Synthesis of 1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives and evaluation of their affinity for MHC class-II proteins

Article abstract of DOI:10.1002/(SICI)1522-2675(19991215)82:12<2432::AID-HLCA2432>3.0.CO;2-H

1,2,5-Thiadiazolidin-3-one 1,1-dioxide derivatives (±)-1a-d and (±)-2 were designed by molecular modeling as MHC (major histocompatibility complex) class-II inhibitors. They were prepared from the unsymmetrically N,N'- disubstituted acyclic sulfamides (±)

Full text of DOI:10.1002/(SICI)1522-2675(19991215)82:12<2432::AID-HLCA2432>3.0.CO;2-H

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Helvetica Chimica Acta ± Vol. 82 (1999)
Synthesis of 1,2,5-Thiadiazolidin-3-one 1,1-Dioxide Derivatives and
Evaluation of Their Affinity for MHC Class-II Proteins
by Laurent Ducry, Stefan Reinelt, Paul Seiler, and François Diederich*
Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Zentrum,
Universitätstrasse 16, CH-8092 Zürich
1
and David R. Bolin, Robert M. Campbell, and Gary L. Olson )
Department of Inflammation/Autoimmune Diseases, F. Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA
1,2,5-Thiadiazolidin-3-one 1,1-dioxide derivatives (Æ)-1a ± d and (Æ)-2 were designed by molecular
modeling as MHC (major histocompatibility complex) class-II inhibitors. They were prepared from the
unsymmetrically N,N'-disubstituted acyclic sulfamides (Æ)-4a ± d (Scheme 1) and (Æ)-11 (Scheme 2). These N-
alkyl-N'-arylsulfamide precursors were synthesized by nucleophilic substitution of either a sulfamoyl-chloride or
a N-sulfamoyloxazolidinone. Extension of base-induced cyclization methods from aliphatic to aromatic
sulfamides gave access to the desired target molecules. The N-alkyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide
derivatives (Æ)-3a ± c were also prepared by the oxazolidinone route (Scheme 4) for coupling to a tetrapeptide
fragment. The X-ray crystal structure of 1,2,5-thiadiazolidin-3-one 1,1-dioxide (Æ)-21a was solved, and the
directionality of the H-bond donor (N H) and acceptor (SO2) groups of the cyclic scaffold determined (Figs. 1
and 2). The pKa value of the N H group in (Æ)-21a was determined by 1H-NMR titration as 11.9 (Fig. 3).
Compounds (Æ)-1a ± d were shown to inhibit competition peptide binding to HLA-DR4 molecules in the single-
digit millimolar concentration range.
1. Introduction. ± Peptides are often the natural substrates of pharmaceutical
targets. However, their poor oral bioavailability and low metabolic stability severely
limit their therapeutic application. Replacement of the peptide structure by a small,
rigid molecule, commonly a cyclic scaffold bearing the side-chains important for
binding, is a strategy to overcome this problem [1 ± 4]. In cases where not only the
peptidic side-chains but also the backbone is involved in key bonding interactions, some
functional groups should be incorporated within the peptidomimetic scaffold in order
to maintain them. Heterocycles, with their restricted conformational mobility and
heteroatoms as intrinsic H-bond donor and acceptor sites best serve this purpose and
have attracted considerable interest in medicinal chemistry (e.g., see [5] [6]).
In this report, we describe the synthesis of 1,2,5-thiadiazolidin-3-one 1,1-dioxide
derivatives as rigid, densely functionalized scaffolds, containing a sulfamide function-
ality, as a bidentate H-bond donor-acceptor unit. These sulfonylurea heterocycles were
designed for the selective blockade of HLA-DR1 and HLA-DR4 proteins [7], two
major histocompatibility complex (MHC) class-II alleles linked to rheumatoid arthritis
[8]. Studies of peptide-MHC interactions [9 ± 11] and attainment of high-resolution X-
ray crystal structures [12] have provided a general understanding of the structural
requirements for HLA-DR complexation. In peptide ligands, the NH and CO of the
1
)
New Address: Provid Research, 10 Knightsbridge Road, Piscataway, New Jersey 08854, USA.

Helvetica Chimica Acta ± Vol. 82 (1999)
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position-2 amino acid form complementary H-bonds to Asn b82 in the HLA-DR
molecule. Similar contacts of the position-4 residue are made with Gln a9 and Asn a62.
Conformationally restricted peptidic ligands, as well as peptidomimetic-peptide
hybrids, have also been obtained [13]. A non-peptidic framework to replace the
anchoring amino acids at positions 1 and 2 in peptidic substrates was, however, highly
desirable. According to molecular modeling, the 1,2,5-thiadiazolidin-3-one 1,1-dioxide
scaffold can serve as surrogate for these positions, the two contiguous H-bonding
donor-acceptor sites NH SO2 being complementary to the amide side chain of
Asn b82 (position 2). The side chain at C(4) of the rigid scaffold nicely points into a
large aromatic pocket that binds aromatic and cycloaliphatic peptide side chains and is
essential for high-affinity binding (position 1). Compounds (Æ)-1a ± d and (Æ)-2 were
designed as non-peptidic HLA-DR inhibitors bearing an N-aryl side chain as vector
towards Gln a9 and Asn a62 (position 4). The heterocyclic ring was also used as a
peptidomimetic scaffold suitable for appending peptidic fragments (compounds (Æ)-
3a ± c) that were chosen from high-affinity hexapeptide analogs (e.g., Ac-(Cha)-
RAMASL-NH2 [13c]).
2. Results and Discussion. ± 2.1. Synthesis. Although many sulfamide-containing
heterocycles have been reported (for a review, see [14]), 1,2,5-thiadiazolidin-3-one 1,1-
dioxides are rarely found. Except for the low-yielding cyclization of an a-amino amide
with sulfuryl chloride [15], the general route towards this heterocyclic ring involves
cyclization of open-chain sulfamides under basic conditions [16 ± 21]. Recently, serine
protease inhibitors incorporating this sulfonylurea scaffold have been prepared by N-
alkylation of the N,N'-unsubstituted heterocycles [22]. Although none of these
examples involved an N-arylsulfamide as required for the synthesis of target
compounds (Æ)-1a ± d, we have planned our synthesis on this base-mediated cyclization
strategy. The synthesis of the unsymmetrically disubstituted N-alkyl-N'-arylsulfamide
precursors (Æ)-4a ± d started with the sequential treatment of methyl 4-aminobenzoate
(5) with ClSO3H and PCl5 to generate in situ the corresponding sulfamoyl chloride [23]
(Scheme 1). Nucleophilic substitution of the (Æ)-a-amino acid methyl ester hydro-
chlorides (Æ)-6a ± d with the sulfamoyl chloride [24] yielded the N-alkyl-N'-arylsulfa-
mides (Æ)-4a ± d. The subsequent cyclization proved more difficult than in the case of
aliphatic sulfamides [16± 21]. Syringe pump addition of (Æ)-4a±d to a dilute solution of
t-BuLi in THF gave the best results and afforded thiadiazolidinone dioxides (Æ)-7a ± d

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in 51 to 86% yield. A low sulfamide concentration was necessary to avoid polymer-
ization. NaH in refluxing THF was later found to also afford the cyclized products in
good yields. Methyl-ester hydrolysis, followed by treatment of the resulting carboxylic
acids with N'-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (EDC)
and 1-hydroxy-1H-benzotriazole (HOBt) formed the corresponding activated esters,
which reacted with NH4OH [25] to give amides (Æ)-1a ± c and (Æ)-1e. The moderate
yields (27 ± 57%) are the result of attack by MeO /HO ions at the electrophilic S-atom
and cleavage of the S(1) N(2) bond in (Æ)-7a ± d during basic ester hydrolysis. This
was established in the case of (Æ)-7b by the isolation of the corresponding methyl
sulfamate (Æ)-8 as side-product (13%). The corresponding sulfamic acid was
presumably also formed but removed during aqueous workup. Deprotection of (Æ)-
1e with CF3CO2H in the presence of pentamethylbenzene (PMB) [26] yielded target
compound (Æ)-1d. PMB has been reported to not only improve the yield of
deprotection but also, by trapping the benzyl cation, to avoid an intramolecular O-
to C-rearrangement of O-benzyltyrosine to 3-benzyltyrosine [26] [27].
Scheme 1. Synthesis of Compounds (Æ)-1a ± d
a) ClSO3H, CH2Cl2, 08 ! r.t., 1 h. b) PCl5, reflux, 3.5 h. c) (Æ)-MeO2CCH(CH2R)NH2 ´ HCl (R ˆ Ph ((Æ)-6a);
R ˆ 2-naphthyl ((Æ)-6b); R ˆ PhCH2 ((Æ)-6c); R ˆ 4-HO C6H4 ((Æ)-6d)], Et3N, CH2Cl2, r.t., 2.5 h. d) t-BuLi,
THF, r.t., 16 h. e) KOH, MeOH, H2O, r.t., 12 h. f) EDC, HOBt, NH4OH, THF, r.t., 5 h. g) CF3CO2H, PMB, r.t.,
1 h.
Attempts to synthesize (Æ)-2, containing a modified N-aryl side chain, by the route
used for (Æ)-1a ± d were unsuccessful. Reaction of ClSO3H with methyl (3-amino-
phenyl)acetate (9), followed by treatment with PCl5, failed to generate the desired
sulfamoyl chloride, leading only to decomposition products. Transamination of a
monosubstituted sulfamide [28] with 9 to provide the unsymmetrically disubstituted
N-alkyl-N'-arylsulfamide (Æ)-11 was also not successful. Alternatively, transsulfamoyl-

Helvetica Chimica Acta ± Vol. 82 (1999)
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ation of N-sulfamoyloxazolidinones with primary and secondary aliphatic amines was
recently reported by Montero and co-workers to give access to various unsymmetrically
disubstituted sulfamides [29]. Thus, the sulfamoyl chloride prepared in situ from
chlorosulfonyl isocyanate and 2-chloroethanol was reacted with ester 9 to afford
oxazolidinone 10 (Scheme 2). The oxazolidinone moiety of 10 was then substituted by
(Æ)-3-(2-naphthyl)alanine methyl ester hydrochloride ((Æ)-6b), giving access to (Æ)-11
in high yield. Attempts at preparing (Æ)-11 by the reversed sequence of construction
failed due to the insufficient nucleophilicity of the aromatic amine 9 in the last step.
This demonstrates that the oxazolidinone strategy by Montero and co-workers [29] can
be extended to the synthesis of N-alkyl-N'-arylsulfamides, provided the oxazolidinone
is introduced on the aromatic amine allowing displacement by an aliphatic amine. Base-
mediated cyclization to thiadiazolidinone dioxide (Æ)-12 under the previously applied
reaction conditions worked smoothly. Subsequent methyl-ester hydrolysis was
achieved with potassium trimethylsilanolate [30] in THF, and the resulting carboxylic
acid was transformed into target compound (Æ)-2. This ester-hydrolysis method avoids
the use of HO and MeO ions, which previously caused partial cleavage of the
sulfonylurea scaffold.
Scheme 2. Synthesis of Compound (Æ)-2
a) OCNSO2Cl, HOCH2CH2Cl, CH2Cl2, 08, 1.5 h, then (Æ)-9, Et3N, CH2Cl2, 08 ! r.t., 12 h; 89%. b) (Æ)-6b,
Et3N, MeCN, reflux, 12 h, 90%. c) t-BuLi, THF, r.t.; 16 h; 86%. d) Me3SiOK, THF, r.t., 24 h. e) EDC, HOBt,
NH4OH, THF, r.t., 5 h, 38% (from (Æ)-12).
For the preparation of (Æ)-3a ± c, suitable for anchoring peptidic fragments that
extend beyond position 2 into the HLA-DR binding site, we attached propionate side
chains to N(2) of the thiadiazolidinone scaffold. Whereas the tert-butyl ester of b-
alanine ± required to construct the N-alkyl-N'-arylsulfamide intermediates ± was
commercially available, the dimethyl-substituted analog 13 was prepared starting from
ester 14 (Scheme 3). A Mitsunobu reaction provided 15, and b-amino acid 16 was
obtained by Gabriel synthesis. (Benzyloxy)carbonyl (Cbz) protection to 17 [31] and
esterification to 18, followed by removal of the Cbz group, provided 13.

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Scheme 3. Synthesis of b-Amino Acid Ester 13
a) Phthalimide, PPh3, N,N'-diethyl azodicarboxylate (DEAD), THF, r.t., 20 h, 77%. b) AcOH, HCl, H2O,
reflux, 16 h; 67%. c) CbzCl, NaOH, dioxane, H2O, r.t., 5 h; 68%. d) Isobutene, H2SO4, CH2Cl2, r.t., 65 h; 85%.
e) H2, Pd/C, MeOH, 3 h, 89%.
Starting from (Æ)-6a ± c, the N-sulfamoyloxazolidinones (Æ)-19a ± c were obtained
in good yields. Replacing the oxazolidinone moiety by b-alanine tert-butyl ester or
the dimethyl-substituted analog 13 afforded the desired disubstituted sulfamides (Æ)-
20a ± d. In the subsequent cyclization, the presence of two ester groups, as well as two
similarly acidic NH groups, could theoretically lead to four different regioisomers.
However, strained three- and four-membered ring compounds were anticipated not to
be formed, and the tert-butyl ester would be sterically too hindered for nucleophilic
attack, thereby preventing formation of undesired six-membered ring product. Indeed,
cyclization selectively afforded the corresponding desired 1,2,5-thiadiazolidin-3-one
1,1-dioxides (Æ)-21a ± d. In the preparation of (Æ)-21a ± b, b-elimination occurred as a
side reaction as evidenced by the isolation of the corresponding N(2)-unsubstituted
1,2,5-thiadiazolidin-3-ones, 1,1-dioxides. Ester cleavage finally yielded (Æ)-3a ± c with
carboxy side chains for peptide attachment.
2.2. Properties of 1,2,5-Thiadiazolidin-3-one 1,1-Dioxides. We were interested in
obtaining structural informations on the class of compounds prepared in this study and
in estimating their H-bonding potential. Crystals of (Æ)-21a suitable for X-ray analysis
were obtained by recrystallization from hexane/AcOEt (for details; see Exper. Part; for
two other X-ray crystal-structure analyses of 1,2,5-thiadiazolidin-3-one 1,1-dioxides,
see [18] and [21]). The extended crystal structure of this molecule is shown in Fig. 1.
The five-membered ring shows an out-of-plane deformation towards an envelope
shape, i.e., the S-Atom deviates by ca. 0.37 Š from the remaining four coplanar atoms.
The two planes passing through the N
S N and the O S O fragments, respectively,
are nearly orthogonal to one another (within ca. 28) [32].
Of particular interest is the orientation of the H-bonding donor (NH) and acceptor
(SO2) groups in the cyclic scaffold. The crystal packing (Fig. 2) shows that there is
a strong intermolecular N H ´´´ OˆC H-bond (N ´´´ O distance 2.73 Š) between
the NH group of the sulfamide moiety and the ester CˆO group. The N H group
is clearly oriented out of the five-membered ring plane and adopts a nearly
eclipsed orientation with one of the vicinal S O bonds (torsion angle H(14)

Helvetica Chimica Acta ± Vol. 82 (1999)
Scheme 4. Synthesis of Compounds (Æ)-3a ± c
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a) OCNSO2Cl, HOCH2CH2Cl, CH2Cl2, 08, 1.5 h. b) (Æ)-6a, (Æ)-6b, or (Æ)-6c, Et3N, CH2Cl2, 08 ! r.t., 12 h. c)
b-Alanine tert-butyl ester or 13, Et3N, MeCN, reflux, 12 h. d) NaH, THF, reflux, 7 h. e) TFA, r.t., 3 h.
Fig. 1. X-Ray crystal structure of (Æ)-21a. Arbitrary numbering. Atomic displacement parameters obtained at
193 K are drawn at the 30% probability level. Selected bond angles [8]: N(14) S(1) N(11): 95.28;
C(8) N(14) S(1): 110.63; N(14) C(8) C(9): 107.0; N(11) C(9) C(8): 110.4; C(9) N(11) S(1): 112.04
N(14) S(1) O(13) ˆ 148), a favorable orientation from the viewpoint of stabiliza-
tion of local dipoles.
With the directionality of the H-bonding centers in the cyclic scaffold established,
we were interested in estimating their H-bonding ability. Ab initio molecular-orbital

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Fig. 2. Crystal packing of (Æ)-21a
calculations had indicated that sulfamide S O bonds are highly polarized with the O-
atoms retaining practically three lone pairs [32]. H-Bonding networks of acyclic N,N'-
disubstituted sulfamides in the solid state have been reported [33], and cyclic
sulfamides were essential structural components in the construction of H-bonding
capsules built from four self-complementary sub-units [34]. Sulfonamide S O groups
were calculated to be poorer H-bond acceptors than P O groups of phosphonamides,
although better than P O groups in phosphonamidates [35]. In a separate study in
CHCl3, S O groups in sulfonamides were reported to be weaker H-bond acceptors
than CˆO groups in amides, carbamates, and even carboxylic esters, although
conformational effects and the use of different H-bond donors might have influenced
this result [36]. Whereas the H-bond acceptor capacity of S O groups in sulfamides
(and sulfonamides) remains therefore unclear, the H-bond donor ability of the N
H
group can be estimated from its pKa value. The acidity of some sulfamide derivatives
had previously been reported [37]. However, none of these compounds is similar to
ours. We, therefore, determined the pKa of (Æ)-21a by 1H-NMR titration [38]. A 0.03m
solution of (Æ)-21a in CD3COCD3/D2O 1:1 was prepared and titrated with a 0.1m
solution of NaOD in D2O up to pH 12.0. Thereafter, at higher pH, the titration was
performed with a 1m solution of the base so as to minimize the dilution. The
deprotonation was monitored by measuring, at different pH, the chemical-shift
difference between the signal of a proton which is affected by the deprotonation
(H C(4'), H C(6'), H C(3)) and the signal of the t-Bu group which remains
practically unchanged. Titration curves were obtained by plotting the difference in
chemical shift against the pH of the solution (Fig. 3). The pH value at the inflection
point of the sigmoidal curve was taken as a measure of the pKa value. With a pKa value
of 11.9, the N H group in (Æ)-21a is quite acidic and should undergo formation of
strong H-bonds. It is even more acidic than that of the N H group in hydantoin analog
(Æ)-22 [39], the pKa value of which was determined as 12.5 by the same method.
Compounds (Æ)-1a ± d, (Æ)-2, as well as (Æ)-3a ± c, attached via an amide bond to
the MASL-NH2 tetrapeptide [40], were tested in a competitive inhibition assay using
the ꢀscintillation proximity assayꢁ method [13c]. None, however, had detectable binding
affinity for HLA-DR4 proteins (IC50 > 100 mm according to the test sensitivity). The

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Fig. 3. 1H-NMR Titration to determine the pKa value of (Æ)-21a. The chemical shift difference between the
signal of H C(6') and the t-Bu group is plotted against pH. Shown is also hydantoin analog (Æ)-22, for which
1
the pKa value was also determined by H-NMR titration (not shown) [39].
higher solubility of benzamides (Æ)-1a ± d in Me2SO/H2O compared to the cyclic
scaffold-peptide hybrids allowed tests under more concentrated conditions, thereby
increasing the detection limit of the assay. They were found to inhibit HLA-DR4
molecules in the single-digit millimolar concentration range (50% inhibition at 5 mm
for compounds (Æ)-1a, (Æ)-1b, and (Æ)-1d, and 35% inhibition for (Æ)-1c). X-Ray
crystal-structure data on MHC-peptide co-crystals [12b] [13c] demonstrated that the N-
Ac group (position 0) is interacting with residues Ser a53 and His b81, and that de-
amino compounds have diminished affinity. Consequently, the properties of the cyclic
scaffold are not factors responsible for the diminished binding. Introduction of
appropriate side chains at C(4) of the cyclic scaffold is planned to test this hypothesis.
3. Conclusion. ± Unsymmetrically disubstituted N-alkyl-N'-arylsulfamides were
synthesized from amino-acid building blocks by two different methods. Compounds
(Æ)-4a ± d were obtained by reaction of amino acid methyl esters with a sulfamoyl
chloride, whereas (Æ)-11 was prepared from a N-sulfamoyloxazolidinone. Cyclization
of aliphatic sulfamides was then extended to the aromatic sulfamides (Æ)-4a ± d and
(Æ)-11 with t-BuLi as base and afforded the N-aryl-1,2,5-thiadiazolidin-3-one 1,1-
dioxide derivatives (Æ)-1a ± d and (Æ)-2, respectively. Compounds (Æ)-3a ± c with a
propionate side chain at N(2) were also prepared by the oxazolidinone method for
attachment to a tetrapeptide fragment. The X-ray crystal structure of 1,2,5-thiadiazo-
lidin-3-one 1,1-dioxide (Æ)-21a was solved, and the directionality of the H-bond donor
(N H) and acceptor (SO2) groups of the cyclic scaffold was determined. Analysis of
the crystal packing showed that the N H bond is oriented out of the five-membered-

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ring plane and adopts a nearly eclipsed orientation with one of the two vicinal S
O
1
bonds. The pKa value of the N H group in (Æ)-21a was determined by H-NMR
titrations as 11.9, making it a strong H-bond donor. Despite low potency so far obtained
for HLA-DR4 molecules, the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffold offers an
interesting opportunity in medicinal chemistry as a rigid, easily accessible heterocycle
featuring H-bonding sites in a quite unique array.
Experimental Part
General. Reagent-grade solvents and reagents were purchased from commercial suppliers and used without
further purification unless otherwise stated. The (Æ)-amino acid methyl ester hydrochlorides (Æ)-6a [41], (Æ)-6b
[42], (Æ)-6c [43], and (Æ)-6d [44] were prepared according to the literature procedures. THF and Et2O were
freshly distilled from sodium benzophenone ketyl. Evaporation in vacuo was conducted at H2O aspirator
pressure. Flash chromatography (FC): silica gel 60 (230 ± 400 mesh, 0.040 ± 0.063 mm) from Fluka. M.p.: Büchi
SMP-20; uncorrected. IR Spectra [cm 1]: Perkin-Elmer 1600-FT IR. NMR Spectra: Bruker AMX 500 and
Varian Gemini 300 or 200 at 296 K, with solvent peak as reference. MS (m/z (%)): EI: VG TRIBRID
spectrometer at 70 eV; FAB: VG ZAB2-SEQ spectrometer with 3-nitrobenzyl alcohol (NOBA) as matrix; ESI:
Finnigan TSQ 7000 spectrometer. Elemental analyses were performed by the Mikrolabor at the Laboratorium
für Organische Chemie, ETH Zürich.
Procedure A. To a soln. of 5 (16.50 mmol) in CH2Cl2 (100 ml) cooled to 08 was added dropwise ClSO3H
(18.00 mmol). After stirring at r.t. for 1 h, PCl5 (18.00 mmol) was added, and the soln. was heated to reflux for
3.5 h. The amino acid methyl ester hydrochloride (15.00 mmol) was added to the soln. of sulfamoyl chloride
prepared in situ. The soln. was made basic (pH 8 ± 9) by the addition of Et3N and stirred at r.t. for 2.5 h. The
reaction was quenched with sat. aq. NaCl soln. (100 ml), the org. phase was separated and the aq. phase
extracted with CH2Cl2 (2 Â 100 ml). The combined org. extracts were dried (MgSO4), evaporated in vacuo, and
purified by FC (SiO2; hexane/AcOEt 6 :4).
Procedure B. To t-BuLi (1.7m soln. in pentane; 5.00 mmol) in dry THF (100 ml) at r.t. under Ar was added a
soln. of sulfamide (2.00 mmol) in THF (20 ml) over 4 h via syringe pump, and the mixture was stirred for 12 h.
The reaction was quenched with sat. aq. NaCl soln. (100 ml) and 1m aq. HCl soln. (50 ml), the org. phase was
separated, and the aq. phase extracted with CH2Cl2 (2 Â 100 ml). The combined org. extracts were dried
(MgSO4), evaporated in vacuo, and purified by FC (SiO2; CH2Cl2/MeOH 9 :1).
Procedure C. A soln. of methyl (1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl)benzoate (2.00 mmol) in MeOH
(50 ml) and 1m aq. KOH soln. (50 ml) was stirred at r.t. for 12 h. The MeOH was evaporated in vacuo, the soln.
made acidic with 1m aq. HCl soln. (60 ml) and extracted with AcOEt (4 Â 100 ml). The combined org. extracts
were dried (MgSO4) and evaporated in vacuo. The residue was dissolved in THF (20 ml), EDC (2 mmol) and
HOBt (2 mmol) were added, and the soln. was stirred at r.t. for 1 h. A 25% aq. NH4OH soln. (2 mmol) was then
added, and stirring was continued for 4 h. The mixture was filtered, the filtrate evaporated in vacuo and purified
by FC (SiO2; CH2Cl2/MeOH/NH3 85 :14 :1).
Procedure D. To a stirred soln. of chlorosulfonyl isocyanate (4.00 mmol) in CH2Cl2 (50 ml) cooled to 08 was
added 2-chloroethanol (4.00 mmol) at such a rate that the reaction temp. did not exceed 58. After stirring at 08
for 1.5 h, a soln. of amine (4.00 mmol) and Et3N (12.00 mmol) in CH2Cl2 (50 ml) was slowly added so that the
reaction temp. remained under 58. When the addition was complete, the soln. was allowed to warm to r.t. and
stirred for 12 h. The reaction was quenched with 2m aq. HCl soln. sat. with NaCl (100 ml), the org. phase was
separated and the aq. phase extracted with CH2Cl2 (2 Â 100 ml). The combined org. extracts were dried
(Na2SO4) and filtered. Et3N (5 ml) was added, and the soln. was stirred at r.t. for 6 h. The reaction was quenched
with 1m aq. HCl soln. (200 ml), the org. phase was separated and the aq. phase extracted with CH2Cl2 (2 Â
100 ml). The combined org. extracts were dried (Na2SO4) and evaporated in vacuo.
Procedure E. A soln. of oxazolidinone (1.00 mmol), amine (1.00 mmol), and Et3N (1 ml) in MeCN (25 ml)
was heated to reflux for 12 h. MeCN was removed in vacuo, 1m aq. HCl soln. (50 ml) was added to the residue,
and the product was extracted with CH2Cl2 (3 Â 50 ml). The combined org. extracts were dried (Na2SO4),
evaporated in vacuo, and purified by FC (SiO2; hexane/AcOEt 7:3).
Procedure F. A soln. of sulfamide (1.00 mmol) and NaH (2.50 mmol) in THF (50 ml) was heated to reflux
for 7 h. The mixture was allowed to cool to r.t., quenched with 1m aq. HCl soln. (50 ml), and extracted with
AcOEt (3 Â 50 ml). The combined org. extracts were dried (MgSO4), evaporated in vacuo, and purified by FC
(SiO2; hexane/AcOEt 8 :2 to 7:3).

Helvetica Chimica Acta ± Vol. 82 (1999)
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Procedure G. A soln. of 1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 mmol) in CF3CO2H (50 ml) was stirred at
r.t. for 3 h. The residue obtained by evaporation in vacuo was recrystallized (hexane/Et2O).
(Æ)-Methyl 4-[({[1-(Methoxycarbonyl)-2-phenylethyl]amino}sulfonyl)amino]benzene-1-carboxylate ((Æ)-
4a). Treatment of (Æ)-6a (5.00 g, 23.18 mmol) according to Procedure A gave (Æ)-4a (6.34 g, 70%). Colorless
solid. M.p. 153 ± 1558 (hexane/AcOEt). IR (KBr): 3223m, 1724s, 1700m, 1610m, 1350m, 1281m, 1154s. 1H-NMR
(200 MHz, CDCl3): 7.93, 7.04 (AA'BB', J ˆ 8.8, 4 H); 7.22 ± 7.16 (m, 3 H); 7.06 ± 7.01 (m, 2 H); 5.31 (d, J ˆ 9.1, 1
H); 4.33 (m, 1 H); 3.90 (s, 3 H); 3.61 (s, 3 H); 3.00 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 171.8; 166.5; 141.2;
‡
134.8; 131.1; 129.2; 128.7; 127.5; 125.4; 117.8; 57.4; 52.8; 52.2; 38.8. DEI-MS: 392 (14, M ), 333 (9), 241 (46), 230
(12), 151 (32), 120 (62), 91 (100). Anal. calc. for C18H20N2O6S (392.4): C 55.09, H 5.14, N 7.14, S 8.17; found:
C 55.26, H 5.12, N 7.21, S 8.09.
(Æ)-Methyl
4-[({[1-(Methoxycarbonyl)-2-(naphthalen-2-yl)ethyl]amino}sulfonyl)amino]benzene-1-car-
boxylate ((Æ)-4b). Treatment of (Æ)-6b (810 mg, 3.05 mmol) according to Procedure A gave (Æ)-4b (1.28 g,
95%). Colorless solid. M.p. 180 ± 1828 (hexane/AcOEt). IR (KBr): 3278m, 3230m, 1717m, 1697s, 1610m, 1436m,
1
1339m, 1290s, 1239m, 1154s. H-NMR (200 MHz, CDCl3): 7.80 ± 7.67 (m, 3 H); 7.70 (d, J ˆ 8.7, 2 H); 7.56 ± 7.44
(m, 3 H); 7.18 (d, J ˆ 8.3, 1 H); 6.92 (d, J ˆ 8.7, 2 H); 6.83 (s, 1 H); 5.26 (d, J ˆ 8.7, 1 H); 4.48 ± 4.38 (m, 1 H); 3.91
(s, 3 H); 3.70 (s, 3 H); 3.28, 3.11 (AB of ABX, JAX ˆ 4.8, JBX ˆ 6.6, JAB ˆ 14.0, 2 H). 13C-NMR (75 MHz, CDCl3/
CD3OD, ca. 99 :1): 172.7; 167.2; 142.2; 133.3; 133.1; 132.5; 130.6; 128.2; 128.1; 127.6 (2Â); 126.8; 126.1; 125.7;
‡
123.8; 116.5; 57.4; 52.4; 51.8; 38.6. DEI-MS: 442 (5, M ), 241 (8), 212 (14), 168 (7), 151 (14), 141 (100), 120 (19).
Anal. calc. for C22H22N2O6S (442.5): C 59.72, H 5.01, N 6.33, S 7.25; found: C 59.92, H 5.16, N 6.52, S 7.16.
(Æ)-Methyl
4-[({[1-(Methoxycarbonyl)-3-phenylpropyl]amino}sulfonyl)amino]benzene-1-carboxylate
((Æ)-4c). Treatment of (Æ)-6c (2.01 g, 8.75 mmol) according to Procedure A gave (Æ)-4c (762 mg, 22%).
Colorless solid. M.p. 143 ± 1458 (hexane/AcOEt). IR (KBr): 3263m, 1722s, 1610m, 1437m, 1349m, 1292s, 1147s,
1106m. 1H-NMR (200 MHz, CDCl3): 8.01 (d, J ˆ 8.3, 2 H); 7.29 ± 7.14 (m, 5 H); 7.06 ± 7.02 (m, 2 H); 4.09 (m, 1
H); 3.91 (s, 3 H); 3.58 (s, 3 H); 2.60 (m, 2 H); 2.17 ± 1.87 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 172.8; 166.8;
‡
141.7; 140.2; 131.4; 128.8; 128.6; 126.6; 125.8; 118.0; 56.0; 52.9; 52.2; 34.4; 31.2. DEI-MS: 406 (20, M ), 347 (7),
182 (9), 151 (100), 120 (40), 117 (74), 105 (29), 91 (97). Anal. calc. for C19H22N2O6S (406.5): C 56.15, H 5.46,
N 6.89, S 7.89; found: C 56.27, H 5.53, N 7.07, S 7.92.
(Æ)-Methyl 4-{[({1-(Methoxycarbonyl)-2-[4-(phenylmethoxy)phenyl]ethyl}amino)sulfonyl]amino}benzene-
1-carboxylate ((Æ)-4d). Treatment of (Æ)-6d (4.50 g, 13.98 mmol) according to Procedure A gave (Æ)-4d
(2.48 g, 36%). Colorless solid. M.p. 152-1548 (hexane/AcOEt). IR (KBr): 3300m, 3224m, 1722s, 1612m, 1514m,
1
1351m, 1278m, 1156m, 1117m. H-NMR (200 MHz, CDCl3): 7.95, 7.05 (AA'BB', J ˆ 8.8, 4 H); 7.45 ± 7.32 (m, 5
H); 6.96, 6.81 (AA'BB', J ˆ 8.7, 4 H); 5.24 (d, J ˆ 9.1, 1 H); 4.99 (s, 2 H); 4.29 (m, 1 H); 3.86 (s, 3 H); 3.63 (s, 3 H);
2.96 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 171.9; 166.5; 158.1; 141.1; 136.9; 131.0; 130.3; 128.6; 128.0; 127.5;
‡
126.9; 125.4; 117.7; 115.0; 69.9; 57.5; 52.8; 52.1; 38.0. DEI-MS: 498 (3, M ), 226 (4), 197 (78), 178 (11), 151 (36),
120 (57), 107 (10), 91 (100). Anal. calc. for C25H26N2O7S (498.6): C 60.23, H 5.26, N 5.62, S 6.43; found: C 60.16,
H 5.30, N 5.78, S 6.43.
(Æ)-Methyl 4-[4-(Phenylmethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]benzoate ((Æ)-7a). Treatment of
(Æ)-4a (1.50 g, 3.82 mmol) according to Procedure B gave (Æ)-7a (1.03 g, 75%). Yellow solid. M.p. 169 ± 1718
(hexane/AcOEt). IR (KBr): 3267m, 1725m, 1605m, 1333m, 1289m, 1153s, 1106m. 1H-NMR (200 MHz,
(CD3)2SO): 8.38 (d, J ˆ 9.4, 1 H); 7.75, 7.05 (AA'BB', J ˆ 8.7, 4 H); 7.16 ± 7.05 (m, 5 H); 3.90 ± 3.84 (m, 1 H); 3.81
(s, 3 H); 2.89 (AB of ABX, JAX ˆ 6.0, JBX ˆ 8.6, JAB ˆ 13.7, 2 H). 13C-NMR (75 MHz, (CD3)2SO): 172.5; 165.9;
‡
143.1; 136.6; 130.0; 128.9; 127.9; 126.3; 122.4; 116.5; 57.2; 51.7; 37.5. DEI-MS: 360 (1, M ), 332 (5), 151 (51), 120
‡
(100), 91 (43). HR-DEI-MS: 360.0779 (M , C17H16N2O5S; calc. 360.0780).
(Æ)-Methyl 4-[4-(Naphthalen-2-ylmethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]benzoate ((Æ)-7b). Treat-
ment of (Æ)-4b (900 mg, 2.03 mmol) according to Procedure B gave (Æ)-7b (425 mg, 51%). Yellow solid. M.p.
172 ± 1758 (hexane/AcOEt). IR (KBr): 3251m, 1722m, 1609s, 1434m, 1406m, 1322m, 1280s, 1148s, 1106m.
1H-NMR (200 MHz, (CD3)2SO): 7.78 ± 7.62 (m, 3 H); 7.67 (d, J ˆ 8.7, 2 H); 7.50 (s, 1 H); 7.40 ± 7.30 (m, 3 H); 7.00
(d, J ˆ 8.7, 2 H); 3.89 ± 3.83 (m, 1 H); 3.77 (s, 3 H); 3.19, 2.98 (AB of ABX, JAX ˆ 4.6, JBX ˆ 7.3, JAB ˆ 14.0, 2 H).
13C-NMR (75 MHz, (CD3)2SO): 173.5; 166.1; 144.0; 136.4; 132.9; 131.8; 130.4; 128.3; 127.8; 127.4 (2Â); 127.1;
‡
125.7; 125.2; 122.2; 116.4; 58.9; 51.7; 38.0. DEI-MS: 410 (1, M ), 169 (2), 151 (55), 141 (9), 120 (100), 92 (19).
‡
HR-DEI-MS: 410.0936 (M , C21H18N2O5S; calc. 410.0936).
(Æ)-Methyl 4-[4-(2-Phenylethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]benzoate ((Æ)-7c). Treatment of
(Æ)-4c (750 mg, 1.85 mmol) according to Procedure B gave (Æ)-7c (592 mg, 86%). Yellow solid. M.p. 105 ±
1078 (hexane/AcOEt). IR (KBr): 3265m, 1718s, 1609s, 1433m, 1322m, 1283s, 1151s, 1106m. 1H-NMR (200 MHz,
(CD3)2SO): 7.89, 7.21 (AA'BB', J ˆ 8.7, 4 H); 7.24 ± 7.13 (m, 3 H); 6.98 ± 6.94 (m, 2 H); 3.83 (s, 3 H); 3.63 ± 3.58
(m, 1 H); 2.50 ± 2.41 (m, 2 H); 1.92 ± 1.80 (m, 2 H). 13C-NMR (75 MHz, (CD3)2SO): 173.8; 166.2; 144.3; 142.1;

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Helvetica Chimica Acta ± Vol. 82 (1999)
‡
130.6; 128.3 (2Â); 125.7; 122.4; 116.6; 56.9; 51.8; 45.3; 34.1. DEI-MS: 374 (2, M ), 346 (3), 343 (2), 270 (22), 191
‡
(11), 151 (90), 120 (100). HR-DEI-MS: 374.0939 (M , C18H18N2O5S; calc. 374.0936).
(Æ)-Methyl 4-(4-{[4-(Phenylmethoxy)phenyl]methyl}-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl)benzoate ((Æ)-
7d). Treatment of (Æ)-4d (1.13 g, 2.27 mmol) according to Procedure B gave (Æ)-7d (0.87 g, 83%). Yellow solid.
M.p. 113 ± 1158 (hexane/AcOEt). IR (KBr): 3262m, 1718m, 1609s, 1513m, 1282s, 1239m, 1152s, 1106m. 1H-NMR
(200 MHz, (CD3)2SO): 7.81, 7.04 (AA'BB', J ˆ 8.6, 4 H); 7.45 ± 7.31 (m, 5 H); 7.04, 6.77 (AA'BB', J ˆ 8.6, 4 H);
5.00 (s, 2 H); 3.77 (s, 3 H); 3.90 ± 3.84 (m, 1 H); 3.00, 2.77 (AB of ABX, JAX ˆ 4.3, JBX ˆ 7.8, JAB ˆ 13.7, 2 H).
13C-NMR (75 MHz, (CD3)2SO): 172.8; 165.8; 156.7; 143.3; 137.1; 130.0 (2Â); 129.1; 128.3; 127.6; 127.4; 122.2;
‡
116.4; 114.0; 68.8; 57.8; 51.6; 36.6. DEI-MS: 466 (3, M ), 435 (2), 197 (17), 178 (5), 151 (49), 134 (3), 120 (100),
‡
91 (42). HR-DEI-MS: 466.1226 (M , C24H22N2O6S; calc. 466.1198).
(Æ)-4-[4-(Phenylmethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]benzene-1-carboxamide ((Æ)-1a). Treat-
ment of (Æ)-7a (500 mg, 1.39 mmol) according to Procedure C gave (Æ)-1a (172 mg, 36%). Colorless solid.
M.p. 174 ± 1768 (Et2O/MeOH). IR (KBr): 3456m, 3367m, 1744m, 1654s, 1606m, 1325s, 1183m, 1161m. 1H-NMR
(200 MHz, (CD3)2SO): 9.08 (s, 1 H); 8.11 (s, 1 H); 8.03, 7.45 (AA'BB', J ˆ 8.6, 4 H); 7.54 (s, 1 H); 7.37 ± 7.27 (m, 5
H); 4.76, 3.28, 3.04 (ABX, JAX ˆ 3.9, JBX ˆ 10.1, JAB ˆ 14.3, 3 H). 13C-NMR (75 MHz, (CD3)2SO): 168.1; 166.8;
‡
136.2; 135.2; 132.7; 129.5; 128.9; 128.2; 126.7 (2Â); 61.0; 36.3. DEI-MS: 345 (2, M ), 317 (11), 146 (19), 136
(13), 118 (28), 91 (100). Anal. calc. for C16H15N3O4S (345.4): C 55.64, H 4.38, N 12.17, S 9.28; found: C 55.78,
H 4.46, N 12.05, S 9.16.
(Æ)-4-[4-(Naphthalen-2-ylmethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]benzene-1-carboxamide ((Æ)-1b).
Treatment of (Æ)-7b (400 mg, 0.97 mmol) according to Procedure C gave (Æ)-1b (104 mg, 27%). Colorless
solid. M.p. > 1758 (dec.). IR (KBr): 1754m, 1742m, 1729m, 1610m, 1322s, 1186s, 1165s. 1H-NMR (200 MHz,
(CD3)2SO): 9.13 (br. s, 1 H); 8.10 (s, 1 H); 8.02 (d, J ˆ 7.8, 2 H); 7.91 ± 7.85 (m, 4 H); 7.52 ± 7.46 (m, 6 H); 4.87 ±
4.84 (m, 1 H); 3.47 ± 3.41 (m, 1 H); 3.26 ± 3.21 (m, 1 H). 13C-NMR (100 MHz, (CD3)2SO): 168.5; 167.0; 135.0;
134.2; 133.2; 132.9; 132.0; 128.8 (2Â); 127.9 (2Â); 127.7; 127.4; 126.5; 126.1; 125.6; 61.3; 36.8. FAB-MS: 396 (25,
‡
‡
MH ), 391 (41), 149 (100), 141 (19). HR-FAB-MS: 396.1015 (MH , C20H18N3O4S; calc. 396.1018).
(Æ)-4-[4-(2-Phenylethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]benzene-1-carboxamide ((Æ)-1c). Treat-
ment of (Æ)-7c (500 mg, 1.34 mmol) according to Procedure C gave (Æ)-1c (270 mg, 57%). Colorless solid.
M.p. 168 ± 1708 (AcOEt). IR (KBr): 3445m, 3378m, 1739m, 1654s, 1606m, 1322m, 1183m, 1161m. 1H-NMR
(200 MHz, (CD3)2SO): 7.87, 7.42 (AA'BB', J ˆ 8.7, 4 H); 7.25 ± 7.07 (m, 5 H); 4.09 (dd, J ˆ 9.5, 4.6, 1 H); 2.92 ±
2.65 (m, 2 H); 2.33 ± 2.05 (m, 2 H). 13C-NMR (75 MHz, (CD3)2SO): 169.5; 169.4; 139.9; 134.3; 133.9; 129.1;
‡
‡
128.8; 128.7; 126.9; 126.6; 59.5; 32.9; 31.5. DEI-MS: 360 (5, MH ), 359 (4, M ), 331 (5), 255 (54), 191 (38), 147
(33), 134 (63), 117 (45), 105 (29), 91 (100). Anal. calc. for C17H17N3O4S (359.4): C 56.81, H 4.77, N 11.69, S 8.92;
found: C 56.54, H 4.80, N 11.76, S 8.93.
(Æ)-4-(4-{[4-(Phenylmethoxy)phenyl]methyl}-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl)benzene-1-carboxamide
((Æ)-1e). Treatment of (Æ)-7d (600 mg, 1.29 mmol) according to Procedure C gave (Æ)-1e (300 mg, 52%).
Colorless solid. M.p. 216 ± 2188 (Et2O/MeOH). IR (KBr): 3222m, 1724m, 1689m, 1672m, 1513m, 1395m, 1317s,
1233m, 1178s. 1H-NMR (200 MHz, (CD3)2SO): 9.06 (s, 1 H); 8.13 (s, 1 H); 8.05 (d, J ˆ 8.7, 2 H); 7.56 (s, 1 H);
7.49 ± 7.34 (m, 7 H); 7.28, 7.01 (AA'BB', J ˆ 8.6, 4 H); 5.12 (s, 2 H); 4.72, 3.22, 3.00 (ABX, JAX ˆ 3.9, JBX ˆ 9.9,
JAB ˆ 14.0, 3 H). 13C-NMR (75 MHz, (CD3)2SO): 168.2; 166.8; 157.2; 137.1; 135.1; 132.8; 130.7; 130.5; 128.8;
‡
128.3; 127.7; 127.5; 126.6; 114.5; 69.0; 61.2; 35.5. DEI-MS: 451 (1, M ), 197 (3), 146 (3), 134 (2), 120 (4), 107 (6),
91 (65). Anal. calc. for C23H21N3O5S (451.5): C 61.19, H 4.69, N 9.31, S 7.10; found: C 61.15, H 4.71, N 9.16, S 7.00.
(Æ)-4-{4-[(4-Hydroxyphenyl)methyl]-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl}benzene-1-carboxamide ((Æ)-
1d). A soln. of (Æ)-1e (330 mg, 0.73 mmol) and pentamethylbenzene (1.08 g, 7.29 mmol) in CF3CO2H
(20 ml) was allowed to stand at r.t. for 1 h. The soln. was evaporated in vacuo, the residue washed with Et2O
(5 ml) and dried in vacuo to give (Æ)-1d (261 mg, 99%). Colorless solid. M.p. > 2008 (dec.; hexane/AcOEt/
MeOH). IR (KBr): 3433m, 3189m, 1728m, 1646s, 1611m, 1511m, 1339s, 1189s, 1167s. 1H-NMR (200 MHz,
(CD3)2SO): 9.22 (s, 1 H); 9.03 (s, 1 H); 8.12 (s, 1 H); 8.05, 7.46 (AA'BB', J ˆ 8.7, 4 H); 7.55 (s, 1 H); 7.15, 6.75
(AA'BB', J ˆ 8.7, 4 H); 4.67, 3.17, 2.95 (ABX, JAX ˆ 3.7, JBX ˆ 9.9, JAB ˆ 14.1, 3 H). 13C-NMR (75 MHz,
‡
(CD3)2SO): 168.5; 167.2; 156.5; 135.4; 133.0; 130.7; 129.1; 126.9; 126.4; 115.2; 61.5; 35.7. DEI-MS: 361 (4, M ),
‡
238 (4), 191 (6), 146 (20), 136 (31), 120 (39), 107 (100). HR-DEI-MS: 361.0729 (M , C16H15N3O5S; calc. 361.0732).
(Æ)-Methyl N-[2-{[4-(Aminocarbonyl)phenyl]amino}-1-(naphthalen-2-ylmethyl)-2-oxoethyl]sulfamate ((Æ)-
8). The procedure described for (Æ)-1b also afforded (Æ)-8 (54 mg, 13%). Colorless solid. M.p. > 1658 (dec.).
IR (KBr): 3489m, 3378m, 1733m, 1659s, 1606m, 1144m. 1H-NMR (200 MHz, (CD3)2SO): 10.08 (br. s, 1 H); 8.62
(br. s, 1 H); 7.86 ± 7.62 (m, 7 H); 7.51 ± 7.43 (m, 2 H); 7.30 ± 7.26 (m, 1 H); 7.20 (s, 1 H); 7.06 (d, J ˆ 8.7, 2 H); 4.18 ±
4.04 (m, 1 H); 3.40 (s, 3 H); 3.09, 2.95 (AB of ABX, JAX ˆ 7.3, JBX ˆ 8.1, JAB ˆ 13.7, 2 H). 13C-NMR (100 MHz,
(CD3)2SO): 171.8; 167.6; 141.4; 134.1; 133.0; 132.0; 128.4; 127.9; 127.8; 127.6; 127.5; 127.5; 127.4; 126.1; 125.8;

Helvetica Chimica Acta ± Vol. 82 (1999)
2443
‡
116.6; 57.2; 51.7; 37.8. DEI-MS: 427 (2, M ), 409 (3), 229 (10), 212 (7), 141 (100). Anal. calc. for C21H21N3O5S
(427.5): C 59.00, H 4.95, N 9.83, S 7.50; found: C 58.82, H 5.15, N 9.60, S 7.30.
Methyl 2-(3-{[(2-Oxo-1,3-oxazolan-3-yl)sulfonyl]amino}phenyl)ethanoate (10). Treatment of 9 (1.00 g,
4.96 mmol) [45] according to Procedure D gave 10 (1.39 g, 89%). Colorless solid. M.p. 72 ± 748 (hexane/AcOEt).
IR (CHCl3): 1773s, 1737s, 1418m, 1388m, 1182s, 1156s. 1H-NMR (200 MHz, CDCl3): 7.39 ± 7.18 (m, 4 H); 4.33 ±
4.25 (m, 2 H); 3.88 ± 3.80 (m, 2 H); 3.70 (s, 3 H); 3.63 (s, 2 H). 13C-NMR (50 MHz, CDCl3): 172.1; 153.4; 136.0;
‡
135.6; 130.1; 128.1; 124.0; 122.0; 63.0; 52.0; 46.5; 40.7. DEI-MS: 314 (100, M ), 255 (24), 165 (63), 163 (54), 106
(69). Anal. calc. for C12H14N2O6S (314.3): C 45.86, H 4.49, N 8.91, S 10.20; found: C 45.93, H 4.52, N 8.76,
S 10.47.
(Æ)-Methyl 2-{[({3-[(Methoxycarbonyl)methyl]phenyl}amino)sulfonyl]amino}-3-(naphthalen-2-yl)propa-
noate ((Æ)-11). Treatment of 10 (2.06 g, 6.55 mmol) and (Æ)-6b (2.06 g, 6.55 mmol) according to Procedure E
gave (Æ)-11 (2.69 g, 90%). Colorless solid. M.p. 128 ± 1308 (hexane/AcOEt). IR (KBr): 3278m, 3222m, 1739m,
1721s, 1350m, 1289m, 1149s. 1H-NMR (200 MHz, CDCl3): 7.81 ± 7.69 (m, 3 H); 7.51 ± 7.44 (m, 3 H); 7.20 ± 7.14 (m,
1 H); 7.08 (d, J ˆ 7.9, 1 H); 6.97 ± 6.88 (m, 3 H); 6.54 (s, 1 H); 5.19 (d, J ˆ 9.1, 1 H); 4.49 ± 4.38 (m, 1 H); 3.66 (s, 3
H); 3.64 (s, 3 H); 3.50 (s, 2 H); 3.28 ± 3.10 (m, 2 H). 13C-NMR (125 MHz, CDCl3): 171.8; 171.6; 137.0; 135.2;
133.3; 132.5; 132.5; 129.3; 128.3; 128.3; 127.6; 127.6; 127.0; 126.2; 125.9; 125.4; 120.7; 118.5; 57.3; 52.6; 52.0; 40.8;
‡
39.0. DEI-MS: 456 (11, M ), 255 (36), 212 (24), 165 (29), 141 (100). Anal. calc. for C23H24N2O6S (456.5):
C 60.51, H 5.30, N 6.14, S 7.02; found: C 60.65, H 5.52, N 6.02, S 7.09.
(Æ)-Methyl 2-(3-{4-[(Naphthalen-2-yl)methyl]-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl}phenyl)ethanoate ((Æ)-
12). Treatment of (Æ)-11 (1.32 g, 2.89 mmol) according to Procedure B gave (Æ)-12 (1.05 g, 86%). Yellow solid.
M.p. 135 ± 1378. IR (KBr): 3256m, 1733m, 1594m, 1561m, 1416m, 1144s. 1H-NMR (200 MHz, (CD3)2SO): 7.81 ±
7.76 (m, 1 H); 7.69 ± 7.65 (m, 2 H); 7.51 (s, 1 H); 7.45 ± 7.29 (m, 3 H); 7.15 ± 7.03 (m, 1 H); 6.96 ± 6.93 (m, 2 H); 6.81
(d, J ˆ 7.5, 2 H); 3.90 ± 3.82 (m, 1 H); 3.55 (s, 3 H); 3.53 (s, 2 H); 3.16, 2.77 (AB of ABX, JAX ˆ 5.4, JBX ˆ 6.2, JAB
ˆ
14.1, 2 H). 13C-NMR (75 MHz, (CD3)2SO): 173.5; 171.6; 139.5; 136.6; 135.1; 133.0; 131.8; 129.0; 128.7; 127.9;
‡
127.5 (2Â); 127.0; 125.7; 125.2; 123.1; 119.0; 116.6; 58.7; 51.6; 45.3; 37.9. DEI-MS: 424 (8, M ), 165 (82), 141
‡
(53), 106 (100). HR-DEI-MS: 424.1116 (M , C22H20N2O5S; calc. 424.1093).
(Æ)-2-(3-{4-[(Naphthalen-2-yl)methyl]-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl}phenyl)acetamide ((Æ)-2). A soln.
of (Æ)-12 (500 mg, 1.18 mmol) and potassium trimethylsilanolate (454 mg, 3.54 mmol) in THF (25 ml) was
stirred at r.t. for 24 h. The reaction was quenched with 1m aq. HCl soln. (50 ml) and the mixture extracted with
AcOEt (3 Â 50 ml). The combined org. extracts were dried (Na2SO4) and evaporated in vacuo. The residue was
dissolved in THF (25 ml), EDC (226 mg, 1.18 mmol) and HOBt (159 mg, 1.18 mmol) were added, and the soln.
was stirred at r.t. for 1 h. A 25% aq. NH4OH soln. (0.09 ml, 1.18 mmol) was added, and stirring was continued for
4 h. The mixture was filtered, evaporated in vacuo, and purified by FC (SiO2; CH2Cl2/MeOH/NH4OH 85 :14 :1)
to give (Æ)-2 (180 mg, 38%). Colorless solid. M.p. 160 ± 1638 (Et2O/CH2Cl2). IR (KBr): 3378m, 1739m, 1656s,
1339m, 1322m, 1178m. 1H-NMR (200 MHz, (CD3)2SO): 7.95 ± 7.88 (m, 4 H); 7.59 ± 7.42 (m, 6 H); 7.30 ± 7.22 (m, 2
H); 6.99 (s, 1 H); 4.87 (dd, J ˆ 9.9, 3.7, 1 H); 3.50 ± 3.42 (m, 1 H); 3.48 (s, 2 H); 3.23 (dd, J ˆ 14.3, 9.9, 1 H).
13C-NMR (75 MHz, (CD3)2SO): 171.8; 168.6; 138.6; 134.3; 133.1; 132.2; 130.7; 130.4; 129.7; 128.1; 128.0 (2Â);
‡
127.9; 127.7 (2Â); 126.3; 125.9; 125.6; 61.0; 41.2; 36.7. DEI-MS: 409 (9, M ), 169 (18), 141 (100). Anal. calc. for
C21H19N3O4S (409.5): C 61.60, H 4.68, N 10.26, S 7.83; found: C 61.39, H 5.08, N 9.83, S 7.66.
Methyl 2,2-Dimethyl-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propanoate (15). To a soln. of phthalimide
(2.52 g, 17.16 mmol), PPh3 (4.50 g, 17.16 mmol), and 14 (1.99 ml, 15.60 mmol) in dry THF (180 ml) was added
DEAD (2.91 ml, 18.72 mmol), and the soln. was stirred at r.t. for 20 h. The reaction was quenched with a sat. aq.
NaCl soln. (100 ml) and the mixture extracted with AcOEt (3 Â 100 ml). The combined org. phases were dried
(MgSO4), evaporated in vacuo, and purified by FC (SiO2; hexane/AcOEt 6 :4) to give 15 (3.60 g, 77%).
Colorless solid. M.p. 92 ± 948. IR (KBr): 1767m, 1719s, 1428m, 1388m, 1344m, 1267m, 1156m. 1H-NMR
(200 MHz, CDCl3): 7.88 ± 7.82 (m, 2 H); 7.77 ± 7.70 (m, 2 H); 3.85 (s, 2 H); 3.73 (s, 3 H); 1.26 (s, 6 H). 13C-NMR
‡
(75 MHz, CDCl3): 176.5; 168.8; 134.3; 132.1; 123.6; 52.4; 46.2; 43.7; 23.4. DEI-MS: 261 (3, M ), 202 (7), 160
(100). Anal. calc. for C14H15NO4 (261.3): C 64.36, H 5.79, N 5.36; found C 64.41, H 5.84, N 5.31.
3-Amino-2,2-dimethylpropionic Acid (16). A soln. of 15 (800 mg, 3.06 mmol) in AcOH (10 ml), conc. aq.
HCl soln. (10 ml), and H2O (10 ml) was heated to reflux for 16 h. The soln. was evaporated in vacuo, the residue
diluted with H2O (50 ml), washed with Et2O (2 Â 50 ml), and purified by ion-exchange chromatography
(Dowex W X 8) to afford 16 (243 mg, 67%). Colorless solid. M.p. > 2008 ([46]: 2398). 1H-NMR (200 MHz,
D2O): 3.04 (s, 2 H); 1.22 (s, 6 H).
3-{[(Benzyloxy)carbonyl]amino}-2,2-dimethylpropionic Acid (17). To 16 (573 mg, 4.89 mmol) in 1m aq.
NaOH soln. (20 ml) at 08 was added dropwise a soln. of benzyl chloroformate (0.90 ml, 6.36 mmol) in dioxane
(3 ml) during 30 min, and the soln. was stirred at r.t. for 5 h. The dioxane was removed in vacuo, the soln. made

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Helvetica Chimica Acta ± Vol. 82 (1999)
acidic with 1m aq. HCl soln. (50 ml) and extracted with AcOEt (3 Â 50 ml). The combined org. extracts were
dried (MgSO4) and evaporated in vacuo to give 17 (830 mg, 68%). Colorless oil. 1H-NMR (200 MHz, CDCl3):
7.39 ± 7.30 (m, 5 H); 5.35 ± 5.25 (m, 1 H); 5.16 (s, 2 H); 3.33 (d, J ˆ 6.6, 2 H); 1.25 (s, 6 H).
tert-Butyl 3-{[(Benzyloxy)carbonyl]amino}-2,2-dimethylpropanoate (18). To a suspension of 17 (2.02 g,
8.04 mmol) in CH2Cl2 (16 ml) in a sealed tube was added conc. H2SO4 (0.08 ml). Isobutene (16 ml) was then
added at 788, and the soln. was shaken at r.t. for 65 h. The mixture was poured into 1m aq. NaOH soln. (50 ml)
and extracted with CH2Cl2 (3 Â 50 ml). The combined org. extracts were dried (Na2SO4), evaporated in vacuo,
and purified by FC (SiO2; hexane/AcOEt 9 :1) to give 18 (2.10 g, 85%). Colorless oil. IR (CHCl3): 2981m, 1719s,
1514s, 1369m, 1314m, 1144s. 1H-NMR (200 MHz, CDCl3): 7.38 ± 7.36 (m, 5 H); 5.32 ± 5.30 (br. s, 1 H); 5.11 (s, 2
H); 3.27 (d, J ˆ 6.2, 2 H); 1.44 (s, 9 H); 1.15 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 176.7; 157.0; 136.9; 128.7; 128.3
‡
(2Â); 80.9; 66.8; 48.9; 44.0; 28.0; 23.1. FAB-MS: 308 (39, MH ), 252 (100), 234 (26), 208 (26), 91 (52). Anal.
calc. for C17H25NO4 (307.4): C 66.43, H 8.20, N 4.56, O 20.82; found C 66.62, H 8.11, N 4.74, O 20.96.
tert-Butyl 3-Amino-2,2-dimethylpropanoate (13). A soln. of 18 (600 mg, 1.95 mmol) in MeOH (50 ml) was
treated with 10% Pd/C (60 mg) under H2 (1 bar) for 3 h. The mixture was filtered and evaporated in vacuo to
give 13 (300 mg, 89%). Colorless oil. IR (CHCl3): 2979m, 1714s, 1474m, 1392m, 1380m, 1295m, 1151s. 1H-NMR
(200 MHz, CDCl3): 2.68 (s, 2 H); 1.44 (s, 9 H); 1.11 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 176.9; 80.3; 51.6; 45.0;
‡
28.1; 22.9. EI-MS: 173 (2, M ), 144 (28), 100 (21), 88 (100).
(Æ)-Methyl 2-{[(2-Oxo-1,3-oxazolan-3-yl)sulfonyl]amino}-3-phenylpropanoate ((Æ)-19a). Treatment of
(Æ)-6a (5.00 g, 23.18 mmol) according to Procedure D gave (Æ)-19a (6.88 g, 91%). Colorless solid. M.p. 132 ±
1338 (hexane/AcOEt). IR (CHCl3): 3196m, 1754s, 1380m, 1223m, 1175m, 1149m. 1H-NMR (200 MHz, CDCl3):
7.38 ± 7.17 (m, 5 H); 4.66 ± 4.60 (m, 1 H); 4.30 (t, J ˆ 7.7, 2 H); 3.86 (t, J ˆ 7.7, 2 H); 3.77 (s, 3 H); 3.18, 3.08 (AB of
ABX, JAX ˆ 6.0, JBX ˆ 7.1, JAB ˆ 14.2, 2 H). 13C-NMR (75 MHz, CDCl3): 171.6; 153.3; 135.3; 129.7; 129.1; 127.7;
‡
62.6; 58.2; 53.1; 45.2; 38.9. DEI-MS: 329 (5, MH ), 269 (7), 237 (17), 182 (12), 177 (10), 162 (100), 150 (24), 118
(26), 91 (67). Anal. calc. for C13H16N2O6S (328.3): C 47.55, H 4.91, N 8.53, S 9.77; found: C 47.48, H 4.84, N 8.51,
S 9.67.
(Æ)-Methyl 3-(Naphthalen-2-yl)-2-{[(2-oxo-1,3-oxazolan-3-yl)sulfonyl]amino}propanoate ((Æ)-19b). Treat-
ment of (Æ)-6b (2.50 g, 9.41 mmol) according to Procedure D gave (Æ)-19b (3.48 g, 98%). Colorless solid. M.p.
115 ± 1178 (hexane/AcOEt). IR (KBr): 3216m, 1751s, 1380m, 1205m, 1181m. 1H-NMR (200 MHz, CDCl3):
7.83 ± 7.78 (m, 3 H); 7.64 (s, 1 H); 7.50 ± 7.42 (m, 2 H); 7.33 ± 7.27 (m, 1 H); 5.71 (br. s, 1 H); 4.78 ± 4.63 (m, 1 H);
4.17 ± 3.97 (m, 2 H); 3.82 ± 3.66 (m, 2 H); 3.77 (s, 3 H); 3.33, 3.20 (AB of ABX, JAX ˆ 5.4, JBX ˆ 7.2, JAB ˆ 14.2, 2
H). 13C-NMR (50 MHz, CDCl3): 171.4; 153.0; 133.4; 132.7; 132.6; 128.6 (2Â); 127.8; 127.6; 127.3; 126.5; 126.1;
‡
‡
‡
62.4; 58.2; 53.0; 45.0; 39.1. ESI-MS: 442 (100, [M ‡ Na ‡ MeCN] ), 401 (49, [M ‡ Na] ), 379 (3, MH ). Anal.
calc. for C17H18N2O6S (378.4): C 53.96, H 4.79, N 7.40, S 8.47; found: C 54.17, H 4.82, N 7.34, S 8.22.
(Æ)-Methyl 2-{[(2-Oxo-1,3-oxazolan-3-yl)sulfonyl]amino}-4-phenylbutanoate ((Æ)-19c). Treatment of (Æ)-
6c (637 mg, 2.77 mmol) according to Procedure D gave (Æ)-19c (540 mg, 57%). Colorless solid. M.p. 87 ± 898
1
(hexane/AcOEt). IR (KBr): 3208m, 1746s, 1385m, 1178m. H-NMR (200 MHz, CDCl3): 7.35 ± 7.21 (m, 5 H);
5.94 (s, 1 H); 4.46 ± 4.38 (m, 2 H); 4.38 ± 4.31 (m, 1 H); 4.12 ± 3.92 (m, 2 H); 3.77 (s, 3 H); 2.82 ± 2.74 (m, 2 H);
2.32 ± 1.98 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 172.2; 153.5; 140.3; 128.8; 128.7; 126.6; 62.8; 56.9; 53.1; 45.5;
‡
‡
34.5; 31.3. DEI-MS: 343 (5, MH ), 342 (4, M ), 283 (2), 132 (52), 117 (100), 91 (82). Anal. calc. for
C14H18N2O6S (342.4): C 49.11, H 5.30, N 8.18, S 9.37; found C 49.23, H 5.35, N 8.01, S 9.35.
(Æ)-Methyl 2-[({[2-(tert-Butoxycarbonyl)ethyl]amino}sulfonyl)amino]-3-phenylpropanoate ((Æ)-20a).
Treatment of (Æ)-19a (3.77 g, 11.48 mmol) and b-alanine tert-butyl ester (2.09 g, 11.48 mmol) according to
Procedure E gave (Æ)-20a (2.61 g, 59%). Light-yellow oil. IR (CHCl3): 1739m, 1721m, 1153s. 1H-NMR
(200 MHz, CDCl3): 7.38 ± 7.13 (m, 5 H); 4.94 ± 4.87 (m, 1 H); 4.86 (d, J ˆ 9.6, 1 H); 4.36 ± 4.21 (m, 1 H); 3.78 (s, 3
H); 3.15 (dd, J ˆ 13.5, 5.6, 1 H); 3.07 ± 2.97 (m, 1 H); 3.09 ± 2.89 (m, 2 H); 2.38 (t, J ˆ 5.8, 2 H); 1.46 (s, 9 H).
13C-NMR (75 MHz, CDCl3): 172.6; 171.8; 135.8; 129.7; 128.9; 127.6; 81.6; 57.1; 52.7; 39.1; 38.8; 34.8; 28.1. DEI-
‡
MS: 387 (1, MH ), 331 (12), 313 (9), 295 (12), 281 (11), 271 (40), 253 (28), 239 (100), 162 (9), 91 (5). HR-DEI-
‡
MS: 387.1595 (MH , C17H27N2O6S; calc. 387.1590).
(Æ)-Methyl
2-[({[2-(tert-Butoxycarbonyl)ethyl]amino}sulfonyl)amino]-3-(naphthalen-2-yl)propanoate
((Æ)-20b). Treatment of (Æ)-19b (500 mg, 1.32 mmol) and b-alanine tert-butyl ester (241 mg, 1.32 mmol)
according to Procedure E gave (Æ)-20b (350 mg, 61%). Colorless oil. IR (CHCl3): 1740m, 1722m, 1150s, 1136s.
1H-NMR (200 MHz, CDCl3): 7.85 ± 7.78 (m, 3 H); 7.66 (s, 1 H); 7.53 ± 7.43 (m, 2 H); 7.33 ± 7.28 (m, 1 H); 4.92 ±
4.88 (m, 2 H); 4.41 ± 4.30 (m, 1 H); 3.76 (s, 3 H); 3.30, 3.19 (AB of ABX, JAX ˆ 5.8, JBX ˆ 6.9, JAB ˆ 13.8, 2 H);
3.11 ± 2.82 (m, 2 H); 2.28 (t, J ˆ 5.8, 2 H); 1.43 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 172.6; 171.8; 133.6; 133.2;
‡
132.8; 128.6 (2Â); 127.9 (2Â); 127.5; 126.5; 126.2; 81.6; 57.1; 52.7; 39.3; 38.8; 34.6; 28.1. DEI-MS: 436 (1, M ),

Helvetica Chimica Acta ± Vol. 82 (1999)
2445
239 (16), 212 (70), 168 (16), 141 (100). Anal. calc. for C21H28N2O6S (436.5): C 57.78, H 6.46, N 6.42, S 7.35;
found: C 57.70, H 6.28, N 6.16, S 7.41.
(Æ)-Methyl 2-[({[2-(tert-Butoxycarbonyl)-2,2-dimethylethyl]amino}sulfonyl)amino]-3-(naphthalen-2-yl)-
propanoate ((Æ)-20c). Treatment of (Æ)-19b (574 mg, 1.52 mmol) and 13 (239 mg, 1.38 mmol) according to
Procedure E gave (Æ)-20c (400 mg, 62%). Colorless solid. M.p. 121 ± 1228 (hexane/AcOEt). IR (KBr): 3263m,
1740s, 1705s, 1162s. 1H-NMR (200 MHz, CDCl3): 7.82 ± 7.78 (m, 3 H); 7.66 (s, 1 H); 7.51 ± 7.44 (m, 2 H); 7.34 ± 7.29
(m, 1 H); 4.93 ± 4.79 (m, 2 H); 4.37 ± 4.26 (m, 1 H); 3.76 (s, 3 H); 3.31, 3.16 (AB of ABX, JAX ˆ 5.4, JBX ˆ 7.1,
JAB ˆ 13.7, 2 H); 2.71 (dd, J ˆ 12.5, 7.1, 1 H); 2.51 (dd, J ˆ 12.5, 6.6, 1 H); 1.41 (s, 9 H); 1.01 (s, 3 H); 0.91 (s, 3 H).
13C-NMR (75 MHz, CDCl3): 176.3; 172.8; 133.7; 133.5; 132.8; 128.7; 128.6; 127.9; 127.9; 127.7; 126.5; 126.1; 81.2;
‡
57.4; 52.7; 50.7; 42.8; 39.3; 27.9; 23.1. DEI-MS : 464 (1, M ), 267 (15), 249 (8), 232 (6), 212 (97), 187 (23), 168
(15), 141 (100). Anal. calc. for C23H32N2O6S (464.6): C 59.46, H 6.94, N 6.03, S 6.90; found C 59.69, H 6.86,
N 6.03, S 7.10.
(Æ)-Methyl 2-[({[2-(tert-Butoxycarbonyl)-2,2-dimethylethyl]amino}sulfonyl)amino]-4-phenylbutanoate
((Æ)-20d). Treatment of (Æ)-19c (747 mg, 2.18 mmol) and 13 (340 mg, 1.96 mmol) according to Procedure E
gave (Æ)-20d (540 mg, 64%). Colorless solid. M.p. 79 ± 818 (hexane/AcOEt). IR (CHCl3): 1739s, 1711m, 1369m,
1348m, 1309m, 1145vs. 1H-NMR (200 MHz, CDCl3): 7.34 ± 7.12 (m, 5 H); 5.02 ± 4.97 (m, 2 H); 4.15 ± 3.99 (m, 1
H); 3.75 (s, 3 H); 3.02 (d, J ˆ 6.6, 2 H); 2.78 ± 2.70 (m, 2 H); 2.24 ± 1.93 (m, 2 H); 1.44 (s, 9 H); 1.19 (s, 3 H); 1.17
(s, 3 H). 13C-NMR (75 MHz, CDCl3): 176.5; 173.4; 140.6; 128.8; 128.7; 126.5; 81.4; 55.7; 52.8; 51.1; 43.1; 34.8;
‡
31.4; 28.0; 23.4. DEI-MS: 429 (1, MH ), 372 (26), 313 (46), 285 (68), 256 (14), 196 (32), 117 (100), 91 (43).
Anal. calc. for C20H32N2O6S (428.6): C 56.05, H 7.53, N 6.54, S 7.48; found C 56.27, H 7.78, N 6.49, S 7.47.
(Æ)-tert-Butyl 3-[4-(Phenylmethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]propanoate ((Æ)-21a). Treatment
of (Æ)-20a (150 mg, 0.39 mmol) according to Procedure F gave (Æ)-21a (70 mg, 51%). Colorless solid. M.p. 86 ±
888. IR (KBr): 3222m, 1722s, 1708s, 1350m, 1327m, 1183m, 1144m. 1H-NMR (200 MHz, CDCl3): 7.43 ± 7.23 (m, 5
H); 4.75 (d, J ˆ 6.6, 1 H); 4.45 ± 4.35 (m, 1 H); 3.88 (t, J ˆ 7.6, 2 H); 3.31, 3.16 (AB of ABX, JAX ˆ 4.4, JBX ˆ 8.5,
JAB ˆ 14.3, 2 H); 2.67 (t, J ˆ 7.6, 2 H); 1.47 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 169.5; 167.8; 134.6; 129.6; 129.5;
‡
128.2; 81.7; 61.7; 36.8; 36.6; 33.5; 28.1. DEI-MS: 355 (1, MH ), 298 (60), 281 (34), 270 (25), 253 (25), 120 (17),
91 (100). Anal. calc. for C16H22N2O5S (354.4): C 54.22, H 6.26, N 7.90, S 9.05; found: C 54.35, H 6.49, N 7.80, S 9.16.
(Æ)-tert-Butyl 3-[4-(Naphthalen-2-ylmethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]propanoate ((Æ)-21b).
Treatment of (Æ)-20b (300 mg, 0.69 mmol) according to Procedure F gave (Æ)-21b (100 mg, 36%). Yellow,
1
highly viscous oil. IR (CHCl3): 1729m, 1333w, 1150s, 1137s. H-NMR (200 MHz, CDCl3): 7.88 ± 7.81 (m, 3 H);
7.71 (m, 1 H); 7.56 ± 7.49 (m, 2 H); 7.38 ± 7.32 (m, 1 H); 4.67 (d, J ˆ 6.2, 1 H); 4.52 ± 4.45 (m, 1 H); 3.89 (t, J ˆ 7.6,
2 H); 3.47, 3.31 (AB of ABX, JAX ˆ 3.9, JBX ˆ 8.5, JAB ˆ 14.3, 2 H); 2.67 (t, J ˆ 7.6, 2 H); 1.45 (s, 9 H). 13C-NMR
(75 MHz, CDCl3): 169.5; 167.9; 133.7; 132.1; 129.4; 128.7; 128.0; 127.9; 127.0; 126.0; 126.0; 11.3; 81.7; 61.7; 36.9;
‡
36.8; 33.5; 28.1. DEI-MS: 404 (5, M ), 348 (10), 331 (5), 303 (4), 168 (6), 141 (100). HR-DEI-MS: 404.1398
‡
(M , C20H24N2O5S; calc. 404.1406).
(Æ)-tert-Butyl 2,2-Dimethyl-3-[4-(naphthalen-2-ylmethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]propanoate
((Æ)-21c). Treatment of (Æ)-20c (340 mg, 0.73 mmol) according to Procedure F gave (Æ)-21c (160 mg, 51%).
Yellow, highly viscous oil. IR (CHCl3): 1726s, 1348m, 1294m, 1183s, 1144s. 1H-NMR (200 MHz, CDCl3): 7.87 ±
7.79 (m, 3 H); 7.70 (s, 1 H); 7.55 ± 7.46 (m, 2 H); 7.36 ± 7.31 (d, J ˆ 8.3, 1.7, 1 H); 4.66 (d, J ˆ 6.7, 1 H); 4.51 ± 4.42
(m, 1 H); 3.82 (s, 2 H); 3.45, 3.34 (AB of ABX, JAX ˆ 4.8, JBX ˆ 7.9, JAB ˆ 13.9, 2 H); 1.45 (s, 9 H); 1.19 (s, 3 H);
1.14 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 174.9; 169.4; 133.7; 133.0; 132.4; 129.2; 128.7; 128.0; 127.9; 127.2;
‡
126.8; 126.5; 81.6; 61.6; 48.9; 43.5; 36.9; 27.8; 23.7; 23.4. DEI-MS: 432 (31, M ), 376 (15), 359 (17), 331 (15), 279
‡
(17), 168 (20), 141 (100). HR-DEI-MS: 432.1732 (M , C22H28N2O5S; calc. 432.1719).
(Æ)-tert-Butyl 2,2-Dimethyl-3-[4-(2-phenylethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]propanoate ((Æ)-21d).
Treatment of (Æ)-20d (450 mg, 1.05 mmol) according to Procedure F gave (Æ)-21d (270 mg, 65%). Colorless
solid. M.p. 98 ± 998 (hexane/AcOEt). IR (KBr): 3165m, 1743s, 1702s, 1351m, 1277m, 1180s, 1151m. 1H-NMR
(200 MHz, CDCl3): 7.38 ± 7.17 (m, 5 H); 5.05 (d, J ˆ 7.5, 1 H); 4.20 ± 4.09 (m, 1 H); 3.81 (s, 2 H); 2.95 ± 2.72 (m, 2
H); 2.42 ± 2.03 (m, 2 H); 1.48 (s, 9 H); 1.22 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 175.0; 170.0; 139.7; 129.0;
‡
‡
128.8; 126.9; 81.6; 60.0; 48.8; 43.5; 33.0; 31.6; 27.9; 23.6. NH4-DCI-MS: 414 (1, [M ‡ NH4] ), 397 (1, MH ), 341
(29), 323 (42), 295 (17), 236 (100). Anal. calc. for C19H28N2O5S (396.5): C 57.55, H 7.12, N 7.07, S 8.09; found
C 57.54, H 7.32, N 7.08, S 8.07.
(Æ)-3-[4-(Naphthalen-2-ylmethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]propanoic Acid ((Æ)-3a). Treat-
ment of (Æ)-21b (100 mg, 0.25 mmol) according to Procedure G gave (Æ)-3a (60 mg, 70%). Colorless solid. M.p.
128 ± 1318. IR (KBr): 1717s, 1344m, 1167m. 1H-NMR (200 MHz, (CD3)2SO): 7.91 ± 7.87 (m, 3 H); 7.81 (s, 1 H);
7.54 ± 7.46 (m, 3 H); 4.68 (dd, J ˆ 9.8, 3.9, 1 H); 3.75 (t, J ˆ 7.5, 2 H); 3.10 ± 2.98 (m, 2 H); 2.61 (t, J ˆ 7.5, 2 H).
13C-NMR (125 MHz, (CD3)2SO): 171.3; 168.4; 134.0; 132.9; 131.9; 127.8; 127.7; 127.6; 127.4 (2Â); 126.0; 125.6;

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Helvetica Chimica Acta ± Vol. 82 (1999)
‡
‡
60.9; 36.8; 36.0; 32.1. DEI-MS: 348 (4, M ), 168 (6), 141 (100). HR-DEI-MS: 348.0775 (M , C16H16N2O5S; calc.
348.0780).
(Æ)-2,2-Dimethyl-3-[4-(naphthalen-2-ylmethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]propanoic Acid ((Æ)-
3b). Treatment of (Æ)-21c (100 mg, 0.23 mmol) according to Procedure G gave (Æ)-3b (60 mg, 69%). Colorless
solid. M.p. 188 ± 1898. IR (KBr): 3344m, 3189m, 1750s, 1730m, 1333m, 1256m, 1190m, 1154m. 1H-NMR
(200 MHz, CD3OD): 7.84 ± 7.76 (m, 4 H); 7.47 ± 7.41 (m, 3 H); 4.53, 3.40, 3.09 (ABX, JAX ˆ 3.9, JBX ˆ 10.0, JAB
ˆ
14.1, 3 H); 3.76 (s, 1 H); 3.74 (s, 1 H); 1.19 (s, 3 H); 1.17 (s, 3 H). 13C-NMR (75 MHz, CD3OD): 179.8; 171.9;
‡
135.6; 135.3; 134.3; 129.6; 129.4; 129.0; 128.9 (2Â); 127.4; 127.1; 63.0; 44.0; 38.7; 24.1. DEI-MS: 376 (7, M ), 169
‡
(23), 167 (23), 141 (100). HR-DEI-MS: 376.1098 (M , C18H20N2O5S; calc. 376.1093).
(Æ)-2,2-Dimethyl-3-[4-(2-phenylethyl)-1,1,3-trioxo-1l6,2,5-thiadiazolan-2-yl]propanoic Acid ((Æ)-3c).
Treatment of (Æ)-21d (190 mg, 0.48 mmol) according to Procedure G gave (Æ)-3c (140 mg, 86%). Colorless
solid. M.p. 105.5 ± 1068 (hexane/AcOEt). IR (KBr): 3199m, 1735s, 1325m, 1264m, 1180m, 1146m. 1H-NMR
(200 MHz, CD3OD): 7.33 ± 7.15 (m, 5 H); 4.12 ± 4.06 (m, 1 H); 3.74 (s, 2 H); 2.87 ± 2.67 (m, 2 H); 2.26 ± 1.90 (m, 2
H); 1.22 (s, 6 H). 13C-NMR (75 MHz, CD3OD): 179.4; 172.7; 142.0; 129.9; 129.9; 127.6; 60.8; 44.0; 34.5; 32.7;
‡
24.1. NH4-DCI-MS: 341 (9, MH ), 323 (12), 295 (4), 236 (12), 218 (12), 134 (43), 104 (74), 91 (100). Anal. calc.
for C15H20N2O5S (340.4): C 52.93, H 5.92, N 8.23, S 9.42; found C 52.99, H 5.78, N 8.09, S 9.33.
X-Ray Crystal Structure of (Æ)-21a. X-Ray crystal data for C16H22N2O5S (Mr ˆ 354.4): monoclinic space
3
group P21/n, Dc ˆ 1.331 g ´ cm
,
Z ˆ 4, a ˆ 14.491(5), b ˆ 7.715(5), c ˆ 15.862(5) Š, b ˆ 93.90(2)8, Vˆ
1769.2(14) Š3, MoKa radiation, l ˆ 0.71070 Š, 1.84 ꢀ q ꢀ 24.998, 3114 unique reflections, Tˆ 193 K. The
structure was solved by direct methods (SHELXS 86) and refined by full-matrix least-squares analysis
(SHELXL-93) using an isotropic extinction correction and an exponentially modified weight factor rˆ 2.5 Š2.
All heavy atoms were refined anisotropically, H-atoms isotropically. H-Positions are based on stereochemical
considerations, except H N(14), which was located from an electron-density-difference map. Final R(F) ˆ
0.0340, wR(F2) ˆ 0.1416 for 243 parameters and 2366 reflections with I > 2s(I).
Crystallographic data (excluding structure factors) for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as deposition No. CCDC-133802. Copies of the data
can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: ‡
44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).
This work was supported by F. Hoffmann-La Roche AG, Basel, Nutley (USA). We thank Dr. Carlo Thilgen
(ETH Zürich) for assistance with the nomenclature.
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Received September 8, 1999