Synthesis and applications of β-aminoethanesulfonyl azides

Article abstract of DOI:10.1055/s-2006-926273

A very efficient method for the synthesis of β-aminoethanesulfonyl azides is descibed. These aliphatic sulfonyl azides are accessible starting from a variety of protected amino acids, including those having functionalized side chains. Furthermore, these s

Full text of DOI:10.1055/s-2006-926273

PAPER
455
Synthesis and Applications of b-Aminoethanesulfonyl Azides
b
-Aminoethanesul
r
fonyl
A
z
w
ide
s
in J. Brouwer, Remco Merkx, Katarzyna Dabrowska, Dirk T. S. Rijkers, Rob M. J. Liskamp*
Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht,
The Netherlands
Fax +31(30)2536655; E-mail: R.M.J.Liskamp@pharm.uu.nl
Received 15 July 2005; revised 22 August 2005
use it for chemical ligation by coupling a peptido-pepti-
Abstract: A very efficient method for the synthesis of b-amino-
dosulfonyl azide with a peptide thio acid.
ethanesulfonyl azides is descibed. These aliphatic sulfonyl azides
are accessible starting from a variety of protected amino acids, in-
cluding those having functionalized side chains. Furthermore, these
sulfonyl azides can be coupled to thio acids, and can be substituted
with different aliphatic amines.
Synthesis of sulfonyl azides in the literature is generally
performed starting from sulfonyl chlorides.8,12 An aque-
ous solution of acetone is mostly used as solvent, in which
both the sulfonyl chloride and sodium azide dissolve. The
b-aminoethanesulfonyl chlorides earlier prepared by us
were protected with either the Fmoc group or the Cbz
group.1 Since the Cbz group is more stable under many re-
action conditions, we decided to start with the preparation
of a Cbz-protected b-aminoethanesulfonyl azide derived
from glycine (Scheme 1).
Key words: sulfonyl azide, sulfonyl chloride, amino acid, sulfon-
amides
There is a continuous interest in easily accessible and ver-
satile building blocks. One of the main objectives in our
group is the preparation of peptidomimetics using differ-
ent building blocks derived from amino acids. Previously
we described the efficient synthesis of b-aminoethane-
sulfonyl chlorides starting from natural amino acids.1
These sulfonyl chlorides have been successfully em-
ployed for use in peptide–peptidomimetic hybrides,2 syn-
thetic receptors,3 ligands for catalysis,4 cyclic
sulfonamides,5 and oligopeptidosulfonamides.6 In a dif-
ferent project, using b-aminoethanesulfonyl chlorides, we
embarked on the sulfonyl azide moiety. Little is described
in the literature about the use of the sulfonyl azide moiety
in biologically active compounds, while a sulfonyl azide
can interact by hydrogen bonding and electrostatic inter-
actions. In one example the sulfonyl azide moiety has suc-
cessfully been used in selective cyclooxygenase-2
inhibitors.7
For this purpose, taurine (1) was Cbz-protected and sub-
sequently reacted with phosgene to give Cbz-protected
taurylsulfonyl chloride (4a).1
O
O
+
H3N
S
–
O
1
1) NaOH, H2O, r.t.
(a) Cbz-Cl, dioxane
(b) Fmoc-Cl, CH3CN
2) COCl2/toluene,
CH2Cl2, DMF, r.t.
O
O
O
O
S
S
CbzN
H
Cl
FmocN
H
Cl
4a
4b
For synthetic applications mostly aromatic sulfonyl
azides are described in the literature, which were mainly
used in thermolysis reactions,8 azidations,9 diazo-transfer
reactions,10 and reactions with alkenes.11 Only few papers
describe reactions other than diazo-transfer reactions10a
with aliphatic sulfonyl azides. One describes the ther-
molytic reaction between pentylsulfonyl azide and cyclo-
hexane, affording an N-cyclohexylsulfonamide.8f The
Staudinger reaction between an aliphatic sulfonyl azide
derived from isoborneol and racemic tertiary phosphines
yielded stable phosphinimines, which were hydrolyzed to
form chiral phosphines.12 Recently Shangguan et al. de-
scribed a new and very interesting reaction of a sulfonyl
azide with a thioacid, which afforded an N-acyl sulfona-
mide.13 If this reaction is selective and also works with
amino acid based sulfonyl azides, it might be possible to
NaN3, H2O,
acetone, r.t.
NaN3, H2O,
acetone, r.t.
O
O
O
O
S
S
CbzN
H
N3
FmocN
H
N3
2a
77%, 3 steps
2b
76%, 3 steps
Scheme 1
The first attempt for reaction of Cbz-protected taurylsul-
fonyl chloride with NaN3 in an acetone–water mixture re-
sulted in a fast and clean conversion to sulfonyl azide 2a
in 90% yield (77% from taurine). In this procedure a solu-
tion of the sulfonyl chloride in acetone was added to an
aqueous solution of NaN3. After these promising results,
we wondered whether the Fmoc group would be stable
under these reaction conditions. For this purpose the
azide-substitution reaction was repeated with Fmoc-pro-
tected taurylsulfonyl chloride (4b).1 Unfortunately the
SYNTHESIS 2006, No. 3, pp 0455–0460
x
x
.
x
x
.2
0
0
6
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926273; Art ID: Z13805SS
© Georg Thieme Verlag Stuttgart · New York

456
A. J. Brouwer et al.
PAPER
yield of Fmoc-protected sulfonyl azide 2b was only 49% corresponding sulfonyl azides in good to excellent yields
due to Fmoc cleavage, which was clearly visible on TLC. (79–99%) (Table 1). Cbz-phenylalanine-derived sulfonyl
During the reaction a white precipitate formed, which azide was also efficiently prepared in high yield (90%),
probably was sulfonyl chloride. To prevent Fmoc cleav- following the procedure used for 2a. For preparation of a
age, it is very important that the azide anions react directly functionalized sulfonyl chloride, 4f, derived from Fmoc-
with the sulfonyl chloride, which is difficult when the sul- Ser(t-Bu)-OH, was selected.1 Sulfonyl azide 2f was pre-
fonyl chloride is not completely dissolved. Thus, after ad- pared in 74% yield, using the standard procedure.
dition of more acetone and inversion of the addition
As a first application we studied the reaction of sulfonyl
sequence, Fmoc-protected sulfonyl azide 2b was obtained
azides with thio acids. The reaction is fast and gives N-
in 90% yield (Table 1).
acyl sulfonamides in high yields. As a proof of principle
Now that both Fmoc- and Cbz-protected glycine-derived Cbz-protected sulfonyl azide 2a was reacted with thioace-
sulfonyl azides were successfully prepared, the next step tic acid in chloroform (Scheme 3).
was the preparation of b-aminoethanesulfonyl azides with
O
different side chains, including functionalized side chains.
O
O
O
O
HSAc, CHCl3
S
S
Fmoc-protected b-aminoethanesulfonyl chlorides 4c–f
were prepared following a procedure which was previous-
ly described by our group, starting from Fmoc- and Cbz-
protected amino acids 3 (Scheme 2).1
CbzN
H
N3
CbzN
H
N
2,6-lutidine
15 min, r.t.
H
5 (quant.)
2a
Scheme 3
1) NMM, DME
O
N-Acyl sulfonamide 514 was obtained in quantitative yield
after only 15 minutes reaction time. This reaction was so
promising that we prepared a set of N-acyl sulfonamides
from sulfonyl azides 2a–f and different thio acids, includ-
ing peptide-based thio acids to explore the scope of the re-
action and for use as a new chemical ligation reaction.14
We found that the reaction was high-yielding and indeed
can be used to couple sulfonyl azides to peptide thio acids.
For use as a chemical ligation reaction N-terminal depro-
tected sulfonyl azides were required, to which amino ac-
ids or peptides can be coupled. For this purpose the N-
terminus of Fmoc-tauryl sulfonyl azide 2b was deprotect-
ed with a large excess of dimethylamine in THF
(Scheme 4).
i-BuOC(O)Cl
2) NaBH4, H2O
–15 °C
H
H
PN
PN
OH
OH
3c–f
R
R
R
MsCl, Et3N
CH2Cl2, 0 °C
Cs2CO3, HSAc
DMF, r.t.
H
H
PN
PN
OMs
SAc
R
R
1) H2O2, HOAc
Pd/C
NaN3, H2O
DMF, acetone
H
PN
H
PN
Cl
N3
O
S
S
2) COCl2/toluene
CH2Cl2, DMF
r.t.
O
O
O
R
4c–f
2c–f
2 P
R
Amino Acid
Val
Phe
O
c Fmoc CH(CH3)2
d Fmoc CH2Ph
O
O
H
BocN
S
N
H
N3
e Cbz
CH2Ph
Phe
Ser
f
Fmoc CH2Ot-Bu
6
O
O
1) Me2NH(aq)
THF
,
x
Scheme 2
Table 1 Yields of Sulfonyl Azides 2a–f
S
FmocN
H
N3
2) Boc-Phe-OH,
BOP, DIPEA,
CH2Cl2
O
2b
O
O
H
BocN
S
N
H
N
Amino Acid
Sulfonyl Azide 2 Yield (%)
7
Cbz-Gly-OH
a
b
c
d
e
f
90
92
79
99
90
74
35% (2 steps)
Fmoc-Gly-OH
Fmoc-Val-OH
Fmoc-Phe-OH
Cbz-Phe-OH
Scheme 4
Boc-Phe-OH was directly coupled to the resulting free
amine using (benzotriazol-1-yloxy)tris(dimethylami-
no)phosphonium hexafluorophosphate (BOP) and N,N-
diisopropylethylamine (DIPEA) in dichloromethane. In-
stead of Fmoc-deprotection followed by coupling, the sul-
fonyl azide underwent a substitution reaction by
dimethylamine leading to 7, and no coupling product 6 re-
taining the sulfonyl azide moiety was found. In attempts
to selectively remove the Fmoc group, different amounts
of either dimethylamine or piperidine were used. In all re-
Fmoc-Ser(t-Bu)-OH
Due to solubility problems in the initial experiments, the
procedure used for 2b was slightly altered by changing the
solvent ratio and by addition of DMF. Fmoc-protected
sulfonyl chlorides 4c–d were smoothly converted to the
Synthesis 2006, No. 3, 455–460 © Thieme Stuttgart · New York

PAPER
b-Aminoethanesulfonyl Azides
457
actions, both Fmoc cleavage and azide substitution were attempted. In the literature a similar reduction is de-
observed. At lower amounts of the amine, the Fmoc cleav- scribed; treatment of the sulfonyl azide with a tertiary
age was slightly favored over the substitution. Since sub- phosphine for 12 h at 60° in THF, affords a phosphin-
stitution of the sulfonyl azide always occurred, we became imine. The phosphinimine is then hydrolyzed using 3 M
interested in exploring the scope of this reaction. To our sulfuric acid in refluxing dioxane for 12 h.12 Since these
knowledge, in contrast to acyl azides, this reaction has conditions are quite harsh, it was decided to first try the
never been described in the literature. A series of test re- common Staudinger conditions.15 Thus, Cbz-protected
actions was carried out with Cbz-tauryl sulfonyl azide 2a, sulfonyl azide 2a was treated with triphenylphosphine and
using different amines (benzylamine, methylamine, dim- water in tetrahydrofuran. To our surprise, sulfonamide 10
ethylamine, piperidine) in different amounts (2–40 equiv- was obtained in 97% yield after only two minutes reaction
alents). All amines were capable of substitution, but at time at room temperature. We also tried to isolate the
least ten equivalents were needed for complete conversion phosphinimine intermediate by repeating the Staudinger
at room temperature overnight. Heating accelerated the reaction in the absence of water. On TLC the intermediate
reaction, but the best improvement was found using mi- was indeed formed but slowly hydrolyzed to the sulfon-
crowave irradiation. As a proof of principle Cbz-tauryl amide, indicating its moisture sensitivity.
sulfonyl azide 2a was reacted with four equivalents of pi-
peridine in tetrahydrofurane at 100 °C with microwave ir-
radiation (Scheme 5).
O
O
O
O
H2, Pd/C
S
S
FmocN
H
N3
FmocN
H
NH2
EtOH, r.t.
30 min
9 (98%)
2b
O
O
O
O
piperidine, THF
S
S
CbzN
H
N3
CbzN
H
N
O
O
O
O
MW, 100 °C
15 min
PPh3, H2O
S
S
8 (96%)
2a
CbzN
H
N3
CbzN
H
NH2
THF, r.t.
2 min
2a
10 (97%)
Scheme 5
Scheme 7
After only 15 minutes reaction time, sulfonamide 8 was
isolated in 96% yield, showing that our sulfonyl azides
can be substituted by amines.
In conclusion, we have developed a very efficient method
for the preparation of b-aminoethanesulfonyl azides start-
ing from different amino acids, including those containing
functionalized side chains. These sulfonyl azides were re-
markably stable, but could be easily substituted by
amines, using microwave irradiation to give sulfona-
mides. The sulfonyl azides were also successfully con-
verted to N-acyl sulfonamides by reaction with thio acids.
Amino acids – and probably peptides – can be coupled to
the N-terminus, providing access to peptido-peptidosulfo-
nyl azides for use in chemical ligation. The chemistry of
sulfonyl azides is currently under further investigation.
Since Fmoc cleavage of sulfonyl azides was not possible,
we decided to cleave the Cbz group. For this purpose, sul-
fonyl azide 2a was treated with HBr/HOAc, and the HBr
salt of the amine was transformed into the HCl salt using
an ion exchange resin (Scheme 6).
1. HBr/HOAc,
CH2Cl2, r.t.
O
O
O
O
O
H
S
BocN
S
CbzN
H
N3
N
H
N3
2. Boc-Phe-OH,
BOP, DIPEA,
CH2Cl2, r.t.
2a
6
85% (2 steps)
Fmoc-protected amino acids were purchased from MultiSynTech
GmbH (Witten, Germany). Peptide-grade solvents for synthesis
were purchased from Biosolve (The Netherlands). Dowex 2 × 8
(Cl-form) was purchased from Fluka. Reactions were carried out at
ambient temperature unless stated otherwise. TLC analysis was per-
formed on Merck pre-coated silica gel 60 F-254 (0.25 mm) plates.
Spots were visualized with UV light, ninhydrin, or Cl2-TDM.16 Sol-
vents were evaporated under reduced pressure at 40 °C. Column
chromatography was performed on ICN silica gel 60 (32–63 m).
Scheme 6
Subsequently, Boc-Phe-OH was coupled using BOP to
give peptido-peptidosulfonyl azide 6 in 85% yield, show-
ing that the N-terminus of our sulfonyl azides can be used
for coupling amino acids and probably peptides. This ex-
ample also shows that the sulfonyl azide moiety is stable
under both strong acidic (HBr/HOAc) and basic (DIPEA) Melting points were measured on a Büchi melting point apparatus
and are uncorrected. Electrospray mass spectra were recorded on a
conditions. Furthermore, under these coupling conditions
Shimadzu LCMS-QP-8000 spectrometer. Elemental analyses were
no substitution products were found from nucleophilic at-
carried out at Kolbe Mikroanalytisches Laboratorium (Mülheim an
tack of the free amine at the sulfonyl azide.
der Ruhr, Germany). Microwave-assisted reactions were carried out
For a different project, primary sulfonamides were need- in a Biotage Initiator. 1H NMR (300 MHz) and 13C NMR (75 MHz)
1
spectra were recorded on a Varian G-300 spectrometer. For H
ed. It was envisioned that these could be obtained by re-
NMR, TMS or DMSO (2.50 ppm) were used as internal standards;
duction of the sulfonyl azides. Thus, after treatment of
for 13C NMR, CDCl3 and THF-d8 (67.4 ppm) were used. 13C NMR
Fmoc-protected sulfonyl azide 2b with hydrogen and pal-
spectra were recorded using the attached proton test (APT) pulse se-
ladium on carbon (Scheme 7), sulfonamide 9 was obained
in 98% yield. Due to the instability of the Cbz protecting
group under these conditions, a Staudinger reduction was
quence. The 13C NMR spectrum of 9 was recorded on a Varian
Inova-500 spectrometer.
Synthesis 2006, No. 3, 455–460 © Thieme Stuttgart · New York

458
A. J. Brouwer et al.
PAPER
Sulfonyl Azides 2a–f; General Procedure
ESI-MS: m/z (%) = 415 [M + H]+, 437 [M + Na]+, 453 [M + K]+.
A solution of NaN3 (195 mg, 3.00 mmol) in H2O (10 mL) was added
dropwise to a solution of the sulfonyl chloride 4a–f (3 mmol) in
acetone (15 mL) and DMF (15 mL). The reaction was stirred at r.t.
for up to 1 h. After evaporation of acetone, H2O (200 mL) was add-
ed and the product precipitated. The mixture was filtered and the
residue was washed with 5% NaHCO3 soln (10 mL), H2O (50 mL),
and dried in vacuo. Sulfonyl azides 2a–f were all obtained as white
solids.
Anal. Calcd for C20H22N4O4S: C, 57.96; H, 5.35; N, 13.52. Found:
C, 57.77; H, 5.28; N, 13.39.
2d (Derived from Fmoc-phenylalanine)17
The reaction (3.0 mmol scale) was carried out using H2O (30 mL),
acetone (20 mL), and DMF (40 mL) as solvents.
Yield: 1.37 g (99%); Rf = 0.56 (MeOH–CH2Cl2, 1:99); mp 168 °C.
IR (KBr): 2131 (s) cm–1.
2a (Cbz-Tau-N3)
1H NMR (300 MHz, THF-d8,): d = 2.95 (dd, 1 H, CHaPh,
Jgem = 13.6 Hz, Jvic = 5.8 Hz), 3.03 (dd, 1 H, CHbPh, Jgem = 13.6 Hz,
Jvic = 8.2 Hz), 3.71 (dd, 1 H, CHaSO2, Jgem = 14.7 Hz, Jvic = 3.9 Hz),
3.88 (dd, 1 H, CHbSO2, Jgem = 14.7 Hz, Jvic = 8.6 Hz), 4.19 [m, 2 H,
NCH, CH (Fmoc)], 4.40 [m, 2 H, CH2 (Fmoc)], 7.01 (d, 1 H, NH),
7.15–7.81 [m, 13 H, Ar-CH (Fmoc, Ph)].
13C NMR (75 MHz, THF-d8): d = 40.0 (CH2Ph), 48.3, 50.3 [NCH,
CH (Fmoc)], 58.4 (CH2SO2), 66.7 [CH2 (Fmoc)], 120.6, 125.9,
127.4, 127.7, 128.3, 129.3, 130.3, 138.5, 142.3, 145.3 [Ar-C (Fmoc,
Ph)], 156.4 [C=O (Fmoc)].
The reaction (16.9 mmol scale) was carried out using H2O (90 mL)
and acetone (90 mL) as solvents. The acetone solution of the sulfo-
nyl chloride was added dropwise to the aq solution of NaN3. Instead
of precipitation, the reaction was worked up by evaporation of ace-
tone, followed by re-dissolving in EtOAc (250 mL) and washing
with 5% NaHCO3 (100 mL), H2O (100 mL), and brine (100 mL).
Drying over Na2SO4 and evaporation of EtOAc afforded the sulfo-
nyl azide.
Yield: 4.3 g (90%); Rf = 0.63 (MeOH–CH2Cl2, 1:99); mp 78 °C.
IR (KBr): 2150 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.55 (m, 2 H, CH2SO2), 3.72 (m,
2 H, NCH2), 5.12 (s, 2 H, CH2Ph), 5.36 (br s, 1 H, NH), 7.35 (s, 5
H, Ar-CH).
ESI-MS: m/z (%) = 463 [M + H]+, 485 [M + Na]+, 501 [M + K]+,
925 [2M + H]+.
Anal. Calcd for C24H22N4O4S: C, 62.32; H, 4.79; N, 12.11. Found:
C, 62.40; H, 4.75; N, 12.03.
13C NMR (75 MHz, CDCl3): d = 35.7 (NCH2), 55.2 (CH2SO2), 67.2
(OCH2Ph), 128.1, 128.4, 128.6, 135.9 (Ar-C), 156.1 [C=O (Cbz)].
2e (Derived from Cbz-phenylalanine)
ESI-MS: m/z (%) = 285 [M + H]+, 307 [M + Na]+, 323 [M + K]+,
The reaction (3.8 mmol scale) was carried out using H2O (19 mL)
and acetone (50 mL) as solvents. The reaction and workup were per-
formed using the same procedure as for 2a.
569 [2M + H]+.
Anal. Calcd for C10H12N4O4S: C, 42.25; H, 4.25; N, 19.71. Found:
C, 42.32; H, 4.21; N, 19.66.
Yield: 1.28 g (90%); Rf = 0.48 (MeOH–CH2Cl2, 1:99); mp 141 °C.
IR (KBr): 2137.57 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.02 (m, 2 H, CHCH2Ph), 3.47
(dd, Jgem = 14.8 Hz, Jvic = 4.4 Hz, 1 H, CHCHaSO2), 3.71 (dd,
Jgem = 14.8 Hz, Jvic = 7.7 Hz, 1 H, CHCHbSO2), 4.32 (m, 1 H,
NCH), 5.09 (s, 2 H, OCH2Ph), 5.23 (d, 1 H, NH), 7.15–7.38 [m, 10
H, Ar-CH (Cbz, Ph)].
2b (Fmoc-Tau-N3)17
The preparation (2.95 mmol scale) was carried out in the absence of
DMF.
Yield: 1.02 g (92%); Rf = 0.54 (MeOH–CH2Cl2, 1:99); mp 118 °C.
IR (KBr): 2141 (s) cm–1.
13C NMR (75 MHz, CDCl3): d = 39.3 (CHCH2Ph), 49.1 (NCH),
57.2 (CH2SO2), 67.0 (OCH2Ph), 127.3, 128.0, 128.2, 128.5, 128.9,
129.2, 135.9, 136.0 [Ar-C (Ph, Cbz)], 155.4 [C=O (Cbz)].
1H NMR (300 MHz, CDCl3): d = 3.53 (m, 2 H, CH2SO2), 3.71 (m,
2 H, NCH2), 4.21 [t, 1 H, CH (Fmoc)], 4.44 [d, 2 H, CH2 (Fmoc)],
5.33 (br s, 1 H, NH), 7.29–7.78 [m, 8 H, Ar-CH (Fmoc)].
13C NMR (75 MHz, CDCl3): d = 35.7 (NCH2), 47.1 [CH (Fmoc)],
55.2 (CH2SO2), 67.1 [CH2 (Fmoc)], 120.0, 124.4, 124.9, 127.1,
127.8, 141.3, 143.6 [Ar-C (Fmoc)], 156.1 [C=O (Fmoc)].
ESI-MS: m/z (%) = 375 [M + H]+, 397 [M + Na]+, 413 [M + K]+,
749 [2M + H]+.
Anal. Calcd for C17H18N4O4S: C, 54.53; H, 4.85; N, 14.96. Found:
C, 54.60; H, 4.78; N, 14.87.
ESI-MS: m/z (%) = 473 [M + H]+, 395 [M + Na]+, 411 [M + K]+,
745 [2M + H]+.
2f (Derived from Fmoc-Ser(t-Bu)-OH)17
Scale: 1.62 mmol; yield: 0.55 g (74%); Rf = 0.73 (MeOH–CH2Cl2,
1:99); mp 103 °C.
Anal. Calcd for C17H16N4O4S: C, 54.83; H, 4.33; N, 15.04. Found:
C, 54.71; H, 4.25; N, 14.92.
IR (KBr): 2137 (s) cm–1.
2c (Derived from Fmoc-valine)17
1H NMR (300 MHz, CDCl3): d = 1.19 [s, 9 H, C(CH3)3], 3.51, 3.64
(2 m, 4 H, CH2SO2, t-BuOCH2), 4.23 [t, 1 H, CH (Fmoc)], 4.35–
4.51 [m, 3 H, CH2 (Fmoc), NCH], 5.33 (br d, 1 H, NH), 7.30–7.78
[m, 8 H, Ar-CH (Fmoc)].
13C NMR (75 MHz, CDCl3): d = 27.4 [C(CH3)3], 47.1, 47.6 [NCH,
CH (Fmoc)], 55.9 (CH2SO2), 61.7 (t-BuOCH2), 67.0 [CH2 (Fmoc)],
73.8 [C(CH3)3], 120,0, 124.9, 125.0, 127.1, 127.8, 141.3, 143.6 [Ar-
C (Fmoc)], 155.5 [C=O (Fmoc)].
Scale: 1.1 mmol; yield: 0.36 g (79%); Rf = 0.54 (MeOH–CH2Cl2,
1:99); mp 158 °C.
IR (KBr): 2139 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.96 [2 d, 6 H, CH(CH3)2], 2.04
[m, 1 H, CH(CH3)2], 3.49 (dd, 1 H, CHaSO2, Jgem = 14.7 Hz,
Jvic = 3.7 Hz), 3.60 (dd, 1 H, CHbSO2, Jgem = 14.7 Hz, Jvic = 8.1 Hz),
4.01 (m, 1 H, NCH), 4.22 [t, 1 H, CH (Fmoc)], 4.45 [m, 2 H, CH2
(Fmoc)], 5.04 (d, 1 H, NH), 7.29–7.77 [m, 8 H, Ar-CH (Fmoc)].
13C NMR (75 MHz, CDCl3): d = 18.1, 19.2 [CH(CH3)2], 31.5
[CH(CH3)2], 47.2 [CH (Fmoc)], 53.0 (NCH), 57.0 (CH2SO2), 66.9
[CH2 (Fmoc)], 119.0, 125.0, 127.1, 127.7, 141.3, 143.6, 143.7 [Ar-
C (Fmoc)], 155.7 [C=O (Fmoc)].
ESI-MS: m/z (%) = 459 [M + H]+, 481 [M + Na]+, 497 [M + K]+,
917 [2M + H]+.
Anal. Calcd for C22H26N4O5S: C, 57.63; H, 5.72; N, 12.22. Found:
C, 57.49; H, 5.66; N, 12.06.
Synthesis 2006, No. 3, 455–460 © Thieme Stuttgart · New York

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b-Aminoethanesulfonyl Azides
459
Peptido-peptidosulfonyl azide 6
mL), and brine (10 mL). Drying over Na2SO4 and concentration in
vacuo afforded 8 as a clear yellowish oil.
To a solution of sulfonyl azide 2a (284 mg, 1.00 mmol) in CH2Cl2
(10 mL) was added a solution of HBr in HOAc (33%, 6 mL). While
stirring for 30 min at r.t., a white precipitate formed. After removal
of the solvents in vacuo, the residue was dissolved in H2O (10 mL),
and Dowex 2 × 8 (0.60 g, Cl-form) was added. Stirring for 5 min at
r.t., followed by filtration and concentration in vacuo, afforded the
HCl-salt (188 mg) in quantitative yield. To the HCl-salt was subse-
quently added CH2Cl2 (40 mL), Boc-Phe-OH (265 mg, 1.00 mmol),
BOP (464 mg, 1.05 mmol), and DIPEA (385 mL, 2.21 mmol). The
mixture was stirred overnight at r.t. The pH was kept at approx. 8
by addition of DIPEA during the reaction. After concentration, the
residue was suspended in EtOAc (100 mL) and was washed with 1.0
M KHSO4 (3 × 50 mL), brine (50 mL), 5% NaHCO3 soln (3 × 50
mL), and brine (50 mL). Drying over Na2SO4, followed by column
chromatography (EtOAc–hexanes–HOAc, 44.5:44.5:1), afforded 6
as a white solid.
Yield : 157 mg (96%); Rf = 0.39 (EtOAc–hexanes, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.59 (m, 6 H, NCH2CH2CH2CH2),
3.06 (t, 2 H, SO2CH2), 3.20 (m, 4 H, 2 × NCH2CH2CH2), 3.65 (m, 2
H, NCH2CH2SO2), 5.10 (s, 2 H, OCH2Ph), 5.61 (m, 1 H, NH), 7.34
[m, 5 H, Ar-CH (Cbz)].
13C NMR (75 MHz, CDCl3): d = 23.5, 25.4 (NCH2CH2CH2CH2),
35.4 (NCH2CH2SO2), 46.4 (NCH2CH2CH2), 48.4 (SO2CH2), 66.7
(OCH2Ph), 127.9, 128.0, 128.4, 136.1 [Ar-CH (Cbz)], 156.1 [C=O
(Cbz)].
ESI-MS: m/z (%) = 349.05 [M + Na]+.
Peptidosulfonamide 9
To a solution of sulfonyl azide 2b (186 mg, 0.500 mmol) in EtOH
(10 mL) was added a cat. amount of Pd/C (10%). The mixture was
stirred for 30 min under H2 (balloon). Filtration over Hyflo Super
Cel medium (Fluka), followed by evaporation of the solvent, afford-
ed 9 as a white solid.
Yield : 336 mg (85%); Rf = 0.39 (EtOAc–hexanes, 1:1); mp 72 °C.
1H NMR (300 MHz, CDCl3): d = 1.40 [s, 9 H, C(CH3)3], 3.06 (d, 2
H, CHCH2Ph), 3.30–3.51 (2 m, 4 H, CH2SO2), 3.72 (m, 2 H,
NCH2CH2SO2), 4.35 [m, 1 H, NCHC(O)], 5.01 [d, 1 H, NHBoc],
6.63 (s, 1 H, NHCH2CH2SO2), 7.18–7.35 [m, 5 H, Ar-CH].
13C NMR (75 MHz, CDCl3): d = 28.2 [C(CH3)3], 33.8
(NHCH2CH2), 38.2 (CH2Ph), 54.6 (CH2SO2), 55.8 [NCHC(O)],
80.5 [C(CH3)3], 127.1, 128.3, 128.7, 129.2, 129.4, 136.3 (Ar-C),
155.4 [C=O (Boc)], 172.0 [CHC(O)NH].
Yield: 169 mg (98%); Rf = 0.60 (MeOH–CH2Cl2, 1:9); mp 126 °C.
1H NMR (300 MHz, DMSO-d6): d = 1.76 (m, 1 H, NH), 3.10 (m, 2
H, CH2SO2), 3.60 (m, 2 H, NCH2), 4.22 [t, 1 H, CH (Fmoc)], 4.25
[d, 2 H, CH2 (Fmoc)], 6.92 (br s, 2 H, NH2), 7.31–7.91 [m, 8 H, Ar-
CH (Fmoc)].
13C NMR (75 MHz, CDCl3–CD3OD, 9:1): d = 35.6 (NCH2), 46.8
[CH (Fmoc)], 53.9 (CH2SO2), 66.5 [OCH2 (Fmoc)], 119.6, 124.7,
126.7, 127.4, 141.0, 143.4 [Ar-CH (Fmoc)], 156.8 [C=O (Fmoc)].
ESI-MS: m/z (%) = 364.05 [M – t-Bu + Na]+, 420.20 [M + Na]+,
461.10 [M + CH3CN + Na]+.
ESI-MS: m/z (%) = 347.35 [M + H]+, 369.15 [M + Na]+, 410.15 [M
Anal. Calcd for C16H23N5O5S: C, 48.35; H, 5.83; N, 17.62. Found:
C, 48.22; H, 5.69; N, 17.77.
+ CH3CN + Na]+.
Anal. Calcd for C17H18N2O4S: C, 58.94; H, 5.24; N, 8.09. Found: C,
59.07; H, 5.15; N, 7.97.
Peptido-peptidosulfonamide 7
To a solution of sulfonyl azide 2b (372 mg, 1.00 mmol) in THF (10
mL) was added aq 40% solution Me2NH (5.1 mL). After stirring for
1 h at r.t., the reaction mixture was concentrated in vacuo and co-
evaporated with toluene (3 × 20 mL). To the residue was added
Boc-Phe-OH (265 mg, 1.00 mmol), BOP (443 mg, 1.00 mmol),
CH2Cl2 (6 mL), and DIPEA (0.36 mL, 2.2 mmol). After stirring for
1.5 h at r.t., the mixture was concentrated and dissolved in EtOAc
(20 mL). After washing with 1.0 M KHSO4 (4 × 10 mL), 1.0 M
NaOH (2 × 10 mL), H2O (10 mL), and brine (10 mL), the organic
layer was dried over Na2SO4 and concentrated. Column chromatog-
raphy (EtOAc–hexanes, 1:2) afforded 7 as a white solid.
Peptidosulfonamide 10
A mixture of sulfonyl azide 2a (56.9 mg, 0.200 mmol), PPh3 (52.5
mg, 0.200 mmol), THF (3 mL), and H2O (2 mL) was stirred at r.t.
After 2 min the sulfonyl azide was completely dissolved and the
evolution of N2 had stopped. The mixture was concentrated in vac-
uo and EtOAc (20 mL) was added. After washing with 1.0 M
KHSO4 (10 mL) and brine (10 mL), the organic layer was dried over
Na2SO4 and concentrated. Column chromatography (MeOH–
CH2Cl2, 4:96) afforded sulfonamide 10 as a white solid.
Yield: 50.1 mg (97%); Rf = 0.21 (MeOH–CH2Cl2, 5:95); mp 78 °C.
Yield: 141 mg (35%); Rf = 0.33 (EtOAc–hexanes, 1:2); mp 123 °C.
1H NMR (300 MHz, DMSO-d6): d = 3.13 (t, 2 H, CH2SO2), 3.38
(m, 3 H, NCH2, NH), 5.03 (s, 2 H, PhCH2), 6.93 (br s, 2 H, NH2),
7.36 [m, 5 H, Ar-CH (Cbz)].
13C NMR (75 MHz, DMSO-d6): d = 35.8, 35.9 (NCH2), 54.1
(CH2SO2), 65.7 (OCH2Ph), 128.0, 128.1, 128.6, 137.2 [Ar-CH
(Cbz)], 156.1, 156.2 [C=O (Cbz)].
1H NMR (300 MHz, CDCl3): d = 1.39 [s, 9 H, C(CH3)3], 2.84–3.08
[m, 10 H, N(CH3)2, CHCH2Ph, CH2SO2), 3.65 (m, 2 H,
NCH2CH2SO2), 4.38 [m, 1 H, NCHC(O)], 5.12 [s, 1 H, NHBoc],
6.79 (s, 1 H, NHCH2CH2SO2), 7.18–7.32 [m, 5 H, Ar-CH].
13C NMR (75 MHz, CDCl3): d = 28.1 [C(CH3)3], 33.6
(NHCH2CH2), 37.2 [N(CH3)2], 38.3 (CH2Ph), 46.9 (CH2SO2), 55.7
[NCHC(O)], 80.0 [C(CH3)3], 126.9, 128.5, 129.2, 136.5 (Ar-C),
155.2 [(CH3)3CC=O], 171.6 [CHC(O)NH].
ESI-MS: m/z (%) = 281.15 [M + Na]+, 322.15 [M + CH3CN + Na]+.
ESI-MS: m/z (%) = 300.05 [M – Boc + H]+, 344.15 [M – t-Bu + H]+,
Acknowledgment
422.35 [M + Na]+, 438.35 [M + K]+.
We thank Mr. C. Versluis from the Department of Biomolecular
Mass Spectrometry for recording some of the mass spectra.
Peptidosulfonamide 8
To a solution of sulfonyl azide 2a (142 mg, 0.500 mmol) in THF (5
mL) was added piperidine (198 mL, 2.00 mmol). The mixture was
irradiated with microwaves for 15 min at 100 °C. After evaporation
of the solvent, the residue was dissolved in EtOAc (20 mL) and
washed with 5% NaHCO3 soln (10 mL), 1.0 M KHSO4 soln (10
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Synthesis 2006, No. 3, 455–460 © Thieme Stuttgart · New York

460
A. J. Brouwer et al.
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Synthesis 2006, No. 3, 455–460 © Thieme Stuttgart · New York