Efficient synthesis of protected sulfonopeptides from N-protected 2-aminoalkyl xanthates and thioacetates

Article abstract of DOI:10.1016/j.tet.2013.08.028

An efficient and convenient method was developed for the synthesis of protected sulfonopeptides via N-chlorosuccimide (NCS)/HCl oxidative chlorination of N-protected 2-aminoalkyl xanthates or thioacetates to the corresponding sulfonyl chlorides followed b

Full text of DOI:10.1016/j.tet.2013.08.028

Tetrahedron 69 (2013) 9068e9075
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of protected sulfonopeptides from N-protected
2-aminoalkyl xanthates and thioacetates
*
Saeed Kakaei, Jiaxi Xu
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology,
Beijing 100029, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and convenient method was developed for the synthesis of protected sulfonopeptides via
N-chlorosuccimide (NCS)/HCl oxidative chlorination of N-protected 2-aminoalkyl xanthates or thio-
acetates to the corresponding sulfonyl chlorides followed by aminolysis with amino esters. In the current
method, sulfonopeptides containing 1- and 2-substituted taurines were prepared in satisfactory to good
yields. It is a useful and efficient strategy for the synthesis of protected sulfonopeptides with function-
alized side-chains.
Received 12 March 2013
Received in revised form 23 July 2013
Accepted 15 August 2013
Available online 20 August 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Oxidative chlorination
Sulfonopeptide
Taurine
Thioacetate
Xanthate
1. Introduction
of N-protected aminoalkanesulfinyl chlorides and amino esters
or peptide esters followed by subsequent oxidation,4e,f,7 or via the
Peptides are important biological substances and have been
widely used as drugs and prodrugs. However, their rapid enzymatic
degradation in human body is one of their intrinsic properties that
limit their utilization. Thus, different peptidomimetics, including
Mannich-type reaction of N-protected 2-aminoalkanesulfonamides,
aldehydes, and aryldichlorophosphines, and subsequent aminolysis
with amino esters.8 Among the above mentioned methods, the
sulfonyl chloride method is more practical one and has been widely
applied in the synthesis of sulfonopeptides.
peptides with
D-amino acid residues, peptides containing non-
coded amino acid residues,
b
-peptides, phosphonopeptides, and
Generally, sulfonyl chlorides were prepared from the corre-
sponding sulfonic acids via chlorination with thionyl chloride,2b
oxalyl chloride,8 phosgene,6c phosphorus pentachloride.9 The re-
action conditions are too harsh so that some protecting groups and
functionalized groups in the side-chains of amino acids cannot
survive during the chlorination. An alternative mild method for the
synthesis of sulfonyl chlorides uses the corresponding disulfides as
starting materials via chlorination with toxic gaseous chlorine in
acetic anhydride7 or in carbon tetrachloride.6b,10 Both of these two
methods are not convenient.
sulfonopeptides, have been developed.1 Sulfonopeptides are one of
the important peptidomimetics and show an abundant structural
diversity2 because
rivatives are unstable3 and
as building blocks in the synthesis of sulfonopeptides.
a
-aminoalkanesulfonic acids and their de-
-aminoalkanesulfonic acids are applied
-Amino-
b
b
alkanesulfonic acids can be 1-substituted or 2-substituted taurines
as different sulfur analogs of naturally occurring amino acids and
structurally diverse substituted taurines have been prepared
efficiently.4,5
Sulfonopeptides are more stable analogs of naturally occurring or
synthetic peptides than phosphonopeptides and have been used as
enzyme inhibitors as well. The sulfonopeptides have been generally
prepared via the reaction of N-protected aminoalkanesulfonyl chlo-
rides and amino acid esters or peptide esters,6 via the condensation
Recently, we worked on the synthesis of substituted taurines as
sulfur analogs of naturally occurring amino acids and have de-
veloped several efficient routes to prepare structurally diverse
substituted taurines.5 Very recently, we synthesized 1-substituted
taurines with different functionalized side-chains via the radical
addition of various xanthates to N-allylphthalimide and subsequent
oxidation with performic acid.11 Herein, we reported the efficient
and convenient synthesis of protected sulfonopeptides via the
NCS/HCl oxidative chlorination of xanthates or thioacetates to the
* Corresponding author. Tel./fax: þ86 10 64435565; e-mail address: jxxu@
mail.buct.edu.cn (J. Xu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.028

S. Kakaei, J. Xu / Tetrahedron 69 (2013) 9068e9075
9069
Table 2
corresponding sulfonyl chlorides and subsequent aminolysis with
amino esters.
Optimizing reaction conditions for the synthesis of sulfonopeptide 6baa
O
O
SO2Cl
PhthN
MeO2C
S
+
PhthN
MeO2C
N
CO2Et
H2N
HCl
CO2Et
5a
2. Results and discussion
H
6ba
4b
Firstly, different xanthates 2 and N-allylphthalimide (1) un-
derwent radical addition with dilauroyl peroxide (DLP) as a radical
initiator in refluxing 1,2-dichloroethane (DCE) to afford S-2-
phthalimidoethyl xanthate derivatives 3 in good to excellent
yields,11 which were readily oxidized to the corresponding
N-phthalimido-1-substituted ethanesulfonyl chlorides 4 in good to
Entry
Solvent
Base
Time (h)
Temp (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
DCM
DCM
THF
MeCN
Me2CO
DCM
DCM
DCM
Et3N
K2CO3
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
12
12
12
12
12
12
24
6
35
35
35
35
78
42
59
73
61
87
86
54
35
0e35c
0e35c
0e35c
excellent yields with N-chlorosuccimide (NCS) and
2 mol/L
hydrochloric acid in acetonitrile at 0 ꢀC under Nishiguchi’s condi-
tions (Table 1).12 The results indicate that steric bulky xanthates 3d
and 3i generated the corresponding sulfonyl chlorides 4d and 4i in
relative low yields (Table 1, entries 4 and 9) (Scheme 1).
a
Reaction was conducted with sulfonyl chloride 4b (1 mmol), GlyOEt$HCl 5a
(1 mmol), and base (2.2 mmol).
b
Isolated yield.
c
Reaction was conducted at 0 ꢀC and allowed to warm to 35 ꢀC.
Table 1
observed when the reaction time was extended to 24 h (Table 2,
entry 7). However, the yield decreased from 87% to 54% when the
reaction was shortened from 12 h to 6 h (Table 2, entry 8). The
results reveal that it is optimal conditions that sulfonyl chloride and
amino ester are mixed under stirring in the presence of triethyl-
amine in DCM at 0 ꢀC and the resulting mixture is further stirred for
12 h and allowed to warm to room temperature. In the current
method, sulfonopeptides with functionalized side-chains were
synthesized from simple starting materials.
Under the optimal conditions, a series of sulfonopeptides 6 was
prepared from various N-protected 2-aminoalkanesulfonyl chlo-
rides 4 with different functional groups, including ketone, ester,
lactone, cyano, and imido groups, in their side-chains and amino
ester hydrochlorides 5 (Table 3). The results indicate that different
sulfonyl chlorides 4 show similar reactivity (Table 3). However, the
product yield obviously depends on the steric hindrance of both
aminoalkanesulfonyl chlorides and amino esters (Table 3, entries 4,
and 8e14). Reactions of sulfonyl chlorides 4, except for 4d, 4h, and
4i, and ethyl glycinate hydrochloride show higher yields than re-
actions involving more steric sulfonyl chlorides (4d, 4h, and 4i) and
amino esters salts, such as methyl (S)-2-alaninate (5b), ethyl (S)-
phenylalaninate hydrochloride (5c), ethyl (S)-tyrosinate hydro-
chloride (5d), and methyl (S)-leucinate hydrochloride (5e). For
sulfonopeptides involving sulfonyl chloride 4h or optically pure
amino esters 5bee, a pair of diastereomeric sulfonopeptides were
Synthesis of sulfonyl chlorides
S
OEt
SO2Cl
NCS/2M HCl
MeCN
PhthN
PhthN
S
R1
R1
4
O
0 C
3
Entry
Xanthate 3
R1
Chloride 4
Isolated yield (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
BnCH2
MeO2C
EtO2C
(EtO2C)2CH
AcCH2
PhCOCH2
NCCH2
4a
4b
4c
4d
4e
4f
83
83
95
63
84
94
84
98
60
4g
4h
4i
a
C4H6O2
PhthNCH2
a
2-Oxotetrahydrofuran-3-yl.
Table 3
Synthesis of sulfonopeptides 6
R2
R2
O
O
SO2Cl
CO2R3
Scheme 1. Synthesis of N-protected 2-aminoalkanesulfonopeptides 6.
H2N
HCl
S
PhthN
PhthN
N
H
CO2R3
5
R1
R1
Et3N, DCM
4
6
The reaction of 5-methoxyl-5-oxo-1-N-phthalimidopentane-
2-sulfonyl chloride (4b) and ethyl glycinate hydrochloride (5a) was
selected as a model reaction to optimize the synthetic conditions of
protected sulfonopeptides 6. It generated the desired sulfonopep-
tide 6ba in 78% yield in the presence of triethylamine as a base in
dichloromethane (DCM) when 4b and 5a were mixed and stirred
for 12 h at room temperature (approximate 35 ꢀC) (Table 2, entry 1).
The yield was decreased from 78% to 42% when triethylamine was
instead with potassium carbonate (Table 2, entry 2). Different sol-
vents (such as THF, MeCN, and acetone) were evaluated. However,
lower yields were obtained in all cases (Table 2, entries 3e5), in-
dicating that DCM is suitable solvent and triethylamine is good base
for the reaction. The yield was improved to 87% when sulfonyl
chloride 4b and ethyl glycinate hydrochloride (5a) were mixed at
0 ꢀC and the resulting mixture was stirred for 12 h and allowed to
warm to room temperature (Table 2, entry 6). No obvious effect was
Entry Chloride 4 AA 5 R2
R3 Peptide 6 Yielda (%) drb
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4b
4b
4b
4b
4c
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
5e
5d
H
H
H
H
H
H
H
H
H
Et
Et
Et
Et
Et
Et
Et
Et
Et
6aa
6ba
6ca
6da
6ea
6fa
6ga
6ha
6ia
81
87
77
55
82
82
79
65
58
61
56
60
65
54
60:40
9
10
11
12
13
14
Me
Bn
Me 6bb
50:50
54:46
50:50
61:39
58:42
Et
6bc
6bd
4-HOC6H4CH2 Et
Me2CHCH2
4-HOC6H4CH2 Et
Me 6be
6cd
a
Isolated yield.
b
Determined on the basis of the integration of the 1H NMR spectrum.

9070
S. Kakaei, J. Xu / Tetrahedron 69 (2013) 9068e9075
obtained in each of cases. For optically pure (S)-amino esters 5bee,
(R,S)-diastereomers of the sulfonopeptides are major products due
to kinetic preference in the coupling reaction. On the basis of the
integration of their 1H NMR spectra, diastereomeric ratios were
determined and no obvious stereoselectivity was observed because
the chiral center is too far away from the reactive center of sulfonyl
chlorides.
3. Conclusion
In conclusion, a series of protected sulfonopeptides with various
functionalized side-chains were synthesized in good to excellent
yields via the NCS/HCl oxidative chlorination of xanthates or thio-
acetates and subsequent aminolysis with amino esters. Sulfono-
peptides containing
a- and b-substituted taurine residues were
When the reaction of sulfonyl chloride 4f and ethyl glycinate
hydrochloride (5a) was conducted in a molar ratio of 1:2 (4f:5a),
the first molecule of glycinate displaced the chloride in the sulfonyl
group, while the second molecule of glycinate condensed with the
keto group in the side-chain of the sulfonyl chloride to generate
a sulfonopeptide 6faa with an imino functionalized side-chain in
75% yield (Scheme 2).
prepared from xanthates and thioacetates, respectively. The current
synthetic route is an efficient and convenient method for synthesis
of protected sulfonopeptides from simple starting materials.
4. Experimental section
4.1. General
Melting points were determined on a melting point apparatus
and are uncorrected. 1H NMR spectra were recorded at 400 MHz in
CDCl3 with TMS as internal standard. 13C NMR spectra were
recorded at 100.6 MHz in CDCl3 with CDCl3 as internal standard. IR
spectra were determined directly. HRMS spectra were performed
on an LC/MSD TOF mass spectrometer. TLC analysis was performed
on glass pre-coated silica gel plate. Spots were visualized with UV
light or iodine. Column chromatography was performed on silica
gel. Dichloromethane was refluxed with calcium hydride and
freshly distilled prior to use.
Scheme 2. Synthesis of N-protected 2-aminoalkane-sulfonopeptide 6faa with an im-
ino functionalized side-chain.
After successful synthesis of sulfonopeptides from xanthates, we
extended the method to 2-(N-Cbz protected amino)alkyl thio-
acetates 7, which can be readily prepared from naturally occurring
or synthetic optically active amino acids via the sodium borohy-
drideeiodine reduction, Cbz protection, and esterification with
thiolacetic acid.5g Thioacetates 7 were oxidized to the correspond-
ing sulfonyl chlorides 8 in good yields with NCS/HCl, which were
directly, without further purification, reacted with amino esters
hydrochlorides 5 to afford sulfonopeptides 9 in good to excellent
yields. Similarly, steric hindrance of both sulfonyl chlorides 8 and
amino esters 5 affects the yield obviously. The current synthetic
route provides an efficient pathway to prepare optically active sul-
fonopeptides as well from simple starting materials (Table 4).
4.2. General procedure for the synthesis of sulfonyl chlorides
4 with NCS/HCl as oxidants
NCS (4e4.67 g, 30e35 mmol) was dissolved in a mixture of 2 M
HCl (6 mL) and MeCN (30 mL). The resulting solution was cooled to
10 ꢀC. A solution of xanthate 3 (5 mmol) in MeCN (5 mL) was added
dropwise to the cooled solution at 0 ꢀC. The resulting solution was
stirred at the same temperature for 15 min, and then diluted with
isopropyl ether (25 mL). The organic layer was washed with aq NaCl
(12%, 3ꢁ25 mL) and then dried over anhydrous Na2SO4. After
concentration in vacuo, the crude residue was purified by flash
column chromatography, eluting with ethyl acetate and petroleum
ether (EA/PE) (0:10e1:10, v/v), to afford pure sulfonyl chloride 4 as
colorless solid.
Table 4
Synthesis of sulfonopeptides 9 from thioacetates 7a
Ph
Ph
NCS/2M HCl
MeCN
SO2Cl
SAc
CbzHN
CbzHN
O
0 C
7a
8a
4.2.1. 4-Phenyl-1-phthalimidobutane-2-sulfonyl
Colorless solid, yield: 83%, mp 153e155 ꢀC. 1H NMR (400 MHz,
CDCl3)
chloride
(4a).
Ph
H2N
HCl
Et3N, DCM
CO2Et
5a
O
O
S
d
: 7.85 (dd, J¼5.4, 3.1 Hz, 2H, ArH), 7.75 (dd, J¼5.4, 3.1 Hz, 2H,
CbzHN
N
H
CO2Et
ArH), 7.21e7.09 (m, 5H, ArH), 4.39 (dd, J¼12.6, 4.6 Hz, 1H in NCH2),
4.10 (dddd, J¼6.8, 6.7, 6.8, 4.6 Hz, 1H, SCH), 4.05 (dd, J¼12.6, 6.7 Hz,
1H in NCH2), 2.95 (ddd, J¼14.1, 7.6, 6.9 Hz, 1H in CH2), 2.89 (ddd,
J¼14.1, 7.6, 7.0 Hz, 1H in CH2), 2.56 (dddd, J¼14.6, 7.6, 6.9, 6.2 Hz, 1H
in CH2), 2.13 (dddd, J¼14.6, 7.6, 7.0, 5.8 Hz, 1H in CH2); 13C NMR
9aa
NCS/2M HCl
MeCN
SO2Cl
SAc
N
N
O
Cbz
Cbz
7b
0 C
8b
(100 MHz, CDCl3) d: 167.4, 139.1, 134.4, 131.6, 128.7, 128.4, 126.6,
R2
123.7, 70.9, 37.6, 32.5, 30.3. IR (nmax, cmꢂ1) 3029.5, 2930.3, 1777.2,
1719.3, 1371.2, 1371.2, 1152.7. HRMS (ESI) calcd for C18H16ClNNaO4S
m/z: 400.0381 [MþNa]þ; found 400.0372.
R2
H2N
HCl
Et3N, DCM
CO2R3
O
O
5
S
N
CO2R3
N
H
Cbz
4.2.2. 4-Methoxy-4-oxo-1-phthalimidobutane-2-sulfonyl chloride
9
(4b). Colorless solid, yield: 83%, mp 101e106 ꢀC. 1H NMR (400 MHz,
Entry Thioacetate 7 Chloride 8 Yield (%) AA 5 Peptide 9 Yieldb (%)
CDCl3)
d
: 7.89 (dd, J¼5.5, 3.1 Hz, 2H, ArH), 7.76 (dd, J¼5.5, 3.1 Hz, 2H,
1
2
3
4
5
7a
7b
7b
7b
7b
8a
8b
8b
8b
8b
87
82
5a
5a
5c
5d
5e
9aa
9ba
9bc
9bd
9be
93
85
81
73
60
ArH), 4.43 (dd, J¼14.5, 6.2 Hz, 1H in CH2N), 4.25 (dddd, J¼6.9, 6.7,
6.2, 4.9 Hz, 1H, SCH), 4.05 (dd, J¼14.5, 6.9 Hz, 1H in CH2N), 3.65 (s,
3H, CH3O), 2.76 (ddd, J¼13.5, 7.9, 6.9 Hz, 1H in CH2), 2.68 (ddd,
J¼13.5, 7.2, 6.2 Hz,1H in CH2), 2.43 (dddd, J¼15.4, 6.9, 6.7, 6.2 Hz,1H
in CH2), 2.21 (dddd, J¼15.4, 7.9, 7.2, 4.9 Hz, 1H in CH2); 13C NMR
a
Reaction was conducted with sulfonyl chloride 8 (1 mmol), AAOEt$HCl 5
(100 MHz, CDCl3) d: 172.1, 167.6, 134.4, 131.6, 123.7, 70.9, 51.9, 37.6,
(1 mmol), and Et3N (2.2 mmol).
30.3, 23.7. IR (nmax, cmꢂ1) 3038.1, 2952.9, 2923.8, 2846.9, 1775.3,
b
Isolated yield.

S. Kakaei, J. Xu / Tetrahedron 69 (2013) 9068e9075
9071
1716.2, 1610.7, 1400.4, 1371.5, 1160.3. HRMS (ESI) calcd for
C
123.9, 117.6, 70.4, 37.3, 24.8, 15.1. IR (nmax, cmꢂ1) 3020.8, 2923.8,
2251.3, 1774.7, 1717.6, 1620.4, 1400.9, 1371.1, 1159.6. HRMS (ESI) calcd
for C13H12ClN2O4S m/z: 327.0201 [MþH]þ; found 327.0202.
14H15ClNO6S m/z: 360.0303 [MþH]þ; found 360.0309.
4.2.3. 4-Ethoxy-4-oxo-1-phthalimidobutane-2-sulfonyl chloride
(4c). Colorless solid, yield: 95%, mp 76e79 ꢀC. 1H NMR (400 MHz,
4.2.8. 3-(2-Oxotetrahydrofuran-3-yl)-1-phthalimidopropane-2-
sulfonyl chloride (4h). Colorless solid, yield: 98%, mp 164e167 ꢀC.
CDCl3)
d: 7.89 (dd, J¼5.5, 3.1 Hz, 2H, ArH), 7.77 (dd, J¼5.5, 3.1 Hz, 2H,
ArH), 4.44 (dd, J¼14.5, 6.3 Hz, 1H in CH2N), 4.27 (dddd, J¼6.8, 6.6,
6.3, 5.2 Hz, 1H, SCH), 4.12 (dq, J¼10.7, 7.1 Hz, 1H in CH2O), 4.08 (dq,
J¼10.7, 7.1 Hz, 1H in CH2O), 4.05 (dd, J¼14.5, 6.8 Hz, 1H in CH2N),
2.74 (ddd, J¼16.0, 7.6, 6.8 Hz, 1H in CH2), 2.66 (ddd, J¼16.0, 7.6,
6.6 Hz, 1H in CH2), 2.43 (dddd, J¼14.4, 6.8, 6.6, 6.6 Hz, 1H in CH2),
2.20 (dddd, J¼14.4, 7.6, 7.6, 5.2 Hz, 1H in CH2), 1.21 (t, J¼7.1 Hz, 3H,
1H NMR (400 MHz, CDCl3)
d
: 7.89 (dd, J¼5.3, 3.1 Hz, 2H, ArH), 7.76
(dd, J¼5.3, 3.1 Hz, 2H, ArH), 4.58e4.51 (m, 1H in CH2O), 4.49 (dd,
J¼14.2, 5.6 Hz, 1H in CH2N), 4.39e4.35 (m, 1H in CH2O), 4.21 (dddd,
J¼6.7, 6.0, 5.6, 2.9 Hz,1H, CHS), 4.04 (dd, J¼14.2, 6.7 Hz,1H in CH2N),
2.99 (dddd, J¼11.9, 7.3, 6.5, 4.6 Hz, 1H, CHCO), 2.59 (ddd, J¼13.9, 7.3,
6.0 Hz, 1H in CH2CS), 2.38 (dddd, J¼15.4, 6.6, 6.5, 6.4 Hz, 1H in
CH2CO) 2.24 (dddd, J¼15.4, 7.2, 4.7, 4.6 Hz, 1H in CH2CO), 2.02 (ddd,
CH3). 13C NMR (100 MHz, CDCl3)
d: 171.6, 167.6, 134.4, 131.6, 123.7,
70.9, 60.9, 37.6, 30.5, 23.7, 14.1. IR (nmax, cmꢂ1) 3034.6, 2926.7,
J¼13.9, 11.2, 2.9 Hz, 1H in CH2CS). 13C NMR (100 MHz, CDCl3)
d:
1775.5, 1717.4, 1641.2, 1400.4, 1371.3, 1160.4. HRMS (ESI) calcd for
177.4, 167.6, 134.6, 131.5, 123.9, 69.5, 66.4, 37.4, 36.3, 29.3, 28.9. IR
C
15H17ClNO6S m/z: 374.0460 [MþH]þ; found 374.0415.
(
nmax, cmꢂ1) 2917.4, 1768.5, 1718.3, 1370.4, 1160.1. HRMS (ESI) calcd
for C15H14ClNNaO6S m/z: 394.0123 [MþNa]þ; found 394.0124.
4.2.4. 4-Ethoxy-3-ethoxycarbonyl-4-oxo-1-phthalimidobutane-2-
sulfonyl chloride (4d). Colorless solid, yield: 63%, mp 61e66 ꢀC. 1H
4.2.9. 1,4-Diphthalimidobutane-2-sulfonyl chloride (4i). Colorless
NMR (400 MHz, CDCl3)
d
: 7.91 (dd, J¼5.0, 3.0 Hz, 2H, ArH), 7.71 (dd,
solid, yield: 60%, mp 166e169 ꢀC. 1H NMR (400 MHz, CDCl3)
d: 7.71
J¼5.0, 3.0 Hz, 2H, ArH), 4.43 (dd, J¼14.3, 5.9 Hz, 1H in CH2N), 4.31
(dddd, J¼7.1, 6.8, 5.9, 4.4 Hz, 1H, CHS), 4.24e4.22 (m, 2H, CH2O),
4.18 (q, J¼7.1 Hz, 2H, CH2O), 4.09 (dd, J¼14.3, 7.1 Hz, 1H, CH2N), 3.88
(dd, J¼9.6, 5.8 Hz, 1H, CH), 2.69 (ddd, J¼15.1, 6.8, 5.8 Hz, 1H in CH2),
2.42 (ddd, J¼15.1, 9.6, 4.4 Hz, 1H in CH2), 1.27 (t, J¼7.1, 3H, CH3), 1.25
(dd, J¼5.5, 3.1 Hz, 4H, ArH), 7.64 (dd, J¼5.5, 3.1 Hz, 4H, ArH), 4.46
(dd, J¼14.2, 6.1 Hz, 1H in CH2N), 4.22 (dddd, J¼6.6, 6.3, 6.2, 6.1 Hz,
1H, CHS), 4.14 (dd, J¼14.2, 6.6 Hz, 1H in CH2N), 3.99 (t, J¼6.7 Hz, 2H,
CH2N), 2.65 (dddd, J¼13.1, 6.7, 6.7, 6.2 Hz, 1H in CH2), 2.23 (dddd,
J¼13.1, 6.7, 6.7, 6.3 Hz, 1H in CH2). 13C NMR (100 MHz, CDCl3)
d:
(t, J¼7.1, 3H, CH3). 13C NMR (100 MHz, CDCl3)
d: 168.0, 167.7, 167.5,
167.9, 167.4, 134.4, 134.1, 131.6, 131.4, 123.6, 123.3, 69.4, 37.5, 35.1,
27.5. IR (nmax, cmꢂ1) 2955.9, 2923.8, 1780.4, 1715.5, 1370.9, 1159.1.
HRMS (ESI) calcd for C20H15ClN2NaO6S m/z: 469.0232 [MþNa]þ;
found 469.0231.
134.4, 131.6, 123.7, 69.3, 62.14, 62.11, 48.9, 37.9, 27.4, 13.92, 13.89. IR
(
nmax, cmꢂ1) 2978.3, 2933.4, 1777.2, 1719.3, 1469.8, 1370.9, 1159.1.
HRMS (ESI) calcd for C18H20ClNNaO8S m/z: 468.0490 [MþNa]þ;
found 468.0492.
4.3. General procedure for the synthesis of protected sulfo-
nopeptides 6
4.2.5. 5-Oxo-1-phthalimidohexane-2-sulfonyl chloride (4e). Colorless
solid, yield: 84%, mp 107e109 ꢀC. 1H NMR (400 MHz, CDCl3)
d: 7.89
(dd, J¼5.5, 3.1 Hz, 2H, ArH), 7.77 (dd, J¼5.5, 3.1 Hz, 2H, ArH), 4.41
(dd, J¼14.3, 5.8 Hz, 1H in CH2N), 4.19 (dddd, J¼7.6, 7.3, 6.5, 5.8 Hz,
1H, SCH), 4.04 (dd, J¼14.3, 7.3 Hz, 1H in CH2N), 2.91 (ddd, J¼14.7,
7.4, 7.3 Hz, 1H in CH2), 2.81 (ddd, J¼14.7, 6.3, 6.1 Hz,1H in CH2), 2.29
(dddd, J¼15.3, 7.3, 6.5, 6.1 Hz, 1H in CH2), 2.20 (dddd, J¼15.3, 7.6,
7.4, 6.3 Hz, 1H in CH2), 2.15 (s, 3H, CH3CO). 13C NMR (100 MHz,
A solution of sulfonyl chloride 4 (1.0 mmol) in 2 mL of DCM was
added dropwise to a solution of amino ester hydrochloride salt 5
(1.0 mmol) and Et3N (222 mg, 2.2 mmol) in 2 mL of DCM under N2
atmosphere in an ice-water bath. The resulting mixture was stirred
overnight and allowed to warm to rt. After dilution with DCM
(10 mL), the mixture was washed with ice cooled 2 M HCl
(2ꢁ10 mL), brine (2ꢁ10 mL), and saturated Na2CO3 (2ꢁ10 mL). The
organic layer was dried over Na2SO4, filtered, and evaporated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (DCM/MeOH 100:1e50:1, v/v) to afford
sulfonopeptide 6.
CDCl3) d: 206.3, 167.6, 134.4, 131.6, 123.7, 71.1, 39.3, 37.6, 29.8, 22.1.
IR (nmax, cmꢂ1) 2922.8, 1774.8, 1716.8, 1400.3, 1370.1, 1158.2. HRMS
(ESI) calcd for C14H14ClNNaO5S m/z: 366.0173 [MþNa]þ; found
366.0172.
4.2.6. 5-Oxo-5-phenyl-1-phthalimidopentane-2-sulfonyl chloride
(4f). Colorless solid, yield: 92%, mp 189e192 ꢀC. 1H NMR (400 MHz,
4.3.1. Ethyl N-(4-phenyl-1-phthalimidobutane-2-sulfonyl)glycinate
CDCl3)
d: 7.90 (d, J¼7.2 Hz, 2H, ArHortho), 7.89 (dd, J¼5.5, 3.1 Hz, 2H,
(6aa). Colorless solid, yield: 81%, mp 156e159 ꢀC. 1H NMR (CDCl3,
ArH), 7.76 (dd, J¼5.4, 3.1 Hz, 2H, ArH), 7.58 (dd, J¼7.6, 7.4 Hz, 1H,
ArHpara), 7.44 (dd, J¼7.6, 7.2 Hz, 2H, ArHmeta), 4.46 (dd, J¼14.3,
5.8 Hz, 1H in CH2N), 4.31 (dddd, J¼7.3, 6.8, 5.8, 4.6 Hz, 1H, SCH), 4.14
(dd, J¼14.3, 7.3 Hz, 1H in CH2N), 3.45 (ddd, J¼14.6, 7.8, 6.9 Hz, 1H in
CH2), 3.35 (ddd, J¼14.6, 6.7, 6.6 Hz, 1H in CH2), 2.49 (dddd, J¼15.6,
6.9, 6.8, 5.8 Hz, 1H in CH2), 2.41 (dddd, J¼15.6, 7.8, 6.7, 4.6 Hz, 1H in
400 MHz)
d: 7.96 (d, J¼7.3 Hz, 2H, ArHortho), 7.85 (dd, J¼5.5, 3.1 Hz,
2H, ArH), 7.73 (dd, J¼5.5, 3.1 Hz, 2H, ArH), 7.56 (dd, J¼7.6, 7.6 Hz,1H,
ArHpara), 7.45 (dd, J¼7.6, 7.3 Hz, 2H, ArHmeta), 5.82 (dd, J¼6.0, 5.6 Hz,
1H, NH), 4.30 (dd, J¼14.9, 6.0 Hz, 1H in NCH2), 4.28 (dd, J¼14.9,
6.3 Hz, 1H in NCH2), 4.22 (q, J¼7.1 Hz, 2H, CH2O), 4.09 (dd, J¼18.3,
6.0 Hz, 1H in CH2N), 4.00 (dd, J¼18.3, 5.6 Hz, 1H in CH2N), 3.61
(dddd, J¼6.5, 6.3, 6.3, 6.0 Hz, 1H, SCH), 3.47 (ddd, J¼18.2, 7.1, 6.8 Hz,
1H in CH2), 3.33 (ddd, J¼18.2, 6.7, 6.2 Hz, 1H in CH2), 2.37 (dddd,
J¼14.7, 6.8, 6.7, 6.5 Hz, 1H in CH2), 2.25 (dddd, J¼14.7, 7.1, 6.3, 6.2 Hz,
CH2). 13C NMR (100 MHz, CDCl3)
d: 197.7, 167.7, 136.1, 134.4, 133.5,
131.7, 128.6, 127.9, 123.7, 71.3, 37.8, 34.7, 22.6. IR (nmax, cmꢂ1) 3038.1,
2922.8, 1772.3, 1714.7, 1369.9, 1154.2. HRMS (ESI) calcd for
C
19H16ClNNaO5S m/z: 428.0330 [MþNa]þ; found 428.0304.
1H in CH2), 1.29 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3)
d:
198.7, 169.9, 168.6, 136.6, 134.2, 133.2, 131.8, 128.6, 128.0, 123.6, 61.9,
60.1, 44.6, 37.3, 35.3, 21.7, 14.1. IR (nmax, cmꢂ1) 3311.4, 2983.7,
2939.9, 1773.6, 1715.9, 1620.3, 1370.6, 1143.8. HRMS (ESI) calcd for
4.2.7. 4-Cyano-1-phthalimidobutane-2-sulfonyl
chloride
(4g).
Colorless solid, yield: 80%, mp 122e125 ꢀC.1H NMR (400 MHz, CDCl3)
d
: 7.90 (dd, J¼5.5, 3.1 Hz, 2H, ArH), 7.79 (dd, J¼5.5, 3.1 Hz, 2H, ArH),
C
22H25N2O6S m/z: 445.1428 [MþH]þ; found 445.1429.
4.46 (dd, J¼14.5, 5.6 Hz,1H in CH2N), 4.19 (dddd, J¼7.7, 7.1, 5.6, 4.8 Hz,
1H, CHS), 4.08 (dd, J¼14.5, 7.1 Hz, 1H in CH2N), 2.83 (ddd, J¼14.4, 8.0,
6.1 Hz,1H in CH2CN), 2.74 (ddd, J¼14.4, 7.9, 7.7 Hz,1H in CH2CN), 2.51
(dddd, J¼15.6, 7.9, 7.7, 6.1 Hz, 1H in CH2), 2.28 (dddd, J¼15.6, 8.0, 7.7,
4.3.2. Ethyl N-(5-methoxy-5-oxo-1-phthalimidopentane-2-sulfonyl)
glycinate (6ba). Colorless solid, yield: 87%, mp 138e139 ꢀC. 1H NMR
(400 MHz, CDCl3)
3.1 Hz, 2H, ArH), 5.85 (dd, J¼6.0, 5.4 Hz, 1H, NH), 4.25 (dd, J¼15.1,
d
: 7.85 (dd, J¼5.3, 3.1 Hz, 2H, ArH), 7.73 (dd, J¼5.3,
4.8 Hz, 1H in CH2). 13C NMR (100 MHz, CDCl3)
d: 167.5, 134.7, 131.4,

9072
S. Kakaei, J. Xu / Tetrahedron 69 (2013) 9068e9075
6.2 Hz, 1H in CH2N), 4.22 (q, J¼7.1 Hz, 2H, OCH2), 4.20 (dd, J¼15.1,
5.1 Hz, 1H in CH2N), 4.09 (dd, J¼18.4, 6.0 Hz, 1H in CH2N), 3.99 (dd,
J¼18.4, 5.4 Hz, 1H in CH2N), 3.67 (s, 3H, OCH3), 3.53 (dddd, J¼6.2,
6.0, 5.8, 5.4 Hz, 1H, CHS), 2.77 (ddd, J¼16.8, 7.2, 6.8 Hz, 1H in CH2),
2.66 (ddd, J¼16.8, 7.2, 6.4 Hz,1H in CH2), 2.29 (dddd, J¼14.4, 6.8, 6.4,
5.8 Hz, 1H in CH2), 2.01 (dddd, J¼14.4, 7.2, 7.2, 6.0 Hz, 1H in CH2),
4.24 (dd, J¼14.9, 5.3 Hz, 1H in CH2N), 4.22 (q, J¼7.1 Hz, 2H, OCH2),
4.09 (dd, J¼18.2, 6.0 Hz, 1H in CH2N), 4.00 (dd, J¼18.2, 5.6 Hz, 1H in
CH2N), 3.53 (dddd, J¼6.4, 6.2, 6.0, 5.3 Hz, 1H, CHS), 3.47 (ddd,
J¼12.8, 7.0, 6.8 Hz, 1H in CH2), 3.33 (ddd, J¼12.8, 7.2, 6.8 Hz, 1H in
CH2), 2.37 (dddd, J¼14.6, 7.0, 6.8, 6.4 Hz, 1H in CH2), 2.25 (dddd,
J¼14.6, 7.2, 6.8, 6.2 Hz, 1H in CH2), 1.29 (t, J¼7.1 Hz, 3H, CH3). 13
C
1.30 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3)
d: 172.9, 169.9,
NMR (100 MHz, CDCl3) d: 198.7, 169.9, 168.6, 136.6, 134.2, 133.2,
168.5, 134.2, 131.8, 123.6, 61.8, 60.0, 51.7, 44.5, 36.9, 30.8, 22.6, 14.1.
IR (nmax, cmꢂ1) 3301.8, 2984.7, 1772.6, 1713.4, 1594.3, 1398.2, 1141.2.
HRMS (ESI) calcd for C18H22N2NaO8S m/z: 449.0989 [MþNa]þ;
found 449.0992.
131.8, 128.6, 128.0, 123.6, 61.9, 60.1, 44.6, 37.3, 35.3, 21.7, 14.1. IR
(
nmax, cmꢂ1) 3304.9, 3058.4, 2920.6, 2853.4, 1772.4, 1743.9, 1712.9,
1685.3, 1594.7, 1399.2, 1140.4. HRMS (ESI) calcd for C23H24N2NaO7S
m/z: 495.1196 [MþNa]þ; found 495.1200.
4.3.3. Ethyl
glycinate (6ca). Colorless solid, yield: 77%, mp 159e162 ꢀC. 1H NMR
(400 MHz, CDCl3)
: 7.85 (dd, J¼5.4, 3.1 Hz, 2H, ArH), 7.73 (dd, J¼5.4,
N-(5-ethoxy-5-oxo-1-phthalimidopentane-2-sulfonyl)
4.3.7. Ethyl N-(5-ethoxycarbonylmethylimino-5-phenyl-1-
phthalimidopentane-2-sulfonyl)glycinate (6faa). Colorless solid,
d
yield: 75%, mp 117e121 ꢀC. 1H NMR (400 MHz, CDCl3)
d: 7.97 (d,
3.1 Hz, 2H, ArH), 5.85 (dd, J¼6.2, 5.4 Hz, 1H, NH), 4.25 (dd, J¼14.9,
6.1 Hz, 1H in CH2N), 4.22 (q, J¼7.1 Hz, 2H, OCH2), 4.21 (dd, J¼15.1,
5.1 Hz, 1H in CH2N), 4.12 (q, J¼7.1 Hz, 2H, OCH2), 4.09 (dd, J¼18.3,
6.2 Hz, 1H in CH2N), 3.99 (dd, J¼18.3, 5.4 Hz, 1H in CH2N), 3.54
(dddd, J¼7.6, 6.9, 6.9, 6.1 Hz, 1H, CHS), 2.75 (ddd, J¼14.9, 7.6, 7.4 Hz,
1H in CH2), 2.64 (ddd, J¼14.9, 7.3, 7.1 Hz, 1H in CH2), 2.29 (dddd,
J¼14.4, 7.6, 7.3, 6.9 Hz,1H in CH2), 2.03 (dddd, J¼14.4, 7.6, 7.4, 7.1 Hz,
J¼8.0 Hz, 2H, ArH), 7.60e7.57 (m, 2H, ArH), 7.53 (dd, J¼5.1, 3.6 Hz,
2H, ArH), 7.46e7.44 (m, 1H, ArH), 7.44e7.40 (m, 1H, ArH), 7.26e7.21
(m, 1H, ArH), 6.31 (dd, J¼6.0, 5.6 Hz, 1H, NH), 4.18 (q, J¼7.1 Hz, 2H,
OCH2), 4.11 (q, J¼7.1 Hz, 2H, OCH2), 4.14e4.08 (m, 2H, CH2N), 4.02
(dd, J¼18.1, 6.0 Hz, 1H in CH2N), 4.02e3.94 (m, 2H, CH2N), 3.79 (dd,
J¼14.9, 6.3 Hz, 1H in CH2N), 3.39 (dddd, J¼6.9, 6.4, 6.3, 6.2 Hz, 1H,
CHS), 3.37 (ddd, J¼13.8, 7.1, 6.8 Hz,1H in CH2), 3.28 (ddd, J¼13.8, 6.9,
6.8 Hz, 1H in CH2), 2.39 (dddd, J¼14.4, 6.9, 6.8, 6.4 Hz, 1H in CH2),
2.17 (dddd, J¼14.4, 7.1, 6.8, 6.2 Hz, 1H in CH2), 1.27 (t, J¼7.1 Hz, 3H,
1H in CH2), 1.29 (t, J¼7.1 Hz, 3H, CH3), 1.25 (t, J¼7.1 Hz, 3H, CH3). 13
C
NMR (100 MHz, CDCl3) d: 172.5, 169.9, 168.6, 134.2, 131.8, 123.6,
61.8, 60.7, 60.1, 44.5, 36.9, 31.1, 22.7, 14.12, 14.07. IR (nmax, cmꢂ1
)
CH3), 1.22 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3)
d: 199.1,
3295.4, 2923.8, 1770.8, 1735.4, 1718.5, 1709.8, 1649.1, 1326.4, 1208.6,
1141.4. HRMS (ESI) calcd for C19H25N2O8S m/z: 441.1326 [MþH]þ;
found 441.1326.
170.4, 169.85, 169.76, 168.8, 136.5, 135.1, 134.1, 133.2, 130.6, 130.2,
128.6, 128.3, 128.0, 61.7, 61.5, 61.3, 44.2, 41.9, 39.1, 35.3, 21.3, 14.1,
13.9. IR (nmax, cmꢂ1) 3344.9, 3156.8, 2955.5, 2876.7, 1789.1, 1772.3,
1766.7, 1695.1, 1604.2, 1409.1, 1448.6, 1200.1. HRMS (ESI) calcd for
4. 3 . 4. Ethyl N- (5-etho xy-4- eth oxycar bo nyl -5 -ox o-1 -
C
27H32N3O8S m/z: 580.1724 [MþNa]þ; found 580.1735.
phthalimidopentane-2-sulfonyl)glycinate (6da). Colorless solid,
yield: 55%, mp 89e91 ꢀC. 1H NMR (400 MHz, CDCl3)
d
: 7.85 (dd,
4.3.8. Ethyl N-(4-cyano-1-phthalimidohexane-2-sulfonyl)glycinate
J¼5.5, 3.1 Hz, 2H, ArH), 7.73 (dd, J¼5.5, 3.1 Hz, 2H, ArH), 5.90e5.79
(s, br, 1H, NH), 4.25 (dd, J¼13.8, 6.7 Hz, 1H in CH2N), 4.22 (q,
J¼7.1 Hz, 6H, 3OCH2), 4.19 (dd, J¼13.8, 6.9 Hz, 1H in CH2N),
4.14e4.02 (m, 2H, CH2N), 3.96 (dd, J¼8.1, 6.8 Hz, 1H, CH), 3.58
(dddd, J¼6.9, 6.9, 6.7, 6.0 Hz, 1H, CHS), 2.51 (ddd, J¼14.6, 6.9, 6.8 Hz,
1H in CH2), 2.31 (ddd, J¼14.6, 8.1, 6.0 Hz,1H in CH2),1.29 (t, J¼7.1 Hz,
(6ga). Colorless solid, yield: 79%, mp 156e159 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
: 7.86 (dd, J¼5.4, 3.1 Hz, 2H, ArH), 7.54 (dd, J¼5.4,
3.1 Hz, 2H, ArH), 6.1 (dd, J¼7.4, 4.9 Hz, 1H, NH), 4.45 (dd, J¼15.3,
4.3 Hz, 1H in CH2N), 4.23 (q, J¼7.1 Hz, 2H, OCH2), 4.17 (dd, J¼15.3,
4.6 Hz, 1H in CH2N), 4.16 (dd, J¼18.5, 7.4 Hz, 1H in CH2N), 3.99 (dd,
J¼18.5, 4.9 Hz, 1H in CH2N), 3.50 (dddd, J¼7.1, 7.0, 4.6, 4.3 Hz, 1H,
CHS), 2.82 (t, J¼7.4 Hz, 2H, CH2CN), 2.36 (dddd, J¼14.5, 7.4, 7.4,
7.1 Hz,1H in CH2), 2.15 (dddd, J¼14.5, 7.4, 7.4, 7.0 Hz,1H in CH2), 1.29
3H, CH3), 1.26 (t, J¼7.1 Hz, 6H, 2CH3). 13C NMR (100 MHz, CDCl3):
d:
169.9, 168.67, 168.63, 168.5, 134.2, 131.8, 123.6, 61.9, 61.8, 61.7, 58.6,
49.2, 44.6, 37.2, 26.5, 14.1, 13.94, 13.93. IR (nmax, cmꢂ1) 3304.9,
2981.5, 2933.5, 1780.4, 1717.6, 1639.1, 1398.2, 1141.8. HRMS (ESI)
calcd for C22H28N2NaO10S m/z: 535.1357 [MþNa]þ; found 535.1356.
(t, J¼7.1 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3)
d: 170.1, 168.8,
134.5, 131.6, 123.7, 118.6, 61.9, 59.9, 44.5, 36.6, 23.7, 15.2, 14.0. IR
(
nmax, cmꢂ1) 3300.2, 2975.1, 2935.8, 2251.3, 1772.3, 1712.5, 1613.9,
1398.4, 1142.6. HRMS (ESI) calcd for C17H19N3NaO6S m/z: 416.0887
4.3.5. Ethyl
N-(5-oxo-1-phthalimidohexane-2-sulfonyl)glycinate
: 7.85
[MþNa]þ; found 416.0885.
(6ea). Colorless oil, yield: 82%. 1H NMR (400 MHz, CDCl3)
d
(dd, J¼5.2, 3.3 Hz, 2H, ArH), 7.73 (dd, J¼5.5, 3.1 Hz, 2H, ArH), 5.82
(dd, J¼5.9, 5.6 Hz, 1H, NH), 4.23 (dd, J¼14.9, 4.1 Hz, 1H in CH2N),
4.22 (q, J¼7.1 Hz, 2H, OCH2), 4.15 (dd, J¼14.9, 5.2 Hz, 1H in CH2N),
4.07 (dd, J¼18.4, 5.9 Hz, 1H in CH2N), 3.99 (dd, J¼18.4, 5.6 Hz, 1H in
CH2N), 3.48 (dddd, J¼7.1, 6.9, 5.2, 4.1 Hz, 1H, CHS), 2.93 (ddd,
J¼14.6, 7.1, 6.6 Hz, 1H in CH2), 2.77 (ddd, J¼14.6, 6.9, 6.6 Hz, 1H in
CH2), 2.17 (s, 3H, CH3CO), 2.16 (dddd, J¼14.0, 7.4, 7.1, 6.6 Hz, 1H in
CH2), 2.01 (dddd, J¼14.0, 6.9, 6.9, 6.6 Hz, 1H in CH2), 1.29 (t,
4 . 3 . 9 . E t h y l N - [ 4 - ( 2 - o x o - t e t r a h y d r o f u r a n - 3 - y l ) - 1 -
phthalimidobutane-2-sulfonyl]glycinate (6ha). Colorless oil, yield:
65%, (Dr 60:40). 1H NMR (400 MHz, CDCl3)
d: 7.85e7.84 (m, 4H,
ArH), 5.92 (dd, J¼5.8, 5.8 Hz, 1H, NH), 4.38 (dd, J¼14.8, 7.6 Hz, 1H in
CH2N), 4.28 (dd, J¼14.8, 6.1 Hz, 1H in CH2N), 4.24e4.19 (m, 4H,
2CH2O), 4.11 (d, J¼18.4 Hz, 1H in CH2N), 4.01 (d, J¼18.4 Hz, 1H in
CH2N), 3.88 (dddd, J¼6.8, 6.7, 6.1, 6.1 Hz,1H, CHS), 3.08 (dddd, J¼7.9,
7.9, 7.6, 7.6 Hz, 1H, CHCO), 2.56 (dddd, J¼14.6, 7.6, 7.1, 7.0 Hz, 1H in
CH2), 2.17 (dddd, J¼14.6, 7.6, 7.2, 6.9 Hz, 1H in CH2), 2.09e2.01 (m,
1H in CH2),1.98 (ddd, J¼14.9, 7.9, 6.4 Hz,1H in CH2),1.29 (t, J¼7.1 Hz,
J¼7.1 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3)
d: 207.5, 169.9,
168.5, 134.2, 131.8, 123.5, 61.8, 59.9, 44.5, 39.9, 37.1, 29.9, 21.2, 14.1.
IR (nmax, cmꢂ1) 3295.4, 2949.5, 1774.0, 1738.8, 1715.6, 1607.5,
1398.7, 1134.2. HRMS (ESI) calcd for C18H22N2NaO7S m/z: 433.1040
[MþNa]þ; found 433.1042.
3H, CH3). Its diastereomer d: 7.85e7.84 (m, 4H, ArH), 6.08 (dd,
J¼6.0, 5.7 Hz, 1H, NH), 4.39 (dd, J¼14.4, 6.8 Hz, 1H in CH2N), 4.17
(dd, J¼14.4, 6.7 Hz, 1H in CH2N), 4.24e4.19 (m, 4H, 2CH2O), 4.09 (d,
J¼18.4 Hz, 1H in CH2N), 4.00 (d, J¼18.4 Hz, 1H in CH2N), 3.80 (dddd,
J¼7.6, 6.1, 5.8, 5.3 Hz, 1H, CHS), 3.24 (dddd, J¼7.6, 7.6, 7.0, 6.6 Hz, 1H,
CHCO), 2.61 (dddd, J¼14.9, 6.6, 6.5, 6.3 Hz, 1H in CH2), 2.56 (dddd,
J¼14.9, 7.0, 6.5, 6.3 Hz, 1H in CH2), 2.44 (ddd, J¼14.9, 7.6, 6.1 1H in
CH2), 1.87 (ddd, J¼14.9, 7.6, 6.1 Hz, 1H in CH2), 1.30 (t, J¼7.1 Hz, 3H,
4.3.6. Ethyl
glycinate (6fa). Colorless solid, yield: 82%, mp 128e130 ꢀC. 1H NMR
(400 MHz, CDCl3)
N-(5-oxo-5-phenyl-1-phthalimidopentane-2-sulfonyl)
d
: 7.97 (d, J¼8.0 Hz, 2H, ArHortho), 7.85 (dd, J¼5.2,
3.0 Hz, 2H, ArH), 7.73 (dd, J¼5.2, 3.0 Hz, 2H, ArH), 7.56 (dd, J¼7.2,
7.2 Hz, 1H, ArHpara), 7.45 (dd, J¼8.0, 7.2 Hz, 2H, ArHmeta), 5.83
(dd, J¼6.0, 5.6 Hz, 1H, NH), 4.30 (dd, J¼14.9, 6.0 Hz, 1H in CH2N),
CH3). 13C NMR (100 MHz, CDCl3)
d
: 178.6, 169.9, 168.5, 134.25,
131.71,123.56, 66.44, 61.9, 58.7, 44.51, 36.63, 36.2, 29.1, 28.6,14.0. Its

S. Kakaei, J. Xu / Tetrahedron 69 (2013) 9068e9075
9073
diastereomer
d
: 178.4, 170.0, 168.8, 134.31, 131.68, 123.61, 66.49,
3288.9, 2949.5, 2930.3, 2872.6, 1777.2, 1741.9, 1715.9, 1610.7, 1339.5,
1144.0. HRMS (ESI) calcd for C25H29N2O8S m/z: 517.1639 [MþH]þ;
found 517.1640.
61.9, 58.3, 44.56, 37.2, 36.63, 29.3, 28.2, 14.0. IR (nmax, cmꢂ1) 3301.7,
2978.5, 2927.3, 1768.1, 1712.7, 1612.1, 1371.4, 1141.6. HRMS (ESI)
calcd for C19H22N2NaO8S m/z: 461.0989 [MþNa]þ; found 461.0990.
4.3.13. Ethyl (S)-N-(methoxy-5-oxo-1-phthalimidopentane-2-
4.3.10. Ethyl
(6ia). Colorless solid, yield: 58%, mp 71e75 ꢀC. 1H NMR (CDCl3,
400 MHz)
N-(1,4-diphthalimidobutane-2-sulfonyl)glycinate
sulfonyl)tyrosinate (6bd). Colorless oil, yield: 60%, (Dr 50:50). 1H
NMR (CDCl3, 400 MHz) d: 7.85e7.83 (m, 2H, ArH), 7.73e7.71 (m, 2H,
d
: 7.80 (dd, J¼5.5, 3.1 Hz, 4H, ArH), 7.71 (dd, J¼5.5, 3.1 Hz,
ArH), 7.11 (d, J¼8.5 Hz, 2H, ArH), 7.01 (d, J¼8.5 Hz, 2H, ArH), 5.65 (d,
J¼9.2 Hz, 1H, NH), 5.59 (s, 1H, OH), 4.45e4.40 (m, 1H, CHN), 4.40
(dd, J¼15.2, 6.8 Hz,1H in CH2N), 4.22 (q, J¼7.1 Hz, 2H, CH2O), 3.66 (s,
3H, CH3O), 3.78 (dd, J¼15.2, 5.2 Hz, 1H in CH2N), 3.31 (dddd, J¼7.1,
6.8, 6.3, 5.2 Hz, 1H, CHS), 3.17e3.09 (m, 2H, CH2Ar), 2.66e2.59 (m,
2H, CH2CO), 2.14 (dddd, J¼15.2, 7.3, 6.9, 6.3 Hz, 1H in CH2), 1.78
(dddd, J¼15.2, 7.7, 7.2, 7.1 Hz, 1H in CH2), 1.27 (t, J¼7.1 Hz, 3H, CH3).
4H, ArH), 5.87 (dd, J¼5.7, 5.6 Hz,1H, NH), 4.38 (dd, J¼15.1, 5.7 Hz,1H
in CH2N), 4.31 (dd, J¼15.1, 4.7 Hz, 1H in CH2N), 4.17 (q, J¼7.1 Hz, 2H,
OCH2), 4.13e3.96 (m, 4H, 2CH2N), 3.49 (dddd, J¼6.7, 6.4, 5.6, 4.8 Hz,
1H, CHS), 2.42 (dddd, J¼14.2, 7.4, 6.9, 6.7 Hz, 1H in CH2), 2.05 (dddd,
J¼14.2, 7.0, 6.6, 6.0 Hz, 1H in CH2), 1.26 (t, J¼7.1 Hz, 3H, CH3). 13C
NMR (100 MHz, CDCl3) d: 169.9, 168.6, 168.2, 134.2, 133.9, 131.9,
131.7, 123.5, 123.3, 61.8, 58.7, 44.6, 36.7, 35.4, 26.5, 14.1. IR (nmax
,
Its diastereomer d: 7.85e7.83 (m, 2H, ArH), 7.73e7.71 (m, 2H, ArH),
cmꢂ1) 3298.6, 2949.5, 2923.8, 2872.6, 1774.0, 1711.8, 1396.5, 1140.8.
HRMS (ESI) calcd for C24H24N3O8S m/z: 536.1098 [MþNa]þ; found
536.1100.
6.78 (d, J¼7.0 Hz, 2H, ArH), 6.76 (d, J¼7.0 Hz, 2H, ArH), 5.59 (s, 1H,
OH), 5.54 (d, J¼9.4 Hz, 1H, NH), 4.41e3.97 (m, 1H, CHN), 4.19 (q,
J¼7.1 Hz, 2H, CH2O), 4.07 (dd, J¼14.8, 7.1 Hz, 1H in CH2N), 3.62 (dd,
J¼14.8, 5.3 Hz, 1H in CH2N), 3.66 (s, 3H, CH3O), 3.24 (dddd, J¼7.1, 7.1,
6.4, 5.3 Hz, 1H, CHS), 3.06e3.99 (m, 2H, CH2Ar), 2.59e2.51 (m, 2H,
CH2CO), 2.06 (dddd, J¼14.5, 7.9, 6.4, 6.4 Hz, 1H in CH2), 1.89 (dddd,
J¼14.5, 7.4, 7.3, 7.1 Hz, 1H in CH2), 1.24 (t, J¼7.1 Hz, 3H, CH3). 13C
4.3.11. Methyl (S)-N-(methoxy-5-oxo-1-phthalimidopentane-2-
sulfonyl)alaninate (6bb). Colorless oil, yield: 61%, (Dr¼50:50). 1H
NMR (CDCl3, 400 MHz)
d
: 7.84e7.81 (m, 4H, ArH), 5.94 (d, J¼8.3 Hz,
1H, NH), 4.29 (dd, J¼14.7, 7.3 Hz, 1H in CH2N), 4.26 (dd, J¼14.7,
7.2 Hz, 1H in CH2N), 4.19 (dd, J¼15.0, 5.1 Hz, 1H, CHN), 3.76 (s, 3H,
CH3O), 3.74 (s, 3H, CH3O), 3.48 (dddd, J¼8.0, 7.2, 6.4, 6.4 Hz, 1H,
CHS), 2.75 (ddd, J¼16.9, 8.0, 7.5 Hz, 1H in CH2CO), 2.72e2.67 (m, 1H
in CH2CO), 2.26 (dddd, J¼14.3, 8.0, 8.0, 6.4 Hz, 1H in CH2), 2.04
(dddd, J¼15.0, 7.8, 7.8, 6.8 Hz, 1H in CH2), 1.51 (d, J¼4.1 Hz, 3H, CH3).
NMR (CDCl3, 100 MHz)
130.8, 127.34, 123.65, 115.7, 61.9, 60.1, 57.8, 51.83, 38.9, 36.9, 30.91,
22.6,14.1. Its diastereomer : 172.98,171.6,168.3,155.1,134.21,131.8,
d: 173.02, 171.7, 168.5, 155.1, 134.22, 131.8,
d
130.8, 127.25, 123.59, 115.6, 61.9, 59.9, 57.6, 51.78, 38.7, 36.9, 30.85,
22.5, 14.1. IR (nmax, cmꢂ1) 3474.7, 3295.4, 2952.7, 2936.7, 1777.2,
1716.1, 1617.1, 1399.9, 1143.5. HRMS (ESI) calcd for C25H28N2NaO9S
m/z: 555.1408 [MþNa]þ; found 555.1409.
Its diastereomer
d: 7.72e7.70 (m, 4H, ArH), 5.73 (d, J¼8.6 Hz, 1H,
NH), 4.26 (dd, J¼14.7, 7.2 Hz, 1H in CH2N), 4.10 (dd, J¼15.0, 5.3 Hz,
1H, CHN), 3.92 (dd, J¼14.7, 6.1 Hz, 1H in CH2N), 3.63 (s, 3H, CH3O),
3.62 (s, 3H, CH3O), 3.48 (dddd, J¼7.2, 7.2, 6.4, 6.1 Hz, 1H, CHS),
2.68e2.66 (m, 1H in CH2CO), 2.65e2.57 (m, 1H in CH2CO), 2.18
(dddd, J¼14.3, 7.5, 7.2, 6.4 Hz, 1H in CH2), 1.97 (dddd, J¼15.0, 7.4, 7.4,
6.8 Hz, 1H in CH2), 1.49 (d, J¼4.1 Hz, 3H, CH3). 13C NMR (CDCl3,
4.3.14. Methyl (S)-N-(methoxy-5-oxo-1-phthalimidopentane-2-
sulfonyl)leucinate (6be). Colorless oil, yield: 65%, (Dr 61:39). 1H
NMR (CDCl3, 400 MHz) d: 7.87e7.85 (m, 2H, ArH), 7.74e7.72 (m, 2H,
ArH), 5.89 (d, J¼9.1 Hz, 1H, NH), 4.26 (ddd, J¼9.1, 5.6, 5.5 Hz, 1H,
CHN), 4.12 (dd, J¼14.2, 7.3 Hz, 1H in CH2N), 4.10 (dd, J¼14.2, 4.9 Hz,
1H in CH2N), 3.76 (s, 3H, CH3O), 3.67 (s, 3H, CH3O), 3.40 (dddd,
J¼6.4, 6.3, 5.0, 4.9 Hz, 1H, CHS), 2.71 (ddd, J¼16.5, 7.8, 7.8 Hz, 1H in
CH2CO), 2.63 (ddd, J¼16.5, 7.8, 6.8 Hz, 1H in CH2CO), 2.11e2.02 (m,
1H in CH2), 1.92e1.87 (m, 1H in CH2), 1.85e1.77 (m, 1H, CH),
1.73e1.66 (m, 2H, CH2), 0.97e0.94 (m, 6H, 2CH3). Its diastereomer
100 MHz)
51.6, 36.9, 30.7, 22.4, 19.9. Its diastereomer
134.1, 131.6, 123.4, 59.6, 52.59, 51.8, 51.6, 36.8, 30.6, 22.4, 19.8. IR
d
: 173.2, 172.8, 168.5, 134.1, 131.6, 123.4, 59.64, 52.60, 51.9,
d: 173.0, 172.8, 168.1,
(
nmax, cmꢂ1) 3299.0, 2927.1, 2843.8, 1741.9, 1712.4, 1399.3, 1139.9.
HRMS (ESI) calcd for C19H25N2O8S m/z: 441.1326 [MþH]þ; found
441.1327.
d: 7.87e7.85 (m, 2H, ArH), 7.74e7.72 (m, 2H, ArH), 5.59 (d, J¼9.4 Hz,
1H, NH), 4.35 (dd, J¼14.8, 4.9 Hz, 1H in CH2N), 4.22 (ddd, J¼9.4, 5.9,
5.8 Hz, 1H, CHN), 3.95 (dd, J¼14.8, 5.4 Hz, 1H in CH2N), 3.79 (s, 3H,
CH3O), 3.68 (s, 3H, CH3O), 3.47 (dddd, J¼6.2, 6.1, 5.9, 5.8 Hz, 1H,
CHS), 2.80 (ddd, J¼15.2, 7.5, 7.5 Hz, 1H in CH2CO), 2.29 (ddd, J¼15.2,
6.8, 6.6 Hz, 1H in CH2CO), 2.17 (dddd, J¼14.2, 6.7, 6.5, 6.3 Hz, 1H in
CH2), 1.95 (dddd, J¼14.2, 7.4, 6.9, 6.9 Hz, 1H in CH2), 1.85e1.77 (m,
1H, CH), 1.65e1.58 (m, 2H, CH2), 0.99e0.97 (m, 6H, 2CH3). 13C NMR
4.3.12. Ethyl (S)-N-(methoxy-5-oxo-1-phthalimidopentane-2-
sulfonyl)phenylalaninate (6bc). Colorless oil, yield: 56%, (Dr
54:46). 1H NMR (CDCl3, 400 MHz)
d: 7.86e7.83 (m, 2H, ArH),
7.73e7.71 (m, 2H, ArH), 7.35e7.25 (m, 5H, ArH), 5.64 (d, J¼9.2 Hz,
1H, NH), 4.50 (ddd, J¼9.2, 7.2, 4.8 Hz,1H, CHN), 4.21 (q, J¼7.2 Hz, 2H,
OCH2), 4.03 (dd, J¼14.8, 7.2 Hz,1H in CH2N), 3.95 (dd, J¼14.8, 6.0 Hz,
1H in CH2N), 3.66 (s, 3H, CH3O), 3.34 (dddd, J¼7.2, 6.4, 6.4, 6.0 Hz,
1H, CHS), 3.23e3.18 (m, 2H, CH2Ar), 2.65 (ddd, J¼16.8, 7.6, 7.6 Hz,
2H, CH2CO), 2.57 (ddd, J¼16.8, 7.2, 7.2 Hz, 1H in CH2CO), 2.13 (dddd,
J¼14.8, 7.6, 7.6, 6.4 Hz, 1H in CH2), 1.89 (dddd, J¼14.8, 7.2, 7.2, 7.2 Hz,
(CDCl3, 100 MHz)
54.8, 52.56, 51.7, 42.4, 36.8, 30.9, 24.4, 22.8, 22.62, 21.46. Its di-
astereomer : 173.6, 172.9, 168.3, 134.23, 131.8, 123.6, 60.2, 55.1,
52.61, 51.8, 42.8, 37.1, 30.9, 24.4, 22.72, 22.65, 21.54. IR (nmax, cmꢂ1
d: 173.6, 172.9, 168.8, 134.26, 131.8, 123.6, 60.2,
d
)
1H in CH2), 1.26 (t, J¼7.2 Hz, 3H, CH3). Its diastereomer
d
: 7.86e7.83
3292.2, 2949.5, 2869.4, 1777.2, 1736.2, 1716.4, 1614.3, 1398.8, 1139.3.
HRMS (ESI) calcd for C21H29N2O8S m/z: 469.1639 [MþH]þ; found
469.1648.
(m, 2H, ArH), 7.73e7.71 (m, 2H, ArH), 7.35e7.25 (m, 5H, ArH), 5.51
(d, J¼9.3 Hz, 1H, NH), 4.45 (ddd, J¼9.3, 7.2, 4.8 Hz, 1H, CHN), 4.19 (q,
J¼7.2 Hz, 2H, CH2O), 4.00 (dd, J¼14.8, 5.2 Hz, 1H in CH2N), 3.75 (dd,
J¼14.8, 5.2 Hz, 1H in CH2N), 3.66 (s, 3H, CH3O), 3.24 (dddd, J¼7.2,
6.4, 5.2, 5.2 Hz, 1H, CHS), 3.13 (dd, J¼7.2, 4.8 Hz, 1H in CH2Ar), 3.09
(dd, J¼7.2, 4.8 Hz, 1H in CH2Ar), 2.65 (ddd, J¼16.8, 7.6, 7.6 Hz, 2H,
CH2CO), 2.53 (ddd, J¼16.8, 7.2, 7.2 Hz, 1H in CH2CO), 2.05 (dddd,
J¼14.8, 7.6, 7.6, 6.4 Hz, 1H in CH2), 1.76 (dddd, J¼14.8, 7.2, 7.2, 6.4 Hz,
4.3.15. Ethyl (S)-N-(ethoxy-5-oxo-1-phthalimidopentane-2-sulfonyl)
tyrosinate (6cd). Colorless oil, yield: 54%, (Dr 58:42). 1H NMR
(CDCl3, 400 MHz) d: 7.86e7.83 (m, 2H, ArH), 7.73e7.71 (m, 2H, ArH),
7.12 (d, J¼8.4 Hz, 2H, ArH), 7.09 (d, J¼8.4 Hz, 2H, ArH), 5.62 (d,
J¼9.2 Hz, 1H, NH), 5.19 (s, 1H, OH), 4.48e4.43 (m, 1H, CHN),
4.15e4.09 (m, 4H, 2CH2O), 4.00 (dd, J¼14.8, 7.2 Hz, 1H in CH2N),
3.78 (dd, J¼14.8, 5.3 Hz, 1H in CH2N), 3.33 (dddd, J¼7.2, 6.1, 5.9,
5.3 Hz,1H, CHS), 3.24 (d, J¼13.6 Hz,1H in CH2Ar), 3.21 (d, J¼13.6 Hz,
1H in CH2Ar), 2.66e2.59 (m, 2H, CH2CO), 2.06 (dddd, J¼14.6, 6.6,
6.5, 6.4 Hz, 1H in CH2), 1.78 (dddd, J¼14.6, 7.7, 7.3, 7.3 Hz, 1H in CH2),
1H in CH2), 1.26 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d:
172.81, 171.6, 168.4, 135.52, 134.2, 131.8, 129.6, 128.7, 127.3, 123.5,
61.9, 59.8, 57.6, 51.71, 39.5, 36.9, 30.9, 22.47, 14.0. Its diastereomer
172.84, 171.4, 168.2, 135.48, 134.2, 131.8, 129.6, 128.6, 127.3, 123.5,
61.9, 60.0, 57.4, 51.71, 39.8, 36.8, 30.8, 22.52, 14.0. IR (nmax, cmꢂ1
d:
)

9074
S. Kakaei, J. Xu / Tetrahedron 69 (2013) 9068e9075
1.27 (t, J¼7.1 Hz, 3H, CH3), 1.26 (t, J¼7.1 Hz, 3H, CH3). Its di-
astereomer : 7.86e7.83 (m, 2H, ArH), 7.73e7.71 (m, 2H, ArH), 6.79
46.5 [46.0 (Rotamer)], 44.2 [43.9 (Rotamer)], 30.7 [30.6 (Rotamer)],
23.5 [22.8 (Rotamer)], 14.0. IR (nmax, cmꢂ1) 3288.2, 2980.4, 2936.7,
2875.8, 1746.9, 1698.3, 1492.2, 1332.6, 1139.2. HRMS (ESI) calcd for
d
(d, J¼8.0 Hz, 2H, ArH), 6.77 (d, J¼8.0 Hz, 2H, ArH), 5.52 (d, J¼9.4 Hz,
1H, NH), 5.19 (s, 1H, OH), 4.48e4.43 (m, 1H, CHN), 4.21 (q, J¼7.1 Hz,
2H, CH2O), 4.19 (q, J¼7.1 Hz, 2H, CH2O), 4.00 (d, J¼6.3 Hz, 1H, CHN),
3.38e3.34 (m, 1H in CH2N), 3.27e3.22 (m, 1H, CHS), 3.64e3.55 (m,
2H, CH2Ar), 2.59e2.49 (m, 2H, CH2CO), 2.13 (dddd, J¼14.4, 6.5, 6.4,
6.4 Hz,1H in CH2),1.89 (dddd, J¼14.4, 7.4, 7.2, 7.1 Hz,1H in CH2),1.27
(t, J¼7.1 Hz, 3H, CH3), 1.26 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3,
C
17H25N2O6S m/z: 385.1428 [MþH]þ; found 385.1434.
4.4.3. Methyl (S)-N-[(S)-N-benzyloxycarbonylpyrrolidine-2-
ylmethanesulfonyl]alaninate (9bb). Colorless oil, yield: 73%. Two
different rotamers exist in a molar ration of approximate 2:1 in
solution due to rigid proline residue. 1H NMR (CDCl3, 400 MHz)
d:
100 MHz)
123.7, 115.7, 61.9, 60.68, 59.9, 57.8, 38.7, 37.78, 36.87, 31.2, 22.5,
14.09. Its diastereomer : 172.64, 171.7, 166.3, 164.9, 134.2, 131.8,
d: 172.68, 171.6, 166.5, 165.0, 134.19, 131.8, 130.8, 127.1,
7.38e7.30 (m, 5H, ArH), 5.94 [5.03 (Rotamer)] (d, J¼8.2 Hz, 1H, NH),
5.13 [5.10 (Rotamer)] (s, 2H, CH2O), 4.56e4.49 [4.40e4.32
(Rotamer)] (m, 1H, CHN), 4.24 [4.00e3.93 (Rotamer)] (dddd, J¼7.5,
7.5, 6.2, 6.2 Hz, 1H, CHN), 3.76 [3.69 (Rotamer)] (s, 3H, CH3O), 3.49
(dd, J¼13.8, 6.2 Hz, 1H in CH2SO2), 3.44 (t, J¼7.2 Hz, 2H, CH2N), 2.99
[2.23 (Rotamer)] (dd, J¼13.8, 7.5 Hz, 1H in CH2SO2), 2.14e2.07 (m,
1H in CH2), 2.05e1.98 (m, 1H in CH2), 1.95e1.89 [1.88e1.82
(Rotamer)] (m, 2H, CH2),1.51 [1.29 (Rotamer)] (d, J¼7.1 Hz, 3H, CH3).
d
130.8, 127.1, 123.7, 115.6, 61.9, 60.75, 60.1, 57.6, 39.0, 37.84, 36.9, 31.1,
22.6, 14.14. IR (nmax, cmꢂ1) 3449.1, 3282.6, 2981.5, 2949.5, 2929.6,
1777.2, 1715.9, 1610.7, 1399.1, 1190.6. HRMS (ESI) calcd for
C
26H31N2O9S m/z: 547.1745 [MþH]þ; found 547.1748.
4.4. General procedure for synthesis of N-benzyloxycarbonyl-
13C NMR (100 MHz, CDCl3)
d: 173.4, 155.4, 136.6, 128.6 [128.5
protected sulfonopeptides 9
(Rotamer)],128.2 [128.02 (Rotamer)],128.08 [127.8 (Rotamer)], 67.2
[67.0 (Rotamer)], 56.2 [55.6 (Rotamer)], 54.0 [53.7 (Rotamer)], 53.1
[52.7 (Rotamer)], 51.8 [51.5 (Rotamer)], 46.6 [46.1 (Rotamer)], 30.6
[30.4 (Rotamer)], 23.5 [23.5 (Rotamer)], 19.7. IR (nmax, cmꢂ1) 3281.2,
3029.5, 2978.3, 2954.6, 2883.6, 1744.1, 1697.2, 1498.1, 1336.0,
1134.43. HRMS (ESI) calcd for C17H25N2O6S m/z: 385.1428 [MþH]þ;
found 385.1434.
NCS (534 mg, 4 mmol) was dissolved in a mixture of 2 M HCl
(0.8 mL) and MeCN (4 mL). The resulting solutionwas cooled to 10 ꢀC.
A solution of thiolacetate 7 (1 mmol) in MeCN (1 mL) was added
dropwise to the cooled solution at below 20 ꢀC. The resulting solution
wasstirredatthe same temperature for 30min, and thendilutedwith
isopropyl ether (5 mL). The organic layer was washed with aq NaCl
(12%, 3ꢁ5 mL) and then dried over anhydrous Na2SO4. After con-
centration in vacuo, the crude sulfonyl chloride 8 was obtained as
colorless solids or pale yellow oil, and used directly without further
purification. The sulfonyl chloride 8 was dissolved in dry dichloro-
methane (2 mL) and the resulting solution was added dropwise into
a solution of amino ester hydrochloride salt 5 (1 mmol) and trie-
thylamine (222 mg, 2.2 mmol) in DCM (1 mL) under stirring at 0e5 ꢀC
in an ice-water bath. After addition, the resulting mixture was stirred
for another 12 h at the same temperature and was allowed to warm to
room temperature. The solution was concentrated in vacuo to afford
the crude product 9. Further recrystallization from ethanol gave rise
to N-Cbz-protected sulfonopeptide as colorless crystals or chroma-
tography gave rise to colorless oil.
4.4.4. Ethyl (S)-N-[(S)-N-benzyloxycarbonylpyrrolidine-2-
ylmethanesulfonyl]tyrosinate (9bd). Colorless oil, yield: 60%. Two
different rotamers exist in a molar ration of approximate 3:2 in
solution due to rigid proline residue. 1H NMR (CDCl3, 400 MHz)
d:
7.43e7.30 (m, 5H, ArH), 7.04 [6.92 (Rotamer)] (d, J¼7.8 Hz, 2H, ArH),
6.72 [6.70 (Rotamer)] (d, J¼7.8 Hz, 2H, ArH), 5.69 [5.22 (Rotamer)]
(s, 1H, OH), 5.12 [5.05e4.94 (Rotamer)] (s, 2H, CH2O), 4.38 (s, br, 1H,
NH), 4.17 [4.13 (Rotamer)] (q, J¼7.1 Hz, 2H, CH2O), 3.45e3.37 (m,
3H, 2CHN & 1H in CH2SO2), 3.10e2.96 (m, 2H, CH2N), 2.76 (dd,
J¼13.4, 7.9 Hz,1H in CH2SO2), 2.24e2.15 (m, 2H, CH2), 2.05e1.95 (m,
2H, CH2), 1.91e1.72 (m, 2H, CH2), 1.25 [1.24 (Rotamer)] (t, J¼7.1 Hz,
3H, CH3). 13C NMR (CDCl3, 100 MHz)
d: 171.7 [171.4 (Rotamer)],
155.2 [155.1 (Rotamer)], 136.5 [136.3 (Rotamer)], 130.9 [130.8
(Rotamer)], 128.6 [128.5 (Rotamer)], 128.2 [128.0 (Rotamer)], 127.9
[127.1 (Rotamer)], 115.7 [115.5 (Rotamer)], 67.2 [67.0 (Rotamer)],
62.0 [61.8 (Rotamer)], 57.5 [57.2 (Rotamer)], 56.1 [55.4 (Rotamer)],
53.6 [52.8 (Rotamer)], 46.2 [46.1 (Rotamer)], 38.8 [38.6 (Rotamer)],
4. 4 .1. E t hyl N - [( S) - N - b e n z ylo xyca r b onyl - 2- am i n o-2 -
phenylethanesulfonyl]glycinate (9aa). Colorless solid, yield: 93%,
mp 122e125 ꢀC. 1H NMR (CDCl3, 400 MHz)
d: 7.38e7.26 (m, 10H,
ArH), 6.07 (s, br, 1H, NH), 5.61 (s, br, 1H, NH), 5.55e5.51 (m, 1H,
CHN), 5.09 (s, 2H, CH2O), 4.21 (q, J¼7.1 Hz, 2H, OCH2), 3.95e3.88
(m, 2H, CH2N), 3.57 (dd, J¼14.6, 10.3 Hz, 1H in CH2SO2),
3.43e3,47 (m, 1H in CH2SO2), 1.27 (t, J¼7.1 Hz, 3H, CH3). 13C NMR
30.1, 23.4 [22.6 (Rotamer)], 14.1 [14.0 (Rotamer)]. IR (nmax, cmꢂ1
)
3285.5, 2981.9, 2,91.9, 2933.1, 2878.7, 1736.8, 1696.9, 1613.3, 1338.4,
1146.1. HRMS (ESI) calcd for C24H31N2O7S m/z: 491.1846 [MþH]þ;
found 491.1854.
(100 MHz, CDCl3): d: 170.4, 156.2, 139.6, 136.2, 129.0, 128.4, 128.1,
126.2, 67.1, 61.9, 58.1, 51.5, 44.4, 14.1. IR (nmax, cmꢂ1) 3317.8,
3295.7, 2984.7, 2939.9, 2917.4, 1743.0, 1689.1, 1536.2, 1371.5,
1140.5. HRMS (ESI) calcd for C20H25N2O6S m/z: 421.1428 [MþH]þ;
found 421.1434.
4.4.5. Methyl
(S)-N-[(S)-N-benzyloxycarbonylpyrrolidine-2-ylme-
thanesulfonyl]leucinate (9be). Colorless oil, yield: 81%. Two differ-
ent rotamers exist in a molar ration of approximate 3:1 in solution
due to rigid proline residue. 1H NMR (CDCl3, 400 MHz)
d: 7.36e7.31
(m, 5H, ArH), 5.92 [4.79 (Rotamer)] (d, J¼9.2 Hz, 1H, NH), 5.14 [5.15
(Rotamer)] (s, 2H, CH2O), 4.58 [4.40 (Rotamer)] (ddd, J¼9.2, 6.5,
6.0 Hz, 1H, CHN), 4.19 [3.99 (Rotamer)] (dddd, J¼8.6, 8.6, 6.9, 6.9 Hz,
1H, CHN), 3.75 [3.66 (Rotamer)] (s, 3H, CH3O), 3.45 (t, J¼7.4 Hz, 2H,
CH2N), 3.39 (dd, J¼13.7, 6.7 Hz, 1H in CH2SO2), 2.97 (dd, J¼13.7,
6.9 Hz, 1H in CH2SO2), 2.16e2.05 [2.24e2.17 (Rotamer)] (m, 2H,
CH2), 1.95e1.92 (m, 2H, CH2), 1.88e1.83 (m, 1H, CH), 1.65e1.61 (m,
4.4.2. Ethyl N-[(S)-N-benzyloxycarbonylpyrrolidine-2-
ylmethanesulfonyl]glycinate (9ba). Colorless oil, yield: 85%. Two
different rotamers exist in a molar ration of approximate 4:1 in
solution due to rigid proline residue. 1H NMR (CDCl3, 400 MHz)
d:
7.43e7.31 (m, 5H, ArH), 5.90 [5.15 (Rotamer)] (s, br, 1H, NH), 5.12 (s,
2H, CH2O), 4.49 [4.31 (Rotamer)] (m, 1H, CHN), 4.24e4.21 (m, 3H,
OCH2 & 1H in CH2N), 3.98e3.90 (m, 1H in CH2N), 3.57 (dd, J¼14.0,
4.9 Hz, 1H in CH2SO2), 3.45 (t, J¼6.4 Hz, 2H, CH2N), 3.05 (dd, J¼14.0,
7.4 Hz, 1H in CH2SO2), 2.17e1.99 (m, 2H, CH2), 1.96e1.83 (m, 2H,
2H, CH2), 0.97e0.93 (m, 6H, 2CH3). 13C NMR (100 MHz, CDCl3)
d:
173.7, 155.43 [155.42 (Rotamer)], 136.6, 128.5 [128.4 (Rotamer)],
128.1 [127.9 (Rotamer)], 127.8 [127.7 (Rotamer)], 67.0, 56.3 [55.7
(Rotamer)], 54.6 [54.4 (Rotamer)], 53.6, 52.9 [52.5 (Rotamer)], 46.4
[45.9 (Rotamer)], 42.2 [42.1 (Rotamer)], 30.7 [30.4 (Rotamer)], 24.4
[24.3 (Rotamer)], 23.43 [23.36 (Rotamer)], 22.78 [22.68 (Rotamer)],
21.6 [21.4 (Rotamer)]. IR (nmax, cmꢂ1) 3272.9, 3032.7, 2956.6, 2874.4,
CH2), 1.28 (t, J¼6.9 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3)
d: 169.8
[169.7 (Rotamer)], 155.34 [155.26 (Rotamer)], 136.5, 128.5 [128.4
(Rotamer)], 128.1 [127.9 (Rotamer)], 127.7, 67.2 [66.9 (Rotamer)],
61.8 [61.7 (Rotamer)], 56.0 [55.4 (Rotamer)], 53.7 [53.0 (Rotamer)],

S. Kakaei, J. Xu / Tetrahedron 69 (2013) 9068e9075
9075
Org. Chem. 1992, 57, 764e766; (c) Braghiroli, D.; Di Bella, M.; Saladini, M.
Tetrahedron: Asymmetry 1996, 7, 831e836; (d) Braghiroli, D.; Di Bella, M.
Tetrahedron: Asymmetry 1997, 8, 2209e2213; (e) Moree, W. J.; van der
Marel, G. A.; Liskamp, R. M. J. Tetrahedron Lett. 1992, 33, 6389e6392; (f)
Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J. J. Org. Chem. 1995, 60,
5157e5169; (g) Monnee, M. C. F.; Marijne, M. F.; Brouwer, A. J.; Liskamp, R.
M. J. Tetrahedron Lett. 2000, 41, 7991e7995; (h) Cordero, F. M.; Cacciarini,
M.; Machetti, F.; De Darlo, F. Eur. J. Org. Chem. 2002, 1407e1411; (i)
Brouwer, A. J.; Ceylan, T.; van der Linden, T.; Liskamp, R. M. J. Tetrahedron
Lett. 2009, 50, 3391e3393.
1744.4, 1698.7, 1492.2, 1336.0, 1139.4. HRMS (ESI) calcd for
C
20H31N2O6S m/z: 427.1897 [MþH]þ; found 427.1906.
Acknowledgements
This work was supported in part by the National Basic Research
Program of China (No. 2013CB328900) and the National Natural
Science Foundation of China (Project No 20972013).
5. (a) Xu, J. X. Tetrahedron: Asymmetry 2002, 13, 1129e1134; (b) Xu, J. X.; Xu, S.
Synthesis 2004, 276e282; (c) Huang, J. X.; Wang, F.; Du, D. M.; Xu, J. X. Synthesis
2005, 2122e2128; (d) Huang, J. X.; Du, D. M.; Xu, J. X. Synthesis 2006, 315e319;
(e) Hu, L. B.; Zhu, H.; Du, D. M.; Xu, J. X. J. Org. Chem. 2007, 72, 4543e4546; (f)
Zhang, W.; Wang, B. Y.; Chen, N.; Du, D. M.; Xu, J. X. Synthesis 2008, 197e200;
(g) Wang, B. Y.; Zhang, W.; Zhang, L. L.; Du, D. M.; Liu, G.; Xu, J. X. Eur. J. Org.
Chem. 2008, 350e355; (h) Yu, H.; Cao, S. L.; Zhang, L. L.; Liu, G.; Xu, J. X. Syn-
thesis 2009, 2205e2209; (i) Chen, N.; Zhu, M.; Zhang, W.; Du, D. M.; Xu, J. X.
Amino Acids 2009, 37, 309e313; (j) Chen, N.; Jia, W. Y.; Xu, J. X. Eur. J. Org. Chem.
2009, 33, 5841e5846; (k) Xu, C. X.; Xu, J. X. Amino Acids 2011, 41, 195e203; (l)
Chen, N.; Xu, J. X. Tetrahedron 2012, 68, 2513e2522.
6. (a) Lowik, D. W. P. M.; Liskamp, R. W. J. Eur. J. Org. Chem. 2000, 1219e1228; (b)
Luisi, G.; Calcagni, A.; Pinnen, F. Tetrahedron Lett. 1993, 34, 2391e2392; (c)
Gude, M.; Piarulli, U.; Potenza, D.; Salom, B.; Gennari, C. Tetrahedron Lett. 1996,
47, 8589e8592; (d) Gennari, C.; Salom, B.; Potenza, D.; Williams., A. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2067e2069.
7. (a) Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J. Tetrahedron Lett. 1991, 32,
409e412; (b) Moree, W. J.; van Gent, L. C.; van der Marel, G. A.; Liskamp, R. M. J.
Tetrahedron 1993, 49, 1133e1150.
8. (a) He, F. D.; Meng, F. H.; Song, X. Q.; Hu, W. X.; Xu, J. X. Org. Lett. 2009, 11,
3922e3925; (b) Meng, F. H.; He, F. D.; Song, X. Q.; Zhang, L. L.; Hu, W. X.; Liu, G.;
Xu, J. X. Amino Acids 2012, 43, 423e429.
9. (a) Frankel, M.; Moses, P. Tetrahedron 1960, 9, 289e294; (b) Kricheldorf, H. R.;
Leppert, E. Synthesis 1976, 43e45.
10. Bischoff, L.; David, C.; Roques, B. P.; Fournie-Zaluski, M.-C. J. Org. Chem. 1999, 64,
1420e1423.
Supplementary data
Copies of the 1H NMR and 13C NMR spectra of all key in-
termediates and final products. Supplementary data related to
this article can be found online at http://dx.doi.org/10.1016/
j.tet.2013.08.028. These data include MOL files and InChiKeys of the
most important compounds described in this article.
References and notes
1. For reviews, see: (a) Marshall, G. R.; Kuster, D. J.; Che, Y. Chemogenomics:
Methods and Applications In Methods in Molecular Biology; Jacoby, E., Ed.;
Humana: Totawa, USA, 2009; pp 123e158; (b) Barret, A. G. M.; Hennessy, A. J.;
Le Vezouet, R.; Procopiou, P. A.; Seale, P. W.; Stefaniak, S.; Upton, R. J.; White, A.
J. P.; Williams, D. J. J. Org. Chem. 2004, 69, 1028e1037; (c) Dougherty, J. M.;
Probst, D. A.; Robinson, R. E.; Moore, J. D.; Klein, T. A.; Snelgrove, K. A.; Hanson,
P. R. Tetrahedron 2000, 56, 9781e9790.
2. (a) For a review, see: Xu, J. X. Chin. J. Org. Chem. 2003, 23, 1e9; (b) For an ex-
ample, see: Carson, K. G.; Schwender, C. F.; Shroff, H. N.; Cochran, N. A.; Gallant,
D. L.; Briskin, M. J. Bioorg. Med. Chem. Lett. 1997, 7, 711e714.
3. (a) Paik, S.; White, E. H. Tetrahedron 1996, 52, 5303e5318; (b) Merricks, D.;
Sammes, P. G.; Walker, E. R. H.; Henrick, K.; McPartlin, M. M. J. Chem. Soc., Perkin
Trans. 1 1991, 2169e2176.
11. Kakaei, S.; Chen, N.; Xu, J. X. Tetrahedron 2013, 69, 302e309.
12. Nishiguchi, A.; Maeda, K.; Miki, S. Synthesis 2006, 24, 4131e4134.
4. (a) Higashiura, H.; Morino, H.; Matsuura, H.; Toyomaki, Y.; Ienaga, K. J.
Chem. Soc., Perkin Trans. 1 1989, 1479e1481; (b) Higashiura, K.; Ienaga, K. J.