New mild and efficient synthesis of peptidosulfonamides

Article abstract of DOI:10.1080/00397910701845340

This article describes a new route to peptidosulfonamide. Our study shows how sulfinamides were first obtained via nucleophilic cleavage of 3,6-dihydrothiazine-1-oxide system and how the products can be subjected to oxidation with m-chloroperbenzoic acid

Full text of DOI:10.1080/00397910701845340

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New Mild and Efficient Synthesis of
Peptidosulfonamides
Giovanni Papandrea a & Fabio Ponticelli a
a Department of Chemistry , University of Siena , Siena, Italy
Published online: 22 Feb 2008.
To cite this article: Giovanni Papandrea & Fabio Ponticelli (2008) New Mild and Efficient Synthesis of
Peptidosulfonamides, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:6, 858-865, DOI: 10.1080/00397910701845340
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Synthetic Communicationsw, 38: 858–865, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701845340
New Mild and Efficient Synthesis
of Peptidosulfonamides
Giovanni Papandrea and Fabio Ponticelli
Department of Chemistry, University of Siena, Siena, Italy
Abstract: This article describes a new route to peptidosulfonamide. Our study shows
how sulfinamides were first obtained via nucleophilic cleavage of 3,6-dihydrothiazine-
1-oxide system and how the products can be subjected to oxidation with m-chloroper-
benzoic acid to give sulfonamides in good yield.
Keywords: 3,6-dihydrothiazine-1-oxide system, m-chloroperbenzoic acid, peptidomi-
metics, peptidosulfonamide, tripeptide
INTRODUCTION
Peptidomimetics are particularly interesting because they can be used to
mimic biologically active peptides.[1] In the past, a wide variety of peptidomi-
metic building blocks has been developed, and one of the most important is the
sulfonamide moiety. This functional group is ubiquitous in bioorganic and
medicinal chemistry,[2] providing a key polar alternative to the amide group
for which it is frequently used as a bioisosteric replacement.
In our previous communication we described the stereospecific synthesis
of cis-4-aminocyclopent-2-ene-1-sulfonic acid.[3] As an extension to this work
and to point out our interest in founding new routes for the formation of sul-
fonamides, herein we present a convenient synthetic route of a particular type
of peptidomimetic building block including a b-aminocyclopentene sulfonic
acid to be used for the preparation of peptidosulfonamides. This successively
Received in Poland July 3, 2007
Address correspondence to Fabio Ponticelli, Department of Chemistry, University
of Siena, via A. Moro 53100, Siena, Italy. E-mail: ponticelli@unisi.it
858

Peptidosulfonamides
859
Figure 1. General structure of a peptidosulfonamide.
could be incorporated in a small peptide. The general structure of these
compounds is shown in Fig. 1.
RESULTS AND DISCUSSION
Before employing amino acids, we began our study with several primary and
secondary amines to obtain simple sulfonamide derivates.
Initially, we investigated various standard methods for the synthesis of the
target sulfonamides. The most frequently used procedure involves the reaction
of a sulfonic acid with thionyl chloride, chlorosulfonic acid, or phosphorus
pentachloride to give the corresponding chlorosulfonyl derivatives, followed
by reaction of the chlorosulfonyl intermediate with the appropriate amine.[4]
Although this method is usually efficient, this route failed under various
reaction conditions when it was applied to our compound (cis-4-aminocyclo-
pent-2-ene-1-sulfonic acid), and the expected sulfonamides could not be
isolated.
Hence, there was need to develop a mild, efficient, and, if possible, one-
pot synthesis of sulfonamides that could avoid laborious purifications. We
therefore tried to reinvestigate the preparation of our aminosulfonic acid,[3]
which, as we previously reported, is obtained from the intermediate 3,6-dihy-
drothiazine-1-oxide system 1, highly susceptible attack by several nucleophi-
lic agents. As a consequence, we tested this reaction with a series of primary
and secondary amines, obtaining several kinds of sulfinamide products
(Table 1, entries a–d).
To assess efficiency of our approach, we extended the range of nucleophi-
lic attack in coupling reaction by amino acids, and we were particularly
encouraged by the observation that this reaction is not limited to simple
amines but is applicable to the synthesis of dipeptidosulfinamides (Table 1,
entries e–g).
Particularly remarkable is compound 2g. This is the only product in which
we recognize the presence of four diastereoisomers in high performance liquid
chromatography (HPLC) analysis. This is possibly due to the presence of the
chiral sulfur of the sulfinamide that shows its optical features. Finally, we
found that the nucleophilic attack can be employed to acquire directly a tripep-
tide too. Indeed, when we reacted a dipeptide, previously synthesized, we
obtained small peptidosulfinamides in good yield and in only one step
(Table 1, entries h and i).

860
G. Papandrea and F. Ponticelli
Table 1. Synthesis of sulfinamides derivates
Entry
a
NuH
Yield (%)a
94
b
86
c
d
e
70
62
72
f
70
74
g
h
i
NH2Val-PheOCH3
NH2Arg(Mtr)-GlyOt-but
72
60
1
aIsolated yield of analytically pure H sulfinamide.
Successively, sulfonamides can be smoothly obtained in good yeld, as
shown for compound 3g, by oxidation with a stoichiometric equivalent of
m-chloroperbenzoic acid and purification by column chromatography
(Scheme 1). The structures of all new compounds were unequivocally
1
confirmed by one- and two-dimensional H and 13C NMR spectra.
Scheme 1. Oxidation of sulfinamides to sulfonamides.

Peptidosulfonamides
861
We think that this method could be generally applicable to different
3,6-dihydrothiazine-1-oxide systems. Our approach offers several advantages
over traditional methods for the synthesis of this particular type of sulfona-
mides. First, it avoids the use of sulfonyl chlorides (highly reactive,
sometimes difficult to prepare, and often unstable species); second, it gives
final products in very good yield. In addition, handling and purification are
very easy, and the procedure shows broad applicability to a wide range of
amines (including aminoacid). Finally, it is possible to get further chemical
modification of the obtained compounds.
CONCLUSION
In summary, we have developed a mild, two-step method, which has shown its
applicability as a building block for sulfonamide synthesis. Further investi-
gations are under way to extend the applicability of this method.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded with a Bruker AC 200 spec-
trometer at 200.13 and 50.33 MHz, respectively and a Bruker Avance 400
NMR instrument. ESI-MS spectra were obtained with a LCQ-DECA
Thermo Finnigan instrument. All new compounds gave satisfactory (within
0.3%) analytical data.
General Procedure for the Synthesis of Peptidosulfinamides 2a–g
In a racemic solution of 1 (3.2 mmol) in toluene (3 mL) and THF (8 mL) at
2608C the corresponding amine or aminoacid previous protected as ester
(3.2 mmol), solubilized in the minimal THF amount was added dropwise,
and the mixture was stirred for 15 min. The solution was evaporated in
vacuo, solubilized in 8 mL of chloroform, and submitted to an easy workup
by extraction with water (2 ꢀ 6 mL). The organic solution was washed with
a saturated NaHCO3 solution (10 mL) and then dried over anhydrous
MgSO4. After removal of solvents under reduced pressure, a white solid or
colorless oil was obtained.
Typical Procedure for the Synthesis of Tripeptidosulfinamides
2h and i
(a) The two amino acids (1 eq. each) were coupled using 4,6-dimethoxy-
[1,3,5]-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM) (3 eq.) in
the presence of N-methylmorpholine (3 eq.) and NaHCO3 (1.5 eq.) in

862
G. Papandrea and F. Ponticelli
methanol solution at room temperature, followed by stirring for 12 h. After the
reaction time, the solution was evaporated in vacuo, solubilized in EtOAc,
extracted with 1 N HCl, and washed successively with water, saturated sodium
bicarbonate, water, and brine. The organic layer was dried over MgSO4. Concen-
tration of the solution under reduced pressure yielded the dipeptide in good yield.
Spectroscopic data are in agreement with previous publications.[5,6]
(b) To a racemic solution of 1 (2 mmol) in toluene (3 mL) and THF (8 mL) at
2308C, the corresponding dipeptide, previously synthesized and protected as
ester (2 mmol) and solubilized in the minimal THF amount, was added
dropwise. The mixture was stirred for 15 min. After the reaction time, the
solution was diluted with 6 mL of water, successively evaporated under
reduced pressure, to give compounds 2h and i as a colorless oil.
Typical Procedure for the Preparation of Sulfonamides from
Sulfinamides
Sulfinamide (2 mmol) was added to a solution of m-chloroperbenzoic acid
(2.2 mmol) in chloroform, and the reaction mixture was stirred for 48 h at
room temperature. After the reaction time, the solution was evaporated in
vacuo, solubilized in 10 mL of chloroform, and submitted to an easy
workup by extraction with a saturated Na2CO3 solution (2 ꢀ 8 mL). The
organic solution was dried over anhydrous MgSO4. After solvents were
removed under reduced pressure, the residue was purified by silica-gel chrom-
atography, eluting with a 3:1 solution of benzine/diethylether to afford a
colorless oil in near quantitative yield.
Analytical and Spectroscopic Data of Compounds
(Z) Pirrolidinsulfinamoyl-cyclopent-2-enyl-4-carbamic acid benzyl ester
1
2a: H NMR (200 MHz CDCl3) d: 1.90 (m, 4H, CH2CH2N), 2.25 (dt, 1H,
J ¼ 14.9, 2.5 Hz, cis H5), 2.55 (dt, 1H, J ¼ 14.9, 8.5 Hz, trans H5), 3.25
(m, 4H, CH2N), 3.76 (m, 1H, H1), 4.75 (m, 1H, H4), 5.05 (s, 2H, PhCH2O),
5.78 (m, 2H, H2,H3), 7.25 (s, 5H, Ph); 13C NMR (CDCl3) d: 25.5
(CH2CH2N), 33.3 (C5), 46.4 (CH2N), 55.6 (C4), 66.5 (OCH2Ph), 66.6, 66.8ꢁ
(C1), 127.9 (Ph), 128.3 (Ph), 128.9 (C3), 129.2 (Ph), 137.1 (C2), 137.5 (Ph),
155.4 (NCOO); MS (ESI), m/z: 335 (M þ H)þ.
(Z) Morpholinsulfinamoyl-cyclopent-2-enyl-4-carbamic acid benzyl ester
2b: 1H NMR (200 MHz CDCl3) d: 1.59 (dt, 1H, J ¼ 14.9, 4.6 Hz, cis H5), 2.45
(dt, 1H, J ¼ 14.9, 6.7 Hz trans H5), 3.05 (m, 4H, CH2N), 3.65 (m, 4H, CH2O),
3.68 (m, 1H, H1), 4.32 (m, 1H, H4), 5.08 (s, 2H, PhCH2O), 5.82 (m, 2H, H2,
*
Double signals due to the presence of diastereoisomers.

Peptidosulfonamides
863
H3), 7.25 (s, 5H, Ph); 13C NMR (CDCl3) d: 32.6 (C5), 45.9 (CH2N), 51.6 (C4),
62.6 (OCH2Ph), 64.1 (CH2O), 66.3, 66.4ꢁ (C1), 127.7 (Ph), 128.2 (C3), 128.4
(Ph), 129.2 (Ph), 137.4 (C2), 138.1 (Ph), 156.0 (NCOO); MS (ESI), m/z: 351
(M þ H)þ.
(Z) Isobutylsulfinamoyl-cyclopent-2-enyl-4-carbamic acid benzyl ester
1
2c: H NMR (200 MHz CDCl3) d: 0.92 (d, 6H, J ¼ 6.8 Hz, CH3CH), 1.68
(m, 1H, CH3CH), 1.81 (dt, 1H, J ¼ 14.9, 1.7 Hz, cis H5), 2.5 (dt, 1H,
J ¼ 14.9, 7.9 Hz, trans H5), 2.90 (m, 2H, CH2N), 3.94 (m, 1H, H1), 4.80
(m, 1H, H4), 5.08 (s, 2H, OCH2Ph), 6.05 (m, 2H, H2-H3), 7.28 (s, 5H, Ph);
13C NMR (CDCl3) d: 19.8 (CH3CH), 30.0 (CH3CH) 33.1 (C5), 52.1 (C4),
55.3 (CH2N), 66.6 (OCH2Ph), 68.0 (C1), 127.8 (Ph), 127.9 (Ph), 128.3 (C3),
128.4 (Ph), 133.1 (Ph), 136.2 (C2), 156.9 (NCOO); MS (ESI), m/z: 337
(M þ H)þ, 359 (M þ Na)þ, 695 (2M þ Na)þ.
(Z) Benzylsulfinamoyl-cyclopent-2-enyl-4-carbamic acid benzyl ester 2d:
1H NMR (200 MHz CDCl3) d: 1.90, (dt, 1H, J ¼ 14.1, 5.05 Hz, cis H5), 2.81
(dt, 1H, J ¼ 14.1, 7.7 Hz, trans H5), 3.24 (m, 1H, H1), 4.05 (s, 2H, NCH2Ph),
4.60 (m, 1H, H4), 4.95 (s, 2H, OCH2Ph), 5.90 (m, 2H, H2-H3), 7.2 (m, 10H,
Ph); MS (ESI), m/z: 393 (M þ Na)þ, 763 (2M þ Na)þ.
(+)-Cis-4-amino-benzyloxycarbonil-cyclopent-2-ene-1-sulfinamoyl-(S)-
valine methyl ester 2e: 1H NMR (400 MHz CD3OD) d: 0.97, 1.03ꢁ (2d, 12H,
J ¼ 2.45 Hz, CH3CH), 1.75, 2.00ꢁ (2dt, 2H, J ¼ 14.9, 4.2 Hz, cis H5), 2.25
(m, 2H, CH3CH), 2.48 (m, 2H, trans, H5), 3.64 (m, 2H, H1), 3.75 (s, 6H,
OCH3), 4.05 (m, 2H, a-CH), 4.68 (m, 2H, H4), 4.98, 5.02ꢁ (2s, 4H,
OCH2Ph), 5.94 (m, 4H, H2,3), 7.22 (s, 10H, Ph); 13C NMR (CD3OD) d:
18.1, 18.3ꢁ (CH3CH), 30.0 (CH3CH), 30.9, 31.6ꢁ (C5), 55.7, 55.8ꢁ (OCH3),
56.7, 57.1ꢁ (C4), 59.3, 59.7ꢁ (a-CH), 64.4, 65.7ꢁ (C1), 67.1, 67.4ꢁ
(OCH2Ph), 128.9, 129.3ꢁ (C3), 127.8, 127.9ꢁ, 128.1, 128.5ꢁ, 128.7, 129.3ꢁ,
138.5, 138.7ꢁ (Ph), 139, 139.6ꢁ (C4), 157.6 (NCOO), 170.3 (COOCH3). MS
(ESI), m/z: 395 (M þ H)þ.
(+)-cis-4-amino-benzyloxycarbonyl-cyclopent-2-ene-1-sulfinamoyl-(S)-
1
triptophane methyl ester 2f: H NMR (200 MHz CD3OD) d: 1.75, 2.02ꢁ
(2dt, 2H, J ¼ 14.6, 3.8 Hz, cis H5), 2.48 (m, 2H, trans H5), 3.31 (m, 4H,
CH2–Ind), 3.60 (s, 6H, OCH3), 3.71 (m, 2H, H1), 4.25 (m, 2H, a-CH), 4.72
(m, 2H, H4), 5.03, 5.05ꢁ (2s, 2H, OCH2Ph), 5.89 (m, 4H, H2,H3), 7.00–7.65
(m, 20H, Ph, Ind); MS (ESI), m/z: 482 (M þ H)þ.
(+)-Cis-4-amino-benzyloxycarbonyl-cyclopent-2-ene-1-sulfinamoyl-(S)-
proline methyl ester 2g: 1H NMR (200 MHz CDCl3) d: 1.50–1.78 (m, 10H,
NCH2CH2CH2; cis H5), 1.90–2.11 (m, 2H, trans H5), 2.60–2.95 (m, 4H,
*
Double signals due to the presence of diastereoisomers.

864
G. Papandrea and F. Ponticelli
NCH2-CH2), 3.42 (m, 2H, H1), 3.48 (s, 6H, OCH3), 3.66 (m, 2H, H1), 3.72 (m, 2H,
a-CH), 4.68 (m, 2H, H4), 4.82 (s, 4H, OCH2), 5.50 (m, 4H, H2,H3), 7.05 (s, 10H,
Ph); MS (ESI), m/z: 415 (M þ Na)þ, 807 (2M þ Na)þ. The HPLC-ESI-MS
analyses were performed on a LCQ-DECA Thermo Finnigan instrument
coupled with P4000 spectra System HPLC pump. The column used was a
250 ꢀ 4.6 mm i.d., 5 mm C18 LiChroCARTw 250–4 Merck. Elution was with
a binary solution of 70% H2O (1% HCOOH) and 30% AcCN. Injection volume
was 80 mL. Retention times were 34.1, 36.3, 38.3, and 44.6 min.
(+)-Cis-4-amino-benzyloxycarbonyl-cyclopent-2-ene-1-sulfinamoyl-(S)-
1
valine-(S)-phenylalanine methyl ester 2h: H NMR (400 MHz CD3OD) d:
0.68, 0.85ꢁ (2d, 12H, J ¼ 7.2 Hz, CH3CH), 1.80–1.98 (m, 4H, CH3CH; cis-
H5), 2.34 (dt, 2H, J ¼ 13.8, 8.9 Hz, trans-H5), 2.95, 3.21ꢁ (2 m, 4H, CH2Ph),
3.29 (m, 2H, H1), 3.32 (s, 6H, OCH3), 3.58 (m, 2H, a-CHval), 4.51 (m, 2H,
a-CHphe), 4.67 (m, 2H, H4), 5.03 (s, 4H, OCH2Ph), 5.84–5.98 (bs, 4H, H2,
13
H3), 7.03–7.41 (m, 20H, Ph); C NMR (CD3OD) d: 17.9, 19.2ꢁ (CH3CH),
30.6 (CH3CH), 32.7 (C5), 39.5 (CH2Ph), 52.9 (a-CHphe), 56.8 (C4), 58.2,
58.7ꢁ (C1), 61.8 (OCH3), 67.3 (a-CHval), 74.7 (OCH2Ph), 135.5, 139.6 (C2/
C3), 127.2, 128.7, 128.8, 129.1, 129.4, 130.4, 131.1, 136.0 (Ph), 176.2
(NCOO), 179.3 (COOCH3); MS (ESI), m/z: 540 (M-H)2.
(+)-Cis-4-amino-benzyloxycarbonyl-cyclopent-2-ene-1-sulfinamoyl-(S)-
arginine(Mtr)-(S)-glycine-t-butyl ester 2i: 1H NMR (200 MHz CDCl3) d: 1.45
(s, 9H, t-but), 1.52 (m, 4H, a-CH2CH2CH2N), 1.82 (dt, 1H, J ¼ 14.9, 3.3 Hz, cis
H5), 2.16 (s, 9H, CH3Ph), 2.52 (m,1H, trans-H5), 2.63 (m, 2H, NCH2CH2CH2),
3.31 (m, 1H, H1), 3.48 (m, 1H, a-CHarg), 3.64 (s, 3H, OCH3), 4.02 (s, 2H,
a-CH2gly), 4.72 (m, 1H, H4), 5.02 (s, 2H, OCH2Ph), 5.94 (m, 2H, H2-H3),
6.65 (s, 1H, H-Ar), 7.25 (s, 5H, Ph); MS (ESI), m/z: 763 (M þ H)þ.
(+)-Cis-4-amino-benzyloxycarbonyl-cyclopent-2-ene-1-sulfonamoyl-(S)-
1
proline methyl ester 3g: H NMR (200 Mhz CD3OD) d: 1.85, 2.12ꢁ (2 m,
10H, NCH2CH2CH2; cis H5), 2.18, 2.38ꢁ (2 m, 2H, trans H5), 2.59, 2.82ꢁ
(2 m, 4H, NCH2CH2), 3.55 (m, 2H, a-CH), 3.69 (s, 6H, OCH3), 3.75
(m, 2H, H1), 4.48 (m, 2H, H4), 5.02 (s, 4H, OCH2), 5.92, 6.08ꢁ (2 m, 4H,
H2/H3), 7.31 (s, 10 H, Ph); MS (ESI), m/z: 431 (M þ H)þ.
ACKNOWLEDGMENTS
The authors thank Laura Salvini (Centro di Analisi e Determinazioni Struttur-
ali, University of Siena) for recording ESI-MS spectra. This work was finan-
cially supported by the University of Siena (Piano di Ateneo per la Ricerce
`
(PAR) Project 2006) and by Ministero Istruzione, Universita e Ricerca
(MIUR) (Piano di Ricerca di Interesse Nazionale (PRIN) project.
*
Double signals due to the presence of diastereoisomers.

Peptidosulfonamides
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