Synthesis of α- and β-substituted aminoethane sulfonamide arginine- glycine mimics

Article abstract of DOI:10.1002/1099-0690(200004)2000:7<1219::AID-EJOC1219>3.0.CO;2-P

In this paper we present a synthesis of both α- and β-substituted aminoethane sulfonamide arginine mimics. The α-substituted sulfonamides were obtained starting from an alkene, whereas the β-substituted sulfonamides were derived from an amino acid derivative.

Full text of DOI:10.1002/1099-0690(200004)2000:7<1219::AID-EJOC1219>3.0.CO;2-P

FULL PAPER
Synthesis of α- and β-Substituted Aminoethane Sulfonamide Arginine–Glycine
Mimics
Dennis W. P. M. Lowik[a][°] and Rob M. J. Liskamp*[a]
Keywords: Peptidomimetics / Peptidosulfonamides / Arginine mimics / Transition-state isosteres
In this paper we present a synthesis of both α- and β-substi-
whereas the β-substituted sulfonamides were derived from
tuted aminoethane sulfonamide arginine mimics. The α-sub- an amino acid derivative.
stituted sulfonamides were obtained starting from an alkene,
Introduction
Peptide bond replacements are important in the develop-
ment of peptidomimetics, because they are often a first step
from a biologically active peptide to analogs having im-
proved properties,[1] e.g. with respect to degradation and
biological activity. Recently, numerous peptide bond ‘‘sur-
Figure 1. α- and β-substituted β-aminoethane sulfonamide mimics
rogates’’ have been reported.[2] This has since been extended
to the development of transition-state isosteres for hydro-
lysis of the peptide–amide bond.[3] Compounds containing
these moieties are of interest as they may be useful in the
development of enzyme inhibitors.[4] Although a wide vari-
ety of transition-state isosteres has hitherto been described,
relatively little attention has been paid to the sulfonamide
isostere.[5] In order to expand the possibilities for investiga-
ting these sulfonamides as transition-state analogs, it was
decided to prepare one of the most challenging amino sul-
fonic acid derivatives, namely the analog corresponding to
the amino acid arginine. Arginine sulfonamide derivatives
are particularly interesting since arginine is often important
as a binding determinant in protein–peptide interactions,
as is the case, for example, in RGD-containing peptides.[6]
Furthermore, arginine is present at the cleavage site of
thrombin in fibrinogen. As a result, arginine derivatives
have been used as starting substrates for the development
of thrombin inhibitors.
We have introduced β-aminosulfonic acid derivatives as
stable analogs of α-aminosulfonic acid derivatives.[7] As a
consequence, two substituted β-aminosulfonic acid mimics
of arginine are possible: one having the arginine side chain
on the α-carbon (with respect to the sulfonamide moiety)
and one with the side chain on the β-carbon atom (Fig-
ure 1). In this paper, we describe the synthesis of α- and β-
substituted aminoethane sulfonamide mimics of the argin-
ine–glycine peptide sequence.
of arginine
Results and Discussion
The synthetic route used to obtain the β-substituted argi-
nine–glycine sulfonamide isosteres was analogous to that
for other β-substituted aminoethane sulfonamides de-
veloped previously by our group.[7] The key synthon along
this route is a β-substituted aminoethane thioacetate 2[7c]
(Scheme 1). Reaction of this thioacetate with sulfuryl chlor-
ide and acetic anhydride gives the corresponding sulfinyl
chloride 3. Coupling of 3 with an appropriate amine gives
a sulfinamide 4, which can be oxidized to the desired sul-
fonamide 5. For the α-substituted arginine sulfonamide
mimic, a new route has been developed starting from alkene
6. This route offers access to the corresponding thioacetate
7 required for the synthesis of the α-substituted sulfonamide
derivatives 8, and nicely complements the existing routes
[a]
Department of Medicinal Chemistry, Utrecht University,
P. O. Box 80082, 3508 TB Utrecht, The Netherlands
Fax: (internat.) ϩ 31-30/253-6655
E-mail: R.M.J.Liskamp@pharm.uu.nl
[°]
Present address: University of Cambridge, Institute of
Biotechnology,
Scheme 1. General representation of the synthesis of α- and β-sub-
stituted aminoethane sulfonamides
Tennis Court Road, Cambridge CB2 1QT, U.K.
Eur. J. Org. Chem. 2000, 1219Ϫ1228
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0407Ϫ1219 $ 17.50ϩ.50/0
1219

D. W. P. M. Löwik, R. M. J. Liskamp
FULL PAPER
that we have developed starting from either an amino acid duction of its in situ prepared mixed anhydride.[10] Alcohol
or an aldehyde.[8]
10 was then transformed into its mesylate 11 in 80% yield,
For two reasons, it was decided to start with the synthesis from which the mesylate moiety was displaced in a substitu-
of an ornithine–glycine sulfonamide isostere. Firstly, it was tion reaction using cesium thioacetate[11] to afford the key
synthetically more attractive to start with ornithine than thioacetate 12 in 69% yield. After conversion into the cor-
with arginine, in view of anticipated problems in finding responding sulfinyl chloride 13 by treatment of this synthon
suitable protective groups for the guanidine moiety of argi- with sulfuryl chloride and acetic anhydride, a coupling reac-
nine. Moreover, a number of convenient methods have been tion with an amine was carried out to obtain the desired
described in the literature[9] for the transformation of an sulfinamide, which was immediately oxidized to the corres-
ornithine side chain into an arginine side chain. Secondly, ponding sulfonamide. For the coupling reaction, two
this strategy involving a side chain containing an amino amines were selected: (i) H–Gly–OEt leading to ornithine–
function will also be applicable to the synthesis of lysine glycine sulfonamide derivative 14, and (ii) ammonia to ob-
sulfonamide mimics.
tain primary sulfonamide 15. In both cases, the amine also
In order to prepare the β-substituted arginine sulfonam- acted as a base, binding the liberated HCl. In this way,
ide mimic (Scheme 2), the di-protected ornithine derivative higher yields were obtained than by using, for example, trie-
9 was converted into amino alcohol 10 in 83% yield by re- thylamine or N-methylmorpholine as the base.[12] The thus
obtained sulfinamides were oxidized with NaIO4 and a
catalytic amount of RuCl3 to produce the ornithine analogs
14 and 15 in overall yields of 57% and 63%, respectively.
Subsequent hydrogenolysis of the Cbz side chain protective
group and reaction with pyrazole 16[9e][9f] gave the protected
arginine–glycine sulfonamide mimics 17 (73%) and 18
(59%). In order to assess whether these sulfonamide mimics
could be incorporated in a peptide sequence, we decided to
couple them first with proline, and then to couple the prod-
uct with -phenylalanine. The resulting sequence can be
considered as a sulfonamide mimic of a substrate sequence
for thrombin. The -Phe–Pro dipeptide moiety was intro-
duced into sulfonamides 17 and 18 in two steps after cleav-
age of the Boc group to afford peptidosulfonamides 21 and
22 in overall yields of 77% and 62%, respectively. Deprotec-
tion of the guanidine function was carried out by hydro-
genolysis to afford the corresponding HCl salts 23 and 24
in 66% and 92% yield, respectively. Subsequent removal of
the Boc group with either HCl in diethyl ether or 1  aque-
ous HCl gave analogs 25, 26, and 27 in quantitative yields.
Our new route to α-substituted aminoethane sulfonamide
arginine mimics started from 4-penten-1-ol 28 (Scheme 3).
The alcohol function of 28 was protected with a benzyl
group in 77% yield. The resulting alkene 29 was then epoxi-
dized with m-CPBA affording epoxide 30 in 74% yield. In
a first attempt to open the epoxide ring, chiral α-methyl-
benzylamine was used[13] since it was anticipated that this
would lead to a separable mixture of diastereoisomers and
perhaps even to a substantial diastereomeric excess of am-
ino alcohol 31. Unfortunately, this was not the case, al-
though the regioselectivity was correct. In an attempt to
optimize the diastereoselectivity of the reaction, it was car-
ried out at several different temperatures. However, the di-
astereomeric ratio remained almost constant, i.e. around
1:1. Furthermore, the diastereomers were barely separable
by TLC. The synthesis was thus continued by removing the
benzyl protective groups from racemic 31 by hydrogenolysis
and then protecting the free amine with a Boc group,
thereby affording diol 32 in 93% yield. Remarkably, a con-
siderable difference in the reactivities of the two diastereo-
isomers was observed during the hydrogenation. Unfortu-
nately, however, it was not possible to take advantage of
Scheme 2. Synthesis of fully protected sulfonamide ‘‘β’’-arginine
mimics and elongation of the N-terminus
1220
Eur. J. Org. Chem. 2000, 1219Ϫ1228

Synthesis of Peptidosulfonamides
FULL PAPER
with regard to the ease of purification of the product. The
use of thioacetic acid, Ph3P, and diisopropyl azodicarboxyl-
ate[15] furnished thioacetate 35 in 69% yield. Subsequent
treatment with acetic anhydride and sulfuryl chloride gave
the corresponding sulfinyl chloride, which was used directly
for coupling with glycine ethyl ester. The sulfinamides thus
obtained were immediately oxidized to the corresponding
sulfonamide 36 in 52% yield using NaIO4 in the presence
of RuCl3 as a catalyst.
Following the strategy for the β-substituted ornithine sul-
fonamide mimic, the peptidosulfonamide derivative 36 was
converted into the arginine–glycine analog by hydrogena-
tion[16] to give the hydrochloric acid salt 37. Subsequent in-
troduction of the protected guanidine group (Scheme 4), us-
ing pyrazole derivative 16,[9e][9f] afforded 38 in 65% yield.
For comparison purposes, both a proline and a -phenylal-
anine residue were introduced into the resulting ‘‘α’’-argin-
ine sulfonamide mimic following a procedure analogous to
that outlined above for the preparation of the ‘‘β’’-arginine
sulfonamide mimic 23. Indeed, after repeated Boc deprotec-
tion steps with TFA and BOP couplings (Scheme 4), 39 and
40 were obtained in yields of 69% and 63%, respectively.
The guanidine group in peptidosulfonamide 40 was depro-
tected by hydrogenolysis, yielding sulfonamide 41 in 72%
yield. Finally, treatment with either HCl in diethyl ether or
1  aqueous HCl afforded analogs 42 and 43 in quantitative
yields (Scheme 4).
Scheme 3. Synthesis of an ‘‘α’’-ornithine–glycine mimic containing
a sulfonamide isostere
this difference to separate the diastereomers. The next step
was to convert the primary hydroxyl function in 32 to a
group that could eventually be converted into the guanidine
functionality of the arginine sulfonamide mimic. For this
purpose, the azido group was chosen as a masked amine
functionality[14] that may be converted into a guanidine
group at a later stage. Reaction of diol 32 with HN3, Ph3P,
and di-tert-butyl azodicarboxylate gave azido alcohol 33 in
55% yield. This azide was converted into the Cbz-protected
34 by catalytic reduction followed by reaction with Cbz–
OSu. The use of di-tert-butyl azodicarboxylate, as opposed
to, for example, the more commonly used diethyl azodicar-
boxylate, was crucial. Using the latter, it was not possible
to separate the hydrazine derivative generated in the reac-
tion from the product. Moreover, a by-product was formed,
which seemingly originated from an intramolecular reac-
tion. This product was obtained in 67% yield by carrying
out a Mitsunobu reaction using diethyl azodicarboxylate
and Ph3P in the absence of HN3, and was identified as the
tetrahydrofuran derivative 33a. Next, the remaining hy-
droxyl function had to be converted into a thioacetate moi-
ety. Unfortunately, it was not possible to prepare the
thioacetate of 34, probably because of interference by the
Cbz-protected amine. Consequently, it was decided to retain
the azide as a masked amino function[14] in 33 and to con-
vert the hydroxy function of this compound into a thioacet-
ate. Again, a Mitsunobu reaction was employed to accom-
plish this. As in the preceding Mitsunobu reaction, the cho-
Scheme 4. Synthesis of an ‘‘α’’-arginine–glycine mimic containing
ice of dialkyl azodicarboxylate reagent proved to be crucial a sulfonamide isostere
Eur. J. Org. Chem. 2000, 1219Ϫ1228
1221

D. W. P. M. Löwik, R. M. J. Liskamp
FULL PAPER
32.8 mmol) was added. MeOH (100 mL) was then added dropwise
with the temperature held at 0 °C. Following the addition, the mix-
ture was stirred for 30 min at room temperature and then the solv-
ent was evaporated. The residue was taken up in water and the
resulting aqueous solution was extracted three times with EtOAc.
The combined organic layers were washed with 1  KHSO4, 5%
NaHCO3 solution, and brine, and dried with Na2SO4. After col-
umn chromatography (eluent: MeOH/DCM, 2:98), evaporation of
the solvent from the appropriate fraction afforded 3.17 g (83%) of
Conclusion
In this paper, we have described the preparation of the
most challenging α- and β-substituted aminoethane sulfon-
amide mimics, viz. those corresponding to the amino acid
arginine. For the β-substituted compounds, the successful
approach described previously was followed starting from
an amino acid derivative. The resulting ‘‘β’’-arginine sulfon-
amide mimic was incorporated into a peptide sequence. Ad-
ditionally, a new method has now been developed for the
synthesis of the ‘‘α’’-arginine sulfonamide mimic. This ap-
proach utilized an alkene derivative as the starting material.
Although the racemic sulfonamide arginine was prepared,
it is envisaged that homochiral compounds should be ac-
cessible by employing alternative chiral amines for ring-
opening of the intermediate epoxide. The strategy presented
in this paper, involving the use of an alkene as the starting
material, might also be applied to the synthesis of other α-
substituted aminoethane sulfonamides. In principle, α-sub-
stituted aminoethane sulfonamides corresponding to all
proteinogenic amino acid analogs are accessible by starting
from the appropriate alkene.
1
alcohol 10. Rf ϭ 0.25 (EtOAc/hexanes, 1:1). – H NMR (CDCl3):
δ ϭ 1.43 [s, 9 H, C(CH3)3], 1.50–1.65 (m, 4 H, CH2CH2CH2N),
2.57 (br. s, 1 H, OH), 3.20 (q, 2 H, CH2N), 3.50–3.70 (m, 3 H,
CHCH2O), 4.75, 4.95 (two br. s, 2 H, NH), 5.10 (s, 2 H, OCH2Ph),
7.35 (m,
5 H, ArH). –
13C NMR (CDCl3): δ ϭ 26.5
(CH2CH2CH2N), 28.3 [C(CH3)3], 28.5 (CH2CH2N), 40.7 (CH2N),
52.2 (CHN), 65.2 (CH2O), 66.6 (OCH2Ph), 79.5 [C(CH3)3], 128.0,
128.4, 136.5 (CAr), 156.3, 156.5 (CϭO).
Mesylate 11: Alcohol 10 (6.78 g, 19.2 mmol) was dissolved in DCM
(100 mL). To this solution, a solution of triethylamine (2.95 mL,
21.12 mmol) and mesyl chloride (1.56 mL, 20.16 mmol) in DCM
(25 mL) was added dropwise at 0 °C. The resulting mixture was
stirred for 90 min at room temperature, and then the solvent was
evaporated and the residue was redissolved in EtOAc. This solution
was washed with 5% NaHCO3 solution and brine, and dried with
Na2SO4. Concentration to dryness and crystallization of the res-
idue from EtOAc/hexanes gave 6.6 g (80%) of mesylate 11. Rf ϭ
1
0.31 (EtOAc/hexanes, 1:1). – H NMR (CDCl3): δ ϭ 1.44 [s, 9 H,
Experimental Section
C(CH3)3], 1.50–1.65 (m, 4 H, CH2CH2CH2N), 3.02 (s, 3 H,
CH3SO2), 3.23 (q, 2 H, CH2N), 3.83 (br. s, 1 H, CHCH2O), 4.20
(m, 2 H, CHCH2O), 4.70, 4.90 (two br. s, 2 H, NH), 5.10 (s, 2 H,
OCH2Ph), 7.37 (m, 5 H, ArH). – 13C NMR (CDCl3): δ ϭ 26.4
(CH2CH2CH2N), 28.3 [C(CH3)3], 28.4 (CH2CH2N), 37.4
(CH3SO2), 40.6 (CH2N), 49.5 (CHN), 66.7 (OCH2Ph), 70.9
(CH2O), 80.0 [C(CH3)3], 128.07, 128.10, 128.5, 136.6 (CAr), 155.3,
156.5 (CϭO).
General Remarks: DCM and DMF were dried with molecular
sieves (4 A). Triethylamine and DIPEA were successively distilled
˚
from ninhydrin and KOH. THF was distilled from LiAlH4. All
other chemicals were used as received from commercial suppliers.
Reactions were carried out at ambient temperature unless stated
otherwise. – TLC analysis was performed on Merck pre-coated sil-
ica gel 60 F-254 (0.25 mm) plates. Spots were visualized with UV
light, ninhydrin, or Cl2-TDM.[17] Solvents were evaporated under
reduced pressure at 40 °C. – Column chromatography was per-
formed on Merck kieselgel 60 (40–63 mm) and flash chromato-
graphy on Merck kieselgel 60H (5–40 mm). Sephadex LH-20 from
Pharmacia was used for gel permeation chromatography. – 1H
NMR spectra were recorded with a Varian G-300 spectrometer
(300.1 MHz); chemical shift values are given in ppm relative to
TMS. – 13C NMR spectra were recorded with a Varian G-300 spec-
trometer (75.5 MHz); chemical shift values are given in ppm relat-
ive to CDCl3 (δ ϭ 77.0) or [D6]DMSO (δ ϭ 39.7). 13C spectra were
recorded using the attached proton test (APT) sequence. – Fast-
atom bombardment (FAB) mass spectrometry was carried out us-
ing a Jeol JMS SX/SX 102A four-sector mass spectrometer coupled
with an HP-9000 data system. LC-electron spray (ES) mass spec-
trometry was carried out with a Shimadzu LCMS-QP8000 spectro-
meter. All compounds were purified by column chromatography,
examined by TLC, and, as far as possible, rigorously characterized
by proton and carbon NMR spectroscopy and electron-spray and
FAB mass spectrometry. Compounds 23–27 and 41–43 were ana-
lyzed by HPLC and were found to be greater than 95% pure. HPLC
analysis was carried out on a Gilson automated HPLC system 205
with a 233XL autosampler and a 119 UV/Vis detector.
Thioacetate 12: To a suspension of Cs2CO3 (2.72 g, 8.35 mmol) in
DMF (100 mL), thioacetic acid (1.29 mL, 18.1 mmol) was added
at 0 °C under argon. After stirring for 15 min, mesylate 11 (6.53 g,
15.2 mmol) in DMF (20 mL) was added and the resulting solution
was stirred overnight. It was then poured into iced water and ex-
tracted three times with EtOAc. The combined organic layers were
washed with water, 5% NaHCO3 solution, and brine, and dried
with Na2SO4. Evaporation of the solvent, column chromatography
of the residue (eluent: diethyl ether/hexanes, 1:1), and subsequent
recrystallization from diethyl ether/hexanes gave 4.32 g (69%) of
1
thioacetate 12. Rf ϭ 0.24 (diethyl ether/hexanes, 2:1). – H NMR
(CDCl3): δ ϭ 1.43 [s, 9 H, C(CH3)3], 1.40–1.65 (m, 4 H,
CH2CH2CH2N), 2.34 (s, 3 H, CH3CO), 3.00 (m, 2 H, CHCH2S),
3.20 (q, 2 H, CH2N), 3.70 (br. s, 1 H, CHCH2S), 4.57, 4.95 (two
br. s, 2 H, NH), 5.09 (s, 2 H, OCH2Ph), 7.37 (m, 5 H, ArH). – 13
C
NMR (CDCl3): δ ϭ 26.4 (CH2CH2CH2N), 28.3 [C(CH3)3], 30.4
(CH3CO), 31.4 (CH2CH2N), 33.8 (CHCH2S), 40.6 (CH2N), 50.2
(CHN), 66.5 (OCH2Ph), 79.3 [C(CH3)3], 128.0, 128.4, 136.6 (CAr),
155.4, 156.4 (CONH), 195.5 (OCS).
Sulfinyl Chloride 13: Thioacetate 12 (1.23 g, 3.0 mmol) was dis-
solved in DCM (10 mL) under an argon atmosphere. After cooling
to –20 °C, Ac2O (283 µL, 3.0 mmol) and sulfuryl chloride (486 µL,
6.0 mmol) were added. The resulting mixture was stirred for 1 h
α-tert-Butyloxycarbonyl-ε-(benzyloxycarbonyl)ornithinol (10): To a
solution of protected ornithine 9 (4.0 g, 10.9 mmol) and triethylam-
ine (1.52 mL, 10.9 mmol) in THF (60 mL), ethyl chloroformate at –5 °C and then the solvent was evaporated and the residue was
(1.04 mL, 10.9 mmol) was added dropwise at –10 °C. The resulting
mixture was stirred for 15 min at 0 °C and then NaBH4 (1.24 g,
dried in vacuo. The crude sulfinyl chloride, which was kept under
argon, was used immediately for the preparation of the sulfinamide.
1222
Eur. J. Org. Chem. 2000, 1219Ϫ1228

Synthesis of Peptidosulfonamides
FULL PAPER
Boc–Orn(Cbz)–ψ[CH2SO2]–Gly–OEt (14): Under argon, sulfinyl
chloride 13 (3.0 mmol) was dissolved in DCM (10 mL) and the
solution was cooled to 0 °C. Then, a suspension of HCl H–Gly–
OEt (837 mg, 6.0 mmol) in DCM (20 mL) containing triethylamine
(836 µL, 6.0 mmol) was added. The resulting mixture was stirred
overnight and then the solvent was evaporated. Flash chromato-
After stirring for 10 min, the solvent was evaporated and the res-
idue was redissolved in EtOAc. This solution was washed with 1 
KHSO4, 5% NaHCO3 solution, water, and brine, and dried with
Na2SO4. Evaporation of the solvent and flash chromatography of
the residue (eluent: EtOAc/hexanes, 4:6) afforded 466 mg (73%) of
sulfonamide 17. Rf ϭ 0.43 (EtOAc/hexanes, 1:1). – 1H NMR
graphy of the residue (eluent: EtOAc) yielded 1.13 g (78%) of the (CDCl3): δ ϭ 1.25 (t, 3 H, CH3CH2O), 1.43 [s, 9 H, C(CH3)3],
sulfinamide. Rf ϭ 0.26 (EtOAc). For the oxidation step, the sulfin-
1.50–1.75 (m, 4 H, CH2CH2CH2N), 3.20 (m, 2 H, CHCH2S), 3.47
amide (2.33 mmol) was dissolved in DCM (5 mL), acetonitrile (q, 2 H, CH2CH2N), 3.95 (two dd, Gly-C2H2), 4.19 (q, 2 H,
(5 mL), and water (8 mL). At 0 °C, NaIO4 (646 mg, 3.0 mmol) and CH3CH2O), 4.42 (br. s, 1 H, CHN), 4.95 (d, 1 H, NHBoc), 5.12,
a catalytic amount of RuCl3 H2O were added to the vigorously
stirred solution. After stirring for 45 min at room temperature,
DCM (25 mL) was added, the layers were separated, and the aque-
ous layer was extracted with three further portions of DCM. The
combined organic layers were dried with MgSO4. After removal of
the solvent in vacuo, the product was purified by flash chromato-
5.17 (two s, 4 H, OCH2Ph), 6.00 (br. s, 1 H, Gly-NH), 7.37 (m, 10
H, ArH), 8.36 (t, 1 H, CH2CH2CH2NH), 11.74 (s, 1 H, NHCbz). –
13C NMR (CDCl3): δ ϭ 14.0 (CH3CH2O), 25.4 (CH2CH2CH2N),
28.3 [C(CH3)3], 31.7 (CH2CH2N), 40.4 (CH2CH2N), 44.4 (Gly-C2),
46.8 (CHN), 57.6 (CH2SO2), 61.6 (CH3CH2O), 67.0, 68.1
(OCH2Ph), 80.1 [C(CH3)3], 127.8, 128.0, 128.3, 128.6, 128.7, 134.5,
graphy (eluent: EtOAc/hexanes, 55:45) yielding 850 mg (73%) of 136.7 (CAr), 153.8, 156.0 (NCO2) 163.6 (CϭN), 170.2 (Gly-C1).
sulfonamide 14. The overall yield was 57%. Rf ϭ 0.68 (EtOAc). –
Boc–Arg(Cbz2)–ψ[CH2SO2]–NH2 (18): Sulfonamide 18 was pre-
1H NMR (CDCl3): δ ϭ 1.20 (t, 3 H, CH3CH2O), 1.43 [s, 9 H,
pared from sulfonamide 15 (274 mg, 0.66 mmol) according to the
C(CH3)3], 1.50–1.70 (m, 4 H, CH2CH2CH2N), 3.10–3.35 (m, 4 H,
procedure described for 17. The product was purified by flash chro-
CHCH2S, CH2CH2N), 3.95 (two dd, Gly-C2H2), 4.15 (q, 2 H,
matography (eluent: 2.5% MeOH in DCM) to give 230 mg (59%)
CH3CH2O), 4.43 (br. s, 1 H, CHN), 4.85 (d, 1 H, NHBoc), 5.08 (s,
of sulfonamide 18. Rf ϭ 0.30 (5% MeOH in DCM). – 1H NMR
2 H, OCH2Ph), 5.38 (br. s, 1 H, NHCbz), 6.10 (br. s, 1 H, Gly-
(CDCl3): δ ϭ 1.43 [s, 9 H, C(CH3)3], 1.50–1.70 (q, 4 H,
NH), 7.37 (m, 5 H, ArH). – 13C NMR (CDCl3): δ ϭ 13.9
CH2CH2CH2N), 3.18 (m, 2 H, CH2CH2N), 3.30–3.60 (m, 2 H,
(CH3CH2O), 25.7 (CH2CH2CH2N), 28.3 [C(CH3)3], 31.2
CHCH2S), 4.22 (m, 1 H, CHN), 5.07 (m, 1 H, NHBoc), 5.11, 5.15,
(CH2CH2N), 39.8 (CH2CH2N), 44.3 (Gly-C2), 46.4 (CHN), 57.6
5.17 (d and s, 4 H, OCH2Ph), 5.43 (br. s, 2 H, NH2), 7.30 (m, 10
(CH2SO2), 61.7 (CH3CH2O), 66.5 (OCH2Ph), 80.1 [C(CH3)3],
H, ArH), 8.38 (t, 1 H, CH2CH2CH2NH), 11.73 (s, 1 H, NHCbz). –
128.0, 128.4, 136.6 (CAr), 156.4, 156.5 (CONH), 170.4 (Gly-C1).
13C NMR (CDCl3): δ ϭ 25.6 (CH2CH2CH2N), 28.3 [C(CH3)3],
Boc–Orn(Cbz)–ψ[CH2SO2]–NH2 (15): 13 (2.0 mmol) was dissolved
in DCM (10 mL) under argon and the solution was cooled to –10
°C. NH3 was then bubbled through the solution for 15 min The
mixture was stirred overnight and then the solvent was evaporated.
Flash chromatography of the residue (eluent: 8% MeOH in DCM)
afforded 586 mg (73%) of the sulfinamide. Rf ϭ 0.43 (10% MeOH
in DCM). The sulfinamide was oxidized as described for 14 and
subsequent column chromatography (eluent: 10% MeOH in DCM)
yielded 520 mg (85%) of sulfonamide 15. The overall yield was
31.4 (CH2CH2N), 39.9 (CH2CH2N), 47.0 (CHN), 59.9 (CH2SO2),
67.1, 68.2 (OCH2Ph), 79.7 [C(CH3)3], 128.0, 128.2, 128.38, 128.43,
128.6, 128.7, 134.5, 136.5 (CAr), 153.8, 156.3, 156.5 [C(O)N], 163.5
(CϭN).
Boc–Pro–Arg(Cbz2)–ψ[CH2SO2]–Gly–OEt (19): To a solution of
sulfonamide 17 (466 mg, 0.688 mmol) in DCM (7 mL), TFA
(2.35 mL) was added at 0 °C. The mixture was stirred for 30 min
and subsequently concentrated to dryness. The remaining TFA was
removed from the residue by threefold coevaporation with THF
and the solid was dissolved in DCM (5 mL). To this solution, Boc–
Pro–OH (148 mg, 0.688 mmol), BOP (304 mg, 0.688 mmol), and
DIPEA (360 µL, 2.06 mmol) were added. The reaction mixture was
stirred overnight and then the solvent was evaporated. The residue
was redissolved in EtOAc and the resulting solution was washed
with 1  KHSO4, 5% NaHCO3 solution, and brine, and dried with
Na2SO4. Evaporation of the solvent and flash chromatography of
the residue (eluent: EtOAc/hexanes, 3:2) gave 460 mg (86%) of pep-
tidosulfonamide 19. Rf ϭ 0.14 (EtOAc/hexanes, 3:2). – 1H NMR
(CDCl3/CD3OD): δ ϭ 1.21 (t, 3 H, CH3CH2O), 1.36 [s, 9 H,
1
63%. Rf ϭ 0.59 (10% MeOH in DCM). – H NMR (CDCl3): δ ϭ
1.43 [s, 9 H, C(CH3)3], 1.45–1.70 (m, 4 H, CH2CH2CH2N), 2.85 (s,
2 H, NH2), 3.05–3.25 (m, 4 H, CHCH2S, CH2CH2N), 4.02 (br. s,
1 H, CHN), 5.03 (s, 2 H, OCH2Ph), 5.50, 5.90 (m and br. s, 2 H,
NHCbz, NHBoc), 7.30 (m, 5 H, ArH). – 13C NMR (CDCl3): δ ϭ
26.1 (CH2CH2CH2N), 28.3 [C(CH3)3], 31.3 (CH2CH2N), 40.1
(CH2CH2N), 47.1 (CHN), 59.0 (CH2SO2), 66.6 (OCH2Ph), 80.2
[C(CH3)3], 127.96, 128.02, 128.4, 136.5 (CAr), 156.3, 156.7
(CONH). – ES-MS; m/z: 437.05 [M ϩ Na]ϩ.
N,NЈ-Bis-Cbz-1-guanylpyrazole (16): This compound was prepared
as described by Wu et al.[9e][9f] Reaction of 1H-pyrazole-1-carbox- C(CH3)3], 1.50–2.10 (m, 8 H, CH2CH2CH2N, Pro-C3H2, Pro-
amidine hydrochloride (1.47 g, 10 mmol) afforded 2.0 g (81%) of
the monoprotected intermediate, which was crystallized from
EtOH. Subsequent reaction of this intermediate with Cbz–OSu
gave 2.1 g (66%) of bis-protected pyrazole 16, which was purified
by column chromatography (eluent: EtOAc/hexanes, 1:2) prior to
crystallization from diethyl ether/hexanes.
C4H2), 3.18–3.43 (m, 6 H, CHCH2S, CH2CH2CH2N, Pro-C5H2),
3.87 (d, Gly-C2H2), 4.14 (q, 2 H, CH3CH2O, Pro-C2H2), 4.45 (br.
s, 1 H, CHN), 4.95 (d, 1 H, NHBoc), 5.06, 5.13 (two s, 4 H,
OCH2Ph), 6.44 (br. s, 1 H, SO2CH2CHNH), 7.31 (m, 10 H, ArH),
7.44 (br. s, 1 H, Gly-NH), 8.36 (t, 1 H, CH2CH2CH2NH), 11.64 (s,
1
H, NHCbz). – δ ϭ 13.8
13C NMR (CDCl3/CD3OD):
(CH3CH2O), 24.0 (Pro-C4), 25.2 (CH2CH2CH2N), 28.1 [C(CH3)3],
29.5 (Pro-C3), 31.0 (CH2CH2N), 40.1 (CH2CH2CH2N), 44.0 (Gly-
C2), 45.3 (Pro-C5), 47.1 (SO2CH2CHN), 56.4 (Pro-C2), 60.6
(CH2SO2), 61.7 (CH3CH2O), 67.1, 68.1 (OCH2Ph), 80.6 [C(CH3)3],
127.8, 128.0, 128.3, 128.5, 128.6, 134.5, 136.4 (CAr), 153.5, 155.8
[NC(O)O], 163.3 (CϭN), 170.5 (Gly-C1), 173.5 (Pro-C1).
Boc–Arg(Cbz2)–ψ[CH2SO2]–Gly–OEt (17): Sulfonamide 14
(471 mg, 0.94 mmol) was dissolved in EtOH (8 mL). A catalytic
amount of 10% Pd/C was added and the mixture was stirred for 4
h under a hydrogen atmosphere. The catalyst was then removed by
filtration and the solution was concentrated to dryness. The residue
was redissolved in THF (5 mL) and pyrazole compound 16
(356 mg, 0.94 mmol) was added. The resulting mixture was stirred Boc–Pro–Arg(Cbz2)–ψ[CH2SO2]–NH2 (20): Peptidosulfonamide 20
overnight and then 2-aminoethanol (57 µL, 0.94 mmol) was added.
Eur. J. Org. Chem. 2000, 1219Ϫ1228
was prepared from sulfonamide 18 (77 mg, 0.13 mmol) and Boc–
1223

D. W. P. M. Löwik, R. M. J. Liskamp
FULL PAPER
Pro–OH (28 mg, 0.13 mmol) according to the procedure described
CH2CH2CH2N, Pro-C3H2, Pro-C4H2), 3.00 (m, 2 H, Phe-C3H2),
3.10 (m, 1 H, Pro-C5Ha), 3.25 (t, 2 H, CH2CH2CH2N), 3.45 (d, 2
for 19. The product was purified by flash chromatography (eluent:
EtOAc/hexanes, 4:1), to yield 81 mg (90%) of 20. Rf ϭ 0.28 (EtOAc/ H, CH2SO2), 3.68 (br. s, 1 H, Pro-C5Hb), 4.00 (s, Gly-C2H2), 4.25
hexanes, 3:1). – 1H NMR (CDCl3): δ ϭ 1.43 [s, 9 H, C(CH3)3], (q, 2 H, CH3CH2O), 4.40 (m, 2 H, CHCH2SO2, Pro-C2H), 4.63
1.50–2.10 (m, 8 H, CH2CH2CH2N), 3.20–3.50 (m, 2 H, CH2CH2N,
(m, 1 H, Phe-C2H), 7.25–7.45 (m, 5 H, ArH). – 13C NMR (D2O):
CHCH2S, Pro-C5H2), 4.19 (dd, 1 H, Pro-C2H), 4.40 (br. s, 1 H, δ ϭ 12.6 (CH3CH2O), 23.3 (Pro-C4), 23.5 (CH2CH2CH2N), 26.8,
CHN), 5.11, 5.13, 5.17 (d and s, 4 H, OCH2Ph), 5.63 (br. s, 2 H,
NH2), 7.17 (m, 1 H, NHCHCH2S), 7.30 (m, 10 H, ArH), 8.38 (t,
1 H, CH2CH2CH2NH), 11.70 (s, 1 H, NHCbz).
26.9 [C(CH3)3], 28.2 (Pro-C3), 30.0 (CH2CH2N), 36.9 (Phe-C3),
39.8 (CH2CH2CH2N), 43.2 (Gly-C2), 44.3 (SO2CH2CHN), 46.8
(Pro-C5), 53.2 (Phe-C2), 55.1 (CH2SO2), 60.1 (Pro-C2), 61.7
(CH3CH2O), 80.3 [C(CH3)3], 126.3, 127.9, 128.6, 135.3 (CAr), 155.8
[NC(O)O], 170.9, 171.3, 171.5, 172.1 (Phe-C1, Gly-C1, Pro-C1). –
ES-MS; m/z: 654.15 [M – HCl ϩ H]ϩ.
Boc–D-Phe–Pro–Arg(Cbz2)–ψ[CH2SO2]–Gly–OEt (21): Peptido-
sulfonamide 21 was prepared from sulfonamide 19 (456 mg,
0.588 mmol) and Boc--Phe–OH (156 mg, 0.588 mmol) according
to the procedure described for 19. The product was purified by
flash chromatography (eluent: EtOAc/hexanes, 3:1) to yield 488 mg
(90%) of 21. Rf ϭ 0.34 (EtOAc/hexanes, 3:1). – 1H NMR (CDCl3):
δ ϭ 1.23 (t, 3 H, CH3CH2O), 1.36 [s, 9 H, C(CH3)3], 1.50–2.05 (m,
8 H, CH2CH2CH2N, Pro-C3H2, Pro-C4H2), 2.63 (m, 1 H, Pro-
C5Ha), 2.91 (d, 2 H, Phe-C3H2), 3.15 (d, 2 H, CHCH2SO2), 3.41
(br. s, 2 H, CH2CH2CH2N), 3.52 (m, 1 H, Pro-C5Hb), 3.89 (q, Gly-
C2H2), 4.16 (q, 2 H, CH3CH2O), 4.24 (m, 1 H, CHCH2SO2), 4.45
(m, 2 H, Phe-C2H, Pro-C2H), 5.09, 5.15 (two s, 4 H, OCH2Ph),
7.14–7.45 (m, 15 H, ArH), 7.44 (br. s, 1 H, Gly-NH), 8.39 (t, 1 H,
CH2CH2CH2NH), 11.70 (s, 1 H, NHCbz). – 13C NMR (CDCl3):
δ ϭ 13.9 (CH3CH2O), 24.1 (Pro-C4), 25.3 (CH2CH2CH2N), 28.2
[C(CH3)3], 28.9 (Pro-C3), 30.9 (CH2CH2N), 38.7 (Phe-C3), 40.1,
40.2 (CH2CH2CH2N), 44.1, 44.2 (Gly-C2), 45.4 (Pro-C5), 47.1
(SO2CH2CHN), 54.0 (Phe-C2), 56.6 (Pro-C2), 60.9 (CH2SO2), 61.8
(CH3CH2O), 67.1, 68.1 (OCH2Ph), 80.2 [C(CH3)3], 127.1, 127.9,
128.0, 128.29, 128.32, 128.5, 128.6, 128.7, 129.3, 134.5, 135.9, 136.6
(CAr), 153.6, 155.6, 155.9, 156.0 [NC(O)O], 163.4 (CϭN), 170.3
(Gly-C1), 171.3, 171.7 (Phe-C1), 172.4, 172.5 (Pro-C1).
Boc–D-Phe–Pro–Argψ[CH2SO2]–NH2 HCl (24): To a solution of
sulfonamide 22 (60 mg, 0.072 mmol) in EtOH (1 mL), acetic acid
(8 µL) and 10% Pd/C (20 mg) were added and the resulting mixture
was stirred for 5 h under a hydrogen atmosphere. The catalyst was
then removed by filtration, the solution was concentrated to dry-
ness, and the residue was freed of excess acetic acid by twofold
coevaporation with DCM. The acetic acid salt was converted into
the hydrochloric acid salt 24 on a DOWEX Cl– column. Lyophiliz-
ation gave 40 mg (92%) of the peptidosulfonamide. – 1H NMR
(D2O):
δ ϭ 1.38 [s, 9 H, C(CH3)3], 1.50–2.05 (m, 8 H,
CH2CH2CH2N, Pro-C3H2, Pro-C4H2), 2.95 (d, 2 H, Phe-C3H2),
3.05 (m, 1 H, Pro-C5Ha), 3.20 (t, 2 H, CH2CH2CH2N), 3.40 (d, 2
H, CH2SO2), 3.63 (br. s, 1 H, Pro-C5Hb), 4.20, 4.35, 4.60 (three m,
3 H, CHCH2SO2, Pro-C2H, Phe-C2H), 7.20–7.40 (m, 5 H, ArH). –
13C NMR (D2O): δ ϭ 21.0, 23.2, 23.4, 23.5 (CH2CH2CH2N, Pro-
C4), 26.6, 28.7 [C(CH3)3], 28.1, 30.0 (Pro-C3), 29.9, 30.7
(CH2CH2N), 35.6, 36.5 (Phe-C3), 39.6 (CH2CH2CH2N), 44.3, 44.4
(SO2CH2CHN), 46.9, 49.1 (Pro-C5), 52.1, 53.2 (Phe-C2), 56.9
(CH2SO2), 59.7, 60.0 (Pro-C2), 80.7 [C(CH3)3], 126.1, 126.5, 127.3,
127.8, 127.9, 128.1, 128.3, 128.5, 128.6, 135.2, 135.8 (CAr), 155.8,
156.3 [NC(O)O], 167.0 (CϭN), 171.7, 172.0, 172.4, 172.8 (Phe-C1,
Gly-C1, Pro-C1). – FAB-MS; m/z: 568.2 [M – HCl ϩ H]ϩ. – ES-
MS; m/z: 568.10 [M – HCl ϩ H]ϩ.
Boc–D-Phe–Pro–Arg(Cbz2)–ψ[CH2SO2]–NH2 (22): Peptidosulfon-
amide 22 was prepared from sulfonamide 20 (81 mg, 0.12 mmol)
and Boc--Phe–OH (31 mg, 0.12 mmol) according to the proced-
ure described for 19. The product was purified by flash chromato-
graphy (eluent: EtOAc/hexanes, 4:1) to yield 68 mg (69%) of 22.
H–D-Phe–Pro–Argψ[CH2SO2]–Gly–OEt 2HCl (25): 23 (10 mg, 14
1
Rf ϭ 0.16 (EtOAc/hexanes, 4:1). – H NMR (CDCl3): δ ϭ 1.40 [s,
µmol) was dissolved in DCM (1 mL) and then HCl-saturated di-
ethyl ether (1 mL) was added. After stirring for 45 min, the solvent
was removed in vacuo and the residue was redissolved in water.
Lyophilization yielded 10 mg of peptidosulfonamide 25. – 1H
NMR (D2O): δ ϭ 1.30 (t, 3 H, CH3CH2O), 1.50–2.15 (m, 8 H,
CH2CH2CH2N, Pro-C3H2, Pro-C4H2), 2.78 (q, 1 H, Pro-C5Ha),
9 H, C(CH3)3], 1.45–1.90 (m, 7 H, CH2CH2CH2N, Pro-C3Ha, Pro-
C4H2), 2.05 (m, 1 H, Pro-C3Hb), 2.60 (m, 1 H, Pro-C5Ha), 2.95 (m,
2 H, Phe-C3H2), 3.20 (m, 2 H, CH2SO2), 3.45 (m, 2 H, CH2CH2N),
3.57 (m, 1 H, Pro-C5Hb), 4.28 (dd, 1 H, Pro-C2H), 4.42 (m, 2 H,
CHN, Phe-C2H), 5.11, 5.13, 5.17 (d and s, 4 H, OCH2Ph), 5.37 (d,
1 H, NHBoc), 5.47 (br. s, 2 H, NH2), 7.07 (m, 1 H, NHCHCH2S),
7.30 (m, 15 H, ArH), 8.38 (t, 1 H, CH2CH2CH2NH), 11.75 (s, 1
H, NHCbz). – 13C NMR (CDCl3): δ ϭ 24.3 (Pro-C4), 25.8
(CH2CH2CH2N), 28.4 [C(CH3)3], 28.7 (Pro-C3), 31.2 (CH2CH2N),
38.7 (Phe-C3), 40.1 (CH2CH2N), 46.0 (NHCHCH2S), 47.2 (Pro-
C5), 54.2 (Phe-C2), 58.7 (CH2SO2), 60.9 (Pro-C2), 67.1, 68.2
(OCH2Ph), 80.3 [C(CH3)3], 127.2, 128.0, 128.2, 128.6, 128.7, 128.8,
129.3, 134.5, 135.8, 136.6 (CAr), 153.8, 155.6, 156.3 (OCN), 163.6
(CϭN), 171.5, 172.1 (Pro-C1, Phe-C1).
3.15–3.60 (m,
7
H, Phe-C3H2, Pro-C5Hb, CH2CH2CH2N,
CH2SO2), 4.01 (s, Gly-C2H2), 4.25 (q, 2 H, CH3CH2O), 4.30, 4.44,
4.59 (three m, 3 H, CHCH2SO2, Pro-C2H, Phe-C2H), 7.30–7.50
(m, 5 H, ArH). – FAB-MS; m/z: 554.2 [M – 2HCl ϩ Hϩ].
H–D-Phe–Pro–Argψ[CH2SO2]–Gly–OH 2HCl (26): Sulfonamide
23 (11 mg, 15 µmol) was dissolved in 1  aq. HCl (1 mL) and
the resulting solution was stirred for 24 h at room temperature.
1
Lyophilization gave 10 mg of peptidosulfonamide 26. – H NMR
(D2O): δ ϭ 1.50–2.15 (m, 8 H, CH2CH2CH2N, Pro-C3H2, Pro-
C4H2), 2.78 (q, 1 H, Pro-C5Ha), 3.15–3.60 (m, 7 H, Phe-C3H2, Pro-
C5Hb, CH2CH2CH2N, CH2SO2), 4.01 (s, Gly-C2H2), 4.32, 4.43,
4.59 (three m, 3 H, CHCH2SO2, Pro-C2H, Phe-C2H), 7.30-7.50 (m,
5 H, ArH). – FAB-MS: m/z ϭ 526.2 [M – 2HCl ϩ Hϩ].
Boc–D-Phe–Pro–Argψ[CH2SO2]–Gly–OEt HCl (23): To a solution
of sulfonamide 21 (194 mg, 0.21 mmol) in EtOH (1 mL), acetic acid
(20 µL) and 10% Pd/C (20 mg) were added and the mixture was
stirred overnight under a hydrogen atmosphere. The catalyst was
then removed by filtration and the solution was concentrated to
dryness. The acetic acid salt was first purified on Sephadex LH-20
(eluent: DCM/MeOH, 1:1) and then converted into the hydro-
chloric acid salt 23 on a DOWEX Cl– column. Lyophilization gave
H–D-Phe–Pro–Argψ[CH2SO2]–NH2 2HCl (27): Sulfonamide 24
(9.9 mg, 16 µmol) was dissolved in DCM (1 mL) and then HCl-
saturated diethyl ether was added. After stirring for 45 min, the
96 mg (66%) of the peptidosulfonamide. Rf ϭ 0.55 (MeOH/37%
NH3 in H2O/CHCl3, 45:20:60). – H NMR (D2O): δ ϭ 1.30 (t, 3 water. Lyophilization gave 9.4 mg of peptidosulfonamide 27. – H
H, CH3CH2O), 1.38 [s, 9 H, C(CH3)3], 1.50–2.10 (m, 8 H,
solvent was removed in vacuo and the residue was redissolved in
1
1
NMR (D2O): δ ϭ 1.50–2.15 (m, 8 H, CH2CH2CH2N, Pro-C3H2,
1224
Eur. J. Org. Chem. 2000, 1219Ϫ1228

Synthesis of Peptidosulfonamides
FULL PAPER
Pro-C4H2), 2.90 (d, 1 H, Pro-C5Ha), 3.10–3.65 (m, 7 H, Pro-C5Hb,
solution was extracted with five portions of EtOAc, the combined
organic layers were dried with Na2SO4, and the solvent was re-
CH2CH2CH2N, CH2SO2, Phe-C3H2), 4.32, 4.41, 4.59 (three m, 3
H, CHCH2SO2, Pro-C2H, Phe-C2H), 7.30–7.50 (m, 5 H, ArH). – moved in vacuo. Column chromatography (eluent: 6% MeOH in
FAB-MS: m/z ϭ 468.2 [M – 2 HCl ϩ Hϩ].
DCM) gave 3.24 g (93%) of diol 32. Rf ϭ 0.28 (10% MeOH in
DCM). – 1H NMR (CDCl3): δ ϭ 1.38 [s, 9 H, C(CH3)3], 1.32–1.67
(m, 4 H, C3H2, C4H2), 2.95, 3.18 (m, 2 H, C1H2), 3.60 (m, 4 H,
CHO, CH2O), 4.03 (br. s, 1 H, C5OH), 4.46 (br. s, 1 H, C2OH),
5.38 (br. s, 1 H, NH). – 13C NMR (CDCl3): δ ϭ 28.3 [C(CH3)3],
28.7 (C3), 31.6 (C4), 46.5 (C1), 62.3 (C5), 70.9 (C2), 79.4 [C(CH3)3],
156.7 (CϭO).
1-Benzyloxy-4-pentene (29): At 0 °C, NaH (1.32 g, 55 mmol) was
added to a solution of 4-penten-1-ol (5.16 mL, 50 mmol) in THF
(75 mL). After stirring for 10 min at room temperature, benzyl
chloride (5.75 mL, 50 mmol) was added and the mixture was re-
fluxed overnight. After neutralization with 1  aq. HCl, the solvent
was evaporated and the residue was redissolved in diethyl ether.
The resulting solution was washed with water (three times) and
Azido Alcohol 33: To a cooled (0 °C) solution of triphenylphos-
with brine, and dried with MgSO4. Evaporation of the solvent and phane (1.51 g, 5.76 mmol) in THF (20 mL) were sequentially added
column chromatography of the residue (eluent: hexanes Ǟ diethyl di-tert-butyl azodicarboxylate (1.32 g, 5.74 mmol), 1.1  HN3 solu-
ether/hexanes, 1:9) yielded 6.75 g (77%) of alkene 29. Rf ϭ 0.51 tion in benzene[18] (5.22 mL), and a solution of diol 32 (1.26 g,
(diethyl ether/hexanes, 1:9). – 1H NMR (CDCl3): δ ϭ 1.78 (q, 2 H,
5.74 mmol) in THF (15 mL). The cooling bath was then removed
C2H2), 2.21 (q, 2 H, C3H2), 3.54 (t, 2 H, C1H2), 4.55 (s, 2 H, and the reaction mixture was stirred overnight at room temper-
CH2Ph), 5.00–5.12 (m, 2 H, C5H2), 5.81–5.94 (m, 1 H, C4H), 7.25– ature. The solvent was subsequently evaporated and the residue was
7.45 (m, 5 H, ArH). – 13C NMR (CDCl3): δ ϭ 29.0 (C2), 30.3 (C3), purified by column chromatography (eluent: EtOAc/hexanes, 1:2).
69.7 (C1), 72.8 (CH2Ph), 114.6 (C5), 127.4, 127.5, 128.3, 138.7
(CAr), 138.2 (C4).
Yield: 775 mg (55%). Rf ϭ 0.40 (EtOAc/hexanes, 1:1). – H NMR
(CDCl3): δ ϭ 1.45 [s, 9 H, C(CH3)3], 1.47–1.85 (m, 4 H, C3H2,
C4H2), 2.67 (br. s, 1 H, OH), 3.05 (q, 1 H, C1H), 3.27 (q, 1 H,
C1H), 3.33 (t, 2 H, C5H2), 3.72 (m, 1 H, C2H), 4.92 (br. s, 1 H,
NH). – 13C NMR (CDCl3): δ ϭ 25.0 (C3), 28.3 [C(CH3)3], 31.6
(C4), 46.8 (C1), 51.4 (C5), 70.9 (C2), 79.7 [C(CH3)3], 156.8 (CϭO).
1
Epoxide 30: 1-Benzyloxy-4-pentene (1.15 g, 6.52 mmol) was dis-
solved in DCM (15 mL). A solution of dried 70% m-CPBA (1.95 g)
in DCM (5 mL) was added and the mixture was stirred overnight.
It was then filtered and further DCM (80 mL) was added. The
diluted solution was washed with 10% Na2S2O3 solution, 5%
NaHCO3 solution (twice), and brine, and dried with MgSO4. Evap-
oration of the solvent and purification of the residue by column
chromatography (eluent: diethyl ether/hexanes, 1:3) gave 930 mg
(74%) of epoxide 30 as an oil. Rf ϭ 0.43 (EtOAc/hexanes, 1:1). –
THF Derivative 33a: To a solution of diol 32 (219 mg, 1.0 mmol)
and triphenylphosphane (262 mg, 1.0 mmol) in THF (4 mL), di-
ethyl azodicarboxylate (DEAD) (164 µL, 1.0 mmol) was added.
The resulting mixture was stirred overnight and then the solvent
was evaporated. Column chromatography of the residue (eluent:
1H NMR (CDCl3): δ ϭ 1.55–1.90 (m, 4 H, C2H2C3H2C4H), 2.47 EtOAc/hexanes, 1:2) furnished 135 mg (67%) of tetrahydrofuran
(q, 1 H, C5HaHbC4H), 2.74 (t, 1 H, CHaHbCH), 2.93 (m, 1 H, derivative 33a as an oil. Rf ϭ 0.50 (EtOAc/hexanes, 1:1). – 1H
C5H2C4H), 3.54 (m, 2 H, C2H2C1H2O), 4.52 (s, 2 H, CH2Ph), 7.25– NMR (CDCl3): δ ϭ 1.43 [s, 9 H, C(CH3)3], 1.50–1.60, 1.83–2.00
7.40 (m, 5 H, ArH). – 13C NMR (CDCl3): δ ϭ 26.1 (C2), 29.2 (C3), (m, 4 H, C3H2, C4H2), 3.06, 3.38 (two m, 2 H, CH2N), 3.69–3.88
46.8 (C5), 51.9 (C4), 69.7 (C1), 72.8 (CH2Ph), 127.4, 127.5, 128.2,
138.4 (CAr).
(m, 2 H, C5H2), 3.93 (m, 1 H, C2 H), 4.88 (br. s, 1 H, NH). – 13C
NMR (CDCl3): δ ϭ 25.8 (C3), 28.4 [C(CH3)3], 28.5 (C4), 44.5
(CH2N), 68.0 (C5), 78.1 (C2), 79.2 [C(CH3)3], 156.1 (CϭO). – FAB-
MS: m/z ϭ 202.16 [M ϩ Hϩ].
Amino Alcohol 31: Epoxide 30 (4.16 g, 21.6 mmol) and (S)-α-
methylbenzylamine (2.78 mL, 21.6 mmol) were dissolved in MeOH
(30 mL) and the mixture was stirred overnight at 50 °C. The solvent Cbz-Protected Azide 34:
A solution of azide 33 (240 mg,
was then removed in vacuo and the product was purified by column
chromatography (eluent: 10% MeOH in DCM) to afford 4.98 g
(73%) of a colorless oil. Rf ϭ 0.46 (10% MeOH in DCM); 0.71,
0.98 mmol) in EtOH (25 mL) and chloroform (0.5 mL) containing
10% Pd/C (50 mg)[16] was shaken for 1 h under hydrogen at 3 bar
in a Parr apparatus. The catalyst was then removed by filtration,
the solution was concentrated to dryness, and the residue was co-
1
0.83 (30% MeOH in DCM). – H NMR (CDCl3): δ ϭ 1.39 (dd, 3
H, CH3), 1.42–1.58 (m, 2 H, C3H2), 1.58–1.81 (m, 2 H, C2H2), evaporated twice with DCM. It was then redissolved in DCM
2.28–2.65 (four dd, 2 H, C5H2), 3.48 (two t, C1H2), 3.48–3.71 (two
(7 mL) and triethylamine (139 µL, 1.0 mmol) and Cbz–OSu
m, 1 H, C4HO), 3.78 (two q, 1 H, CHN). – 13C NMR (CDCl3): (244 mg, 0.98 mmol) were added. After stirring overnight, the solv-
δ ϭ 23.8, 24.1 (CH3), 25.9 (C2), 31.9, 32.0 (C3), 52.9, 53.5 (C5), ent was removed in vacuo. The residue was redissolved in EtOAc,
57.7, 58.5 (CHN), 69.4, 69.9 (C4), 70.2 (C1), 72.8 (CH2Ph), 126.4, washed with 1  KHSO4, 5% NaHCO3 solution, water, and brine,
127.5, 128.2, 128.4, 144.8, 145.1, 126.9, 127.4, 138.3 (CAr).
and dried with Na2SO4. After evaporation of the EtOAc, the prod-
uct was purified by flash chromatography (eluent: 4% MeOH in
DCM), yielding 220 mg (64%) of alcohol 34. Rf ϭ 0.25 (4% MeOH
Diol 32: 31 (4.98 g, 15.9 mmol) was dissolved in dioxane (100 mL),
water (37 mL), and acetic acid (37 mL). After the addition of 20%
Pd(OH)2 on carbon (750 mg), the mixture was shaken for 4 days
under hydrogen at 3 bar in a Parr apparatus. The catalyst was then
removed by filtration and the solution was concentrated to dryness.
The residue was freed of acetic acid by coevaporation with EtOH
and then dissolved in dioxane (50 mL) and water (50 mL). A solu-
tion of Boc2O (3.47 g, 15.9 mmol) in dioxane (50 mL) was added
and the pH was adjusted to 8 with 1  aq. NaOH. During the
course of the reaction, the pH was kept at 8 by the addition of
further 1  NaOH. When the amine had been completely con-
sumed (TLC control), the volatiles were removed in vacuo and the
residue was redissolved in a small volume of water. The resulting
1
in DCM). – H NMR (CDCl3): δ ϭ 1.43 [s, 9 H, C(CH3)3], 1.50–
1.70 (m, 4 H, C3H2, C4H2), 3.00 (m, 2 H, C1H), 3.20 (m, 4 H,
C1H2, C2H, C5H2), 3.65 (br. s, 1 H, OH), 5.05 (s, 2 H, CH2Ph),
5.15 (m, 2 H, NH), 7.30 (m, 5 H, ArH). – 13C NMR (CDCl3):
δ ϭ 26.0 (C3), 28.2 [C(CH3)3], 31.5 (C4), 40.8 (C5), 46.7 (C1), 66.6
(CH2Ph), 71.0 (C2), 79.6 [C(CH3)3], 128.0, 128.4, 136.6 (CAr), 156.6
(CϭO).
Thioacetate 35: To a solution of triphenylphosphane (2.69 g,
10.3 mmol) in THF (40 mL), DIAD (2.02 mL, 10.3 mmol) was ad-
ded at 0 °C. After stirring for 30 min at 0 °C, a precipitate had
formed and the temperature was lowered to –10 °C. A solution of
Eur. J. Org. Chem. 2000, 1219Ϫ1228
1225

D. W. P. M. Löwik, R. M. J. Liskamp
FULL PAPER
alcohol 33 (1.25 g, 5.12 mmol) and thioacetic acid (730 µL,
10.3 mmol) in THF (15 mL) was then added. The resulting mixture
was allowed to warm to room temperature and stirred overnight.
After evaporation of the solvent, the product was purified by col-
umn chromatography (eluent: EtOAc/hexanes, 1:4), to yield 1.07 g
(69%) of thioacetate 35. Rf ϭ 0.16 (EtOAc/hexanes, 1:5). – 1H
NMR (CDCl3): δ ϭ 1.43 [s, 9 H, C(CH3)3], 1.50–1.80 (m, 4 H,
(CDCl3): δ ϭ 1.25 (t, 3 H, CH3CH2), 1.43 [s, 9 H, C(CH3)3], 1.60–
2.05 (m, 4 H, CH2CH2CH2NH), 3.20 (m, 1 H, CH), 3.45
(CH2CH2NH), 3.47, 3.72 (m, 2 H, CHCH2N), 3.85 (s, 2 H, Gly-
C2H2), 4.18 (q, 2 H, CH2O), 5.10, 5.15 (two s, 4 H, OCH2Ph), 5.35
(t, 1 H, NHBoc), 5.88 (br. s, 1 H, NHSO2), 7.20–7.45 (m, 10 H,
ArH), 8.38 (t, 1 H, CH2NHC), 11.75 (s, 1 H, NHCbz). – 13C NMR
(CDCl3):
δ ϭ 14.0 (CH3CH2), 24.0 (CH2CH2CH2N3), 26.0
C3H2, C4H2), 1.32 (s, 3 H, CH3CO), 3.15–3.40 (m, 4 H, C1H2, (CH2CH2N3), 28.3 [C(CH3)3], 39.2 (NCH2CH), 40.3 (CH2CH2N),
C5H2), 3.55 (m, 1 H, C2H), 4.78 (br. s, 1 H, NH). – 13C NMR 44.3 (Gly-C2), 61.7 (CH3CH2O), 62.5 (CH), 67.1, 68.2 (OCH2Ph),
(CDCl3): δ ϭ 26.3 (C3), 28.3 [C(CH3)3], 29.0 (C4), 30.7 (CH3CO), 79.8 [C(CH3)3], 128.0, 128.3, 128.4, 128.5, 128.6, 128.7, 134.6, 136.7
44.3 (C1), 44.7 (C2), 51.0 (C5), 79.5 [C(CH3)3], 155.8 [C(O)NH],
195.1 [C(O)CH3].
(CAr), 153.8 (CO2CH2Ph), 156.1 [CO2C(CH3)], 163.5 (CϭN), 169.8
(Gly-C1). – ES-MS: m/z ϭ 678.10 [M ϩ H]ϩ.
Peptidosulfonamide 39: To a solution of sulfonamide 38 (168 mg,
0.25 mmol) in DCM (1.5 mL), TFA (0.5 mL) was added. After stir-
ring for 30 min, the solvent was evaporated and the residue was
freed of TFA by threefold coevaporation with DCM. The residue
was taken up in DCM (2 mL) and Boc–Pro–OH (62 mg,
0.29 mmol), BOP (128 mg, 0.29 mmol), and DIPEA (151 µL,
0.87 mmol) were added. The mixture was stirred overnight, and
then the solvent was evaporated and the residue was redissolved in
EtOAc. This solution was washed with 1  KHSO4, 5% NaHCO3
solution, and brine, and dried with Na2SO4. Evaporation of the
solvent and purification of the product by column chromatography
(eluent: EtOAc/hexanes, 2:1) afforded 133 mg (69%) of peptidosul-
fonamide 39. Rf ϭ 0.23 (EtOAc/hexanes, 2:1). – 1H NMR (CDCl3):
δ ϭ 1.27 (t, 3 H, CH3CH2), 1.43 [s, 9 H, C(CH3)3], 1.50–2.25 (m,
8 H, CH2CH2CH2NH, Pro-C3H2, Pro4H2), 3.20–3.75 (m, 4 H, Pro-
C5H2, CHCH2N, CHCHaN), 3.46 (q, 2 H, CH2CH2CH2NH), 3.92
(m, 3 H, Gly-C2H2, CHCHbN), 4.19 (m, 2 H, CH2CH3, Pro-C2H),
5.12, 5.17 (two s, 4 H, OCH2Ph), 5.88, 6.17 (two br. s, 1 H,
NHSO2), 7.27–7.41 (m, 11 H, ArH, CH2NHCO), 8.37 (t, 1 H,
CH2CH2CH2NH), 11.72 (NHCbz). – 13C NMR (CDCl3): δ ϭ 14.1
(CH3CH2), 24.1 (CH2CH2CH2NH), 24.5 (br., Pro-C4), 26.1 (Pro-
C3, CH2CH2NH), 28.4 [C(CH3)3], 38.0 (NCH2CHS), 40.4, 40.5
(CH2CH2CH2NH), 44.3, 44.4 (Gly-C2), 47.1 (Pro-C5), 60.7 (Pro-
C2), 61.8 (CH3CH2O), 62.0 (CHS), 67.1, 68.2 (OCH2Ph), 80.5, 80.6
[C(CH3)3], 127.9, 128.1, 128.39, 128.44, 128.67, 128.75, 134.6, 136.7
(CAr), 153.8, 156.16 (CO2CH2Ph), 156.19 [CO2C(CH3)3], 163.6
(CϭN), 170.2 (Gly-C1), 173.2 (Pro-C1).
Sulfonamide 36: Thioacetate 35 (1.023 g, 3.38 mmol) was dissolved
in DCM (10 mL) under argon. After cooling to –20 °C, Ac2O (319
µL, 3.38 mmol) and sulfuryl chloride (549 µL, 6.78 mmol) were
added. The resulting mixture was stirred for 1 h at –5 °C and then
the volatiles were evaporated and the residue was dried in vacuo.
The crude sulfinyl chloride (3.38 mmol) was used immediately for
the next reaction. It was dissolved in DCM (10 mL) and then a
suspension of H–Gly–OEtHCl (944 mg, 6.76 mmol) in DCM
(20 mL) containing triethylamine (943 µL, 6.78 mmol) was added
under argon. The reaction mixture was stirred overnight and then
the solvent was removed in vacuo. Flash chromatography of the
residue (eluent: 5% MeOH in DCM) furnished 770 mg (60%) of
the sulfinamide. Rf ϭ 0.26 (5% MeOH in DCM). This sulfinamide
(2.04 mmol) was dissolved in a mixture of DCM (5 mL), acetonitr-
ile (5 mL), and water (7.5 mL). The resulting solution was cooled
to 0 °C, whereupon NaIO4 (567 mg, 2.67 mmol) and a catalytic
amount of RuCl3 H2O were added under vigorous stirring. The
mixture was allowed to warm to room temperature and, after stir-
ring for 20 min, the aqueous layer was extracted three times with
DCM. The combined organic layers were dried with MgSO4 and
the solvent was removed in vacuo. Flash chromatography of the
residue (eluent: 3% MeOH in DCM) gave 695 mg (87%) of sulfona-
mide 36. The overall yield was 52%. Rf ϭ 0.43 (5% MeOH in
1
DCM). – H NMR (CDCl3): δ ϭ 1.29 (t, 3 H, CH3CH2), 1.43 [s,
9 H, C(CH3)3], 1.60–2.10 (m, 4 H, CH2CH2CH2), 3.11 (m, 1 H,
CH), 3.34 (t, 2 H, CH2N3), 3.53, 3.75 (m, 2 H, CHCH2N), 3.94
(dd, 2 H, Gly-C2H2), 4.22 (q, 2 H, CH2O), 5.27 (t, 1 H, NHCO),
5.45 (NHSO2). – 13C NMR (CDCl3): δ ϭ 14.0 (CH3CH2), 24.0
(CH2CH2CH2N3), 26.0 (CH2CH2N3), 28.3 [C(CH3)3], 39.0
(NCH2CH), 44.4 (Gly-C2), 51.1 (CH2N3), 61.9 (CH2O), 62.6 (CH),
80.0 [C(CH3)3], 156.1 [C(O)NH], 169.8 (Gly-C1). – ES-MS; m/z:
416.00 [M ϩ Na]ϩ.
Peptidosulfonamide 40: Peptidosulfonamide 40 was prepared ac-
cording to the procedure described for 39. Starting from peptido-
sulfonamide 39 (133 mg, 0.172 mmol), 100 mg (63%) of peptidosul-
fonamide 40 was isolated following column chromatography (elu-
ent: EtOAc/hexanes, 7:3). Rf ϭ 0.32 (EtOAc/hexanes, 3:1). – 1H
NMR (CDCl3): δ ϭ 1.28 (dt, 3 H, CH3CH2), 1.39 [s, 9 H,
α-Substituted Aminoethane Sulfonamide Ornithine–Glycine Analog
37: A solution of azide 36 (151 mg, 0.38 mmol) in EtOH (25 mL)
and chloroform (0.5 mL)[16] containing Pd/C was shaken under hy-
drogen at 3 bar in a Parr apparatus for 2.5 h. The catalyst was then
removed by filtration and the solution was concentrated to dryness,
to afford the hydrochloric acid salt 37 in quantitative yield. The
crude product was used directly for the preparation of sulfonam-
ide 38.
C(CH3)3], 1.45–2.15 (m,
8
H, CH2CH2CH2NH, Pro-C3H2,
Pro4H2), 2.67 (m, 1 H, Pro-C5Ha), 2.93 (m, Phe-C3H2), 3.23 (br. s,
1 H, CHS), 3.45 (t, 2 H, CH2CH2CH2NH), 3.50–3.80 (m, 3 H,
NCHaCHS, Pro-C5Hb), 3.94 (m, 3 H, NCHbCHS, Gly-C2H2), 4.19
(dq, 2 H, CH3CH2O), 4.37 (two dd, 1 H, Pro-C2H), 4.48 (q, 1 H,
Phe-C2H), 5.11, 5.16 (two s, 4 H, OCH2Ph), 5.44 (d, 1 H, Phe-
NH), 6.20, 6.32 (two t, 1 H, NHSO2), 7.15–7.48 (m, 16 H, ArH,
CHCH2NH), 8.37 (t, 1 H, CH2CH2CH2NH), 11.72 (NHCbz). –
α-Substituted Aminoethane Sulfonamide Arginine–Glycine Analog 13C NMR (CDCl3):
δ ϭ 14.0 (CH3CH2), 24.0, 24.2, 24.5
38: Sulfonamide 37 (0.38 mmol) was dissolved in THF (4 mL) and
then pyrazole compound 16 (145 mg, 0.38 mmol) and triethylamine
(53 µL, 0.38 mmol) were added. After stirring overnight, the solv-
ent was removed in vacuo and the residue was redissolved in
EtOAc. This solution was washed with 1  KHSO4 and 5%
NaHCO3 solution, and dried with Na2SO4. After evaporation of
the solvent and purification of the residue by flash chromatography
(eluent: 2.5% MeOH in DCM), 168 mg (65%) of sulfonamide 38
(CH2CH2CH2NH, Pro-C4), 26.1, 26.2 (CH2CH2N3), 28.3
[C(CH3)3], 28.5 (Pro-C3), 38.5, 38.8 (NCH2CHS, Phe-C3), 40.5
(CH2CH2CH2NH), 44.2, 44.3 (Gly-C2), 46.8, 47.0 (Pro-C5), 54.0
(Phe-C2), 60.3, 60.5 (CHS), 61.6, 61.8 (Pro-C2), 61.6, 61.7
(CH3CH2O), 67.0, 68.0 (OCH2Ph), 80.1 [C(CH3)3], 127.0, 127.1,
127.8, 128.0, 128.3, 128.36, 128.45, 128.6, 128.7, 129.3, 134.6,
136.0, 136.1, 136.7 (CAr), 153.7 (CO2CH2Ph), 155.5 [CO2C(CH3)3],
156.0 (CO2CH2Ph), 163.6 (CϭN), 170.4, 170.5 (Gly-C1), 171.4,
was obtained. Rf ϭ 0.75 (10% MeOH in DCM). – 1H NMR 171.7 (Pro-C1), 172.2 (Phe-C1).
1226
Eur. J. Org. Chem. 2000, 1219Ϫ1228

Synthesis of Peptidosulfonamides
Peptidosulfonamide 41: Peptidosulfonamide 40 (102 mg,
FULL PAPER
D. T. S. Rijkers of our department for recording the LC-ES mass
0.111 mmol) was dissolved in EtOH (1 mL) containing acetic acid spectra. Finally, we wish to thank Mr. J. van Ameijde for carefully
(10 µL). 10% Pd/C (20 mg) was added and the mixture was stirred
overnight under a hydrogen atmosphere. The catalyst was then re-
moved by filtration and the solution was concentrated to dryness.
The acetic acid salt thus obtained was purified on a DOWEX Cl–
column. Lyophilization gave 55 mg (72%) of peptidosulfonamide
41. Rf ϭ 0.62 (MeOH/37% NH3 in H2O/CHCl3, 45:20:60). – 1H
NMR (D2O): δ ϭ 1.25 (t, 3 H, CH3CH2O), 1.43 [s, 9 H, C(CH3)3],
1.60–2.10 (m, 8 H, CH2CH2CH2NH, Pro-C3H2, Pro-C4H2), 3.00
(d, 3 H, Phe-C3H2, Pro-C5Ha), 3.15 (t, 2 H, CH2CH2CH2NH), 3.40
(m, 1 H, CHS), 3.60–3.85 (m, 3 H, NHCH2CHS, Pro-C5Hb), 4.03
(s, 2 H, Gly-C2H2), 4.28 (q, 2 H, CH3CH2O), 4.32 (m, 1 H, Pro-
C2H), 4.66 (m, 1 H, Phe-C2H), 7.20–7.50 (m, 5 H, ArH). – 13C
NMR (D2O): δ ϭ 13.6 (CH3CH2O), 23.7 (CH2CH2CH2NH), 24.2
(CH2CH2CH2NH), 25.3 (Pro-C4), 27.9 [C(CH3)3], 29.4 (Pro-C3),
37.5 (Phe-C3), 38.0 (NHCH2CHS), 41.0 (CH2CH2CH2NH), 44.3
(Gly-C2), 47.9 (Pro-C5), 54.4 (Phe-C2), 61.1 (CHS), 61.5 (Pro-C2),
63.0 (CH3CH2O), 82.0 [C(CH3)3], 127.6, 129.0, 129.6, 136.2 (CAr),
157.1 [CϭN, CO2C(CH3)3], 172.2, 174.4 (CϭO). – FAB-MS: m/z ϭ
654.3 [M – HCl ϩ H]ϩ. – ES-MS; m/z: 654.45 [M – HCl ϩ H]ϩ.
reading and correcting the manuscript.
[1] [1a]
R. M. J. Liskamp, Angew. Chem. Int. Ed. Engl. 1994, 33,
[1b]
305. –
1699. –
J. Gante, Angew. Chem. Int. Ed. Engl. 1994, 33,
A. Giannis, T. Kolter, Angew. Chem. Int. Ed. Engl.
[1c]
1993, 32, 1244.
[2]
See, for example: [2a] R. J. Simon, R. S. Kania, R. N. Zuckerm-
ann, V. D. Huebner, D. A. Jewell, S. Banville, S. Ng, L. Wang,
S. Rosenberg, C. K. Marlowe, D. C. Spellmeyer, R. Tan, A. D.
Frankel, D. V. Santi, F. E. Cohen, P. A. Bartlet, Proc. Natl.
[2b]
Acad. Sci. USA 1992, 89, 9367. –
J. A. W. Kruijtzer, R. M.
[2c]
J. Liskamp, Tetrahedron Lett. 1995, 36, 6969. –
K. Burgess,
C. Y. Cho, E. J. Moran, S. R. Cherry, J. C. Ste-
D. S. Linthicum, H. Shin, Angew. Chem. Int. Ed. Engl. 1995,
[2d]
34, 907. –
phans, S. P. A. Fodor, C. L. Adams, A. Sundaram, J. W. Jacobs,
[2e]
P. G. Schultz, Science 1993, 261. –
K. M. Bol, R. M. J.
[2f]
Liskamp, Tetrahedron Lett. 1992, 48, 6425. –
T. Sommer-
field, D. Seebach, Angew. Chem. Int. Ed. Engl. 1995, 34, 553. –
[2g]
P. Lin, A. Ganesan, Bioorg. Med. Chem. Lett. 1998, 8, 511.
R. Wolfenden, Acc. Chem. Res. 1972, 5, 10. –
[3] [3a]
[3b]
G. E.
Lienhard, Science 1973, 180, 149.
[4]
M. A. Ondetti, D. W. Cushman, Biopolymers 1981, 20, 2001.
[5] [5a]
N. Choy, H. Choi, H. J. Won, C. R. Kim, H. Yoon, S. C.
[5b]
Kim, T. G. Lee, J. S. Koh, J. Med. Chem. 1997, 7, 2635. –
Peptidosulfonamide 42: Peptidosulfonamide 41 (14 mg, 20.3 µmol)
was dissolved in DCM (1 mL) and then HCl-saturated diethyl ether
(2 mL) was added. After stirring for 45 min, the volatiles were re-
moved in vacuo and the residue was redissolved in water. Lyophiliz-
ation gave 12 mg (94%) of peptidosulfonamide 42. – 1H NMR
(D2O): δ ϭ 1.31 (t, 3 H, CH3CH2O), 1.60–2.10 (m, 8 H,
CH2CH2CH2NH, Pro-C3H2, Pro-C4H2), 2.80 (q, 1 H, Pro-C5Ha),
3.15–3.33 (m, 2 H, Phe-C3H2), 3.27 (t, 2 H, CH2CH2CH2NH), 3.42
(m, 1 H, CHS), 3.55 (m, 1 H, Pro-C5Hb), 3.73 (m, 2 H,
NCH2CHS), 4.04 (d, 2 H, Gly-C2H2), 4.30 (q, 2 H, CH3CH2O),
4.36 (dd, 2 H, Pro-C2H), 4.60 (t, 1 H, Phe-C2H), 7.25–7.50 (m, 5
H, ArH). – 13C NMR (D2O): δ ϭ 13.6 (CH3CH2O), 23.9
(CH2CH2CH2NH), 24.3 (CH2CH2CH2NH), 25.5, 25.6 (Pro-C4),
29.7, 29.8 (Pro-C3), 36.8 (Phe-C3), 37.8, 37.9 (NHCH2CHS), 41.1
(CH2CH2CH2NH), 44.4 (Gly-C2), 47.2 (Pro-C5), 52.6, 53.4 (Phe-
C2), 61.0 (CHS), 61.5, 61.7 (Pro-C2), 63.1 (CH3CH2O), 128.7,
129.7, 130.0, 133.9 (CAr), 157.1 (CϭN), 168.5 (Phe-C1), 172.2,
174.4 (Pro-C1, Gly-C1). – FAB-MS; m/z: 554.2 [M – 2HCl ϩ Hϩ].
C. P. Decicco, J. L. Seng, K. E. Kennedy, M. B. Covington, P.
K. Welch, E. C. Arner, R. L. Magolda, D. J. Nelson, J. Med.
[5c]
Chem. 1997, 7, 2331. –
S. Paik, E. H. White, Tetrahedron
[5d]
1996, 52, 5303. –
F. Benedetti, F. Berti, A. Colombatti, C.
[5e]
Ebert, P. Linda, F. Tonizzo, Chem. Commun. 1996, 1417. –
[5f]
M. Mulliez, C. Naudy, Tetrahedron 1994, 50, 5401. –
G. P.
Zecchini, M. P. Paradisi, I. Torrini, G. Lucente, E. Gavuzzo, F.
[5g]
Mazza, G. Pochetti. –
C. Gennari, D. Salom, D. Potenza,
[5h]
A. Williams, Angew. Chem. Int. Ed. Engl. 1994, 33, 2067. –
See also ref.[7]
[6]
J. A. Zablocki, F. S. Tjoeng, P. R. Bovy, M. Miyano, R. B.
Garland, K. Williams, L. Schretzman, M. E. Zupec, J. G. Rico,
R. J. Lindmark, M. V. Toth, D. E. McMackins, S. P. Adams,
S. G. Panzer-Knodle, N. S. Nicholson, B. B. Taite, A. K. Saly-
ers, L. W. King, J. G. Campion, L. P. Feigen, Bioorg. Med.
Chem. 1995, 3, 539 and references cited therein.
[7] [7a]
D. B. A. de Bont, G. H. den Dijkstra, J. A. J. Hartog, R.
[7b]
M. J. Liskamp, Bioorg. Med. Chem. Lett. 1996, 6, 3035. –
D. B. A. de Bont, W. J. Moree, R. M. J. Liskamp, Bioorg. Med.
Chem. 1996, 4, 667. – [7c] W. J. Moree, G. A. van der Marel, R.
M. J. Liskamp, J. Org. Chem. 1995, 60, 5157. – [7d] W. J. Moree,
A. Schouten, J. Kroon, R. M. J. Liskamp, Int. J. Pept. Prot.
[7e]
Res. 1995, 45, 501. –
W. J. Moree, G. A. van der Marel, R.
Peptidosulfonamide 43: Peptidosulfonamide 41 (15 mg, 21.7 µmol)
was dissolved in 1  HCl (3 mL) and the resulting solution was
stirred for 48 h at room temperature. Lyophilization gave 13 mg
(100%) of peptidosulfonamide 43. – 1H NMR (D2O): δ ϭ 1.60–
2.10 (m, 8 H, CH2CH2CH2NH, Pro-C3H2, Pro-C4H2), 2.80 (q, 1
H, Pro-C5Ha), 3.15–3.33 (m, 2 H, Phe-C3H2), 3.27 (t, 2 H,
CH2CH2CH2NH), 3.43 (m, 1 H, CHS), 3.56 (m, 1 H, Pro-C5Hb),
3.72 (m, 2 H, NCH2CHS), 4.02 (d, 2 H, Gly-C2H2), 4.36 (dd, 2 H,
Pro-C2H), 4.60 (dd, 1 H, Phe-C2H), 7.25–7.50 (m, 5 H, ArH). –
[7f]
M. J. Liskamp, Tetrahedron 1993, 49, 1133. –
W. J. Moree,
G. A. van der Marel, R. M. J. Liskamp, Tetrahedron Lett. 1992,
[7g]
33, 6389. –
W. J. Moree, G. A. van der Marel, R. M. J.
[7h]
Liskamp, Tetrahedron Lett. 1991, 32, 409. –
Ph. D. Thesis 1994, Leiden University.
W. J. Moree,
As described in ref.[7c] Unfortunately, these routes proved less
successful for the preparation of this difficult arginine sulfona-
mide mimic.
[8]
[9] [9a]
C. Levallet, J. Lerpiniere, S. Y. Ko, Tetrahedron 1997, 53,
[9b]
5291. –
Chem. 1997, 62, 1540. –
Doherty, Tetrahedron Lett. 1996, 37, 8711. –
Y. F. Yong, J. A. Kowalski, M. A. Lipton, J. Org.
[9c]
D. R. Kent, W. L. Cody, A. M.
13C NMR (D2O):
δ ϭ 23.8, 23.9 (CH2CH2CH2NH), 24.2
[9d]
D. S. Dodd,
(CH2CH2CH2NH), 25.4, 25.5 (Pro-C4), 29.58, 29.65 (Pro-C3), 36.7
(Phe-C3), 37.7, 37.9 (NHCH2CHS), 41.0 (CH2CH2CH2NH), 44.1
(Gly-C2), 48.0 (Pro-C5), 53.2 (Phe-C2), 61.0 (Pro-C2), 61.3, 61.5
(CHS), 128.5, 129.4, 129.7, 133.7 (CAr), 157.1 (CϭN), 168.2, 174.40
(CϭO). – FAB-MS; m/z: 526.2 [M – 2HCl ϩ Hϩ].
[9e]
A. P. Kozikowski, Tetrahedron Lett. 1994, 35, 977. –
M. S.
Bernatowicz, Y. Wu, G. R. Matsueda, Tetrahedron Lett. 1993,
34, 3389. – [9f] Y. Wu, G. R. Matsueda, M. Bernatowicz, Synth.
[9g]
Commun. 1993, 23, 3055. –
J. Org. Chem. 1987, 52, 1700.
G. Kokotos, Synthesis 1990, 299.
R. J. Bergeron, J. S. McManis,
[10]
[11]
[12]
[13]
K. Higashiura, K. Ienaga, J. Org. Chem. 1992, 57, 764.
This was also found by Moree et al.; see ref.[7g]
[13a]
For two examples, see:
C. A. De Parodi, E. Juarista, L.
Acknowledgments
Quintero, A. Clara-Sosa, Tetrahedron: Asymmetry 1997, 8,
[13b]
1075. –
4155.
L. E. Overman, S. Sugai, J. Org. Chem. 1985, 50,
This research has been supported by the Council for Chemical Sci-
ences of the Netherlands Organization for Scientific Research
(CW–NWO) with financial aid from the Technology Foundation
(STW). We thank Mr. C. Versluis (Department of Biomolecular
Mass Spectrometry) for recording the FAB mass spectra and Dr.
[14]
[14a]
Two typical examples:
D. Hendry, L. Hough, A. C. Rich-
[14b]
ardson, Tetrahedron Lett. 1987, 28, 4601. –
G. L. Greene, G. A. Heavner, R. L. Letsinger, J. Org. Chem.
1975, 40, 1659.
W. S. Mungal,
Eur. J. Org. Chem. 2000, 1219Ϫ1228
1227

D. W. P. M. Löwik, R. M. J. Liskamp
FULL PAPER
[15]
[18]
R. P. Volante, Tetrahedron Lett. 1984, 22, 3119.
The hydrazoic acid solution was prepared according to: H.
[16]
Wolff, Org. React., 1947, 3, 327.
J. A. Secrist III, M. W. Logue, J. Org. Chem. 1972, 37, 335.
[17]
E. von Arx, M. Faupel, M. Bruggen, J. Chromat. 1976, 120,
Received February 23, 1999
[O99115]
224.
1228
Eur. J. Org. Chem. 2000, 1219Ϫ1228