Investigation of synthetic routes towards derivatives of 3-(phenylsulfonimidoyl)propanoic acid

Article abstract of DOI:10.1002/1522-2675(200210)85:10<3272::AID-HLCA3272>3.0.CO;2-P

The synthesis of a range of 3-(phenylsulfonimidoyl)propanoate derivatives is described. A number of strategies for the imination of the key sulfoxide methyl 3-(penylsulfinyl)propanoate are discussed including the use of O-(mesitylsulfonyl)hydroxylamine (M

Full text of DOI:10.1002/1522-2675(200210)85:10<3272::AID-HLCA3272>3.0.CO;2-P

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Helvetica Chimica Acta Vol. 85 (2002)
Investigation of Synthetic Routes towards Derivatives of
3-(Phenylsulfonimidoyl)propanoic Acid
by Heather Tye* and Catharine L. Skinner
School of Chemical Sciences, The University of Birmingham, Edgbaston, Birmingham, B152TT, UK
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
The synthesis of a range of 3-(phenylsulfonimidoyl)propanoate derivatives is described. A number of
strategies for the imination of the key sulfoxide methyl 3-(penylsulfinyl)propanoate are discussed including the
use of O-(mesitylsulfonyl)hydroxylamine (MSH) and iminoiodane reagents (PhÀIˆNÀSO2R). A successful
strategy for the preparation of the target compounds was the use of MSH followed by in situ coupling with a N-
Boc-protected amino acid. The pseudo-dipeptides thus formed exhibited interesting conformational properties
in CDCl3 solution giving evidence of intramolecular H-bonds in all cases, except for the proline derivative.
Introduction. As part of an ongoing programme of research into peptidomimetics
containing sulfonimide1) units for use in protein engineering, we were interested in the
preparation of b-carboxylic sulfonimide derivatives A, which could potentially be
incorporated into normal a-peptide sequences. Since its discovery by Bentley et al. in
1949 [1], the sulfonimide unit has seen little use as an amide replacement in peptide
chemistry. In 1989, Mock et al. employed a sulfonimide-derivatised peptide as a
transition-state-analogue inhibitor for carboxypeptidase A [2]. More recently, Bolm et
al. reported the preparation of a range of pseudopeptides incorporating an a-carboxylic
sulfonimide unit B. They have shown that these novel compounds appear to adopt a
turn conformation in solution and, because of the unusual nature of the sulfonimide
unit, they may exhibit resistance to enzymatic degradation [3]. Our expectation is that
b-carboxylic sulfonimides will also induce a turn when incorporated into short peptide
sequences and may prove useful tools for modifying the stability of turn motifs in
protein architectures (Fig. 1). To this end, we set about the preparation of a range of b-
carboxylic sulfonimide derivatives to be used as building blocks in the synthesis of
pseudopeptides. The results of our preliminary synthetic studies are presented herein.
Fig. 1. H-Bond-turn motif
1
)
Also known as sulfoximide or sulfoximine.

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Results and Discussion. Preparation of Methyl 3-(Phenylsulfonimidoyl)propa-
noate (1; R ˆ Me). Retrosynthetic analysis of sulfonimide 1 can follow a variety of
paths depending on the point in the synthesis when the sulfonimide group is introduced.
Ultimately, it is desirable to achieve an enantioselective synthesis to control the
configuration at the S-atom, however, we thought it expedient to develop a racemic
synthesis first with a view to return to the issue of stereocontrol later in the project.
With this in mind, the simplest synthetic strategy leads back to racemic 3-(phenyl-
sulfinyl)propanoate (2) as a key intermediate (Scheme 1). It was envisaged that
preparation of 2 could be achieved by oxidation of the corresponding sulfide 3, which
results from a conjugate addition of a phenyl thiolate to an acrylate species.
Scheme 1. Retrosynthetic Analysis of Sulfonimide 1
Reaction of PhSNa with methyl acrylate according to the procedure of Ahern et al.
[4] in MeOH resulted in the formation of the desired sulfide 3 in a disappointing yield.
The major product 4 of the reaction was the result of competing addition of MeOH to
the electrophile. Formation of 4 could be avoided by performing the reaction in MeCN
‡
with t-BuOH (1.1 equiv.) acting as a H -source (Scheme 2). By this method, sulfides
3a c could be prepared cleanly, although still in relatively poor yield. Many attempts to
improve the conversion of this reaction were made, but to no avail.
Scheme 2. Synthesis of Sulfides 3a
c

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Oxidation of sulfide 3a could be achieved with either 3-chloroperbenzoic acid (m-
CPBA) in CH2Cl2 or NaIO4 in MeOH/H2O. When m-CPBA was employed, a
significant amount of sulfone was also isolated resulting from overoxidation. The
reaction with IOÀ4 as oxidant proved to be more reliable, providing 2a in 95% yield as
the sole product (Scheme 3).
Scheme 3. Oxidation of Sulfide 3a
Having prepared the desired sulfoxide intermediate 2a, we turned our attention to
the installation of the sulfonimide functionality. Several methods are available for the
introduction of the imide-N-atom [5], the most popular being the use of O-
‡
(mesitylsulfonyl)hydroxylamine (MSH) as an NH2 source [6]. Due to the unstable
nature of MSH, it was prepared immediately prior to use. Imination of 2a with MSH
gave disappointing results (Scheme 4). At the first attempt, the cyclic derivative 5 was
isolated in a poor yield of 8%. This type of lactamisation has been reported previously
by Levenson and Meyer in their work on sulfonimide derivatives of cysteine [7]. This
side reaction could be avoided by careful exclusion of acidic conditions during workup
with Na2SO4 as drying agent and neutral Al2O3 for chromatography. Despite this care,
sulfonimide 1 was isolated in a pitiful 6% yield, the remaining material being recovered
starting material.
Scheme 4. Direct Imination of 2a with O-(Mesitylsulfonyl)hydroxylamine (MSH)
Alternative Imination Methodology. At this stage, we decided that it might be better
to introduce the sulfonimide functionality in a N-protected form. A recently reported
method for the imination of sulfoxides with the iminoiodane reagent PhÀIˆNÀTs [8]
appeared to be promising, especially since analogous reagents with more readily
removable N-protecting groups (nosyl (ˆ2-nitrophenylsulfonyl), 4-nitrophenylsulfon-
yl [9], and 2-(trimethylsilyl)ethylsulfonyl (SES) [10]) were known to be available. The
imination of sulfoxide 2a by this method proved to be much more successful giving N-
tosyl sulfonimide 6a in 78% yield, N-nosyl sulfonimide 6b in 55% yield, and N-SES
sulfonimide 6c in 50% yield, respectively (Scheme 5). Since a free sulfonimide was
required for further synthesis, the deprotection of 6b and 6c was then attempted.

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Scheme 5. Imination of 2a with Iminoiodane Reagents
Conditions for the removal of the nosyl and SES groups have been developed by us
in previous work [11]. Treatment of 6b with PhSH and Cs2CO3 in MeCN resulted in
formation of a complex mixture of products. The deprotection of 6c with Bu4NF in
THF was likewise complicated by the formation of a number of side-product that could
not be separated from the desired product 1.
Imination by MSH with in situ Peptide Coupling. Having failed to deprotect the
sulfonimide derivatives 6b and 6c, we sought an alternative imination strategy. Yabuchi
and Kusumi have previously reported the coupling of a sulfonimide salt (formed with
MSH) with a chiral carboxylic acid to determine the enantiomer excess of sulfoxides
[12]. Encouraged by their results, we attempted the imination of sulfoxide 2a and in situ
coupling of the corresponding sulfonimide salt with an N-Boc-amino acid (Scheme 6).
Treatment of 2a with MSH in CH2Cl2 over a period of 3 7 d (reaction controlled by
1H-NMR) followed by direct coupling with N-Boc-l-Ala resulted in the formation of
the desired sulfonimide 7a in 37% yield as a mixture of diastereoisomers. This
procedure was repeated with a range of N-Boc-amino acids (Scheme 6) giving
moderate yields in all cases.
Scheme 6. Imination of 2a by in situ Coupling with N-Boc-Amino Acids to Pseudodipeptides 7a
f
NMR Studies on Sulfonimide Derivatives 7a f. Analysis of the sulfonimides 7a f
by NMR in CDCl3 was carried out by 1H,1H- and 1H,13C-COSY methods to enable full
assignment. The 1H-NMR spectra of the sulfonimides 7a d appeared to be very similar
showing double peaks for the MeO and t-Bu groups due to the presence of
diastereoisomers (Fig. 2). Compound 7e derived from glycine was also similar but
with no peak doubling due to the lack of a second stereocentre. The spectrum of 7f
(Fig. 2,b), derived from proline, was very different from the others showing extensive

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peak doubling. A series of temperature-variable NMR experiments revealed that this
extra doubling was due to a rotamer effect (Figs. 3 and 4). Coalescence of signals
corresponding to HÀC(a)(Pro) and t-Bu(Boc) was observed at 331.7 and 346.1 K,
respectively, corresponding to a rotation barrier of 17.2 Æ 0.2 kcal molÀ1. These
observations lead us to the conclusion that compounds 7a e benefit from an
intramolecular H-bond (Fig. 5), which gives rise to a single conformation in CDCl3
Fig. 2. 1H-NMR Spectra (500 MHz) of a) alanine derivative 7a and b) proline derivative 7f

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solution, whereas 7f cannot form a H-bond due to the proline residue and hence
exhibits conformational freedom in CDCl3 solution.
Conclusions. Our synthetic studies have shown that it is possible to prepare a
range of methyl 3-(phenylsulfonimidoyl)propanoate derivatives in moderate yield via
an imination/coupling strategy. The pseudodipeptides thus prepared, except in the case
of the proline derivative, are believed to exhibit an intramolecular H-bond resulting,
most likely, in a turn conformation adopted in CDCl3 solution. Further NMR studies
involving dilution, deuterium-exchange, and titration experiments are underway to
confirm this hypothesis. The synthesis of enantiomerically pure derivatives and their
incorporation into larger peptide sequences is in progress and will be reported in due
course.
We would like to thank Dr. Neil Spencer for carrying out the 2-D and temperature-variable NMR
experiments. We are grateful to The University of Birmingham, EPSRC, and AstraZeneca for financial support.
Experimental Part
General. Solvents were purified by standard procedures. TLC: Merck 60 F254 SiO2-coated aluminium sheets,
0.2 mm. Flash column chromatography (FC): Merck 60, 230 400 mesh, SiO2; Aldrich activated neutral
Brockmann-1, std. grade CA 150 mesh, Al2O3. M.p.: Electrothermal 9200, uncorrected. IR: Perkin-Elmer 1600-
FTIR spectrometer, in CHCl3; nÄ in cmÀ1. NMR: Bruker AC-300 (300 MHz (1H), 75.5 MHz (13C)), DRX-500
(500 MHz, (1H)); in CDCl3; chemical shift (d) in ppm refer to residual CHCl3 (7.27 ppm (1H)) and CDCl3
(77.0 ppm (13C)); J in Hz. MS: VG ProSpec spectrometer in EI or ES mode; m/z (rel. %).
Synthesis of Methyl 3-(Phenylsulfanyl)propanoate (3a). PhSNa (5 g, 37.8 mmol) was dissolved in t-BuOH
(20 ml) and MeCN (10 ml). A soln. of methyl acrylate (3.4 ml, 37.8 mmol) in t-BuOH (20 ml) was added at r.t.
The resulting soln. was refluxed for 6h and quenched at r.t. by addition of H 2O. The aq. layer was extracted with
CHCl3 (3 Â 50 ml). The combined org. extracts were dried (MgSO4), filtered, and the solvent was removed
under reduced pressure. The crude brown oil was purified by FC (Et2O/hexane 1:4) to afford 3a (1.42 g, 22%).
1
Colourless oil. IR: 1738.2 (CˆO). H-NMR (300 MHz): 7.32 7.20 (m, 5 arom. H); 3.67 (s, MeO); 3.16( t, J ˆ
7.3, CH2S); 2.62 (t, J ˆ 7.3, CH2CO). 13C-NMR: 170.5 (CO); 128.4 (arom. C); 127.3 (arom. CH); 124.9
‡
(arom. CH); 121.8 (arom. CH); 50.1 (CH2); 32.6(CH 2); 27.4 (Me). EI-MS: 196(100, M ), 165 (10), 136 (43),
123 (57), 109 (36), 87 (10), 77 (11), 65 (19), 59 (17), 51 (12), 45 (11), 39 (10).
Synthesis of Ethyl 3-(Phenylsulfanyl)propanoate (3b). As described for 3a, affording 3b (359 mg, 23%).
Colourless oil. IR: 1709.4 (CˆO). 1H-NMR (300 MHz): 7.37 7.18 (m, 5 arom. H); 4.13 (q, J ˆ 7.0, MeCH2);
3.16( t, J ˆ 7.3, CH2S); 2.61 (t, J ˆ 7.3, CH2CO); 1.25 (t, J ˆ 6.6, Me). 13C-NMR: 171.0 (CO); 130.2 (arom. C);
128.4 (arom. CH); 127.4 (arom. CH); 124.9 (arom. CH); 59.0 (CH2); 32.8 (CH2); 27.4 (CH2); 12.6(Me). EI-MS:
‡
210 (100, M ), 165 (17), 136 (64), 123 (63), 117 (10), 101 (24), 91 (10), 73 (30), 65 (20), 51 (14), 45 (17), 39 (13).
Synthesis of tert-Butyl 3-(Phenylsulfanyl)propanoate (3c). As described for 3a affording 3c (6.91 g, 36%).
Pale yellow oil. 1H-NMR (300 MHz): 7.33 7.20 (m, 5 arom. H); 3.13 (t, J ˆ 7.35, CH2S); 2.54 (t, J ˆ 7.35,
CH2CO); 1.45 (s, t-Bu). 13C-NMR: 171.0 (CO); 135.6(arom. C); 130 (arom. CH); 129 (arom. CH); 126.4 (arom.
‡
CH); 80.9 (Me3C); 35.6(CH 2); 29.2 (CH2); 28.1 (Me). EI-MS: 238 (100, M ), 182 (85), 123 (85), 109 (84), 57
(100), 51 (12), 41 (80). HR-MS: 238.103353 (C13H18O2S, calc. 238.102752).
Synthesis of Methyl 3-(Phenylsulfinyl)propanoate (2a). Compound 3a (1.39 g, 7.09 mmol) was dissolved in
MeOH (20 ml), and to this NaIO4 (1.51 g, 7.09 mmol) in H2O (20 ml) was added dropwise at 08. The resulting
white soln. was stirred for 7 h at r.t. The white slurry was filtered and washed with MeOH (50 ml), and the soln.
was concentrated to a quarter of the volume. The aq. layer was extracted with CH2Cl2 (3 Â 50 ml), and the
combined org. phase was dried (MgSO4), filtered, and concentrated under reduced pressure to afford 2a (1.42 g,
95%). Pale yellow oil. IR: 1727.6(C ˆO), 1050.2 (SˆO). 1H-NMR (300 MHz): 7.52 7.36( m, 5 arom. H); 3.53
(s, Me); 3.18 3.09 (m, 1 H, CH2); 2.90 2.81 (m, 1 H, CH2); 2.77 2.66 (m, 1 H, CH2); 2.48 2.38 (m, 1 H,
CH2). 13C-NMR: 171.5 (CO); 142.9 (arom. C); 131.1 (arom. CH); 129.2 (arom. CH); 124.0 (arom. CH); 52.0
‡
‡
(CH2); 51.0 (CH2); 25.8 (Me). ES-MS: 235 (100, [M ‡ Na] ). HR-MS: 235.0414 (C10H12NaO3S , calc.
235.0405).

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1
Fig. 3. Temperature-variable H-NMR spectra of 7f showing coalescence of the HÀC(a)(Pro) signal

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Fig. 4. Temperature-variable 1H-NMR spectra of 7f showing coalescence of the t-Bu(Boc) signal. Plotted at
2.5 Hz cmÀ1
.
Fig. 5. Postulated structure of 7a e with intramolecular H-bond

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Synthesis of Methyl 3-(Phenylsulfonimidoyl)propanoate (1). Compound 2a (200 mg, 0.94 mmol) was
dissolved in CH2Cl2 (7 ml) and stirred at 08. A soln. of O-(mesitylsulfonyl)hydroxylamine (MSH) (1.5 g,
7 mmol) in CH2Cl2 (7 ml) was then added, and the resulting soln. was stirred at r.t. for 4 d. The soln. was
concentrated to a quarter of the volume, hexane (20 ml) was added, and the soln. was left in the freezer
overnight. The pale greasy yellow solid was filtered off and washed with ice-cold hexane (2 Â 20 ml). The
resulting soln. was taken up in CH2Cl2 (20 ml) and washed with 10% aq. Na2CO3 soln. (20 ml). The phases
were separated and the aq. layer was washed with CH2Cl2 (5 Â 20 ml). The combined org. extracts were dried
(NaSO4), filtered, and the solvent was removed in vacuo. Purification by FC (Al2O3 , AcOEt) gave 1 (13 mg,
6%). Colourless oil. 1H-NMR (300 MHz): 7.93 7.45 (m, 5 arom. H); 3.57 (s, Me); 3.42 (t with fine coupling,
‡
J ˆ 5.8, 1.4, CH2); 2.7 (q with fine coupling, J ˆ 5.8, 1.0, CH2). ES-MS: 250 (100, [M ‡ Na] ).
Synthesis of 4,5-Dihydro-1-phenyl-3H-1l6-isothiazole-1,3-dione (5). Compound 2a (400 mg, 1.88 mmol)
was dissolved in CH2Cl2 (10 ml) and stirred at 08. A soln. of MSH (1.62 g, 7.55 mmol) in CH2Cl2 (10 ml) was then
added, and the resulting soln. was stirred at r.t. for 4 d. The soln. was concentrated to a quarter of the volume,
hexane (20 ml) was added, and the soln. was left in the freezer overnight. The pale greasy yellow solid was
separated by decanting off the solvent and washed with ice-cold hexane (2 Â 20 ml). The resulting soln. was
taken up in CH2Cl2 (20 ml) and washed with 10% aq. Na2CO3 soln. (20 ml). The phases were separated, and the
aq. layer was washed with CH2Cl2 (5 Â 20 ml). The combined org. extracts were dried (MgSO4), filtered, and the
solvent was removed in vacuo. Purification by FC (SiO2, AcOEt) gave 5 (28 mg, 8%). Colourless oil. M.p. 136
1378. IR: 1697.0 (CˆO). 1H-NMR (300 MHz): 7.90 7.45 (m, 5 arom. H); 3.77 3.56( m, CH2); 3.19 3.08
(m, 1 H, CH2); 2.99 2.88 (m, 1 H, CH2). 13C-NMR: 178.8 (CO); 135.0 (arom. C); 133.5 (arom. CH); 128.4
‡
(arom. CH); 126.7 (arom. CH); 52.0 (CH2); 31.2 (CH2). ES-MS: 218 (100, [M ‡ Na] ). Anal. calc. for
C9H9NO2S: C 55.3, H4.64, N 7.17, S 16.38; found: C 55.4, H 4.65, N 6.81, S 15.83.
Synthesis of Methyl 3-{N-[(4-Methylphenyl)sulfonyl](phenyl)sulfonimidoyl}propanoate (6a). To a stirred
soln. of 2a (400 mg, 1.89 mmol) in MeCN (10 ml) CuPF6 (cat.), and 4-methyl-N-(phenyl-l3-iodanylidene)-
benzenesulfonamide (774 mg, 2.07 mmol) were added at 08 under an inert atmosphere. The resulting soln. was
stirred overnight, and the solvent was removed in vacuo. The resulting green oil was taken up in AcOEt (10 ml),
filtered (SiO2), and washed with AcOEt (3 Â 10 ml). The filtrate was concentrated to a quarter of the volume.
Crystallization from hexane gave 6a (0.563 g, 78%). White solid. M.p. 70 718. IR: 1740.7 (CˆO). 1H-NMR
(300 MHz): 7.97 (d, J ˆ 4.56, 2 arom. H); 7.82 (d, J ˆ 5.01, 2 arom. H); 7.70 (t, J ˆ 4.47, 1 arom. H); 7.59 (t, J ˆ
4.56, 2 arom. H); 7.24 (d, J ˆ 4.89, 2 arom. H); 3.88 3.75 (m, CH2); 3.58 (s, MeO); 2.82 2.70 (m, CH2); 2.38
(s, Me(Ts)). 13C-NMR: 169.9 (CO); 136.5 (arom. C); 134.6 (arom. CH); 129.7 (arom. CH); 129.2 (arom. CH);
128.4 (arom. CH); 126.6 (arom. CH); 53.5 (CH2S); 52.3 (MeO); 27.6(CH 2); 21.5 (Me(Ts)). EI-MS: 381 (8,
‡
[M ‡ Na] ), 350 (8), 294 (100), 182 (10), 155 (80), 139 (62), 125 (55), 91 (100), 77 (53), 51 (32), 39 (22).
Synthesis of Methyl 3-{N-[(2-Nitrophenyl)sulfonyl](phenyl)sulfonimidoyl}propanoate (6b). As described
for 6a, with 2-nitro-N-(phenyl-l3-iodanylidene)benzene sulfonamide affording 6b (212 mg, 55%). White solid.
M.p. 70 718. IR: 1740.7 (CˆO). 1H-NMR (300 MHz): 8.37 (d, J ˆ 8.83, 2 arom. H); 8.03 (d, J ˆ 8.83,
2 arom. H); 7.94 (d, J ˆ 8.83, 2 arom. H); 7.86( t, J ˆ 7.35, 1 arom. H); 7.71 (t, J ˆ 7.35, 2 arom. H); 4.17 3.97
(m, CH2); 3.51 (s, MeO); 2.74 2.62 (m, CH2). 13C-NMR: 135.3 (arom. C); 135.1 (arom. CH); 129.9
(arom. CH); 128.3 (arom. CH); 127.7 (arom. CH); 124.5 (arom. CH); 52.3 (CH2S); 52.1 (MeO); 26.8 (CH2).
‡
ES-MS: 435 (100, [M ‡ Na] ).
Synthesis of Methyl 2,2-Dimethyl-5,5,7-trioxo-7-phenyl-5l6,7l6-dithia-6-aza-2-siladec-6-en-10-oate (6c). As
described for 6a, with 2-(trimethylsilyl)-N-(phenyl-l3-iodanylidene)ethanesulfonamide affording 6c (50%).
Waxy solid. IR: 3022.1, 2454.2, 1741.1, 1316.5, 1258.1, 1170.3, 1136.8. 1H-NMR (300 MHz): 7.6 8.0
(m, 5 arom. H); 4.85 (m, CH2); 3.6( s, MeO); 3.1 (m, CH2); 2.8 (m, CH2); 1.1 (m, CH2); 0.0 (s, Me3Si).
13C-NMR: 169.7 (CO); À1.8 (Me3Si). 136.1 (arom. C); 10.4 (CH2); 134.8 (arom. CH); 27.9 (CH2); 129.8
‡
(arom. CH); 52.5 (Me); 128.5 (arom. CH); 53.5 (CH2); 53.8 (CH2). ES-MS: 414.0 (100, [M ‡ Na] ). HR-MS:
414.0826(C 25H25NNaO5S2Si, calc. 414.0841).
General Procedure for the Synthesis of Pseudodipeptides 7a f. Compound 2a (100 mg, 0.47 mmol) was
dissolved in CH2Cl2 (5 ml) and stirred at 08. A soln. of MSH (172 mg, 0.80 mmol) in CH2Cl2 (5 ml) was added,
and the resulting soln. was stirred at r.t. for 4 d. 2,6-Dimethylpyridine (540 mg, 5.19 mmol), 1-hydroxybenzo-
triazole (HOBT, 127 mg, 0.94 mmol), [(1H-benzotriazol-1-yl)oxy]tris(pyrrolidin-1-yl)phosphonium
hexafluorophosphate (PyBOP; 490 mg, 0.94 mmol), and N-Boc-protected amino acid (0.94 mmol) were added.
The soln. was stirred at r.t. for 18 h and was then diluted with AcOEt (5 ml), washed with 5% HCl (15 ml), sat.
aq. NaHCO3 soln. (10 ml), and brine (10 ml). The combined org. phase was dried (NaSO4), filtered, and the
solvent removed in vacuo.

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NOTE: Doubling of signals can be observed in the NMR data due to the formation of diastereoisomers.
This is particularly apparent in the 13C-NMR data, but is also seen in the complex multiplicity of signals in the
1
1H-NMR data. Attention is drawn especially to the signals in the H-NMR spectra for the MeO and the t-Bu
protons. Extra doubling and splitting of signals is observed in the 1H-NMR spectrum of the proline derivative 7f
due to an added rotamer effect.
Alanine Derivative Methyl (6S,9RS)-2,2,6-Trimethyl-4,7,9-trioxo-9-phenyl-3-oxa-9l6-thia-5,8-diazadodec-8-
en-12-oate (7a). Purification by FC (SiO2, MeOH/AcOEt 1:4 4 :1) gave 7a (69 mg, 37%). Colourless oil that
formed white crystals upon addition of Et2O. M.p. 68 708. IR: 3425.9, 3040.6, 2431.9, 1739.4, 1707.2, 1649.7,
1239.9, 1166.1. 1H-NMR (500 MHz): 7.92 7.90 (m, 2 arom. H); 7.67 7.66 (m, 1 arom. H); 7.60 7.56 (m, 2 ar-
om. H); 5.19 (br., NH); 4.29 4.20 (m, HÀC(a)(Ala)); 3.81 3.64 (m, CH2S); 3.60, 3.59 (2s, MeO); 2.78 2.74
(m, CH2CO); 1.41, 1.40 (2s, t-Bu); 1.38 (s, Me(Ala)). 13C-NMR: 181.2 (CO(Ala)); 170.49 (CO2Me); 154.53
(CO(Boc)); 135.6(arom. CS); 134.16, 134.13 (arom. CH); 129.7 (arom. CH); 127.89, 127.85 (arom. CH); 79.5
(Me3C); 52.5 (HÀC(a)(Ala)); 52.3 (MeO); 51.4, 51.23 (CH2S); 28.3 (Me3C); 27.37, 27.24 (CH2CO); 19.27, 19.21
‡
(Me(Ala)). ES-MS: 420 (100, [M ‡ Na] ), 320 (60). Anal. calc. for C18H26N2O6S: C 54.26, H 6.58, N 7.03; found:
C 54.21, H 6.61, N 7.01.
Phenylalanine Derivative Methyl (6S,9RS)-6-Benzyl-2,2-dimethyl-4,7,9-trioxo-9-phenyl-3-oxa-9l6-thia-5,8-
diazadodec-8-en-12-oate (7b). Purification by FC (SiO2, Et2O) gave 7b (69 mg, 24%). Pale yellow oil. IR:
3435.8, 3020.0, 2400.0, 1739.2, 1706.4, 1646.5, 1244.5, 1166.4. 1H-NMR (500 MHz): 7.95 7.88 (m, 1 arom. H);
7.83 7.74 (m, 1 arom. H); 7.73 7.45 (m, 5 arom. H); 7.31 7.16( m, 3 arom. H); 4.90 (br. s, NH); 4.00 3.90
(m, HÀC(a)(Phe)); 3.84 3.65 (m, CH2S); 3.61 (s, MeO); 3.26 2.64 ( m, CH2(Phe), CH2CO); 1.42 (s, t-Bu).
13C-NMR: 179.95, 179.91 (CO(Phe)); 170.04, 169.98 (CO2Me); 155.36, 155.26 (CO(Boc)); 137.18 (arom. C);
136.17, 136.11 (arom. C); 134.26, 134.15 (arom. CH); 129.79, 129.66 (arom. CH); 129.41, 129.30 (arom. CH);
128.47, 128.29 (arom. CH); 128.18, 127.92 (arom. CH); 79.44, 79.34 (Me3C); 57.55, 57.46(H ÀC(a)(Phe)); 52.37
(MeO); 51.59, 51.37 (CH2S); 38.91, 38.51 (CH2(Phe)); 28.34 (Me3C); 27.33, 27.19 (CH2CO). ES-MS: 497.1 (100,
‡
[M ‡ Na] ). HR-MS: 497.1740 (C24H30N2O6NaS, calc. 497.1722).
Isoleucine Derivative Methyl (6S,9RS)-2,2-Dimethyl-6-(1-methylpropyl)-4,7,9-trioxo-9-phenyl-3-oxa-9l6-
thia-5,8-diazadodec-8-en-12-oate (7c). Purification by FC (SiO2, Et2O) gave 7c (122 mg, 39%). Colourless
oil. IR: 3435.0, 3011.9, 2478.5, 1739.2, 1709.0, 1644.3, 1257.1, 1169.8. 1H-NMR (500 MHz): 7.93 7.85
(m, 2 arom. H); 7.6 9 7.6 1 m( , 1 arom. H); 7.6 1 7.51 (m, 2 arom. H); 5.11 (br., NH); 4.25 4.16
(m, HÀC(a)(Ile)); 3.83 3.61 (m, CH2S); 3.59, 3.58 (2s, MeO); 2.79 2.69 (m, CH2CO); 1.98 1.82
(m, HÀC(b)(Ile)); 1.54 1.41 (m, 1 H, CH2(g)(Ile)); 1.41, 1.39 (2s, t-Bu); 1.21 1.13 (m, 1 H, CH2(g)(Ile));
0.97 0.84 (m, 2 Me(Ile)). 13C-NMR: 180.73, 180.60 (CO(Ile)); 170.00, 169.96 (CO2Me); 155.88, 155.80
(CO(Boc)); 136.34, 136.28 (arom. CS); 134.09, 134.02 (arom. CH); 129.63, 129.57 (arom. CH); 128.07, 127.82
(arom. CH); 79.40, 79.09 (Me3C); 61.07, 60.87 (HÀC(a)(Ile)); 52.25 (Me); 51.48, 51.36(CH 2S); 38.21, 37.83
(HÀC(b)(Ile)); 28.26( Me3C); 27.34, 27.14 (CH2CO); 24.76, 24.48 (CH2(g)(Ile)); 15.71, 15.39 (Me(Ile)); 11.71,
‡
11.58 (Me(Ile)). ES-MS: 463.1 (100, [M ‡ Na] ), 363.1 (10). HR-MS: 463.1876 (C21H32N2NaO6S, calc.
463.1879).
Valine Derivative Methyl (6S,9RS)-6-Isopropyl-2,2-dimethyl-4,7,9-trioxo-9-phenyl-3-oxa-9l6-thia-5,8-diaza-
dodec-8-en-12-oate (7d). Purification by FC (SiO2, Et2O) gave 7d (87 mg, 29%). Colourless oil that formed
white crystals, which were recrystallized from Et2O. IR: 3436.3, 3062.0, 2407.0, 1739.7, 1709.3, 1644.0, 1246.1,
1160.2. 1H-NMR (500 MHz): 7.96 7.88 ( m, 2 arom. H); 7.70 7.54 (m, 3 arom. H); 5.08 (m, NH); 4.21
(m, HÀC(a)(Val)); 3.85 3.68 (m, CH2S); 3.61, 3.60 (2s, MeO); 2.84 2.70 (m, CH2CO); 2.29 2.20
(m, HÀC(b)(Val)); 1.41, 1.39 (2s, Me3C); 0.99 (d, J ˆ 6.6, 1.5 H, Me(g)(Val)); 0.96( d, J ˆ 6.8, 1.5 H,
Me(g)(Val)); 0.88 (d, J ˆ 6.8, 1.5 H, Me(g)(Val)); 0.82 (d, J ˆ 6.6, 1.5 H, Me(g)(Val)). 13C-NMR: 180.79,
180.61 (CO(Val)); 170.04, 170.00 (CO2Me); 156.04, 155.97 (CO(Boc)); 136.40, 136.35 (arom. CS); 134.13,
134.07 (arom. CH); 129.70, 129.37 (arom. CH), 128.14, 127.87 (arom. CH); 79.14 (Me3C); 61.49, 61.41
(HÀC(a)(Val)); 52.32, 52.29 (MeO); 51.57, 51.43 (CH2S); 31.59, 31.45 (HÀC(b)(Val)); 28.31 (Me3C); 27.42,
‡
27.20 (CH2CO); 19.58, 19.48 (Me(g)(Val)); 17.27, 17.05 (Me(g)(Val)). ES-MS: 449.0 (100, [M ‡ Na] ). HR-
MS: 449.1739 (C20H30N2NaO6S, calc. 449.1722).
Glycine Derivative Methyl (9RS)-2,2-Dimethyl-4,7,9-trioxo-9-phenyl-3-oxa-9l6-thia-5,8-diazadodec-8-en-12-
oate (7e). Purification by FC (SiO2, Et2O) gave 7e (91 mg, 51%). Colourless oil. IR: 3437.2, 3024.0, 2449.6, 1739.0,
1710.1, 1655.1, 1246.5, 1167.6. 1H-NMR (300 MHz): 7.93 7.91 (m, 2 arom. H); 7.71 7.50 (m, 3 arom. H); 5.11 (br.,
NH); 3.97 3.95 (m, CH2(a)(Gly)); 3.84 3.63 (m, CH2S); 3.62 (s, MeO); 2.80 2.74 (m, CH2CO); 1.42 (s, Me3C).
13C-NMR: 180.78 (CO(Gly)); 170.0 (CO2Me); 155.94 (CO(Boc)); 138.47 (arom. CS); 136.59 (arom. CH); 132.13
(arom. CH); 130.25 (arom. CH); 81.66 (Me3C); 54.70 (MeO); 53.93 (CH2(a)(Gly)); 48.85 (CH2S); 30.69 (Me3C);
‡
29.67 (CH2CO). ES-MS: 407.2 (100, [M ‡ Na] ). HR-MS: 407.1257 (C17H24N2NaO6S, calc. 407.1253).

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Helvetica Chimica Acta Vol. 85 (2002)
Proline Derivative tert-Butyl (2S)-2-({[(RS)-(3-Methoxy-3-oxopropyl)(oxo)phenyl-l6-sulfanylidene]ami-
no}carbonyl)pyrrolidine-1-carboxylate (7f). Purification by FC (SiO2, Et2O) gave 7f (69 mg, 27%). Colourless
1
oil. IR: 3054.1, 2306.2, 1739.8, 1682.2, 1669.4, 1266.4, 1164.1. H-NMR (500 MHz): 8.05 7.96( m, 1 arom. H);
7.73 7.84 (m, 1 arom. H); 7.74 7.40 (m, 3 arom. H); 4.38 4.16( m, HÀC(a)(Pro)); 3.89 3.64 (m, CH2S);
3.60, 3.58, 3.56 (3s, MeO); 3.56 3.43 ( m, CH2(d)(Pro)); 3.43 3.28 (m, CH2CO); 2.27 1.75 (m, CH2(b)(Pro),
CH2(g)(Pro)); 1.44, 1.42, 1.41 (3s, t-Bu). 13C-NMR: 182.29, 182.15 (CO(Pro)); 170.25, 170.20 (CO2Me); 154.68,
154.53 (CO(Boc)); 136.63, 136.57 (arom. CS); 134.06, 133.97 (arom. CH); 129.59, 129.27 (arom. CH); 128.41,
128.09 (arom. CH); 79.58, 79.20 (Me3C); 62.84, 62.39 (HÀC(a)(Pro)); 52.30, 52.15 (MeO); 51.55, 51.25
(CH2S); 46.79, 46.45 (CH2(d)(Pro)); 30.24, 30.15 (CH2(b)(Pro)); 28.45, 28.39 (Me3C); 27.66, 27.44 (CH2CO);
‡
24.23, 23.41 (CH2(g)(Pro)). ES-MS: 447.1 (100, [M ‡ Na] ). HR-MS: 447.1575 (C20H28N2NaO6S, calc.
447.1566).
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Received June 11, 2002