Substituted 1,2-Thiazetidine 1,1-Dioxides. Synthesis and Properties of N-Alkylated and N-Acylated Derivatives of 1,2-Thiazetidine-3-acetic Acid 1,1-Dioxide

Article abstract of DOI:10.1007/s00706-003-0105-2

1,2-Thiazetidine-3-acetic acid 1,1-dioxide was N-alkylated using bromoacetates, and N-acylated using either acyl chlorides, protected amino acid fluorides, or N-protected amino acid NCA, which seemed to be the most universal method. Most of the obtained "

Full text of DOI:10.1007/s00706-003-0105-2

Monatshefte f€ur Chemie 135, 55–68 (2004)
DOI 10.1007/s00706-003-0105-2
Substituted 1,2-Thiazetidine 1,1-Dioxides.
Synthesis and Properties of N-Alkylated
and N-Acylated Derivatives
of 1,2-Thiazetidine-3-acetic Acid 1,1-Dioxide
ꢀ
¨
Till Rohrich, Bassam Abu Thaher, and Hans-Hartwig Otto
Department of Pharmaceutical=Medicinal Chemistry (PMC), Institute of Pharmacy,
Ernst-Moritz-Arndt-University Greifswald, 17487 Greifswald, Germany
Received August 20, 2003; accepted August 25, 2003
Published online October 20, 2003 # Springer-Verlag 2003
Summary. 1,2-Thiazetidine-3-acetic acid 1,1-dioxide was N-alkylated using bromoacetates, and N-
acylated using either acyl chlorides, protected amino acid fluorides, or N-protected amino acid NCA,
which seemed to be the most universal method. Most of the obtained ‘‘ꢀ-sultam peptides’’ were
sensitive against humidity, they hydrolyzed forming sulfonic acids, and reactions with amines resulted
in sulfonamides. Reactions of N-acylated products showed that the sulfonyl group was faster attacked
than the imide structure.
Keywords. 1,2-Thiazetidine 1,1-dioxide; ꢀ-Sultam; ꢀ-Sultam peptide.
Introduction
1,2-Thiazetidine 1,1-dioxide (ꢀ-sultam) is the sulfone analogue of the ꢀ-lactam
ring. Its reactivity is depending on the substituents usually higher than that of the
analogue ꢀ-lactam system. Therefore, it should be highly interesting to replace the
ꢀ-lactam ring in special compounds by the ꢀ-sultam moiety, and to study proper-
ties and specific reactivity. We have described a number of ꢀ-lactam peptides
showing inhibitor activity against the serine protease elastase and=or the cysteine
protease papain [1, 2]. In continuation of this project, we synthesized derivatives of
1,2-thiazetidine-3-acetic acid 1,1-dioxide (ꢀ-sultam-3-acetic acid) at the C-termi-
nus with esters of amino acids or dipeptides [3]. Here we report about reactions at
the nitrogen atom of 1, and about the properties of those structures obtained by
combination of both reactions.
ꢀ
Corresponding author. E-mail: ottohh@pharmazie.uni-greifswald.de

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Results and Discussion
To explore the alkylation at the nitrogen atom of the ꢀ-sultam ring, we first studied
the reaction between 1 and alkyl bromoacetates. The deprotonation was successful
only with BuLi. Using NaOH, KOH, or amines we observed always partial or
complete ring opening. The alkylation finally was best done at ꢁ78ꢂC in THF
in the presence of HMPT [4], whereby yields of up to 80% of 2a or 2b were
isolated. Without HMPT the yields were completely unsatisfactory. After purifica-
tion by CC, 2a and 2b were obtained as colourless viscous liquids, which had to be
stored under N2 at low temperature. By hydrogenolytic cleavage of the benzyl ester
group at the C-terminus we obtained the carboxylic acids 3a and 3b as very
unstable compounds. Therefore, they were immediately reacted with amino acid
esters using the NHS/DCC methodology yielding the N-alkylated ‘‘sultam pep-
tides’’ 4a–4e. These compounds may be interpreted as peptide analogues with
two protected C-terminals, as the substituent at the nitrogen can be seen as a
built-in glycine. We tried different methods to obtain the free diacids, but all
experiments failed completely until today. Probably, these diacids are much more
sensitive than the acids 3.
The structures of the diesters were confirmed by the characteristic C–H bands around ꢁꢀ¼
3020 cmꢁ1 of the protons in position 4 of the ꢀ-sultam ring [5], the SO2 bands at ꢁꢀ¼ 1320 and
1
1150 cmꢁ1, and the bands of other functional groups in their IR spectra. The H NMR spectra are
characterized by the ABX system of the ring protons 3-H (A), 4-Htrans (B), and 40-Hcis (X) with
coupling constants, e.g. for 4b, JAB ¼ 6, JAX ¼ 8.25, and JBX ¼ 12.5 Hz. The protons of the acetyl part
at C-3 show a geminal coupling of J ¼ 15.8Hz, and couplings with 3-H of J ¼ 6 and 7.5Hz, while the
coupling constant of the acetyl protons next to the nitrogen is 18Hz. The protons of the fourth
methylene group finally exhibit a clear doublet with J ¼ 6 Hz. From these values one might deduce
a pseudo equatorial orientation of the protons in the structure of 4b (Fig. 1). It has to be noted that all
Scheme 1

Substituted 1,2-Thiazetidine 1,1-Dioxides
57
1
Fig. 1. Structure of 4b (R ¼ CH2CO2C(CH3)3) as deduced from H NMR data
Scheme 2
1
compounds 4 were isolated as a mixture of two diastereomers as can be detected in the 300 MHz H
NMR spectra, and which is caused by the two possible configurations at C-3 of the ꢀ-sultam ring.
By analogous reactions between 1 and dipeptide esters compounds 5 were
obtained, and the diester 5a was hydrolyzed yielding the sulfonic acid 6. Using
a ChiraSpher NT column we could demonstrate in a HPLC experiment, that during
the synthesis of 5a no racemization had occurred in the peptide part. Only two lines
were found.
Another possibility of substitution at the nitrogen is opened by acylation of the
ꢀ-sultam. The success of these reactions depends very strongly on the reaction
conditions [6]. Reactions between 1 and acyl chlorides in THF in the presence
of triethylamine as reported for similar systems [7] or in the presence of NaH [8]
failed. But, when the reactions were done at ꢁ78ꢂC using BuLi, the N-acylated ꢀ-
sultams 7a and 7b were isolated with yields of 60–70%. While 7a is a stable solid
compound, 7b was obtained as an unstable viscous liquid, which after a short time,
decomposed with release of chloroacetic acid. Nevertheless, we tried to use the
reactive chlorine for substitution reactions by nucleophils. Reactions of 7b with
ammonia, phthalimide potassium in DMF, benzylamine, or sodium azide gave no
isolable ꢀ-sultam derivatives. Only from the reaction with benzylamine we isolated
N-benzylchloroacetamide [9]. However, the replacement of chlorine by iodine was
successful, and 8 was obtained as a viscous liquid with 56% yield. When 8 was
stirred with benzylamine the iodine was replaced by benzylamine, but the benzyl-
amine also attacked the ꢀ-sultam ring yielding the open chain sulfonamide 11 as a

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T. Rohrich et al.
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Scheme 3
stable solid. An attack to the imide structure as in the reaction of 7b with benzyl-
amine was not observed.
Next we studied the acylation of 1 with N-protected amino acid halogenides.
Phthaloylglycine [10] was transformed into the stable acid chloride with PCl5
[11, 12], and reacted with 1 in an inverse reaction, the solution of 1 with BuLi was
added to the solution of the acyl chloride, yielding the N-(phthaloylglycyl)-ꢀ-sultam
9 with 44% yield. As deprotection of 9 with hydrazine was not successful, no defined
product could be found, we tried the ‘‘soft method’’ of Schwyzer et al. [13] using
hydrazine acetate in methanol. The obtained product 10 demonstrated once more
that the ꢀ-sultam ring is much easier attacked by nucleophiles than the imide
structure.
Reactions between 1 and N-protected amino acid fluorides [14, 15] failed with
Z-L-Ala-F and Boc-Gly-F, probably caused by a base catalyzed intramolecular
formation of oxazolinones [16], but were successful when we used Boc- or Z-L-
Pro-F yielding 12a and 12b. The benzyl ester group of 12b was hydrogenated
giving the acid 13, but deprotection of the proline nitrogen was not possible.
The most versatile method for the acylation of 1 with amino acid derivatives was
the reaction with Boc- or Z-protected amino acid N-carboxyanhydrides (NCA)
[17, 18] at ꢁ78ꢂC in THF in the presence of BuLi. Using this method, we obtained
the N-substituted ꢀ-sultams 14a–14c as relatively stable compounds with yields
about 60%. Compound 14c, obtained from Z-L-Ala-NCA and 1 was partially hydro-
lyzed to the sulfonic acid during purification by CC. 14a and 14b were transformed
into the acids 15a and 15b by hydrogenolysis in the presence of Pd-C.
The IR spectra of the N-acylated ꢀ-sultams show a shift of 20cmꢁ1 to higher wave numbers for the
sulfonyl bands. Furthermore, they are characterized by the C–H bands of the protons at C-4 of the ꢀ-
sultam around ꢁꢀ¼ 3040 cmꢁ1. In their 1H NMR spectra we found the typical ABX system, 4-H (A), 3-

Substituted 1,2-Thiazetidine 1,1-Dioxides
59
Scheme 4
H (B), and 40-H (X) with the coupling constants Jcis ¼ 8, Jtrans ¼ 4, and Jgem ¼ 13 Hz (e.g. for 9).
The diastereotopic protons of the acetyl part at C-3 show the coupling constants Jgem ¼ 17, Jcis ¼ 3.5,
and Jtrans ¼ 10Hz.
Scheme 5

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The reaction of 13, 15b, or 15a with L-Phe-OMe or Gly-OBn using the NHS/DCC
method gave no defined product. Therefore, we tried the opposite sequence starting
with the ‘‘sultam peptides’’ 16 and 19 [2]. When these compounds were acylated with
Boc- or Z-L-Ala-NCAwe isolated the compounds 17, 20a, and 20b as solid compounds
with yields between 80 and 90%. By hydrogenation of 17 the acid 18 was accessible
(yield 97%), but all experiments to deprotect the N-terminus were unsuccessful so for.
The reactivity against nucleophiles and thereby the stability of substituted ꢀ-
sultams vary strongly with the substitution pattern at the nitrogen, as can be
deduced from the described experiments. A big substituent like the tert-butyldi-
methylsilyl group inhibits the attack to the sulfonyl group [19], while smaller
groups like alkyl or trimethylsilyl do not stabilize the system. Compounds 4 behave
similar. N-Acylated products are much more reactive and sensitive. The ꢀ-sultam
ring might be opened either by acid or by base catalyzed attack. This probably
explains why we obtained free acids only in some special cases. The isolated
products of hydrolysis are described in the experimental part, following the
description of the parent ꢀ-sultam. Further experiments concerning stability and
reactivity are under investigation.
Using standard procedures a selected number of compounds were tested as
inhibitors of proteases and=or as antiinfectives, but no exciting biological activity
was found.
Experimental
Melting points: Linstr€om apparatus (uncorrected); IR spectra (KBr): Perkin-Elmer IR 1310, Beck-
1
man IR 4240, IR 33; H NMR spectra: Varian T 60 (60 MHz), Bruker WP 80 (80MHz), WP 250
(250 MHz), AM 400 (400 MHz), Varian U-300 (300 MHz), room temperature, internal TMS, values
from 80MHz spectra, CDCl3, if not noted otherwise, MS spectra: Finnigan GC MS 4000, MAT
312, MAT 44 S; elemental analyses: Institute of Pharmacy, or Chemisches Laboratorium, Uni-
versity of Freiburg: the results agreed with the calculated values within experimental error. Tetra-
hydrofuran (THF) was stored over CaCl2 or KOH, then refluxed with Na and benzophenone, and
distilled prior to use. Other solvents were dried=purified according to literature procedures.
Abbreviations:BuLi¼ n-Butyllithium,15%inhexane;CC ¼ Columnchromatography(Silicagel60,
Merck 7734, 0.063–0.200 mm); DCC ¼ Dicyclohexyl carbodiimide; AcOEt¼ Ethyl acetate; HMPT ¼
Hexamethylphosphortrisamide;NHS ¼ N-Hydroxysuccinimide;TEA ¼Triethylamine; TLC ¼ thinlayer
chromatography (DC Fertigplatten Silica gel 60 F254, Merck 5549 or 5715).
Benzyl (RS)-1,2-Thiazetidine-3-acetate 1,1-Dioxide (1)
See Ref. [7a].
General Procedure for the N-Alkylation of 1
At ꢁ78ꢂC and under a N2 atmosphere, 10 mmol of BuLi were added to a solution of 2.55 g of 1
(10 mmol), and 3.6 g of HMPT (20 mmol) in 100 cm3 of THF. After 2 min, 20 mmol of the bromoacetate
in 20 cm3 of THF were added dropwise. Stirring was continued for 15 min at ꢁ78ꢂC, then the mixture
was warmed to room temperature, and hydrolyzed with a satd. solution of NaCl (100cm3). The organic
layer was dried(Na2SO4), and evaporatedinvacuo. The residuewas dissolvedin200 cm3 ofdiethyl ether,
it was washed with 3ꢃ100 cm3 of H2O, dried (Na2SO4), and the solvent was evaporated.

Substituted 1,2-Thiazetidine 1,1-Dioxides
61
tert-Butyl (RS)-3-(Benzyloxycarbonylmethyl)-1,2-thiazetidine-2-acetate
1,1-Dioxide (2a)
See Ref. [7a].
Methyl (RS)-3-(Benzyloxycarbonylmethyl)-1,2-thiazetidine-2-acetate
1,1-Dioxide (2b, C14H17NO6S)
From 3.06g (20 mmol) of methyl bromoacetate. Purification by CC (CHCl3:AcOEt¼ 9:1). Yield 2.9 g
(87%); colourless viscous liquid; IR (Film): ꢁꢀ¼ 3030, 2960 (CH), 1495, 750 (ar), 1735 (CO), 1325,
1
1150 (SO2) cmꢁ1; H NMR: ꢂ ¼ 2.85 (m, 5-H, 5-H0), 3.83 (s, NCH2), 3.88 (m, 3-H), 3.90 (m, 4-H),
4.35 (dd, J ¼ 15, 9 Hz, 4-H0), 5.05 (s, CH2), 7.25 (s, 5arom H) ppm.
General Procedure for the Hydrogenolysis of the Benzyl Ester
The benzyl ester (5mmol) was dissolved in 50cm3 of THF, 0.3 g of Pd-C (10%) were added, and the
mixture was hydrogenated (1atm) at room temperature until the ester was completely converted (TLC
control, ꢄ2 h). The catalyst was filtered off, the solvent was removed in vacuo, and the residue was
dried for 1 h at 0.3 Torr.
General Procedure for the Reaction with Amino Acid or Dipeptide Ester
The residue of the hydrogenolysis or 5 mmol of the isolated acid 3 was dissolved in 50 cm3 of CH2Cl2,
1.16g of NHS (10 mmol), a suspension of 8 mmol of the ester salt, and 0.8mmol of TEA in 20cm3 of
CH2Cl2 were added. The mixture was cooled to ꢁ10ꢂC, and 10mmol of DCC in CH2Cl2 were added.
After 3 h at ꢁ10ꢂC and 12 h stirring at room temperature, the mixture was filtered, and the solvent was
evaporated in vacuo.
N-{2-[(RS)-2-(Methoxycarbonylmethyl)-1,1-dioxo-1,2-thiazetidine-3-yl]acetyl}glycine
Benzyl Ester (4a, C16H20N2O7S)
From 2b (0.83 g, 2.5 mmol), Gly-OBn-tosylate (1.35 g, 0.4 mmol), NHS (0.58 g, 5 mmol), TEA (0.4g,
0.4 mmol), and DCC (0.65 g, 3.3mmol). Purification by CC (AcOEt). Yield 750 mg (78%); viscous
liquid; IR (Film): ꢁꢀ¼ 3380 (NH), 3020, 2950 (CH), 1740, 1660 (CO), 1540 (Amide), 1320, 1150
(SO2) cmꢁ1; 1H NMR: ꢂ ¼ 2.80 (d, J ¼ 7 Hz, 5-H, 5-H0), 3.73 (s, OCH3), 4.00 (s, 2H, 1-H0), 4.08 (s, 2ꢃ-
H), 3.80–4.23 (m, 4-H, 4-H0, 3-H), 5.15 (s, CH2), 6.93 (m, NH), 7.24 (s, 5arom H) ppm.
N-{2-[(RS)-2-(tert-Butoxycarbonylmethyl)-1,1-dioxo-1,2-thiazetidine-3-yl]acetyl}-glycine
Methyl Ester (4b, C13H22N2O7S)
From 2a (1.85 g, 5 mmol), NHS (1.16 g, 10mmol), Gly-OMe-HCl (1.06 g, 10 mmol), TEA (1.0g,
10mmol), and DCC (1.3 g, 6.6mmol). Purification by CC (AcOEt). Yield 1.35g (77%); colourless
solid; mp 105ꢂC (diethyl ether); IR: ꢁꢀ¼ 3330 (NH), 3080, 3040, 2980, 2930, 2850 (CH), 1760, 1745,
1
1675 (CO), 1550 (Amide), 1320, 1165, 1150 (SO2) cmꢁ1; H NMR: ꢂ ¼ 1.48 [s, C(CH3)3], 2.80 (dd,
J ¼ 6, 15.8Hz, 5-H), 2.90 (dd, J ¼ 7.5, 15.8Hz, 5-H0), 3.72 (s, OCH3), 3.88 (AB, J ¼ 18Hz, 2H, 1-H0),
3.95, 4.05 (d, J ¼ 6 Hz, 2ꢃ-H), 4.15 (dd, J ¼ 6, 12.7Hz, 4-H), 4.35 (dd, J ¼ 8.25, 12.7 Hz, 4-H0), 7.25,
7.35 (d, J ¼ 6 Hz, NH) ppm.
(RS)-5-Aza-2-[(tert-butoxycarbonylmethyl)amino]-4,7-dioxo-
7-methoxyheptane-1-sulfonic Acid (C13H24N2O8S, Product of Hydrolysis)
Colorless solid; mp 141ꢂC (dec); IR: ꢁꢀ¼ 1741, 1673 (CO), 1558 (Amide), 1230, 1158, 1033 (SO3H)
cmꢁ1; 1H NMR (DMSO-d6): ꢂ ¼ 1.47 [s, C(CH3)3], 2.74 (d, J ¼ 6 Hz, 2H, 3-H), 2.89 (d, J ¼ 6 Hz, 2H,

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1-H), 3.62 (s, OCH3), 3.87 (d, J ¼ 6 Hz, 2H, 2-H0), 3.95 (d, J ¼ 6 Hz, 2H, 6-H), 3.87 (m, 2-H), 8.60
(t, J ¼ 6 Hz, NH), 9.08 (s, NH2þ) ppm.
N-{2-[(RS)-2-(tert-Butoxycarbonylmethyl)-1,1-dioxo-1,2-thiazetidine-3-yl]acetyl}-L-
phenylalanine Methyl Ester (4c, C20H28N2O7S)
From 2a (0.7g, 2 mmol), L-Phe-OMe-HCl (0.8g, 0.4 mmol), NHS (0.58 g, 5 mmol), TEA (0.8g,
4 mmol), and DCC (0.5g). Purification by CC (AcOEt:CHCl3 ¼ 1:1). Yield 630 mg (72%); viscous
liquid; IR (Film): ꢁꢀ¼ 3360 (NH), 3030, 2980, 2940, 2860 (CH), 1745, 1670 (CO), 1535 (Amide),
1330, 1150 (SO2) cmꢁ1; 1H NMR: ꢂ ¼ 1.40 [s, C(CH3)3], 2.68 (d, J ¼ 7 Hz, 2H, 5-H), 3.08 (m, 2ꢀ-H),
3.68 (s, OCH3), 3.80 (s, 2H, 1-H0), 4.79 (m, ꢃ-H), 3.90–4.40 (m, 4-H, 4-H0, 3-H), 6.65 (d, J ¼ 9 Hz,
25
NH), 7.23 (m, 5arom H) ppm; ½ꢃꢅD ¼ þ27 ꢆ 10ꢁ10 cm2 gꢁ1 (c ¼ 1, CHCl3).
N-{2-[(RS)-2-(Methoxycarbonylmethyl)-1,1-dioxo-1,2-thiazetidine-3-yl]acetyl}-L-
phenylalanine Methyl Ester (4d, C17H22N2O7S)
From 2b (1.6g, 5 mmol), L-Phe-OMe-HCl (1.6g, 0.8 mmol), TEA (0.8g, 0.8 mmol), and DCC (1.3g).
Purification by CC (AcOEt:CHCl3 ¼ 1:1). Yield 1.45g (73%); colourless solid; mp 74ꢂC (n-hexane=
CHCl3); IR: ꢁꢀ¼ 3320 (NH), 3050, 3030, 2950, 2930, 2850 (CH), 1740, 1640 (CO), 1530 (Amide),
13150, 1150 (SO2) cmꢁ1; 1H NMR: ꢂ ¼ 2.70 (d, J ¼ 7 Hz, 2H, 5-H), 3.08 (m, 2ꢀ-H), 3.68 (s, 2OCH3),
3.80 (s, 2H, 1-H0), 4.73 (m, ꢃ-H), 3.90–4.40 (m, 4-H, 4-H0, 3-H), 6.60 (s, NH), 7.25 (m, 5arom H)
25
ppm; ½ꢃꢅD ¼ þ25 ꢆ 10ꢁ10 cm2 gꢁ1 (c ¼ 1.1, CHCl3).
N-{2-[(RS)-2-(tert-Butoxycarbonylmethyl)-1,1-dioxo-1,2-thiazetidine-3-yl]acetyl}-
L-nitroarginine Methyl Ester (4e, C17H30N6O9S)
From 3a (0.88 g, 3.2 mmol), nitro-Arg-OMe-HCl (1.35 g, 5 mmol), NHS (0.72 g, 6.3 mmol), TEA
(0.75 ml, 5 mmol), and DCC (0.71 g, 3.5 mmol). Purification by CC (AcOEt:EtOH ¼ 5:1). Rf ¼ 0.43;
20
yield 0.8 g (51%); mp 91ꢂC (dec); ½ꢃꢅD ¼ ꢁ5:04 ꢆ 10ꢁ10 cm2 gꢁ1 (c ¼ 0.83, MeOH); IR: ꢁꢀ¼ 3328
(NH), 2928, 2851 (CH), 1738, 1624 (CO), 1534 (NO2), 1320, 1156 (SO2) cmꢁ1; 1H NMR (300 MHz,
2D-COSY, CD3OD, 27ꢂC): ꢂ ¼ 1.42 [s, C(CH3)3], 2.79 (2dd, J ¼ 15.4, 6.4 Hz, 5-H, 5-H0), 3.28 [m, 2ꢂ-
H(Arg)], 3.73, 3.74 (2s, CH3O), 3.76 (dd, J ¼ 17.8, 3.4 Hz, CHN), 3.91 (dd, J ¼ 17.8, 5.6 Hz, CNH0),
ꢀ
3.85 (m, 3-H), 4.07 (ddd, J ¼ 13.9, 5.8, 2.4 Hz, 4-H), 4.39 (ddd, J ¼ 13.9, 8.3, 1.0 Hz, 4-H0), 4.41 [m,
ꢃ-H(Arg)] ppm; MS (Fab 26 kV 3): m/z ¼ 541 [MþNa]þ , 517 [Mþ1]þ , 394 [MꢁBoc]þ , 154
þ
þ
ꢀ
[p-O2N-Ph-CH2OH] , 136 [O¼ C-CH2-Ph] . Ratio of diastereomers ¼ 1:1 (from NMR).
N-{2-[(RS)-2-(tert-Butoxycarbonylmethyl)-1,1-dioxo-1,2-thiazetidine-3-yl]acetyl}-L-
nitroarginylglycine Methyl Ester (5a, C19H33N7O10S)
Compound 3a (1.5g, 5.4 mmol), and 1.2g of NHS (10.8 mmol) were dissolved in 100cm3 of dioxane,
a solution of 3.0g of nitro-Arg-Gly-OMe-HCl (6mmol) and 0.8 cm3 of TEA (6 mmol) in 200cm3 of
dioxane was added, and the mixture was cooled to ꢁ10ꢂC. Then, DCC (1.2g, 6 mmol) dissolved in
20cm3 of dioxane was added, and the mixture was stirred for 12–15h. The mixture was filtered, and
the solvent was evaporated in vacuo. Purification of the residue by CC (AcOEt:EtOH¼ 5:1). Yield
20
350 mg (18%); colourless solid; mp 86ꢂC (dec); ½ꢃꢅD ¼ ꢁ5:83 ꢆ 10ꢁ10 cm2 gꢁ1 (c ¼ 0.6, MeOH); IR:
ꢁꢀ ¼ 3364 (NH), 2980, 2951 (CH), 1739, 1654 (CO), 1536 (NO2), 1320, 1300, 1264, 1154 (SO2)
1
cmꢁ1; H NMR (300 MHz, 2D-COSY, CD3OD, 27ꢂC): ꢂ ¼ 1.45 [s, C(CH3)3], 1.72–1.91 [m, 2ꢀ-
ꢀ
H(Arg), 2ꢄ-H(Arg)], 2.77 (2dd, J ¼ 17.0, 5.3Hz, 5-H, 5-H0), 3.23 [m, 2ꢂ-H(Arg)], 3.71, 3,72 (2s,
CH3O), 3.76 (dd, J ¼ 17.6, 2.4 Hz, CHN), 3.91 (m, CH0N), 3.83 (m, 3-H), 4.02 [m, 2ꢃ-H(Gly)], 4.19
(dd, J ¼ 12.9, 5.9 Hz, 4-H), 4.39 (dd, J ¼ 12.9, 8.3 Hz, 4-H0), 4.43 [m, ꢃ-H(Arg)] ppm; MS (FAB 26kV

Substituted 1,2-Thiazetidine 1,1-Dioxides
63
3): m=z ¼ 574 [MþNa]þ , 552 [M]þ , 496 [Mþ-NO2], 153 [p-O2N-Ph-CH2OH]þ , 150 [p-O2N-Ph-
C¼O]þ , 136 [O¼C-CH2-Ph]þ , 107 [PhCH2O]þ ; HPLC: t1 ¼ 14.00, t2 ¼ 15.15 min, ChiraSpher NT,
n-hexane:EtOH¼ 1:1.
N-{2-[(RS)-2-(tert-Butoxycarbonylmethyl)-1,1-dioxo-1,2-thiazetidine-3-yl]acetyl}-L-
nitroarginyl-phenylalanine Methyl Ester (5b, C26H39N7O10S)
From 3a (1.3g, 4.5mmol), NHS (1.0g, 9.0 mmol), nitro-Arg-Phe-OMe-HCl (2.2g, 5.2 mmol), TEA
(0.8ml, 5.2mmol), and DCC (1.2g, 6 mmol) as described for 5a. Yield 150 mg (5.2%); mp 80ꢂC (dec);
20
½ꢃꢅD ¼ ꢁ5:19 ꢆ 10ꢁ10 cm2 gꢁ1 (c ¼ 0.27, EtOH); IR: ꢁꢀ ¼ 3318 (NH), 2934 (CH), 1740, 1657 (CO),
1
1535 (NO2), 1321, 1290, 1264, 1153 (SO2) cmꢁ1; H NMR (300 MHz, CD3OD, 27ꢂC): ꢂ ¼ 1.42
[s, C(CH3)3], 1.62–1.95 [m, 2ꢀ-H(Arg), 2ꢄ-H(Arg)], 2.73 (m, 5-H, 5-H0), 2.86 (2dd, J ¼ 15.0,
ꢀ
8.8 Hz, CH-Ph), 3.14–3.25 [m, 2ꢂ-H(Arg), CH0-Ph], 3.71, 3.73 (2s, CH3O), 3.74–3.96 (m, CH2N,
3-H), 4.09 (m, 4-H), 4.29–4.39 [m, ꢃ-H(Arg)], 4.71 [m, ꢃ-H(Phe)], 7.24 (m, 5arom H) ppm; MS (FAB
26kV 3): m=z ¼ 688 [Mþ2Na]þ , 642 [M]þ , 597 [M-NO2þ1]þ , 586 [M-Bocþ1]þ , 153 [p-O2N-Ph-
CH2OH]þ , 150 [p-O2N-Ph-C¼ O]þ , 136 [O¼C-CH2-Ph]þ , 107 [PhCH2O]þ .
(RS)-5,8-Diaza-2-[(tert-butoxycarbonylmethyl)amino]-4,7,10-trioxo-6-
[3-(nitroguanidyl)propyl]-10-methoxydecane-1-sulfonic Acid (6, C19H35N7O11S)
From 5a (50 mg, 0.09 mmol) by hydrolysis. Yield 30mg (58%); colourless solid; mp 112–114ꢂC (dec);
27
½ꢃꢅD ¼ ꢁ21:5 ꢆ 10ꢁ10 cm2 gꢁ1 (c ¼ 0.55, 1 N HCl); IR: ꢁꢀ ¼ 3371 (NH), 2985, 2950 (CH), 1738, 1638
1
(CO), 1544 (NO2), 1256, 1220, 1154, 1038 ðSOꢁ3 Þ cmꢁ1; H NMR (300MHz, DMSO-d6, 50ꢂC):
ꢂ ¼ 1.46 [s, C(CH3)3], 1.55 [m, 2ꢄ-H(Arg)], 1.72 [m, 2ꢀ-H(Arg)], 2.76 (dd, J ¼ 5.9, 17.3Hz, 3-H),
2.79 (dd, J ¼ 5.9, 17.3Hz, 3-H), 2.88 (dd, J ¼ 4.7, 14.0Hz, 1-H), 2.93 (dd, J ¼ 7.0, 14.0 Hz, 1-H), 3.15
[m, 2ꢂ-H(Arg)], 3.62 (s, CH3O), 3.74–3.84 (m, NCH2, 2-H), 3.90 [dd, J ¼ 8.8, 16.9Hz, ꢃ-H(Gly)],
3.99 [dd, J ¼ 7.1, 16.9Hz, ꢃ-H0(Gly)], 4.27 [m, ꢃ-H(Arg)], 7.81 (s, NH2), 8.34 (m, 3NH), 9.00 (s,
SO3H) ppm; MS FAB-Gun (Xe, 8 kV, 1 mA), 3 kV: m=z ¼ 570 [M]þ , 154 [p-O2N-Ph-CH2OHþ1]þ ,
150 [p-O2N-Ph-C¼O]þ , 136 [O¼C-CH2-Ph]þ , 107 [PhCH2O]þ .
General Procedure for the Acylation of 1 with Acyl Chlorides
At ꢁ78ꢂC and under a N2 atmosphere, 3.9 mmol of BuLi were added to a solution of 1.0 g of 1
(3.9mmol) in 50 cm3 of THF. After 5 min stirring 3.9 mmol of the acyl chloride in 10cm3 of THF were
added dropwise. Stirring was continued for 15min at ꢁ78ꢂC, and after warming to room temperature,
the mixture was hydrolyzed with a satd. solution of NaCl (100cm3), the organic layer was dried
(Na2SO4), and the solvent was evaporated in vacuo.
Benzyl (RS)-(2-Acetyl-1,2-thiazetidine-3-yl)acetate 1,1-Dioxide (7a, C13H15NO5S)
From 1 (1.0g, 3.9 mmol), BuLi (3.9mmol), and acetyl chloride (3.5g, 3.9mmol). Yield 0.81g (70%);
colourless solid; mp 51ꢂC; IR (Film): ꢁꢀ ¼ 3040, 2970 (CH), 1735, 1690 (CO), 1310, 1340, 1160 (SO2)
1
cmꢁ1; H NMR: ꢂ ¼ 2.25 (s, CH3), 2.71 (dd, 2H, 5-H), 4.26 (m, 3-H), 4.06 (dd, J ¼ 13, 3 Hz, 4-H),
4.42 (dd, J ¼ 13, 9 Hz, 4-H0), 5.14 (s, CH2), 7.34 (s, 5arom H) ppm.
(RS)-2-Amino-4-oxo-4-benzyloxybutane-1-sulfonic Acid
(C11H15NO5S, Product of Hydrolysis)
1
Colourless solid; mp 145ꢂC (dec); IR: ꢁꢀ ¼ 1732 (CO), 1236, 1041 (SO3H) cmꢁ1; H NMR (DMSO-
d6): ꢂ ¼ 2.72 (dd, J ¼ 3.8, 11 Hz, 3-H), 2.76 (dd, J ¼ 2.3, 11 Hz, 3-H0), 2.85 (dd, J ¼ 4.5, 15.8Hz, 1-H),
2.94 (dd, J ¼ 6, 15.8Hz, 1-H0), 3.75 (m, 2-H), 5.13 (s, CH2), 7.37 (s, 5arom H), 7.92 (s, NHþ3 ) ppm.

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Benzyl (RS)-(2-Chloroacetyl-1,2-thiazetidine-3-yl)acetate 1,1-Dioxide (7b, C13H14ClNO5S)
From 1 (1.0g, 3.9 mmol), BuLi (3.9mmol), and chloroacetyl chloride (0.44 g, 3.9 mmol). Yield 0.74g
(57%); viscous liquid; IR (Film): ꢁꢀ ¼ 3040, 2960, 2940, 2870 (CH), 1740 (CO), 1360, 1170, 1190
1
(SO2) cmꢁ1; H NMR: ꢂ ¼ 2.63 (dd, J ¼ 10, 17Hz, 5-H), 3.38 (dd, J ¼ 5, 17Hz, 5-H0), 4.01 (dd,
J ¼ 13, 3 Hz, 4-H), 4.03 (m, 3-H), 4.19 (s, CH2Cl), 4.52 (dd, J ¼ 13, 9 Hz, 4-H0), 5.11 (s, CH2), 7.30 (s,
5arom H) ppm; MS (70 eV): m=z (%) ¼ 270 (2.43) [M-SO2], 242 (16.09) [M-Benzyl], 65 (9.75)
½SO2þꢅ, 77 (22.92) [COCH2Cl], 91 (100) [Benzyl].
Benzyl (RS)-(2-Iodoacetyl-1,2-thiazetidine-3-yl)acetate 1,1-Dioxide (8, C13H14INO5S)
Compound 7b (0.7g, 2.1 mmol), and 0.639 of NaI (4.2mmol) in 30cm3 of acetone were refluxed for
2 h. After cooling to room temperature, the mixture was filtered, and the solvent was evaporated in
vacuo. Purification by CC (AcOEt). Yield 0.5 g (56%); yellow viscous liquid; IR (Film): ꢁꢀ¼ 3040,
2960, 2870 (CH), 1740, 1700 (CO), 1350, 1165 (SO2) cmꢁ1; 1H NMR: ꢂ ¼ 2.55 (dd, J ¼ 9, 17Hz, 5-
H), 3.28 (dd, J ¼ 4, 17Hz, 5-H0), 3.78 (s, CH2I), 4.08 (m, 3-H), 4.10 (dd, J ¼ 4, 13Hz, 4-H), 4.45 (dd,
J ¼ 13, 9 Hz, 4-H0), 5.05 (s, CH2), 7.20 (s, 5arom H) ppm; MS (70 eV): m=z (%) ¼ 423 (4.24) [Mþ ],
254 (3.12) [M-Iodoacetyl], 91 (100) [Benzyl], 107 (37.22) [O-Benzyl], 127 (5.26) [Iodine], 169 (1.21)
[Iodoacetyl], 254 (3.12) [PS-58-H].
General Procedure for the Acylation of ß-Sultams with Boc-=Z-L-Amino
Acid N-Carboxyanhydrides (NCA) or Amino Acid Fluorides
At ꢁ78ꢂC and under a N2 atmosphere, 3.9mmol of BuLi were added with stirring to a solution of 1.0 g
of 1 (3.9mmol) in 50cm3 of THF, and after 3 min 3.9 mmol of the acylation reagent in 10cm3 of THF
were dropwise added. Stirring was continued for 15 min at ꢁ78ꢂC, then the mixture was warmed to
room temperature, and hydrolyzed with a satd. solution of NaCl. The aqueous layer was twice
extracted with AcOEt, the combined organic layers were dried (Na2SO4), and the solvent was evapo-
rated in vacuo. Purification by CC (cyclohexane:AcOEt¼ 1:1), if not noted otherwise.
Benzyl (RS)-2-(Phthaloylglycyl)-1,2-thiazetidine-3-acetate 1,1-Dioxide (9, C21H18N2O7S)
From 1 and phthalylglycyl chloride (0.87 g, 3.9 mmol). Yield 750mg (44%); colourless crystals; mp
125ꢂC (MeOH); IR: ꢁꢀ¼ 3040, 2980, 2930 (CH), 1774, 1725 (CO), 1365, 1345, 1300, 1163 (SO2)
1
cmꢁ1; H NMR: ꢂ ¼ 2.74 (dd, J ¼ 10, 17 Hz, 5-H), 3.35 (dd, J ¼ 3.5, 17Hz, 5-H0), 4.05 (dd, J ¼ 4,
13Hz, 4-H), 4.34–4.43 (m, 3-H), 4.50 (dd, J ¼ 8, 13Hz, 4-H0), 4.59, 4.60 [s, 2ꢃ-H(Gly)], 5.06
(s, CH2), 7.28 (s, 5arom H), 7.82=7.83, 7.68=7.69 (AB, J ¼ 5.5 Hz, 4arom H) ppm; MS (70 eV):
m=z (%) ¼ 442 (0.49) [Mþ þ1], 255 (0.82) [PS-58], 160 (78.42) [Phthalimide].
Benzyl (RS)-4-(Hydrazinosulfonyl)-3-[2-(phthalimido)acetylamino]butanoate
(10, C21H22N4O7S)
2.5 cm3 of a 1 M solution of hydrazine acetate in MeOH were added with stirring to a suspension of
1.0 g of 9 (2.26 mmol) in 25 cm3 of MeOH. After 1 h of stirring, the precipitate was separated. Yield
0.9 g (84%); mp 132ꢂC (CHCl3); IR: ꢁꢀ¼ 3070, 3040, 2980, 2930 (CH), 1777, 1725, 1677 (CO), 1371,
1346, 1321, 1172 (SO2) cmꢁ1; 1H NMR: ꢂ ¼ 2.86 (dd, J ¼ 5, 10.5Hz, 2-H), 3.08 (dd, J ¼ 4.5, 10.5Hz,
2-H0), 3.50 (dd, J ¼ 5.5, 15Hz, 4-H), 3.70 (dd, J ¼ 7, 15 Hz, 4-H0), 3.80 (m, NH), 3.80 (s, NH2), 4.30
(s, 2ꢃ-H), 4.65 (m, 3-H), 5.13 (s, CH2), 6.83, 7.08 (d, J ¼ 9 Hz, NH), 7.33 (s, 5arom H), 7.80
(m, 4arom H) ppm; MS (70 eV): m=z (%) ¼ 474 (0.24) [Mþ þ1], 160, 161 (100) ½C9H6NO2þꢅ, 91
(100) [C7H7], 77 (100) [C6H5], 104 (100) [C8H8].

Substituted 1,2-Thiazetidine 1,1-Dioxides
65
Benzyl (RS)-4-(Benzylaminosulfonyl)-3-[2-(benzylamino)acetylamino]butanoate
(11, C27H31N3O5S)
A mixture of 0.5g of 8 (1.2mmol) and 2 cm3 of freshly distilled benzylamine was stirred at room
temperature for 30min. Purification by CC (CH2Cl2:AcOEt¼ 8:2). Yield 350 mg (57%); colourless
solid; mp 87ꢂC (CH2Cl2=diethyl ether); IR (Film): ꢁꢀ¼ 3150–2850 (CH), 1735, 1650 (CO), 1320, 1140
(SO2) cmꢁ1; 1H NMR: ꢂ ¼ 1.83 (s, NH), 2.50 (dd, J ¼ 6, 17.5Hz, 2-H), 2.55 (dd, J ¼ 6, 17.5 Hz, 2-H0),
2.98 (dd, J ¼ 4.5, 15 Hz, 4-H), 3.20 (AB, J ¼ 17.3Hz, 2ꢃ-H), 3.28 (dd, J ¼ 9.75, 15Hz, 4-H0), 3.69
(AB, J ¼ 13 Hz, CH2), 4.23 (s, CH2), 4.55 (m, 3-H), 5.10 (s, CH2), 5.90 (t, J ¼ 4.5 Hz, NH), 7.28 (s,
15arom H), 7.98 (d, J ¼ 13 Hz, NH) ppm; MS (70 eV): m=z (%) ¼ 601 (0.69) [Mþþ1], 235 (1.41)
[Mꢁ 3Benzyl], 106 (77.7) [C7H8N], 91 (100) [C7H7], 77 (13.51) [C6H5], 65 (30.99) [C5H5].
Benzyl (RS)-2-(Z-L-Prolyl)-1,2-thiazetidine-3-acetate 1,1-Dioxide (12a, C24H26N2O7S)
From 1 (0.77 g, 3 mmol), and Z-L-Pro-F (3mmol). CC (n-hexane:AcOEt ¼ 1:1). Yield 0.4 g (27%);
viscous liquid; IR (Film): ꢁꢀ¼ 3060, 3030, 2960, 2880 (CH), 1710 (CO), 1352, 1166 (SO2) cmꢁ1; 1H
NMR: ꢂ ¼ 1.79–2.06 (m, ꢀ-H, 2ꢄ-H), 2.30 (m, ꢀ-H), 2.77, 2.81 (dd, J ¼ 10, 17Hz, 5-H), 3.03, 3.12
(dd, J ¼ 3.5, 17Hz, 5-H0), 3.59 (m, 2ꢂ-H), 3.82, 3.87 (dd, J ¼ 4.5, 13Hz, 4-H), 4.22–4.36 (m, 3-H),
4.22, 4.36 (dd, J ¼ 7, 13Hz, 4-H0), 4.40–4.53 (m, ꢃ-H), 4.95–5.20 (m, 2CH2), 7.33 (s, 10arom H)
23
ppm; ½ꢃꢅD ¼ ꢁ20.3ꢆ 10ꢁ 10 cm2 gꢁ1 (c ¼ 1, AcOEt:CHCl3 ¼ 1:1); MS (70 eV): m=z (%) ¼ 486 (5.04)
[Mþ], 351 (44.27) [M–Z], 205=204 (100) [C12H14NO3þ], 91=92 (100) [C7H7þ], 70 (100) [C4H8Nþ],
65 (100) [SO2H].
Benzyl (RS)-2-(Boc-L-Prolyl)-1,2-thiazetidine-3-acetate 1,1-Dioxide (12b, C21H28N2O7S)
From 1 (0.94 g, 3.69mmol), and Boc-L-Pro-F (0.8g, 3.7 mmol). CC (diethyl ether). Yield 1.15g
(66%); light yellow viscous liquid; IR: ꢁꢀ¼ 3030, 2980, 2930, 2880 (CH), 1705, 1695 (CO), 1351,
1
1163 (SO2) cmꢁ1; H NMR: ꢂ ¼ 1.39, 1.42 [s, C(CH3)3], 1.73–2.08 (m, ꢀ-H, 2ꢄ-H), 2.26 (m, ꢀ-H),
2.66, 2.70 (dd, J ¼ 9, 17Hz, 5-H), 3.34, 3.36 (dd, J ¼ 4, 17Hz, 5-H0), 3.50 (m, 2ꢂ-H), 3.99, 3.95 (dd,
J ¼ 4, 16Hz, 4-H), 4.38 (m, ꢃ-H, 3-H), 4.33, 4.43 (dd, J ¼ 9, 16 Hz, 4-H0), 5.10, 5.11 (m, CH2), 7.31,
23
7.32 (s, 5arom H) ppm; ½ꢃꢅD ¼ ꢁ38.43 ꢆ 10ꢁ 10 cm2 gꢁ1 (c ¼ 2.61, CHCl3); MS (70 eV): m=z
(%) ¼ 453 (1.73) [Mþ], 523 (2.88) [MþC4H8Nþ], 361 (1.2) [M–Benzyl], 170 (66.79) [Boc-Pro], 91
(70.58) [C7H7þ], 70 (100) [C4H8Nþ].
(RS)-2-(Boc-L-Prolyl)-1,2-thiazetidine-3-acetic Acid 1,1-Dioxide (13, C14H22N2O7S)
From 12a (0.7g, 1.5 mmol) according to the general procedure. Purification by CC (diethyl ether).
Yield 350 mg (65%); viscous liquid; IR (Film): ꢁꢀ¼ 2980, 2930 (CH), 1707 (CO), 1367, 1352, 1164
1
(SO2) cmꢁ1; H NMR: ꢂ ¼ 1.38, 1.41 [s, C(CH3)3], 1.83–2.18 (m, ꢀ-H, 2ꢄ-H), 2.34 (m, ꢀ-H), 2.68,
2.72 (dd, J ¼ 9, 17Hz, 5-H), 3.41, 3.43 (dd, J ¼ 4, 17Hz, 5-H0), 3.50 (m, 2ꢂ-H), 4.03, 4.07 (dd, J ¼ 4,
17Hz, 4-H), 4.44 (m, ꢃ-H, 3-H), 4.39, 4.55 (dd, J ¼ 9, 16Hz, 4-H0), 8.77 (s, OH) ppm;
23
½ꢃꢅD ¼ ꢁ60.0ꢆ 10ꢁ 10 cm2 gꢁ1 (c ¼ 2.61, CHCl3); MS (70 eV): m=z (%) ¼ 363 (3.91) [Mþþ1], 432
(0.67) [MþC4H8Nþ], 292 (2.01) [M–C4H8Nþ], 170 (48.59) [Boc-Pro], 70 (100) [C4H8Nþ].
Benzyl (RS)-2-(Boc-Glycyl)-1,2-thiazetidine-3-acetate 1,1-Dioxide (14a, C18H24N2O7S)
From 1 (1.0g, 3.9 mmol, BuLi (3.9mmol), and Boc-Gly-NCA (0.78 g, 3.9 mmol). Yield 1.0g (62%);
colourless solid; mp 102ꢂC (EtOH); IR: ꢁꢀ¼ 3324 (NH), 3070, 3040, 2980, 2940 (CH), 1708, 1683
1
(CO), 1367, 1335, 1161 (SO2) cmꢁ1; H NMR: ꢂ ¼ 1.40 [s, C(CH3)3], 2.71 (dd, J ¼ 9, 17Hz, 5-H),

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3.38 (dd, J ¼ 4.5, 17 Hz, 5-H0), 4.03 [d, J ¼ 7 Hz, 2ꢃ-H(Gly)], 4.03 (m, 4-H), 4.38 (m, 3-H), 4.46 (dd,
J ¼ 9, 15Hz, 4-H0), 5.10 (s, CH2), 5.10 (s, NH), 7.30 (s, 5arom H) ppm.
Benzyl (RS)-2-(Boc-L-Alanyl)-1,2-thiazetidine-3-acetate 1,1-Dioxide (14b, C19H26N2O7S)
From 1 (1.0g, 3.9 mmol), BuLi (3.9mmol), and Boc-L-Ala-NCA (0.84 g, 3.9 mmol). Yield 1.1 g (65%);
viscous liquid; IR (Film): ꢁꢀ¼ 3370 (NH), 3040, 2980, 2940, 2880 (CH), 1708 (CO), 1367, 1351, 1165
(SO2) cmꢁ1; 1H NMR: ꢂ ¼ 1.43 [m, C(CH3)3, ꢀ-H(Ala)], 2.74, 2.88 (dd, J ¼ 9, 16 Hz, 5-H), 3.34, 3.44
(dd, J ¼ 4, 16Hz, 5-H0), 4.00 (dd, J ¼ 4, 12.5 Hz, 4-H), 4.41 (m, ꢃ-H, 4-H0, 3-H), 5.13 (s, CH2), 5.27,
23
5.22 (d, J ¼ 7 Hz, NH), 7.41 (s, 5arom H) ppm; ½ꢃꢅD ¼ þ2.08ꢆ 10ꢁ10 cm2 gꢁ1 (c ¼ 1.5, CHCl3); MS
(70 eV): m=z (%) ¼ 427 (0.52) [Mþþ1], 371 (5.45) [M-C4H9þ], 327 (8.52) [M-Boc], 167 (1.67) [Boc-
Ala], 91 (68.39) [C7H7], 44 (100).
Benzyl (RS)-2-(Z-L-Alanyl)-1,2-thiazetidine-3-acetate 1,1-Dioxide (14c, C22H24N2O7S)
From 1 (1.0g, 3.9mmol), BuLi (3.9 mmol), and Z-L-Ala-NCA (0.97 g, 3.9 mmol). Yield 750 mg (43%);
1H NMR: ꢂ ¼ 1.43
colourless solid; mp 84ꢂC; IR: ꢁꢀ¼ 1720 (CO), 1355, 1155 (SO2) cmꢁ1
;
(d, J ¼ 10Hz, CH3), 2.75 (dd, J ¼ 10, 17Hz, 5-H), 3.34, 3.45 (dd, J ¼ 5, 17Hz, 5-H0), 3.98 (m,
4-H), 4.36 (m, ꢃ-H, 3-H), 4.48, 4.35 (dd, J ¼ 7, 15Hz, 4-H0), 5.11 (s, 2CH2), 5.39 (d, J ¼ 7 Hz,
23
NH) 7.33 (s, 10arom H) ppm; ½ꢃꢅD ¼ þ1.3 ꢆ 10ꢁ10 cm2 gꢁ1 (c ¼ 1, CHCl3); MS (70 eV): m=z
(%) ¼ 460 (9.03) [Mþ], 324 (28.33) [M–Z], 91=92 (100) [C7H7], 65 (100) [SO2H].
(RS)-2-[(Z-L-Alanyl)amino]-4-benzyloxy-4-oxobutane-1-sulfonic Acid (C22H26N2O8S,
Product of Hydrolysis)
Colourless solid; mp 117ꢂC (dec); IR: ꢁꢀ¼ 3380 (NH), 3070, 3040, 2970, 2960 (CH), 1731, 1711 (CO),
1530 (Amide), 1332, 1166 (SO3H) cmꢁ1
;
1H NMR: ꢂ ¼ 1.24, 1.26 (d, J ¼ 7.5 Hz, CH3), 2.79
(d, J ¼ 7 Hz, 2H, 3-H), 3.43, 3.38 (dd, J ¼ 7, 10Hz, 2H, 1-H), 4.08 [m, ꢃ-H(Ala)], 4.60 (m, 2-H),
5.06 (s, 2CH2), 5.22 (s, NH, SO3H), 6.91 (d, J ¼ 9 Hz, NH), 7.29 (s, 5arom H) ppm; MS (70 eV): m=z
(%) ¼ 385 (2.10) [Mþþ1–C7H7], 296 (0.26) [Mþꢁ2ꢃC7H7], 179 (39.82), 91 (100) [C7H7]þ.
(RS)-2-(Boc-Glycyl)-1,2-thiazetidine-3-acetic Acid 1,1-Dioxide (15a, C11H18N2O7S)
From 14a (1.4g, 3.5 mmol) by hydrogenolysis according to the general procedure. Yield 700mg
(62%); colourless solid; mp 53ꢂC; IR: ꢁꢀ¼ 3410 (OH), 1719 (CO), 1513 (Amide), 1368, 1350, 1163
(SO2) cmꢁ1; 1H NMR: ꢂ ¼ 1.34 [s, C(CH3)3], 2.71 (dd, J ¼ 10, 19Hz, 5-H), 3.30 (dd, J ¼ 3, 19Hz, 5-
H0), 4.01 [d, J ¼ 7 Hz, 2H, ꢃ-H(Gly)], 4.01 (m, 4-H), 4.48 (m, 3-H), 4.53 (dd, J ¼ 8, 16Hz, 4-H0), 5.28
(s, NH), 8.55 (s, OH) ppm.
(RS)-2-(Boc-L-Alanyl)-1,2-thiazetidine-3-acetic Acid 1,1-Dioxide (15b, C12H20N2O7S)
From 14b (1.5g, 3.5mmol) by hydrogenolysis according to the general procedure. Yield 900 mg
(76%); colourless solid; mp 45ꢂC; IR: ꢁꢀ¼ 3376 (NH), 3050, 2980, 2940, 2880 (CH), 1713 (CO),
1
1509 (Amide), 1394, 1354, 1162 (SO2) cmꢁ1; H NMR: ꢂ ¼ 1.46 [s, C(CH3)3, ꢀ-H(Ala)], 2.63, 2.68
(dd, J ¼ 9, 17Hz, 5-H), 3.30, 3.40 (dd, J ¼ 4, 17Hz, 5-H0), 4.00–4.63 (m, 3-H, 4-H, 4-H0, ꢃ-H), 5.22
23
(m, NH), 7.90 (s, OH) ppm; ½ꢃꢅD ¼ þ11.9ꢆ 10ꢁ 10 cm2 gꢁ1 (c ¼ 1.45, CHCl3).
(RS)-N-[(1,1-Dioxo-1,2-thiazetidine-3-yl)acetyl]glycine Benzyl Ester (16)
See Ref. [3].

Substituted 1,2-Thiazetidine 1,1-Dioxides
67
(RS)-N-{[2-(Boc-L-Alanyl)-1,1-dioxo-1,2-thiazetidine-3-yl]acetyl}glycine Benzyl Ester
(17, C21H29N3O8S)
From 16 (620mg, 2 mmol), BuLi (1.25 cm3, 2 mmol), and Boc-Ala-NCA (0.43 g, 2 mmol). Yield
800 mg (83%); colourless solid; mp 45ꢂC; IR: ꢁꢀ¼ 3377 (NH), 3040, 2980, 2960 (CH), 1750, 1711
1
(CO), 1520 (Amide), 1353, 1163 (SO2) cmꢁ1; H NMR: ꢂ ¼ 1.39 [s, C(CH3)3, ꢀ-H(Ala)], 2.62 (dd,
J ¼ 9, 16Hz, 5-H), 2.75 (dd, J ¼ 6, 16 Hz, 5-H), 3.12, 3.19 (d, J ¼ 16Hz, 5-H0), 3.96, 4.05 [dd, J ¼ 6,
18Hz, 2ꢃ-H(Gly)], 4.18 (dd, J ¼ 6, 13.5Hz, 4-H), 4.20 (m, 3-H), 4.35 (dd, J ¼ 9, 13.5Hz, 4-H0), 4.38
[m, ꢃ-H(Ala)], 5.11 (s, CH2), 5.35, 5.23 (d, J ¼ 6 Hz, NH), 6.98 [s, NH(Boc)], 7.31 (s, 5arom H) ppm;
23
½ꢃꢅD ¼ þ7.74ꢆ 10ꢁ10 cm2 gꢁ1 (c ¼ 1, CHCl3).
(RS)-N-{[2-(Boc-L-Alanyl)-1,1-dioxo-1,2-thiazetidine-3-yl]acetyl}glycine
(18, C14H23N3O8S)
From 17 (800 mg, 1.65mmol) by hydrogenolysis according to the general procedure. Yield 630 mg
(97%); colourless solid; mp 79ꢂC; IR: ꢁꢀ¼ 3367 (OH), 3040, 2980, 2940 (CH), 1706 (CO), 1534
1
(Amide), 1349, 1164 (SO2) cmꢁ1; H NMR: ꢂ ¼ 1.38 [s, C(CH3)3, ꢀ-H(Ala)], 2.67 (m, 5-H), 3.21
(m, 5-H0), 3.96 [s, 2ꢃ-H(Gly)], 4.21 (m, 4-H, 3-H), 4.40 [m, 4-H0, ꢃ-H(Ala)], 5.39, 5.47 (s, NH), 7.32
23
[s, NH(Boc)] ppm; ½ꢃꢅD ¼ þ4.2 ꢆ 10ꢁ 10 cm2 gꢁ1 (c ¼ 1,1, CHCl3); MS (70 eV): m=z (%) ¼ 292 (0.23)
[Mþþ1-Boc].
N-[(RS)-(1,1-Dioxo-1,2-thiazetidine-3-yl)acetyl]-L-phenylalanylglycine Methyl Ester (19)
See Ref. [3].
N-{[(RS)-2-(Boc-L-Alanyl)-1,1-dioxo-1,2-thiazetidine-3-yl]acetyl}-L-phenylalanyl-glycine
Methyl Ester (20a, C24H34N4O9S)
From 19 (500 mg, 1.3 mmol), BuLi (0.81 cm3, 1.3 mmol), and Boc-L-Ala-NCA (0.28 g, 1.3 mmol) by
acylation. Yield 650 mg (90%); colourless solid; mp 83ꢂC (CHCl3=CCl4); IR: ꢁꢀ¼ 3309 (NH), 3070,
1
3030, 2980, 2940 (CH), 1750, 1700, 1660 (CO), 1528 (Amide), 1350, 1162 (SO2) cmꢁ1; H NMR:
ꢂ ¼ 1.38 [m, ꢀ-H(Ala)], 1.40 [s, C(CH3)3], 2.47 (dd, J ¼ 9, 15Hz, 5-H), 2.87 (dd, J ¼ 9, 14Hz, ꢀ-H),
3.02 (dd, J ¼ 4.5, 15 Hz, 5-H0), 3.18 (dd, J ¼ 6, 14Hz, ꢀ-H0), 3.69 (s, OCH3), 3.86, 4.10 (dd, J ¼ 4.5,
13.5Hz, 4-H), 3.90 [dd, J ¼ 6, 18Hz, ꢃ-H(Gly)], 3.93 [dd, J ¼ 6, 18Hz, ꢃ-H0 (Gly)], 4.20 (m, 3-H),
4.35 [m, ꢃ-H(Ala)], 4.30, 4.40 (dd, J ¼ 7.5, 13.5Hz, 4-H0), 4.63 [m, ꢃ-H(Phe)], 5.46 (s, NH), 6.86
23
(d, J ¼ 7 Hz, NH), 7.00 (s, NH), 7.25 (m, 5arom H) ppm; ½ꢃꢅD ¼ ꢁ28.6ꢆ 10ꢁ10 cm2 gꢁ1 (c ¼ 1.1,
AcOEt); MS (70 eV): m=z (%) ¼ 492 (21.09) [Mþþ1–SO2], 57 (100) [C4H9þ].
N-{[(RS)-2-(Z-L-Alanyl)-1,1-dioxo-1,2-thiazetidine-3-yl]acetyl}-L-
phenylalanyl-glycine Methyl Ester (20b, C27H32N4O9S)
From 19 (500 mg, 1.3 mmol), BuLi (0.81 cm3, 1.3 mmol), and Z-L-Ala-NCA (0.33 g, 1.3 mmol) by
acylation. Yield 600 mg (78%); colourless solid; mp 105ꢂC (CHCl3=CCl4); IR: ꢁꢀ¼ 3323 (NH), 3060,
1
3030, 2960 (CH), 1700, 1639 (CO), 1534 (Amide), 1351, 1162 (SO2) cmꢁ1; H NMR: ꢂ ¼ 1.42
[d, J ¼ 7.5 Hz, ꢀ-H(Ala)], 2.43 (dd, J ¼ 7.5, 15Hz, 5-H), 3.06 (m, 5-H0), 2.90, 2.96 (d, J ¼ 7 Hz, ꢀ-H),
3.11, 3.18 (d, J ¼ 7 Hz, ꢀ-H0), 3.64 (s, OCH3), 3.82 (m, 3-H), 3.82, 4.03 [dd, J ¼ 6, 18Hz, 2ꢃ-H(Gly)],
4.35 [m, 4-H, 4-H0, ꢃ-H(Ala)], 4.71 [m, ꢃ-H(Phe)], 5.04 (AB, J ¼ 9, 15Hz, CH2), 5.57, 6.90 (d, J ¼ 6 Hz,
23
NH), 6.93 (m, 2NH), 7.17 (m, 5arom H), 7.25 (s, 5arom H) ppm; ½ꢃꢅD ¼ ꢁ28.6ꢆ 10ꢁ10 cm2 gꢁ1 (c ¼ 1.1,
CHCl3).

€
T. Rohrich et al.: Substituted 1,2-Thiazetidine 1,1-Dioxides
68
Acknowledgments
We thank Dr. J. Loose, Department of Pharmaceutical=Medicinal Chemistry (PMC), University of
Greifswald, for the inhibition tests. Furthermore, we wish to thank Degussa AG, for generous support
with chemicals, E. Merck KGaG, Darmstadt, for a general biological screening, for support with
chromatography materials, and the HPLC experiments, and we thank the ‘‘Fonds der Chemischen
Industrie’’ for financial support. B.A.T. thanks the DAAD for a study (Ph.D.) grant.
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