Fast and selective synthesis of novel cyclic sulfamide HIV-1 protease inhibitors under controlled microwave heating

Article abstract of DOI:10.1016/j.tet.2005.11.094

A novel and highly selective silver-promoted monobenzylation method was developed to promote synthesis of nonsymmetrical sulfamide-based HIV-1 inhibitors. Microwave-accelerated palladium-catalyzed N-amide arylation- and aminocarbonylation reactions were e

Full text of DOI:10.1016/j.tet.2005.11.094

Tetrahedron 62 (2006) 4671–4675
Fast and selective synthesis of novel cyclic sulfamide HIV-1
protease inhibitors under controlled microwave heating
a
Henrik Gold, Anna Ax, Lotta Vrang, Bertil Samuelsson, Anders Karlen,
a
b
b
a
´
Anders Hallberga and Mats Larheda,
*
aOrganic Pharmaceutical Chemistry, Department of Medicinal Chemistry,
Uppsala University, Uppsala Biomedical Centre, PO Box-574, SE-75123 Uppsala, Sweden
bMedivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden
Received 25 October 2005; revised 29 November 2005; accepted 29 November 2005
Available online 24 March 2006
Abstract—A novel and highly selective silver-promoted monobenzylation method was developed to promote synthesis of nonsymmetrical
sulfamide-based HIV-1 inhibitors. Microwave-accelerated palladium-catalyzed N-amide arylation- and aminocarbonylation reactions were
employed for rapid and reliable compound generation. With this class of inhibitory agents, six active inhibitors were identified, the most potent
inhibitor possessing a Ki-value of 20 nM.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of inhibitors in complex with the HIV-1 protease.10,11 The
preparative route to these inhibitors was complex and the
inhibitors were lipophilic and of high-molecular weight. To
investigate if properly functionalized benzylic side-chains
could span from P2/P20 to P1/P10 and thus simplify the
otherwise cumbersome synthetic pathway, a set of C2-sym-
metric ortho-functionalized sulfamide derivatives were syn-
thesized and evaluated. The most potent inhibitor from this
series (Ki¼0.53 mM), substituted with two benzofuran moi-
eties, was identified as a lead structure for further optimiza-
tion (Fig. 1).12 Thus, based on isosteric replacement and
modeling, it was hypothesized that an amide function
(–CONH) might be of interest to incorporate in the two
ortho-positions (R-) of the dibenzylated cyclic sulfamide
5 to act as a mimic for the furan ring (Fig. 1, Scheme 1).
In addition, we decided to investigate the inverted amides
(–NHCO). Reactants were selected in order to vary flexibil-
ity and size of the ortho-substituents. With the aim to reduce
Since the mid-1980s, a large number of studies have demon-
strated that an acceleration of chemical rates can be achieved
by employing high-density microwave irradiation instead of
traditional sources of heat.1–4 Although high yields and
clean reactions are commonly obtained with microwave
heating, reduced selectivities have been reported at high
temperatures.5,6 Hence, development of fast and highly
selective reaction protocols, remains a challenge.
The recent development of palladium-catalyzed gas-free
aminocarbonylations7 and N-amide arylations8 has enabled
direct attachment of amide functionalities to sp2-carbons
that were previously difficult to accomplish. However, the
commonly tedious fine-tuning of the appropriate reaction
parameters, and the requirement for inert conditions and
long reaction times, has limited the usage of these direct
transformations in medicinal chemistry.
A large number of very potent urea-based cyclic HIV-1 pro-
tease inhibitors carrying four-side chains has been prepared
and evaluated following the pioneering work by Lam and co-
workers.9 Interestingly, by switching the water-mimicking
group from urea to sulfamide, an unanticipated flipped bind-
ing mode was obtained according to X-ray crystal structures
Keywords: Microwave; Aminocarbonylation; Goldberg; HIV-1 protease
inhibitor.
* Corresponding author. Tel.: +46 18 4714667; fax: +46 18 4714474;
e-mail: mats@orgfarm.uu.se
Figure 1. Superposition of benzofuran and anilide (5a) o-substituted N,N0-
dibenzylic seven-membered sulfamide structures. The molecular graphics
image was produced using the UCSF program Chimera.13
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.094

4672
H. Gold et al. / Tetrahedron 62 (2006) 4671–4675
Table 1. Microwave-heated palladium-catalyzed coupling reactions on
symmetric and nonsymmetric cyclic sulfamides 3 and 4
Br
O
O
O
O
Ag2O,
2-Bromobenzyl bromide
S
S
HN
NH
HN
N
Reactanta,
routeb
R-group
Symmetric
Nonsymmetric
(yield)c, Ki (nM) (yield)c, Ki (nM)
CH2Cl2
MW, 100 °C, 60 min
O
O
1
O
O
97%
2
O
a, A
5a (59%),
>20,000
6a (77%),
>20,000
N
H
K2CO3
2-Bromobenzyl bromide
DMF, 100 °C, 16 h
K2CO3
Benzyl bromide
DMF, 100 °C, 1 h
O
b, A
5b (80%),
8600
6b (74%),
>20,000
Br
Br
Br
O
N
H
O
O
O
S
S
N
N
N
N
O
c, B
5c (72%),
>20,000
6c (77%),
>20,000
99%
4 95%
O
O
O
O
3
N
H
Palladium-Catalyzed
Amidation Reactions
MW, 15-60 min
Deprotection
O
d, B
e, B
5d (53%),
1200
6d (51%),
>20,000
N
R
R
R
H
O
O
O
O
S
S
N
N
N
N
O
5e (54%),
1300
6e (68%),
7700
N
H
O
HO
OH
HO
OH
5a-f
6a-f
O
f, B
5f (57%),
20
6f (66%),
140
Scheme 1.
N
H
the size of the inhibitors and to produce nonsymmetrically
decorated dibenzyl sulfamides, precursor 2 was much de-
sired.
a
a: Aniline, b: Benzylamine, c: Benzamide, d: 2-Phenylacetamide, e: 2-(3-
Methoxyphenyl)acetamide, f: 2-(2-Naphthyl)acetamide.
A: Aminocarbonylation, B: N-amide arylation.
b
c
Isolated yields after deprotection.
In this communication, a microwave promoted and chemo-
selective procedure for monoalkylation of the sulfamide
scaffold 1 is reported (Scheme 1). Furthermore, a number
of direct palladium-catalyzed ortho-amidations of the P2/
P20 benzyl groups have been conducted, delivering 12 new
HIV-1 protease inhibitors.
Aminocarbonylations of parent 4 with Mo(CO)6 as the
CO-source smoothly produced the monofunctionalized
products 6a,b (74 and 77%, Table 1). Similarly, 6c–f were
prepared as reported for the symmetric analogs 5c–f in
51–77% yields after deprotection. The Ki-values for the
synthesized compounds were determined as previously
described.16,17
2. Results and discussion
2.1. Synthetic strategies
2.2. Discussion
Six active inhibitors were identified. Apparently, incorpora-
tion of the amide function alone was not sufficient, and an
extra methylene spacer was required in order to yield active
symmetrical compounds (5b, 5d–f). The most potent com-
pound 5f possessed low nanomolar activity with a Ki-value
of 20 nM. The high activity of 5f was obtained by steric
replacement of phenylacetamide for 1-naphthylacetamide.
To our satisfaction, the smaller nonsymmetric compounds,
occupying only three subsites, also proved to be active (6e,
6f). With these structures, both the extra methylene spacer
and further enlargement of the R-group was essential for
activity.
The core structure 1 served as the precursor to provide the
symmetric and nonsymmetric aryl bromide derivatives 3
and 4, respectively (Scheme 1). Compound 3 was obtained,
as previously reported, in 99% yield after N,N-dibenzylation
with 2-bromobenzyl bromide in the presence of K2CO3.10
Double ortho-amidations of 3 by palladium-catalyzed cou-
pling reactions and deprotection, provided the symmetrical
inhibitors in good yields (Table 1). More specifically, the
aminocarbonylation products 5a,b were obtained in 59 and
14
ꢀ
80% yield after 60 min of heating at 150 C, respectively.
The corresponding N-amide arylations delivered the in-
verted amides 5c–f in 53–72% yields after only 15 min of ir-
ꢀ
radiation (160 C). Early attempts to prepare unsymmetrical
4 from 1 showed an increased reactivity of the monoalkyl-
ated product 2 towards concomitant dialkylation, resulting
in unwanted 3. Fortunately, by initial addition of 1.5 equiv
Ag2O, subsequent microwave-assisted benzylation afforded
pure aryl bromide 2 with excellent selectivity (2/3¼99:1,
Scheme 1). The yield of 2 was 97% despite the high-reaction
3. Conclusion
In conclusion, the concept of ortho-extension from benzylic
P2/P20 side-chains to reach the P1/P10 binding sites pro-
vided highly active HIV-1 protease inhibitors. With regard
to inhibition potency, improved Ki-values were achieved
using mono- and di-ortho-elongated structures with flexi-
ble three-atom spacers between the aromatic moieties.
ꢀ
temperature (100 C). Related monoalkylations of symmet-
rical diols have been performed in presence of Ag2O.15

H. Gold et al. / Tetrahedron 62 (2006) 4671–4675
4673
ꢀ
Furthermore, single-mode microwave heating at 100 C for
60 min was exploited without compromising the selectivity
in the key monobenzylation step.
C14H19BrN2O4S: C, 42.98; H, 4.89; N, 7.16. Found: C,
43.30; H, 5.04; N, 7.19.
4.2.2. 3,4,5,6-Tetrahydro-(4S,5S )-2-(2-bromobenzyl)-7-
benzyl-4,5-O-isopropylidene-1,2,7-thiadiazepine 1,1-di-
oxide (4). White solid. LC–MS, m/z¼482 [M+H+]. 1H
NMR (400 MHz, CDCl3): d¼7.57 (m, 1H), 7.54 (m, 1H),
7.40–7.29 (m, 6H), 7.18 (m, 1H), 4.58 (d, 1H, J¼15.4 Hz),
4.50 (d, 1H, J¼15.4 Hz), 4.49 (d, 1H, J¼14.6 Hz), 4.36 (d,
1H, J¼14.6 Hz), 4.31–4.18 (m, 2H), 3.50 (dd, 1H, J¼4.5,
13.0 Hz), 3.46 (dd, 1H, J¼4.6, 12.8 Hz), 3.11 (dd, 1H,
J¼9.2, 13.0 Hz), 3.02 (dd, 1H, J¼9.3, 12.8 Hz), 1.38 (d,
1H, J¼0.6 Hz), 1.37 (d, 1H, J¼0.6 Hz). 13C NMR
(100.5 MHz, CDCl3): d¼136.1, 135.5, 133.2, 130.3, 129.7,
129.0, 128.7, 128.4, 128.2, 123.8, 110.1, 77.9, 77.7, 55.4,
54.8, 49.3, 48.6, 27.1. Anal. Calcd (%) for C21H25N2O4S:
C, 52.39; H, 5.23; N, 5.82. Found: C, 52.46; H, 5.29; N, 5.79.
4. Experimental
4.1. General
The microwave-assisted reactions were performed in a
single-mode microwave cavity (Smith Synthesizer, Biotage
AB, Uppsala, Sweden) producing controlled irradiation at
2450 MHz. Reaction temperatures were determined and
controlled via the built-in, on-line IR-sensor. Flash column
chromatography was performed using Merck Silica gel 60
(0.040–0.063 mm). Analytical HPLC–MS analyses were
performed using a Gilson HPLC system with a Chromolith
SpeedROD RP-18e column (50ꢁ4.6 mm) and a Finnigan
AQA quadropole mass spectrometer using a 4 mL/min
CH3CN/H2O gradient (0.05% HCOOH), employing UV-
detection (214 and 254 nm) and mass selective detector
(ESI+). 1H and 13C NMR spectra were recorded on a Varian
Mercury-400 spectrometer at 399.8 and 100.6 MHz, re-
spectively. All starting materials and reagents were com-
mercially available and used as received. Xantphos,
(4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene) was
purchased from Aldrich. Herrmann’s palladacycle, trans-
di(m-acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipalladium
(II) was purchased from Strem and Mo(CO)6 was obtained
from Acros.
4.3. General method for aminocarbonylation of both
symmetrical (3) and nonsymmetrical (4) sulfamide
scaffolds
Cyclic sulfamide (0.083 mmol), Herrmann’s catalyst
(8.3 mmol, 7.8 mg), Mo(CO)6 (0.017 mmol, 47 mg), DBU
(0.83 mmol, 136 mg) and amine (2.5 mmol) were put in
a 2–5 mL Smith process vial.ꢀTHF (2.5 mL) was added
and the reaction was run at 150 C for 60 min. After cooling
the reaction mixture was filtered through a plug of Celite and
the organic solvent was evaporated under reduced pressure.
Flash column chromatography and removal of the protective
group using 1 mL 2.2 M HCl/ether and 2 mL methanol at rt
for 45 min, followed by a second rapid flash column chroma-
tography yielded pure products in all cases.
4.2. Method for monobenzylation of cyclic sulfamides
Cyclic sulfamide 1 (0.45 mmol, 100 mg) and Ag2O
(0.67 mmol, 156 mg) were mixed in a Smith process vial
for 5 min in 2 mL of CH2Cl2. After addition of o-bromoben-
zyl bromide (0.47 mmol, 117 mg) and another 3 mL of
CH2Cl2, the vial was cappeꢀd with a septum. The microwave
synthesizer was set to 100 C for 1 h. After cooling, the re-
action mixture was filtered through a plug of Celite and im-
mediately transferred to a short flash column and 2 was
easily purified using 9:1 iso-hexane/EtOAc as the eluent
4.3.1. 3,4,5,6-Tetrahydro-(4S,5S )-2,7-bis(N-phenyl-2-
amido-benzyl)-4,5-dihydroxy-1,2,7-thiadiazepine 1,1-di-
1
oxide (5a). White solid. LC–MS, m/z¼601 [M+H+]. H
NMR (400 MHz, CDCl3): d¼8.09 (s, 2H), 7.62–7.54 (m,
6H), 7.46–7.40 (m, 4H), 7.36–7.24 (m, 6H), 7.15 (tt, 2H,
J¼7.4, 1.2 Hz), 4.64 (d, 2H, J¼15.8 Hz), 4.58 (d, 2H,
J¼15.8 Hz), 3.61–3.56 (m, 2H), 3.35 (d, 1H, J¼15.4 Hz),
3.34 (d, 1H, J¼15.4 Hz), 3.22 (d, 1H, J¼15.4 Hz), 3.20
(d, 1H, J¼15.4 Hz). 13C NMR (100.5 MHz, CDCl3):
d¼168.3, 137.9, 136.2, 136.0, 131.3, 130.2, 129.4, 128.2,
127.1, 125.2, 120.5, 72.4, 50.6, 48.9.
1
(>95% purity by H NMR and GC–MS). In a subsequent
benzylation, 2 (0.68 mmol, 266 mg), benzyl bromide
(1.36 mmol, 232 mg) and K2CO3 (3.33 mmol, 460 mg)
were mixed in a process vial withꢀ 5 mL DMF. Reaction
was heated in a heating block at 60 C overnight. The reac-
tion mixture was concentrated in vacuo and purified over
silica, using 2:1–1:1 iso-hexane/CH2Cl2 as the eluent.
4.3.2. 3,4,5,6-Tetrahydro-(4S,5S )-2,7-bis(N-benzyl-2-
amido-benzyl)-4,5-dihydroxy-1,2,7-thiadiazepine 1,1-di-
1
oxide (5b). White solid. LC–MS, m/z¼629 [M+H+]. H
NMR (400 MHz, CDCl3): d¼7.68 (ddd, 2H, J¼7.8, 1.2,
0.6 Hz), 7.49 (ddd, 2H, J¼7.8, 7.3, 1.5 Hz), 7.42–7.27 (m,
14H), 6.34 (br t, 2H, J¼5.8 Hz), 4.78 (d, 2H, J¼15.4 Hz),
4.73 (d, 2H, J¼15.4 Hz), 4.64 (dd, 2H, J¼14.7, 5.8 Hz),
4.59 (dd, 2H, J¼14.7, 5.8 Hz), 3.76–3.72 (m, 2H), 3.58–
3.54 (m, 2H), 3.53–3.47 (m, 2H), 327–3.20 (m, 2H). 13C
NMR (100.5 MHz, CDCl3): d¼169.9, 137.8, 136.2, 135.8,
131.3, 130.9, 129.2, 128.22, 128.18, 128.1, 126.9, 72.5,
49.9, 47.2, 44.5.
4.2.1. 3,4,5,6-Tetrahydro-(4S,5S )-2-(2-bromobenzyl)-
4,5-O-isopropylidene-1,2,7-thiadiazepine 1,1-dioxide
(2). White solid. LC–MS, m/z¼392 [M+H+]. 1H NMR
(400 MHz, acetone-d6): d¼7.62 (dd, 1H, J¼1.2, 8.0 Hz),
7.56 (dd, 1H, J¼1.7, 7.8 Hz), 7.44 (ddd, 1H, J¼1.2, 7.4,
7.8 Hz), 7.26 (ddd, 1H, J¼1.7, 7.4, 8.0 Hz), 6.72 (br m,
1H), 4.51 (d, 1H, J¼16.0 Hz), 4.46 (d, 1H, J¼16.0 Hz),
4.32–4.22 (m, 2H), 3.59 (ddd, 1H, J¼3.9, 4.7, 12.8 Hz),
3.50 (dd, 1H, J¼4.2, 13.6 Hz), 3.15 (ddd, 1H, J¼0.6, 9.4,
13.6 Hz), 3.08 (ddd, 1H, J¼7.0, 9.5, 12.8 Hz), 1.37 (m,
3H), 1.36 (m, 3H). 13C NMR (100.5 MHz, acetone-d6):
d¼136.5, 132.9, 1230.0, 129.6, 128.3, 128.2, 109.2, 78.7,
77.8, 54.0, 49.4, 43.5, 26.6, 26.5. Anal. Calcd (%) for
4.3.3. 3,4,5,6-Tetrahydro-(4S,5S )-2-(N-phenyl-2-amido-
benzyl)-7-benzyl-4,5-dihydroxy-1,2,7-thiadiazepine 1,1-
dioxide (6a). White solid. LC–MS, m/z¼482 [M+H+].
1H NMR (400 MHz, acetone-d6): d¼9.57 (br s, 1H),

4674
H. Gold et al. / Tetrahedron 62 (2006) 4671–4675
7.87–7.82 (m, 2H), 7.70 (m, 1H), 7.62 (m, 1H), 7.55 (m, 1H),
7.46–7.27 (m, 8H), 7.13 (m, 1H), 4.97 (d, 1H, J¼16.8 Hz),
4.82 (d, 1H, J¼16.8 Hz), 4.68 (d, 1H, J¼15.8 Hz), 4.55 (d,
1H, J¼15.8 Hz), 4.26 (d, 1H, J¼3.9 Hz), 4.22 (d, 1H,
J¼4.3 Hz), 3.42–3.23 (m, 3H), 3.15 (dd, 1H, J¼15.2,
3.2 Hz). 13C NMR (100.5 MHz, acetone-d6): d¼168.2,
140.3, 138.5, 137.3, 137.3, 131.2, 129.6, 129.4, 129.2,
128.8, 128.34, 128.30, 128.0, 124.7, 120.8, 73.1, 73.0,
53.2, 50.9, 49.3, 48.5. Anal. Calcd (%) for C25H27N3O5S:
C, 62.35; H, 5.65; N, 8.73. Found: C, 62.21; H, 5.80; N, 8.61.
4.68 (d, 2H, J¼15.5 Hz), 4.52 (d, 2H, J¼15.5 Hz), 4.23
(br s, 2H), 3.76 (s, 4H), 3.30–3.17 (m, 4H), 3.16–3.02 (m,
2H). 13C NMR (100.5 MHz, acetone-d6): d¼169.6, 137.5,
136.2, 130.1, 129.5, 128.9, 128.6, 128.0, 126.9, 124.9,
123.7, 72.5, 49.5, 48.5, 43.9.
4.4.3. 3,4,5,6-Tetrahydro-(4S,5S )-2,7-bis{2-[2-(3-me-
thoxy-phenyl)-acetamido]-benzyl}-4,5-dihydroxy-1,2,7-
thiadiazepine 1,1-dioxide (5e). White solid. LC–MS,
m/z¼689 [M+H+]. 1H NMR (400 MHz, acetone-d6):
d¼8.88 (s, 2H), 7.93 (dm, 2H, J¼8.1 Hz), 7.48 (dd, 2H,
J¼1.6, 7.6 Hz), 7.34 (ddd, 2H, J¼1.6, 7.6, 7.6 Hz), 7.23–
7.15 (m, 4H), 7.02 (m, 2H), 6.99 (dm, 2H, J¼7.6 Hz), 6.80
(ddd, 2H, J¼1.0, 2.6, 8.2 Hz), 4.68 (d, 2H, J¼15.5 Hz),
4.52 (d, 2H, J¼15.5 Hz), 4.21 (br s, 2H), 3.77 (s, 6H), 3.73
(s, 4H), 3.32–3.18 (m, 4H), 3.17–3.08 (m, 2H). 13C NMR
(100.5 MHz, acetone-d6): d¼167.8, 146.2, 138.7, 138.2,
137.9, 130.1, 129.8, 129.7, 129.3, 128.8, 126.9, 73.1, 50.9,
49.0, 46.2, 44.1.
4.3.4. 3,4,5,6-Tetrahydro-(4S,5S )-2-(N-benzyl-2-amido-
benzyl)-7-benzyl-4,5-dihydroxy-1,2,7-thiadiazepine 1,1-
1
dioxide (6b). White solid. LC–MS, m/z¼496 [M+H+]. H
NMR (400 MHz, acetone-d6): d¼8.13 (br t, 1H), 7.67
(ddd, 1H, J¼7.8, 1.2, 0.6 Hz), 7.57–7.22 (m, 13H), 4.89
(d, 1H, J¼16.6 Hz), 4.78 (d, 1H, J¼16.6 Hz), 4.70 (d,
1H, J¼15.8 Hz), 4.61 (d, 2H, J¼6.0 Hz), 4.56 (d, 1H,
J¼15.8 Hz), 4.29 (d, 1H, J¼3.8 Hz), 4.26 (d, 1H,
J¼4.2 Hz), 3.67–3.56 (m, 2H), 3.40–3.12 (m, 4H). 13C
NMR (100.5 MHz, acetone-d6): d¼169.7, 140.3, 138.6,
137.2, 137.1, 131.0, 129.42, 129.40, 129.3, 128.9, 128.4,
128.3, 128.1, 128.1, 127.8, 73.1, 73.0, 53.2, 50.6, 49.0,
48.5, 43.9. Anal. Calcd (%) for C26H29N3O5S: C, 63.01;
H, 5.90; N, 8.48. Found: C, 62.89; H, 6.06; N, 8.43.
4.4.4. 3,4,5,6-Tetrahydro-(4S,5S )-2,7-bis{2-[2-(2-naph-
thyl)-acetamido]-benzyl}-4,5-dihydroxy-1,2,7-thiadiaze-
pine 1,1-dioxide (5f). White solid. LC–MS, m/z¼729
[M+H+]. 1H NMR (400 MHz, acetone-d6): d¼8.91 (s, 2H),
8.25 (ddd, 2H, J¼0.9, 2.1, 8.5 Hz), 7.90 (dm, 2H,
J¼8.2 Hz), 7.83 (dd, 2H, J¼1.2, 8.0 Hz), 7.82 (dm, 2H,
J¼8.2 Hz), 7.60–7.39 (m, 10H), 7.31 (ddd, 2H, J¼1.6, 7.5,
7.7 Hz), 7.16 (ddd, 2H, J¼1.3, 7.5, 7.5 Hz), 4.63 (d, 2H,
J¼15.6 Hz), 4.51 (d, 2H, J¼15.6 Hz), 4.27 (s, 4H), 4.22
(br s, 2H), 3.32–3.22 (m, 4H), 3.20–3.08 (m, 2H). 13C
NMR (100.5 MHz, acetone-d6): d¼170.2, 138.0, 134.9,
133.4, 133.1, 130.6, 129.43, 129.39, 129.3, 129.0, 128.5,
127.1, 126.6, 126.4, 125.8, 125.3, 124.9, 73.2, 50.1, 49.2,
42.1. Anal. Calcd (%) for C42H40N4O6S: C, 69.2; H, 5.53;
N, 7.69. Found: C, 68.95; H, 5.66; N, 7.50.
4.4. General method for N-amide arylation of both
symmetrical (3) and nonsymmetrical (4) sulfamide
scaffolds
Cyclic sulfamide (0.083 mmol), Pd(dba)2 (4 mmol, 2.4 mg),
Xantphos (6.2 mmol, 3.6 mg), Cs2CO3 (0.4 mmol, 135 mg)
and amide (0.8 mmol) were put in a Smith process vial,
with 2.5 mL 10% NMP in dioxane as the solvent. The reac-
ꢀ
tion mixture was heated in the microwave at 160 C for
15 min. After cooling the reaction mixture was filtered
through a plug of Celite and the organic solvent was evapo-
rated under reduced pressure. Flash column chromatography
and removal of the protecting group using 1 mL of 2.2 M
HCl/ether and 2 mL methanol at rt for 45 min followed by
a second rapid flash column chromatography yielded pure
products in all cases.
4.4.5. 3,4,5,6-Tetrahydro-(4S,5S )-2-(2-benzamidoben-
zyl)-7-benzyl-4,5-dihydroxy-1,2,7-thiadiazepine 1,1-di-
1
oxide (6c). White solid. LC–MS, m/z¼482 [M+H+]. H
NMR (400 MHz, CDCl3): d¼8.73 (br s, 1H), 7.93 (dd, 2H,
J¼1.3, 8.4 Hz), 7.86 (dm, 1H, J¼8.1 Hz), 7.55 (m, 2H),
7.49–7.42 (m, 2H), 7.39–7.23 (m, 7H), 7.20 (m, 1H), 4.60
(d, 1H, J¼14.8 Hz), 4.58 (d, 1H, J¼15.5 Hz), 4.34 (d, 1H,
J¼14.8 Hz), 4.30 (d, 1H, J¼15.5 Hz), 3.42 (m, 1H), 3.30
(dd, 1H, J¼9.2, 14.6 Hz), 3.26–3.08 (m, 4H), 3.03 (dd,
1H, J¼3.9, 15.2 Hz), 2.84 (br s, 1H). 13C NMR
(100.5 MHz, CDCl3): d¼167.7, 136.5, 136.2, 134.0, 132.5,
131.1, 129.7, 129.1, 128.9, 128.44, 128.43, 128.2, 127.9,
126.4, 125.7, 73.2, 72.4, 53.2, 50.0, 48.7, 47.9. Anal. Calcd
(%) for C25H27N3O5S: C, 62.35; H, 5.65; N, 8.73. Found: C,
62.51; H, 5.79; N, 8.64.
4.4.1. 3,4,5,6-Tetrahydro-(4S,5S )-2,7-bis(2-benzamido-
benzyl)-4,5-dihydroxy-1,2,7-thiadiazepine 1,1-dioxide
1
(5c). White solid. LC–MS, m/z¼601 [M+H+]. H NMR
(400 MHz, acetone-d6): d¼9.31 (br s, 2H), 8.05 (dd, 4H,
J¼1.4, 8.4 Hz), 7.80 (dd, 2H, J¼1.4, 8.0 Hz), 7.61–7.56
(m, 2H), 7.55–7.47 (m, 6H), 7.38 (ddd, 2H, J¼1.6, 7.5,
7.7 Hz), 7.26 (ddd, 2H, J¼1.4, 7.5, 7.5 Hz), 4.72 (d, 2H,
J¼16.2 Hz), 4.68 (d, 2H, J¼16.2 Hz), 4.32 (br d, 2H,
J¼4.1 Hz), 3.54–3.45 (m, 2H), 3.30 (dd, 2H, J¼9.2,
15.1 Hz), 3.18 (dd, 2H, J¼2.9, 15.1 Hz). 13C NMR
(100.5 MHz, acetone-d6): d¼166.15, 137.0, 135.0, 131.9,
130.6, 129.7, 128.6, 128.5, 127.9, 125.9, 125.7, 72.6, 49.5,
48.3.
4.4.6. 3,4,5,6-Tetrahydro-(4S,5S )-2-(2-phenylacetamido-
benzyl)-7-benzyl-4,5-dihydroxy-1,2,7-thiadiazepine 1,1-
dioxide (6d). White solid. LC–MS, m/z¼496 [M+H+].
1H NMR (400 MHz, acetone-d6): d¼8.93 (s, 1H), 8.06
(dd, 1H, J¼1.2, 8.1 Hz), 7.51–7.39 (m, 7H), 7.37–7.30
(m, 2H), 7.29–7.18 (m, 3H), 7.14 (ddd, 1H, J¼1.3,
7.5, 7.5 Hz), 4.78 (d, 1H, J¼15.7 Hz), 4.70 (d, 1H,
J¼15.3 Hz), 4.54 (d, 1H, J¼15.7 Hz), 4.42 (d, 1H,
J¼15.3 Hz), 4.21–4.19 (m, 2H), 3.74 (s, 1H), 3.57 (m,
1H), 3.44–3.04 (m, 5H). 13C NMR (100.5 MHz, acetone-
d6): d¼169.5, 137.7, 137.5, 136.2, 130.5, 129.5, 128.9,
4.4.2. 3,4,5,6-Tetrahydro-(4S,5S )-2,7-bis[2-(2-phenyl-
acetamido)-benzyl]-4,5-dihydroxy-1,2,7-thiadiazepine
1,1-dioxide (5d). White solid. LC–MS, m/z¼629 [M+H+].
1H NMR (400 MHz, acetone-d6): d¼8.92 (s, 2H), 7.94
(dm, 2H, J¼8.1 Hz), 7.49 (dm, 2H, J¼7.5 Hz), 7.42 (dm,
4H, J¼7.5 Hz), 7.37–7.26 (m, 6H), 7.25–7.15 (m, 4H),

H. Gold et al. / Tetrahedron 62 (2006) 4671–4675
4675
128.6, 128.3, 127.9, 127.4, 126.9, 125.4, 124.5, 123.0, 73.1,
71.9, 52.4, 49.6, 48.8, 48.1, 43.9. Anal. Calcd (%) for
C26H29N3O5S: C, 63.01; H, 5.90; N, 8.48. Found: C,
63.23; H, 6.23; N, 8.13.
with synthesis and Biotage AB for providing the Smith Syn-
thesizer.
References and notes
4.4.7. 3,4,5,6-Tetrahydro-(4S,5S )-2-[2-(3-methoxy-
phenyl-acetamido)-benzyl]-7-benzyl-4,5-dihydroxy-
1,2,7-thiadiazepine 1,1-dioxide (6e). White solid. LC–MS,
m/z¼526 [M+H+]. 1H NMR (400 MHz, acetone-d6): d¼8.90
(br s, 1H), 8.02 (dd, 1H, J¼1.3, 8.2 Hz), 7.50–7.29 (m, 7H),
7.20–7.12 (m, 2H), 7.03 (m, 1H), 6.98 (dm, 1H, J¼7.5 Hz),
6.97 (ddd, 1H, J¼1.0, 2.6, 8.3 Hz), 4.76 (d, 1H, J¼15.7 Hz),
4.68 (d, 1H, J¼15.3 Hz), 4.55 (d, 1H, J¼15.7 Hz), 4.43 (d,
1H, J¼15.3 Hz), 4.22–4.19 (m, 2H), 3.76 (s, 3H), 3.71 (s,
2H), 3.58 (m, 1H), 3.40–3.06 (m, 5H). 13C NMR
(100.5 MHz, acetone-d6): d¼170.1, 160.7, 138.3, 138.2,
138.1, 131.1, 130.2, 129.6, 129.5, 128.9, 128.6, 125.3,
123.9, 122.4, 115.7, 113.1, 73.7, 72.6, 55.4, 53.1, 50.3,
49.4, 48.8, 44.7.
1. Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
¨
2001, 57, 9225–9283.
2. Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002,
35, 717–727.
3. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284.
4. Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R.
J. Comb. Chem. 2002, 4, 95–105.
5. Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A. J. Org.
Chem. 1999, 64, 1082–1083.
6. Nilsson, P.; Gold, H.; Larhed, M.; Hallberg, A. Synthesis 2002,
1611–1614.
7. Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43,
5580–5588.
8. Yin, J. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043–
6048.
9. Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru,
Y.; Bacheler, L. T.; Meek, O. M. J.; Rayner, M. M. Science
1994, 263, 380–384.
4.4.8. 3,4,5,6-Tetrahydro-(4S,5S )-2-{2-[2-(2-naphthyl)-
acetamido]-benzyl}-7-benzyl-4,5-dihydroxy-1,2,7-thia-
diazepine 1,1-dioxide (6f). White solid. LC–MS, m/z¼546
[M+H+]. 1H NMR (400 MHz, acetone-d6): d¼8.98 (s, 1H),
8.27 (dm, 1H, J¼8.4 Hz), 7.90 (m, 2H), 7.82 (dm, 1H,
J¼8.2 Hz), 7.61–7.27 (m, 11H), 7.15 (ddd, 1H, J¼1.2, 7.5,
7.5 Hz), 4.75 (d, 1H, J¼15.8 Hz), 4.66 (d, 1H,
J¼15.4 Hz), 4.55 (d, 1H, J¼15.8 Hz), 4.46 (d, 1H,
J¼15.4 Hz), 4.27 (s, 1H), 4.26 (d, 1H, J¼4.4 Hz), 4.24 (d,
1H, J¼4.2 Hz), 3.60 (m, 1H), 3.40–3.10 (m, 5H). 13C
NMR (100.5 MHz, acetone-d6): d¼169.5, 137.6, 137.5,
134.2, 132.8, 132.5, 130.2, 128.9, 128.74, 128.73, 128.4,
128.2, 127.9, 127.8, 126.4, 125.9, 125.8, 124.8, 124.7,
123.7, 72.9, 72.0, 52.5, 49.5, 48.7, 48.1, 41.4. Anal. Calcd
(%) for C30H31N3O5S: C, 66.04; H, 5.73; N, 7.70. Found:
C, 66.05; H, 5.85; N, 7.68.
¨
10. Backbro, K.; Lowgren, S.; Oesterlund, K.; Atepo, J.; Unge, T.;
¨
¨
´
´
Hulten, J.; Bonham, N. M.; Schaal, W.; Karlen, A.; Hallberg,
A. J. Med. Chem. 1997, 40, 898–902.
11. Schaal, W.; Karlsson, A.; Ahlsen, G.; Lindberg, J.; Andersson,
H. O.; Danielson, U. H.; Classon, B.; Unge, T.; Samuelsson, B.;
Hulten, J.; Hallberg, A.; Karlen, A. J. Med. Chem. 2001, 44,
155–169.
12. Ax, A.; Schaal, W.; Vrang, L.; Samuelsson, B.; Hallberg, A.;
Karlen, A. Bioorg. Med. Chem. 2005, 13, 755–764.
13. Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.;
Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. J. Comput.
Chem. 2004, 25, 1605.
14. Wannberg, J.; Larhed, M. J. Comb. Chem. 2003, 68, 5750–
5753.
Acknowledgments
15. Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38, 5945–5948.
16. Danielson, H.; Lindgren, M. T.; Markgren, P. O.; Nillroth, U.
Adv. Exp. Med. Biol. 1998, 436, 99–103.
We acknowledge the financial support from the Swedish Re-
search Council, Knut and Alice Wallenberg’s Foundation
and Medivir AB. We thank Shane Peterson for linguistic
´
17. Nillroth, U.; Vrang, L.; Markgren, P.-O.; Hulten, J.; Hallberg,
A.; Danielson, U. H. Antimicrob. Agents Chemother. 1997,
41, 2383–2388.
˚
advice, Sara Sundholm and Anders Hanell for assistance