Synthesis of taurine-containing peptides, sulfonopeptides, and N - And O -conjugates

Article abstract of DOI:10.1021/jo500181g

Taurine-containing water-soluble peptidomimetics were designed and synthesized. N-terminal taurine acylations allowed synthesis of a number of taurine-containing peptides. N-protection of taurine with Cbz and SO ₂-activation with benzotriazole followed by coupling with various amino esters, dipeptides and nucleophiles provided taurine N- and O-conjugates and sulfonopeptides.

Full text of DOI:10.1021/jo500181g

Article
pubs.acs.org/joc
Synthesis of Taurine-Containing Peptides, Sulfonopeptides, and N-
and O‑Conjugates
Peter Vertesaljai,§,∥ Suvendu Biswas,§,∥ Iryna Lebedyeva,§ Evan Broggi,§ Abdullah M. Asiri,‡,⊥
and Alan R. Katritzky*,§,⊥,#
§Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, United
States
‡Center of Excellence for Advanced Materials Research (CEAMR), King Abdulaziz University, Jeddah 21589, Saudi Arabia
⊥Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
S
* Supporting Information
ABSTRACT: Taurine-containing water-soluble peptidomimetics were
designed and synthesized. N-terminal taurine acylations allowed
synthesis of a number of taurine-containing peptides. N-protection of
taurine with Cbz and SO2-activation with benzotriazole followed by
coupling with various amino esters, dipeptides and nucleophiles
provided taurine N- and O-conjugates and sulfonopeptides.
thioacetates into 1 and 2,5 (ii) Mannich-type reactions of N-
protected 2-aminoalkanesulfonamides, aldehydes, and aryldi-
INTRODUCTION
■
Peptides are widely used as drug delivery systems, biopharma-
chlorophosphines, followed by aminolysis with amino esters to
ceuticals, prodrugs, and bioactive moieties.1 However, when
form 3,17 and (iii) reaction of β-aminoalkanesulfone amides
they are introduced into living systems, peptides show rapid
with C-terminal α-aminoalkylphosphinic acids.17 Liskamp
enzymatic degradation, which significantly limits their utiliza-
synthesized α- or β-substituted aminoethane sulfonamide
tion in vivo.2 For decades, various peptidomimetics, including
arginine−glycine peptidomimetics 4 and 513 and also the
phosphonopeptides,3 ureidopeptides,4 and sulfonopeptides,5,6
various peptidomimetics 6−8, which contained mono- and
disulfonyl moieties.6 Gennari and colleagues reported the
have been developed and reported.
synthesis7 and conformational study of chiral vinylogous
Aminoalkanesulfonic acid peptidomimetics are hydrolysis-
resistant sulfono analogues of naturally occurring peptides.7,8
The sulfonamide group increases the polarity and hydrogen-
bonding ability of the molecule, since the SO2−NH2 group is
more acidic (pKa 11−12) than the amide bond CO−NH2.9
Accordingly, the conjugate base is weaker than that of the
amide bond and therefore is less prone to protonation, the first
step in acidic hydrolysis of amides and peptides. Synthesis of α-
or β-substituted aminoalkylsulfonates and sulfonamidopeptides
has allowed the preparation of a large number of oligomers
which structurally mimic native peptides10 and render extended
conformation in contrast to cis or trans isomers of their native
peptide analogues.11
aminosulfonic acids18 (vs-amino acids) and corresponding
oligomers 9 (vs-peptides) (Figure 1).8
The synthesis and utility of taurine peptidomimetics and
conjugates involving the sulfono group have not yet been
Sulfonopeptides can be prepared by the reaction of N-
protected aminoalkanesulfonyl chlorides with amino acid12 or
peptide esters8,13 or by condensation of N-protected amino-
alkanesulfinyl chlorides and amino or peptide esters followed
by oxidation.14 Chlorination of sulfono acids usually requires
harsh reaction conditions (e.g., use of thionyl chloride, oxalyl
chloride, phosgene, phosphorus pentachloride, and high
temperatures), which may cause loss of chirality and affect N-
protecting groups.12,15,16 Alternative routes to sulfonopeptides
lie in (i) NCS/HCl oxidative chlorination of xanthines and
Figure 1. Some sulfonopeptides reported in the literature.
Received: January 24, 2014
Published: February 25, 2014
© 2014 American Chemical Society
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Article
explored in full.12,19−22 The high hydrophilicity of taurine
challenges its synthetic incorporation into peptides; therefore,
convenient methods to design β-aminosulfonic acid containing
peptides need to be developed. The present work describes
general and high-yielding synthetic routes for incorporation of
the taurine unit into di-, tri-, and tetrapeptides. The synthetic
protocol was explored and utilized for a series of taurine
acylations at its C-terminus23 (SO3H group), which allowed
synthesis of sulfonopeptides and taurine N- and O-conjugates.
Table 1. Preparation of Taurine-Containing Dipeptides 12
compd
Pg
R
target 12
yield, %
12a
12b
12b,b′
12c
12d
12e
12f
Cbz
Cbz
Cbz
Cbz
Boc
H
Cbz-Gly-Tau-OH
Cbz-L-Ala-Tau-OH
Cbz-DL-Ala-Tau-OH
Cbz-L-Met-Tau-OH
Boc-L-Ala-Tau-OH
78
87
84
82
88
86
76
82
86
90
82
88
Me
Me
CH2CH2SMe
Me
Boc
CH(OBn)OMe Boc-L-Thr(OBn)-Tau-OH
Boc
H
Boc-Gly-Tau-OH
12g
12h
12i
Boc
CH(Me)2
(3-indolyl)CH2
H
Boc-L-Val-Tau-OH
Boc-L-Trp-Tau-OH
Fmoc-Gly-Tau-OH
Fmoc-L-Leu-Tau-OH
Fmoc-L-Phe-Tau-OH
RESULTS AND DISCUSSION
■
Boc
Our group has developed an expertise in the synthesis of
peptides which contain non-natural amino acid units such as
hydrazino-,24 aza-,25 aminoxy-,25 depsi-,26 and oxyazapeptides.27
In this work, the replacement of an amide bond by a
sulfonamide unit led to the facile synthesis of hybrid
sulfonopeptidomimetics and conjugates composed of taurine
and natural amino acids, peptides, and bioactive moieties.
Synthesis of Taurine-Containing Dipeptides. N-Acyl-
benzotriazoles have been advantageous reagents to construct
peptides, peptidomimetics, and peptide conjugates.23−27
Several activated amino acids 11 were prepared following our
reported procedures.24,27 Utilization of our well-developed
methodology showed the general applicability and scope of this
synthetic protocol to prepare water-soluble taurine dipeptides
12 (Scheme 1). MeCN was employed as the solvent, and a few
Fmoc
Fmoc
Fmoc
12j
CH2CH(Me)2
CH2Ph
12k
Synthesis of Taurine-Containing Tri- and Tetrapep-
tides. To prepare longer taurine-containing tri- and tetrapep-
tides, a series of peptidoyl benzotriazoles 13 were synthesized
using the benzotriazole methodology.23 Products 14 were
prepared in good to excellent yields by reacting Pg-di- and Pg-
tripeptidoyl benzotriazoles 13 with taurine 10. The synthetic
route was applied to various Cbz, Boc, and Fmoc N-protected
di- and tripeptides 13 (Scheme 2 and Table 2). Products 14
were isolated in good to excellent yields (73−93%), which
proved the general applicability and effectiveness of the
developed methodology.
Scheme 1. Incorporation of Taurine Unit To Prepare
Dipeptides 12
Scheme 2. Incorporation of the Taurine Unit into Tri- and
Tetrapeptides 14
Table 2. Preparation of Taurine-Containing Tri- and
Tetrapeptides 14
drops of water were used to dissolve taurine 10, using DIPEA
as base. After completion of the reaction, the mixture was
evaporated to dryness and diethyl ether was added to the crude
product; this mixture was then stirred for 20 min and dried
again. During acylations of the taurine N-terminus we paid
special attention to complete elimination of water from the
reaction mixture. Due to the high polarity of reaction products
12, water would dissolve them, lowering the reaction yields
when present even at trace amounts. Acidification of the
reaction mixture was provided by dropwise addition of dry 4 N
HCl solution in dioxane for N-Cbz- and N-Fmoc-protected
products. For N-Boc-protected products HCl was diluted in
ether prior to addition to the mixture and the solvent was then
evaporated. C-Terminus taurine dipeptides 12 were then
isolated by flash column chromatography (1/1 EtOAc/hexanes
to remove any impurities other than products and then MeOH
was passed to isolate products 12). With this methodology we
managed to synthesize taurine−dipeptides in excellent yields
(12; Scheme 1 and Table 1; 76−90%), and this purification
concept has proved to be effective for all of the reaction
products.
compd
Pg
AA1-AA2
L-Phe-Gly
product 14
yield, %
14a
14b
14c
14d
14e
14f
Cbz
Cbz
Cbz
Cbz
Cbz
Boc
Boc
Boc
Cbz-L-Phe-Gly-Tau-OH
Cbz-L-Ala-Gly-Tau-OH
Cbz-L-Phe-L-Met-Tau-OH
Cbz-L-Val-Gly-Tau-OH
Cbz-L-Phe-Gly-Gly-Tau-OH
Boc-L-Ala-Gly-Tau-OH
Boc-L-Pro-L-Ala-Tau-OH
89
91
73
93
85
75
78
80
L-Ala-Gly
L-Phe-L-Met
L-Val-Gly
L-Phe-Gly-Gly
L-Ala-Gly
14g
14h
L-Pro-L-Ala
L-Ala-L-Pro-L-
Ala
Boc-L-Ala-L-Pro-L-Ala-Tau-
OH
14i
14j
14k
Fmoc L-Val-L-Ala
Fmoc L-Val-Gly
Fmoc-L-Val-L-Ala-Tau-OH
Fmoc-L-Val-Gly-Tau-OH
78
90
84
Fmoc L-Leu-Gly-Gly
Fmoc-L-Leu-Gly-Gly-Tau-
OH
It was observed that, in some cases, the starting material
(especially Fmoc-AA-Bt compounds) did not dissolve com-
pletely in the MeCN, but as the reaction proceeded (within
10−20 min) the reaction mixture became clear. The current
protocol can also be applied to longer peptide fragments with a
hydrophobic sequence. The methodology was very efficient,
even when the starting material was not completely soluble.
Synthesis of Taurine Sulfonopeptides. A library of
sulfono di- and tripeptides has been synthesized via the N-
protection of taurine with Cbz to form 15 followed by SO2
activation with thionyl chloride to form 16 (Scheme 3 and
Almost every coupling reaction was completed within 1−2 h,
and in the presence of water/base the benzotriazole
intermediates 11 show sufficient stability to afford high yields
of the reaction products. The stability of benzotriazole
intermediates in water solution has been studied in detail in a
number of research papers from our group.23
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Article
the threonine moiety was displaced during the isolation of the
O-acylated taurine conjugate to afford 19d, most probably due
to the acidic silica column. O-Acylation of L-menthol gave 19e
in 62% yield, and the product was isolated via column
chromatography.
Scheme 3. Synthesis of Taurine Sulfonopeptides 18
Generally, isolation of 19 was easily performed by extraction
of the final products with EtOAc from 3 N HCl solution
followed by recrystallization from DCM/hexanes or flash
column chromatography. Thus, the general SO2-activating
methodology proved to be effective for the synthesis of taurine
N- and O-conjugates.
Table 3). N-Cbz-protected taurine chloride 16 was an unstable
oil that decomposed within 72 h. To stabilize the SO2-active
CONCLUSION
■
Table 3. Preparation of Sulfono Di- and Tripeptides 18
In conclusion, a viable synthetic route toward sulfonopeptides,
taurine−peptides, and conjugates is reported. Moisture-
sensitive taurine peptidomimetics with a series of amino acids
and di- and tripeptides have been conveniently synthesized and
isolated in high yields. Taurine-containing peptidomimetics and
sulfonopeptides mimic natural peptides and therefore represent
attractive scaffolds for drug delivery as well as prodrug and tool
applications. We believe that our general and straightforward
synthetic approach represents a significant development in the
peptide field which could further facilitate the synthesis and
evaluation of sulfonopeptides and related bioconjugated
systems.
compd
amino ester
sulfono peptide 18
yield, %
18a
18b
18c
18d
18e
18f
H-Gly-OBn
Cbz-Tau-Gly-OBn
82
80
86
78
70
75
H-L-Val-OtBu
H-L-Met-OMe
H-L-Phe-OBz
H-L-Leu-OMe
H-Gly-Gly-OMe
Cbz-Tau-L-Val-OtBu
Cbz-Tau-L-Met-OMe
Cbz-Tau-L-Phe-OBz
Cbz-Tau-L-Leu-OMe
Cbz-Tau-Gly-Gly-OMe
intermediate, we employed benzotriazole and obtained the N-
Cbz-taurine sulfonyl benzotriazole 17 in good yield (72%).
Reaction of 17 with a number of amino esters or dipeptide
esters formed N-protected taurine sulfonopeptides 18 (Scheme
3) in good to excellent yields (70−86%). Isolation of the final
products was achieved by extraction with EtOAc from 3 N HCl
followed by either recrystallization (DCM/hexanes) or flash
chromatography (EtOAc/hexanes) to give 18. Synthesis of SO2
active taurine intermediate 17 via the benzotriazole method-
ology allowed fast incorporation of the taurine unit as an N-
terminus amino acid in the peptide chains.
It is important to show that no racemization occurs in our
synthetic protocol. In previous studies we confirmed that the
chiral integrity of the products was maintained.26,27 In this work
we studied the chiral purity of our products by measuring the
optical rotation of all the chiral compounds.
Synthesis of Taurine N- and O-Conjugates. The
synthetic route to 19 employed stable N-protected taurine
benzotriazole 17 to acylate N- and O-nucleophilic compounds.
Coupling of N-Cbz-protected SO2Bt-activated taurine 17 with
N-nucleophiles allowed the formation of sulfonoamides 19a−c.
The reactions proceeded at room temperature overnight,
forming products 19a−c (Scheme 4 and Table 4) in good
EXPERIMENTAL SECTION
■
All commercial materials were used without further purification. All
solvents were reagent grade or HPLC grade. Melting points were
determined on a capillary point apparatus equipped with a digital
1
thermometer and are uncorrected. H NMR and 13C NMR spectra
were recorded in CDCl3, DMSO-d6, CD3OD, and D2O using 300 and
500 MHz spectrometers (with TMS as an internal standard). All 13C
NMR spectra were recorded with complete proton decoupling. The
coupling constants are reported in Hz. Reaction progress was
monitored by thin-layer chromatography (TLC) and visualized by
UV light. Elemental analyses were performed. DCM was dried and
distilled over CaH2, whereas tetrahydrofuran (THF) was used after
distillation over Na−benzophenone. N-Pg-(α-aminoacyl)-
benzotriazoles 11a−k and N-Pg-(α-di- and α-tripeptidoyl)-
benzotriazoles 13a−k were prepared according to the literature
methods.23
General Methods for the Preparation of Taurine-Containing
Dipeptides 12a−k and Tri- and Tetrapeptides 14a−k. N-Pg-(α-
peptidoyl)benzotriazoles 11a−k and 13a−k (1.0 equiv, 1.0 mmol) and
taurine (1.1 equiv, 1.1 mmol, 0.14 g) were dissolved in MeCN (20
mL) and 2 drops of water. DIPEA (0.21 mL, 1.2 equiv) was added to
the reaction mixture, which was then stirred for 1 h at room
temperature. After the reaction was complete (monitored by TLC),
the solvent was evaporated and ether (20.0 mL) was added to the
mixture, and it was then acidified with 4 N HCl in dioxane. The
solvent was evaporated again, and the residue was dried overnight
under vacuum. The crude product was purified by column
chromatography (1/1 EtOAc to remove any impurities and then
100% MeOH) to give the corresponding taurine-containing dipeptides
12a−k and tri- and tetrapeptides 14a−k.
Scheme 4. Synthesis of Taurine N- and O-Conjugates 19
Table 4. Preparation of Taurine N- and O-Bioconjugates 19
entry
Nu
product 19
yield, %
(Z)-Gly-Tau-OH (12a): white solid, 0.25 g, 78%, mp 244.5−246.0
°C; 1H NMR (300 MHz, DMSO-d6) δ 7.90 (br s, 1H), 7.51 (t, J = 5.7
Hz, 1H), 7.40−7.26 (m, 5H), 5.03 (s, 2H), 3.55 (d, J = 6.0 Hz, 2H),
3.35−3.27 (m, 2H), 2.56 (t, J = 7.0 Hz, 2H); 13C NMR (75 MHz,
DMSO-d6) δ 169.3, 157.1, 137.7, 129.0, 128.4, 128.3, 66.2, 51.0, 44.4,
36.1; HRMS (ESI−TOF) m/z [M − H]− calcd for C12H15N2O6S
315.0656, found 315.0667.
1
2
3
4
5
−NH2
−NHBn
−N(CH2)2O(CH2)2
−O-L-Thr
−O-L-menthol
19a
19b
19c
19d
19e
70
73
64
78
62
(Z)-L-Ala-Tau-OH (12b): white solid, 0.29 g, 87%, mp 162.2−163.8
20
1
yields (64−73%). For the O-acylation of threonine Cbz-N-Tau-
Bt (17) and Boc-Thr were coupled (1:1, o/n, room
temperature) using excess DIPEA as base. The Boc group of
°C; [α]D = −16.0° (c 1.0, CH3OH); H NMR (300 MHz, DMSO-
d6) δ 7.92 (t, J = 5.4 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.42−7.24 (m,
5H), 5.01 (s, 2H), 4.03−3.86 (m, 1H), 3.37−3.24 (m, 2H), 2.59 (t, J =
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7.0 Hz, 2H), 1.20 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
δ 172.1, 155.7, 137.0, 128.3, 127.8, 127.7, 65.4, 50.4, 50.3, 35.5, 18.1;
HRMS (ESI-TOF) m/z [M − H]− calcd for C13H17N2O6S 329.0813,
found 329.0820.
(Z)-DL-Ala-Tau-OH (12b,b′): white solid, 0.28 g, 84%, mp 224.0−
246.0 °C; 1H NMR (300 MHz, DMSO-d6) δ 7.80 (t, J = 5.4 Hz, 1H),
7.43−7.25 (m, 6H), 5.03 (s, 2H), 4.08−3.88 (m, 1H), 3.44−3.29 (m,
1H), 2.61 (t, J = 6.9 Hz, 2H), 1.21 (d, J = 7.2 Hz, 3H); 13C NMR (75
MHz, DMSO-d6) δ 172.1, 155.8, 137.1, 128.8, 127.9, 126.8, 65.5, 50.5,
50.4, 35.6, 18.2; HRMS (ESI-TOF) m/z [M − H]− calcd for
C13H17N2O6S 329.0813, found 329.0829.
Fmoc-L-Phe-Tau-OH (12k): white solid, 0.44 g, 88%, mp 203.0−
20
1
204.5 °C; [α]D = −14.0° (c 1.0, CH3OH); H NMR (300 MHz,
DMSO-d6) δ 8.06 (t, J = 5.7 Hz, 1H), 7.87 (d, J = 7.5 Hz, 2H), 7.73−
7.58 (m, 3H), 7.40 (t, J = 7.4 Hz, 2H), 7.33−7.13 (m, 7H), 4.27−4.05
(m, 4H), 3.40−3.20 (m, 2H), 3.03 (dd, J = 13.8, 4.5 Hz, 1H), 2.79
(dd, J = 13.6, 10.2 Hz, 1H), 2.57 (t, J = 6.3 Hz, 2H); 13C NMR (75
MHz, DMSO-d6) δ 170.9, 155.8, 143.8, 143.7, 140.6, 138.3, 129.2,
128.0, 127.6, 127.1, 126.2, 125.4, 125.3, 120.0, 65.7, 56.5, 50.4, 46.6,
37.5, 35.6; HRMS (ESI-TOF) m/z [M − H]− calcd for C26H25N2O6S
493.1439, found 493.1450.
(Z)-L-Phe-Gly-Tau-OH (14a): white solid, 0.41 g, 89%, mp 172.5−
20
1
(Z)-L-Met-Tau-OH (12c): white solid, 0.32 g, 82%, mp 148.6−150.6
174.1 °C; [α]D = −13.0° (c 1.0, CH3OH); H NMR (300 MHz,
DMSO-d6) δ 8.43 (t, J = 5.4 Hz, 1H), 7.87 (t, J = 5.4 Hz, 1H), 7.55 (d,
J = 8.7 Hz, 1H), 7.37−7.17 (m, 10H), 4.97 (d, J = 12.9 Hz, 1H), 4.91
(d, J = 13.5 Hz, 1H), 4.37−4.21 (m, 1H), 3.68 (d, J = 5.4 Hz, 2H),
3.40−3.30 (m, 2H), 3.17−3.00 (m, 1H), 2.78 (dd, J = 13.6, 10.6 Hz,
1H), 2.63 (t, J = 7.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ
172.0, 168.4, 156.0, 138.3, 137.0, 129.3, 128.3, 128.1, 127.7, 127.5,
126.2, 65.3, 56.3, 50.4, 42.3, 37.3, 35.5; HRMS (ESI-TOF) m/z [M −
H]− calcd for C21H24N3O7S 462.1340, found 462.1353.
20
1
°C; [α]D = −17.0° (c 1.0, CH3OH); H NMR (300 MHz, DMSO-
d6) δ 8.00 (t, J = 5.4 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.45−7.23 (m,
5H), 5.01 (s, 2H), 4.11−3.92 (m, 1H), 3.40−3.23 (m, 2H), 2.59 (t, J =
7.0 Hz, 2H), 2.50−2.35 (m, 2H), 2.01 (s, 3H), 1.94−1.67 (m, 2H);
13C NMR (75 MHz, DMSO-d6) δ 171.1, 156.0, 137.0, 128.3, 127.7,
127.6, 65.5, 54.0, 50.3, 35.5, 31.4, 29.8, 14.6; HRMS (ESI-TOF) m/z
[M − H]− calcd for C15H21N2O6S2 389.0847, found 389.0865.
Boc-L-Ala-Tau-OH (12d): white solid, 0.26 g, 88%, mp 187.9−189.2
20
1
(Z)-L-Ala-Gly-Tau-OH (14b): white solid, 0.35 g, 91%, mp 216.0−
°C; [α]D = −12.0° (c 1.0, CH3OH); H NMR (300 MHz, D2O) δ
4.00−3.82 (m, 1H), 3.60−3.41 (m, 2H), 2.99 (t, J = 7.8 Hz, 2H), 1.33
(s, 9H), 1.24 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, D2O) δ 176.0,
157.3, 81.5, 50.8, 49.6, 35.0, 27.6, 16.8; HRMS (ESI-TOF) m/z [M −
H]− calcd for C10H19N2O6S 295.0969, found 295.0978.
20
1
218.0 °C; [α]D = −17.0° (c 1.0, CH3OH); H NMR (300 MHz,
DMSO-d6) δ 8.14 (s, 1H), 7.71 (s, 1H), 7.58−6.95 (m, 6H), 4.92 (s,
2H), 4.14−3.81 (m, 1H), 3.68−3.43 (m, 2H), 3.43−3.02 (m, 4H),
1.12 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 172.9,
168.5, 155.9, 137.0, 128.4, 127.9, 65.6, 50.4, 50.3, 42.3, 35.5, 18.0;
HRMS (ESI-TOF) m/z [M − H]− calcd for C15H20N3O7S 386.1027,
found 386.1036.
Boc-L-Thr(OBn)-Tau-OH (12e): white solid, 0.35 g, 86%, mp 180−
20
1
182.5 °C; [α]D = −21.0° (c 1.0, CH3OH); H NMR (300 MHz,
D2O) δ 7.41−7.11 (m, 5H), 4.44 (d, J = 12.0 Hz, 1H), 4.30 (d, J =
12.0 Hz, 1H), 4.07−3.80 (m, 2H), 3.53−3.34 (m, 2H), 2.91 (t, J = 6.9
Hz, 2H), 1.32 (s, 9H), 1.09 (d, J = 5.4 Hz, 3H); 13C NMR (75 MHz,
D2O) δ 172.3, 157.4, 137.6, 128.6, 128.2, 128.1, 81.5, 74.3, 70.9, 59.3,
49.6, 35.2, 27.6, 16.0; HRMS (ESI-TOF) m/z [M − H]− calcd for
C18H27N2O7S 415.1544, found 415.1558.
(Z)-L-Phe-L-Met-Tau-OH (14c): white solid, 0.39 g, 73%, mp 230.0−
20
1
232.0 °C; [α]D = +4.0° (c 1.0, CH3OH); H NMR (300 MHz,
CD3OD) δ 7.42−7.11 (m, 10H), 5.26−4.96 (m, 2H), 4.52−4.20 (m,
2H), 3.69−3.44 (m, 2H), 3.05−2.88 (m, 3H), 2.62−2.33 (m, 1H),
2.16−1.79 (m, 5H); 13C NMR (75 MHz, D2O) δ 174.5, 173.5, 158.6,
138.6, 138.2, 130.5, 129.8, 129.6, 129.6, 129.1, 129.0, 128.9, 128.9,
127.9, 68.0, 58.9, 54.0, 51.3, 38.6, 36.8, 31.3, 31.1, 15.4; HRMS (ESI-
TOF) m/z [M − H]− calcd for C24H30N3O7S2 536.1531, found
536.1528.
Boc-Gly-Tau-OH (12f): white solid, 0.21 g, 76%, mp 212.0−213.0
°C; 1H NMR (300 MHz, D2O) δ 3.64 (br s, 2H), 3.58−3.42 (m, 2H),
3.08−2.88 (m, 2H), 1.33 (s, 9H); 13C NMR (75 MHz, D2O) δ 164.4,
158.1, 81.7, 49.5, 48.2, 34.9, 27.5; HRMS (ESI-TOF) m/z [M − H]−
calcd for C9H17N2O6S 281.0813, found 281.0823.
(Z)-L-Val-Gly-Tau-OH (14d): white solid, 0.42 g, 93%, mp 176.4−
20
1
178.8 °C; [α]D = −15.0° (c 1.0, CH3OH); H NMR (300 MHz,
DMSO-d6) δ 8.28 (d, J = 4.6 Hz, 1H), 7.87−7.78 (m, 1H), 7.51−7.23
(m, 6H), 5.03 (d, J = 5.4 Hz, 2H), 3.98−3.82 (m, 1H), 3.66 (d, J = 6.0
Hz, 2H), 3.42−3.27 (m, 2H), 2.62 (t, J = 6.9 Hz, 2H) 2.10−1.87 (m,
1H), 0.86 (d, J = 6.3 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ
171.7, 168.5, 156.4, 137.0, 128.4, 127.9, 127.8, 65.6, 60.4, 50.5, 42.2,
35.6, 30.1, 19.3, 18.2; HRMS (ESI-TOF) m/z [M − H]− calcd for
C17H24N3O7S 414.1340, found 414.1348.
Boc-L-Val-Tau-OH (12g): white solid, 0.27 g, 82%, mp 150.3−152.5
20
1
°C; [α]D = −15.0° (c 1.0, CH3OH); H NMR (300 MHz, DMSO-
d6) δ 7.88 (br s, 1H), 6.66 (d, J = 7.8 Hz, 1H), 3.77−3.60 (m, 1H),
3.42−3.21 (m, 2H), 2.59 (t, J = 7.2 Hz, 2H), 1.99−1.83 (m, 1H), 1.38
(s, 9H), 0.82 (d, J = 6.0 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ
171.0, 155.5, 78.0, 56.1, 50.5, 35.4, 30.2, 28.2, 19.2, 18.1; HRMS (ESI-
TOF) m/z [M − H]− calcd for C12H23N2O6S 323.1282, found
323.1289.
(Z)-L-Phe-Gly-Gly-Tau-OH (14e): white solid, 0.44 g, 85%, mp
Boc-L-Trp-Tau-OH (12h): white solid, 0.35 g, 86%, mp 182.0−184.0
20
1
20
1
232.0−234.0 °C; [α]D = −26.0° (c 1.0, CH3OH); H NMR (300
MHz, DMSO-d6) δ 8.34 (t, J = 5.4 Hz, 1H), 8.18 (t, J = 5.6 Hz, 1H),
7.91 (t, J = 4.9 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.43−7.07 (m, 10H),
4.96 (d, J = 13.1 Hz, 1H), 4.91 (d, J = 13.1 Hz, 1H), 4.39−4.17 (m,
1H), 3.78 (d, J = 5.4 Hz, 2H), 3.65 (d, J = 5.7 Hz, 2H), 3.37−3.28 (m,
2H), 3.06 (dd, J = 13.7, 3.8 Hz, 1H), 2.86−2.68 (m, 1H), 2.58 (t, J =
7.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 171.9, 169.1, 168.2,
155.9, 138.2, 137.0, 129.2, 128.3, 128.0, 127.6, 127.4, 126.2, 65.2, 56.3,
50.3, 42.2, 42.1, 37.3, 35.4; HRMS (ESI-TOF) m/z [M − H]− calcd
for C23H27N4O8S 519.1555, found 519.1548.
°C; [α]D = −11.0° (c 1.0, CH3OH); H NMR (300 MHz, D2O) δ
7.42 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.12−6.84 (m, 3H),
4.29−3.98 (m, 1H), 3.50−3.17 (m, 4H), 2.68−2.53 (m, 2H), 1.18 (s,
9H); 13C NMR (75 MHz, D2O) δ 172.1, 155.5, 136.5, 127.6, 125.8,
123.8, 121.6, 119.1, 111.7, 109.7, 79.8, 65.9, 50.2, 35.7, 28.8, 28.3;
HRMS (ESI-TOF) m/z [M − H]− calcd for C18H24N3O6S 410.1391,
found 410.1390.
Fmoc-Gly-Tau-OH (12i): white solid, 0.36 g, 90%, mp 177.0−179.0
°C; 1H NMR (300 MHz, D2O) δ 7.39 (d, J = 6.6 Hz, 2H), 7.29 (d, J =
7.2 Hz, 2H), 7.25−7.05 (m, 4H), 4.81−4.69 (m, 3H), 4.14 (d, J = 8.1
Hz, 2H), 3.66−3.53 (m, 2H), 3.09 (t, J = 6.9 Hz, 2H); 13C NMR (75
MHz, D2O) δ 171.6, 164.3, 143.5, 140.6, 127.5, 127.0, 124.9, 119.7,
66.6, 54.0, 49.5, 46.4, 34.9; HRMS (ESI-TOF) m/z [M − H]− calcd
for C19H19N2O6S 403.0969, found 403.0973.
Boc-L-Ala-Gly-Tau-OH (14f): white solid, 0.27 g, 75%, mp 163.0−
20
1
164.5 °C; [α]D = −18.0° (c 1.0, CH3OH); H NMR (300 MHz,
D2O) δ 3.98 (q, J = 7.2 Hz, 1H), 3.82 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H),
3.00 (t, J = 6.9 Hz, 2H), 1.34 (s, 9H), 1.26 (d, J = 7.2 Hz, 3H); 13C
NMR (75 MHz, D2O) δ 164.6, 164.3, 157.6, 81.6, 49.5, 48.6, 42.5,
35.1, 27.6, 16.7; HRMS (ESI-TOF) m/z [M − H]− calcd for
C12H22N3O7S 352.1184, found 352.1189.
Fmoc-L-Leu-Tau-OH (12j): white solid, 0.38 g, 82%, mp 180.0−
20
1
182.0 °C; [α]D = −22.0° (c 1.0, CH3OH); H NMR (300 MHz,
CDCl3) δ 7.77−7.64 (m, 3H), 7.60−7.49 (m, 2H), 7.37−7.29 (m,
3H), 7.29−7.20 (m, 2H), 4.50−4.00 (m, 4H), 3.64−3.39 (m, 2H),
3.15−2.85 (m, 2H), 1.80−1.50 (m, 3H), 0.91 (d, J = 4.5 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 172.9, 156.4, 143.9, 141.3, 127.8, 127.2,
125.40, 120.0, 67.1, 58.1, 50.6, 47.3, 42.7, 35.8, 24.9, 23.2, 21.9; HRMS
(ESI-TOF) m/z [M − H]− calcd for C23H27N2O6S 459.1595, found
459.1607.
Boc-L-Pro-L-Ala-Tau-OH (14g): white solid, 0.31 g, 78%, mp 130.0−
20
1
132.0 °C; [α]D = −43.0° (c 1.0, CH3OH); H NMR (300 MHz,
DMSO-d6) δ 8.10 (d, J = 7.4 Hz, 1H), 7.95−7.85 (m, 1H), 4.24−3.98
(m, 2H), 3.38−3.15 (m, 4H), 2.56 (t, J = 7.2 Hz, 2H), 2.19−1.63 (m,
4H), 1.30 (s, 9H), 1.19 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
DMSO-d6) δ 172.2, 171.6, 153.2, 78.3, 59.3, 50.2, 48.2, 46.5, 35.5,
2691
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Article
30.8, 28.0, 23.2, 18.3; HRMS (ESI-TOF) m/z [M − H]− calcd for
C15H26N3O7S 392.1497, found 392.1497.
32.1, 30.0, 15.4; HRMS (ESI-TOF) m/z [M − H]− calcd for
C16H23N2O6S2 403.1003, found 403.1000.
20
Boc-L-Ala-L-Pro-L-Ala-Tau-OH (14h): white solid, 0.37 g, 80%, mp
Cbz-Tau-L-Phe-OBz (18d): 0.39 g, 78%, colorless oil; [α]D
=
20
1
1
130.0−132.0 °C; [α]D = −59.0° (c 1.0, CH3OH); H NMR (300
MHz, DMSO-d6) δ 8.08−7.86 (m, 1H), 7.75 (s, 1H), 6.97 (s, 1H),
4.43−3.91 (m, 3H), 3.56 (s, 2H), 3.33 (s, 2H), 3.12−2.95 (m, 1H),
2.59 (s, 2H), 2.10−1.80 (m, 4H), 1.37 (s, 9H), 1.25 (d, J = 4.8 Hz,
3H), 1.25 (d, J = 7.5 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ
171.7, 171.3, 161.6, 155.1, 78.0, 59.5, 53.0, 50.3, 48.4, 47.7, 35.5, 28.9,
28.2, 24.6, 18.0, 16.8; HRMS (ESI-TOF) m/z [M − H]− calcd for
C18H31N4O8S 463.1868, found 463.1874.
−19.0° (c 1.0, CH3OH); H NMR (300 MHz, CDCl3) δ 7.30−6.97
(m, 16H), 5.87−5.67 (m, 1H), 5.21−4.94 (m, 4H), 4.53−4.22 (m,
1H), 3.45−3.25 (m, 2H), 3.18−3.04 (m, 1H), 3.03−2.76 (m, 3H); 13C
NMR (75 MHz, CDCl3) δ 171.9, 156.8, 136.4, 135.8, 135.0, 129.7,
129.2, 128.9, 128.8, 128.7, 128.4, 128.2, 127.8, 127.5, 68.0, 67.2, 57.8,
53.4, 39.3, 36.0; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C26H28N2O6SNa 519.1560, found 519.1577.
20
Cbz-Tau-L-Leu-OMe (18e): 0.27 g, 70%, colorless oil; [α]D
=
1
Fmoc-L-Val-L-Ala-Tau-OH (14i): white solid, 0.52 g, 78%, mp
−30.0° (c 1.0, CH3OH); H NMR (300 MHz, CDCl3) δ 7.28 (m,
5H), 6.51 (d, J = 9.2 Hz, 1H), 6.23−6.02 (m, 1H), 5.03 (s, 2H), 4.19−
3.99 (m, 1H), 3.72 (q, J = 6.8 Hz, 2H), 3.64 (s, 3H), 3.33−3.16 (m,
2H), 1.84−1.47 (m, 3H), 0.92−0.67 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 173.9, 157.1, 136.3, 128.7, 128.3, 128.1, 67.2, 54.9, 53.5,
52.9, 41.9, 36.2, 24.6, 22.9, 21.5; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C17H26N2O6SNa 409.1404, found 409.1417.
20
1
202.0−203.2 °C; [α]D = −26.0° (c 1.0, CH3OH); H NMR (300
MHz, DMSO-d6) δ 8.13 (d, J = 7.5 Hz, 1H), 7.96−7.56 (m, 5H),
7.55−7.14 (m, 5H), 4.35−4.08 (m, 3H), 4.07−3.94 (m, 1H), 3.93−
3.67 (m, 1H), 3.45−3.02 (m, 2H), 2.67−2.39 (m, 2H), 2.10−1.75 (m,
1H), 1.34−0.98 (m, 3H), 0.95−0.65 (m, 6H); 13C NMR (75 MHz,
DMSO-d6) δ 171.6, 170.8, 156.1, 143.9, 143.8, 140.7, 127.6, 127.1,
125.4, 120.1, 65.7, 60.2, 50.5, 48.3, 46.7, 35.6, 30.4, 19.2, 18.2, 18.1;
HRMS (ESI-TOF) m/z [M − H]− calcd for C25H30N3O7S 516.1810,
found 516.1804.
Cbz-Tau-Gly-Gly-OMe (18f): white solid, 0.29 g, 75%, mp 66.2−
1
67.8 °C; H NMR (300 MHz, CDCl3) δ 7.30−7.08 (m, 5H), 6.71−
6.47 (m, 1H), 6.25−6.01 (m, 1H), 5.04 (d, J = 3.9 Hz, 2H), 3.92 (t, J =
5.2 Hz, 2H), 3.85−3.68 (m, 2H), 3.60 (d, J = 4.0 Hz, 3H), 3.47−3.14
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 176.0, 170.9, 157.2, 136.3,
128.7, 128.3, 128.1, 67.3, 62.5, 53.3, 52.8, 44.3, 36.3. Anal. Calcd for
C15H21N3O7S: C, 46.50; H, 5.46; N, 10.85. Found: C, 46.18; H, 5.31;
N 11.14.
Fmoc-L-Val-Gly-Tau-OH (14j): white solid, 0.45 g, 90%, mp 195.7−
20
1
197.4 °C; [α]D = −11.0° (c 1.0, CH3OH); H NMR (300 MHz,
DMSO-d6) δ 8.28 (t, J = 4.5 Hz 1H), 7.90−7.60 (m, 5H), 7.51 (t, J =
9.0 Hz, 1H), 7.45−7.23 (m, 4H), 4.35−4.15 (m 3H), 3.95−3.82 (m,
1H), 3.76−3.64 (m, 2H), 3.43−3.23 (m, 2H), 2.59 (t, J = 7.2 Hz, 2H),
2.10−1.92 (m, 1H), 0.86 (d, J = 5.4 Hz, 6H); 13C NMR (75 MHz,
DMSO-d6) δ 171.6, 168.4, 156.2, 143.9, 140.7, 127.7, 127.1, 125.4,
120.1, 65.7, 60.4, 50.5, 46.7, 42.1, 35.6, 30.3, 19.3, 18.3; HRMS (ESI-
TOF) m/z [M − H]− calcd for C24H28N3O7S 502.1653, found
502.1649.
Cbz-Tau-NH2 (19a): white solid, 0.18 g, 70%, mp 161.2−163.3 °C;
1H NMR (300 MHz, DMSO-d6) δ 7.42−7.26 (m, 5H), 6.91 (s, 2H),
5.03 (s, 2H), 3.50−3.24 (m, 2H), 3.13 (t, J = 7.5 Hz, 2H); 13C NMR
(75 MHz, DMSO-d6) δ 156.0, 137.0, 128.4, 127.8, 127.8, 65.5, 53.9,
35.8. Anal. Calcd for C10H14N2O4S: C, 46.50; H, 5.46; N, 10.85.
Found: C, 46.47; H, 5.71; N, 10.75.
Cbz-Tau-NH-Bn (19b): white solid, 0.25 g, 73%, mp 107.6−109.2
°C; 1H NMR (300 MHz, CDCl3) δ 7.45−7.12 (m, 10H), 5.48 (s, 1H),
5.22 (s, 1H), 5.07 (s, 2H), 4.25 (s, 2H), 3.65−3.43 (m, 2H), 3.08 (t, J
= 8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 156.6, 136.8, 136.3,
129.1, 128.7, 128.4, 128.3, 128.3, 128.2, 67.2, 52.7, 47.3, 36.1. Anal.
Calcd for C17H20N2O4S: C, 58.60; H, 5.79; N, 8.04. Found: C, 58.27;
H, 5.91; N, 8.11.
Fmoc-L-Leu-Gly-Gly-Tau-OH (14k): white solid, 0.48 g, 84%, mp
20
1
171.0−173.0 °C; [α]D = −22.0° (c 1.0, CH3OH); H NMR (300
MHz, DMSO-d6) δ 8.48−8.07 (m, 2H), 8.02−7.81 (m, 3H), 7.83−
7.52 (m, 3H), 7.52−7.19 (m, 4H), 4.45−3.90 (m, 4H), 3.83−3.47 (m,
6H), 2.59 (t, J = 7.5 Hz, 2H), 1.75−1.22 (m, 3H), 0.85 (d, J = 5.7 Hz,
6H); 13C NMR (75 MHz, DMSO-d6) δ 172.8, 169.1, 168.3, 156.1,
143.9, 140.7, 127.6, 127.1, 125.3, 120.1, 65.6, 53.2, 50.3, 46.7, 42.2,
42.1, 35.4, 24.2, 23.1, 21.4; HRMS (ESI-TOF) m/z [M − H]− calcd
for C27H33N4O8S 573.2025, found 573.2028.
Cbz-Tau-NH-morph (19c): white solid, 0.23 g, 64%, mp 92.8−94.2
General Methods for the Preparation of Sulfono Peptides
18a−f and N- and O-Acylated Taurine Conjugates 19a−e. Cbz-
Tau-Bt (0.36 g, 1 mmol, 1 equiv) and the amino ester (1.1 mmol, 1.1
equiv) were dissolved in dry MeCN (20 mL). DIPEA (0.44 mL, 2.5
equiv) was added dropwise, and the mixture was stirred overnight at
room temperature. Evaporation of the solvent followed by column
chromatography (EtOAc/hexanes 1/2) gave N- and O-acylated taurine
conjugates 18a−f. To prepare 19a−e, a similar protocol was used with
various N- and O-nucleophiles.
1
°C; H NMR (300 MHz, CDCl3) δ 7.42−7.28 (m, 5H), 5.55 (t, J =
6.3 Hz, 1H), 5.11 (s, 2H), 3.77 (t, J = 7.8 Hz, 4H), 3.65 (t, J = 6.2 Hz,
2H), 3.27−3.14 (m, 4H), 3.10 (t, J = 6.0 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 156.4, 136.3, 128.7, 128.4, 128.2, 67.1, 66.5, 48.4,
45.7, 35.6. Anal. Calcd for C14H20N2O5S: C, 51.21; H, 6.14; N, 8.53.
Found: C, 51.36; H, 6.41; N, 8.14.
Cbz-Tau-O-L-Thr (19d). Cbz-N-Tau-Bt (17; 0.36 g, 1 mmol, 1
equiv) and Boc-Thr-OH (0.24 g, 1.1 mmol, 1.1 equiv) were dissolved
in dry MeCN (20 mL), DIPEA (0.44 mL, 2.5 equiv) was added
dropwise, and the mixture was stirred overnight at room temperature.
Evaporation of the solvent followed by column chromatography
(EtOAc/hexanes 1/2) gave O-acylated taurine conjugate 19d. The
Boc group of the threonine moiety was displaced due to the acidic
silica column during the isolation of the product: white solid, 0.33 g,
78%, mp 156.0−157.0 °C; [α]D20 = −10.0° (c 1.0, CH3OH); 1H NMR
(300 MHz, DMSO-d6) δ 7.42−7.13 (m, 5H), 7.06 (t, J = 5.1 Hz, 1H),
4.94 (s, 2H), 4.11−3.84 (m, 1H), 3.34−3.07 (m, 2H), 3.05−2.95 (m,
1H), 2.57 (t, J = 6.9 Hz, 2H), 1.20 (d, J = 6.3 Hz, 3H); 13C NMR (75
MHz, DMSO) δ 163.8, 156.5, 137.7, 129.0, 128.4, 128.3, 65.9, 53.6,
51.3, 42.0, 37.9, 18.2. Anal. Calcd for C14H20N2O7S: C, 46.66; H, 5.59;
N, 7.77. Found: C, 46.78; H, 5.83; N, 7.42.
Cbz-Tau-Gly-OBn (18a): white solid, 0.33 g, 82%, mp 90.6−92.7
1
°C; H NMR (300 MHz, CDCl3) δ 7.43−7.28 (m, 10H), 5.53 (t, J =
6.0 Hz, 1H), 5.41 (t, J = 6.3 Hz, 1H), 5.18 (s, 2H), 5.11 (s, 2H), 3.97
(s, 2H), 3.73−3.65 (m, 2H), 3.25 (t, J = 6.0 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 170.0, 156.7, 136.4, 134.9, 129.0, 128.9, 128.7, 128.4,
128.3, 67.9, 67.2, 53.4, 44.4, 36.2. Anal. Calcd for C19H22N2O6S: C,
56.15; H, 5.46; N, 6.89. Found: C, 56.12; H, 5.71; N, 6.93.
Cbz-Tau-L-Val-OtBu (18b): white solid, 0.33 g, 80%, mp 81.9−82.6
°C; [α]D20 = −3.0° (c 1.0, CH3OH); 1H NMR (300 MHz, CD3OD) δ
7.41−7.42 (m, 5H), 5.07 (s, 2H), 3.74 (d, J = 5.4 Hz, 1H), 3.58 (t, J =
6.0 Hz, 2H), 3.23−2.90 (m, 2H), 2.15−1.95 (m, 1H), 1.47 (s, 9H),
0.99 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CD3OD) δ 172.7, 158.6, 138.2, 129.5, 129.1, 128.9, 83.3, 67.6, 63.4,
53.8, 37.0, 36.9, 32.4, 28.4, 19.8, 18.1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C19H30N2O6SNa 437.1717, found 437.1715.
Cbz-Tau-O-L-menthol (19e): white solid, 0.25 g, 62%, mp 67.1−
20
1
67.9 °C; [α]D = −39.0° (c 1.0, CH3OH); H NMR (300 MHz,
CDCl3) δ 7.58−7.19 (m, 5H), 5.58 (s, 1H), 5.10 (s, 2H), 4.71−4.43
(m, 1H), 4.23−3.93 (m, 1H), 3.81−3.50 (m, 2H), 3.36−3.12 (m, 2H),
2.34−2.13 (m, 1H), 2.10−1.93 (m, 2H), 1.8−1.58 (m, 2H), 1.55−1.30
(m, 2H), 1.33−1.14 (m, 2H), 0.97−0.87 (m, 6H), 0.81 (d, J = 4.2 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 156.3, 136.3, 128.6, 128.2, 128.1,
83.7, 67.0, 51.8, 47.5, 42.2, 35.9, 33.7, 31.7, 25.8, 23.1, 21.9, 20.9, 15.6;
Cbz-Tau-L-Met-OMe (18c): white solid 0.35 g, 86%, mp 68.5−69.5
20
1
°C; [α]D = +8.0° (c 1.0, CH3OH); H NMR (300 MHz, CDCl3) δ
7.34−7.12 (m, 5H), 6.20 (d, J = 9.0 Hz, 1H), 6.04−5.57 (m, 1H), 5.03
(d, J = 5.7 Hz, 2H), 4.43−4.16 (m, 1H), 3.85−3.53 (m, 5H), 3.24 (s,
2H), 2.55 (s, 2H), 2.19−1.81 (m, 5H); 13C NMR (75 MHz, CDCl3) δ
172.9, 156.9, 136.3, 128.7, 128.4, 128.2, 67.2, 55.0, 53.4, 53.2, 36.2,
2692
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The Journal of Organic Chemistry
Article
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C20H31NO5SNa
420.1815, found 420.1829.
(20) Sapronov, N. S.; Khnychenko, L. K.; Polevshchikov, A. V. Bull.
Exp. Biol. Med. 2001, 131, 142−144.
(21) Brouwer, A. J.; Ceylan, T.; van der Linden, T.; Liskamp, R. M. J.
Tetrahedron Lett. 2009, 50, 3391−3393.
ASSOCIATED CONTENT
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(22) Kothandam, H.; Biradugadda, P.; Maganti, B.; Keerthi, T.;
Vegunta, B.; Kopparapu, V.; Venkatesh Palaniyapan, V. Asian J.
Biomed. Pharm. Sci. 2012, 2, 21−27.
(23) Panda, S. S.; Hall, C. D.; Scriven, E.; Katritzky, A. R. Aldrichim.
Acta 2013, 46, 43.
(24) Panda, S. S.; El-Nachef, C.; Bajaj, K.; Katritzky, A. R. Eur. J. Org.
Chem. 2013, 4156−4162.
(25) Abo-Dya, N. E.; Biswas, S.; Basak, A.; Avan, I.; Alamry, K. A.;
Katritzky, A. R. J. Org. Chem. 2013, 78, 3541−3552.
(26) Avan, I.; Tala, S. R.; Steel, P. J.; Katritzky, A. R. J. Org. Chem.
2011, 76, 4884−4893.
(27) Biswas, S.; Abo-Dya, N. E.; Oliferenko, A.; Khiabani, A.; Steel, P.
J.; Alamry, K. A.; Katritzky, A. R. J. Org. Chem. 2013, 78, 8502−8509.
S
* Supporting Information
Figures giving 1H and/or 13C spectra of all compounds given in
the Experimental Section. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
*E-mail for A.R.K.: katritzky@chem.ufl.edu.
Author Contributions
∥These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
#Prof. Alan R. Katritzky died on February 10, 2014.
ACKNOWLEDGMENTS
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We thank the University of Florida and the Kenan Foundation
for financial support. This paper was also funded in part by
generous support from King Abdulaziz University, under Grant
No. D-006/431. The authors, therefore, acknowledge the
technical and financial support of KAU. The authors are
grateful to Mr. G. G. Pillai, Dr. A. Oliferenko, Dr. C. D. Hall,
Mrs. Galyna Vakulenko, and Mr. Z. Wang for helpful
discussions and to Dr. M. C. A. Dancel (University of Florida,
Mass Spectrometry Services) for HRMS analysis.
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