Synthesis of a small library of non-symmetric cyclic sulfamide HIV-1 protease inhibitors

Article abstract of DOI:10.1016/j.tet.2010.04.023

A set of 11 non-symmetric cyclic sulfamide HIV-1 protease inhibitors were synthesized and evaluated. The use of a key microwave-assisted silver(I) oxide mediated selective mono N-benzylation reaction enabled fast and straightforward synthesis. The K_i

Full text of DOI:10.1016/j.tet.2010.04.023

Tetrahedron 66 (2010) 4049e4056
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Tetrahedron
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Synthesis of a small library of non-symmetric cyclic sulfamide HIV-1 protease
inhibitors
Anna Ax a, Advait A. Joshi a, Kristina M. Orrling a, Lotta Vrang b, Bertil Samuelsson b, Anders Hallberg a,
,
Anders Karlén a, Mats Larhed a
*
a Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden
b Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A set of 11 non-symmetric cyclic sulfamide HIV-1 protease inhibitors were synthesized and evaluated.
The use of a key microwave-assisted silver(I) oxide mediated selective mono N-benzylation reaction
Received 11 November 2009
Received in revised form 16 March 2010
Accepted 6 April 2010
enabled fast and straightforward synthesis. The Ki values of the new inhibitors ranged between 0.28
and >20 M.
mM
m
Available online 10 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
HIV-1
Protease inhibitor
Microwave
Palladium catalysis
Benzylation
1. Introduction
three atom amide tether furnished a highly active inhibitor (Fig. 1,
B) with a Ki value of 20 nM.5 Molecular modelling suggested a dif-
ference in the occupation of the S1 and S10 sub-sites and it was
shown that non-symmetric inhibitors might exhibit good activity
despite reduced molecular weight (Fig. 1, C).5 Thus, we embarked
upon a study of a class of P2/P20 non-symmetric ortho-decorated
HIV/AIDS has become a major challenge for mankind to deal
with. The testimony to this fact is provided by the latest report by
WHO/UNAIDS, which states that the number of people living with
HIV has escalated to 33.4 million and 7400 people get infected
everyday.1 As an outcome of extensive research to arrest the pan-
demic, combination therapies using HIV-1 nucleoside reverse
transcriptase inhibitors and HIV-1 protease inhibitors have been
launched to ensure a decline in HIV/AIDS related mortality. How-
ever, gradual resistance towards the marketed HIV inhibitors is
leading to a failure of antiretroviral therapy.1 Hence, there is
a constant need of novel HIV-1 inhibitors to combat the disease.
In the quest of discovering novel HIV-1 protease inhibitors, Lam
and co-workers reported the potent urea-based cyclic compounds
with four side-chains.2 With an aim of introducing further struc-
tural diversity and improving potency, we modified the water
mimicking urea group in Lam’s compounds to a sulfamide group.3
This enabled us to develop a series of moderately active (Ki values of
Ki (nM)
R
1 = R2
O
N
O
N
A
S
530
O
R2
R1
O
HO
OH
N
H
B
20
R1
=
O
0.53e9.7 mM) symmetric cyclic sulfamide based HIV-1 protease
C
inhibitors with biaryl side-chains designed to span from P2/P20 to
N
H
140
P1/P10 (Fig. 1, A).4 Furthermore, di-ortho-extension using a flexible
R2 = H
* Corresponding author. Tel.: þ46 18 471 4667; fax: þ46 18 471 4474; e-mail
Figure 1. Symmetric and non-symmetric cyclic sulfamide based HIV-1 protease
inhibitors.
address: mats.larhed@orgfarm.uu.se (M. Larhed).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.023

4050
A. Ax et al. / Tetrahedron 66 (2010) 4049e4056
cyclic N-benzylsulfamide based HIV-1 protease inhibitors. To en-
able smooth compound production, a selective and fast route to
three N-monobenzylated sulfamide key intermediates would be
highly beneficial.
Controlled microwave (MW) heating using sequential single-
mode reactors has had a profound impact on drug discovery
chemistry.6e8 Controlled MW radiation has proven to be a powerful
tool for both speeding up chemical optimizations and for efficient
preparation of new target compounds, enabling facile synthesis of
small chemical libraries. Raising the reaction temperature well
above that applied in conventional heating of a specific reaction
may, however, lead to reduced selectivity between competing
reaction routes.9e11
We herein report the use of a microwave-promoted silver(I)
oxide mediated mono N-benzylation procedure as a key step for
preparation of three seven-membered N-monobenzylated sulfa-
mide core structures 2aec from the parent structure 1. Based on
this synthetic methodology, a small library of 11 non-symmetric
novel cyclic HIV-1 protease inhibitors (3aek) were synthesized and
evaluated.
to deliver 3a and 3b in 83% and 71% yields, respectively. In-
termediate 2b was reacted with 2-phenethylbenzyl bromide and
the product was deprotected using HCl/ether (2 M) to afford 3c in
33% yield. The non-symmetrically alkylated sulfonamide 4a was
prepared by alkylating 2a with 2-bromobenzyl bromide using po-
tassium carbonate in DMF in 73% yield. Intermediate 4a was ortho-
substituted with styrene using a microwave-promoted palladium
(0)-catalyzed Heck reaction13 followed by deprotection to generate
3d in 45% yield. Compound 2c was N-benzylated in the same
fashion as 2a to give dialkylated 4b and 4c in 74% and 73% yields,
respectively (Scheme 2).
The bromo derivatives 4b and 4c were subjected to microwave
mediated Heck couplings13 with styrene (150 ꢀC, 20 min), followed
by deprotection (2 M HCl/ether) to afford compounds 3e and 3f in
14% and 54% isolated yields, respectively. Compound 2d was pro-
duced in 85% yield from 2c via a Negishi-coupling14 with benzyl-
zinc bromide (oil bath, 80 ꢀC, 64 h). Intermediate 2d served as the
precursor for the synthesis of 3g, 3h and 3i, which were obtained
via benzylation with the corresponding alkylating agent and sub-
sequent deprotection to afford the final inhibitors in 49%, 72% and
26% yields, respectively (Scheme 2). Inhibitor 3j was prepared in
20% yield from 2d, through an alkylation with 2-bromobenzyl
2. Results and discussion
bromide followed by
a
microwave-assisted Heck cou-
plingedeprotection sequence.
The seven-membered cyclic scaffold 1, prepared as previously
reported,4 served as the starting point for the synthesis of com-
pounds 3aek, as depicted in Schemes 1 and 2. The alkylating
reactant 2-phenethylbenzyl bromide was synthesized from 2-
phenethylbenzyl alcohol using phosphorus tribromide.12 Selective
mono N-alkylations of 1 to afford compounds 2a,5 2b and 2c were
performed using 1.5 equiv of silver(I) oxide and either benzyl
bromide, 2-phenylbenzyl bromide or 2-bromobenzyl bromide
(Scheme 1).
HIV-1 protease inhibitor 3k was synthesized by alkylating 2c
with N-[2-(bromomethyl)phenyl]-2-(naphthalen-1-yl)acetamide 8
(44% yield) followed by deprotection with 2 M HCl/ether in MeOH
(64% yield, Scheme 3).
Building block 8 was prepared by coupling 6 (obtained by TBS
protection of 2-aminobenzyl alcohol 5 in 91% isolated yield)15 with
1-naphthaleneacetic acid in presence of EDCI, HOBt and N-meth-
ylmorpholine to provide amide 7 (83%), which was then depro-
i. K2CO3, DMF
for
3a
Ag2O, DCM
for
: 2-phenylbenzyl
2a
: benzyl bromide
bromide
2b
: 2-phenylbenzyl
3b, 3c: 2-phenethylbenzyl
bromide
bromide
O
N
O
N
O
HN
O
NH
O
N
O
NH
S
2c: 2-bromobenzyl
S
S
80 ºC, 2 h
bromide
R2
R1
ii. HCl/ether (2 M) in MeOH
rt, 2 h
R
MW, 100 ºC, 1 h
O
O
O
O
HO
OH
3a R1: H R2: Ph
83%
1
2a R: H 70%
3b R1: H R2: CH2CH2Ph 71%
2b
R: Ph 88%
2c R: Br 85%
1
2
3c
R : Ph R : CH2CH2Ph 33%
i. styrene, Pd(OAc)2
PPh3, DIEA, DMF/
H2O (5:1)
O
N
O
N
O
N
O
N
K2CO3, DMF
2-bromobenzyl
bromide
S
S
MW, 150 ºC, 20 min
2a
Br
80 ºC, 2 h
73%
ii. HCl/ether (2 M)
in MeOH, rt, 2 h
O
O
HO
OH
45%
4a
3d
Scheme 1. Synthesis of HIV-1 protease inhibitors 3aed.
The reactions were heated by single-mode microwave irradia-
tion in a sealed vessel to 100 ꢀC for 1 h, yielding a ratio of mono-/
dibenzylation of >95:5. Monofunctionalized 2a was thereafter
alkylated with either 2-phenylbenzyl bromide or 2-pheneth-
ylbenzyl bromide using potassium carbonate in DMF, and the
resulting products were directly deprotected using HCl/ether (2 M)
tected and brominated in a one-pot fashion using phosphorous
tribromide (yield: 60%). Buchwald amidation reaction using Pd
(OAc)2, Xantphos and caesium carbonate in THF to further decorate
inhibitor 3k did not succeed.16,17 Moreover, Buchwald amidation
using the aforementioned conditions proved to be unsuccessful on
the protected intermediate 9 as well. Interestingly, the reaction

A. Ax et al. / Tetrahedron 66 (2010) 4049e4056
4051
i. styrene, Pd(OAc)2
PPh3, DIEA, DMF/
O
N
O
N
O
N
O
N
H2O (5:1)
S
S
MW, 150 ºC
20 min
R
Br
80 ºC, 2 h
R
K2CO3, DMF
for
ii. HCl/ether (2 M)
in MeOH
rt, 2 h
O
O
HO
OH
4b
: 2-phenylbenzyl
bromide
4c
: 2-phenethylbenzyl
4b R: Ph
74%
3e R: Ph
14%
bromide
4c R: CH2CH2Ph 73%
3f R: CH2CH2Ph 54%
i. K2CO3, DMF
2c
for
3g: benzyl bromide
3h: 2-phenylbenzyl
bromide
O
N
O
N
Benzylzinc bromide
PdCl2, DPPF, THF
80 ºC, 64 h
85%
O
N
O
3i: 2-phenethylbenzyl
bromide
S
S
NH
80 ºC, 2 h
R
ii. HCl/ether (2 M)
in MeOH
HO
OH
O
O
rt, 2 h
3g
R: H
49%
72%
2d
3h
R: Ph
3i R: CH2CH2Ph 26%
i. K2CO3, DMF
2-bromobenzyl bromide
80 ºC, 2 h
ii. styrene, Pd(OAc)2, PPh3
DIEA, DMF/H2O (5:1)
MW, 150 ºC, 20 min
iii. HCl/ether (2 M) in MeOH
rt, 2 h
O
N
O
N
S
HO
OH
20%
3j
Scheme 2. Synthesis of HIV-1 protease inhibitors 3eej.
1-naphthalene
acetic acid, EDCI
O
OH
OTBS
HOBt, N-methyl
morpholine
CH2Cl2
N
H
NaH, THF
TBDMSCl
H2N
H2N
OTBS
0 ºC - rt, 2 h
91%
0 ºC - rt, 15 h
83%
7
6
5
O
O
N
O
N
2c
, K2CO3
S
N
H
DMF
PBr3, CH2Cl2
HN
80 ºC, 15 h
44%
Br
0 ºC - rt, 30 min
60%
Br
O
O
O
9
8
O
N
O
N
S
HCl/ether
(2 M), MeOH
HN
Br
0 ºC - rt, 2 h
64%
HO
OH
O
3k
Scheme 3. Synthesis of HIV-1 protease inhibitor 3k.

4052
A. Ax et al. / Tetrahedron 66 (2010) 4049e4056
Table 1 (continued)
Table 1
Inhibitory potency of non-symmetric cyclic sulfamide based HIV-1 protease
inhibitors 3aek
Inhibitor
R1
R2
Ki (mM)
O
N
O
N
S
R1
R2
3i
7.5
HO
OH
Inhibitor
R1
R2
Ki (mM)
H
3a
>20
3j
1.8
H
Br
3b
3c
3d
>20
3k
0.28
O
NH
Saquinavir
d
d
0.000218
worked very well with full conversion when the same set of con-
ditions was applied to model substrates (indole-3-acetamide and
2-bromotoluene). We speculate that the reason the amidation re-
action failed in the case of 3k and 9 might be attributable to trap-
ping of the palladium catalyst by the substrate. The fact that the
starting materials (3k and 9) were recovered in more than 80% yield
after the reaction supports this theory. The inhibitory activities of
compounds 3aek and the approved inhibitor Saquinavir18 are
summarized in Table 1.
9.3
H
>20
The four mono-substituted compounds (3a, 3b, 3d, 3g) and
compound 3f were found to be inactive (Ki >20
compounds showed moderate inhibitory activity with Ki values
between 1.8 M and 9.3 M, except for the three atom ortho-
elongated aryl bromide 3k, which gave a Ki value of 0.28 M. The
mM). The remaining
m
m
m
best of the P2/P20 group ortho substituent appeared to be the
naphthyl acetamide group, as in 3k. Taken together, all the non-
symmetric compounds, except 3j and 3k, were less potent than the
previously published symmetrically substituted compounds.4 This
indicated that incorporating non-symmetry around the cyclic sul-
famide core 1 was not always beneficial for improving activity.
However, careful selection of substituents to impart non-symmetry
was equally important.
3e
4.9
The mono N-benzylation of 1 was the key transformation to
provide non-symmetric inhibitors 3aek (Scheme 1). The mono-/
dibenzylation quotient was remarkably improved by addition of
silver(I) oxide to the reaction mixture, yielding an impressive ratio
of >95:5. Successful application of this reaction in the preparation
of 2b and 2c suggests a more general scope of the methodology.
Most likely, coordination of silver(I) to the sulfamide functionality
of 1 results in the high chemoselectivity. Unfortunately, the selec-
tive mono N-benzylation reaction did not work with cyclic ureas
because of competing O-benzylation (unpublished findings). In-
terestingly, silver(I) oxide has also been successfully applied for the
selective monoprotection of symmetric diols.19
3f
>20
>20
H
3g
3. Conclusion
3h
6.3
In summary, a series of non-symmetric cyclic sulfamide HIV-1
protease inhibitors with elongated ortho-P2/P20 substituents were

A. Ax et al. / Tetrahedron 66 (2010) 4049e4056
4053
synthesized by employing a selective microwave-assisted and sil-
ver mediated N-monobenzylation reaction and different palladium
(0)-catalyzed coupling reactions. The ratio between mono- and
dibenzylation in the selective N-alkylation was >95:5 after 100 ꢀC
microwave heating for 1 h. Out of 11 inhibitors, the most potent
(d, J¼14.7 Hz, 1H), 7.27 (m, 1H), 7.31 (m, 1H), 7.34e7.48 (m, 6H), 7.53
(m, 1H); 13C NMR (100 MHz, CDCl3):
26.8, 26.9, 43.6, 47.4, 51.3,
77.4, 77.9, 109.5, 127.4, 127.9, 128.1, 128.4, 129.3, 129.4, 130.4, 132.9,
140.7, 142.0. Anal. Calcd for C20H24N2O4S: C, 61.84; H, 6.23; N, 7.21.
Found: C, 62.02; H, 6.3; N, 7.33.
d
compound (3k) possessed a Ki value of 0.28
mM.
4.3.3. 3,4,5,6-Tetrahydro-(4S,5S)-2-(2-bromobenzyl)- 4,5-O-isoprop-
ylidene-1,2,7-thiadiazepine 1,1-dioxide (2c). Column chromatogra-
phy was performed in ethyl acetate/iso-hexane 3:7. Yield 75 mg
(85%) as a white solid; mp 138e140 ꢀC; 1H NMR (400 MHz, CDCl3):
4. Experimental
4.1. General information
d
1.36 (m, 3H), 1.37 (m, 3H), 3.08 (ddd, J¼7.0, 9.5, 12.8 Hz, 1H), 3.15
The microwave reactions were performed in an Emrys Synthe-
sizer single-mode cavity producing controlled irradiation at
2450 MHz. The reaction temperature and pressure were de-
termined using the built-in on-line sensors. Fourier transform in-
frared spectroscopy was performed by Varian 1000 FT-IR (Scimitar
Series) apparatus. 1H and 13C NMR spectra were recorded at 399.8
and 100.6 MHz, respectively. Chemical shifts are reported as
(ddd, J¼0.6, 9.4,13.6 Hz,1H), 3.50 (dd, J¼4.2,13.6 Hz,1H), 3.59 (ddd,
J¼3.9, 4.7, 12.8 Hz, 1H), 4.22e4.32 (m, 2H), 4.46 (d, J¼16.0 Hz, 1H),
4.51 (d, J¼16.0 Hz, 1H), 6.72 (br m, 1H), 7.26 (ddd, J¼1.7, 7.4, 8.0 Hz,
1H), 7.44 (ddd, J¼1.2, 7.4, 7.8 Hz, 1H), 7.56 (dd, J¼1.7, 7.8 Hz, 1H),
7.62 (dd, J¼1.2, 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 26.5, 26.6,
43.5, 49.4, 54.0, 77.8, 78.7, 109.2, 128.2, 128.3, 129.6, 130.0, 132.9,
136.5. Anal. Calcd for C14H19BrN2O4S: C, 42.98; H, 4.89; N, 7.16.
Found: C, 43.30; H, 5.04; N, 7.19.
d
values (ppm) indirectly referred to TMS by the solvent or the
solvent residual signal. Elemental analyses were performed by
Analytische Laboratorium Lindlar, Germany and were within ꢁ0.4%
of calculated values. Melting points were determined using Elec-
trothermal melting point apparatus. All column chromatography
purifications were performed with silica gel 60. Analytical RP-LC/
MS was performed on a Gilson HPLC system with a Chromolith
Performance RP-18e, 4.6ꢂ100 mm column, with an electrospray
ionization quadropole mass spectrometer at a flow rate of 4 mL/
min (H2O/CH3CN/0.05% HCOOH). A metal block was used for con-
ventional heating.
4.4. 3,4,5,6-Tetrahydro-(4S,5S)-4,5-O-isopropylidene-2-(2-
phenylmethyl)benzyl-1,2,7-thiadiazepine 1,1-dioxide (2d)
In an oven-dried vial were placed 2c (89 mg, 0.227 mmol), pal-
ladium chloride (2.8 mg, 0.0159 mmol), DPPF (3.8 mg, 6.81 mmol)
and THF (2 mL), which was capped and then flushed with nitrogen
gas. After a few minutes, benzylzinc bromide (2.27 mL, 1.133 mmol)
was added to the reaction mixture and the vial was heated to 80 ꢀC
for 64 h. The reaction mixture was filtered through Celite and con-
centrated in vacuo. The crude product was purified by column
chromatography (ethyl acetate/iso-hexane 3:7) to yield 78 mg (85%)
4.2. HIV-1 protease inhibition
as a white solid; mp 50e52 ꢀC; 1H NMR (400 MHz, CDCl3):
d 1.26 (s,
HIV-1 protease was cloned and heterologously expressed in
Escherichia coli and purified as described previously.20 The Ki values
for the synthesized compounds were determined using a fluoro-
metric assay.20 In all assays, Saquinavir was used as a reference
3H),1.29 (s, 3H), 2.78 (m, 2H), 3.16 (dd, J¼4.2,13.4 Hz,1H), 3.45 (ddd,
J¼3.9, 5.4,12.5 Hz,1H), 3.72 (dm, J¼3.9 Hz,1H), 3.98 (m,1H), 4.01 (d,
J¼16.0 Hz, 1H), 4.07 (s, 1H), 4.08 (d, J¼16.0 Hz, 1H), 4.20 (d,
J¼14.0 Hz, 1H), 4.29 (d, J¼14.0 Hz, 1H), 7.03 (m, 2H), 7.13 (m, 2H),
compound (Ki¼0.0002
m
M).18
7.18e7.31 (m, 5H); 13C NMR (100 MHz, CDCl3):
d 26.8, 26.9, 38.3,
43.4, 47.4, 51.9, 76.9, 78.1,109.6,126.1,127.0,128.4,128.5,130.4,131.7,
133.5, 139.1, 140.9. Anal. Calcd for C21H26N2O4S: C, 62.66; H, 6.51; N,
6.96. Found: C, 62.91; H, 6.61; N, 7.00.
4.3. General procedure for selective mono alkylation
Cyclic sulfamide scaffold 1 (0.225 mmol, 1 equiv), silver(I) oxide
(78.2 mg, 0.337 mmol, 1.5 equiv) and benzyl bromide (41
m
L,
4.5. General procedure for standard benzylation and
subsequent deprotection
0.225 mmol, 1 equiv) were added to a 2.0e5.0 mL microwave re-
action vial and dissolved in 3 mL of dichloromethane. The reaction
mixture was heated to 100 ꢀC for 1 h using microwave irradiation.
The reaction mixture was filtered using a centrifuge tube equipped
with a filter and concentrated in vacuo. The crude product was
purified by column chromatography. The selectivity for mono-/
dibenzylation was >95:5 according to RP-LC/MS and 1H NMR.
The sulfamide precursor (0.101 mmol, 1 equiv), substituted
benzyl bromide (26.4 mg, 0.106 mmol, 1.05 equiv) and K2CO3
(141 mg, 1.01 mmol, 10 equiv) were added to a reaction vial and
dissolved in 3 mL of DMF. Thereafter, the vial was capped and the
reaction mixture was heated to 80 ꢀC for 2 h. The reaction mixture
was concentrated in vacuo, using toluene as a co-solvent. The res-
idue was filtered through a short silica column using ethyl acetate
and concentrated under reduced pressure. The resulting crude
dialkylated product was dissolved in 5 mL of methanol and 1.5 mL
of 2 M HCl/ether was added. The reaction mixture was stirred at
room temperature for 2 h. After concentration in vacuo the crude
product was purified by column chromatography.
4.3.1. 3,4,5,6-Tetrahydro-(4S,5S)-2-benzyl-4,5-O-isopropylidene-
1,2,7-thiadiazepine 1,1-dioxide (2a). Column chromatography was
performed in ethyl acetate/iso-hexane 3:7. Yield 49 mg(70%) as a pale
colouredoil;1HNMR(400 MHz,CDCl3):
d1.37(s,3H),1.40(s, 3H), 3.07
(m, 2H), 3.47(dd,J¼13.6, 4.3 Hz,1H), 3.59(ddd, J¼3.9,4.7,12.5 Hz,1H),
4.14 (m, 2H), 4.28 (d, J¼14.5 Hz, 1H), 4.40 (d, J¼14.5 Hz, 1H), 4.69 (s,
1H), 7.38 (m, 4H); 13C NMR (100 MHz, CDCl3):
d 26.9, 43.6, 48.1, 54.3,
77.4, 78.1,109.6,128.1,128.3,128.8,135.7. Anal. Calcd for C14H20N2O4S:
C, 53.83; H, 6.45; N, 8.97. Found: C, 54.12; H, 6.36; N, 9.11.
4.5.1. 3,4,5,6-Tetrahydro-(4S,5S)-2-benzyl-4,5-dihydroxy-7-[(2-phe-
nyl)benzyl]-1,2,7-thiadiazepine 1,1-dioxide (3a). Column chroma-
tography was performed in methanol/dichloromethane 1:99. Yield
75 mg(83%) asa palecoloured oil; 1H NMR (400 MHz, acetone-d6 and
4.3.2. 3,4,5,6-Tetrahydro-(4S,5S)-2-[(2-phenyl)benzyl]-4,5-O-iso-
propylidene-1,2,7-thiadiazepine 1,1-dioxide (2b). Column chroma-
tography was performed in ethyl acetate/iso-hexane 2:8. Yield
77 mg (88%) as a pale coloured oil; 1H NMR (400 MHz, CDCl3):
D2O):
d
2.94 (dd, J¼3.1, 14.8 Hz, 1H), 3.03 (dd, J¼3.4,15.2 Hz, 1H), 3.18
(ddd, J¼1.1, 10.0, 15.2 Hz, 1H), 3.28 (ddd, J¼1.1, 10.0, 14.8 Hz, 1H), 3.35
(m, 1H), 3.50 (m, 1H), 4.42 (d, J¼3.04 Hz, 1H), 4.47 (d, J¼3.04 Hz, 1H),
4.62 (d, J¼7.50 Hz, 1H), 4.67 (d, J¼7.50 Hz, 1H), 7.18e7.48 (m, 13H),
d
1.29 (s, 3H), 1.32 (s, 3H), 2.88 (m, 2H), 3.26 (dd, J¼4.3, 13.4 Hz, 1H),
3.43 (m, 1H), 3.88 (m, 2H), 4.02 (m, 1H), 4.24 (d, J¼14.7 Hz, 1H), 4.51
7.64 (d, J¼0.8, 7.7 Hz, 1H); 13C NMR (100 MHz, acetone-d6):
d 48.3,

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A. Ax et al. / Tetrahedron 66 (2010) 4049e4056
48.6, 50.5, 52.8, 72.5, 72.7, 127.8, 128.1, 128.4, 128.5, 128.9, 129.1, 129.7,
130.5, 135.2, 138.2, 141.2, 142.4. Anal. Calcd for C24H26N2O4S: C, 65.73;
H, 5.98; N, 6.39. Found: C, 65.94; H, 6.14; N, 6.47.
(dd, J¼9.0, 12.6 Hz, 1H), 3.34 (dd, J¼4.1, 13.2 Hz, 1H), 3.58 (dd, J¼5.0,
12.6 Hz, 1H), 4.19e4.34 (m, 4H), 4.49 (d, J¼15.3 Hz, 1H), 4.62 (d,
J¼15.3 Hz,1H), 7.14e7.38 (m,11H), 7.54 (m, 2H); 13C NMR (100 MHz,
CDCl3):
d 26.8, 26.9, 34.2, 37.6, 47.6, 49.2, 51.7, 55.1, 76.7, 76.9, 77.9,
4.5.2. 3,4,5,6-Tetrahydro-(4S,5S)-2-benzyl-4,5-dihydroxy-7-[(2-
phenethyl)benzyl]-1,2,7-thiadiazepine 1,1-dioxide (3b). Column
chromatography was performed in methanol/dichloromethane
2:98. Yield 23.5 mg (71%) as a pale coloured oil; 1H NMR (400 MHz,
109.8,123.5,126.0,126.5,127.9,128.3,128.6,129.4,129.7,130.1,130.2,
132.9, 133.0, 135.3, 140.8, 141.3. Anal. Calcd for C29H33BrN2O4S: C,
59.49; H, 5.68; N, 4.78. Found: C, 59.32; H, 5.84; N, 4.84.
acetone-d6):
d
2.84e3.08 (m, 8H), 3.14 (m, 2H), 3.32 (m, 2H), 3.63
4.5.7. 3,4,5,6-Tetrahydro-(4S,5S)-2-benzyl-4,5-dihydroxy-7-[(2-phen-
ylmethyl)benzyl]-1,2,7-thiadiazepine 1,1-dioxide (3g). Column chro-
matography was performed in methanol/dichloromethane 2:98.
(m, 2H), 4.55 (d, J¼16.1 Hz, 2H), 4.59 (d, J¼16.1 Hz, 2H), 4.70 (d,
J¼15.3 Hz, 2H), 4.72 (d, J¼15.3 Hz, 2H), 7.18e7.20 (m, 1H), 7.25e7.31
(m, 8H), 7.34e7.41 (m, 2H), 7.45e7.47 (m, 3H); 13C NMR (100 MHz,
1
Yield 18.3 mg (49%) as a pale coloured oil; H NMR (400 MHz, ace-
acetone-d6):
d
35.0, 38.1, 48.5, 48.8, 50.5, 53.2, 73.0, 73.2, 126.7,
tone-d6):
d
3.09 (dd, J¼3.1, 14.9 Hz, 1H), 3.15 (dd, J¼3.3, 15.1 Hz, 1H),
127.2, 128.3, 128.6, 128.9, 129.1, 129.4, 129.7, 130.7, 135.5, 138.5,
141.3, 142.6. Anal. Calcd for C26H30N2O4S: C, 66.93; H, 6.48; N, 6.00.
Found: C, 67.21; H, 6.36; N, 6.06.
3.30 (dd, J¼3.1, 9.5 Hz, 1H), 3.34 (dd, J¼3.3, 9.7 Hz, 1H), 3.54 (m, 1H),
3.62 (m, 1H), 4.16 (m, 3H), 4.25 (d, J¼4.6 Hz, 1H), 4.53 (d, J¼16.0 Hz,
1H), 4.58 (d, J¼15.5 Hz,1H), 4.68 (d, J¼15.5 Hz,1H), 4.69 (d, J¼16.0 Hz,
1H), 7.20 (m, 4H), 7.30 (m, 5H), 7.38 (m, 2H), 7.44 (m, 2H), 7.54 (m,1H);
4.5.3. 3,4,5,6-Tetrahydro-(4S,5S)-4,5-dihydroxy-2-[(2-phenyl)benzyl]-
7-[(2-phenethyl)benzyl]-1,2,7-thiadiazepine 1,1-dioxide (3c). Column
chromatography was performed in methanol/dichloromethane 2:98.
Yield 33.4 mg (33%) as a white solid; mp 44e46 ꢀC; 1H NMR
13C NMR (100 MHz, acetone-d6):
d 38.7, 48.6, 48.7, 50.6, 53.2, 73.0,
73.2, 126.9, 127.5, 128.4, 128.6, 128.9, 129.3, 129.4, 129.6, 129.8, 131.5,
135.9, 138.5, 140.3, 141.4. Anal. Calcd for C25H28N2O4S: C, 66.35; H,
6.24; N, 6.19. Found: C, 66.13; H, 6.20; N, 6.13.
(400 MHz, acetone-d6):
d
2.84e3.10 (m, 6H), 3.23 (dd, J¼9.5, 14.9 Hz,
1H), 3.29 (dd, J¼9.8, 15.1 Hz, 1H), 3.44 (m, 1H), 3.55 (m, 1H), 4.20 (d,
J¼3.7 Hz, 1H), 4.24 (d, J¼4.4 Hz, 1H), 4.52 (d, J¼16.4 Hz, 1H), 4.58 (d,
J¼15.7 Hz, 1H), 4.70 (d, J¼15.7 Hz, 1H), 4.72 (d, J¼16.4 Hz, 1H),
7.18e7.30 (m, 9H), 7.34e7.42 (m, 4H), 7.43e7.50 (m, 4H), 7.71 (m,
4.5.8. 3,4,5,6-Tetrahydro-(4S,5S)-4,5-dihydroxy-2-[(2-phenyl)ben-
zyl]-7-[(2-phenylmethyl)benzyl]-1,2,7-thiadiazepane
1,1-dioxide
(3h). Column chromatography was performed in methanol/
dichloromethane 2:98. Yield 15.2 mg (72%) as a pale coloured oil;
1H); 13C NMR (100 MHz, acetone-d6):
d
35.0, 38.0, 48.3, 49.0, 50.4,
1H NMR (400 MHz, acetone-d6):
d 3.0 (m, 2H), 3.24 (m, 2H), 3.43 (m,
51.0, 72.9, 73.0, 126.7, 127.1, 128.1, 128.5, 128.6, 128.7, 129.1, 129.2,
129.4, 129.7, 130.0, 130.7, 130.8, 135.4, 135.5, 141.2, 141.5, 142.6, 142.7.
Anal. Calcd for C32H34N2O4S: C, 70.82; H, 6.31; N, 5.16. Found: C,
70.59; H, 6.48; N, 5.28.
2H), 4.14 (s, 2H), 4.59 (d, J¼16.6 Hz,1H), 4.54 (d, J¼15.8 Hz,1H), 4.64
(d, J¼15.8 Hz, 1H), 4.70 (d, J¼16.6 Hz, 1H), 7.14e7.32 (m, 9H),
7.33e7.51 (m, 8H), 7.78 (m, 1H); 13C NMR (100 MHz, acetone-d6):
d
38.0, 47.7, 48.3, 49.9, 50.3, 72.1, 72.2, 126.2, 126.9, 127.4, 127.5,
127.9, 128.0, 128.1, 128.6, 129.0, 129.1, 129.3, 130.2, 130.8, 134.8,
135.2, 139.7, 140.7, 140.9, 142.1. Anal. Calcd for C31H32N2O4S: C,
70.43; H, 6.10; N, 5.30. Found: C, 70.69; H, 6.23; N, 5.42.
4.5.4. 3,4,5,6-Tetrahydro-(4S,5S)-2-benzyl-7-[(2-bromo)benzyl]-4,5-
O-isopropylidene-1,2,7-thiadiazepine
1,1-dioxide
(4a). Column
chromatography was performed in ethyl acetate/iso-hexane 3:7.
Yield 35.7 mg (73%) as a pale coloured oil; 1H NMR (400 MHz,
4.5.9. 3,4,5,6-Tetrahydro-(4S,5S)-4,5-dihydroxy-2-[(2-phenethyl)-
benzyl]-7-(2-phenylmethyl)]benzyl-1,2,7-thiadiazepane 1,1-dioxide
(3i). Column chromatography was performed in methanol/
dichloromethane 2:98. Yield 7.2 mg (26%) as a pale coloured oil; 1H
CDCl3):
d
1.26 (s, 3H), 1.27 (s, 3H), 3.02 (dd, J¼9.2, 12.8 Hz, 1H), 3.11
(dd, J¼9.1, 12.9 Hz, 1H), 3.46 (dd, J¼4.5, 12.8 Hz, 1H), 3.50 (dd, J¼4.5,
12.9 Hz, 1H), 4.24 (m, 2H), 4.36 (d, J¼14.7 Hz, 1H), 4.49 (d,
J¼14.68 Hz, 1H), 4.50 (d, J¼15.32 Hz, 1H), 4.59 (d, J¼15.32 Hz, 1H),
7.18 (m, 1H), 7.29e7.39 (m, 6H), 7.54 (dd, J¼1.7, 7.7 Hz, 1H) 7.57 (dd,
NMR (400 MHz, acetone-d6):
d 2.8e3.0 (m, 2H), 3.05 (m, 2H), 3.12
(m, 2H), 3.33 (m, 2H), 3.62 (m, 2H), 4.17 (s, 2H), 4.24 (d, J¼4.3 Hz,1H),
4.31 (d, J¼4.3 Hz,1H), 4.59 (d, J¼15.6 Hz,1H), 4.60 (d, J¼15.6 Hz,1H),
4.69 (d, J¼15.6 Hz, 1H), 4.47 (d, J¼15.6 Hz, 1H), 7.16e7.33 (m, 16H),
J¼1.3, 7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 26.9 (corresponds
to both methyl groups according to HSQC), 48.3, 49.0, 54.5, 55.2,
77.4, 77.6, 109.8, 123.5, 127.9, 128.1 128.4, 128.8, 129.4, 130.1, 132.9,
135.2, 135.9. Anal. Calcd for C21H25BrN2O4S: C, 52.39; H, 5.23; N,
5.82. Found: C, 52.52; H, 5.42; N, 5.79.
7.48 (m, 1H), 7.54 (m, 1H); 13C NMR (100 MHz, acetone-d6):
d 35.0,
38.1, 38.7, 48.5, 48.6, 50.6, 50.7, 73.1, 73.2, 126.7, 126.9, 127.2, 127.5,
128.6,129.1,129.3,129.5,129.6,129.7,129.8,130.7,131.5,135.4,135.9,
140.4, 141.3, 141.4, 142.6. Anal. Calcd for C33H36N2O4S: C, 71.20; H,
6.52; N, 5.03. Found: C, 71.44; H, 6.54; N, 5.16.
4.5.5. 3,4,5,6-Tetrahydro-(4S,5S)-2-[(2-bromo)benzyl]-4,5-O-iso-
propylidene-2-(2-phenyl)benzyl-1,2,7-thiadiazepine 1,1-dioxide (4b).
Column chromatography was performed in ethyl acetate/iso-hex-
ane 3:7. Yield 35 mg (74%) as a pale coloured oil; 1H NMR (400 MHz,
4.6. General procedure for Heck coupling and subsequent
deprotection
CDCl3):
d
1.26 (s, 3H), 1.29 (s, 3H), 2.78 (m, 1H), 3.16 (dd, J¼4.2,
13.4 Hz, 1H), 3.45 (ddd, J¼3.9, 5.4, 12.5 Hz, 1H), 3.72 (dm, J¼3.9 Hz,
1H), 3.98 (m, 1H), 4.01 (d, J¼16.0 Hz, 1H), 4.07 (s, 1H), 4.08 (d,
J¼16.0 Hz, 1H), 4.20 (d, J¼14.0 Hz, 1H), 4.29 (d, J¼14.0 Hz, 1H), 7.03
(m, 4H), 7.13 (m, 4H), 7.18e7.31 (m, 5H); 13C NMR (100 MHz, CDCl3):
The sulfamide precursor (0.067 mmol, 1 equiv), styrene (76.9
0.671 mmol, 10 equiv), Pd(OAc)2 (1.5 mg, 6.71
PPh3 (5.3 mg, 0.020 mmol, 0.3 equiv) and DIEA (71.9
m
L,
m
mol, 0.1 equiv),
mL,
0.403 mmol, 6 equiv) were added to a 0.5e2.0 mL microwave re-
action vial and dissolved in 1 mL of DMF and 200 L of water. The
d
26.8, 26.9, 38.3, 43.4, 47.4, 51.9, 76.9, 78.1, 109.6, 126.1, 127.4, 127.7,
m
127.8, 127.9, 128.4, 128.8, 129.2, 129.4, 130.1, 130.2, 132.9, 133.5,
139.1, 140.9. Anal. Calcd for C27H29BrN2O4S: C, 58.17; H, 5.24; N,
5.02. Found: C, 58.37; H, 5.32; N, 5.14.
reaction mixture was heated to 150 ꢀC for 20 min using microwave
irradiation. The reaction mixture was filtered to remove palladium
black and concentrated in vacuo, using toluene as a co-solvent. The
crude product was filtered through a short silica column before
proceeding with the deprotection.
4.5.6. 3,4,5,6-Tetrahydro-(4S,5S)-2-[(2-bromo)benzyl]-7-[(2-phen-
ethyl)benzyl]-4,5-O-isopropylidene-1,2,7-thiadiazepine
1,1-dioxide
(4c). Column chromatography was performed in ethyl acetate/iso-
4.6.1. 3,4,5,6-Tetrahydro-(4S,5S)-2-benzyl-4,5-dihydroxy-7-[(2-
styryl)benzyl]-1,2,7-thiadiazepine 1,1-dioxide (3d). Column chro-
matography was performed in methanol/dichloromethane 2:98.
hexane 3:7. Yield 33.6 mg (73%) as a pale coloured oil; 1H NMR
(400 MHz, CDCl3): d 1.37 (s, 3H),1.40 (s, 3H), 2.85e3.03 (m, 5H), 3.07

A. Ax et al. / Tetrahedron 66 (2010) 4049e4056
4055
Yield 13.9 mg (45%) as a pale coloured oil; 1H NMR (400 MHz, ac-
etone-d6):
NMR (400 MHz, CDCl3):
d
0.00 (s, 6H), 0.83 (s, 9H), 4.07 (br s, 2H),
d
3.01 (dd, J¼3.78, 15.0 Hz, 1H), 3.12 (m, 1H), 3.29e3.42
4.61 (s, 2H), 6.57e6.64 (m, 2H), 6.94e7.04 (m, 2H); 13C NMR
(m, 3H), 3.56 (m, 1H), 4.17 (m, 2H), 4.50 (d, J¼16.0 Hz, 1H), 4.60 (d,
J¼15.0 Hz, 1H), 4.74 (d, J¼16.0 Hz, 1H), 4.92 (d, J¼15.0 Hz, 1H), 7.21
(d, J¼16.4 Hz,1H), 7.23e7.53 (m,11H), 7.72 (d, J¼8.2 Hz, 2H), 7.80 (d,
J¼16.4 Hz, 1H), 7.83 (d, J¼7.7 Hz, 1H); 13C NMR (100 MHz, acetone-
(100 MHz, CDCl3): d 0.0, 23.5, 31.1, 70.1, 120.9, 123.1, 130.5, 133.6,
133.9, 151.4; MS (ESI) m/z 238.2 (Mþ1)þ.
4.8. N-[2-{((tert-Butyldimethylsilyloxy)methyl)phenyl}]-
(naphthalen-1-yl)acetamide (7)
d6):
d
48.6, 48.7, 51.2, 52.9, 73.1, 73.3,126.0,126.5,127.8,128.4,128.5,
128.6, 128.7, 129.3, 129.4, 129.5, 131.2, 131.7, 134.9, 137.9, 138.4,
138.5. Anal. Calcd for C26H28N2O4S: C, 67.22; H, 6.07; N, 6.03. Found:
C, 67.08; H, 5.84; N, 6.15.
To a cooled (0 ꢀC) suspension of 1-naphthaleneacetic acid (3.5 g,
18.8 mmol), 6 (5.8 g, 24.4 mmol) and HOBt (2.9 g, 19.0 mmol) in
anhydrous DCM (50 mL) was added N-methylmorpholine (4.8 g,
47.4 mmol) and stirred for 30 min under nitrogen atmosphere. To
this was added EDCI (5 g, 26 mmol) at 0 ꢀC and the reaction mixture
was gradually warmed toroom temperature and stirred for 15 h. The
reaction mixture was successively washed with water (2ꢂ20 mL),
brine (2ꢂ20 mL) and the organic phase was dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash column
chromatography (EtOAc/iso-hexane 5:95 to 20:80) to yield the title
4.6.2. 3,4,5,6-Tetrahydro-(4S,5S)-4,5-dihydroxy-7-[(2-phenyl)ben-
zyl]-2-[(2-styryl)benzyl]-1,2,7-thiadiazepine 1,1-dioxide (3e). Col-
umn
dichloromethane 2:98. Yield 7.4 mg (14%) as a pale coloured oil; 1H
NMR (400 MHz, acetone-d6): 2.82 (m, 2H), 3.05 (m, 1H), 3.27 (m,
chromatography
was
performed
in
methanol/
d
4H), 4.10 (s, 2H), 4.43 (d, J¼16.50 Hz, 1H), 4.54 (d, J¼14.8 Hz, 1H),
4.74 (d, J¼16.5 Hz, 1H), 4.90 (d, J¼14.8 Hz, 1H), 7.18e7.50 (m, 13H),
7.68e7.85 (m, 5H); 13C NMR (100 MHz, acetone-d6):
d
47.9, 48.1,
compound (6 g, 83%) as a light yellow solid; mp 84e86 ꢀC; IR (film)
3048, 2873, 2853, 1649, 1588, 1539, 1456, 1392, 1347, 1289, 1253,
1112, 1070, 971, 937, 836, 671, 568, 530 cmꢃ1 1H NMR (400 MHz,
CDCl3): 0.00 (s, 6H), 0.87 (s, 9H), 4.31 (s, 2H), 4.35 (s, 2H), 7.11e7.15
n
50.0, 50.6, 72.2, 72.6, 125.4, 125.8, 127.2, 127.4, 127.5, 127.8, 127.9,
128.0, 128.5, 128.6, 128.8, 129.3, 130.2, 130.6, 131.0, 134.2, 134.7,
137.2, 137.8, 140.9, 142.1. Anal. Calcd for C32H32N2O4S$½H2O: C,
71.09; H, 5.97; N, 5.18. Found: 70.89; H, 6.13; N, 5.07.
;
d
(m, 2H), 7.36e7.41 (m, 1H), 7.56e7.67 (m, 4H), 7.94e8.02 (m, 2H),
8.22 (d, J¼8 Hz, 2H), 8.54 (br s,1H); 13C NMR (100 MHz, CDCl3):
d 0.0,
4.6.3. 3,4,5,6-Tetrahydro-(4S,5S)-4,5-dihydroxy-7-[(2-phenethyl)ben-
zyl]-2-[(2-styryl)benzyl]-1,2,7-thiadiazepine 1,1-dioxide (3f). Column
chromatography was performed in methanol/dichloromethane 2:98.
23.4, 31.0, 48.5, 69.5, 127.5, 129.1, 129.2, 130.9, 131.3, 131.9, 133.1,
133.4, 133.7, 133.8, 134.0, 135.2, 136.2, 137.4, 139.2, 142.3, 174. 6; MS
(ESI) m/z 406.4 (Mþ1)þ. HRMS calcd for m/z C25H31NO2SiþHþ:
406.2202, found: 406.2182. Anal. Calcd for C25H31NO2Si: C, 74.03; H,
7.70; N, 3.45. Found: C, 74.32; H, 7.91; N, 3.34.
1
Yield 13.4 mg (54%) as a pale coloured oil; H NMR (400 MHz, ace-
tone-d6): d 2.84e3.20 (m, 6H), 3.36 (m, 3H), 3.62 (m, 1H), 4.18 (s, 1H),
4.19 (s, 1H), 4.57 (d, J¼15.4 Hz, 1H), 4.61 (d, J¼14.6 Hz, 1H), 4.79 (d,
J¼15.4 Hz, 1H), 4.94 (d, J¼14.6 Hz, 1H), 7.16e7.55 (m, 13H), 7.72e7.86
4.9. N-[2-(Bromomethyl)phenyl]-2-(naphthalen-1-yl)-
acetamide (8)
(m, 5H); 13C NMR (100 MHz, acetone-d6):
d
34.4, 37.4, 47.8, 47.9, 49.8.
50.7, 72.3, 72.8, 125.4, 125.8, 126.1, 126.5, 127.2, 127.8, 127.9, 127.9,
128.4, 128.6, 128.8, 128.8, 128.9, 130.0, 130.6, 131.0, 134.2, 134.7, 137.3,
137.9 140.6, 142.0. Anal. Calcd for C34H36N2O4S: C, 71.80; H, 6.38; N,
4.93. Found: C, 71.59; H, 6.49; N, 4.68.
To a cooled (0 ꢀC) solution of 7 (5.8 g, 14.3 mmol) in anhydrous
DCM (20 mL) was added dropwise phosphorous tribromide (7.7 g,
28.6 mmol) under nitrogen atmosphere and stirred for 10 min. The
cooling source was removed and the reaction mixture was stirred at
room temperaturefor30 min. Thereactionmixturewascooledto0 ꢀC
and neutralized with saturated NaHCO3 solution. The reaction mix-
ture was successively washed with water (2ꢂ10 mL), brine (2ꢂ10 mL)
and the organic phase was dried over Na2SO4 and concentrated in
vacuo. The residue was triturated with iso-hexane (3ꢂ15 mL) and
dried under vacuum to yield the title compound as a light yellow solid
4.6.4. 3,4,5,6-Tetrahydro-(4S,5S)-4,5-dihydroxy-2-[(2-phenylmethyl)
benzyl]-7-[(2-styryl)-benzyl]-1,2,7-thiadiazepine 1,1-dioxide (3j). Col-
umn chromatography was performed in methanol/dichloromethane
1:99. Yield 11 mg (20%) as a pale coloured oil; 1H NMR (400 MHz,
acetone-d6):
d
2.94 (dd, J¼3.3,14.9 Hz,1H), 3.12 (m,1H), 3.28e3.42(m,
3H), 3.48 (m, 1H), 4.14 (m, 4H), 4.56 (d, J¼16.2 Hz, 1H), 4.59 (d,
J¼14.7 Hz, 1H), 4.71 (d, J¼16.2 Hz, 1H), 4.91 (d, J¼14.7 Hz, 1H),
7.15e7.42 (m, 12H), 7.51 (m, 2H), 7.71e7.84 (m, 4H); 13C NMR
(3 g, 60%); mp 130e132 ꢀC; IR (film)
n
3251, 1659, 1586, 1524, 1452,
3.64
1343,1191, 871, 703, 606, 528 cmꢃ1; 1H NMR (400 MHz, CDCl3):
d
(100 MHz, acetone-d6):
d
38.7, 48.5, 48.6, 50.5, 51.3, 72.9, 73.3, 126.1,
(s, 2H), 4.20 (s, 2H), 6.93e7.03 (m, 2H), 7.21e7.29 (m, 2H), 7.43e7.51
126.5, 126.9, 127.6, 127.9, 128.5, 128.6, 129.3, 129.5, 129.6, 131.2, 131.5,
131.7, 134.8, 135.9, 137.9, 138.5, 140.3, 141.3. Anal. Calcd for
C33H34N2O4S:C,71.45;H, 6.18;N,5.05. Found:C,71.12;H,5.98;N, 4.92.
(m, 4H), 7.79e7.87 (m, 3H), 7.97e8.0 (m, 1H); 13C NMR (100 MHz,
CDCl3): d 30.5, 43.2,123.8,124.4,125.5,126.2,126.6,127.3,128.5,129.3,
129.4,129.5,129.9,130.1,130.4,132.3,134.6,136.2,169.6; MS (ESI) m/z
354.2 (M)þ, 356.2 (Mþ2)þ. HRMS calcd for m/z C19H16BrNOþHþ:
354.0484, found: 354.0483. Anal. Calcd for C19H16BrNO: C, 64.42; H,
4.55; N, 3.95. Found: C, 64.06; H, 4.67; N, 4.09.
4.7. 2-[(tert-Butyldimethylsilyloxy)methyl]aniline (6)
To a cooled (0 ꢀC), stirred suspension of NaH (60% dispersion in
mineral oil, 2.3 g, 58.1 mmol) in anhydrous THF (10 mL) was added
dropwise a solution of 2-aminobenzyl alcohol 5 (6.5 g, 52.8 mmol)
in anhydrous THF (15 mL) and the mixture was stirred at 0 ꢀC for
15 min under nitrogen atmosphere. To this was added dropwise
a solution of tert-butyldimethylsilyl chloride (9.5 g, 63.3 mmol) in
anhydrous THF (15 mL) and the reaction mixture was gradually
warmed to room temperature and stirred for 2 h. The reaction
mixture was cooled to 0 ꢀC and crushed ice was carefully added to
quench the reaction. This was extracted with EtOAc (3ꢂ20 mL) and
the combined extracts were washed with brine (2ꢂ10 mL), dried
over Na2SO4 and concentrated in vacuo. The residue was purified by
flash column chromatography (EtOAc/iso-hexane 0:100 to 10:90) to
yield the title compound (11 g, 91%) as a dark yellow, viscous oil; 1H
4.10. 3,4,5,6-Tetrahydro-(4S,5S)-2-(2-bromobenzyl)-7-[(2-
naphthyl)-acetamidobenzyl]-4,5-O-isopropylidene-1,2,7-
thiadiazepine-1,1-dioxide (9)
To a solution of 2c (67 mg, 0.17 mmol) in anhydrous DMF (3 mL)
was added anhydrous, powdered K2CO3 (36 mg, 0.26 mmol) and
the resulting suspension was stirred at 50 ꢀC for 20 min. To this was
added 8 (73 mg, 0.21 mmol) and the reaction mixture was stirred at
80 ꢀC for 15 h under nitrogen atmosphere. Water was added to the
reaction mixture and it was extracted with EtOAc (3ꢂ10 mL). The
combined extracts were washed with brine (2ꢂ10 mL), dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
flash column chromatography (EtOAc/iso-hexane 10:40 to 50:50) to

4056
A. Ax et al. / Tetrahedron 66 (2010) 4049e4056
yield the title compound (50 mg, 44%) as a white solid; mp
72e74 ꢀC; IR (film)
3373, 2984, 1689, 1591, 1519, 1449, 1333, 1230,
1152, 1090, 910, 869, 779, 728, 656 cmꢃ1 1H NMR (400 MHz,
CDCl3):
Acknowledgements
n
;
We thank the Swedish Foundation for Strategic Research (SSF),
Knut and Alice Wallenberg’s Foundation, the Swedish Research
Council (VR) and Medivir AB for support.
d
1.33 (d, J¼4.4 Hz, 6H), 2.92e3.03 (m, 2H), 3.28 (dd, J¼4,
13.6 Hz, 1H), 3.52 (dd, J¼4.8, 12.4 Hz, 1H), 4.14e4.23 (m, 6H), 4.46
(d, J¼15.2 Hz, 1H), 4.59 (d, J¼15.2 Hz, 1H), 6.99e7.54 (m, 10H), 7.70
(d, J¼8 Hz, 1H), 7.77 (d, J¼8 Hz, 1H), 7.95 (d, J¼8 Hz, 1H), 8.13 (d,
Supplementary data
J¼8 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 27.2, 42.4, 47.5, 49.6,
52.0, 55.6, 76.9, 110.2, 123.8, 123.9, 124.4, 124.7, 125.9, 126.1, 126.6,
128.2, 128.3, 128.5, 128.9, 129.8, 129.9, 130.4, 130.9, 131.6, 132.5,
133.4, 134.1, 135.1, 137.4, 170.1; MS (ESI) m/z 664.5 (M)þ, 666.5
(Mþ2)þ. HRMS calcd for m/z C33H34BrN3O5SþHþ: 664.1481, found:
664.1470. Anal. Calcd for C33H34BrN3O5S: C, 59.64; H, 5.16; N, 6.32.
Found: C, 59.78; H, 5.42; N, 6.02.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.023.
References and notes
1. UNAIDS/WHO, 2009.
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4.11. 3,4,5,6-Tetrahydro-(4S,5S)-2-[2-{2-(2-naphthyl)-
acetamido}-benzyl]-7-(2-bromobenzyl)-4,5-dihydroxy-
1,2,7-thiadiazepine-1,1-dioxide (3k)
4. Ax, A.; Schaal, W.; Vrang, L.; Samuelsson, B.; Hallberg, A.; Karlén, A. Bioorg. Med.
Chem. 2005, 13, 755e764.
5. Gold, H.; Ax, A.; Vrang, L.; Samuelsson, B.; Karlén, A.; Hallberg, A.; Larhed, M.
Tetrahedron 2006, 62, 4671e4675.
6. Wannberg, J.; Ersmark, K.; Larhed, M. Microwave Methods in Organic Synthesis
Top. Curr. Chem. 2006, 266, 167e198.
To a cooled (0 ꢀC) solution of 9 in MeOH (1 mL) was added
a solution of HCl (2 M in diethyl ether, 4 mL). The reaction mixture
was warmed to room temperature and stirred for 2 h. The volatiles
were removed under reduced pressure and the residue was taken
up in water, neutralized with saturated NaHCO3 solution and
extracted with EtOAc (2ꢂ10 mL). The combined extracts were
washed with brine (2ꢂ10 mL), dried over Na2SO4 and concentrated
in vacuo. Flash chromatography (methanol/dichloromethane 5:95)
yielded the title compound (30 mg, 64%) as a pale coloured oil; IR
7. Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Discov. 2006, 5, 51e63.
8. Larhed, M.; Hallberg, A. Drug Discov. Today 2001, 6, 406e416.
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Synthesis 2000, 1004e1008.
11. Prasad, A.; Van der Eycken, E. Eur. J. Org. Chem. 2008, 1133e1155.
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13. Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582e9584.
14. Negishi, E.; de Meijere, A.; Bäckvall, J. E.; Cacci, S.; Hayashi, T. Handbook of
Organopalladium Chemistry for Organic Synthesis; Wiley-Interscience: New
York, NY, 2002; Vol. 1, pp 229e248.
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574e583.
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607e615.
19. Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38, 5945e5948.
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Antimicrob. Agents Chemother. 1997, 41, 2383e2388.
(film)
1023, 954, 903, 874, 785, 750, 628, 524 cmꢃ1
acetone-d6): 3.21e3.43 (m, 6H), 3.67e3.71 (m, 1H), 4.29 (s, 2H),
n
3331, 1662, 1591, 1513, 1441, 1332, 1296, 1233, 1153, 1100,
;
1H NMR (400 MHz,
d
4.53 (d, J¼15.6 Hz, 1H), 4.70 (d, J¼16.8 Hz, 2H), 4.89 (d, J¼16.8 Hz,
1H), 7.14e7.65 (m, 11H), 7.82e7.93 (m, 3H), 8.29 (d, J¼8.8 Hz, 1H);
13C NMR (100 MHz, acetone-d6):
d 41.4, 48.4, 48.5, 49.6, 52.9, 71.9,
72.8, 122.8, 123.7, 123.9, 124.6, 124.9, 125.7,125.9, 126.4, 127.8, 128.3,
128.7, 128.8, 129.4, 129.6, 130.2, 132.5, 132.8, 133.1, 134.2, 136.6,
137.3, 137.4, 169.5; MS (ESI) m/z 624.4 (M)þ, 626.4 (Mþ2)þ. Anal.
Calcd for C30H30BrN3O5S: C, 57.69; H, 4.84; N, 6.73. Found: C, 57.44;
H, 5.07; N, 6.51.