Hydrogen-bonding donor/acceptor scales in β-sulfonamidopeptides

Article abstract of DOI:10.1002/(SICI)1521-3765(19981002)4:10<1924::AID-CHEM1924>3.0.CO;2-P

The conformational preferences of β-sulfonamidopeptides in chloroform solution were investigated by variable-temperature ¹H NMR spectroscopy and FT-IR spectroscopy. The following hydrogen-bonding acceptor scale was derived from the experiments:

Full text of DOI:10.1002/(SICI)1521-3765(19981002)4:10<1924::AID-CHEM1924>3.0.CO;2-P

FULL PAPER
Hydrogen-Bonding Donor/Acceptor Scales in b-Sulfonamidopeptides
Cesare Gennari,* Markus Gude, Donatella Potenza,* and Umberto Piarulli
Abstract: The conformational prefer-
ences of b-sulfonamidopeptides in
chloroform solution were investigated
results complementary to those descri-
bed above: the N ± H stretch bands of N-
methylacetamide and N-methyl metha-
nesulfonamide in chloroform were fol-
lowed during titration with excess meth-
anesulfonylpyrrolidine and N,N-dime-
1
by variable-temperature H NMR spec-
thylacetamide.
Shifts
to
lower
troscopy and FT-IR spectroscopy. The
following hydrogen-bonding acceptor
scale was derived from the experiments:
RCON ꢀ tBuOCON > COOMe ꢁ RS-
O2N. An intermolecular study gave
frequencies were observed which are
correlated with the hydrogen-bond
strengths and show that the amide is a
stronger hydrogen-bond acceptor than
the sulfonamide.
Keywords: beta-sulfonamidopepti-
des ´ conformational preferences ´
hydrogen bonds ´ peptides ´ sulfon-
amides
b-Sulfonamidopeptides have a covalent framework that
should be essential for the formation of well-defined folded
structures by intramolecular hydrogen bonding; the repeating
backbone structure contains both hydrogen-bond donors (N ±
Introduction
The attention of organic and medicinal chemists has recently
been attracted by unnatural biopolymer scaffolds (carba-
mates, peptoids, ureas, sulfonamides, b-peptides, b-peptoids,
etc.)[1] because of the affinities and specificities of these
compounds towards biological receptors and the simplicity
with which large libraries can be synthesized combinatorially.
The ability to efficiently assemble large synthetic oligomers
also provides an opportunity to generate unnatural polymers
with defined secondary and tertiary structures. Such struc-
tures should provide increased insight into the relationships
between monomer structure and polymer conformation,
and may provide new classes of folded polymers with
novel properties.[1m±q, 2] In particular, b-sulfonamidopep-
tides[1h,i, 2b±d, 3] are peptide surrogates with increased polarity
and hydrogen-bond donation capability. Furthermore, the
sulfonamido bond should show enhanced metabolic stability
and structural similarity to the tetrahedral transition state
involved in the amide bond enzymatic hydrolysis, thus making
sulfonamidopeptides interesting candidates in the develop-
ment of both protease inhibitors and new drugs.[3h]
ˆ
ˆ
H) and hydrogen-bond acceptors (C O and S O). b-Sulfo-
namidopeptides are interesting compounds with which to
study the local folding propensities, and the competition
between sulfonamide, ester, carbamate, and carboxyamide as
donor/acceptor groups in the formation of intramolecular
hydrogen bonds.
Results and Discussion
The conformational preferences of b-sulfonamidopeptides in
chloroform solution were investigated by variable-temper-
ature 1H NMR spectroscopy and FT-IR spectroscopy. A
(sulfon)amide N ± H chemical shift is very sensitive to that
protonꢀs hydrogen-bonded status. Typically, it moves upfield
as the temperature is raised, which is interpreted as heat-
induced disruption of hydrogen bonding. Equilibration be-
tween hydrogen-bonded and non-hydrogen-bonded states is
fast on the NMR time scale, which means that observed
chemical shifts are weighted averages of the chemical shifts of
the contributing states.[2a, 4, 5] In contrast to NMR, hydrogen-
bonding equilibria are slow on the IR time scale, giving rise to
discrete N ± H stretch bands for hydrogen-bonded and non-
hydrogen-bonded states of a given secondary (sulfon)amide
group.[2a, 4, 5]
[*] Prof. Dr. C. Gennari, Dr. M. Gude, Dr. D. Potenza
Dipartimento di Chimica Organica e Industriale
Á
Universita di Milano
Centro CNR per lo Studio delle Sostanze Organiche Naturali
via G. Venezian 21, I-20133 Milano (Italy)
Fax : (‡ 39)2-236-4369
E-mail: cesare@iumchx.chimorg.unimi.it
Dr. U. Piarulli
A sulfonamide N ± H is more acidic (pKa is approximately
11 ± 12) and is therefore a stronger hydrogen-bond donor than
a carbamate or an amide N ± H.[2a] The hydrogen-bonding
Istituto di Scienze Mat. Fis. e Chimiche
Á
Á
II Facolta di Scienze dellꢀUniversita di Milano
via Lucini 3, 22100 Como (Italy)
1924
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Chem. Eur. J. 1998, 4, No. 10

1924±1931
acceptor scale is much more intriguing, and was derived from
the following analysis.
The DdNH/DT values for the sulfonamide protons of 1
(H[1] and H[2], Scheme 1) are similar and also rather small;[6]
for both hydrogens the SO2N groups act as the hydrogen-bond
acceptors. The more conservative conclusion is that both the
that the amide is a much better hydrogen-bond acceptor
(eight-membered-ring hydrogen bond involving H2) than the
sulfonamide (six-membered-ring hydrogen bond involving
H1) or the methyl ester (nine-membered-ring hydrogen bond
involving H1). The IR spectrum of 3 in chloroform (Figure 1
and Table 2) confirms that even at room temperature the
H[1]
N
H[2]
N
X
Y
S
O
O
R
H
1 X = CH3SO2; Y = Bn; R = H
2 X = tBuOCO; Y = Bn; R = H
3 X = CH3CO; Y = CH2COOMe; R = Et
4 X = CH3SO2; Y = CH2COOMe; R = Et
Scheme 1. Structures of the b-sulfonamidopeptides 1 ± 4.
eight-membered-ring hydrogen bond involving H2 and the
six-membered-ring hydrogen bond involving H1 are relatively
unimportant (Table 1). The large temperature dependence of
Figure 1. N ± H stretch bands (cm 1) for compound 3. Band 1: 3433
(CONH); band 2: 3370 (SO2NH); band 3: 3213 (SO2NH).
Table 1. dNH (ppm) at 300 K and DdNH/DT (ppbK 1) values for 1mm
CDCl3 solutions of b-sulfonamidopeptides 1 ± 4 in the 240 ± 300 K temper-
ature range.[a, b]
Table 2. Stretch band positions (cm 1) for compounds 3 ± 11 in 1mm CHCl3
solutions at 298 K.
ˆ
ˆ
ˆ
Com-
pound
nÄN-H
(CONH) (SO2NH)
nÄN-H
nÄ C O
nÄC O
nÄC O
Compound
dH1
dH2
Dd(NH[1])/DT
Dd(NH[2])/DT
(CO-NH) (O-CO-NH) (CO-OMe)
1
2
3
4
5.00
5.07
5.66
5.29
4.66
4.81
5.92
5.32
3.8
1.7
1.1
5.3
9.1
11.0
2.3
3
4
5
6
7
8
9
3433
±
3370, 3213
3379, 3295
3363, 3252
3370, 3238
3370, 3219
3381, 3266
1664
±
±
1752
1748
±
±
±
±
±
3446
3428
3437
3436
3431
1700
1693
1696
±
10.8
±
[a] The resonances of N-H protons are resolved at all temperatures studied.
These resonances were assigned either by their splitting patterns or by
homonuclear decoupling experiments. [b] For all compounds described,
NMR experiments show that the N-H proton chemical shifts are
independent of concentration at 240 ± 300 K, at or below 5 Â 10 3 m, and
therefore all experiments were conducted using 1 Â 10 3 m solutions.
1741
1742
±
1664
3376, 3315, 1671
3270, 3250
±
10
11
±
3379, 3352,
3307
±
±
±
1747
±
3428
3381, 3309, 1672
3285
H2 in compound 2 (DdNH[2]/DTˆ 9.1 ppb/K)[6] shows that
the carbamate is a better hydrogen-bond acceptor (eight-
membered-ring hydrogen bond involving H2) than the
sulfonamide. In addition, the large temperature dependence
of H2 in compound 3 (DdNH[2]/DTˆ 11.0 ppb/K)[6] shows
sulfonamide proton (H2) is largely hydrogen-bonded to the
amide carbonyl group.[7] The large temperature dependence
of H1 in compound 4 (DdNH[1]/DTˆ 10.8 ppb/K)[6] shows
that even the methyl ester (nine-membered-ring hydrogen
bond involving H1) is a better hydrogen-bond acceptor than
the sulfonamide (eight-membered-ring hydrogen bond in-
volving H2) (Figure 2). The IR spectrum of 4 in chloroform at
room temperature (Figure 3 and Table 2) shows a hydrogen-
bonded SO2N ± H, a nonhydrogen-bonded SO2N ± H, and a
weakly hydrogen-bonded ester carbonyl group CO ± OMe.[7]
It is worth noting that the above preferences are not
consistent with entropic effects (a more negative entropy
value is expected for a large-ring formation than for a small-
ring formation).
Interpretation of the data for larger molecules 5 ± 11
(Scheme 2) is more difficult since there seem to be many
hydrogen-bonding possibilities in these cases. However, some
common features are still evident and worthy of comment.
Given the relative unimportance of the six- and eight-
membered-ring hydrogen bonds involving a sulfonamide as
Abstract in Italian: Le preferenze conformazionali dei b-
solfonammidopeptidi in soluzione di cloroformio sono state
studiate mediante spettroscopia 1H-NMR a temperatura varia-
bile e spettroscopia FT-IR. Dagli esperimenti Ø stata ricavata la
seguente scala di efficacia come accettore di legame ad
idrogeno: RCON ꢀ tBuOCON > COOMe ꢁ RSO2N. Uno stu-
dio intermolecolare ha fornito risultati che sono complemen-
tari a quelli descritti qui sopra: le bande di stiramento degli
N ± H della N-metilacetammide e della N-metil metansolfo-
nammide in cloroformio sono state seguite durante titolazione
con eccesso di metansolfonilpirrolidina e N,N-dimetilacetam-
mide. Furono osservati spostamenti a frequenze piœ basse, che
sono correlati alla forza dei legami ad idrogeno, e che
mostrano che lꢀammide Ø un accettore di legame ad idrogeno
Á
piu forte della solfonammide.
Chem. Eur. J. 1998, 4, No. 10
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C. Gennari, D. Potenza et al.
FULL PAPER
(DdNH[2]/DTˆ 1.6 ± 7.3 ppb/K) owing to a less impor-
tant competing eight-membered-ring hydrogen bond involv-
ing the carbamate or the carboxyamide as hydrogen-bond
acceptors (and/or nine-membered-ring hydrogen bond in-
volving the methyl ester as acceptor in the case of 7 and 8).
The IR spectra of 5 and 6 in chloroform at room temper-
ature (Table 2) confirm the presence of a sulfonamide proton
largely hydrogen-bonded to the carbamate carbonyl group.[7]
The IR spectra of 7 and 8 (Table 2) show a hydrogen-bonded
SO2N ± H, a non-hydrogen-bonded SO2N ± H, a non-hydro-
gen-bonded CON ± H, a hydrogen-bonded carbamate carbon-
yl group (7), a hydrogen-bonded amide carbonyl group (8),
and a weakly hydrogen-bonded ester carbonyl group (Fig-
ure 4).[7]
H
H
O
O
O
O
O
S
O
H1
H1
N
N
S
S
N
N
S
O
O
H2
O
H2
O
O
O
Figure 2. Compound 4: the methyl ester (nine-membered-ring H-bond
involving H[1]) is a better hydrogen-bond acceptor than the sulfonamide
(eight-membered-ring H-bond involving H[2]).
Figure 3. N ± H stretch bands (cm 1) for compound 4. Band 1: 3379
(SO2NH); band 2: 3295 (SO2NH).
acceptor, b-sulfonamidopeptides 5 ± 8 (Scheme 2) show a
strong preference for a twelve-membered-ring hydrogen
Figure 4. N ± H stretch bands (cm 1) for compound 7. Band 1: 3437
(CONH); band 2: 3370 (SO2NH); band 3: 3219 (SO2NH).
H[1]
N
H[2]
N
H[3]
N
X
S
S
Y
The strong temperature dependence of protons H2 and H3
1O
O
H
O
R
O
H
R
of b-sulfonamidopeptide 9 indicates the preference for a
ˆ
twelve-membered-ring hydrogen bond (H3 ± O C ± N,
5 X = tBuOCO; Y = Bn; R = R1 = H
6 X = tBuOCO; Y = Bn; R = R1 = Bn
7 X = tBuOCO; Y = CH2COOMe; R = R1 = Bn
8 X = CH3CO; Y = CH2COOMe; R = Me; R1 = Et
9 X = CH3CO; Y = CH2CONH[4]Bn; R = Me; R1 = Et
10 X = CH3SO2; Y = CH2COOMe; R = Me; R1 = Et
11 X = CH3SO2; Y = CH2CONH[4]Bn; R = Me; R1 = Et
DdNH[3]/DTˆ 9.7 ppb/K), a eight- and a nine-membered-
ˆ
ring hydrogen bond (H2 ± O C ± N, DdNH[2]/DTˆ
10.6 ppb/K), all of which involve carboxyamides as hydro-
gen-bond acceptors.[6] The IR spectrum of compound 9 (four
different N ± H groups, two carboxyamides and two sulfona-
mides) shows five different N ± H peaks (Table 2 and Fig-
ure 5). A tentative attribution is as follows: a non-hydrogen-
Scheme 2. The structures of b-sulfonamidopeptides 5 ± 11.
bonded CON ± H (3431 cm 1),
a non-hydrogen-bonded
SO2N ± H (3376 cm ), a weakly hydrogen-bonded SO2N ± H
(3315 cm ), two differently hydrogen-bonded SO2N ± H
(3270, 3250 cm ), and a hydrogen-bonded amide carbonyl
group (Figure 5).[7] The 3315 cm SO2N ± H is probably
1
ˆ
bond (H3 ± O C, DdNH[3]/DTˆ 8.6 ± 19.0 ppb/K) in-
1
volving the carbamate or the carboxyamide as hydrogen-
bond acceptors (Table 3). Sulfonamide protons H2 show a
reduced temperature dependence in compounds 5 ± 8
1
1
Table 3. dNH (ppm) at 300 K and DdNH/DT (ppbK 1) values for 1mm CDCl3 solutions of b-sulfonamidopeptides 5 ± 11 in the 240 ± 300 K temperature
range.[a, b]
Compound
dH1
dH2
dH3
dH4
Dd(NH[1])/DT
Dd(NH[2])/DT
Dd(NH[3])/DT
Dd(NH[4])/DT
5
6
7
8
9
10
11
5.04
4.62
4.60
5.57
5.75
4.91
5.13
5.44
5.06
5.92
5.84
6.21
5.48
6.16
5.85
5.52
6.92
6.63
6.52
5.52
5.84
±
±
±
±
6.45
±
6.36
0.7
0.0
0.0
1.0
4.4
2.3
6.6
4.5
1.6
6.0
7.3
10.6
9.3
19.0
8.6
13.6
14.3
9.7
±
±
±
±
4.1
±
8.5
7.0
9.1
8.5
[a] The resonances of N-H protons are resolved at all temperatures studied. These resonances were assigned either by their splitting patterns or by
homonuclear decoupling experiments. [b] For all compounds described, NMR experiments show that the N-H proton chemical shifts are independent of
concentration at 240 ± 300 K, at or below 5 Â 10 3 m, and therefore all experiments were conducted using 1 Â 10 3 m solutions.
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b-Sulfonamidopeptides
1924±1931
influence the DdNH/DT values. For example, in a flexible
molecule small DdNH/DT values can be associated with
amide protons that are either completely free of hydrogen
bonding (as in our case) or completely locked in an intra-
molecular hydrogen bond over the temperature range exam-
ined. These two extreme possibilities were distinguished by
analysis of the IR spectrum, and by observation of the
chemical shift value in comparison with the appropriate
reference molecules.[6] Furthermore, the magnitude of DdNH/
DT depends on the total difference in chemical shift between
fully hydrogen-bonded and completely non-hydrogen-bonded
states. Thus, for example, for the same N ± H donor, the fully
hydrogen-bonded state is not as far downfield when the
acceptor is a sulfonamide (or an ester) as when it is an amide,
which means that alternative folding patterns involving such
systems cannot be directly compared with DdNH/DT values,
particularly when numerical differences are small. For these
reasons we confirmed our conclusions with an intermolecular
study which gave results that are complementary to those
described above with the DdNH/DT data. The N ± H stretch
bands of N-methylacetamide (12) and N-methyl methanesul-
fonamide (13) in chloroform were followed during titration
with excess methanesulfonylpyrrolidine and N,N-dimethyla-
cetamide (Table 4). Shifts to lower frequencies were observed
which are correlated with the hydrogen-bond strengths and
show that the amide is a stronger hydrogen-bond acceptor
than the sulfonamide.
Figure 5. N ± H stretch bands (cm 1) for compound 9. Band 1: 3431
(CONH); band 2: 3376 (SO2NH); band 3: 3315 (SO2NH); band 4: 3270
(SO2NH); band 5: 3250 (SO2NH).
hydrogen-bonded to a sulfonamide (see the SO2N ± H values
in Table 4 and the discussion).
Table 4. N ± H stretch bands (cm 1) for N-methylacetamide (12) and N-
methylmethanesulfonamide (13) in 10mm CHCl3 solutions at 298 K:
titration experiments.
Compound nÄN ± H
nÄ N ± H with excess
methanesulfonyl-
pyrrolidine
nÄN ± H with excess N,N-
dimethylacetamide
12
13
3466
3397
3466, 3410
3397, 3307
3466, 3342
3397, 3255
In summary, the following hydrogen-bonding acceptor scale
was derived from the above experiments: RCON ꢀ
tBuOCON > COOMe ꢁ RSO2N. While the position in the
scale of the first three functional groups is expected (an ester
carbonyl group is known to be a weaker hydrogen-bond
acceptor than an amide carbonyl group),[4a, d] the very poor
acceptor ability of the sulfonamide group is more noticeable,
and confirms the recent theoretical studies by Houk et al.[8a]
Analysis of a number of X-ray structures also reveals that the
Substitution of the terminal acetamide of 8 with a
methanesulfonamide gives compound 10, where both H2
[DdNH[2]/DTˆ 9.3 ppb/K, sulfonamide (eight-membered
ring) and ester (nine-membered ring) as acceptors] and H3
[DdNH[3]/DTˆ 8.5 ppb/K, sulfonamide (eight- and twelve-
membered rings) as acceptor] exhibit a rather strong temper-
ature dependence. The IR spectrum of 10 in chloroform at
room temperature (Table 2) shows three different SO2N ± H
ˆ ˆ
N ± H ± O S O hydrogen bond is much weaker than the N ±
1
[8b, c]
peaks [weakly bonded (3307, 3352 cm ) and non-hydrogen
ˆ
H ± O C hydrogen bond.
Even structures which are
1
bonded (3379 cm )], and a weakly hydrogen-bonded ester
intramolecularly hydrogen-bonded in the crystal with the
oxygen of RSO2N as acceptor group[2a, d] will use different
acceptors (for example carbonyls, if available) in chloroform
solution.
1
carbonyl group.[7] The 3307 and 3352 cm SO2N ± H are
probably hydrogen-bonded to a sulfonamide or an ester (see
the SO2N ± H values in Table 4 and the relevant discus-
sion).
Substitution of the terminal acetamido group of 9 with a
methanesulfonamido group yields compound 11, in which H2
experiences a larger temperature dependence (DdNH[2]/
DTˆ 9.1 ppb/K, nine-membered-ring hydrogen-bond in-
volving the carboxyamide as acceptor) than H3 (DdNH[3]/
DTˆ 7.0 ppb/K, eight- and twelve-membered-ring hydro-
gen bonds involving the sulfonamide as acceptor).
The DdNH/DT data discussed above may sometimes be
difficult to interpret, and should be used cautiously to infer
hydrogen-bond strength. In fact it is true that the DdNH/DT
values are related to the effect of temperature on the
equilibrium between hydrogen-bonded and non-hydrogen-
bonded states, which is in turn related to the enthalpy
difference between these two states and between alternative
folding patterns (at least in weakly polar solvents like
chloroform). However, a number of other factors can also
Experimental Section
General: NMR spectra were recorded on Bruker AC-200, AC-300, AC-
500, Varian XL-200 and XL-400 instruments. IR spectra were recorded
with a Jasco-FT300E spectrometer. All products were purified by flash
chromatography with a 230 ± 400 mesh silica gel (Merck). TLC analyses
were performed with 0.25 mm 60F254 silica plates (Merck). All solvents
were distilled over drying agents under a nitrogen atmosphere: tetrahy-
drofuran (THF), Et2O, benzene, toluene over sodium; dichloromethane
(DCM), diisopropylethylamine (DIPEA), triethylamine (TEA), N,N-
dimethylformamide (DMF) over CaH2; MeOH over BaO. All reactions
were carried out under nitrogen. Organic extracts were dried over Na2SO4.
Synthetic procedures: The synthesis of compounds 1, 2,
5 (taurine
derivatives) followed the guidelines reported in ref. [1i]; the synthesis of
compounds 6, 7 followed the guidelines reported in ref. [3e]. The synthesis
of compounds 3, 4, 8 ± 11 was performed on solid-phase support by means
of a Fmoc-protection adapted strategy: Fmoc-Gly-OH was attached as a
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C. Gennari, D. Potenza et al.
FULL PAPER
linker to the polymeric support (Wang ± Merrifield resin, P-CH2OH),[9] by
removed in vacuo. The crude product was purified by flash chromatog-
raphy (DCM/MeOH 10:1) to give the desired methyl esters in 85 ± 95%
yields.
[10]
Â
means of the coupling procedure of Patek et al.
The loading was
determined by Fmoc deprotection (see details below) and quantitative
picric acid monitoring,[11] and was found to be about 0.72 mmolg 1. The
resin Fmoc-Gly-OCH2-P was subjected to an iterative deprotection-
(coupling-deprotection)n scheme (n ˆ 1 for compounds 3, 4; n ˆ 2 for
compounds 8 ± 11), followed by final capping and cleavage, as outlined
below.
7) Cleavage from the resin to give an acid, and subsequent transformation
into a benzylamide (for compounds 9, 11): A suspension of the resin
(0.144 mmol) in TFA/water (95:5, 4 mL) was shaken (wrist-shaker) for
2.5 h. The resin was filtered and washed with TFA (2 Â 3 mL) and DCM
(2 Â 3 mL), and the combined organic phases were removed in vacuo. The
crude product (a white solid) was dissolved in DMF (1.9 mL), cooled to
08C, and treated with benzylamine (0.016 mL, 0.144 mmol), 2,4,6-trime-
thylpyridine (0.039 mL, 0.288 mmol), and O-(7-azabenzotriazole-1-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (54 mg,
0.144 mL). Stirring was continued for 1 h at 08C and for 17 h at room
temperature, then the mixture was diluted with water (10 mL), and the
aqueous phase extracted with DCM (3 Â 3 mL). The organic phase was
washed with an aqueous solution of citric acid (2  3 mL, pH ˆ 2.5) and
dried. The solvent was removed in vacuo, and the crude product was
purified by flash chromatography (DCM/MeOH 10:1) to give the desired
benzylamides in 65 ± 75% yields.
1) Fmoc deprotection: The resin (containing Fmoc-protected amino groups,
0.144 mmol) was treated with 20% piperidine in DMF [1 Â 3 mL (3 min),
1 Â 3 mL (17 min)], followed by washings with DMF (4 Â 3 mL) and DCM
(4 Â 3 mL).
2) Preparation of (S)-Fmoc-NHCH(Me)CH2SO2Cl and (S)-Fmoc-
‡
NHCH(Et)CH2SO2Cl: The substituted taurines[3e, 12] [ NH3CH(Me)-
‡
CH2SO3 and NH3CH(Et)CH2SO3 ] (0.50 mmol) and nBu4NOH ´ 30H2O
(400 mg, 0.50 mmol) were dissolved in water (0.40 mL). The mixture was
stirred for 5 min, cooled to 08C, and treated with NaHCO3 (42 mg,
0.5 mmol) and Fmoc-O-succinimide (Fmoc-ONSu) (185 mg, 0.55 mmol).
Stirring was continued overnight (08C to room temperature), then the
reaction mixture was diluted with water (20 mL), and the aqueous phase
extracted with DCM (3 Â 10 mL). The extracts were combined, washed
with brine (2 Â 5 mL), and dried. The solvent was removed in vacuo, and
the crude product was dissolved in DCM (3.6 mL) and treated with DMF
(3.4 mg, 0.046 mmol). The reaction mixture was cooled to 08C and a
solution of triphosgene (83 mg, 0.31 mmol) in DCM (1 mL) was added
dropwise. Stirring was continued for 1 h at 08C and 30 min at room
temperature. The mixture was purified by flash chromatography (10:1
EtOAc/DCM) to give the desired sulfonyl chloride as a white powder.
(S)-Fmoc-NHCH(Me)CH2SO2Cl (95 mg, 50%). 1H NMR (200 MHz,
CDCl3): d ˆ 1.50 (d, J ˆ 6.5 Hz, 3H, CH3CH), 3.75 ± 4.60 (m, 3H,
CH2SO2 ‡ CHN), 4.25 (t, J ˆ 6 Hz, 1H, ArCHCH2O), 4.48 (m, 2H,
ArCHCH2O), 7.30 ± 7.49 (m, 4H, aromatic H), 7.60 (d, J ˆ 7.8 Hz, 2H,
aromatic H), 7.78 (d, J ˆ 8.3 Hz, 2H, aromatic H); 13C NMR (CDCl3): d ˆ
19.5 (CH3), 44.4 (CH2SO2), 47.1 (CHN), 66.8 (CHCH2O), 69.3 (CHCH2O),
CH3SO2NHCH2CH2SO2NHBn (1):
A solution of BocNHCH2CH2-
SO2NHBn (2) (1.335 g, 4.25 mmol; for the preparation of 2, see details
below) in dichloromethane (21.25 mL) was treated with trifluoroacetic acid
(21.25 mL) at 08C. The mixture was stirred for 20 min, then evaporated
under vacuum to give the crude trifluoroacetate salt (1.394 g, 100%). A
solution of mesyl chloride (0.487 g, 4.25 mmol) in dichloromethane
(10 mL) was cooled to 08C and treated with a solution of the above
trifluoroacetate salt (1.394 g, 4.25 mmol) and 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) (1.518 mL, 10.19 mmol) in dichloromethane (2.5 mL) by
dropwise addition (20 min). The mixture was stirred overnight at room
temperature, then diluted with dichloromethane (20 mL), washed with
aqueous NH4Cl sat. soln. (10 mL) and brine (10 mL), and then dried and
evaporated. The crude product was purified by flash chromatography (n-
hexane/EtOAc 1:2) to give the desired taurine derivative 1 (0.633 g, 51%),
m.p. ˆ 129 ± 1308C; 1H NMR (200 MHz, [D6]acetone): d ˆ 2.98 (s, 3H,
CH3SO2), 3.30 (t, J ˆ 6.7 Hz, 2H, CH2SO2), 3.53 (brt, J ˆ 6.7 Hz, 2H,
CH2NHSO2), 4.33 (d, 2H, NHCH2Ph), 6.20 (brt, 1H, NH), 6.70 (brt, 1H,
NH), 7.25 ± 7.45 (m, 5H, aromatic H); C10H16N2O4S2 (292.4): calcd C 41.08,
H 5.52, N 9.58; found C 40.75, H 5.68, N 9.39.
ˆ
ˆ
ˆ
ˆ
119.9 (C ), 124.8 (C ), 127.0 (C ), 127.7 (C ); C18H18ClNO4S (379.86):
calcd C 56.92, H 4.78, N 3.69; found C 56.81, H 4.90, N 3.60.
(S)-Fmoc-NHCH(Et)CH2SO2Cl (116 mg, 59%). 1H NMR (200 MHz,
CDCl3): d ˆ 1.0 (t, J ˆ 7 Hz, 3H, CH3CH2), 1.7 (q, J ˆ 7 Hz, 2H, CH2CH3),
3.9 ± 4.2 (m, 3H, CHN ‡ CH2SO2), 4.23 (t, J ˆ 6 Hz, 1H, ArCHCH2O), 4.45
(m, 2H, ArCHCH2O), 5.06 (m, 1H, NH), 7.38 ± 7.50 (m, 4H, aromatic H),
7.62 (d, J ˆ 8 Hz, 2H, aromatic H), 7.79 (d, J ˆ 7 Hz, 2H, aromatic H);
C19H20ClNO4S (393.89): calcd C 57.94, H 5.12, N 3.56; found C 57.76, H 5.07,
N 3.49.
BocNHCH2CH2SO2NHBn (2):[1i] A solution of taurine (4.0 g, 32 mmol) in
aqueous NaOH (2.0m, 16.0 mL, 32 mmol) was treated by dropwise
addition with a solution of (Boc)2O (6.98 g, 32 mmol) in THF (10.0 mL)
at room temperature, while being stirred (CO2 evolved). The mixture was
stirred at room temperature for 15 h and the disappearance of (Boc)2O was
monitored by TLC; the resulting mixture was extracted once with ethyl
ether (20 mL). The aqueous phase was diluted with water (170 mL), treated
with LiOH ´ H2O (1.342 g, 32 mmol) and nBu4NHSO4 (10.86 g, 32 mmol),
and stirred at room temperature for 30 min. The resulting mixture was then
extracted with dichloromethane (3 Â 120 mL), the organic phase dried and
evaporated at reduced pressure, and the product pumped (0.1 mmHg). N-
3) Coupling reactions: A suspension of the resin (containing free amino
groups, 0.144 mmol) in dichloromethane (3 mL) was treated with the
Fmoc-protected
sulfonyl
chloride
(S)-Fmoc-NHCH(R)CH2SO2Cl
(0.288 mmol), 1-methoxy-2-methyl-1-trimethylsilyloxypropene[3e] (100 mg,
0.57 mmol) and 4-dimethylaminopyridine (DMAP) (7 mg, 0.057 mmol).
The mixture was shaken for 18 h (wrist-shaker), the resin filtered and
washed with DMF (4 Â 3 mL) and DCM (4 Â 3 mL). The progress of the
coupling reactions (absence of free amino groups) was followed with the
trinitrobenzenesulfonic acid test.[13]
‡
Boc-taurine nBu4N salt (13.57 g, 91%) was used in the next reactions
without further purification. 1H NMR (200 MHz, CDCl3): d ˆ 1.0 [t, J ˆ
‡
7.7 Hz, 12H, (CH3CH2CH2CH2)4N ], 1.40 [s, 9H, (CH3)3C], 1.4 ± 1.6 [m,
‡
‡
8H, (CH3CH2CH2CH2)4N ], 1.6 ± 1.8 [m, 8H, (CH3CH2CH2CH2)4N ], 2.9
‡
4) Capping with mesyl chloride (for compounds 4, 10, 11): A suspension of
the resin (0.144 mmol) in DCM (3 mL) was treated with MsCl (0.035 mL,
0.43 mmol), 1-methoxy-2-methyl-1-trimethylsilyloxypropene[3e] (0.20 mL,
0.86 mmol) and DMAP (8 mg, 0.058 mmol). The mixture was shaken
(wrist-shaker) for 18 h, and the resin was filtered and washed with DMF
(4 Â 3 mL) and DCM (4 Â 3 mL). The progress of the capping reactions
(absence of free amino groups) was followed with the trinitrobenzenesul-
fonic acid test.[13]
(m, 2H), 3.3 [t, J ˆ 7.7 Hz, 8H, (CH3CH2CH2CH2)4N ], 3.57 (m, 2H), 6.19
(br, 1H, NH).
‡
A solution of N-Boc-taurine nBu4N salt (3.728 g, 8.0 mmol) in dichloro-
methane (28 mL) was treated with DMF (0.064 mL, 0.82 mmol) and then
with triphosgene (0.952 g, 3.20 mmol) at room temperature, with stirring.
The reaction mixture was stirred at room temperature for a further 30 min,
then cooled to 08C and treated with
a solution of DBU (2.5 mL,
16.80 mmol) and benzylamine (1.3 mL, 12.0 mmol) in dichloromethane
(4.0 mL) by dropwise addition (20 min). The mixture was stirred overnight
at room temperature, then diluted with dichloromethane (28 mL), washed
with aqueous NH4Cl sat. soln. (50 mL) and brine (50 mL), and then dried
and evaporated. The crude product was purified by flash chromatography
(n-hexane/EtOAc 1:1) to give the desired N-benzyl sulfonamide (2)
(2.047 g, 81.5%). 1H NMR (200 MHz, CDCl3): d ˆ 1.40 [s, 9H, (CH3)3C],
3.1 (t, J ˆ 6.6 Hz, 2H, CH2SO2), 3.5 (q, J ˆ 6.6 Hz, 2H, CH2NHCO), 4.3 (d,
J ˆ 6.6 Hz, 2H, NHCH2Ph), 4.81 (brt, 1H, NH), 5.07 (t, J ˆ 6.6 Hz, 1H,
NH), 7.3 ± 7.4 (m, 5H, aromatic H); C14H22N2O4S (314.4): calcd C 53.48, H
7.05, N 8.91; found C 53.29, H 7.12, N 8.81.
5) Capping with acetylimidazole (for compounds 3, 8, 9): A suspension of
the resin (0.144 mmol) in DCM (3 mL) was treated with acetylimidazole
(160 mg, 1.44 mmol). The mixture was shaken (wrist-shaker) for 18 h, and
the resin was filtered and washed with DMF (4 Â 3 mL) and DCM (4 Â
3 mL). The progress of the capping reactions (absence of free amino
groups) was followed with the trinitrobenzenesulfonic acid test.[13]
6) Cleavage from the resin to give a methyl ester (for compounds 3, 4, 8, 10):
A suspension of the resin (0.144 mmol) in MeOH/NEt3 (9:1 v/v, 3 mL) was
shaken (wrist-shaker) for 60 h. The resin was filtered and washed with
MeOH/NEt3 (9:1 v/v, 2 Â 3 mL), and the combined organic phases were
1928
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0410-1928 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 10

b-Sulfonamidopeptides
1924±1931
(S)-CH3CONHCH(Et)CH2SO2NHCH2COOMe (3): This compound was
synthesized according to the solid-phase protocol described above in the
paragraph synthetic procedures. IR (CHCl3): nÄ ˆ 1664 cm 1 (CO-NH), 1752
(CO-OMe), 3213 (SO2-NH), 3370 (SO2-NH), 3433 (CO-NH); 1H NMR
(200 MHz, CDCl3): d ˆ 0.98 (t, J ˆ 7 Hz, 3H, CH3), 1.56 ± 1.76 (m, 2H,
CH2), 2.0 (s, 3H, CH3CO), 3.12 (dd, J ˆ 10, 14 Hz, 1H, CHaHbSO2), 3.29
(dd, J ˆ 3.5, 14 Hz, 1H, CHaHbSO2), 3.75 (s, 3H, CH3O), 3.92 (dd, J ˆ 5,
19 Hz, 1H, CHaHbCO), 4.08 (dd, J ˆ 7, 19 Hz, 1H, CHaHbCO), 4.59 (m, 1H,
CHN), 5.66 (d, J ˆ 9 Hz, 1H, NHCH), 5.92 (dd, J ˆ 5, 7 Hz, 1H, NHCH2);
13C NMR (CDCl3): d ˆ 10.1 (CH3CH2), 23.2 (CH3CO), 27.5 (CH3CH2), 44.1
(CH2SO2), 47.2 (CHN), 52.4 (CH3O), 56.7 (CH2CO); C9H18N2O5S (266.32):
calcd C 40.59, H 6.81, N 10.52; found C 40.48, H 6.90, N 10.41.
benzylamine (11 mg, 0.10 mmol) in DCM (0.5 mL) was added. Stirring was
continued for 2 h and the organic phase was washed with an aqueous
solution of citric acid (1 mL, pH ˆ 4) and dried. The solvent was removed in
vacuo and the crude product was purified by flash chromatography (10:1
EtOAc/DCM) to give the desired product as a white/pale-yellow solid
(39 mg, 96%). 1H NMR (200 MHz, CDCl3): d ˆ 1.38 [s, 9H, C(CH3)3], 2.81
(m, 2H, CH2Ph), 2.96 (dd, J ˆ 4, 15 Hz, 1H, CHaHbSO2), 3.10 (dd, J ˆ 8,
15 Hz, 1H, CHaHbSO2), 4.20 (m, 1H, CHN), 4.23 (d, J ˆ 6 Hz, 2H,
NCH2Ph), 4.90 (d, J ˆ 9 Hz, 1H, NHCO), 5.60 (m, 1 H, NHCH2), 7.1 ± 7.4
(m, 4H, aromatic H); 13C NMR (CDCl3): d ˆ 28.2 [C(CH3)3], 40.1 (CH2Ph),
47.2 (CH2SO2), 48.1 (CHN), 56.0 (NCH2), 81.0 [C(CH3)3], 127.0, 128.3,
128.9, 130.0, 136.8, 137.0 (6C ˆ ), 155.9 (NCO); C21H28N2O4S (404.53): calcd
C 62.35, H 6.98, N 6.92; found C 62.15, H 7.07, N 6.88.
(S)-CH3SO2NHCH(Et)CH2SO2NHCH2COOMe (4): This compound was
synthesized according to the solid-phase protocol described above in the
c) (S)-BocNHCH(Bn)CH2SO2NHBn (21.4 mg, 0.053 mmol) was dissolved
in a HCl solution (3m) in MeOH (1 mL) and stirred until TLC analysis
indicated the absence of starting material (ca. 20 h). The solvent was
removed in vacuo and the crude product was dissolved in DCM (1.5 mL).
(S)-BocNHCH(Bn)CH2SO2Cl (27 mg, 0.081 mmol), DMAP (1 mg,
1
paragraph synthetic procedures. IR (CHCl3): nÄ ˆ 1748 cm (CO-OMe),
3295 (SO2-NH), 3379 (SO2-NH); 1H NMR (200 MHz, CDCl3): d ˆ 1.0 (t,
J ˆ 7 Hz, 3H, CH3), 1.64 ± 1.84 (m, 2H, CH2), 3.05 (s, 3H, CH3SO2), 3.3 (m,
2H, CH2SO2), 3.8 (s, 3H, CH3O), 3.9 ± 4.1 (m, 3H, CH2CO ‡ CHN), 5.29
(m, 1H, NH), 5.32 (m, 1H, NH); 13C NMR (CDCl3): d ˆ 9.7 (CH3CH2),
29.5 (CH3CH2), 41.8 (CH3SO2), 44.1 (CH2SO2), 51.6 (CHN), 52.7 (CH3O),
56.7 (CH2CO); C8H18N2O6S2 (302.37): calcd C 31.79, H 6.00, N 9.26; found
C 31.60, H 6.09, N 9.21.
0.008 mmol),
and
1-methoxy-2-methyl-1-trimethylsilyloxypropene[3e]
(36 mg, 0.21 mmol) were added and stirring was continued for 6 h. The
organic phase was washed with an aqueous solution of citric acid (1 mL,
pH ˆ 4) and dried. The solvent was removed in vacuo and the crude
product was purified by flash chromatography (10:1 EtOAc/DCM) to give
the desired product 6 as a white solid (22 mg, 69%). IR (CHCl3): nÄ ˆ
BocNHCH2CH2SO2NHCH2CH2SO2NHBn (5):[1i]
A
solution of
BocNHCH2CH2SO2NHBn (2) (1.335 g, 4.25 mmol) in dichloromethane
(21.25 mL) was treated with trifluoroacetic acid (21.25 mL) at 08C. The
mixture was stirred for 20 min, then evaporated under vacuum to give the
crude trifluoroacetate salt (1.394 g, 100%). A solution of N-Boc-taurine
1
1693 cm (O-CO-NH), 3238 (SO2-NH), 3370 (SO2-NH), 3428 (CO-NH);
1H NMR (200 MHz, CDCl3): d ˆ 1.37 [s, 9H, C(CH3)3], 2.5 ± 3.1 (m, 8H,
CH2SO2 ‡ CH2-Ph), 2.8 ± 4.1 (m, 3H, NHCH ‡ NCH2Ph), 4.36 (brs, 1H,
NHCH), 4.62 (brs, 1H, NHCO), 5.06 (brs, 1H, SO2NHCH), 5.52 (brs, 1H,
SO2NHBn), 7.19 (m, 15H, aromatic H); 13C NMR (CDCl3): d ˆ 28.3
[C(CH3)3], 40.0 ‡ 42.0 (CH2Ph), 47.0 ‡ 48.0 (CH2SO2), 51.9 (2CHN), 56.0
‡
nBu4N salt (1.32 g, 2.83 mmol) (see details above in the preparation of 2)
in dichloromethane (10 mL) was treated with DMF (0.025 mL, 0.32 mmol)
and then with triphosgene (0.336 g, 1.132 mmol) at room temperature, with
stirring. The reaction mixture was stirred at room temperature for 30 min,
then cooled to 08C and treated with a solution of the above trifluoroacetate
salt (1.394 g, 4.25 mmol) and DBU (1.518 mL, 10.19 mmol) in dichloro-
methane (2.5 mL) by dropwise addition (20 min). The mixture was stirred
overnight at room temperature, then diluted with dichloromethane
(20 mL), washed with aqueous NH4Cl sat. soln. (10 mL) and brine
(10 mL), and then dried and evaporated. The crude product was purified
by flash chromatography (n-hexane/EtOAc 1:2) to give the desired taurine
dimer 5 (0.751 g, 63%), m.p. ˆ 132 ± 1338C; IR (CHCl3): nÄ ˆ 1700 cm 1 (O-
CO-NH), 3252 (SO2-NH), 3363 (SO2-NH), 3446 (CO-NH); 1H NMR
(200 MHz, CDCl3): d ˆ 1.40 [s, 9H, C(CH3)3], 3.1 (brt, 2H), 3.2 (t, J ˆ
6.3 Hz, 2H), 3.4 ± 3.6 (m, 4H), 4.33 (d, J ˆ 5.8 Hz, 2H, NHCH2Ph), 5.04 (br,
1H, NH), 5.44 (br, 1H, NH), 5.85 (br, 1H, NH), 7.3 ± 7.4 (m, 5H, aromatic
H); 13C NMR (CDCl3): d ˆ 28.960 (3CH3), 36.375, 38.717, 47.799, 52.001,
(NCH2Ph), 81.1 [C(CH3)3], 126.8, 127.3, 128.0, 128.2, 128.6, 128.9, 129.5,
‡
ˆ
129.7, 136.3, 136.7, 136.8 (11C ), 155.7 (NCO); MS (FAB ): m/z ˆ 694
‡
‡
‡
[M ‡glycerol‡H], 623 [M ‡Na H], 501 [M
C5H8O2]; C30H39N3O6S2
(601.79): calcd C 59.88, H 6.53, N 6.98; found C 59.70, H 6.61, N 6.91.
(S,S)-BocNHCH(Bn)CH2SO2NHCH(Bn)CH2SO2NHCH2CO2Me (7)
a) (S)-BocNHCH(Bn)CH2SO2NHCH2CO2Me.
A
solution of (S)-
BocNHCH(Bn)CH2SO2Cl (200 mg, 0.60 mmol) in DCM (6 mL) was
treated with glycine methyl ester hydrochloride (75 mg, 0.60 mmol) and
DMAP (147 mg, 1.20 mmol). Stirring was continued for 3 h and the solvent
was removed in vacuo. The crude product was purified by flash
chromatography (10:1 EtOAc/DCM) to give the desired product as a
clear syrup (160 mg, 69%). 1H NMR (200 MHz, CDCl3): d ˆ 1.38 [s, 9H,
C(CH3)3], 2.92 (m, 2H, CH2Ph), 3.18 (m, 2H, CH2SO2), 3.73 (s, 3H, OCH3),
3.92 (t, J ˆ 6 Hz, 2H, CH2CO), 4.59 (m, 1H, CHN), 4.92 (m, 1H, NH), 5.80
(m, 1H, NH); 13C NMR (CDCl3): d ˆ 28.2 [C(CH3)3], 40.6 (CH2Ph), 44.2
(CH2SO2), 48.2 (CHN), 52.4 (OCH3), 56.3 (CH2CO), 80.2 [C(CH3)3], 126.9,
ˆ
ˆ
ˆ
53.034, 81.257, 128.780 (2CH ), 128.916 (1CH ), 129.650 (2CH ), 137.347
‡
ˆ
ˆ
(C ), 156.876 (C O); MS (FAB ): m/z ˆ 91, 106, 125, 215, 232, 276, 322,
366, 422 (M‡1); C16H27N3O6S2 (421.5): calcd C 45.59, H 6.46, N 9.97; found
C 45.40, H 6.60, N 9.85.
ˆ
128.6, 129.4, 136.4 (4C ), 155.9 (NCO), 170.5 (COOCH3); C17H26N2O6S
(386.47): calcd C 52.83, H 6.78, N 7.25; found C 52.72, H 6.83, N 7.16.
(S,S)-BocNHCH(Bn)CH2SO2NHCH(Bn)CH2SO2NHBn (6):
b) (S)-BocNHCH(Bn)CH2SO2NHCH2CO2Me (151 mg, 0.39 mmol) was
dissolved in a HCl solution (3m) in MeOH (2 mL) and stirred until TLC
analysis indicated the absence of starting material (ca. 20 h). The solvent
was removed in vacuo and the crude product was dissolved in DCM
(5.8 mL). (S)-BocNHCH(Bn)CH2SO2Cl (193 mg, 0.58 mmol) and DMAP
(95 mg, 0.78 mmol) were added and stirring was continued for 3 h. The
organic phase was washed with water (2 mL) and dried. The solvent was
removed in vacuo and the crude product was purified by flash chromatog-
raphy (10:1 EtOAc/DCM) to give the desired product 7 as a white solid
‡
a) (S)-BocNHCH(Bn)CH2SO2Cl: (S)-2-benzyltaurine[3e, 12] [ NH3CH-
(Bn)CH2SO3 ] (100 mg, 0.46 mmol) and nBu4NOH ´ 30H2O (409 mg,
0.51 mmol) were dissolved in water (0.64 mL). The mixture was stirred
for 5 min and a solution of Boc2O (101 mg, 0.46 mmol) in THF (0.92 mL)
was added. Stirring was continued overnight, then the reaction mixture was
diluted with water (10 mL) and the aqueous phase extracted with DCM
(3 Â 5 mL). The extracts were combined, washed with brine (5 mL) and
dried. The solvent was removed in vacuo and the crude product was
dissolved in DCM (3.6 mL) and treated with DMF (3.4 mg, 0.046 mmol).
The reaction mixture was cooled to 08C and a solution of triphosgene
(83 mg, 0.31 mmol) in DCM (1 mL) was added dropwise. Stirring was
continued for 1 h at 08C and 30 min at room temperature. The mixture was
purified by flash chromatography (10:1 EtOAc/DCM) to give the desired
sulfonyl chloride as a white powder (107 mg, 70%). 1H NMR (200 MHz,
CDCl3): d ˆ 1.43 [s, 9H, C(CH3)3], 3.09 (m, 2H, CH2Ph), 3.90 (dd, J ˆ 5,
15 Hz, 1H, CHaHbSO2), 4.00 ± 4.45 (m, 2H, CHaHbSO2 ‡ CHN), 4.90 (m,
1H, NH), 7.18 ± 7.42 (m, 5H, aromatic H); C14H20ClNO4S (333.83): calcd C
50.37, H 6.04, N 4.20; found C 50.28, H 6.16, N 4.17.
1
(99 mg, 43%). IR (CHCl3): nÄ ˆ 1696 cm (O-CO-NH), 1741 (CO-OMe),
3219 (SO2-NH), 3370 (SO2-NH), 3437 (CO-NH); 1H NMR (200 MHz,
CDCl3): d ˆ 1.34 [s, 9H, C(CH3)3], 2.8 ± 3.1 (m, 4H, CH2-Ph), 3.2 (m, 4H,
CH2SO2), 3.70 (s, 3H, CH3O), 3.86 (dd, J ˆ 4, 19 Hz, 1H, CHaHbCO), 4.07
(dd, J ˆ 9, 19 Hz, 1H, CHaHbCO), 4.18 (m, 1H, CHNH), 4.44 (m, 1H,
CHNH), 4.60 (d, J ˆ 10 Hz, 1H, NHCO), 5.92 (d, J ˆ 9 Hz, 1H,
CHNHSO2), 6.92 (brs, 1H, CH2NHSO2), 7.25 (m, 10H, aromatic H); 13C
NMR (CDCl3): d ˆ 28.2 [C(CH3)3], 40.3 ‡ 42.8 (CH2Ph), 44.2 (CH2SO2),
47.4 (CHN), 52.2 (CH3O), 52.7 (CHN), 55.2 (CH2SO2), 56.1 (CH2CO), 80.3
[C(CH3)3], 126.9, 127.1, 128.6, 128.8, 129.6, 129.7, 136.2 (7C ˆ ); MS
‡
‡
‡
‡
b) (S)-BocNHCH(Bn)CH2SO2NHBn:
(S)-BocNHCH(Bn)CH2SO2Cl
(50 mg, 0.15 mmol) was dissolved in DCM (2 mL), and a solution of 1-
methoxy-2-methyl-1-trimethylsilyloxypropene[3e] (35 mg, 0.20 mmol) and
(FAB ): m/z ˆ 606 [M ‡Na], 584 [M ‡H], 484 [M
C5H7O2];
C26H37N3O8S2 (583.73): calcd C 53.50, H 6.39, N 7.20; found C 53.48, H
6.60, N 7.13.
Chem. Eur. J. 1998, 4, No. 10
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0410-1929 $ 17.50+.25/0
1929

C. Gennari, D. Potenza et al.
FULL PAPER
(S,S)-CH3CONHCH(Me)CH2SO2NHCH(Et)CH2SO2NHCH2COOMe
(8): This compound was synthesized according to the solid-phase protocol
described above in the paragraph synthetic procedures. IR (CHCl3): nÄ ˆ
Paikoff, P. G. Schultz, Tetrahedron Lett. 1996, 37, 5305 ± 5308; c) J.-M.
Kim, T. E. Wilson, T. C. Norman, P. G. Schultz, Tetrahedron Lett. 1996,
37, 5309 ± 5312; d) R. N. Zuckermann, J. M. Kerr, S. B. H. Kent, W. H.
Moos, J. Am. Chem. Soc. 1992, 114, 10646 ± 10647; e) C. Y. Cho, E. J.
Moran, S. R. Cherry, J. C. Stephans, S. P. A. Fodor, C. L. Adams, A.
Sundaram, J. W. Jacobs, P. G. Schultz, Science 1993, 261, 1303 ± 1305;
f) K. Burgess, D. S. Linthicum, H. Shin, Angew. Chem. 1995, 107, 975,
Angew. Chem. Int. Ed. Engl. 1995, 34, 907 ± 909; g) H. Han, K. D.
Janda, J. Am. Chem. Soc. 1996, 118, 2539 ± 2544; h) W. J. Moree, G. A.
van der Marel, R. M. J. Liskamp, J. Org. Chem. 1995, 60, 5157 ± 5169;
i) C. Gennari, B. Salom, D. Potenza, A. Williams, Angew. Chem. 1994,
106, 2181 ± 2183, Angew. Chem. Int. Ed. Engl. 1994, 33, 2067 ± 2069;
j) C. Gennari, H. P. Nestler, B. Salom, W. C. Still, Angew. Chem. 1995,
107, 1892 ± 1893, Angew. Chem. Int. Ed. Engl. 1995, 34, 1763 ± 1765;
Angew. Chem. 1995, 107, 1894 ± 1896, Angew. Chem. Int. Ed. Engl.
1995, 34, 1765 ± 1768; k) J. A. W. Kruijtzer, D. J. Lefeber, R. M. J.
Liskamp, Tetrahedron Lett. 1997, 38, 5335 ± 5338; l) K. Burgess, J.
Ibarzo, D. S. Linthicum, D. H. Russel, H. Shin, A. Shitangkoon, R.
Totani, A. J. Zhang, J. Am. Chem. Soc. 1997, 119, 1556 ± 1564; m) D. H.
Appella, L. A. Christianson, I. L. Karle, D. R. Powell, S. H. Gellman,
J. Am. Chem. Soc. 1996, 118, 13071 ± 13072; n) D. H. Appella, L. A.
Christianson, D. A. Klein, D. R. Powell, X. Huang, J. J. Barchi, Jr.,
S. H. Gellman, Nature 1997, 387, 381 ± 384; o) S. Krauthauser, L. A.
Christianson, D. R. Powell, S. H. Gellman, J. Am. Chem. Soc. 1997,
119, 11719 ± 11720; p) D. Seebach, J. L. Matthews, Chem. Commun.
1997, 2015 ± 2022, and references therein; q) T. D. Clark, L. K.
Buehler, M. R. Ghadiri, J. Am. Chem. Soc. 1998, 120, 651 ± 656;
r) B. C. Hamper, S. A. Koldziej, A. M. Scates, R. G. Smith, E. Cortez,
J. Org. Chem. 1998, 63, 708 ± 718.
1
1664 cm (CO-NH), 1742 (CO-OMe), 3266 (SO2-NH), 3381 (SO2-NH),
3436 (CO-NH); 1H NMR (200 MHz, CHCl3): d ˆ 0.95 (t, J ˆ 7 Hz, 3H,
CH3CH2), 1.32 (d, J ˆ 7 Hz, 3H, CH3CH), 1.75 (q, J ˆ 7 Hz, 2H, CH3CH2),
2.0 (s, 3H, CH3CO), 3.1 ± 3.3 (m, 4H, CH2SO2), 3.75 (CH3O), 3.95 (m, 1H,
CHEt), 3.95 (dd, J ˆ 7, 19 Hz, 1H, CHaHbCO), 4.10 (dd, J ˆ 5, 19 Hz, 1H,
CHaHbCO), 4.55 (q, J ˆ 7 Hz, 1H, CHMe), 5.57 (d, J ˆ 8 Hz, 1H,
CONHCHMe), 5.84 (d, J ˆ 8 Hz, 1H, SO2NHCHEt), 6.63 (t, J ˆ 5, 7 Hz,
1H, SO2NHCH2); 13C NMR (CDCl3): d ˆ 9.2 (CH3CH2), 20.3 (CH3CH),
23.2 (CH3CO), 29.3 (CH3CH2), 41.8 (CHN), 44.1 (CH2SO2), 51.7 (CHN),
52.6 (CH3O), 55.8 (CH2SO2), 58.0 (CH2CO); C12H25N3O7S2 (387.48): calcd
C 37.20, H 6.50, N 10.84; found C 37.13, H 6.55, N 10.77.
(S,S)-CH3CONHCH(Me)CH2SO2NHCH(Et)CH2SO2NHCH2CONHBn
(9): This compound was synthesized according to the solid-phase protocol
described above in the paragraph synthetic procedures. IR (CHCl3): nÄ ˆ
1
1671 cm (CO-NH), 3250 (SO2-NH), 3270 (SO2-NH), 3315 (SO2-NH),
1
3376 (SO2-NH), 3431 (CO-NH); H NMR (200 MHz, CDCl3): d ˆ 0.95 (t,
J ˆ 7 Hz, 3H, CH3CH2), 1.35 (d, J ˆ 7 Hz, 3H, CH3CH), 1.75 (q, J ˆ 7 Hz,
2H, CH2CH3), 2.0 (s, 3H, CH3CO), 3.1 ± 3.4 (m, 4H, CH2SO2), 3.8 ± 4.1 (m,
3H, CH2CO ‡ CHEt), 4.45 (d, J ˆ 6 Hz, 2H, CH2Ph), 4.5 (m, 1H, CHMe),
5.75 (d, J ˆ 8 Hz, 1H, CONHCHMe), 6.21 (d, J ˆ 8 Hz, 1H, SO2NHCHEt),
6.45 (t, J ˆ 6 Hz, 1H, CONHBn), 6.52 (t, J ˆ 6 Hz, 1H, SO2NHCH2); 13C
NMR (CDCl3): d ˆ 12.5 (CH3CH2), 23.1 (CH3CO), 25.2 (CH3CH), 32.5
(CH3CH2), 42.6 ‡ 45.5 (CHN), 46.5 ‡ 48.8 (CH2SO2), 60.2 (CH2Ph), 61.5
ˆ
(CH2CO), 130.7, 130.9, 131.2, 131.7, 131.9, 132.5 (6C ); C18H30N4O6S2
(462.59): calcd C 46.74, H 6.54, N 12.11; found C 46.65, H 6.59, N 12.07.
(S,S)-CH3SO2NHCH(Me)CH2SO2NHCH(Et)CH2SO2NHCH2COOMe
(10): This compound was synthesized according to the solid-phase protocol
described above in the paragraph synthetic procedures. IR (CHCl3): nÄ ˆ
[2] a) C. Gennari, B. Salom, D. Potenza, C. Longari, E. Fioravanzo, O.
Carugo, N. Sardone, Chem. Eur. J. 1996, 2, 644 ± 655; b) W. J. Moree,
A. Schouten, J. Kroon, R. M. J. Liskamp, Int. J. Peptide Protein Res.
1995, 45, 501 ± 507; c) A. Calcagni, E. Gavuzzo, F. Mazza, F. Pinnen, G.
Pochetti, D. Rossi, Gazz. Chim. Ital. 1992, 122, 17 ± 23; d) A. Calcagni,
D. Rossi, M. Paglialunga Paradisi, G. Lucente, E. Gavuzzo, F. Mazza,
G. Pochetti, M. Paci, Biopolymers 1997, 41, 555 ± 567.
[3] a) W. J. Moree, G. A. van der Marel, R. M. J. Liskamp, Tetrahedron
Lett. 1992, 33, 6389 ± 6392; b) W. J. Moree, G. A. van der Marel,
R. M. J. Liskamp, Tetrahedron Lett. 1991, 32, 409 ± 412; c) W. J. Moree,
L. C. van Gent, G. A. van der Marel, R. M. J. Liskamp, Tetrahedron
1993, 49, 1133 ± 1150; d) D. B. A. de Bont, W. J. Moree, R. M. J.
Liskamp, Bioorg. Med. Chem. 1996, 4, 667 ± 672; e) M. Gude, U.
Piarulli, D. Potenza, B. Salom, C. Gennari, Tetrahedron Lett. 1996, 37,
8589 ± 8592; f) D. W. P. M. Loewik, S. J. E. Mulders, Y. Cheng, Y. Shao,
R. M. J. Liskamp, Tetrahedron Lett. 1996, 37, 8253 ± 8256; g) D. B. A.
de Bont, G. D. H. Dijkstra, J. A. J. den Hartog, R. M. J. Liskamp,
Bioorg. Med. Chem. Lett. 1996, 6, 3035 ± 3040; h) K. G. Garson, C. F.
Schwender, H. N. Shroff, N. A. Cochran, D. L. Gallant, M. J. Briskin,
Bioorg. Med. Chem. Lett. 1997, 7, 711 ± 714.
[4] a) S. H. Gellman, G. P. Dado, G.-B. Liang, B. R. Adams, J. Am. Chem.
Soc. 1991, 113, 1164 ± 1173; b) G.-B. Liang, C. J. Rito, S. H. Gellman, J.
Am. Chem. Soc. 1992, 114, 4440 ± 4442; c) G. P. Dado, S. H. Gellman,
J. Am. Chem. Soc. 1993, 115, 4228 ± 4245; d) E. A. Gallo, S. H.
Gellman, J. Am. Chem. Soc. 1993, 115, 9774 ± 9788; e) G. P. Dado,
S. H. Gellman, J. Am. Chem. Soc. 1994, 116, 1054 ± 1062; f) T. S.
Haque, J. C. Little, S. H. Gellman, J. Am. Chem. Soc. 1994, 116, 4105 ±
4106; g) R. R. Gardner, G.-B. Liang, S. H. Gellman, J. Am. Chem. Soc.
1995, 117, 3280 ± 3281; h) R. R. Gardner, S. H. Gellman, J. Am. Chem.
Soc. 1995, 117, 10411 ± 10412; i) R. R. Gardner, S. H. Gellman,
Tetrahedron 1997, 53, 9881 ± 9890; j) D. T. McQuade, S. L. McKay,
D. R. Powell, S. H. Gellman, J. Am. Chem. Soc. 1997, 119, 8528 ±
8532.
[5] a) V. Dupont, A. Lecoq, J.-P. Mangeot, A. Aubry, G. Boussard, M.
Marraud, J. Am. Chem. Soc. 1993, 115, 8898 ± 8906, and references
therein; b) M. Paradisi Paglialunga, I. Torrini, G. Zecchini Pagani, G.
Lucente, E. Gavuzzo, F. Mazza, G. Pochetti, Tetrahedron 1995, 51,
2379 ± 2386; c) B. W. Gung, Z. Zhu, Tetrahedron Lett. 1996, 37, 2189;
d) B. W. Gung, Z. Zhu, J. Org. Chem. 1996, 61, 6482 ± 6483; e) B. W.
Gung, Z. Zhu, J. Org. Chem. 1997, 62, 2324 ± 2325; f) B. W. Gung, Z.
Zhu, B. Everingham, J. Org. Chem. 1997, 62, 3436 ± 3437; g) B. W.
Gung, Z. Zhu, J. Org. Chem. 1997, 62, 6100 ± 6101; h) U. Schopfer, M.
Stahl, T. Brandl, R. W. Hoffmann, Angew. Chem. 1997, 109, 1805 ±
1
1747 cm (CO-OMe), 3307 (SO2-NH), 3352 (SO2-NH), 3379 (SO2-NH);
1H NMR (200 MHz, CDCl3): d ˆ 1.0 (t, J ˆ 7 Hz, 3H, CH3CH2), 1.45 (d, J ˆ
7 Hz, 3H, CH3CH), 1.75 (m, 2H, CH2CH3), 3.05 (s, 3H, CH3SO2), 3.3 ± 3.5
(m, 4H, CH2SO2), 3.8 (s, 3H, CH3O), 3.9 ± 4.1 (m, 4H, CHMe ‡ CH2CO ‡
CHEt), 4.91 (d, J ˆ 8 Hz, 1H, SO2NHCHMe), 5.48 (d, J ˆ 8 Hz, 1H,
SO2NHCHEt), 5.52 (t, J ˆ 6 Hz, 1H, SO2NHCH2); 13C NMR (CDCl3): d ˆ
9.5 (CH3CH2), 21.8 (CH3CH), 29.6 (CH3CH2), 41.6 (CH3SO2), 44.0 ‡ 56.2
(CH2SO2), 46.4 ‡ 51.8 (CHN), 52.8 (CH3O), 59.6 (CH2CO); C11H25N3O8S3
(423.53): calcd C 31.20, H 5.95, N 9.92; found C 31.10, H 6.10, N 9.90.
(S,S)-CH3SO2NHCH(Me)CH2SO2NHCH(Et)CH2SO2NHCH2CONHBn
(11): This compound was synthesized according to the solid-phase protocol
described above in the paragraph synthetic procedures. IR (CHCl3): nÄ ˆ
1
1672 cm (CO-NH), 3285 (SO2-NH), 3309 (SO2-NH), 3381 (SO2-NH),
3428 (CO-NH); 1H NMR (200 MHz, CDCl3): d ˆ 1.0 (t, J ˆ 7 Hz, 3H,
CH3CH2), 1.45 (d, J ˆ 7 Hz, 3H, CH3CH), 1.7 (m, 2H, CH2CH3), 3.0 (s, 3H,
CH3SO2), 3.15 ± 3.45 (m, 4H, CH2SO2), 3.90 (m, 3H, CH2CO ‡ CHEt), 4.05
(m, 1H, CHMe), 4.45 (d, J ˆ 6 Hz, 2H, CH2Ph), 5.13 (d, J ˆ 8 Hz, 1H,
SO2NHCHMe), 5.84 (t, J ˆ 6 Hz, 1H, SO2NHCH2CO), 6.16 (d, J ˆ 8 Hz,
1H, SO2NHCHEt), 6.36 (t, J ˆ 6 Hz, 1H, CONHBn); 13C NMR (CDCl3):
d ˆ 9.7 (CH3CH2), 21.8 (CH3CH), 29.0 (CH3CH2), 41.6 (CH3SO2), 43.6 ‡
45.6 (CH2SO2), 46.4 ‡ 51.6 (CHN), 55.3 (CH2CO), 59.5 (CH2Ph), 127.6 ‡
ˆ
128.7 (C ); C17H30N4O7S3 (498.64): calcd C 40.95, H 6.06, N 11.24; found C
40.79, H 6.11, N 11.18.
Acknowledgments: We thank the Commission of the European Union for
financial support and for a postdoctoral research fellowship to M. Gude
(Fixed Contribution Contract for Training through Research ERB FMB
ICT 950328), N.A.T.O. (Collaborative Research Grant to C. Gennari and
H. P. Nestler, Cold Spring Harbor Laboratory, N.Y., USA) and also Merck
(Merckꢀs Academic Development Program Award to C. Gennari, 1996 ±
97) for financial support. We thank Professor S. H. Gellman (University of
Wisconsin) for helpful discussions and comments.
Received: March 9, 1998 [F1041]
[1] a) For recent reviews, see: R. M. J. Liskamp, Angew. Chem. 1994, 106,
661, Angew. Chem. Int. Ed. Engl. 1994, 33, 633 ± 636; S. Borman,
Chem. Eng. News 1997, June 16, 32 ± 35; b) J.-M. Kim, Y. Bi, S. J.
1930
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0947-6539/98/0410-1930 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 10

b-Sulfonamidopeptides
1924±1931
1807, Angew. Chem. Int. Ed. Engl. 1997, 36, 1745 ± 1747; i) A. I.
derivatives show weak intramolecular
five-membered-ring (C5-type) hydrogen
bonding (ref. [4c], Scheme 3)].
H
O
5
Â
Jimenez, R. Vanderesse, M. Marraud, A. Aubry, C. Cativiela,
N
O
CH3SO2
Tetrahedron Lett. 1997, 38, 7559 ± 7562; j) M. L. Skar, J. S. Svendsen,
Tetrahedron 1997, 53, 17425 ± 17440.
[8] a) J. L. Radkiewicz, M. A. McAllister, E.
Goldstein, K. N. Houk, J. Org. Chem.
1998, 63, 1419 ± 1428; b) V. Bertolasi, V.
Ferretti, P. Gilli, P. G. De Benedetti, J.
Chem. Soc. Perkin Trans 2, 1993, 213 ±
219; c) R. Taylor, O. Kennard, W. Versichel, Acta Crystallogr. Sect. B,
1984, 40, 280 ± 288.
[9] S. S. Wang, J. Am. Chem. Soc. 1973, 95, 1328 ± 1333.
Scheme 3. Intramolec-
ular five-membered-
ring (C5-type) hydrogen
bonding.
[6] Reference molecules (1mm CDCl3 solutions): CH3SO2NHCH2Ph,
dNH ˆ 4.50 at 300 K, DdNH/DT
ˆ
2.8 ppb/K;[2a] tBuO-CO-
NHCH2Ph, dNH ˆ 4.85 at 300 K, DdNH/DT
ˆ
1.0 ppb/K;[2a]
CH3SO2NHCH2COOCH3, dNH ˆ 4.74 at 300 K, DdNH/DT
ˆ
2.1 ppb/K.
[7] Reference molecules: CH3CO-NHCH3, N ± H stretch band at
1
1
ˆ
3466 cm , amide I C O stretch band at 1675 cm in dilute chloro-
Â
Â
form (Table 4, ref. [4j]). tBuO-CO-NHCH2Ph, N ± H stretch band at
[10] Z. Flegelova, M. Patek, J. Org. Chem. 1996, 61, 6735 ± 6738.
[11] B. Gisin, Anal. Chim. Acta 1972, 58, 248 ± 249.
1
1
3458 cm , C O stretch band at 1730 cm in dilute chloroform;[2a]
ˆ
CH3SO2NHCH3, N ± H stretch band at 3397 cm 1 in dilute chloroform
[12] K. Higashiura, H. Morino, H. Matsuura, Y. Toyomaki, K. Ienaga, J.
Chem. Soc. Perkin Trans 1 1989, 1479 ± 1481.
[13] W. S. Hancock, J. E. Battersby, Anal. Biochem. 1976, 71, 260 ± 264.
1
(Table 4); CH3SO2NHCH2COOCH3, N ± H stretch band at 3381 cm
ester C O stretch band at 1750 cm in dilute chloroform [glycine
,
1
ˆ
Chem. Eur. J. 1998, 4, No. 10
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0410-1931 $ 17.50+.25/0
1931