A simple synthesis of N β-Fmoc/Z-amino alkyl thiols and their use in the synthesis of N β-Fmoc/Z-amino alkyl sulfonic acids

Article abstract of DOI:10.1055/s-0029-1219584

A simple and efficient protocol for the synthesis of N^β- Fmoc/Z-amino alkyl thiols is described. The approach uses sodium pyrosulfite-mediated hydrolysis of isothiouronium salts resulting from the reaction between N-protected aminoalkyl iodides and thiourea. N-Protected taurines were prepared through performic acid oxidation of the thiols and the products were further utilized for the synthesis of dipeptidosulfonamides. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219584

LETTER
1037
A Simple Synthesis of Nb-Fmoc/Z-Amino Alkyl Thiols and their use in the
Synthesis of Nb-Fmoc/Z-Amino Alkyl Sulfonic Acids
b
N
-Fmoc/Z-Amino
.
A
lkyl Thiol
V
s
in Synthesis . Sureshbabu,* T. M. Vishwanatha, B. Vasantha
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi,
Bangalore University, Bangalore 560001, India
E-mail: sureshbabuvommina@rediffmail.com; E-mail: hariccb@hotmail.com
Received 10 December 2009
Abstract: A simple and efficient protocol for the synthesis of Nb-
Fmoc/Z-amino alkyl thiols is described. The approach uses sodium
pyrosulfite-mediated hydrolysis of isothiouronium salts resulting
SH
BocHN
from the reaction between N-protected aminoalkyl iodides and thio-
urea. N-Protected taurines were prepared through performic acid
oxidation of the thiols and the products were further utilized for the
synthesis of dipeptidosulfonamides.
1. LiAlH4, THF
2. (Boc)2O, CH2Cl2
3. DIAD, Ph3P, AcSH, THF
4. KOH, MeOH
1. LiAlH4
2. HBr, Ph3P
or SOBr2
HS
3. thiourea, EtOH
H
R
Key words: alkyl iodides, thiourea, alkyl thiols, N-protected tau-
rines, isothiuronium salts
Amino acid
Bn2N
CHO
H2N
1. RMgX, THF
1. LiAlH4, THF
2. MeCS2Me, Et3N,
THF, 0 °C
3. MsCl, Et3N
4. HCl aq, 5 M, reflux
2. H2, Pd/C, MeOH
3. R1Br, K2CO3, MeCN
4, MeSO2Cl, Et3N,
AcSH, Et3N
Thiols are important structural motifs in various biologi-
cally active molecules.1 Compounds containing this func-
tionality have served as key starting materials in the
synthesis of a variety of organosulfur compounds that
demonstrate pesticidal, fungicidal, antimicrobial, antibac-
terial, and antiviral activities.2 Chiral b-amino alkyl thiols
have found application as enzyme inhibitors,3 radio-pro-
tective agents,4 and also as intermediates for the synthesis
of libraries of biological interest.5 In peptide chemistry,
the thiol group of cysteine is utilized in various synthetic
applications, such as in the construction of S-glycopep-
tides.6 Often, oxygen or nitrogen atoms of native peptides
are replaced with sulfur to obtain novel thio-analogs,7 sev-
eral of which possess higher biological activities than the
corresponding natural materials. For example, replace-
ment of an amide bond in peptides by CH2–S linkages has
lead to surrogates that are potent inhibitors of aminopep-
tidase M.8 The amino thiols: cysteine, homocysteine and
pencillamine, are present in many complex biomole-
cules,9 and alkyl thiols are key precursors in the prepara-
tion of many medicinally important classes of molecules,
such as: thiocarbamates,10 thiocarbonates,11 and tau-
rines.12 They are also being employed as catalysts for
enantioselective organic synthesis.13
5. LiALH4, Et2O, 0 °C
HS
SH
N
HCl⋅H2N
R
R
Scheme 1
Some of the important routes employed for the synthesis
of amino alkyl thiols from amino acids are depicted in
Scheme 1. One example of an N-urethane-protected ami-
no alkyl thiol was reported by Myllamaki et al., who syn-
thesized Boc-Val-y[CH2SH] starting from valine. The
methodology involved the conversion of Boc-valinol into
the corresponding thioacetate using thioacetic acid under
Mitsunobu conditions, followed by KOH-mediated hy-
drolysis.18 Yang’s group described the synthesis of 1,2-
substituted amino thiols using dibenzyl-protected 1,2-
substituted b-amino thioacetates.19 An alternative route
for the synthesis of amino thiols employing methyl dithio-
acetate as a sulfur transfer reagent is also known.20 Otto’s
group has isolated free amino alkyl thiols (derived from
L-Ala, L-Val, L-Leu, L-Ile, and L-Phe) in three steps by
treating bromoalkylammonium hydrobromides with thio-
urea.21 In that report, the isolated yield of amino thiols was
in the range of 38–48% only. Although the authors em-
ployed various brominating reagents, such as HBr, PBr3
and SOBr2, for the conversion of the alcohols into bro-
mides, the reaction was not complete, which made the iso-
lation of the intermediates tedious. Overall, the multi-step
sequences, low yields, formation of byproducts and con-
sequent tedious product isolation procedures involved in
the above protocols, evoke the need for alternative meth-
odologies to be developed.
Thiols can be synthesized through deprotection of thioac-
etates by heating at reflux with NaBH4,14 by reaction of an
alkyl halide with NaSH,15 or through reaction of an acti-
vated alcohol in the form of tosylate/mesylate or that of
alkyl bromides with thiourea followed by hydrolysis us-
ing 1 N NaOH.16 However, in the latter cases, the harsh
conditions employed for such deprotection often leads to
dialkyl sulfides.17
SYNLETT 2010, No. 7, pp 1037–1042
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Advanced online publication: 17.03.2010
DOI: 10.1055/s-0029-1219584; Art ID: D35909ST
© Georg Thieme Verlag Stuttgart · New York

1038
V. V. Sureshbabu et al.
LETTER
Aminoalkylsulfonic acids,22 known as taurines, have a conditions.30 The method also facilitates the isolation of
significant role in various physiological processes23 and product with a simple work-up. Accordingly, treatment of
are found in mammalian tissues and other organisms.24 2c with sodium pyrosulfite in CH2Cl2–H2O (5:2) at reflux
They can serve as starting materials for the synthesis of for 30 minutes brought about complete hydrolysis of the
sulfonopeptides,25 wherein the peptide linkage is replaced isothiouronium salt. A simple aqueous work-up, followed
with a sulfonamide. Thus, owing to the vast number of by column purification, led to the desired thiol 3c as a pure
synthetic applications of amino acid derived thiols and solid in 88% yield.42,43 The generality of this protocol was
taurines, we report herein, a simple and high-yielding ap- demonstrated by the synthesis of several examples of
proach to the synthesis of Nb-Fmoc/Z-amino alkyl thiols thiols derived from N-Fmoc amino acids, including two
via the isothiouronium intermediate. Furthermore, subse- bifunctional products: Lys (2f) and Glu(OBn) (2g)
quent oxidation leading to Nb-protected amino alkyl sul- (Table 1).
fonic acids is described, the utility of which in the
preparation of a few N-Fmoc-protected dipeptidosulfon-
Table 1 Isothiouronium Salts 2
amides is also demonstrated.
Product PG
R
HRMS [M – I]+
Calcd Found
Yield (%)
In view of the general stability of the Fmoc group, its im-
mense utility in solid-phase peptide synthesis and han-
dling advantages associated with these compounds,26 we
initiated our study employing Fmoc chemistry. Fmoc-
amino acids were reduced to the corresponding alcohols
2a
2b
Fmoc
H
341.1198 341.1172 92
355.1354 355.1310 94
431.1667 431.1651 91
383.1667 383.1621 94
397.1824 397.1801 88
546.2301 546.2271 94
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Z
Me
via the mixed anhydride using the N-methyl morpholine/ 2c
Bn
ethyl chloroformate system, followed by treatment with
2d
i-Pr
NaBH4.27 The resulting N-Fmoc aminols were then con-
verted into the corresponding alkyl iodides28 under
2e
i-Bu
Mitsunobu conditions (Ph3P/imidazole/I2) in quantitative
yield. The next step was to insert a thiol group in place of
2f
(CH2)4NHZ
the iodide functionality, to afford the title molecules. We
chose N-Fmoc-Phe-y[CH2-I] (1c) as a typical example to
establish the optimal reaction conditions. To this end,
treatment of a solution of 1c in acetone with thiourea un-
der reflux (argon atmosphere) for 8–10 hours led to the
formation of isothiouronium salt 2c (Scheme 2).40 Evapo-
ration of the solvent followed by a single recrystallization
of the crude material, afforded the intermediate isothiou-
ronium salt as a pure white, stable solid in good yield
(91%). Similar results with respect to both yield and puri-
ty were observed when the reaction was repeated with
several other N-protected amino acids (Table 1); all the
2g
2h
2i
(CH2)2CO2Bn 503.1879 503.1771 93
-(CH2)3-
Bn
382.1589 382.1534 91
344.1433 344.1409 92
310.1589 310.1558 87
402.1488 402.1471 93
330.1276 330.1245 94
2j
2k
2l
Z
s-Bu
Z
CH2CO2Bn
Ph
Z
In a continuation of this study, several Z-amino alkyl io-
dides were also converted into their corresponding thiols
(3i–l) in good yields. All the thiols synthesized were
found to be stable for long periods on storage at low tem-
peratures. However, efforts to simplify this two-step pro-
tocol into a one-pot procedure starting from N-protected
amino alkyl iodide, obviating the isolation of the isothio-
uronium salt intermediate, gave only low overall yields.
products were characterized by H, 13C NMR and mass
1
analyses,41 and all were found to be stable for several
weeks at room temperature.
R
R
thiourea
I
S
NH2
NH2 I–
PGNH
PGNH
acetone, 60 °C
8–10 h
Having established a protocol for the conversion of N-
Fmoc-amino alkyl iodides into the corresponding isothio-
uronium salts, leading to the preparation of thiols, we ex-
amined the feasibility of following a similar protocol with
related intermediates such as N-Fmoc amino alkyl tosy-
lates and mesylates. For this, Fmoc-Phe-y[CH2OH] was
converted into its tosylate by employing a reported proce-
dure.31 On treatment of this intermediate with thiourea un-
der similar conditions to those described for the iodide
counterpart, the formation of the isothiouronium salt was
observed with no more than 50–60% conversion even af-
ter continuing the reaction for longer periods at reflux
(>18 h). Moreover, the isolation of the intermediate was
tedious due to the formation of several byproducts. A sim-
ilar result was obtained with Fmoc-amino acid derived
+
1a–l
2a–l
R
Na2S2O5
SH
PG = Fmoc, Z
PGNH
CH2Cl2–H2O
3a–l
Scheme 2
In the next set of experiments, we carried out the hydrol-
ysis of the isothiouronium salts leading to the title mole-
cules. Although base hydrolysis is widely used for this,29
such conditions are not compatible with Fmoc chemistry.
During our quest for an alternative procedure, a literature
survey revealed that aqueous sodium pyrosulfite is a mild
reagent for carrying out such hydrolysis under neutral
Synlett 2010, No. 7, 1037–1042 © Thieme Stuttgart · New York

LETTER
Nb-Fmoc/Z-Amino Alkyl Thiols in Synthesis
1039
mesylate {Fmoc-Phe-y[CH2OMs]}. Owing to the low Previously, the same group had reported a few other pro-
yield and other synthetic difficulties encountered in the cedures.36 Xu et al. have established a route for the synthe-
synthesis of the isothiouronium salt itself, the -OTs and sis of substituted taurines via oxidation of Z-b-amino
-OMs intermediates were judged to be less attractive for thioacetates employing performic acid.37 Aziridine ring-
the efficient preparation of thiols.
opening with thioacetic acid leading to the formation of
acetyl-b-amino thiols followed by oxidation is also
known.38 Although taurines have been prepared from
Boc- and Z-protected compounds, their synthesis using
Fmoc-chemistry has yet to be demonstrated. It was envis-
aged that performic acid oxidation would be a suitable
method for the conversion of our thiols into Nb-Fmoc/Z-
amino alkane sulfonic acids (Scheme 3). Accordingly, in
a typical reaction, a solution of thiol 3c in 98% formic acid
was added slowly to the oxidant solution at 0 °C; the mix-
ture was then allowed to warm to room temperature and
then stirred for one day. After removal of the solvent, the
crude material was purified on a silica gel column to af-
ford N-Fmoc-Phe-y[CH2SO3H] (4c) in 78% yield.44 The
protocol was successfully employed for the synthesis of a
The next part of the study involved the synthesis of N-pro-
tected taurines. Among the various methods available for
their preparation, direct conversion of amino alcohols via
sulfite displacement32 and performic acid oxidation of
Boc/Z-b-amino thioacetates are attractive.33 Gude et al.,
prepared a Boc-NH-Xaa-y[SO2Cl] series via betaines
obtained from mesylates of Boc-b-amino alcohols.34
Liskamp’s group reported the synthesis of N-Fmoc-b-amino-
ethanesulfonyl chlorides via the oxidation of N-Fmoc-b-
amino thioacetates generated by Cs2CO3-promoted reac-
tion of N-Fmoc-b-amino alkyl mesylate with thioacetic
acid. This intermediate step requires 18 hours and the
yields of corresponding thioacetates are usually low.35
Table 2 Thiols 3 and Sulfonic Acids 4
25
25
Entry Thiol 3
Mp (°C)
[a]D
Yield (%) N-Protected Taurines 4
Yield (%) [a]D
Mp (°C)
(c 1, CHCl3)
(c 1, CHCl3)
a
118
96
–
86
85
79
–
136
148
SH
SH
SO3H
FmocHN
FmocHN
b
–11.6
92
–23.1
–28.0
SO3H
FmocHN
FmocHN
Ph
Ph
c
109
98
+3.0
88
88
82
133
129
SH
SH
SO3H
FmocHN
FmocHN
d
–0.70
91
–41.3
–10.8
SO3H
FmocHN
FmocHN
e
81
–20.1
+5.6
84
86
81
135
119
SH
SO3H
FmocHN
FmocHN
NHZ
NHZ
f
113
88
–7.4
4
4
SH
COOBn
SO3H
FmocHN
FmocHN
CHOOBn
g
92
78
+3.4
–28.3
+6.8
94
71
87
69
70
65
–14.5
–39.2
–41.0
–9.5
113
125
131
115
98
2
2
SH
SO3H
FmocHN
FmocHN
SH
SO3H
h
79
N
N
Fmoc
Fmoc
Ph
Ph
i
105
96
91
SH
SH
SO3H
ZHN
ZHN
j
–10.8
+7.1
88
SO3H
ZHN
ZHN
COOBn
SH
COOBn
k
72
85
+1.2
SO3H
ZHN
ZHN
Ph
Ph
l
104
–48.3
90
73
+20.0
137
SO3H
SH
ZHN
ZHN
Synlett 2010, No. 7, 1037–1042 © Thieme Stuttgart · New York

1040
V. V. Sureshbabu et al.
LETTER
In summary, we have demonstrated a mild and efficient
route for the synthesis of N-Fmoc/Z-amino alkyl thiols
starting from the corresponding iodides. Performic acid
oxidation of the thiols afforded the respective taurines,
which were employed as precursors for the preparation of
a number of N-protected dipeptidyl sulfonamides. All the
products, including the isothiouronium salts, were isolat-
ed and adequately characterized.
R
R
H2O2
SH
SO3H
PGNH
HCOOH
PGNH
88%
4a–l
3a–l
Scheme 3
series of N-protected taurines in good yield and purity
(Table 2).45
In the next set of experiments, the utility of taurines for the
preparation of dipeptidosulfonamides was demonstrated
by coupling Fmoc-protected sulfonic acids with amino
Acknowledgment
We thank the Council of Scientific and Industrial Research [Grant
No. 01(2323)/09/EMR-II], New Delhi, India for financial support.
acid esters. In
a typical reaction, N-Fmoc-Val-
y[CH2SO3H] (4d) was converted into its sulfonyl chloride
by treatment with triphosgene and a catalytic amount of
DMF.39,46 The resulting sulfonylchloride was obtained in
71% yield after purification by flash chromatography.47
N-Fmoc-Val-y[CH2SO2Cl] (5d) was then coupled with
alanyl methyl ester in the presence of Et3N to obtain
dipeptidosulfonamide 6a in 72% yield after column puri-
fication (Scheme 4).48 In a similar manner, N-Fmoc-Phe-
y[CH2SO2]-Leu-OMe (6b) was also obtained in good
yield. Additionally, two epimeric sulfonopeptides 6c and
6d were prepared by coupling N-Fmoc-Ala-y[CH2SO2Cl]
(3b) with H-Phg-OMe (both L and D) in a separate set of
References and Notes
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triphosgene
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5
4
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N
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6
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Ph
O
O
O
O
S
S
FmocHN
N
COOMe
FmocHN
N
COOMe
Ph
H
H
6a
6b
Ph
O
O
O
O
S
S
FmocHN
N
COOMe
FmocHN
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COOMe
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Scheme 4
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This, in turn, also implies that N-Fmoc-Ala-y[CH2SH] is
optically pure. Therefore, it was concluded that the
present protocol, starting from the synthesis of thiols and
leading to the generation of taurines and peptidosulfon-
amides is free from racemization at levels detectable by
NMR analysis.
Synlett 2010, No. 7, 1037–1042 © Thieme Stuttgart · New York

LETTER
Nb-Fmoc/Z-Amino Alkyl Thiols in Synthesis
1041
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J = 6.8 Hz, 1 H), 5.02 (br, 1 H), 6.97–7.67 (m, 13 H); 13
C
NMR (100 MHz, CDCl3): d = 30.8, 40.3, 47.1, 52.8, 67.4,
120.4, 125.6, 127.0, 127.8, 128.5, 129.3, 137.0, 141.7,
144.5, 155.8. 3j: IR (KBr): 1694 cm–1; 1H NMR (400 MHz,
CDCl3): d = 0.85 (t, J = 2.8 Hz, 3 H), 0.96 (d, J= 4.2 Hz,
3 H), 1.12–1.35 (m, 2 H), 2.05 (s, 1 H), 2.32–2.45 (m, 1 H),
2.71 (dd, J = 2.7 Hz, 1 H), 3.01 (dd, J = 3.1 Hz, 1 H), 3.56–
3.71 (m, 1 H), 4.90 (br, 1 H), 5.05 (s, 2 H), 7.21 (s, 5 H); 13
C
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15.0 mL) was dissolved in 98% formic acid (35.0 mL) at
0 °C and the mixture was stirred at this temperature for 1 h
to afford performic acid. Fmoc/Z-amino alkyl thiol in 98%
formic acid (3.0 mL) solution was added dropwise to the
performic acid solution and the resulting reaction mixture
was stirred at r.t. for 1 d. After removal of the solvent, the
product was purified by column chromatography (CHCl3–
MeOH, 8:1) to afford N-protected taurines as colorless
solids.
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1996, 7, 2745.
(33) Higashiura, K.; Lenaga, K. J. Org. Chem. 1992, 57, 764.
(34) Gude, M.; Piarulli, U.; Potenza, D.; Salom, B.; Gennari, C.
Tetrahedron Lett. 1996, 37, 8589.
(35) Brouwer, A.; Monnee, M. C. F.; Liskamp, R. M. J. Synthesis
2000, 1579.
(45) Selected spectroscopic data: 4b: IR (KBr): 1708, 1211,
1118 cm–1; 1H NMR (400 MHz, DMSO-d6): d = 1.11 (d,
J = 6.53 Hz, 3 H), 2.58 (dd, J = 2.9 Hz, 1 H), 2.78 (dd,
J = 3.0 Hz, 1 H), 3.25–3.45 (m, 1 H), 4.15 (t, J = 6.8 Hz,
1 H), 4.41 (d, J = 4.8 Hz, 2 H), 6.13 (br, 1 H), 7.02–7.57 (m,
8 H); 13C NMR (100 MHz, DMSO-d6): d = 17.5, 41.2, 46.8,
57.5, 64.8, 120.1, 125.2, 126.9, 127.8, 141.1, 142.8, 155.03.
4j: IR (KBr): 1691, 1217, 1170 cm–1; 1H NMR (400 MHz,
DMSO-d6): d = 0.76 (t, J = 2.3 Hz, 3 H), 0.98 (d, J = 5.0 Hz,
3 H), 1.31–1.40 (m, 2 H), 2.12–2.31 (m, 1 H), 2.75 (dd,
J = 2.5 Hz, 1 H), 3.03 (dd, J = 3.1 Hz, 1 H), 3.57–3.62 (m,
1 H), 4.68 (s, 2 H), 5.92 (br, 1 H), 6.98 (s, 5 H); 13C NMR
(100 MHz, DMSO-d6): d = 0.2, 13.6, 24.6, 37.8, 45.8, 55.3,
64.4, 128.1, 128.8, 137.5, 154.8.
(46) General procedure for the synthesis of Fmoc-Xaa-
y[CH2SO2Cl](5): To a suspension of 4 (1.0 mmol) in
anhydrous CH2Cl2 (10.0 mL) at 0 °C, triphosgene (0.7
mmol) and a catalytic amount of DMF were added and the
mixture was stirred overnight. The mixture was diluted with
CH2Cl2 (10 mL) and the organic layer was washed with H2O
(2 × 10 mL) and brine (10 mL), then dried over anhydrous
sodium sulfate. The solvent was removed under reduced
pressure and the crude product was purified by flash column
chromatography (silica gel, 100–150 mesh; EtOAc–hexane,
10%).
(36) (a) Lowik, D. W. P. M.; Liskamp, R. M. J. Eur. J. Org.
Chem. 2000, 1219. (b) Moree, W. J.; van der Marcel, G. A.;
Liskamp, R. M. J. J. Org. Chem. 1995, 60, 5157.
(c) Lowik, D. W. P. M.; Mulders, S. J. E.; Cheng, Y.; Shao,
Y.; Liskamp, R. M. J. Tetrahedron Lett. 1996, 37, 8253; see
also ref. 31.
(37) (a) Wang, B.; Zhang, W.; Zhang, L.; Du, D.-M.; Liu, G.; Xu,
J. Eur. J. Org. 2008, 350. (b) Xu, J. Tetrahedron:
Asymmetry 2002, 13, 1129. (c) Xu, J. Synthesis 2004, 276.
(d) Xu, J.; Xu, S.; Zhang, Q. Heteroat. Chem. 2005, 16, 466.
(38) Hu, L.; Zhu, H.; Du, D.-M.; Xu, J. J. Org. Chem. 2007, 72,
4543.
(39) (a) Gennari, C.; Solam, B.; Potenza, D.; Williams, A.
Angew. Chem. Int. Ed. Engl. 1994, 33, 2067. (b) de Bont,
D. B. A.; Dijkstra, D. H.; den Hratog, J. A. J.; Liskamp,
R. M. J. Bioorg. Med. Chem. Lett. 1996, 24, 3035.
(40) General procedure for 2a–l: A solution of Nb-Fmoc/Z-
amino alkyl iodide 1a–l (1.0 mmol) and thiourea (2.1 g, 3.0
mmol) in anhydrous acetone (10.0 mL) was heated at reflux
under an argon atmosphere for 8–10 h. The consumption of
the iodide was monitored by TLC. The solvent was
evaporated under vacuum and the isothouronium salt was
isolated as the pure compound by recrystallization from
acetone–diethyl ether.
(41) Spectroscopic data for 2d: IR (KBr): 1703, 1657, 3211 cm–1;
1H NMR (400 MHz, DMSO-d6): d = 0.91 (2 × d, J = 6.1 Hz,
6 H), 1.76–2.08 (m, 1 H), 2.98–3.10 (m, 2 H), 3.96–4.01 (m,
1 H), 4.18 (t, J = 6.9 Hz, 1 H), 4.39 (d, J= 4.9 Hz, 2 H), 5.01
(br, 1 H), 6.94–7.77 (m, 8 H), 9.10 (br, 2 H), 9.32 (br, 2 H);
13C NMR (100 MHz, DMSO-d6): d = 17.8, 25.4, 30.1, 47.3,
55.2, 66.1, 119.5, 124.8, 125.5, 127.0, 127.9, 141.0, 143.8,
144.2, 156.3, 161.2.
(42) General procedure for 3a–l: Isothiouronium salt 2 (1.0
mmol) and sodium pyrosulfite (1.5 mmol) were dissolved in
CH2Cl2 (10.0 mL) and H2O (2.0 mL) and heated at reflux
under argon atmosphere until completion of reaction. The
mixture was diluted with excess CH2Cl2, and the organic
extract was washed with H2O (2 × 10 mL) and brine (10
mL), and dried over anhydrous sodium sulfate. Solvent was
removed under reduced pressure and the crude product was
purified by column chromatography (silica gel; 100–150
mesh; EtOAc–hexane, 15%).
(47) Spectroscopic data for 5a: Yield 78%; white solid; mp
151 °C. IR (KBr): 1708 cm–1; 1H NMR (400 MHz, CDCl3):
d = 1.35 (d, J = 6.0 Hz, 3 H), 3.58 (dd, J = 2.8 Hz, 1 H), 3.65
(d, J = 3.5 Hz, 2 H), 3.97–4.08 (m, 1 H), 4.20 (t, J = 6.8 Hz,
1 H), 4.31–4.39 (m, 1 H), 5.11 (br, 1 H), 7.04–7.70 (m, 8 H);
13C NMR (100, MHz, CDCl3): d = 19.3, 44.0, 46.9, 66.8,
69.1, 119.5, 125.6, 127.2, 128.0, 141.2, 143.8, 155.5.
(48) General procedure for the synthesis of 6: To an ice-cooled
solution of N-Fmoc-Xaa-y[CH2SO2Cl] (1.0 mmol) in
anhydrous CH2Cl2, was added a solution of amino acid
methyl ester in CH2Cl2 (1.0 mmol, obtained by neutralizing
the corresponding hydrochloride salt using zinc dust),
followed by Et3N (1.0 mmol). The resulting suspension was
stirred for 6–8 h. After dilution with excess CH2Cl2 (25 mL),
it was washed with 1M HCl (2 × 10 mL), sat. NaHCO3
(2 × 10 mL), and brine (10 mL), dried over anhydrous
sodium sulfate and the solvent was evaporated under
reduced pressure. The crude product was purified by column
Synlett 2010, No. 7, 1037–1042 © Thieme Stuttgart · New York

1042
V. V. Sureshbabu et al.
LETTER
chromatography (silica gel, 100–150 mesh; EtOAc–hexane,
30%).
30.6, 37.2, 47.3, 50.3, 63.2, 66.7, 120.2, 125.6, 127.3, 127.8,
141.3, 143.6, 154.6, 170.2. 6c: White solid; mp 143 °C. 1H
NMR (400 MHz, DMSO-d6): d = 1.17 (d, J = 5.4 Hz, 3 H),
3.10 (s, 3 H), 3.59 (dd, J = 2.2 Hz, 1 H), 3.63–3.75 (m, 1 H),
4.04 (s, 1 H), 4.12 (d, J = 5.6 Hz, 2 H), 5.23–5.64 (br, 2 H),
7.12–7.82 (m, 13 H); 13C NMR (100 MHz, DMSO-d6): d =
18.9, 34.5, 50.6, 54.8, 62.7, 66.1, 47.4, 120.6, 125.1, 127.4,
127.1, 141.0, 143.1, 155.0, 170.1.
(49) Selected spectroscopic data: 6a: White solid; mp 163 °C.
1H NMR (400 MHz, DMSO-d6): d = 0.98–1.12 (m, 6 H),
1.23 (d, J = 5.9 Hz, 3 H), 2.08–2.15 (m, 1 H), 3.06 (d, J = 4.5
Hz, 1 H), 3.21 (s, 3 H), 3.78 (dd, J = 2.6 Hz, 1 H), 3.98 (t,
J = 3.8 Hz, 1 H), 4.01 (dd, J = 3.0 Hz, 1 H), 4.12 (d, J = 5.8
Hz, 2 H), 4.21–4.31 (m, 1 H), 5.06–5.11 (br, 2 H), 7.12–7.69
(m, 8 H); 13C NMR (100 MHz, DMSO-d6): d = 7.0, 18.2,
Synlett 2010, No. 7, 1037–1042 © Thieme Stuttgart · New York

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