1, 2, and 31
and 2 in the MES test in mice, on oral administration.
The comparative data (Table 4) clearly show that 2
retains significant anticonvulsant activity out past 24
h, while 1 does not, and suggest that 2 has about a 2-fold
longer duration of action than 1. Peak activity for both
compounds was observed in the range of 1-4 h. Com-
parative data were also acquired in the MES test in rats,
on oral administration (Table 4). Hence, 2 was found
to have impressive potency, with an 8-h ED50 value of
1.0 mg/kg, and an impressive duration of action, with
significant anticonvulsant activity out past 48 h! Peak
activity for 1 occurred at 4 h, whereas that for 2 occurred
in the range of 4-12 h. Four close analogues of 2, 83a ,
83b, 83j, and 83m , were also studied in the MES test
in rats and found to be quite potent, with ED50 values
(95% confidence limits) at 4 h, po, of 2.7 (1.9-3.4), 1.2
(1.0-1.4), 2.5 (1.5-3.4), and 2.1 (1.7-2.5) mg/kg. The
ED50 values (mg/kg) for 1 and 2 on intraperitoneal
dosing, respectively, were as follows: 47 (36-66; 2 h)
and 7.6 (5.2-13.7; 1 h) in mice; 24 (16-43; 2 h) and 1.8
(0.9-2.8; 1 h) in rats (95% confidence limits; time).
compd
D
pH pKa
P
log P P7.4 log P7.4 clogP
1
2
3.26 7.25 8.66 3.34 0.53
2.44 7.35 8.51 2.61 0.42
3.21
2.42
0.51
0.38
1.50
0.50
-1.01
1.55
31
30.4 7.61 8.62 33.4
1.52 31.5
than methyl, nor connected into a ring. The sugar
oxygen atoms at C1, C2, and C3 are important, whereas
the one at C6 can be replaced.
log P a n d p Ka Deter m in a tion s. Octanol-water
partition coefficients, via log P values, can be important
for determining biological properties in vivo, particularly
with respect to compounds affecting the central nervous
system (CNS).61 The transport of drugs across the
blood-brain barrier, a key factor in the potency of CNS
agents, appears to be optimal at a log P value of 2.0.
For the most part, compounds with log P values that
exceed this value by (2, i.e., >4.0 or <0, do not readily
cross the blood-brain barrier to enter the CNS by
passive mechanisms and thus exhibit poor CNS activity,
although some compounds may enter the CNS by means
of an active transport process.
Compound 2, like 1, showed no activity in mice
against convulsions induced by pentylenetetrazole (>500
mg/kg), bicucculine (>500 mg/kg), and picrotoxin (>500
mg/kg). In vitro binding and uptake assays with ca. 25
various CNS receptor preparations (e.g., benzodiaz-
epine/GABA-A, dopamine D-1 and D-2, adrenergic R-1
and R-2, serotonin S-1A and S-2, GABA uptake,
glutamate uptake, adenosine uptake, and serotonin
uptake) showed virtually no activity (IC50 > 10 µM). A
similar lack of activity in the binding and uptake assays
was observed with 1 and phenytoin. Thus, 2 appears
to have an anticonvulsant profile similar to that of 1
and phenytoin.
We determined the log P and pKa values for 1, 2, and
31 (Table 3). The apparent octanol-water partition
coefficients, D, were measured in unbuffered water (pH
7.2-7.6) because the pH 7.4 buffer interfered with the
HPLC refractive index assay. The pKa values at 25 °C,
obtained by potentiometric titration, are the range of
8.5-8.7, reflecting the weak acidity of the sulfamate
group. The true partition coefficients, P, which are
independent of dissociation, and the apparent partition
coefficients at pH 7.4 (P7.4) were calculated from the
expressions: P ) D{1 + 10(pH - pKa)] and P7.4 ) P/[1 +
10(7.4 - pKa)]. Calculated log P values were obtained by
using the MedChem (Daylight) clogP program.62
The experimentally determined log P value for 1 of
0.53 is less than optimal, but it is not outside of the
acceptable range for CNS active drugs. Although the
log P value for 31 is 1.52, which would have been
predicted given ca. 0.5 units/CH2 group, the potency of
31 relative to 1 is not enhanced, rather it is actually
about 2-fold lower (Table 1). The log P values for 1 and
31 are in close agreement with the clogP values,
whereas this is not the case for 2 (possibly due to a lack
of parametrization in the program for the cyclic sulfate
group). Indeed, the clogP value for 2 of -1.01 initially
raised concern until we obtained the biological data,
which showed 2 to be significantly more potent than 1.
The experimentally determined log P value was 0.42 for
2, which is nearly the same as that for 1. Thus, the
increase in potency for 2 over 1 is probably due to
intrinsic activity of the 4,5-cyclic sulfate moiety, and not
to improved bioavailability. The well-known anticon-
vulsants phenytoin and carbamazepine have log P
values close to 2.0: the log P of phenytoin is 2.47 and
the clogP of carbamazepine is 1.98. Certain analogues
were thought promising for increased potency because
of their favorable clogP values in conjunction with minor
steric perturbation according to the developed SAR
profiles, namely 47 (clogP ) 2.01), 83m (1.47), and 86
(1.48). However, no enhancement in potency was ob-
tained: 47 is less potent than 1, 86 is less potent than
2, and 83m is equipotent with 2 (Table 1).
The neurotoxicity of 2 was explored in a standard
rotorod test in mice and rats, which assesses motor
impairment.63 The respective TD50 values of >1000 mg/
kg and >500 mg/kg established excellent neurotoxicity
indices (TD50/ED50) of >150 (2 h) in mice and >250 (4
h) in rats. These results compare favorably to the TD50/
ED50 ratios for 1 (mice, 9.3; rats, >115), phenytoin (mice,
4.2; rats, >50), and carbamazepine (mice, 7.1; rats, 21).
The oral LD50 values for 2 in mice and rats were also
quite favorable: >1000 and >500 mg/kg.
The importance of an SO2NH2 moiety for potent
anticonvulsant activity in several compounds prompted
us to be interested in carbonic anhydrase isozymes.64
At least seven isozymes of carbonic anhydrase (EC
4.2.1.1) are now recognized:64 erythrocytes contain CA-I
and CA-II; kidney membranes contain CA-IV; myelin
contains CA-II; mitochondria contain CA-V; skeletal
muscle and adipose tissue contain CA-III; and parotid
tissue and saliva contain CA-VI and CA-VII. Our
earlier work demonstrated that topiramate is a weak
inhibitor of erythrocyte carbonic anhydrase in several
species.2a The present study was undertaken to evalu-
ate selected compounds, particularly 2, for carbonic
anhydrase inhibitory activity in various rat tissues:
erythrocytes (blood), kidney membranes, and subcellular
fractions of the brain, i.e., myelin, synaptosomes, and
brain supernatant (see experimental). The IC50 values
for 2 in inhibition of carbonic anhydrase from blood,
kidney membranes, myelin, high-density synaptosomes,
and brain supernatant ranged from 21 to 130 nM,
Ad d ition a l Biologica l Stu d ies on 2 a n d Rela ted
An a logu es. Time-course studies were conducted on 1

1326 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
Ta ble 4. Comparative Time-Course Data for 1 and 2 in Mice and Rats (po)a
time (h)
no.
1
2
4
8
12
16
24
48
Mice
1
2
43.8 (31-61) 47.6 (33-66) 53.5 (36-77)
8.6 (7.9-9.6) 6.6 (4.5-8.8) 6.3 (5.1-7.6)
246 (197-303) 720 (592-928) >1000
23 (18-27)
ca. 50
72 (57-87)
Rats
1
2
15 (0.1-??)
16 (12-51)
6.7 (5.1-8.1) 15 (6.4-19)
34 (20-51)
1.3 (1.0-1.8)
103 (64-137)
2.5 (1.7-3.0)
153 (76-473)
2.6 (1.5-3.5)
>1000
3.8 (1.2-6.7) 5.1 (2.2-7.7) 1.7 (1.1-2.5) 1.0 (0.6-1.4)
18 (10-26)
a
Doses for each time point are reported as ED50 values (mg/kg); 95% confidence limits are given in parentheses.
Ta ble 5. Inhibition of Carbonic Anhydrase by 1, 2, and Acetazolamidea
compd
blood
kidney
myelin
synaptosomes
brain
1
2
8890 (3600-21800)
84 (30-236)
37 (25-54)
8350 (4200-16600)
130 (56-308)
650 (110-4080)
1360 (570-3230)
52 (7-377)
24 (10-58)
4840 (860-27400)
21 (6-72)
4550 (1170-17700)
27 (5-158)
12 (3-44)
azmb
7 (3-15)
a
Inhibition of carbonic anhydrase from blood, kidney membranes, myelin, high-density synaptosomes, and brain supernatant (see the
b
Experimental Section). IC50 values are reported in nM units, followed by 95% confidence limits in parentheses. azm ) acetazolamide.
depending on the tissue preparation (Table 5). The
potency range for 2 is generally comparable to that for
acetazolamide (7-650 nM), a well-known reference
inhibitor (Table 5). The results for topiramate (1)
indicate that it is a markedly less potent carbonic
anhydrase inhibitor (Table 5). Clearly, 2 is a more
potent inhibitor than topiramate by a factor of 25-250
depending on the tissue source. We also determined
IC50 values for several topiramate analogues for blood
carbonic anhydrase (compound, IC50): 31, 56 000; 83a ,
1 310 000; 83j, inactive; 86, 120; 106, 180 000; 107, 6060
nM. It is noteworthy that 31, with diethyl groups on
the 4,5-ring, is 8 times weaker than 1, but 86, with
diethyl groups on the 2,3-ring, is nearly equipotent with
2; that L-topiramate (106) is ca. 20 times weaker than
1 and 107 is ca. 70 times weaker than 2; and that
monosubstitution of the nitrogen of 2 with small alkyl
groups, which is still associated with potent anticon-
vulsant activity, strongly attenuates activity (cf. 83a and
83j with 2). The greatly diminished carbonic anhydrase
inhibition of 83a and 83j is most likely due to an
inability of the substituted sulfamate group to interact
with Zn(II) in the enzyme’s active site.65 Given the
results with 83a and 83j, relative to 2, potent anticon-
vulsant activity is probably independent of carbonic
anhydrase inhibition, similar to what we experienced
previously.2a Thus, inhibition of carbonic anhydrase
may not be a critical mechanism of anticonvulsant
action for 2 (vide infra).
We sent 2 to the National Institute of Neurological
Disorders and Stroke (NINDS) for independent evalu-
ation (ADD-182013).66 It was found to have ED50 values
in the MES test of 6.1 (4.6-7.2) mg/kg (2 h, ip, mice)
and 1.06 (0.81-1.44) mg/kg (4 h, po, rats), compared to
33 and 11.4 mg/kg for 1, respectively.2a Rotorod TD50
values for 2 were 400 (125-500) mg/kg (1 h, ip, mice)
and >500 mg/kg (4 h, po, rats), reflecting excellent
neurotoxicity indices of 66 and >472 (cf. phenytoin at
6.6 and >22). In mice, 2 was inactive (ED50 > 500 mg/
kg) in blocking convulsions induced by pentylenetetra-
zole, bicucculine, picrotoxin, and strychnine.
sugar sulfamates are probably much better in prevent-
ing the spread of seizures, rather than in raising the
seizure threshold.67 Topiramate has been found to block
tonic and clonic seizures in spontaneous epileptic rats
and mice genetically predisposed to epilepsy (DBA/2
mice).68 Also, it blocks electrically kindled seizures in
rats and clonic-tonic seizures in rats subjected to global
ischemia.67,69 Hence, topiramate appears to be broadly
effective in animal models of epilepsy.2b,67-69
Clinical trials with topiramate have indicated that
this antiepileptic drug is highly effective in adjunctive
therapy and monotherapy for generalized, absence, and
complex-partial seizures.70 However, the pharmacologi-
cal basis for topiramate’s anticonvulsant activity has not
yet been firmly established. Recent studies have re-
vealed an intriguing combination of properties that may
account for its seizure-blocking activity.71 Topiramate
significantly lowers glutamate and aspartate levels in
spontaneous epileptic rats, while showing no effect on
normal Wistar rats, suggesting that a reduction of
abnormally high extracellular levels of these excitatory
amino acid neurotransmitters in the hippocampus may
be related to its anticonvulsant activity.71a Cellular
biochemical and electrophysiological studies have iden-
tified several other properties that may contribute to
the anticonvulsant activity. Topiramate (a) positively
modulates some types of GABA-A receptors,71b,c (b)
antagonizes kainate/AMPA receptors,71d and (c) inhibits
generation of action potentials in neurons by exerting
a state-dependent, voltage-sensitive antagonism of so-
dium ion channels.71e,f In the latter case, elevation of
the action-potential threshold would block the spread
of seizures. All of these biological actions are concen-
tration-dependent and occur within a physiologically
relevant concentration range of 1-100 µM. Topiramate
inhibits some carbonic anhydrase isozymes, such as CA-
II and CA-IV, in this concentration range, and 2 is even
more potent as a carbonic anhydrase inhibitor. How-
ever, the very weak carbonic anhydrase inhibition of
cyclic sulfate analogues 83a and 83j, relative to 2, would
serve to dissociate anticonvulsant activity from enzyme
inhibition, deemphasizing carbonic anhydrase inhibition
as a relevant mechanism of anticonvulsant action.
Taking these observations together, it is reasonable to
Mech a n ism of Action of Top ir a m a te (1) a n d 2.
Topiramate is effective in blocking maximal electroshock
seizures, but not chemically induced seizures, in analogy
to phenytoin.2b The same can be said for 2. Thus, the

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1327
speculate that 2 would share many of the mechanisms
of action of 1.
are not readily accessible because of fewer ether oxygen
atoms than, say 1, the vicinal coupling between H3 and
H4 of 2.4 Hz is consistent with a skew cyclohexane ring
for this compound.54 Thus, the loss of potency for 95,
relative to 1, is likely caused by electronic effects from
three O f CH2 replacements, not by conformational
(steric) effects.
Str u ctu r a l a n d Con for m a tion a l Asp ects
Topiramate (1) adopts a skew conformation (3S0) for
the tetrahydropyran ring in solution and in the solid
state.2a,29 This skew conformation is presumably fa-
vored over the possible chair conformations because of
the two five-membered rings that are cis-fused onto the
central pyranose ring. We have suggested that such a
skew conformation may be critical for the potent anti-
convulsant activity of topiramate.2a,29 In our study of
topiramate analogues, we have synthesized and biologi-
cally tested some compounds with the 4,5-isopropylidene
ring absent, such as 63-68. Diethers 63 and 64 are
virtually devoid of anticonvulsant activity, but R-L-
sorbopyranoses such as 67 and 68 are nearly twice as
potent as topiramate (Table 1). This surprising obser-
vation can be explained by considering the conforma-
tions of these molecules.29 As expected, 63 and 64 favor
chair conformations (5C2/2C5), while 67 and 68 favor a
skew conformation (3S0),29 consistent with our structural
hypothesis for topiramate’s bioactivity.
It is interesting to note that there is a consistency in
optical rotations for compounds having the skew con-
formation, with no additional chromophore that could
significantly perturb the ORD spectrum (Table 1). For
example, 1-9 have [R]D values in MeOH of -34.0°,2a
-28.8°, -34.2°,2a -35.0°,2a -27.0°,2a -25.9°, -18.2°,
-29.5°, -18.7°, despite different substitution at C1; 29-
32 and 34-38 have [R]D values in MeOH of -29.9°,2a
-33.9°, -25.6°, -18.9°, -25.9°, -25.3°, -19.3°, -19.5,
-29.3°, despite different substitution on the 4,5-ring.
By contrast, compounds without the 4,5-ring that would
principally adopt chair conformations, such as 28 and
63-65, have consistent [R]D values in MeOH of +25.7°,
+27.0°, +28.4°, and +27.1°. In this vein, 76 (-39.8°)
and 77 (-22.3°) appear to be mainly in the skew
conformation, as would be expected from the constraint
imposed by a three-membered-ring fused at the 4,5-
position. However, 43 (+1.3°), with a less constrained
six-membered-ring fusion, appears to be a mixture of
skew and chair forms. Indeed, 400-MHz NMR spectral
data for 43 and 77 are consistent with this interpreta-
tion (see the Experimental Section). The long-range
W-pathway coupling for 43, J 46e ) 1.4 Hz, is especially
noteworthy since it is diagnostic for the 5C2 chair
conformation in the â-fructopyranose system; the 2C5
chair and 3S0 skew conformations lack the proper
geometry to manifest it.73 This J 46e coupling is also
observed for 28 (0.7 Hz)2a and for 63 (0.9 Hz) in CDCl3,
but it was unresolved for 64. Proton NMR data (300
MHz, CDCl3) for 77 show the absence of a J 46e coupling,
as well as vicinal proton-proton couplings of less than
1 Hz for J 34, J 56a and J 56e, consistent with the 3S0
conformation. Furthermore, it is interesting that alkene
66, which should exist in a flattened half-chair confor-
mation,22 has an optical rotation (-0.9°) that is between
the skew (-20° to -35°) and chair (+25° to +30°)
extremes, as would be expected from the preceding
analysis.
The conformational preferences for 2,3-O-isopropyli-
dene-R-L-sorbopyranose derivatives 67, 68, and 80 were
determined by using high-field 1H NMR data in com-
bination with empirical force-field calculations.29
A
twist-boat (or skew) conformation (3S0) prevails over
possible chair forms for each, with 67 being an ca. 4:1
3
2
mixture of the S0 and C5 conformers (good fit between
calculated and observed NMR coupling values).29 This
conformational distribution for 67 was essentially con-
stant with different solvents and temperatures, and the
3S0 skew conformation for 67 was also manifested in the
solid state.29
Proton NMR data for 63 and 64 (400 MHz) indicate
that the compounds strongly prefer a chair conformation
and predominantly adopt the one with the CH2SO2NH2
group axial. In particular, the vicinal proton-proton
coupling constants J 56a ) 8.6 Hz and J 56e ) 4.9 Hz,
together with the characteristic long-range, W-pathway
coupling constant J 46e ) 0.9 Hz, indicate that 63 exists
in CDCl3 at 24 °C as a 3:1 mixture of 5C2/2C5 chair forms
(J 34 ) 3.7 Hz, J 45 ) 3.2 Hz).72 Thus, for SAR purposes,
a direct comparison of 63 or 64 with 1, wherein the
central pyran ring adopts a skew conformation, is not
feasible.
The optical rotations are also worth analyzing from
a standpoint of orientation of substituents on the 4,5-
ring, for the 4,5-ketals and the 4,5-cyclic sulfur deriva-
tives. Compounds 1, 29, 30, and 31, in which the two
substituents are identical, have fairly constant [R]D
values of -34.0°,2a -29.9°,2a -33.9°, and -25.6°, indi-
cating minimal impact of the size of the substituents
at this position. However, the optical rotations for 33a
(-29.3°; R isomer) and 33b (-18.1°; S isomer) are
distinctive for the orientation of the methyl substituent
relative to the hydrogen. This configurational feature
seems to apply, as well, to the 4,5-cyclic sulfite diaster-
eomers 87b (-43.5°; R isomer) and 87a (-14.9°; S
isomer), although a tetrahedral sulfur atom occupies the
4,5-ring and the substituent (oxygen) is quite polar. The
4,5-ketals 34 and 35, with ca. 85-90% R isomer (NMR),
have rotations that are consistent with this picture
(-25.9° and -25.3°), whereas 36 and 37, with 100% R
isomer (NMR), have rotations that are not consistent
Proton NMR spectra for 1 have indicated a skew
conformation, which also exists in the solid state.2a We
1
have now acquired 400-MHz H NMR data for both 1
and 2 in different solvents. For 1 in CDCl3, CD3OD,
and D2O, the vicinal couplings J 34, J 45, J 56a, and J 56e
were essentially unchanged (2.6, 8.0, 0.8, and 1.9 Hz,
respectively). For 2 in DMSO-d6, CD3OD, and D2O, the
vicinal couplings J 34, J 45, J 56a, and J 56e were also
essentially unchanged (2.7, 7.8, <0.3, and 2.0 Hz,
respectively). The coupling constants for the tetrahy-
3
dropyran ring protons confirm that the skew S0 con-
former predominates at room temperature in nonaque-
ous and aqueous media. The X-ray crystal structure of
2 (vide infra) also shows a skew conformation. Hydrin-
dane analogue 95, which also has a skew conformation
in the solid state by X-ray analysis (vide infra), was
examined by 400-MHz 1H NMR in C6D6. Although
many of the proton-proton coupling constants for 95

1328 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
F igu r e 2. Perspective drawing of 1 from X-ray crystal-
lography with non-hydrogen atoms represented by thermal
ellipsoids drawn to encompass 50% of their electron density.
Hydrogen atoms are arbitrarily represented by small spheres.
F igu r e 3. Perspective drawing of 2 from X-ray crystal-
lography with non-hydrogen atoms represented by thermal
ellipsoids drawn to encompass 50% of their electron density.
Hydrogen atoms are arbitrarily represented by small spheres.
(-19.3° and -19.5°). Perhaps, the bulky tert-butyl
group induces a change in the local conformation of the
1,3-dioxolane unit. Compound 46, with 90% S isomer,
has an optical rotation (-26.8°) that also seems to
deviate from the pattern. Consequently, this parameter
cannot be utilized as a stereochemical diagnostic for the
4,5-ring.
IR measurements of 4 in CD3CN or CHCl3 (at ca. 10%
vs 0.3% concentrations) indicated that intramolecular
hydrogen bonding exists, consistent with literature
results for 4 in CCl4.73a This presumably involves an
interaction between the hydroxyl group and O4 in the
skew conformation, to impose a constraint on the
structure of the molecule. Consequently, we became
interested in determining if there was a hydrogen-
bonded structure for the active sulfamates. In CD3CN
or CHCl3, alcohol 4 shows OH stretches (νmax) at 3532
or 3493 cm-1 (intramolecular) and 3570 or 3597 cm-1
(free), whereas sulfamate 1 shows NH stretches at 3262
or 3290 cm-1 (intermolecular) and 3570 or 3353/3432
cm-1 (free) in CHCl3.74 Like 1, 2 in CD3CN shows inter-
molecular (3265 cm-1) and free (3574 cm-1) bands, with
no intramolecular band. We could not examine 2 in
CHCl3 because of poor solubility; however, 83b is a suit-
able surrogate. In CDCl3, 83b showed only intermolecu-
lar (3350 cm-1) and free (3394 cm-1) IR bands. Thus,
neither 1 (in CD3CN or CHCl3) nor 2 (in CD3CN) display
a significant level of intramolecular hydrogen bonding.
We have determined crystal structures for topiramate
(1) and four analogues: 2, 21a , 67, and 95;75,76 details
for the X-ray studies of 1, 2, and 95 are presented
herein.77 All five compounds (1, 2, 21a , 67, and 95)
adopt a skew 3S0 conformation in the solid state (see
Figures 2-4), and a skew conformation is also observed
F igu r e 4. Perspective drawing of 95 from X-ray crystal-
lography with non-hydrogen atoms represented by thermal
ellipsoids drawn to encompass 50% of their electron density.
Hydrogen atoms are arbitrarily represented by small spheres.
52, 53) 1,3-dioxolane rings, (4) the constitution of the
4,5-fused 1,3-dioxolane ring (2, 54, 55, 63-68, 76, 77,
80, 83a -r , 84-87, 90a , 91a , 93a ), (5) the ring oxygen
atoms (95, 96, 100-102, 104, 105), and (6) the absolute
stereochemistry (106 and 107). This work led to the
impressive cyclic sulfate analogue RWJ -37947 (2), which
has potent anticonvulsant activity (ca. 8 times greater
than 1 in mice at 4 h and ca. 15 times greater than 1 in
rats at 8 h), a long duration of action (>24 h in mice
and rats, po), and very low neurotoxicity (TD50 value of
>1000 mg/kg, po in mice). The absence of activity for
2 against chemically induced seizures in mice, as well
as in diverse in vitro receptor binding and reuptake
assays, denotes an anticonvulsant profile similar to that
of phenytoin and topiramate, although 2 also turned out
1
for 1, 2, and 95 in solution by H NMR (vide supra).
to be a potent inhibitor of carbonic anhydrase (IC50
)
Some specific methods and results for the X-ray studies
on 1, 2, and 95 are provided in the Experimental
Section.75,76
21-130 nM for enzymes from various rat tissues).
Examination of analogues of the potent 4,5-cyclic sulfate
2, namely 83a -r , 85-87, 90a , 91a , and 93a , indicated
that potent anticonvulsant activity is associated with
relatively small alkyl substituents on the nitrogen (Me/
H, 83a ; Me/Me, 83m ; Et/H, 83b; allyl/H, 83e; c-Pr/H,
83j; c-Bu/H, 83k ) and with very limited changes in the
cyclic sulfate group, such as cyclic sulfite 87a /b. Inter-
estingly, the potent anticonvulsants 83a and 83j had
significantly diminished carbonic anhydrase inhibitory
activity, suggesting that inhibition of this enzyme may
not be responsible for the anticonvulsant activity.
Con clu sion
Structure-activity relationships surrounding the clini-
cally efficacious antiepileptic drug topiramate (1), a
unique sugar sulfamate anticonvulsant, were explored.
Structural alterations were made to probe the impor-
tance of (1) the sulfamate group (6-8, 22-25, 27, 84),
(2) the linker between the sulfamate group and the
pyran ring (9, 10, 21a ,b), (3) the substituents on the
2,3- (58-60, 85, 86) and 4,5-fused (30-38, 43, 45-47,

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1329
On the basis of 400-MHz 1H NMR data, 1 and 2
predominantly adopt the 3S0 skew conformation at
ambient temperature in nonaqueous and aqueous me-
dia. From our earlier work,29 R-L-sorbopyranose 67,
which is nearly twice as potent as 1, also mainly adopts
this skew conformation in solution. The X-ray struc-
tures for 1, 2, and 95 (as well as 21a and 67) depict the
skew 3S0 conformer in the solid state, as well. This skew
conformation appears to be a critical structural feature
relative to obtaining potent anticonvulsant activity.
Considering all of the SAR results to date, we perceive
1 and 2 as possessing two key structural elements for
interaction with relevant biological targets in the CNS:
(1) a tetrahydropyran unit in a skew conformation with
sterically unencumbered five-membered 1,3-dioxo rings,
and (2) a polar sulfamate group spaced at a suitable
distance from the monosaccharide nucleus and not
burdened by oversized substituents. There seems to be
a preferred topography for the hydrophobic skew 2,3-
dioxolanopyran segment of 1, 2, and 67 that requires
the 2,3-ether oxygen atoms and minimal steric bulk.
Clinical trials with topiramate have indicated that
this drug is highly effective in adjunctive therapy and
monotherapy for epilepsy. Although a pharmacological
basis for topiramate’s anticonvulsant activity has not
yet been firmly established, some interesting biochemi-
cal mechanisms have been pinpointed to account for its
seizure-blocking activity.71 Topiramate has a positive
modulatory effect on some types of GABA-A receptors,71b,c
antagonizes kainate/AMPA receptors,71d and inhibits
the generation of action potentials in neurons via
antagonizing the activation of Na+ channels.71e,f Pre-
sumably, 2 would function in a similar manner. Al-
though 2 is a potent inhibitor of carbonic anhydrase
isozymes, this is not viewed a being critical to its potent
anticonvulsant activity. In the final analysis, topira-
mate analogue 2, a novel sugar sulfamate cyclic sulfate,
is a promising anticonvulsant that may be clinically
useful in patients suffering from generalized tonic-clonic
and/or complex partial seizures.
MS) were recorded on a VG 7070E high-resolution or Finnigan
TSQ-70B triple-quadrupole mass spectrometer by using an
argon beam at 7 kV and 2 mA of current in a thioglycerol
matrix. The X-ray crystallography for 1, 2, 21a , and 95 was
performed by Crystalytics Co., Lincoln, NE. Elemental analy-
ses were performed by Atlantic Microlab, Inc. (Norcross, GA),
Galbraith Laboratories, Inc. (Knoxville, TN), or Oneida Labo-
ratories (Oneida, NY). TLC separations were conducted on
250-µm silica gel plates with visualization by iodine staining
or by charring with ethanol/H2SO4 (95:5). Chromatographic
separations were carried out by using HPLC-grade solvents
on (1) a Waters Prep-500 HPLC equipped with two PrepPak
cartridges (column, 47 × 300 mm; silica gel, 55-105 µm, 125
Å) connected in series and a refractive index detector (“LC”),
or (2) flash-column chromatography with silica gel (40-63 µm;
“CC”). Preparative TLC purification was performed with
Analtech 1000-µm silica gel GF plates.
2,3-O-(Isop r op ylid en e)-4,5-O-su lfon yl-â-D-fr u ctop yr a n -
ose Su lfa m a te (2). Diol 282a (50.0 g, 0.167 mol) was combined
with ethyl acetate (1.7 L) and pyridine (31.7 g, 0.401 mol),
heated to effect dissolution, and cooled to -60 °C. Sulfuryl
chloride (49.6 g, 0.370 mol) was added dropwise with mechan-
ical stirring under argon over 45 min (-60 to -50 °C). The
resulting white slurry was stirred at -60 °C for 1 h, warmed
to 23 °C, stirred for 2 h, and filtered through diatomaceous
earth. The filtrate was rinsed sequentially with brine, 1 N
HCl, saturated aqueous NaHCO3, and brine, then dried
(MgSO4), and concentrated in vacuo to furnish 85.6 g (100%)
of 110 (eq 5) as a white solid, which was used without further
purification. A sample was purified by flash-column chroma-
tography (CH2Cl2/ethyl acetate, 19:1): mp 119-121 °C dec;
CI-MS m/z 513 (M + NH4)+. A solution of this material (83.1
g, 0.167 mol) in methanol (418 mL) was combined with
NaHCO3 (84.2 g, 1.0 mol) and stirred at 23 °C for 18 h, filtered
through diatomaceous earth, and concentrated in vacuo. The
residue was dissolved in ethyl acetate, rinsed twice with brine,
dried (MgSO4), and concentrated in vacuo. The crude product
was purified by preparative HPLC (CH2Cl2/ethyl acetate, 9:1)
and recrystallized from ethanol/water to afford 2 (31.4 g) as a
white solid: mp 150-151 °C dec; 1H NMR (400 MHz, DMSO-
d6) δ 1.38/1.53 (2 s, 6H, 2 Me) 3.90-4.10 (m, 4H, H1 and H6),
4.59 (d, 1H, J 34 ) 2.7 Hz, H3), 5.49 (d, 1H, J 45 ) 7.8 Hz, H5),
5.70 (dd, 1H, J 34 ) 2.7 Hz, J 45 ) 7.8 Hz, H4), 7.75 (br s, 2H,
NH2); 13C NMR (100 MHz, DMSO-d6) δ 25.0 (Me), 25.9 (Me),
59.2 (CH2), 67.8 (CH2), 68.1 (CH), 73.2, (CH), 77.7 (CH), 100.7
(C), 110.2 (C); IR (KBr) νmax 3373 (s), 3267 (s), 1567 (m), 1377
(s), 1213 (s), 1189 (s) cm-1; FAB-MS m/z 362 (MH)+, 384 (M +
Na)+. Anal. (C9H15NO10S2) C, H, N.
Exp er im en ta l Section
Gen er a l Meth od s. Reactions were generally conducted
under argon or nitrogen in molecular sieve-dried solvents,
unless noted otherwise. During concentration in vacuo, the
materials were never heated above 40 °C unless otherwise
noted. Amines were scrupulously dried (distilled from BaO)
before use. Rigorously anhydrous conditions were used for
chlorosulfate displacement reactions to prevent hydrolysis of
1-[(Am in osu lfon yl)a m in o]-1-d eoxy-2,3:4,5-b is-O-(iso-
p r op ylid en e)-â-D-fr u ctop yr a n ose (6). A mixture of NaH
(60% oil dispersion, 1.34 g, 0.033 mol) in DMF (50 mL) was
treated with 115 (6.67 g, 0.02 mol), and the reaction was stirred
at 0 °C for 30 min. Sulfamoyl chloride (4.47 g, 0.039 mol) was
added portionwise at 0-10 °C. After being stirred for 1 h, the
mixture was poured into ice and extracted into ethyl acetate
twice. The combined extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo to a syrup, which was
purified by preparative HPLC (hexane/ethyl acetate, 1:1) to
give 6 (2.06 g, 20%) as a colorless solid: mp 50-52 °C; 1H NMR
(90 MHz) δ 1.29/1.35/1.48/1.50 (4 s, 12H, 4 Me), 2.40 (m, 2H,
CH2N), 3.84 (m, 2H, H6), 4.22 (m, 2H, H3 and H5), 4.64 (dd,
1H, H4), 4.70-4.90 (br s, 2H, NH2), 5.00 (t, 1H, NH). Anal.
(C11H22N2O7S‚0.1C7H8) C, H, N.
1-[(Am in osu lfon yl)m et h yla m in o]-1-d eoxy-2,3:4,5-b is-
O-(isop r op ylid en e)-â-D-fr u ctop yr a n ose (7). A mixture of
iodine (88 g, 0.35 mol), imidazole (26 g, 0.38 mol), and
triphenylphosphine (151 g, 0.57 mol) in 1.5 L toluene/aceto-
nitrile (9:1) was stirred for 30 min under nitrogen and then
treated with fructose bis-acetonide (4, 50 g, 0.19 mol). The
mixture was heated at reflux for 3 days, cooled to 23 °C, and
concentrated to a syrup. The syrup was triturated with a
mixture of petroleum ether and ethyl ether (1:1, 225 mL) and
filtered. The filtrate was concentrated to a syrup that was
the chlorosulfate. Melting points were determined on
a
Thomas-Hoover apparatus calibrated with a set of melting
point standards. Optical rotations were measured on a Perkin-
Elmer 241 polarimeter at the sodium D line (λ ) 589 nm).
Infrared spectra were recorded on a Nicolet SX-60 spectrom-
eter with a resolution of 4.0 cm-1 (s ) strong, m ) medium).
1H NMR spectra (referenced to Me4Si; s ) singlet, d ) doublet,
t ) triplet, q ) quartet, m ) multiplet, br ) broad) were
obtained at 400.13 MHz on a Bruker AM-400, at 300.13 MHz
on a Bruker AC-300, at 600.13 MHz on a Bruker DMX-600,
or at 90 MHz on a Varian EM-390 instrument, in CDCl3 unless
indicated otherwise. 13C NMR spectra (referenced to Me4Si)
were obtained at 100.61 MHz on a Bruker AM-400 in CDCl3;
distortionless enhancement by polarization-transfer experi-
ments with an editing pulse at 135° (DEPT-135) were used to
assign carbon multiplicities. Chemical-ionization mass spectra
(CI-MS) were recorded on a Finnigan 3300 mass spectrometer
with ammonia as the reagent gas, unless methane is specifi-
cally indicated. Fast-atom-bombardment mass spectra (FAB-

1330 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
purified by preparative HPLC (hexane/ethyl acetate, 4:1) to
give iodide 12 as a syrup. The iodide (6 g, 0.02 mol) was
refluxed in DMF (45 mL) with N-methylbenzylamine (3.96 g,
0.032 mol) and Na2CO3 (3.13 g, 0.029 mol) for 2 days, cooled,
poured into water, and extracted with ethyl acetate. The
organic solution was washed with brine, dried (Na2SO4), and
concentrated to syrupy 13, which was dissolved in ethanol (60
mL), treated with 10% Pd/C (4.0 g), and shaken on a Paar
apparatus with hydrogen (50 psig) for 16 h. After filtration,
the solvent was concentrated in vacuo to give amine 14 as a
syrup. To a cold solution of NaH (60% oil dispersion, 0.48 g,
0.012 mol) in DMF (10 mL) was added amine 14 (2.14 g, 0.008
mol). After the reaction stirred for 45 min, sulfamoyl chloride
(2.12 g, 0.018 mol) was added portionwise at 0 °C and the
mixture was stirred for 45 min. After 60 min more at 23 °C,
it was poured into cold water and extracted with ethyl acetate.
The organic solution was concentrated in vacuo, and the
residue was purified by preparative HPLC (hexane/ethyl
acetate, 1:1) to give 7 (0.25 g, 7%) as a pale yellow syrup: 1H
NMR (400 MHz) δ 1.34/1.42/1.50/1.60 (4 s, 12H, 4 Me), 3.05
(s, 3H, Me), 3.50-3.69 (dd, 2H, H1), 3.75-3.91 (dd, 2H, H6),
4.15-4.30 (m, 2H, H3 and H5), 4.51-4.65 (m, 1H, H4), 4.80
(br s, 2H, NH2). Anal. (C13H24N2O7S‚0.1C4H8O2‚0.1C3H7NO)
H, N; C: calcd, 44.65; found, 45.30.
aldehyde 15 (30 g, 0.12 mol) in THF (300 mL), and the mixture
was stirred for an additional 45 min. It was treated with cold
water and extracted twice with ether. The combined extract
was washed with 3% hydrogen peroxide solution, dried (Na2-
SO4), concentrated in vacuo, triturated with ether, filtered, and
concentrated again to a syrup that was purified by preparative
HPLC (ethyl acetate/hexanes, 1:9) to give pure olefin 18 as a
colorless syrup. A solution of 18 (19.5 g, 0.076 mol) in THF
(80 mL) was cautiously treated with BH3‚THF (1 M in THF,
80 mL) dropwise, under 40 °C. After addition, the reaction
was stirred for an additional 30 min, cooled to 5 °C, and
cautiously treated with 3 N NaOH (28 mL), followed by
hydrogen peroxide (30% aqueous solution, 28 mL). The
mixture was refluxed for 15 min, cooled, and extracted twice
with ethyl acetate. The combined extract was washed with
brine, dried (Na2SO4), and concentrated in vacuo to give alcohol
19 as a syrup. A mixture of NaH (60% oil dispersion, 0.98 g,
0.025 mol) in DMF (20 mL) was treated with a solution of
alcohol 19 (4.45 g, 0.016 mol) in DMF (20 mL), and the mixture
was stirred for 15 min at 5 °C. Sulfamoyl chloride (3.0 g, 0.026
mol) was added portionwise, and the mixture was allowed to
warm to 23 °C. After 2 h of stirring, the mixture was treated
with cold water and extracted with ethyl acetate three times.
The combined organic extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo to a syrup, which was
purified by preparative HPLC (hexanes/ethyl acetate, 1:1) to
give 9 (2.30 g, 41%) as a colorless foam: 1H NMR (400 MHz)
δ 1.35/1.36/1.49/1.55 (4 s, 12H, 4 Me), 2.20-2.32 (m, 2H, CH2),
3.64-3.82 (dd, 2H, H6), 4.15 (m, 1H, H3), 4.17-4.20 (m, 1H,
H5), 4.47-4.50 (m, 2H, CH2O), 4.55-4.60 (m, 1H, H4), 5.30
(br s, 2H, NH2). Anal. (C13H23NO8S‚0.3H2O) C, H, N, H2O.
1-[(Am in osu lfon yloxy)eth yl]-1-d eoxy-2,3:4,5-bis-O-(iso-
p r op ylid en e)-â-D-fr u ctop yr a n ose (10). A mixture of alde-
hyde 15 (26.3 g, 0.10 mol) and methyl (triphenylphosphora-
nylidene)acetate (65.9 g, 0.20 mol) in dry acetonitrile (536 mL)
was refluxed for 2 h, cooled, and triturated with petroleum
ether twice. The combined filtrate was concentrated to a syrup
that was purified by preparative HPLC (hexanes/ethyl acetate,
2:1) to give the enoate as a 13:1 mixture of E:Z isomers. A
mixture of alkene (18.5 g, 0.6 mol) in ethanol (180 mL) and
PtO2 (3.6 g) was shaken with hydrogen on a Paar apparatus
(50 psig) for 4 h. After filtration, the solvent was evaporated
in vacuo to give the ester as a colorless syrup. To a slurry of
LiAlH4 (2.09 g, 0.055 mol) in ether (150 mL) was added a
solution of the ester (15.9 g, 0.05 mol) in ether (100 mL),
dropwise. The reaction was stirred for 2 h, treated cautiously
with water (2.2 mL), 15% NaOH (2.1 mL), and water (6.3 mL),
stirred for 16 h, filtered, and concentrated to give alcohol 20
as a colorless syrup. A mixture of NaH (60% oil dispersion,
0.98 g, 0.025 mol) in DMF (40 mL) was treated with a solution
of alcohol 20 (4.53 g, 0.016 mol) in DMF (40 mL), and the
mixture was stirred for 15 min at 5 °C. Sulfamoyl chloride
(3.50 g, 0.03 mol) was added portionwise and the reaction was
allowed to warm to 23 °C. After 2 h of stirring, the mixture
was treated with cold water and extracted with ethyl acetate
three times. The combined extract was washed with brine,
dried (Na2SO4), and concentrated in vacuo. The residue was
purified by preparative HPLC (hexanes/ethyl acetate, 1:1) to
give 10 (3.10 g, 53%) as a pale yellow syrup: 1H NMR (400
MHz) δ 1.28/1.31/1.48/1.55 (4 s, 12H, 4 Me), 2.10 (m, 4H, 2
CH2), 3.65-3.85 (dd, 2H, H6), 4.10 (m, 1H, H3), 4.16-4.21 (m,
1H, H5), 4.22-4.30 (m, 2H, CH2O), 4.51-4.60 (m, 1H, H4), 5.15
(br s, 2H, NH2). Anal. (C14H25NO8S‚0.7H2O) C, H, N, H2O.
2-[1,2:3,4-Bis-O-(isop r op ylid en e)-â-D-a r a bin op yr a n os-
1-yl]eth ylsu lfon a m id e (8). A mixture of ethyl methane-
sulfonate (17.7 g, 0.14 mol) in THF (350 mL) was treated with
butyllithium (2.5 M in hexane, 65.5 mL, 0.16 mol) at -70 °C;
after 45 min of stirring, the mixture was treated with diphenyl
phosphorochloridate (44.1 g, 0.16 mol) and then stirred at -70
°C for 60 min more. The reaction was treated with brine,
warmed to 23 °C, and extracted twice with CH2Cl2. The
combined extract was washed with 4% aqueous NH4Cl, dried
(Na2SO4), and concentrated to a syrup, which was purified by
preparative HPLC to give the phosphonate reagent as a solid.
A mixture of this reagent (10.95 g, 0.03 mol) in THF (150 mL)
was treated with butyllithium (2.5 M in hexane, 14.7 mL, 0.04
mol) at -70 °C. After 45 min of stirring, it was treated with
a mixture of aldehyde 15 (10.46 g, 0.04 mol) in THF. The
reaction was stirred at -70 °C for 45 min, stirred at 23 °C for
2 h, treated with brine, and extracted twice with ethyl acetate.
The combined extract was dried (Na2SO4) and concentrated
in vacuo to a semisolid, which was redissolved in CH2Cl2,
washed with brine, dried (Na2SO4), and concentrated to a
syrup. It was purified by preparative HPLC to give alkene
16 as a syrup, which crystallized on standing. A mixture of
alkene (8.0 g, 0.022 mol) in ethanol (150 mL) and PtO2 (4.0 g)
was shaken on a Paar apparatus with hydrogen (40 psig) for
4 h, filtered, and concentrated in vacuo to a solid, which was
recrystallized from ethanol-water to give pure sulfonate as a
colorless solid. A solution of NaOH (2.28 g) in water (25 mL)
was treated with sulfonate (2.80 g, 0.008 mol), and the mixture
was refluxed for 90 min, cooled, treated with acetic acid (3.32
g), and stirred for 5 min. It was triturated with ethyl acetate
and concentrated in vacuo to give the sulfonic acid as a white
solid. The sulfonic acid (2.71 g, 0.008 mol) in a mixture of 10
mL of DMF and 20 mL of CH2Cl2 was treated with thionyl
chloride (0.95 g, 0.008 mol) at -15 °C for 45 min, treated with
ammonia-saturated chloroform (60 mL), stirred at 23 °C for
60 min, treated with water, and extracted with CH2Cl2. The
organic solution was washed with brine, dried (Na2SO4), and
concentrated in vacuo to a thick syrup, which was purified by
preparative HPLC (hexane/ethyl acetate, 1:1) to furnish sul-
fonamide 8 (0.80 g, 25%) as a white solid: mp 142-143 °C;
1H NMR (400 MHz) δ 1.35/1.39/1.48/1.51 (4 s, 12H, 4 Me),
2.22-2.45 (m, 2H, CH2), 3.39-3.52 (m, 2H, CH2S), 3.70-3.1
(dd, 2H, H6), 4.13 (m, 1H, H3), 4.23 (m, 1H, H5), 4.52-4.60 (m,
1H, H4), 4.71 (br s, 2H, NH2). Anal. (C13H23NO7S) C, H, N.
1-C-Met h yl- a n d 1-C-E t h yl-2,3:4,5-b is-O-(isop r op yli-
d en e)-â-D-fr u ctop yr a n ose Su lfa m a tes (21a a n d 21b). A
mixture of aldehyde 15 (10.45 g, 0.04 mol) in THF (150 mL)
and ether (100 mL) was treated with methylmagnesium
bromide (3 M in ether, 20 mL, 0.06 mol) at 25-40 °C and
refluxed slowly for 3 h. After cooling, the reaction mixture
was treated with cold water (50 mL) and 10% ammonium
chloride (100 mL) and extracted twice with ethyl acetate. The
combined extract was washed with brine, dried (Na2SO4), and
concentrated in vacuo to a mixture of diastereomeric alcohols
(ca. 10:1), which was purified by preparative HPLC (hexanes/
1-[(Am in osu lfon yloxy)m et h yl]-1-d eoxy-2,3:4,5-b is-O-
(isop r op ylid en e)-â-D-fr u ctop yr a n ose (9). A solution of
methyltriphenylphosphonium bromide (103.5 g, 0.29 mol) in
anhydrous THF (470 mL) was treated with potassium tert-
butoxide (32.5 g, 0.29 mol), and the mixture was stirred for
45 min. The reaction was treated dropwise with a solution of

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1331
ethyl acetate, 2:1). A mixture of sodium hydride (60% oil
dispersion, 1.11 g, 0.028 mol) in DMF (45 mL) was treated
with a solution of alcohols containing mainly the major isomer
(4.90 g, 0.018 mol) in DMF (45 mL), and the reaction was
stirred for 15 min at 10 °C. Sulfamoyl chloride (4.16 g, 0.036
mol) was added portionwise, and the mixture was warmed to
23 °C. After being stirred for 2 h, the mixture was treated
with cold water and extracted three times with ethyl acetate.
The combined extract was washed with brine, dried (Na2SO4),
and concentrated in vacuo. The syrupy residue was purified
by preparative HPLC (hexanes/ethyl acetate, 2:1) to give 21a
(2.43 g, 43%) as a waxy solid: 1H NMR (400 MHz) δ 1.33/1.42/
1.48/1.53 (4 s, 12H, 4 Me), 1.54 (d, 3H, Me), 3.84 (pair of d,
2H, H6), 4.22 (dd, 1H, H1), 4.43 (d, 1H, H3), 4.6-4.7 (m, 2H,
H4 and H5), 5.30 (br s, 2H, NH2); the material was almost
entirely one isomer; 13C NMR (100 MHz) δ 15.4/15.5 (R/â), 24.2,
25.7, 26.1, 27.0, 61.5, 70.2, 70.5, 70.9, 80.2/80.3 (R/â), 102.9/
103.5 (C2-R/C2-â), 108.8 (â),109.3, 109.6; the R/â ratio was
estimated as ca. 20:1 from integration of the anomeric C2
resonances. Anal. (C13H23NO8S) C, H, N. A sample was
recrystallized from ethanol-water (1:3) to afford small color-
less prisms of diastereomerically pure material, mp 152-153
°C. X-ray crystallographic analysis on a well-formed crystal
served to establish the configuration at C1 in the major (R)
isomer as R.77
mp 48-50 °C; 1H NMR (400 MHz) δ 0.95 (t, 3H, Me), 1.35/
1.42/1.49/1.53 (4 s, 12H, 4 Me), 1.40 (m, 2H, CH2), 1.60 (m,
2H, CH2), 3.10-3.20 (m, 2H, CH2N), 3.71-3.94 (dd, 2H, H6),
4.12-4.22 (dd, 2H, H1), 4.25 (m, 1H, H3), 4.35 (m, 1H, H5),
4.55 (t, 1H, NH), 4.60 (m, 1H, H4). Anal. (C16H29NO8S) C, H,
N.
Chlorosulfate 26 (6.00 g, 16.7 mmol) was dissolved in 167
mL of THF and treated with benzylamine (5.38 g, 50.2 mmol)
at 23 °C while being stirred under nitrogen. After 6 h, the
reaction was treated with more benzylamine (5.38 g, 50.2
mmol), stirred for 18 h, and filtered through diatomaceous
earth. The filtrate was concentrated in vacuo, and the residue
was purified by preparative HPLC (hexanes/ethyl acetate, 7:3)
to furnish 24 (4.01 g, 76%) as an amber glass: 1H NMR (400
MHz) δ 1.34/1.41/1.46/1.53 (4 s, 12H, 4 Me), 3.70-3.95 (m, 2H,
H6), 4.10-4.35 (m, 6H, 2H1, H3, H5, NCH2), 4.61 (dd, 1H, J 34
) 2.6 Hz, J 45 ) 7.9 Hz, H4), 4.94 (t, 1H, J ) 5.2 Hz, NH), 7.34
(s, 5H, arom.); IR (KBr) νmax 2994 (m), 2941 (m), 1567 (m),
1374 (s), 1173 (s), 910 (s) cm-1; FAB-MS m/z 430 (MH)+, 447
(M + Na)+. Anal. (C19H27NO8S) C, H, N.
2,3:4,5-Bis-O-(isop r op ylid en e)-â-D-fr u ctop yr a n ose N-
Acetylsu lfa m a te (25). Topiramate (1, 3.39 g, 10 mmol) and
1-acetylimidazole (1.30 g, 12 mmol) were combined in 25 mL
of dry toluene and heated on a steam bath for 5 h. Since the
reaction was not completed (TLC), 1-acetylimidazole (0.4 g)
was added and the mixture was heated for 2 h. After being
cooled to 0 °C, the precipitate was collected, dried (4.40 g of
off-white solid, 98%), and recrystallized (ethyl acetate/MeOH,
20:1) to furnish 3.50 g (78%) of TLC-homogeneous off-white
crystals: mp 152-154 °C; 1H NMR (400 MHz, CDCl3/DMSO-
d6, 1:1) δ 1.32/1.38/1.43/1.50 (4 s, 12H, 4 Me), 2.04 (s, 3H, Ac),
3.67 (d, 1H, H6), 3.86, (d, 1H, H6), 4.1-4.3 (m, 3H, H1 and H3),
4.33 (d, 1H, J ) ca. 2 Hz, H5), 4.57 (dd, 1H, H4), 7.12 (s, 2H,
Im), 7.93 (s, 1H, Im), 7.43 (br s, 1H, exch H); IR (KBr) νmax
3171/3160 (Im), 2993, 1614 (CdO, s), 1322, 1299, 1155, 1077,
843 cm-1. Anal. (C14H23NO9S‚C3H4N2) C, H, N.
Rea ction of Diol 28 w ith Tr im eth ylsilyl En ol Eth er s
of Cyclop en ta n on e (for 30) a n d 3-P en ta n on e (for 31). A
mixture of diol 28 (6.88 g, 0.022 mol), 1-(trimethylsilyloxy)-
cyclopentene (9.8 g, 0.062 mol) in THF (40 mL), and concen-
trated HCl (2 mL) was stirred for 90 min. It was reacted with
water (1 mL), neutralized with solid Na2CO3, and filtered. The
filtrate was concentrated in vacuo to a syrup, which was
purified by preparative HPLC (hexanes/ethyl acetate, 2:1) to
give 30 (2.46 g, 42%) as a solid: mp 142-144 °C; 1H NMR
(400 MHz) δ 1.48/1.60 (2 s, 6H, 2 Me), 1.75 (m, 6H, 3 CH2),
1.98 (m, 2H, CH2), 3.78-3.96 (dd, 2H, H6), 4.19-4.28 (dd, 2H,
H1), 4.30-4.42 (m, 2H, H3 and H5), 4.50 (m, 1H, H4), 4.95 (br
s, 2H, NH2). Anal. (C14H23NO8S) C, H, N.
Similarly, aldehyde 15 (9.75 g, 0.04 mol) in THF (150 mL)
and ether (100 mL) was treated with ethylmagnesium bromide
(3 M in ether, 23 mL, 0.06 mol) at 25-40 °C and refluxed for
3 h. The reaction was worked up to give a mixture of
diastereomeric alcohols, which was purified by preparative
HPLC (hexanes/ethyl acetate, 2:1). A mixture of sodium
hydride (60% oil dispersion, 2.5 g, 0.06 mol) in DMF (100 mL)
was treated with a solution of diastereomeric alcohols (11.33
g, 0.04 mol) in DMF (45 mL), and the reaction was stirred for
15 min at 10 °C. After addition of sulfamoyl chloride (9.31 g,
0.08 mol), as above, the mixture was worked up and the
residue was purified by preparative HPLC (hexanes/ethyl
acetate, 2:1) to give 21b (6.60 g, 75%) as a syrup: 1H NMR
(400 MHz) δ 1.00-1.10 (2 t, 3H, Me), 1.34/1.43/1.49/1.54 (4 s,
12H, 4 Me), 1.75-1.90 (m, 1H, CH2 of Et), 1.98-2.08 (m, 1H,
CH2 of Et), 3.78-3.93 (2 overlapping dd, 2H, H6), 4.25 (dd,
1H, H1), 4.39/4.48 (d, 1H, J ) 2.3 Hz, H3, R/â ) 7.5:1), 4.60-
4.70 (m, 2H, H4 and H5), 5.27/5.32 (br s, 2H, NH2, â/R ) 1:7.5);
R/â ratio was estimated as ca. 7:1; 13C NMR (100 MHz) δ 10.7/
10.9 (R/â), 23.0/23.2 (â/R, CH2 of Et), 24.1, 25.6, 25.82 (â), 25.88,
26.7 (â), 26.9, 61.1/61.3 (R/â, CH2), 70.45, 70.54 (â), 70.7, 70.8,
72.1 (â), 87.4/87.6 (â/R) 103.6/103.8 (C2-â/C2-R), 109.0, 109.6;
R/â ratio was estimated as ca. 5:1 from integration of the
anomeric C2 resonances. Anal. (C14H25NO8S) C, H, N. By
analogy with 21a , we assigned the R configuration to C1 in
the major (R) isomer of 21b.
2,3:4,5-Bis-O-(isop r op ylid en e)-â-D-fr u ctop yr a n ose N-
Eth ylsu lfa m a te (22), a n d Its N-Bu tyl (23) a n d N-Ben zyl
(24) Con gen er s. A saturated solution of ethylamine in THF
(70 mL) at -78 °C was treated with chlorosulfate 26 (8.21 g,
0.023 mol). The mixture was stirred for 60 min in a pressure
bottle, allowed to warm to 23 °C, stirred for 2 h, and
concentrated in vacuo to a semisolid. The residue was dis-
solved in ethyl acetate and washed once with water, and the
organic extract was dried (Na2SO4) and concentrated to a
syrup, which was purified by preparative HPLC (hexanes/ethyl
acetate, 3:1) to give 22 (5.0 g, 59%) as a syrup: 1H NMR (400
MHz) δ 1.25 (t, 3H, Me), 1.40/1.41/1.50/1.58 (4 s, 12H, 4 Me),
3.20-3.30 (m, 2H, CH2N), 3.71-3.98 (dd, 2H, H6), 4.12-4.22
(dd, 2H, H1), 4.25-4.28 (m, 1H, H3), 4.48 (m, 1H, H5), 4.55 (t,
1H, NH), 4.61-4.65 (m, 1H, H4). Anal. (C14H25NO8S‚0.15C4-
H8O2) C, H, N.
Similarly, a mixture of diol 28 (5.0 g, 0.016 mol), 3-(tri-
methylsilyloxy)pentene (8.15 g, 0.051 mol), THF (50 mL), and
concentrated HCl (0.6 mL) yielded 31 (2.0 g, 34%) as white
1
solid: mp 127-130 °C; H NMR (400 MHz) δ 0.95 (2 t, 6H, 2
Me), 1.42/1.58 (2 s, 6H, 2 Me), 1.65 (q, 2H, CH2), 1.75 (q, 2H,
CH2), 3.79-3.92 (dd, 2H, H6), 4.22-4.30 (dd, 2H, H1), 4.30-
4.45 (m, 2H, H3 and H5), 4.70 (m, 1H, H2), 5.00 (br s, 2H, NH2).
Anal. (C14H25NO8S) C, H, N.
2,3-O-(Isop r op ylid en e)-4,5-O-m eth ylen e-â-D-fr u ctop y-
r a n ose Su lfa m a te (32) a n d Diol In ter m ed ia te 40.
A
mixture of NaH (60% oil dispersion, 8.4 g, 0.21 mol) in DMF
(100 mL) was cooled to 0 °C, treated with a solution of 4 (50
g, 0.19 mol) in DMF (100 mL), and stirred for 30 min.
A
solution of benzyl bromide (32.9 g, 0.19 mol) in DMF (25 mL)
was added, and the reaction was stirred for 30 min, poured
into cold water, and extracted twice with ethyl acetate. The
combined extract was washed with brine, dried (Na2SO4), and
concentrated to 39, a thick syrup. Benzyl ether 39 (10.0 g,
0.29 mol) was treated with a mixture of 6 N HCl (90 mL) and
THF (180 mL) and stirred at 38-50 °C for 3 h. It was
cautiously neutralized with solid Na2CO3 and filtered. The
filtrate was washed with brine, dried (Na2SO4), and concen-
trated to a syrup that was purified by preparative HPLC
(hexanes/ethyl acetate, 1:1) to give diol 40 as a soft, light yellow
solid, which was used without further manipulation: CI-MS
A mixture of chlorosulfate 26 (6.0 g, 0.016 mol) and
butylamine (7.9 g, 0.11 mol) in THF (70 mL) was heated on a
steam bath in a pressure bottle for 2 h, then cooled, concen-
trated, and redissolved in ethyl acetate. The solution was
washed with water, dried (Na2SO4), and concentrated in vacuo
to a syrup, which was purified by preparative HPLC (hexanes/
ethyl acetate, 2:1) to give 23 (4.22 g, 67%) as a waxy solid:

1332 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
m/z 311 (MH+); 1H NMR (400 MHz) δ 1.34/1.55 (2 s, 6H, 2
Me), 3.15-3.20 (d, 1H, OH), 3.49-3.52 (d, 1H, J ) 10 Hz, H1),
3.76 (m, 1H, H6), 3.85 (m, 1H, H5), 3.96 (m, 1H, H6), 4.15 (m,
1H, H4), 4.29-4.30 (d, 1H, J 34 ) 2.7 Hz, H3), 4.57-4.69 (pair
of d, 2H, J ) 12 Hz, CH2Ph), 7.32-7.36 (m, 5H, arom).
orthoformate (10 g), and H2SO4 (0.4 mL) gave a syrup, which
was purified by preparative HPLC (hexanes/ethyl acetate, 2:1)
to give 37 (5.60 g, 55%) as a syrup and a single isomer (S).
The material eventually crystallized on standing: mp 130-
133 °C; 1H NMR (400 MHz) δ 1.10 (s, 9H, Me), 1.29/1.45/1.55
(3 s, 9H, 3 Me), 3.79-3.91 (dd, 2H, H6), 4.21 (d, 1H, H5), 4.30-
4.36 (m, 3H, H1 and H3), 4.62 (m, 1H, H4), 4.95 (br s, 2H, NH2).
Anal. (C15H27NO8S) H, N; C: calcd, 47.23; found, 47.87.
A solution of diol 40 (4.00 g, 12.9 mmol) and tetrabutylam-
monium bromide (0.40 g, 1.24 mmol) in dibromomethane (124
g, 713 mmol) was combined with 50% aqueous NaOH (200 g,
2.5 mol) and vigorously stirred at 60 °C for 2 h. The layers
were separated, and the aqueous layer was extracted twice
with dichloromethane. The combined extracts were washed
twice with brine, dried (MgSO4), and concentrated in vacuo.
The residue was purified by preparative HPLC (hexanes/ethyl
acetate, 9:1) to afford 2.48 g (60%) of 41 as a clear oil: 1H NMR
(400 MHz) δ 1.43/1.55 (2 s, 6H, 2 Me), 3.54/3.62 (pair of d, 2H,
D. Com p ou n d s 33a a n d 33b. A mixture of diol 28 (10.0
g, 0.033 mol), acetal (70 mL), and concentrated H2SO4 (0.5 mL)
was stirred at 45 °C for 2 h and neutralized with solid Na2-
CO3. It was filtered and concentrated to a waxy solid, which
was purified by preparative HPLC (hexanes/ethyl acetate, 2:1)
to give diastereomers 33a (3.34 g, 32%) and 33b (0.69 g, 6.4%),
1
each as a syrup. For 33a : H NMR (400 MHz) δ 1.40 (br s,
6H, 2 Me), 1.55 (s, 3H, Me), 3.70-3.80 (dd, 2H, H6), 4.19 (d,
1H, H5), 4.20-4.30 (m, 2H, H1), 4.35 (d, 1H, H3), 4.45 (m, 1H,
J ab ) 10.6 Hz, H1), 3.75-4.00 (m, 2H, H6), 4.18 (d, 1H, J 45
)
7.9 Hz, H5), 4.43 (dd, 1H, J 34 ) 2.1 Hz, J 45 ) 7.9 Hz, H4), 4.53
(d, 1H, J 34 ) 2.1 Hz, H3), 4.56/4.70 (pair of d, 2H, J ) 13.2 Hz,
CH2Ph), 4.81 (s, 1H), 5.11 (s, 1H), 7.25-7.35 (m, 5H, arom).
Compound 41 (2.72 g, 8.4 mmol) was combined with 20% Pd-
(OH)2 on carbon (1.36 g) in anhydrous ethanol (42 mL), placed
on a Parr apparatus under hydrogen (50 psig), and heated at
50 °C. After 2.5 h, the reaction was cooled to 23 °C, filtered
through a Nylon-66 filter (0.45 µm), and concentrated in vacuo
to afford 1.98 g (99%) of 42, as an oil that crystallized on
standing. A white solid was obtained from hexanes/ethyl
acetate: mp 71-73 °C; [R]25D -27.4° (c 1.00, MeOH); 1H NMR
(400 MHz) δ 1.42/1.56 (2 s, 6H, 2 Me), 1.98 (dd, 1H, J ) 5.9
Hz, J ) 7.8 Hz, OH), 3.60-3.75 (m, 2H, H1), 3.75-4.05 (m,
2H, H6), 4.19 (d, 1H, J 45 ) 8.1 Hz, H5), 4.40-4.50 (m, 2H, H3
and H4), 4.82 (s, 1H), 5.17 (s, 1H), 7.25-7.35 (m, 5H, arom.);
IR (KBr) νmax 3402 (s), 2998 (m), 2931 (m), 2856 (m), 1253 (m),
1374 (s), 1079 (s), 901 (s), 538 (m) cm-1; CI-MS m/z 233 (MH)+,
250 (M + NH4)+. To NaH (60% oil dispersion; 0.53 g, 8.0 mmol,
washed with ether) suspended in 6 mL of DMF at 5 °C was
added 42 (1.68 g, 6.31 mmol) with stirring. The reaction was
stirred for 1 h, treated with sulfamoyl chloride (1.23 g, 10.6
mmol), slowly warmed to 23 °C over 1 h, diluted with water,
and extracted three times with ethyl acetate. The organic
solution was rinsed twice with brine, dried (MgSO4), and
concentrated in vacuo. The residue was purified by prepara-
tive HPLC (hexanes/ethyl acetate, 7:3) and recrystallized from
ethyl acetate/hexanes to yield 32 (1.21 g, 79%) as a white
H4), 5.0 (m, 1H, R-CH), 5.15 (br s, 2H, NH2). Anal. (C11H19
-
NO8S) C, H, N. For 33b: 1H NMR (400 MHz) δ 1.32/1.43/
1.55 (3 s, 9H, 3 Me), 3.82-4.00 (dd, 2H, H6), 4.20-4.30 (dd,
2H, H1),4.19 (d, 1H, H5), 4.40 (d, 1H, H3), 4.60 (m, 1H, H4),
5.15 (br s, 2H, NH2), 5.45 (m, 1H, S-CH). Anal. (C11H19
NO8S‚0.1C4H8O2) C, H, N.
-
E. Com p ou n d 34. A mixture of diol 28 (10.0 g, 0.033 mol),
propionaldehyde diethyl acetal (80 mL), and concentrated H2-
SO4 (0.5 mL) was stirred at 23 °C for 24 h and neutralized
with solid Na2CO3. It was filtered and concentrated to a syrup,
which was purified by preparative HPLC (hexanes/ethyl
acetate, 2:1) to give 34 (3.77 g, 34%) as a syrupy mixture of
diastereomers (R:S ) 9:1). The material eventually crystal-
lized on standing and was then recrystallized from ethyl
acetate-hexanes: mp 131-132 °C; 1H NMR (400 MHz) δ 0.90
(t, 3H, Me), 1.40/1.60 (2 s, 6H, 3 Me), 1.80 (q, 2H, CH2), 3.80-
3.95 (dd, 2H, H6), 4.19 (d, 1H, H5), 4.25-4.38 (dd, 2H, H1),
4.40 (d, 1H, H3), 4.50 (m, 1H, H4), 4.85 (m, 0.9H, R-CH), 5.00
(br s, 2H, NH2), 5.30 (t, 0.1H, S-CH). Anal. (C12H21
NO8S‚0.1C4H8O2) C, H, N.
-
F . Com p ou n d 36. A mixture of diol 28 (8.0 g, 0.027 mol),
trimethylacetaldehyde diethyl acetal (9.0 g, 0.056 mol; pre-
pared from trimethylacetaldehyde, triethyl orthoformate, eth-
anol, and p-TsOH), THF (20 mL), and concentrated H2SO4 (0.4
mL) was stirred at 23 °C for 6 h and neutralized with solid
Na2CO3. It was filtered and concentrated to a solid, which
was recrystallized from ethanol-water to give 36 (4.50 g, 45%),
the R-isomer: mp 164-165 °C; 1H NMR (400 MHz) δ 1.00 (s,
9H, Me), 1.45/1.55 (2 s, 6H, 2 Me), 3.80-3.95 (dd, 2H, H6),
4.15 (d, 1H, H5), 4.25-4.35 (dd, 2H, H1), 4.40 (d, 1H, H3), 4.50
(d, 1H, H4), 4.52 (s, 1H, CH), 4.90 (br s, 2H, NH2). Anal.
(C14H25NO8S) C, H, N.
1
solid: mp 131-133 °C; H NMR (400 MHz) δ 1.43/1.56 (2 s,
6H, 2 Me), 3.83-4.02 (m, 2H, H6), 3.75-4.05 (m, 2H, H6), 4.20
(d, 1H, J 45 ) 7.9 Hz, H5), 4.26 (s, 2H, H1), 4.40-4.48 (m, 2H,
H3 and H4), 4.81 (s, 1H), 5.06 (s, 2H, NH2), 5.19 (s, 1H); IR
(KBr) νmax 3377 (s), 3270 (s), 1564 (m), 1363 (s), 1076 (s), 904
(m) cm-1; CI-MS m/z 312 (MH)+, 329 (M + NH4)+. Anal.
(C10H17NO8S) C, H, N, S.
G. Com p ou n d 38. A mixture of diol 28 (10.0 g, 0.033 mol),
benzaldehyde dimethyl acetal (70 mL), and concentrated H2-
SO4 (0.5 mL) was stirred at 23 °C for 24 h, then neutralized
with solid Na2CO3, filtered, and concentrated in vacuo to a
syrup, which was purified by preparative HPLC (hexanes/ethyl
acetate, 2:1) to give 38 (5.80 g, 45%) as a syrupy mixture of
diastereomers (R:S ) 3:1): 1H NMR (400 MHz) δ 1.41/1.62 (2
s, 6H, 2 Me), 3.95-4.12 (m, 2H, H6), 4.19-4.31 (dd, 1H, H1),
4.35 (m, 1H, H5), 4.45 (d, 1H, H3), 4.65 (m, 1H, H4), 4.72 (br s,
2H, NH2), 5.25 (s, 0.75H, R-CH), 6.28 (s, 0.25H, S-CH). Anal.
(C16H21NO8S) C, H, N.
4,5-O-(1,2-E t h a n o)-2,3-O-(isop r op ylid en e)-â-D-fr u ct o-
p yr a n ose Su lfa m a te (43). A mixture of 40 (10.0 g, 0.032
mol), 1,2-dibromoethane (50 mL), and tetrabutylammonium
bromide (2.0 g) was stirred at 50 °C while 50% aqueous NaOH
(503 g) was added cautiously. The reaction was allowed to
stand until gas evolution ceased, after which additional
dibromoethane (210 mL, 2.5 mol total) was added while the
temperature was kept under 60 °C. The mixture was stirred
for 2 h at 55 °C, treated with ice-water, and extracted twice
with ethyl acetate. The combined extract was dried (Na2SO4)
and concentrated in vacuo. The residue was purified by
preparative HPLC (hexanes/ethyl acetate, 1:1) to supply the
1,4-dioxane product as a syrup. A mixture of product (3.19 g,
0.087 mol) in ethanol (42 mL) was treated with Pd(OH)2 on
Rea ction of Diol 28 w ith Ca r bon yl Com p ou n d s in th e
P r esen ce of Tr ieth yl Or th ofor m a te. A. Gen er a l P r oce-
d u r e. In a typical reaction, a mixture of ketone (excess,
sometimes used as a solvent), concentrated sulfuric acid (0.5
mL), triethyl orthoformate (10.0 g, 0.07 mol), and ethanol (10
mL, used only when ketone could not be used as solvent) was
stirred for 3 h and then treated with a mixture of diol 28 (10.0
g, 0.03 mol) in 20 mL of THF (only when ketone could not be
used as solvent). After 24 h of stirring, the mixture was
neutralized with Na2CO3 (to pH ) 7), filtered, and concen-
trated in vacuo to the respective product, which was purified
by preparative HPLC.
B. Com p ou n d 35. A mixture of diol 28 (8.0 g, 0.027 mol),
2-butanone (100 mL), triethyl orthoformate (10.0 g), and H2-
SO4 (0.4 mL) gave a syrup, which was purified by preparative
HPLC (hexanes/ethyl acetate, 2:1) to give 35 (7.55 g, 79%) as
a syrupy mixture of diastereomers. The material eventually
crystallized on standing: mp 97-99 °C; 1H NMR (400 MHz) δ
1.00 (t, 3H, Me), 1.29/1.45/1.58 (3 s, 9H, 3 Me), 1.75 (q, 2H,
CH2), 3.70-3.92 (dd, 2H, H6), 4.20-4.30 (m, 2H, H1), 4.31-
4.35 (m, 2H, H3 and H5), 4.62 (m, 1H, H4), 4.75 (br s, 2H, NH2).
Anal. (C13H23NO8S) C, H, N.
C. Com p ou n d 37. In a similar way, a mixture of diol 28
(8.0 g, 0.027 mol), 3,3-dimethyl-2-butanone (100 mL), triethyl

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1333
carbon (1.36 g) and shaken with hydrogen at 50 °C for 3 h. It
was cooled, filtered, and concentrated to 44, as a syrup, which
was used in the next step. A solution of alcohol 44 (2.19 g,
0.009 mol) in DMF (25 mL) with triethylamine (1.8 g, 0.018
mol) was stirred for 45 min at 5 °C, treated with sulfamoyl
chloride (1.57 g, 0.013 mol), and stirred for 15 min at 5 °C
and then 45 min at 23 °C. The mixture was poured into cold
water and extracted twice with ethyl acetate. The combined
extract was dried (Na2SO4) and concentrated in vacuo to a
syrup, which was purified by preparative HPLC (hexane/ethyl
acetate, 1:1) to give 43 (1.60 g, 55%) as a soft white solid: mp
cooled to -60 °C, and hexafluoroacetone (18.0 g, 108 mmol)
was condensed into the tube. The tube was sealed and heated
at 120 °C in a silicone oil bath for 38 h. After being cooled to
23 °C, the mixture was filtered through diatomaceous earth
and concentrated in vacuo. The residue was dissolved in ethyl
acetate, washed sequentially twice with NaHCO3 (saturated
aqueous) and twice with brine, dried (MgSO4), and concen-
trated in vacuo to give an orange oil, which was purified by
preparative HPLC (hexanes/ethyl acetate, 9:1) to furnish 50
(3.48 g, 70%) as a clear viscous oil. Compound 50 (3.16 g, 6.9
mmol) was combined with 20% Pd(OH)2 on carbon (0.32 g) in
anhydrous ethanol (69 mL) and placed on a Parr apparatus
with hydrogen (50 psig) at 23 °C. After 2 h, the reaction was
filtered through diatomaceous earth and concentrated in vacuo
to afford 51 (2.57 g, 100%) as a white solid, which was used
without further purification. Sulfamoyl chloride (1.07 g, 9.3
mmol) was added to a solution of 51 (2.27 g, 6.2 mmol) and
triethylamine (1.29 mL, 9.3 mmol) in dry DMF (31 mL) at 5
°C with stirring under argon. After 1 h, the reaction was
diluted with brine and extracted three times with ethyl
acetate. The combined extracts were rinsed twice with 3 N
HCl, twice with NaHCO3 (saturated aqueous), and twice with
brine, then dried (MgSO4), and concentrated in vacuo. The
residue was purified by preparative HPLC (hexanes/ethyl
acetate, 7:3) to give 47 (2.23 g, 81%) as a white foam: 1H NMR
(400 MHz) δ 1.45/1.56 (2 s, 6H, 2Me), 4.15-4.35 (m, 2H, H6),
4.49 (d, 1H, J 34 ) 2.2 Hz, H3), 4.71 (d, 1H, J 45 ) 7.9 Hz), 4.90
(s, 2H, NH2), 4.98 (d, 1H, J 45 ) 7.9 Hz); IR (KBr) νmax 3363
(m), 3282 (m), 3264 (m), 1389 (m), 1235 (s), 1139 (s), 977 (s),
710 (m) cm-1; CI-MS m/z 448 (MH)+, 465 (M + NH4)+. Anal.
(C12H15F6NO8S) C, H, N, S.
2,3-O-(Isop r op ylid en e)-4,5-O-(m eth ylbor yl)-â-D-fr u cto-
p yr a n ose Su lfa m a te (54). Methylboronic acid (2.00 g, 33.4
mmol) was added to solution of diol 282a (5.00 g, 16.7 mmol)
in methanol (100 mL) at 23 °C with stirring under argon. After
18 h, the reaction was concentrated in vacuo; the residue was
dissolved in ethyl acetate, washed twice with NaHCO3 (satu-
rated aqueous), dried (MgSO4), and concentrated in vacuo to
an oil, which was crystallized (benzene/hexanes, 1:1) to furnish
54 (2.68 g, 50%) as a white solid: mp 88-89 °C; 1H NMR (360
MHz, C6D6) δ 0.41 (s, 3H, Me), 1.21/1.30 (2 s, 6H, 2 Me), 3.50-
3.75 (m, 2H, H6), 3.85 (d, 1H, J 45 ) 8.7 Hz, H5), 3.95-4.15 (br
s, 2H, NH2), 4.17/4.23 (pair of d, 2H, J 1a1b ) 10.6 Hz, H1), 4.29
(d, 1H, J 34 ) 2.4 Hz, H3), 4.40 (dd, 1H, J 34 ) 2.4 Hz, J 45 ) 8.7
Hz, H4); IR (KBr) νmax 3348 (s), 3271 (m), 1364 (m), 1205 (s),
1053 (s), 912 (m), 816 (m) cm-1; CI-MS m/z 324 (MH)+, 341
(M + NH4)+. Anal. (C10H18BNO8S) C, H, N.
1
122-124 °C; H NMR (400 MHz) δ 1.40/1.55 (2 s, 6H, 2 Me),
3.50-3.72 (dd, 2H, H6), 3.80-4.00 (m, 4H, 2 CH2), 4.15 (m,
2H, H1), 4.19 (d, 1H, H5), 4.30 (d, 1H, H3), 4.32-4.45 (dd, 1H,
H4), 5.15 (br s, 2H, NH2); 1H NMR (400 MHz, C6D6/D2O) δ 1.35/
1.45 (2 s, 6H, 2 Me), 3.00-3.13 (m, 1H, OCH2), 3.20-3.35 (m,
2H, OCH2), 3.40-3.57 (m, 1H, OCH2), 3.85-3.95 (m, 2H, H5
and H6a), 3.95-4.05 (m, 1H, H6e), 4.05-4.10 (m, 1H, H4,
decoupled at H5: J 46e ) 1.4 Hz, J 34 ) 3.3 Hz), 4.15 (d, 1H, J 34
) 3.3 Hz, H3), 4.32/4.42 (pair of d, 2H, J ab ) 11.4 Hz, H1), 4.94
(br s, 2H, NH2). Anal. (C11H19NO8S) C, H, N.
4,5-O-(Dim et h oxym et h ylen e)-2,3-O-(isop r op ylid en e)-
â-D-fr u ctop yr a n ose Su lfa m a te (45). Diol 282a (6.00 g, 20
mmol), tetramethyl orthocarbonate (16.4 g, 120 mmol), and
p-toluenesulfonic acid (0.60 g, 3.2 mmol) were dissolved in 1,4-
dioxane (200 mL) and stirred at 23 °C for 22 h. The mixture
was concentrated in vacuo, basified with NaHCO3 (saturated
aqueous), and extracted three times with ethyl acetate. The
combined extracts were rinsed twice with NaHCO3 (saturated
aqueous), dried (MgSO4), and concentrated in vacuo. The
residue was purified by preparative HPLC (CH2Cl2/ethyl
acetate, 9:1) to furnish 45 (2.60 g, 42%) as a glass: 1H NMR
(400 MHz) δ 1.46/1.60 (2 s, 6H, 2 Me), 3.41 (s, 3H, Me), 3.54
(s, 3H, Me), 3.90-4.05 (m, 2H, H6), 4.28-4.43 (m, 1H, H5),
4.74 (dd, 1H, J 34 ) 2.4 Hz, J 45 ) 8.0 Hz, H4), 5.30 (s, 2H, NH2),
5.19 (s, 1H); IR (KBr) νmax 3435 (m), 3354 (m), 3264 (m), 1385
(s), 1133 (s), 1086 (s), 1015 (s), 910 (m) cm-1; CI-MS m/z 372
(MH)+. Anal. (C12H21NO10S‚0.1H2O) C, H, N, H2O.
4,5-O-[(S)-Eth oxym eth ylen e]-2,3-O-(isop r op ylid en e)-â-
D-fr u ctop yr a n ose Su lfa m a te (46). A mixture of diol 28 (5
g, 0.017 mol), triethyl orthoformate (12.4 g, 0.08 mol), p-
toluenesulfonic acid (0.14 g), and THF (20 mL) was stirred at
23 °C for 4 h and neutralized with solid Na2CO3. It was
filtered and concentrated in vacuo to a residue, which was
purified by preparative HPLC (hexanes/ethyl acetate, 2:1) to
give 46 (2.67 g, 44%) as a syrupy mixture of diastereomers
(R:S ) 1:9): 1H NMR (400 MHz) δ 1.20 (t, 3H, Me), 1.41/1.59
(2 s, 6H, 2 Me), 3.62 (q, 2H, CH2), 3.8-3.95 (dd, 2H, H6), 4.25
(m, 2H, H1), 4.35 (d, 1H, H3), 4.45 (m, 1H, H5), 4.75 (m, 1H,
H4), 5.00 (br s, 2H, NH2), 5.79 (s, 0.1H, R-CH), 5.92 (s, 0.9H,
S-CH). Anal. (C12H21NO9S) C, H, N.
2,3-O-(Isop r op ylid en e)-4,5-[2,2,2-t r iflu or o-1-(t r iflu o-
r om eth yl)eth yliden e]-â-D-fr u ctopyr an ose Su lfam ate (47).
A solution of diol 40 (10.0 g, 32.2 mmol) and pyridine (10.4
mL, 129 mmol) in chloroform (133 mL) was cooled to -60 °C
with mechanical stirring. Sulfuryl chloride (8.6 mL, 107 mmol)
was added dropwise over 15 min, and the reaction was slowly
warmed to 23 °C over 18 h. The reaction was stirred at 23 °C
for 5 d, filtered through diatomaceous earth, washed sequen-
tially twice with water, twice with NaHCO3 (saturated aque-
ous), and twice with brine, then dried (MgSO4), and concen-
trated in vacuo. The residue was purified by preparative
HPLC (hexanes/ethyl acetate, 9:1) to give 48 (5.01 g, 47%) as
a white foam. A solution of 48 in methanol (114 mL) was
treated with K2CO3 (4.72 g, 34 mmol), stirred at 23 °C for 16
h, filtered through diatomaceous earth, and concentrated in
vacuo. The residue was partitioned between water and ethyl
acetate, and the aqueous layer was extracted twice with ethyl
acetate. The combined extract was washed twice with brine,
dried (MgSO4), and concentrated in vacuo to give 49 (3.48 g,
100%) as an amber oil, which was used without further
purification. A screw-topped pressure tube containing a
solution of 49 (3.18 g, 10.9 mmol) and tetrabutylammonium
iodide (1.20 g, 3.3 mmol) in 1,2-dimethoxyethane (22 mL) was
2,3-O-(Isop r op ylid en e)-4,5-O-(p h en ylbor yl)-â-D-fr u cto-
p yr a n ose Su lfa m a te (55). A solution of phenylboronic acid
(2.00 g, 33.4 mmol) in methanol (50 mL) was added to solution
of diol 282a (4.07 g, 33.4 mmol) in water (100 mL) and stirred
at 23 °C for 2 h. The white precipitate was isolated by
filtration and purified by preparative HPLC (CH2Cl2/ethyl
acetate, 9:1). Recrystallization from hot benzene furnished 55
(5.90 g, 92%) as a white solid: mp 151-152 °C; 1H NMR (400
MHz) δ 1.10/1.21 (2 s, 6H, 2 Me), 2.47 (s, 0.8H, H2O), 3.45-
3.80 (m, 4H, H1 and H6), 4.19 (d, 1H, J 35 ) 2.6 Hz, H3), 4.32
(d, 1H, J 45 ) 8.5 Hz, H5), 4.61 (dd, 1H, J 34 ) 2.6 Hz, J 45 ) 8.5
Hz, H4), 6.48 (bs, 2H, NH2), 6.95-7.50 (m, 5H, Ph); IR (KBr)
νmax 3372 (s), 3292 (s), 2974 (m), 1362 (s), 1152 (s), 1035 (s),
913 (m) cm-1; CI-MS m/z 403 (M + NH4)+. Anal. (C15H20
BNO8S) C, H, N.
-
2,3:4,5-Bis-O-(cycloh exyliden e)-â-D-fr u ctopyr an ose Su lf-
a m a te (58). Concentrated H2SO4 (75 mL) was added dropwise
over 15 min to a suspension of D-fructose (150 g, 0.833 mol) in
cyclohexanone (750 mL) at 23 °C. The reaction was warmed
to 55 °C, stirred for 1 h, cooled to 23 °C, cautiously basified
with a mixture of 50% NaOH (150 mL) and ice (200 g), diluted
with water, and extracted with ether. The extract was washed
with water, dried (Na2SO4), and concentrated in vacuo to an
oil, which was concentrated on a Kugelrohr apparatus (130
°C, 0.15 mmHg) to yield a dark reddish-brown glass. Purifica-
tion by preparative HPLC (hexanes/ethyl acetate, 9:1) afforded
2,3:4,5-bis-O-(cyclohexylidene)-â-D-fructopyranose (24.2 g, 8.5%)

1334 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
as a tacky amber glass: 1H NMR (300 MHz) δ 1.25-1.90 (m,
20H), 2.14 (dd, 1H, J ) 4.3 Hz, 8.4 Hz, OH), 3.55-3.85 (m,
3H, 2 H1 and H6a), 3.94 (dd, J 56e ) 1.6 Hz, J 6a6e) 13.1 Hz, 1H,
H6e), 4.24 (d, 1H, J 45 ) 7.9 Hz, H5), 4.36 (d, 1H, J 34 ) 2.7 Hz,
H3), 4.64 (dd, 1H, J 34 ) 2.7 Hz, J 45 ) 7.9 Hz, H4). Most of this
material (22.6 g, 66.4 mmol) and pyridine (6.30 g, 79.7 mmol)
were dissolved in toluene (150 mL) and added dropwise over
20 min to a vigorously stirred solution of sulfuryl chloride (8.75
g, 64.9 mmol) in toluene (150 mL) at -20 °C. The reaction
was slowly warmed to 23 °C over 4 h and diluted with water.
The toluene layer was washed three times with citric acid (10%
aqueous), three times with NaHCO3 (saturated aqueous), and
twice with brine; it was dried (MgSO4) and concentrated in
vacuo to give 33.1 g of crude 2,3:4,5-bis-O-(cyclohexylidene)-
â-D-fructopyranose chlorosulfate, which was dissolved in 132
mL of THF and reacted with anhydrous ammonia (30 psig) in
a vigorously stirred autoclave for 18 h. The mixture was
filtered through diatomaceous earth, concentrated in vacuo,
and purified by preparative HPLC (hexanes/ethyl acetate, 7:3)
to furnish 20.3 g (73%) of 58 as a hard white foam: 1H NMR
(400 MHz) δ 1.35-1.90 (m, 20H), 3.75-4.00 (m, 2H, H6), 4.20-
4.40 (m, 4H, 2 H1, H3 and H5), 4.64 (dd, 1H, J 34 ) 2.3 Hz, J 45
) 7.8 Hz, H4), 5.03 (s, 2H, NH2); IR (KBr) νmax 3372 (m), 3277
(m), 2897 (s), 2859 (m), 1450 (m), 1372 (s), 1187 (s), 1087 (s),
935 (s) cm-1; CI-MS m/z 420 (MH)+, 437 (M + NH4)+. Anal.
(C18H29NO8S) C, H, N, S.
with NaHCO3 (saturated aqueous), and twice with brine, then
dried (MgSO4), and concentrated in vacuo. The excess ben-
zaldehyde was removed by distillation on a Kugelrohr ap-
paratus (70 °C, 0.35 Torr). The residue, which contained at
least three bis-acetal isomers (two major) by GLC, was
partially purified by preparative HPLC (hexanes/ethyl acetate,
4:1) to give 32.3 g of an isomeric mixture. This mixture was
recrystallized once from hot carbon tetrachloride (350 mL),
once from methanol (80 mL), and again from hot CCl4 (180
mL) to afford 2,3-(S):4,5-(R)-bis-O-(phenylmethylene)-â-D-fruc-
topyranose33 as a white solid (9.13 g, 5%): [R]20D -20.7° (c 2.82,
1
CHCl3); H NMR (400 MHz) δ 2.01 (dd, 1H, J ) 5.2, 8.1 Hz,
OH), 3.75-4.05 (m, 4H, H1 and H6), 4.35 (dd, 1H, J 45 ) 8.1
Hz, J 56e ) 1.4 Hz, H5), 4.55 (d, 1H, J 34 ) 2.4 Hz, H3), 4.78 (dd,
1H, J 34 ) 2.4 Hz, J 45 ) 8.1 Hz, H4), 5.79 (s, 1H), 5.90 (s, 1H),
7.35-7.65 (m, 10H, 2 Ph); 13C NMR (100 MHz) δ 61.0 (CH2),
65.4 (CH2), 71.4 (CH), 71.8 (CH), 102.8 (CH), 103.0 (C), 103.8
(CH), 126.2 (CH), 127.0 (CH), 128.5 (CH), 128.6 (CH), 129.8
(CH), 130.0 (CH), 135.9 (C), 135.4 (C); CI-MS m/z 357 (MH)+,
374 (M + NH4)+. A solution of this material (8.89 g, 25 mmol)
and triethylamine (5.2 mL, 37.4 mmol) in dry DMF (125 mL)
was cooled to 5 °C with stirring. Sulfamoyl chloride (4.32 g,
37.4 mmol) was added, and the mixture was stirred for 1 h at
5 °C and diluted with brine (300 mL). It was extracted three
times with ethyl acetate, and the combined extracts were
washed with 3 N HCl, twice with NaHCO3 (saturated aque-
ous), and twice with brine, then dried (MgSO4), and concen-
trated in vacuo. The residue was purified by flash column
chromatography (hexanes/ethyl acetate, 3:2) and recrystallized
(EtOH/water, 5:1) to provide 6034 (7.84 g, 72%) as a white
2,3:4,5-Bis-O-(et h ylp r op ylid en e)-â-D-fr u ct op yr a n ose
Su lfa m a te (59). Concentrated H2SO4 (60 mL) was added
dropwise at 40 °C over 20 min to a stirred suspension of
d-fructose (100.0 g, 0.56 mol) in 3-pentanone (2.3 L, 1.13 mol).
After 25 min, the reaction was cooled to 5 °C, cautiously
basified to pH 11 with 3 N NaOH, concentrated in vacuo,
diluted with water, and extracted three times with CH2Cl2.
The extracts were washed twice with water, dried (Na2SO4),
and concentrated in vacuo. The residue was purified by
preparative HPLC (hexanes/ethyl acetate, 19:1) to give 9.4 g
(5.3%) of 2,3:4,5-bis-O-(1-ethylpropylidene)-â-D-fructopyranose
as a white crystalline solid: mp 46-48 °C; [R]25D -36.6° (c 1.00,
MeOH); 1H NMR (300 MHz) δ 0.60-1.10 (m, 12H), 1.50-1.80
(m, 8H); 2.02 (dd, 1H, J ) 4.9 and 8.2 Hz, OH), 3.50-4.00 (m,
4H, H1 and H6), 4.15 (dd, 1H, J 45 ) 7.8 Hz, J 56e ) 1.7 Hz),
4.25 (d, 1H, J 34 ) 2.6 Hz, H3), 4.54 (dd, 1H, J 34 ) 2.6 Hz, J 45
) 7.8 Hz, H4); IR (KBr) νmax 3510 (m), 2977 (m), 2944 (m),
1462 (m), 1176 (s), 1077 (s), 934 (s) cm-1; CI-MS m/z 317(MH)+,
334 (M + NH4)+. Anal. Calcd for C16H28O6: C, 60.74; H, 8.92.
Found: C, 60.77; H, 8.93. This material (17.2 g, 54.1 mmol)
and pyridine (5.13 g, 64.9 mmol) were dissolved in toluene (73
mL) and added dropwise over 15 min at -20 °C to a vigorously
stirred solution of sulfuryl chloride (8.75 g, 64.9 mmol) in 75
mL of toluene. The reaction was slowly warmed to 23 °C over
3 h and then diluted with water. The toluene layer was
washed three times with citric acid (10% aqueous), three times
with NaHCO3 (saturated aqueous), and twice with brine; it
was dried (Na2SO4) and concentrated in vacuo to afford 25.4
g of crude 2,3:4,5-bis-O-(1-ethylpropylidene)-â-D-fructopyra-
nose chlorosulfate. The crude product was dissolved in THF
(300 mL) and placed in a vigorously stirred autoclave under
30 psig of anhydrous ammonia for 18 h. The mixture was
filtered through diatomaceous earth, concentrated in vacuo,
and purified by preparative HPLC (hexanes/ethyl acetate, 3:1)
to give 59 (2.48 g, 79%) as a clear syrup: 1H NMR (400 MHz)
δ 0.80-1.05 (m, 12H), 1.55-1.85 (m, 8H), 3.75-4.00 (m, 2H,
1
solid: mp 156-158 °C; H NMR (400 MHz) δ 3.90-4.25 (m,
2H, H6), 4.30-4.55 (m, 4H, 2 H1, H3 and H5), 4.55 (d, 1H, J 34
) 2.4 Hz, H3), 4.61 (s, 2H, NH2), 4.77 (dd, 1H, J 34 ) 2.4 Hz,
J 45 ) 8.2 Hz, H4), 5.79 (s, 1H), 5.90 (s, 1H), 7.35-7.60 (m, 10H,
2 Ph); IR (KBr) νmax 3384 (m), 1460 (m), 1391 (s), 1106 (s),
1069 (s), 999 (s), 759 (s) cm-1; FAB-MS m/z 436 (MH)+, 458
(M + Na)+. Anal. (C20H21NO8S) C, H, N, S.
2,3-O-(Isop r op ylid en e)-4,5-O-d im eth yl-â-D-fr u ctop yr a -
n ose Su lfa m a te (63). A mixture of NaH (60% oil dispersion,
1.28 g, 0.032 mol) in DMF (5 mL) was treated with a soultion
of diol 40 (3.2 g, 0.01 mol) in 20 mL of DMF, and the reaction
was stirred at 0 °C for 30 min. The reaction mixture was
treated dropwise with methyl iodide (3.84 mL, 0.062 mol),
stirred for 30 min, allowed to warm to 23 °C, stirred for 2 h,
treated with cold water, and extracted with ethyl acetete three
times. The combined extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo to afford 1.80 g (53%) of
the syrupy dimethoxy analogue, some of which (0.005 mol) was
combined with 10% Pd/C (0.85 g) in anhydrous ethanol (30
mL), placed on a Parr apparatus with hydrogen (50 psig),
shaken for 24 h, filtered through a Nylon-66 filter (0.45 µm),
and concentrated in vacuo to afford 1.22 g (92%) of the alcohol
as a syrup. This alcohol (1.15 g, 0.005 mol) in DMF (10 mL)
was added to a mixture of NaH (60% oil dispersion, 0.24 g,
0.006 mol) in DMF (10 mL), and the reaction was stirred at 0
°C for 30 min. Sulfamoyl chloride (1.06 g, 0.009 mol) was
added portionwise at 0-10 °C. After 1 h of stirring, the
mixture was poured onto ice and extracted with ethyl acetate
twice. The combined extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo to a syrup, which was
purified by preparative HPLC (ethyl acetate/hexanes, 1:1) to
give 63 (0.96 g, 58%) as a white solid: mp 135-138 °C; 1H
NMR (400 MHz) δ 1.44/1.57 (2 s, 6H, 2 Me), 3.45/3.58 (2 s,
H6), 4.20-4.40 (m, 4H, 2 H1, H3 and H5), 4.62 (dd, 1H, J 34
)
2.4 Hz, J 45 ) 7.9 Hz, H4), 4.93 (s, 2H, NH2); IR (CHCl3) νmax
3435 (m), 3354 (m), 3293 (m), 1482 (s), 1377 (s), 1170 (m), 1083
(s), 909 (s) cm-1; CI-MS m/z 396 (MH)+, 413 (M + NH4)+. Anal.
(C16H29NO8S) C, H, N, S.
6H, 2 OMe), 3.73 (ddd, 1H, J 45 ) 3.2 Hz, J 56a ) 8.4 Hz, J 56e )
4.9 Hz, H5), 3.81 (dd, 1H, J 6a6e ) 11.3 Hz, J 56a ) 8.4 Hz, H6a),
3.88 (ddd, 1H, J 6a6e ) 11.3 Hz, J 56e ) 4.9 Hz, J 46e ) 0.9 Hz,
H6e), 3.92 (ddd, 1H, J 34 ) 3.6 Hz, J 45 ) 3.2 Hz, J 46e ) 0.9 Hz,
H4), 4.24 (d, 1H, J 34 ) 3.6 Hz, H3), 4.34/4.45 (pair of d, 2H, J ab
) 11.5 Hz, H1), 5.01 (br s, 2H, NH2). Anal. (C11H21NO8S) C,
H, N.
2,3-(S):4,5-(R)-Bis-O-(p h en ylm eth ylen e)-â-D-fr u ctop y-
r a n ose Su lfa m a te (60). Anhydrous zinc chloride (80 g, 0.59
mol) was added over 20 min at 5 °C to a stirred suspension of
D-fructose (100.0 g, 0.56 mol) in benzaldehyde (250 mL, 2.46
mol). After 60 min, the reaction was warmed to 23 °C, stirred
for 5 d, and concentrated in vacuo. The residue was treated
with ethyl acetate and washed three times with 1 N HCl, once
4,5-O-Diet h yl-2,3-O-(isop r op ylid en e)-â-D-fr u ct op yr a -
n ose Su lfa m a te (64). A mixture of NaH (60% oil dispersion,
1.40 g, 0.036 mol) in DMF (10 mL) was treated with a mixture
of diol 40 (3.5 g, 0.011 mol) in 20 mL of DMF, and the reaction

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1335
was stirred at 0 °C for 30 min. The mixture was treated
dropwise with ethyl iodide (5.7 mL, 0.07 mol), stirred for 30
min, allowed to warm to 23 °C, stirred for 2 h, treated with
cold water, and extracted with ethyl acetete three times. The
combined extracts were washed with brine, dried (Na2SO4),
and concentrated in vacuo to afford 3.22 g (80%) of the syrupy
diethoxy analogue, some of which (0.009 mol) was combined
with 10% Pd/C (1.79 g) in anhydrous ethanol (60 mL), placed
on a Parr apparatus under hydrogen (50 psig), shaken for 24
h, filtered through a Nylon-66 filter (0.45 µm), and concen-
trated in vacuo to afford 1.98 g (78%) of the alcohol as a syrup.
Similar to 63, reaction of this alcohol (1.96 g, 0.007 mol) with
NaH (0.37 g, 0.009 mol) in DMF (20 mL) and sulfamoyl
chloride (1.63 g, 0.014 mol) furnished a syrup, which was
purified by preparative HPLC (ethyl acetate/hexane, 1:1) to
give 64 (1.32 g, 54%) as a syrup: 1H NMR (400 MHz) δ 1.22/
1.24 (2 overlapping t, 6H, J ) 7.1 Hz, 2 Me), 1.42/1.56 (2 s,
6H, 2 Me), 3.45-3.65 (m, 2H, OCH2), 3.65-3.80 (m, 2H,
OCH2), 3.80-3.90 (m, 3H, H5 and H6), 3.99 (m, 1H, H4,
decoupled at H5 and H3: J 34 ) 3.6 Hz, J 45 ) 2.8 Hz), 4.19 (d,
1H, J 34 ) 3.6 Hz, H3), 4.29/4.49 (pair of d, 2H, J ab ) 11.3 Hz,
H1), 5.22 (br s, 2H, NH2). Anal. (C13H25NO8S‚0.1H2O) C, H,
N.
water and extracted with ethyl acetate twice. The combined
organic extract was washed with brine, dried (Na2SO4), and
concentrated in vacuo to a syrup, which was purified by
preparative HPLC (ethyl acetate/hexanes, 1:1) to afford 0.84
g (50%) of 76 as a syrup: 1H NMR (600 MHz) δ 1.45/1.55 (2 s,
6H, 2 Me), 1.85 (dd, 1H, J 45 ) 11.0 Hz, J 56e ) 3.6 Hz, H5), 2.15
(d, 1H, J 45 ) 11.0 Hz, H4), 4.12/4.18 (pair of d, 2H, J ab ) 10.9
Hz, H1), 4.20 (d, 1H, J 6a6e ) 12.6 Hz, H6a), 4.30 (s, 1H, H3),
4.35 (dd, 1H, J 6a6e ) 12.6 Hz, J 56e ) 3.6 Hz, H6e), 4.95 (br s,
2H, NH2). Anal. (C10H15Cl2NO6S) H; C: calcd, 34.49; found,
34.05; N: calcd, 4.02; found, 3.55.
4,5-An h yd r o-2,3-O-(isop r op ylid en e)-â-D-fr u ct op yr a n -
ose Su lfa m a te (77). Sodium hydride (60% oil dispersion; 0.89
g, 22.3 mmol, washed with ether) was suspended in 15 mL of
DMF, cooled to 5 °C with stirring, and treated with epoxide
7926 (3.00 g, 14.8 mmol). The mixture was stirred for 1.5 h,
treated with sulfamoyl chloride (1.23 g, 10.6 mmol), and slowly
warmed to 23 °C over 3 h. The reaction was diluted with cold
water, and extracted three times with CH2Cl2. The combined
extract was rinsed twice with brine, dried (MgSO4), and
concentrated in vacuo. The residue was purified by prepara-
tive HPLC (CH2Cl2/ethyl acetate, 4:1) and recrystallized (2-
propanol) to yield 77 (2.19 g, 53%) as a white solid: 1H NMR
(300 MHz) δ 1.46/1.53 (2 s, 6H, 2 Me), 3.28 (d, 1H, J 45 ) 3.8
Hz, H5), 3.32 (d, 1H, J 45 ) 3.8 Hz, H4), 4.08/4.32 (pair of d,
2H, J ab ) 11.6 Hz, H1), 4.10 (d, 1H, J 6a6e ) 13.5 Hz, H6a), 4.22
(d, 1H, J 6a6e ) 13.5 Hz, H6e), 4.39 (s, 1H, H3), 4.96 (br s, 2H,
NH2); IR (KBr) νmax 3341 (s), 3239 (m), 1380 (s), 1187 (s), 1071
(s), 1010 (s), 817 (s) cm-1; CI-MS m/z 282 (MH)+, 299 (M +
NH4)+. Anal. (C9H15NO7S) C, H, N, S.
4,5-Did eoxy-2,3-O-(isop r op ylid en e)-â-D-fr u ct op yr a n -
ose Su lfa m a te (65). Alkene 6629 (2.48 g, 9.4 mmol) was
combined with PtO2 (0.25 g) in anhydrous ethanol (40 mL) and
placed in a Parr apparatus under hydrogen (50 psig) at 23 °C.
After 1 h, the reaction was filtered through a Nylon-66 filter
(0.45 µm) and concentrated in vacuo. The residue was
recrystallized (benzene/hexanes, 1:1) to give 2.20 g (88%) of
1
65 a white solid: H NMR (400 MHz) δ 1.40 (s, 3H, Me), 1.58
Syn th esis of N-Su bstitu ted 2,3-O-(Isop r op ylid en e)-4,5-
O-su lfon yl-â-D-fr u ctop yr a n ose Su lfa m a te (83). A. Gen -
er a l P r oced u r e. A solution of alcohol 8126,76 and pyridine
(10.0 g, 127 mmol) in toluene (420 mL) was added dropwise
to a solution of sulfuryl chloride (17.1 g,127 mmol) in 100 mL
of toluene over 45 min at -55 to -60 °C with vigorous stirring.
After 2 h, the mixture was filtered through diatomaceous
earth, and the filtrate was extracted sequentially with water,
twice with 1 N H2SO4, twice with NaHCO3 (saturated aque-
ous), twice with brine, then dried (MgSO4), and concentrated
in vacuo to afford a brown oil. This material was purified by
preparative HPLC (CH2Cl2) to provide 28.9 g (72%) of 82 as a
white solid. An analytical sample was recrystallized from
absolute ethanol: mp 93-95 °C; [R]25D -35.4° (c 0.86, MeOH);
1H NMR (400 MHz) δ 1.46/1.61 (2 s, 6H, 2 Me), 4.00-4.25 (m,
2H, H6), 4.42/4.66 (pair of d, 2H, J ab ) 10.8 Hz, H1), 4.53 (d,
1H, J 34 ) 2.7 Hz, H3), 5.03 (d, 1H, J 45 ) 7.9 Hz, H5), 4.94 (dd,
1H, J 34 ) 2.7 Hz, J 45 ) 7.9 Hz, H4); 13C NMR (100 MHz) δ
25.1 (Me), 26.4 (Me), 59.5 (CH2), 68.7 (CH), 72.1 (CH), 72.3,
(CH2), 75.4 (CH), 100.0 (C), 111.6 (C); IR (KBr) νmax 1409 (s),
1219 (s), 1089 (s), 990 (s), 834 (m) cm-1; CI-MS m/z 398 (M +
NH4)+. Anal. Calcd for C9H13ClO10S2: C, 28.39; H, 3.44; Cl,
9.31; S, 16.84. Found: C, 28.53; H, 3.46; Cl, 9.17; S, 16.98.
Sulfamates 8376 were prepared by treating this chlorosulfate
with 2-4 equiv of the requisite anhydrous nucleophile in dry
THF or acetonitrile with stirring at 0 °C. The reaction was
warmed to 23 °C (if necessary) over 0.5-18 h, and the resulting
white slurry was either quenched with water and concentrated
in vacuo or filtered through diatomaceous earth and concen-
trated in vacuo. The resulting residue was dissolved in ethyl
acetate and washed three times with 1 N H2SO4, twice with
NaHCO3 (saturated aqueous), twice with brine, then dried
(MgSO4), concentrated in vacuo, and purified by preparative
HPLC.
(s, 3H, Me), 1.59-1.90 (m, 3H), 2.05-2.20 (m, 1H), 3.60-3.75
(m, 1H, H6), 3.90-4.05 (m, 1H, H6), 4.20-4.30 (m, 1H, H3),
4.25 (s, 2H, H1), 5.21 (br s, 2H, NH2); IR (KBr) νmax 3362 (m),
3243 (m), 1563 (m), 1382 (s), 1184 (s), 1055 (s), 837 (s), 759 (s)
cm-1; FAB-MS m/z 268 (MH)+, 290 (M + Na)+. Anal. (C9H17
-
NO6S) C, H, N.
4,5-Dideoxy-2,3-O-(isopr opyliden e)-â-D-fr u ctopyr an ose-
7,7-d ich lor ocyclop r op a n e 1-Su lfa m ic Acid Ester (76)
fr om Diol 40. A mixture of diol 40 (10.0 g, 0.032 mol) and
1,1′-thiocarbonyldiimidazole (13.8 g, 0.08 mol) in THF (145 mL)
was stirred at 23 °C for 24 h. The solvent was evaporated in
vacuo, and the residue was dissolved in ethyl acetate, washed
twice with water and once with 1 N HCl, dried (Na2SO4), and
concentrated to afford 10.48 g (92%) of the crude thiocarbonate
as a solid. A mixture of thiocarbonate (15.3 g, 0.04 mol) and
trimethyl phosphite (92 mL) was refluxed for 3 h and concen-
trated in vacuo to a syrup, which was purified by preparative
HPLC (hexane/ethyl acetate. 3:1) to afford the alkene (10.3
g, 86%) as a syrup. A mixture of alkene (5.76 g, 0.02 mol),
benzyltriethylammonium chloride (0.29 g), 50% NaOH (180
mL), and chloroform (180 mL) was stirred at 23 °C for 24 h.
The resultant semiemulsion was filtered through glass wool
and separated. The organic solution was washed sequentially
with water and brine, dried (Na2SO4), and concentrated in
vacuo to afford 8.5 g of the crude bis-chloro adduct 74
(contaminated with solvent), as a brown syrup. A solution of
this material (8.2 g) in methylene chloride (1 L) was treated
with water (10 mL) and N-bromosuccinimide (6.0 g), and the
solution was degassed with argon for 60 min by using a gas
dispersion tube. More NBS (20.0 g; 0.15 mol total) was added
portionwise followed by the addition of water (5 mL). The
mixture was stirred for 10 min while being irradiated with a
150-W Phillips flood lamp. The mixture was treated with
cyclohexene (5 mL) and triethylamine (5 mL), stirred for 5 min,
and concentrated in vacuo to afford a gum, which was treated
with ethyl acetate and filtered. The filtrate was concentrated
to a syrup which was purified by preperative HPLC (hexanes/
ethyl acetate, 4:1) to afford 1.35 g of 75 (18% based on pure
74) as a syrup. A mixture triethylamine (0.96 g, 9.5 mmol) in
DMF (10 mL) was treated with 75 (1.30 g, 4.8 mmol) in DMF
(5 mL), the mixture was stirred at 0 °C for 30 min, and
sulfamoyl chloride (1.13 g, 9.8 mmol) was added portionwise
at 0-10 °C. After 1 h of stirring, the mixture was poured into
B. 2,3-O-(Isop r op ylid en e)-4,5-O-su lfon yl-â-D-fr u ctop y-
r a n ose Meth ylsu lfa m a te (83a ). A solution of the chloro-
sulfate (2.48 g, 6.5 mmol) in dry THF (33 mL) was cooled to 5
°C with stirring. Excess anhydrous methylamine was bubbled
through the solution over 30 min at 5-10 °C. After 30 min,
the reaction was filtered through diatomaceous earth and
concentrated in vacuo. The residue was purified by prepara-
tive HPLC (hexanes/ethyl acetate, 6:1) to furnish 2.21 g (90%)
of 83a as a hard glass: 1H NMR (400 MHz, CD3OD/CDCl3) δ
1.48/1.60 (2 s, 6H, 2 Me), 2.76 (s, 3H, NMe), 3.95-4.25 (m,

1336 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
4H, 2 H1 and 2 H6), 4.63 (br s, 1H, H3), 5.10-5.25 (m, 1H, H5),
5.35-5.50 (m, 1H, H4); IR (CHCl3) νmax 3402 (m), 1407 (s), 1182
(s), 1093 (s), 981 (s) 865 (s); CI-MS m/z 300 (M + NH4)+. Anal.
(C10H17NO10S2) C, H, N.
2,3-O-(Cycloh exylid en e)-4,5-O-su lfon yl-â-D-fr u ctop yr a -
n ose Su lfa m a te (85). Compound 58 (20.4 g, 48.6 mmol) was
dissolved in THF (408 mL), acidified with 204 mL of 6 N HCl,
and heated at 47-50 °C for 5 h with vigorous stirring. The
reaction was cooled to 5 °C, the pH was cautiously adjusted
to pH 7 with Na2CO3, and the aqueous layer was saturated
with NaCl. The aqueous layer was extracted three times with
THF, and then the combined THF extracts were dried (MgSO4)
and concentrated in vacuo. The residue was purified by
preparative HPLC (ethyl acetate/CH2Cl2, 3:2) to give 2.85 g
(17%) of 2,3-O-(cyclohexylidene)-â-D-fructopyranose 1-sulfa-
mate as a white foam. This product (2.33 g, 6.9 mmol) was
combined with pyridine (1.22 mL, 15.1 mmol), dissolved in
ethyl acetate (69 mL), and reacted with sulfuryl chloride (1.33
mL, 16.5 mmol) as described above to provide the bis-
chlorosulfate. Analogous dechlorosulfation of this bis-chloro-
sulfate with NaHCO3 (3.76 g, 44.8 mmol) in methanol (70 mL),
followed by purification by preparative HPLC (hexanes/ethyl
acetate, 7:3), provided 1.42 g of solid, which was recrystallized
from 20 mL of EtOH/water (1:1) to provide 1.21 g (44%) of 85
as a white solid: mp 139-141 °C; [R]25D -31.5° (c 1.00, MeOH);
1H NMR (400 MHz, DMSO-d6) δ 1.30-1.80 (m, 10H), 3.95-
4.10 (m, 4H, 2 H1 and 2 H6), 4.58 (d, 1H, J 34 ) 2.5 Hz, H3),
5.49 (d, 1H, J 45 ) 7.8 Hz, H5), 5.70 (dd, 1H, J 34 ) 2.5 Hz, J 45
) 7.8 Hz, H4), 7.72 (s, 2H, NH2); IR (KBr) νmax 3390 (m), 3269
(m), 2957 (m), 1378 (s), 1214 (s), 1107 (s), 1051 (s), 818 (m)
cm-1; CI-MS m/z 419 (M + NH4)+. Anal. (C12H19NO10S2) C,
H, N, S.
C. 2,3-O-(Isop r op ylid en e)-4,5-O-su lfon yl-â-D-fr u ctop y-
r a n ose Dieth ylsu lfa m a te (83n ). A solution of chlorosulfate
(3.00 g, 7.9 mmol) in dry THF (40 mL) was cooled to 5 °C and
treated with anhydrous diethylamine (1.73 g, 23.6 mmol). After
4 h, the reaction was quenched with water (5 mL), concen-
trated in vacuo, and dissolved in ethyl acetate. The ethyl
acetate solution was washed three times with 1 N H2SO4, twice
with NaHCO3 (saturated aqueous), twice with brine, then
dried (MgSO4), and concentrated in vacuo. The residue was
purified by preparative HPLC (hexanes/ethyl acetate, 7:3) to
give 1.55 g (44%) of 83n as a white foam: 1H NMR (400 MHz)
δ 1.22 (t, 6H, J ) 7.1 Hz, 2 Me), 1.45/1.58 (2 s, 6H, 2 Me),
3.25-3.45 (m, 4H, 2 CH2), 3.95-4.25 (m, 4H, 2 H1 and 2 H6),
4.58 (d, 1H, J 34 ) 2.5 Hz, H3), 4.98 (d, 1H, J 45 ) 7.9 Hz, H5),
5.28 (dd, 1H, J 34 ) 2.5 Hz, J 45 ) 7.9 Hz, H4); IR (KBr) νmax
2990, 1395, 1364, 1213, 1167, 1090, 1053, 969, 796 cm-1; CI-
MS m/z 435 (M + NH4)+. Anal. (C13H23NO10S2) C, H, N, S.
D. 2,3-O-(Isop r op ylid en e)-4,5-O-su lfon yl-â-D-fr u ctop y-
r a n ose Im id a zole-1-su lfon a te (83q). A solution of the
chlorosulfate (2.00 g, 5.3 mmol) in dry THF (40 mL) was cooled
to 5 °C with stirring, treated with imidazole (1.07 g, 15.8
mmol), and allowed to warm to 23 °C. After 6 h, the reaction
was filtered through diatomaceous earth, and the filtrate was
concentrated in vacuo. The residue was purified by prepara-
tive HPLC (hexanes/ethyl acetate, 3:2) to afford 1.75 (81%) as
a hard white foam: 1H NMR (400 MHz) δ 1.44/1.61 (2 s, 6H,
2,3-O-(Eth ylp r op ylid en e)-4,5-O-su lfon yl-â-D-fr u ctop y-
r a n ose Su lfa m a te (86). Compound 59 (14.56 g, 36.8 mol)
was dissolved in THF (360 mL), heated to 43 °C, and acidified
with 185 mL of 6 N HCl with vigorous stirring. After 1 h, the
reaction was cooled to 5 °C, the pH was adjusted to pH 7 with
Na2CO3, and the aqueous layer was saturated with NaCl. The
aqueous layer was extracted twice with THF, and the com-
bined extract was dried (MgSO4) and concentrated in vacuo.
The residue was purified by preparative HPLC (ethyl acetate/
CH2Cl2, 3:2) to give 2.53 g (21%) of 2,3-O-(1-ethylpropylidene)-
â-D-fructopyranose 1-sulfamate as a clear syrup: [R]25D +22.7°
(c 1.00, MeOH); 1H NMR (400 MHz, CD3OD) δ 0.85-1.00 (m,
6H, 2 Me), 1.67 (q, 2H, J ) 7.5 Hz), 1.76 (q, 2H, J ) 7.6 Hz),
3.53 (dd, J 56a ) 4.9 Hz, J 6a6e ) 11.0 Hz, 1H, H6a), 3.65 (dd, J 56e
) 5.5 Hz, J 6a6e ) 11.0 Hz, 1H, H6e), 3.90-3.95 (m, 1H, H5),
2 Me), 3.95-4.15 (m, 2H, H6), 4.25/4.37 (pair of d, 2H, J ab
10.9 Hz, H1), 4.46 (d, 1H, J 34 ) 2.7 Hz, H3), 5.02 (d, 1H, J 45
)
)
7.9 Hz, H5), 5.32 (dd, 1H, J 34 ) 2.7 Hz, J 45 ) 7.9 Hz, H4), 7.24
(s, 1H), 7.41, (s, 1H), 8.05 (s, 1H); IR (KBr) νmax 1380 (m), 1210
(s), 1055 (m), 990 (m), 852 (m) cm-1; CI-MS m/z 413 (MH)+.
Anal. (C12H16N2O10S2) C, H, N, S.
2,3-O-(Isop r op ylid en e)-4,5-O-su lfon yl-â-D-fr u ctop yr a -
n ose Azid osu lfa te (83r ). The chlorosulfate (2.00 g, 5.3 mmol)
was combined with pyridine (0.83 g, 1.05 mmol) in 26 mL of
acetonitrile (26 mL) with stirring at 23 °C. Sodium azide (0.68
g, 0.0105 mol) was added, and the reaction was stirred for 18
h, filtered through diatomaceous earth, and concentrated in
vacuo. The residue was purified by preparative HPLC (hex-
anes/ethyl acetate, 4:1) to provide 1.76 g (87%) of 83r as a clear
glass: 1H NMR (400 MHz) δ 1.46/1.61 (2 s, 6H, 2 Me), 4.00-
4.20 (m, 2H, H6), 4.34/4.48 (pair of d, 2H, J ab ) 11.0 Hz, H1),
4.52 (d, 1H, J 34 ) 2.6 Hz, H3), 5.02 (d, 1H, J 45 ) 7.9 Hz, H5),
5.33 (dd, 1H, J 34 ) 2.6 Hz, J 45 ) 7.9 Hz, H4); IR (KBr) νmax
4.00-4.10 (m, 2H, H3 and H4), 4.15/4.19 (pair of d, 2H, J ab
)
10.5 Hz, H1); IR (KBr) νmax 3408 (m), 2957 (m), 2914 (m), 1377
(s), 1214 (s), 994 (s) cm-1; CI-MS m/z 345 (M + NH4)+. Anal.
Calcd for C11H21NO8S: C, 40.36; H, 6.47; N, 4.28; S, 9.79.
Found: C, 40.46; H, 6.50; N, 4.12; S, 9.66. This product (1.82
g, 5.6 mol) and pyridine (1.06 mL, 13.4 mmol) were dissolved
in ethyl acetate (55 mL) and reacted with sulfuryl chloride
(1.65 g, 12.2 mmol) as described above to provide the bis-
chlorosulfate. Treatment with NaHCO3 (2.67 g, 31.8 mmol)
in MeOH (16 mL), followed by preparative TLC purification
(ether/hexanes, 7:3), provided 1.03 g (47%) of 86 as a white
solid: mp 130-133 °C; [R]25D -23.1° (c 1.17, MeOH); 1H NMR
(400 MHz, DMSO-d6) δ 0.83 (t, 3H, Me), 0.91 (t, 3H, Me), 1.66
(q, 2H, J ) 7.5 Hz), 1.77 (q, 2H, J ) 7.6 Hz), 3.95-4.10 (m,
4H, H1 and H6), 4.56 (d, 1H, J 34 ) 2.6 Hz, H3), 5.49 (d, 1H, J 45
) 7.9 Hz, H5), 5.70 (dd, 1H, J 34 ) 2.6 Hz, J 45 ) 7.9 Hz), 7.73
(br s, 2H, NH2); IR (KBr) νmax 3403 (m), 3299 (m), 2986 (m),
2914 (m), 1567 (m), 1380 (s), 1217 (s), 1178 (s), 979 (s), 930 (s)
cm-1; CI-MS m/z 407 (M + NH4)+. Anal. (C11H19NO10S2) C,
H, N, S.
2148 (s), 1410 (s), 1181 (m), 1093 (s), 1002 (s), 843 (m) cm-1
;
CI-MS m/z 405 (M + NH4)+. Anal. (C9H13N3O10S2) C, H, N;
S: calcd, 16.30; found, 15.84.
2,3-O-(Isop r op ylid en e)-4,5-O-su lfon yl-â-D-fr u ctop yr a -
n ose Ca r ba m a te (84). A solution of alcohol 8126,76 (3.75 g,
13.3 mmol) and pyridine (1.1 mL, 13.3 mmol) in THF (18 mL)
was added dropwise over 15 min at 5 °C to a stirred solution
of trichloromethyl chloroformate (1.60 mL, 13.3 mmol) in THF
(18 mL). The reaction was slowly warmed to 23 °C over 2 h,
filtered through diatomaceous earth, and concentrated in
vacuo. The residue was dissolved in THF (36 mL), cooled to 5
°C, and treated with an excess of ammonia gas over 10 min
with stirring. The reaction was filtered through diatomaceous
earth and concentrated in vacuo. The residue in ethyl acetate
was rinsed twice with NaHCO3 and once with brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified
by preparative HPLC (hexanes/ethyl acetate, 1:1) to give 84
(3.06 g, 71%) as a hard white foam: 1H NMR (400 MHz) δ
1.41/1.57 (2 s, 6H, 2 Me), 4.00-4.15 (m, 2H, H6), 4.17/4.35 (pair
of d, 2H, J ab ) 11.7 Hz, H1), 4.46 (d, 1H, J 34 ) 1.5 Hz, H3),
4.90 (br s, 2H, NH2), 5.02 (d, 1H, J 45 ) 8.0 Hz, H5), 5.33 (dd,
1H, J 34 ) 1.5 Hz, J 45 ) 8.0 Hz, H4); IR (KBr) νmax 3494 (m),
Isom er ic Mixtu r e (5.3:1) of 2,3-O-(Isop r op ylid en e)-(S)-
a n d 2,3-O-(Isop r op ylid en e)-(R)-4,5-O-su lfin yl-â-D-fr u cto-
p yr a n ose Su lfa m a tes (87a /b). Thionyl chloride (10 mL, 137
mmol) was added dropwise over 15 min (exothermic) to a
solution of diol 40 (4.00 g, 13.4 mmol) in THF (40 mL) at 23
°C with stirring. After 1.5 h, the mixture was concentrated
in vacuo, dissolved in ethyl acetate, washed twice with
NaHCO3 (saturated aqueous), dried (MgSO4), and concentrated
in vacuo. The residue was crystallized from absolute ethanol
to give a 5.3:1 mixture of 87a and 87b (2.63 g, 57%) as an
3396 (m), 1733 (s), 1211 (s), 1094 (s), 983 (m), 851 (m) cm-1
;
CI-MS m/z 326 (MH)+, 343 (M + NH4)+. Anal. (C10H15NO9S)
1
C, H, N, S.
off-white solid: H NMR (400 MHz, DMSO-d6) δ 1.37/1.51 (2

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1337
s, 6H, 2 Me), 3.75-4.25 (m, 4H, 2 H1 and 2 H6), 4.49 (d, 0.16
H, J 34 ) 2.6 Hz, H3R), 4.54 (d, 0.84 H, J 34 ) 2.6 Hz, H3S), 5.09
(d, 0.16H, J 45 ) 7.9 Hz, H5R), 5.20 (dd, 0.16H, J 34 ) 2.6 Hz,
J 45 ) 7.9 Hz, H4R), 5.31 (d, 0.84H, J 45 ) 7.9 Hz, H5S), 5.43 (dd,
0.84H, J 34 ) 2.6 Hz, J 45 ) 7.9 Hz, H4S), 7.67 (s, 0.32H, NH2-
R), 7.68 (s, 1.68H, NH2-S); IR (KBr) νmax 3381 (s), 3286 (m),
1359 (s), 1208 (s), 1088 (s), 966 (m), 911 (m), 800 (m), 710 (m)
cm-1; FAB-MS m/z 346 (MH)+, 363 (M + H2O)+, 368 (M +
Na)+. Anal. (C9H15NO9S2) C, H, N, S.
12.2 mol) to provide a mixture of isomers (R/S ) 2.4:1), which
were separated by preparative HPLC (hexanes/ether, 3:2) to
provide (R)-2,3-O-(isopropylidene)-4,5-O-sulfinyl-â-D-fructopy-
ranose (1.09 g, 34%) as a clear oil: 1H NMR (400 MHz) δ 1.41/
1.56 (2 s, 6H, 2 Me), 2.60-2.75 (m, 1H, OH), 3.55-3.70 (m,
1H, H1a), 3.85-4.15 (m, 3H, H1b and 2 H6), 4.64 (d, 1H, J 34
)
2.2 Hz, H3), 4.90 (dd, 1H, J 45 ) 8.8 Hz, J 56e ) 2.3 Hz, H5), 5.01
(dd, 1H, J 34 ) 2.1 Hz, J 45 ) 8.8 Hz, H4); CI-MS m/z 267 (MH)+,
284 (M + NH4)+. This material was reacted with sulfamoyl
chloride (2.86 g, 24.8 mmol), and the crude product was
recrystallized from ethanol to furnish 87b (0.25 g, 18%) as a
2,3-O-(Isopr opyliden e)-(S)- an d 2,3-O-(Isopr opyliden e)-
(R)-(4,5-O-su lfin yl)-â-D-fr u ctop yr a n ose Su lfa m a tes (87a
a n d 87b). Diol 40 (6.00 g, 19.3 mmol) was dissolved in 75
mL of anhydrous 1,4-dioxane and heated to reflux with
stirring. Thionyl chloride (28 mL, 384 mmol) was added
dropwise over 10 min to the refluxing solution. After 15 min,
the mixture was cooled to 23 °C and concentrated in vacuo.
The residue was dissolved in ethyl acetate, rinsed twice with
NaHCO3 (saturated aqueous) and twice with brine, then dried
(MgSO4), and concentrated in vacuo to yield a 2:1 mixture of
the S and R isomers of 1-O-benzyl-2,3-O-(isopropylidene)-4,5-
O-sulfinyl-â-D-fructopyranose (6.50 g, 95%). The diastereo-
mers were separated by preparative HPLC (hexanes/ethyl
acetate, 9:1). The fractions containing the faster-eluting
isomer were combined and concentrated in vacuo to give the
S isomer (4.05 g) as a white solid: mp 92-94 °C; 1H NMR
(400 MHz) δ 1.44/1.57 (2 s, 6H, 2 Me), 3.48/3.66 (pair of d, 2H,
J ab ) 10.8 Hz, H1), 3.85 (d, 1H, J 6a6e ) 13.7 Hz, H6a), 4.06 (dd,
J 56e ) 1.7 Hz, J 6a6e) 13.7 Hz, 1H, H6e), 4.50-4.70 (m, 3H, H3
and CH2Ph), 5.04 (dd, 1H, J 45 ) 7.9 Hz, J 56e ) 1.5 Hz, H5),
5.33 (dd, 1H, J 34 ) 2.2 Hz, J 45 ) 7.9 Hz, H4), 7.33 (s, 5H, Ph);
CI-MS m/z 374 (M + NH4)+. Similarly, the fractions contain-
ing the slower-eluting isomer were combined and concentrated
in vacuo to give the R isomer (1.93 g) as a clear oil: 1H NMR
(400 MHz) δ 1.46/1.57 (2 s, 6H, 2 Me), 3.48/3.69 (pair of d, 2H,
J ab ) 10.9 Hz, H1), 3.98 (d, 1H, J 6a6e ) 13.9 Hz, H6a), 4.11 (dd,
J 56e ) 2.3 Hz, J 6a6e) 13.9 Hz, 1H, H6e), 4.50-4.70 (m, 3H, H3
and CH2Ph), 4.83 (dd, 1H, J 45 ) 8.6 Hz, J 56e ) 2.3 Hz, H5),
4.97 (dd, 1H, J 34 ) 2.3 Hz, J 45 ) 8.6 Hz, H4) 7.34 (s, 5H, Ph);
CI-MS m/z 374 (M + NH4)+.
1
white solid: mp 197-199 °C; H NMR (400 MHz, DMSO-d6)
δ 1.37/1.51 (2 s, 6H, 2 Me), 3.82-3.97 (m, 2H, H6), 3.98/4.22
(pair of d, 2H, J ab ) 10.5 Hz, H1), 4.49 (d, 1H, J 34 ) 2.2 Hz,
H3), 5.10 (d, 1H, J 45 ) 8.7 Hz, H5), 5.20 (dd, 1H, J 34 ) 2.2 Hz,
J 45 ) 8.7 Hz, H4), 7.67 (br s, 2H, NH2); 13C NMR (100 MHz,
DMSO-d6) δ 25.1 (Me), 26.0 (Me), 59.7 (CH2), 67.8 (CH2), 69.1
(CH), 75.5, (CH), 78.2 (CH), 100.7 (C), 108.8 (C). Anal. (C9H15
NO9S2) C, H, N, S.
-
2,3-O-(Isop r op ylid en e)-(S)-4,5-O-[N-(4-m eth ylben zen e-
su lfon yl)im id osu lfin yl]-â-D-fr u ct op yr a n ose Su lfa m a t e
(90a ). A solution of N-(p-toluenesulfonyl)imidothionyl chlo-
ride49 (34.1 g, 125 mmol; crude material) in benzene (120 mL)
was added dropwise at 5 °C over 15 min with vigorous stirring
to a solution diol 28 (10.0 g, 33.4 mmol) in THF (120 mL). The
reaction was slowly warmed to 23 °C over 2 h and concentrated
in vacuo. The residue was cautiously quenched with NaHCO3
(saturated aqueous) and extracted three times with ethyl
acetate. The combined extracts were rinsed with NaHCO3
(saturated aqueous) and brine, then dried (MgSO4), and
concentrated in vacuo. The residue was dissolved in 200 mL
of warm CH2Cl2/ethyl acetate (19:1) and the p-toluenesulfona-
mide precipitated on cooling to 23 °C. The solid was removed
by filtration, and the filtrate was concentrated in vacuo. The
residue was purified by preparative HPLC (CH2Cl2/ethyl
acetate, 19:1) to provide 90a (9.35 g, 56%) as a white foam,
which was contaminated with 0.1 molar equiv of 87a /b: 1H
NMR (400 MHz, DMSO-d6) δ 1.37/1.52 (2 s, 6H, 2 Me), 3.80-
4.05 (m, 4H, 2 H1 and 2 H6), 4.60 (s, 1H, H3), 5.52 (s, 2H, H4
and H5), 7.42 (d, 2H, J ) 8.0 Hz), 7.70 (br s, 2H, NH2), 7.77 (d,
2H, J ) 8.2 Hz); 13C NMR (100 MHz, DMSO-d6) δ 21.1 (Me),
24.9 (Me), 25.9 (Me), 59.5 (CH2), 68.5 (CH2), 69.2 (CH), 75.4,
(CH), 80.0 (CH), 100.7 (C), 109.7 (C), 126.2 (CH), 129.8 (CH),
139.2 (C), 143.6 (C); IR (KBr) νmax 3365 (m), 3275 (m), 1383
(s), 1159 (s), 1087 (s), 963 (m), 685 (m) cm-1; CI-MS m/z 499
(MH)+. Anal. (C16H22N2O10S3‚0.1C9H15NO9S2) C, H, N, S.
2,3-O-(Isopr opyliden e)-4,5-O-[N-(4-m eth ylben zen esu lfo-
n yl)im id osu lfon yl]-â-D-fr u ctop yr a n ose Su lfa m a te (91a ).
Compound 90a (3.10 g, 6.2 mmol) was dissolved in acetonitrile
(19 mL) and diluted with CCl4 (19 mL) and water (28 mL).
This mixture was cooled to 5 °C with vigorous mechanical
stirring. Sodium periodate (2.92 g, 13.6 mmol) was added
followed by a catalytic amount of RuCl3‚H2O (0.030 g, 0.15
mmol). The reaction was slowly warmed to 23 °C over 20 h.
The mixture was extracted three times with ethyl acetate, and
the combined extracts were washed with brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by
preparative HPLC (ether/hexanes, 4:1) to give a syrup, which
was dissolved in CH2Cl2 and concentrated in vacuo to provide
91a (0.72 g, 23%) as a white foam that was contaminated with
0.09 molar equiv of 2: 1H NMR (400 MHz, DMSO-d6) δ 1.39/
1.54 (2 s, 6H, 2 Me), 2.41 (s, 3H, Me), 3.85-4.2 (m, 4H, 2 H1
and 2 H6), 4.68 (d, 1H, J 34 ) 2.4 Hz, H3), 5.82 (d, 1H, J 45 ) 8.2
Hz, H5), 5.88 (dd, 1H, J 34 ) 2.4 Hz, J 45 ) 8.2 Hz, H4), 7.44 (d,
2H, J ) 8.0 Hz), 7.75 (s, 2H, NH2), 7.83 (d, 2H, J ) 8.2 Hz);
13C NMR (100 MHz, DMSO-d6) δ 21.0 (Me), 25.0 (Me), 25.8
(Me), 59.1 (CH2), 67.5 (CH2), 67.9 (CH), 76.7, (CH), 81.6 (CH),
100.7 (C), 110.2 (C), 126.5 (CH), 129.8 (CH), 138.1 (C), 144.0
(C); IR (KBr) νmax 3395 (m), 3282 (m), 1385 (m), 1339 (s), 1164
(s), 1090 (s), 970 (m), 810 (m) cm-1; CI-MS m/z 532 (M + NH4)+,
515 (MH)+. Anal. (C16H22N2O11S3‚0.09C9H15NO10S2‚0.2CH2-
Cl2‚0.1C6H14) C, H, N, S.
The S isomer (3.99 g, 112 mmol) was dissolved in CH2Cl2
(560 mL) that had been saturated with water. N-Bromosuc-
cinimide (1.99 g, 112 mmol) was added, and the solution was
sparged with nitrogen for 60 min. The solution was cooled to
5 °C, irradiated with a 150-W incandescent floodlight for 15
min, quenched with excess cyclohexene (7 mL), basified with
triethylamine (1.56 mL), and concentrated in vacuo. The
residue was mixed with 200 mL of ethyl acetate and filtered
through diatomaceous earth. The filtrate was concentrated
in vacuo to provide a mixture of isomers (S/R ) 17:1), which
were separated by preparative HPLC (hexanes/ether, 3:2) to
furnish (S)-2,3-O-(isopropylidene)-4,5-O-sulfinyl-â-D-fructopy-
ranose (2.43 g, 81%) as a clear oil: 1H NMR (400 MHz) δ 1.45/
1.59 (2 s, 6H, 2 Me), 1.82 (dd, 1H, J ) 5.3, 8.9 Hz, OH), 3.42-
3.75 (m, 2H, H1), 3.85-4.15 (m, 2H, H6), 4.52 (d, 1H, J 34 ) 2.2
Hz, H3), 5.06 (dd, 1H, J 45 ) 7.8 Hz, J 56e ) 1.5 Hz, H5), 5.36
(dd, 1H, J 34 ) 2.2 Hz, J 45 ) 7.9 Hz, H4); CI-MS m/z 267 (MH)+,
284 (M + NH4)+. This product (2.29 g, 8.6 mmol) and
triethylamine (14 mL) were dissolved in ethyl acetate (86 mL)
and cooled to -60 °C with stirring. Sulfamoyl chloride (6.45
g, 55.8 mmol) was added, and the reaction was slowly warmed
to 23 °C over 18 h. The reaction was washed twice with 3 N
HCl, twice with NaHCO3 (saturated aqueous), and twice with
brine, then dried (MgSO4), and concentrated in vacuo. The
crude product was crystallized from ethanol to provide 87a
1
(1.20 g, 40%) as a white solid: mp 151.5-153.5 °C; H NMR
(400 MHz, DMSO-d6) δ 1.38/1.52 (2 s, 6H, 2 Me), 3.75-4.05
(m, 4H, 2 H1 and 2 H6), 4.54 (d, 1H, J 34 ) 2.3 Hz, H3), 5.31 (d,
1H, J 45 ) 8.0 Hz, H5), 5.43 (dd, 1H, J 34 ) 2.3 Hz, J 45 ) 8.0 Hz,
H4), 7.67 (br s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6) δ
24.9 (Me), 25.9 (Me), 59.4 (CH2), 68.2 (CH2), 68.9 (CH), 72.3,
(CH), 76.7 (CH), 100.6 (C), 109.4 (C). Anal. (C9H15NO9S2) C,
H, N, S.
In the same manner, the R isomer (4.33 g, 12.2 mmol) was
oxidatively debenzylated with N-bromosuccinimide (2.17 g,
2,3-O-(Isop r op ylid en e)-(S)-4,5-O-[N-(1,1-d im et h ylet h -
oxyca r b on yl)im id osu lfin yl]-â-D-fr u ct op yr a n ose Su lfa -

1338 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
m a te (93a ). N,N-Dichloro-tert-butylcarbamate (10.0 g, 53.7
mmol) was combined with elemental sulfur (1.72 g, 53.7 mmol)
and tetrabutylammonium bromide (1.73 g, 5.4 mmol) in 50
mL of dry benzene. The suspension was heated at 40 °C for
2 h with vigorous stirring. After cooling to 23 °C, this solution
of crude N-(tert-butoxycarbonyl)imidothionyl chloride was
added dropwise at 5 °C over 15 min to a vigorously stirred
solution of diol 28 (5.19 g, 17.3 mmol) and dry pyridine (4.60
mL, 56.8 mmol) in 173 mL of dry THF. The reaction was
stirred at 5 °C for 3 h, filtered through diatomaceous earth,
and concentrated in vacuo. The residue was dissolved in ethyl
acetate and washed twice with NaHCO3 (saturated aqueous)
and twice with brine, then dried (MgSO4), and concentrated
in vacuo. The residue was purified by preparative HPLC
(hexanes/ethyl acetate, 7:3) and recrystallized from absolute
ethanol to yield pure 93a (2.11 g, 27%) as a white solid: 1H
NMR (400 MHz, DMSO-d6) δ 1.36 (s, 3H, Me), 1.40 (s, 9H,
t-Bu), 1.50 (s, 3H, Me), 3.80-3.95 (m, 2H, H6), 3.99 (s, 2H,
H1), 4.53 (d,1H, J 34 ) 1.7 Hz, H3), 5.30-5.40 (m, 2H, H4 and
H5), 7.69 (s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6) δ 24.9
(Me), 26.0 (Me), 27.5 (Me), 59.9 (CH2), 68.5 (CH2), 69.3 (CH),
76.9 (CH), 80.7 (C), 80.8 (CH), 100.7 (C), 109.4 (C), 155.3 (C);
IR (KBr) νmax 3398 (m), 3288 (m), 1689 (m), 1650 (m), 1371
(s), 1277 (s), 1184 (s), 1155 (s), 1086 (m), 967 (m), 832 (m),
730 (m), 701 (m) cm-1; CI-MS m/z 446 (MH)+. Anal.
(C14H24N2O10S2) C, H, N, S.
4.09 (d, 1H, J ) 9.1 Hz); IR (KBr) νmax 3327, 3217, 3111, 2941,
1456, 1353, 1186, 1028, 973, 938 cm-1. Anal. (C13H23NO5S)
C, H, N.
[3a r,5a â,8a â,8br](Octa h yd r o-2,2,7,7-tetr a m eth yl-5a H-
in d en o[4,5-d ]-1,3-d ioxol-5a -yl)m eth yl Su lfa m ic Acid Es-
ter (96).54 A solution of methyl 2-oxo-4,4-dimethylcyclopent-
1-ylcarboxylate76 (21.7 g, 0.13 mol) and methyl vinyl ketone
(10.6 mL, 0.13 mol) in 100 mL of benzene was stirred for 4 d.
The mixture was concentrated in vacuo, and the residue was
distilled (95-98 °C at 0.015 Torr) to afford 17.1 g (54%) of
methyl [3,3-dimethyl-2-oxo-1-(3-oxobutyl)-cyclopent]-1-ylcar-
boxylate as a pale yellow oil: 1H NMR (90 MHz) δ 1.11 (s,
3H), 1.16 (s, 3H), 1.72-2.77 (overlapping m, 8H), 2.14 (s, 3H),
3.72 (s, 3H); FAB-MS m/z 241 (MH+). The keto ester (1.0 g,
78
4.2 mmol) in 100 mL of benzene was treated with Al(t-BuO)3
(1.5 g, 6.2 mmol) and refluxed for 60 h. The mixture was
cooled to 23 °C, quenched with 3 N HCl (11 mL), and extracted
twice with ether. The combined extracts were dried (Na2SO4)
and concentrated, and the residue was dissolved in 10 mL of
benzene and treated again with Al(t-BuO)3 (0.75 g, 3.1 mmol).
After 18 h of reflux, the mixture was cooled and worked up as
described above. The residue was purified by flash column
chromatography (hexanes/ethyl acetate, 3:1) to afford 0.24 g
(28% based on consumed starting material) of methyl 2,2-
dimethyl-1,2,3,4,5,6-hexahydro-6-oxo-3aH-inden-3a-ylcarboxy-
late as an oil: 1H NMR (90 MHz) δ 0.9-2.95 (m, 8H, Me s at
δ 1.02 and 1.15), 3.5 (s, 3H), 5.93 (m, 1H). A solution of enone
(0.2 g, 0.90 mmol) in 95% ethanol was treated with p-
toluenesulfonyl hydrazide (0.184 g, 1.0 mmol) and warmed on
a steam bath. After 20 min of heating, the mixture was
concentrated to afford 0.29 g of the corresponding tosylhydra-
zone: 1H NMR (90 MHz) δ 0.63-1.8 (overlapping m, 10H, Me
singlets at δ 0.93 and 1.08), 1.83-2.87 (overlapping m, 8H,
Me s at δ 2.38) 3.62, (s, 3H), 5.90 (br s, 1H), 7.22-7.87 (m,
4H). The tosylhydrazone was dissolved in 2 mL of chloroform
and cooled to 0 °C, and catecholborane (0.10 mL, 0.94 mmol)
was added dropwise. After 3 h at 0 °C, the mixture was
treated with NaOAc‚3H2O (0.35 g, 2.55 mmol) and refluxed
for 4 h. The mixture was quenched with ice and extracted
with chloroform; the extract was dried (Na2SO4) and concen-
trated. The residue was purified by flash column chromatog-
raphy (hexanes/ether, 3:1) to give 0.10 g (51% from enone) of
methyl 2,2-dimethyl-1,2,3,4,5,7a-hexahydro-cis-3aH-inden-3a-
ylcarboxylate as a clear viscous oil: 1H NMR (90 MHz) δ 0.98
(s, 3H), 1.00 (s, 3H), 1.20-2.14 (m, 8H), 3.03-3.23 (m, 1H),
3.62 (s, 3H), 5.7 (m, 2H). A solution of olefin (1.13 g, 5.4 mmol)
in THF (4 mL) was added dropwise to a suspension of LiAlH4
(0.31 g, 8.1 mmol) in THF (4 mL) at 0 °C. After stirring for
0.5 h at 0 °C and 23 °C for 2.5 h, the reaction was quenched
at 0 °C with moist Na2SO4 and filtered through Dicalite.
Concentration of the filtrate gave 1.0 g of oily (2,2-dimethyl-
1,2,3,4,5,7a-hexahydro-cis-3aH-inden-3a-yl)methanol: 1H NMR
(90 MHz) δ 1.00-2.36 (overlapping m, 9H, Me s at δ 1.00 and
1.07), 3.23-3.87 (overlapping m, 3H), 5.67 (br s, 2H). This
product was added to a mixture of NMO (0.70 g, 5.94 mmol),
water (5 mL), acetone (2.5 mL), tert-butyl alcohol (0.9 mL),
and OsO4 (4.3 mg, 0.017 mmol), and the reaction was stirred
for 18 h at 23 °C, then treated with a slurry of Na2SO4 (42
mg, 0.24 mmol), 0.8 g of Florisil, and 5 mL of water. After 5
min of stirring, the mixture was filtered, and the filtrate was
neutralized with 1 N H2SO4. The volatiles were removed in
vacuo, and the aqueous residue was adjusted to pH 3 with 1
N H2SO4. The mixture was extracted three times with ethyl
acetate, and the combined extracts were dried (Na2SO4) and
concentrated to give 0.62 g of triol, as a yellow oil. The crude
material was dissolved of 2,2-dimethoxypropane (8 mL),
treated with catalytic amount of p-toluenesulfonic acid, and
stirred for 18 h. The mixture was diluted with chloroform and
water, the layers were separated, and the aqueous layer was
extracted twice with chloroform. The combined extracts were
washed with water, dried (Na2SO4), and concentrated to a
residue that was purified by flash column chromatography
(hexanes/ethyl acetate, 4:1) to furnish [3aR,5aâ,8aâ,8bR]-
(octahydro-2,2-dimethyl-5aH-indeno[4,5-d]-1,3-dioxol-5a-yl)-
[3ar,5aâ,8aâ,8br](Octah ydr o-2,2-dim eth yl-5aH-in den o-
[4,5-d ]-1,3-d ioxol-5a -yl)m eth yl Su lfa m ic Acid Ester (95).54
To a mixture of N-methylmorpholine N-oxide (2.0 g,17.3
mmol), water (9 mL), acetone (3.6 mL), tert-butyl alcohol (2.5
mL), and OsO4 (12 mg, 0.05 mmol) was added 9776 (2.47 g,
16.3 mmol) at 0 °C. After gradual warming to 23 °C and
stirring overnight, the mixture was treated with a slurry of
Na2S2O4 (0.16 g), Florisil (2 g), and water (13 mL) with stirring.
The slurry was filtered through Dicalite, the filter cake was
rinsed with acetone, and the filtrate was adjusted to pH 7 with
1 N H2SO4. The acetone was removed under reduced pressure;
the aqueous residue was adjusted to pH 3 with 1 N H2SO4
and extracted four times with ethyl acetate. The combined
extracts were rinsed with brine, dried (Na2SO4), and concen-
trated to afford 2.6 g (86%) of the corresponding triol as a
semisolid that was used in the next step without further
purification: 1H NMR (90 MHz) δ 1.07-2.30 (m, 1H), 3.27-
3.63 (m, 5H), 3.63-3.97 (m, 2H); CI-MS (CH4) m/z 187 (MH+).
A solution of 4.7 g (25.3 mmol) of the triol in 54 mL of 2,2-
dimethoxypropane was treated with 0.3 g of p-toluenesulfonic
acid and stirred for 4h. The mixture was diluted with 250
mL of chloroform and washed with excess NaHCO3 (saturated
aqueous). The aqueous phase was washed with chloroform,
and the combined extracts were dried (Na2SO4) and concen-
trated to give 3.41 g (60%) the corresponding acetonide, as a
pale yellow oil that was used without further purification: 1H
NMR (90 MHz) δ 0.95-2.28 (overlapping m, 16H, contains
gem-Me2 at δ 1.32 and 1.48), 2.92 (br s, 1H, OH), 3.34 (br s,
2H), 4.27-4.51 (m, 2H). A solution of the acetonide (3.4 g,
15.0 mmol) in 35 mL of DMF was added to a suspension of
NaH (0.5 g, 19.5 mmol, washed with hexanes) at 0 °C. After
1 h, 3.5 g (30 mmol) of sulfamoyl chloride was added in two
portions, and the mixture was stirred at 0 °C for 2 h. After
quenching at 0 °C with excess NaHCO3 (saturated aqueous),
the mixture was extracted four times with ethyl acetate, and
the combined extracts were washed with water, dried (Na2-
SO4), and concentrated. The residue was purified by flash
column chromatography (CH2Cl2/ethyl acetate, 9:1) and re-
crystallized from ethyl acetate/hexanes to give 1.1 g (24%) of
1
95 as a white solid: mp 168-170 °C; H NMR (400 MHz) δ
1.26-1.48 (m, 5H), 1.51-1.88 (m, 9H), 1.88-1.92 (m, 2H),
2.08-2.13 (m, 1H), 3.95/4.26 (pair of d, 2H, J ) 9 Hz), 4.28-
1
4.75 (m, 2H); H NMR (360 MHz, C6D6) δ 0.82-0.87 (m, 1H),
0.94-1.00 (m, 1H), 1.18-1.35 (m, 4H), 1.22 (s, 3H), 1.46 (s,
3H), 1.51-1.73 (m, 4H), 1.89 (ddd, 1H, J ) 12.0, 2.4, 7.8 Hz),
3.41 (br s, 2H), 3.81 (d, 1H, J ) 9.1 Hz), 3.95-4.00 (m, 2H),

Anticonvulsant Sugar Sulfamates Related to Topiramate
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1339
9.0 Hz), 4.81 (s, 2H), 5.61-5.70 (m, 2H); IR (CHCl3) νmax 3282,
methanol (0.54 g, 39% from indene carboxylate) as a clear
viscous oil: 1H NMR (90 MHz) δ 0.57-2.13 (overlapping m,
20H, Me s at δ 1.00, 1.03, 1.23, and 1.48), 2.30-2.63 (m, 1H),
2.93-3.63 (overlapping m, 3H), 3.87 (m, 2H). A solution of
the alcohol (0.53 g, 2.09 mmol) and triethylamine (0.44 mL,
3.13 mmol) in DMF (5 mL) was cooled to 0 °C and treated
with sulfamoyl chloride in one portion. After 1.5 h at 0 °C,
the mixture was quenched with ice and extracted three times
with ethyl acetate. The combined extracts were washed with
water, dried (Na2SO4), and concentrated. Purification by flash
column chromatography (CH2Cl2/MeOH, 95:5) and recrystal-
lization from ethyl acetate/hexanes afforded 0.28 g (40%) of
96 as a white solid, mp 152-154 °C. 1H NMR δ (400 MHz,
CDCl3/DMSO-d6) δ 1.07 (s, 3H, Me), 1.04 (s, 3H, Me), 1.30 (s,
3H, Me), 1.32-1.42 (m, 2H), 1.40 (d, 1H, J ) 14.0 Hz), 1.47 (s,
3H, Me), 1.58-1.67 (m, 4H), 1.84 (d, 1H, J ) 14.0 Hz), 2.31-
2.36 (m, 1H), 3.97/4.20 (pair of d, 2H, J ) 9.0 Hz), 4.25 (m,
2H), 6.54 (br s, 2H); IR (KBr) νmax 3339, 3239, 3124, 2947, 2866,
1587, 1466, 1373, 1185, 1029, 975 cm-1. Anal. (C15H27NO5S)
C, H, N.
2950, 2872, 1556, 1456, 1361, 1182, 948 cm-1. Anal. (C10H17
NO3S) C, H, N.
-
cis-1,2,3,4,5,6,7,7a-Octah ydr o-3aH-in den e-3a-m eth yl Su l-
fa m ic Acid Ester (102). A mixture of 97 (2.4 g, 15 mmol) in
20 mL of 95% ethanol was treated with 0.2 g of 10% Pd-C
and hydrogenated at 50 psig for 2.5 h. The mixture was
filtered and concentrated, and the residue was purified by flash
column chromatography (ethyl acetate/hexanes, 1:1) to afford
2.3 g (94%) of the saturated alcohol: 1H NMR (90 MHz) δ
0.97-1.75 (m, 16H), 3.00-3.95 (m, 2H). A solution of this
alcohol (2.3 g, 15 mmol) in 35 mL of DMF was added to a
suspension of 0.45 g (0.02 mmol) of NaH (washed with
hexanes) in 35 mL of DMF at 0 °C. After 0.75 h, sulfamoyl
chloride (3.45 g, 30 mmol) was added in one portion. After
being warmed to 23 °C, the reaction was stirred for 2 h and
then quenched with excess NaHCO3 (saturated aqueous). The
mixture was extracted five times with ethyl acetate, and the
extracts were dried (Na2SO4) and concentrated in vacuo. The
residue was purified by flash column chromatography (hex-
anes/ethyl acetate, 4:1) to afford 2.37 g (68%) of 102 as an
amorphous solid: 1H NMR (400 MHz) δ 1.24-1.75 (m, 15H),
3.82/4.28 (pair of d, 2H, J ) 9.3 Hz), 4.82 (br s, 2H); IR (CHCl3)
[3ar,5aâ,8aâ,8br](Octah ydr o-2,2-dioxo-5aH-in den o[4,5-
d ]-1,3-d ioxol-2-t h ia -5a -yl)m et h yl Su lfa m ic Acid E st er
(100).54 To a solution of 9876 (0.23 g, 0.83 mmol) in 16 mL of
THF was added NaH (61 mg, 2.5 mmol, washed with hexanes)
at 0 °C, and the mixture was stirred for 0.5 h. A solution of
sulfuryldiimidazole (0.19 g, 0.95 mmol) in 8 mL of THF was
added dropwise at 0 °C, and the mixture was stirred for 3.5 h
at 23 °C. The mixture was filtered through Dicalite, and the
filter cake was washed with THF. The filtrate was concen-
trated, and the residue was purified by flash column chroma-
tography (hexanes/ethyl acetate, 3:1) to afford 0.16 g (50%) of
the 6,7-cyclic sulfate derivative as a clear oil: 1H NMR (90
MHz) δ 0.9-2.1 (m, 10H), 2.21-2.57 (m, 1H), 3.20/3.40 (pair
of d, 2H, J ) 9.0 Hz), 4.48 (br s, 2H), 5.67-4.80 (m, 2H), 7.31
(s, 5H); FAB-MS m/z 339 (MH+). A solution of this cyclic
sulfate (3.1 g, 9.1 mmol) in 18 mL of 95% ethanol was added
to 1.6 g of 10% Pd-C and hydrogenated at 50 psig on a Parr
apparatus for 40 h. The mixture was filtered through Dicalite,
and the filtrate was concentrated. The residue was purified
by flash column chromatography (hexanes/ethyl acetate, 3:2)
to afford 0.6 g of 99 (71%) as a white solid: mp 91-94 °C; 1H
NMR (400 MHz) δ 1.30-2.14 (m, 11H, contains OH), 2.35-
2.41 (m, 1H), 3.40/3.71 (pair of d, 2H, J ) 10.5 Hz), 5.01-5.07
(m, 2H); IR (KBr) νmax 3234, 2945, 2876, 1456, 1374, 1208,
νmax 3443, 3353, 3297, 2933, 2862, 1370, 1181 cm-1
(C10H19NO3S) C, H, N.
. Anal.
[3ar,5aâ,6aâ,6br](1,2,3,4,5,5a,6,6a-Octah ydr ocyclopr op-
[e]in d en -3a -yl)m eth yl Su lfa m ic Acid Ester (104). A solu-
tion of 97 (2.3 g, 15 mmol) in 23 mL of tert-butylmethyl ether
was cooled to 0 °C and treated with 3.3 mL (32 mmol) of
diethylzinc, followed by dropwise addition of 2.0 mL (25 mmol)
of diiodomethane. The mixture was refluxed for 3.5 h, then
cooled to 23 °C, and poured onto a mixture of ice and dilute
HCl. It was extracted five times with ether, and the combined
extracts were washed with water, dried (Na2SO4), and con-
centrated in vacuo. The residue was purified by flash column
chromatography (hexanes/ethyl acetate, 4:1) to give 1.6 g (64%)
of 103 as a clear oil: 1H NMR (90 MHz) δ 0.17-0.27 (m, 1H),
0.29-0.35 (m, 1H), 0.59-0.67 (m, 1H), 0.94-0.98 (m, 1H),
1.14-2.01 (m, 12H), 3.19 (br s, 2H). A solution of 103 (1.5 g,
9.0 mmol) in 9.0 mL of DMF was added to a suspension of
NaH (0.28 g, 11.7 mmol, washed with hexanes) in 5 mL of
DMF at 0 °C, and the mixture was stirred for 45 min.
Following treatment with sulfamoyl chloride (2.8 g, 24.6 mmol)
at 0 °C in two portions, the mixture was allowed to warm to
23 °C. After being stirred overnight, it was quenched with
ice, and the mixture was extracted five times with ethyl
acetate. The combined extracts were washed with water, dried
(Na2SO4), and concentrated in vacuo. The residue was purified
by flash column chromatography (hexanes/ethyl acetate, 5:1)
and recrystallized (hexanes/ether) to afford 1.6 g (72%) of 104
as a white solid: 1H NMR (400 MHz,) δ 0.18-0.22 (m, 1H),
0.33-0.39 (m, 1H), 0.61-0.67 (m, 1H), 0.97-1.01 (m, 1H),
1.24-1.39 (m, 2H), 1.43-1.58 (m, 4H), 1.66-1.83 (m, 2H),
1.84-1.99 (m, 3H), 3.79 (s, 2H), 4.70 (br s, 2H); IR (KBr) νmax
1040, 952, 842 cm-1
. Anal. Calcd for C10H16O5S: C, 48.37;
H, 6.50. Found: C, 48.71; H, 6.76. A solution of 99 (1.3 g, 5.2
mmol) and triethylamine (1.1 mL, 7.9 mmol) in 5 mL of DMF
was cooled to 0 °C, and sulfamoyl chloride (0.9 g, 7.8 mmol)
was added in one portion. The mixture gradually reached 23
°C and, after a total of 2 h, was quenched with ice and
extracted four times with ethyl acetate. The combined extracts
were dried (Na2SO4) and concentrated in vacuo at 23 °C
(compound is heat sensitive!!). The residue was purified by
flash column chromatography (hexanes/ethyl acetate, 1:1) to
afford 0.94 g (55%) of 100 as a white solid: mp 70 °C (dec); 1H
NMR (400 MHz) δ 1.33-1.75 (m, 7H), 1.87-1.94 (m, 2H),
1.99-2.08 (m, 1H), 2.29-2.34 (m, 1H), 3.69/4.12 (pair of d, 2H,
J ) 9.4 Hz), 5.28-5.31 (m, 1H), 5.42-5.47 (m, 1H), 7.52 (br s,
2H, NH2); IR (KBr) νmax 3389, 3280, 2962, 2878, 1557, 1466,
1386, 1354, 1203, 1172 cm-1. Anal. (C10H17NO7S2) C, H, N.
3364, 3272, 2955, 2902, 2866, 1569, 1359, 1181, 932 cm-1
Anal. (C11H19NO3S) C, H, N.
.
2,3:4,5-Bis-O-(isop r op ylid en e)-â-L-fr u ctop yr a n ose Su l-
fa m a te (106). L-Fructose59 (2.40 g, 13.3 mmol) was reacted
with H2SO4 (2.33 mL, 8.3 mmol) in acetone (57 mL) according
to the procedure for the preparation of 46 to furnish 2,3:4,5-
bis-O-(isopropylidene)-â-L-fructopyranose (1.93 g, 56%) as
white needles, after recrystallization twice from ether/pentane
(1:1), mp 94-96 °C. A portion of this material (1.71 g, 6.57
mmol) was combined with pyridine (0.64 mL g, 7.99 mmol) in
toluene (8.8 mL) and added dropwise over 15 min at -15 °C
to a vigorously stirred solution of sulfuryl chloride (0.63 mL,
7.88 mmol) in 8.8 mL of toluene. The reaction was slowly
warmed to 23 °C over 3 h and diluted with water. The toluene
layer was extracted three times with citric acid (10% aq), three
times with NaHCO3 (saturated aqueous), and twice with brine,
then dried (Na2SO4), and concentrated in vacuo to afford crude
2,3:4,5-bis-O-(isopropylidene)-â-L-fructopyranose chlorosulfate
as an amber oil. The crude material was dissolved in THF
(150 mL) and placed in a vigorously stirred autoclave with
cis-1,2,3,4,5,7a -Hexa h yd r o-3a H-in d en e-3a -m eth yl Su l-
fa m ic Acid Ester (101). A solution of 97 (3.4 g, 22.3 mmol)
in 33 mL of DMF was added dropwise to a suspension of 0.7
g (29 mmol) of NaH (washed with pentane) in 2.9 mL of DMF
at 0 °C. After 45 min, 5.1 g (44.6 mmol) of sulfamoyl chloride
was added in two portions at 0 °C, and the mixture was
allowed to reach 23 °C gradually. After being stirred over-
night, the mixture was cooled to 0 °C, quenched slowly with
NaHCO3 (saturated aqueous), and extracted four times with
ethyl acetate. The combined extracts were washed with brine,
dried (Na2SO4), and concentrated in vacuo. The residue was
purified by flash chromatography (hexanes/ethyl acetate, 3:1)
to afford 2.1 g (41%) of 101, as a waxy solid: 1H NMR δ 1.36-
1.97 (m, 7H), 1.78-2.39 (m, 4H), 3.81/4.21 (pair of d, 2H, J )

1340 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
anhydrous ammonia (30 psig) over 48 h. After being filtered,
the white precipitate was washed with hexanes and recrystal-
lized from 20 mL of ethanol/water (1:1) to afford 106 (1.61 g,
C-C-H angles ranging from 100 to 116°. The remaining
hydrogen atoms were included in the structure factor calcula-
tions as idealized atoms. The isotropic thermal parameters
for H1N1 and H1N2 refined to a final value of 3(1) Å2; the
isotropic thermal parameter of each remaining hydrogen atom
was set at 1.2 times the equivalent isotropic thermal param-
eter for its associated carbon atom. The molecular structure
of 1 is depicted in Figure 2.
1
72%) as a white crystalline solid: mp 125-126 °C; H NMR
(400 MHz) δ 1.35 (s, 3H, Me), 1.42 (s, 3H, Me), 1.49 (s, 3H,
Me), 1.55 (s, 3H, Me), 3.70-3.95 (m, 2H, H6), 4.15-4.40 (m,
4H, 2 H1, H3, and H5), 4.62 (dd, 1H, J 34 ) 2.0 Hz, J 45 ) 7.8
Hz, H4), 5.36 (br s, 2H, NH2); 13C NMR (100 MHz) δ 23.9 (Me),
25.0 (Me), 25.7 (Me), 26.3 (Me), 61.5 (CH2), 69.7 (CH), 70.3
(CH), 70.7 (CH2), 76.9 100.8 (C), 109.2 (C), 109.3 (C); IR (KBr)
νmax 3383 (s), 3245 (m), 3212 (m), 3113 (m), 2997 (m), 1579
(m), 1356 (s), 1211 (s), 1183 (s), 1072 (s), 958 (m), 882 (m),
791 (m) cm-1; CI-MS m/z 340 (MH)+, 357 (M + NH4)+. Anal.
(C12H21NO8S) C, H, N.
Sin gle-Cr ysta l X-r a y An a lysis of 2.75,76 Crystals of C9H15
-
NO10S2 (MW 361.3, colorless rectangular parallelpipeds) are
hexagonal [space group P61; a ) b ) 9.760(2) Å, c ) 27.070(8)
Å, V ) 2235(1) Å3, Z ) 6]. The intensity data were collected
from a single crystal by using full ω scans and graphite-
monochromated Mo KR radiation (λ ) 0.710 73 Å). A total of
2041 independent reflections having intensities 2.0θ(Mo KR)
< 55.0° were used, and the structure was solved by Direct
Methods. The resulting structural parameters were refined
to convergence [R1(unweighted, based on F) ) 0.039 for 1752
independent reflections]. The molecular structure of 2 is
depicted in Figure 3.
2,3-O-(Isop r op ylid en e)-4,5-O-su lfon yl-â-L-fr u ct op yr a -
n ose Su lfa m a te (107). A solution of 106 (14.4 g, 42.4 mmol)
in THF (70 mL) was diluted with 3 N HCl (70 mL) and heated
at 40-45 °C with stirring. After 3 h, the mixture was cooled
to 23 °C and adjusted to pH 7 with Na2CO3 (11.5 g) and
saturated NaCl (17.5 g). The aqueous layer was extracted
three times with THF, and the combined extracts were dried
(MgSO4) and concentrated in vacuo. The residue was purified
by preparative HPLC (ethyl acetate/dichloromethane, 7:3) to
furnish 2,3-O-(isopropylidene)-â-L-fructopyranose sulfamate
(4.75 g, 38%) as a white solid. A solution of this material (4.30
g, 14.4 mmol) and pyridine (2.74 g, 34.5 mmol) in ethyl acetate
(143 mL) was reacted with sulfuryl chloride (2.54 mL, 31.6
mmol) and processed as described for 2 (D-isomer of 107) to
afford 4,5-bis-O-chlorosulfonyl-2,3-O-(isopropylidene)-â-L-fruc-
topyranose sulfamate as a white solid (3.40 g, 48%). This
material was dissolved in methanol (22 mL), treated with
NaHCO3 (3.75 g, 44.7 mmol), and processed as for 2. The
crude product was purified by preparative HPLC (dichlo-
romethane/ethyl acetate, 9:1) and recrystallized from ethanol/
water (1:1) to give 107 (1.25 g, 51%) as a white crystalline
solid: mp 128-129 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ
1.38 (s, 3H, Me), 1.53 (s, 3H, Me), 3.90-4.10 (m, 4H, 2 H1 and
2 H6), 4.59 (d, 1H, J 34 ) 2.7 Hz, H3), 5.49 (d, 1H, J 45 ) 7.8 Hz,
H5), 5.70 (dd,1H, J 34 ) 2.7 Hz, J 45 ) 7.8 Hz, H4), 7.75 (br s,
2H, NH2); 13C NMR (100 MHz, DMSO-d6) δ 25.0 (Me), 26.0
(Me), 59.2 (CH2), 67.9 (CH2), 68.1 (CH), 73.2, (CH), 77.6 (CH),
100.7 (C), 110.2 (C); IR (KBr) νmax 3376 (s), 3267 (s), 1568 (m),
1377 (s), 1213 (s), 1189 (s), 1050 (s), 832 (m) cm-1; FAB-MS
Sin gle-Cr ysta l X-r a y An a lysis of 95.75,76 Crystals of
C
13H23NO5S (MW 305.4, colorless rectangular parallelpipeds)
are monoclinic [space group P21/n; a ) 10.094(3) Å, b ) 11.712-
(4) Å, c ) 13.239(4) Å, â ) 103.04(3)°, V ) 1525(1) Å3, Z ) 4].
The intensity data were collected from a single crystal by using
ω scans and graphite-monochromated Mo KR radiation.
A
total of 3493 independent reflections having intensities greater
than 2.0θ(Mo KR) < 55.0° were used, and the structure was
solved by using Direct Methods. The resulting structural
parameters were refined to convergence [R1(unweighted, based
on F) ) 0.048 for 2689 independent reflections]. The molecular
structure of 95 is depicted in Figure 4.
Ma xim a l Electr osh ock Seizu r e (MES) Assa y.60 This
anticonvulsant test was performed according to the procedure
described previously.2a Our standard protocol was to evaluate
each test compound in mice at 1 and 4 h by both intraperito-
neal and oral administration, generally with 10 mice per group.
The oral 4-h testing results are reported in Table 1.
In h ibition of Ca r bon ic An h yd r a se.79 Details are pro-
vided in the Supporting Information.76
Ack n ow led gm en t. We thank Mary Schott, Paul
Lobben, and Delene Mitchell for technical support; Allen
Reitz and Harvey Kupferberg for helpful advice and
discussions; Harold Almond, J r., for molecular modeling
work and computational advice and discussions; Frank
Chrzanowski and A. Adair for measurement of partition
coefficients and pKa values. Gary Caldwell, J ohn Ma-
succi, Gregory Leo, Diane Gauthier, and David Graden
for NMR, mass, and IR spectroscopic support, and for
optical rotation measurements. We are grateful to the
National Institute for Neurological Disorders and Stroke
(NINDS) for supplying us with biological data on 2.
m/z 362 (MH)+, 379 (M + H2O)+, 384 (M + Na)+. Anal. (C9H15
NO10S2) C, H, N, S.
-
Sin gle-Cr ysta l X-r a y An a lysis of Top ir a m a te (1).75,76
The procedure used for 1 is representative of that used for 2,
21a , and 95, experimental details and results for which are
supplied in Supporting Information.76 Crystals of C12H21NO8S
(MW 339.36, colorless rectangular parallelpipeds from ethanol/
water) are orthorhombic (space group P212121) with a ) 7.2432-
(9) Å, b ) 11.004(1) Å, c ) 19.636(2) Å, R ) â ) γ ) 90.0°, V
) 1565.1(3) Å3, and dcalcd ) 1.440 g/cm3 for Z ) 4. The
intensity data were collected from a single crystal (0.40 × 0.50
× 0.55 mm) on a computer-controlled Four-Circle Nicolet
autodiffractometer at 293 K by using θ-2θ scans and nickel-
filtered Cu KR radiation (λ ) 1.541 84 Å). We used 1369
independent reflections having intensities greater than 2.0θ-
(Cu KR) < 120.0° (equivalent of 0.65 limiting Cu KR spheres).
The structure was solved by using Direct Methods with a
modified Siemens SHELXTL-PC software package. The re-
sulting structural parameters were refined to convergence [R1-
(unweighted, based on F) ) 0.042 for 1300 independent
reflections with 2.0θ(Cu KR) < 120.0° and I > 3σ(I)] by using
counter-weighted, full-matrix least-squares methods and a
structural model that incorporated anisotropic thermal pa-
rameters for all non-hydrogen atoms and isotropic thermal
parameters for all hydrogen atoms. Hydrogen atoms on the
NH2 group, H1N1 and H1N2, were located from a difference
Fourier map and refined as independent isotropic atoms. The
four methyl groups (C8, C9, C11, C12, and their hydrogen
atoms) were included in the structural model as rigid rotors
with sp3 geometry and a C-H bond distance of 0.96 Å. The
refined positions for the rigid rotor methyl groups gave
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 81, 97, 98, and methyl (4,4-dimethyl-2-oxo-cyclo-
pent)-1-yl-carboxylate; 1H NMR spectral data for 83b-m , 83o,
and 83p ; detailed data for the X-ray analyses of 1, 2, and 95,
including tables of atomic coordinates, bond lengths, bond
angles, and thermal parameters, as well as experimental
details and results for 2 and 95; procedure for carbonic
anhydrase inhibition; 95% confidence limits for the ED50 values
in Table 1 (34 pages). Ordering information is given on any
current masthead page.
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1342 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Maryanoff et al.
(34) The relative disposition of the phenyl substituents in this alcohol
intermediate was determined by 1H NMR NOE experiments.
Strong positive NOE’s were observed (400 MHz, CDCl3) between
H3 (δ 4.55, d) and the 2,3-benzylidene methine (δ 5.90, s),
between H4 (δ 4.78, dd) and the 4,5-benzylidene methine (δ 5.78,
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(δ 4.35, dd).
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(46) Chlorosulfate 82 is surprisingly stable. In THF/water (1:1) at
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However, addition of excess primary amine to a THF/water
solution of 82 caused rapid hydrolysis (complete in less than 5
min).
(47) Treatment of 82 with diisopropylamine did not yield desired
product, and tert-butylamine yielded just a trace of product. The
product in these reactions was alcohol 81. Since the starting
amines were anhydrous (distilled from BaO), 81 was probably
formed nonhydrolytically, such as by N-chlorination and frag-
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(49) (a) This reagent was prepared from TsNCl2 (Heintzelman, R.
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(b) Borovikova, G. S.; Levchenko, E. S.; Borovik, E. I. Reaction
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formation for 90a and 93a was conducted between 5 °C and
ambient temperature, it is presumed that the strongly biased
stereoselectivity was in favor of the exo isomer, as obseved in
the synthesis of 87a /b from diol 28 and 88a /b from diol 40.
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49a
(53) This new reagent was prepared from BocNCl2 and elemental
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(74) Spectra were obtained at dilutions (w/w) of 9.3-11.3% (0.015-
mm path) and 0.3% (0.5-mm path). The symmetric (νs) and
asymmetric (νas) free NH stretches for 1 and 2 were not resolved
in CD3CN.
(75) Details for the crystallography are given in the Supporting
Information.
(76) See the paragraph at the end of this paper regarding Supporting
Information.
(77) Details for 67 have already been published,29 and the details
for 21a will be published separately.
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(79) We thank Prof. Wendy Cammer (Albert Einstein College of
Medicine, Bronx, NY) for communicating this method to us prior
to publication.
J M970790W