Simple and efficient synthesis of allo- and threo-3,3′-dimethylcystine derivatives in enantiomerically pure form

Article abstract of DOI:10.1016/j.tetasy.2008.06.001

A simple and efficient method for the synthesis of allo- and threo-3,3′-dimethylcystine derivatives is reported. Various tosyl and bromo derivatives of Cbz-, Boc-, and Fmoc- protected threonine methyl esters have been prepared and subjected to nucleophili

Full text of DOI:10.1016/j.tetasy.2008.06.001

Tetrahedron: Asymmetry 19 (2008) 1425–1429
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Simple and efficient synthesis of allo- and threo-3,30-dimethylcystine
derivatives in enantiomerically pure form
,
*
R. B. Nasir Baig, V. Sai Sudhir, Srinivasan Chandrasekaran
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
A simple and efficient method for the synthesis of allo- and threo-3,30-dimethylcystine derivatives is
reported. Various tosyl and bromo derivatives of Cbz-, Boc-, and Fmoc- protected threonine methyl esters
have been prepared and subjected to nucleophilic substitution with potassium thiocyanate in acetonitrile
to yield the corresponding thiocyanate derivatives in moderate yield. The thiocyanates are readily con-
verted to the corresponding allo- and threo-3,30-dimethylcystine derivatives via reductive dimerization
with benzyltriethylammonium tetrathiomolybdate.
Article history:
Received 22 March 2008
Accepted 2 June 2008
Available online 27 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
problem with this approach was competitive ring opening by oxy-
gen, leading to the formation of a thionoester byproduct along with
A complete understanding of the stereochemical requirement of
the side chain of amino acid residues is important in peptide
ligand–receptor interaction and also has a crucial role in the ra-
tional design of bioactive peptides and their non-peptide mimetics.
This approach can be realized by the incorporation of conforma-
tionally constrained novel amino acids into peptide or non-peptide
templates.1 Among these, cystine and b-substituted cystine deriv-
atives which are incorporated in many peptide sequences are
known to possess diverse biological activities.2,3 The introduction
of an appropriate b-substituted cystine into a peptide sequence
preserves the side chain orientation and restricts the C–S–S–C
dihedral angle. Hence, there is a need for an efficient approach
for the synthesis of b-substituted cystine and its diastereomers in
enantiomerically pure form. There are number of reports in the
literature for the synthesis of b-substituted cystines. Morell
et al.4 have reported that the displacement reaction of an O-tosyl
threonine derivative with potassium thioacetate gave (S)-acetyl-
3-methylcysteine, which was converted to 3,30-dimethylcystine
by hydrolysis and oxidation. However, this method is not very
effective for making enantiomerically pure cysteine or 3,30-dimeth-
ylcystine. Carter et al.5 and Hoogmatens et al.6 prepared 3-methyl-
cysteine via addition of thiol to 2-phenyl 4-ethylidene-5(4H)-
oxazoline. However, the procedure required a tedious resolution
strategy to obtain the enantiomerically pure product. Wakamiya
reported the synthesis of threo-3,30-dimethylcystine via the ring
opening reaction of an aziridine with thiobenzoic acid.7 The major
the desired product. Hydrogen sulfide has also been used as a
nucleophile, but its high toxicity makes its use inconvenient, espe-
cially on a large-scale preparation.8 Recently, VenNiewenhze9 re-
ported the synthesis of orthogonally protected 3-methylcysteine,
where the ring opening reaction of an Ns-aziridine with alkyl thiols
in the presence of BF3ꢀOEt2 was utilized. Deprotection of the Ns
group and protection with Boc or Fmoc allowed them to use these
compounds for peptide synthesis. The deprotection of the alkyl
group followed by oxidation gave the desired cystine derivatives.
However, the limitation of this procedure was that too many pro-
tection and deprotection steps were involved.
In our laboratory, we have utilized the chemistry of benzyltri-
ethylammonium tetrathiomolybdate [BnNEt3]2MoS4 1 for the syn-
thesis of structurally diverse molecules.10 Previously, we reported
the synthesis of cystine, selenocystine and their higher analogues
using tetrathiomolybdate 1 as the key reagent.11 Since, there is a
growing interest for the synthesis of 3-alkyl cysteine and cystine
derivatives, we decided to extend our methodology to the synthe-
sis of 3,30-dimethylcystine and its diastereomers from threonine;
the results of this investigation are presented in this paper.
2. Results and discussion
We began our synthesis by treating the tosyl derivative of
L
-threonine12 3a with 1 (1.2 equiv, CH3CN, 28 °C, 24 h).
Surprisingly it did not furnish the expected disulfide 5a, instead
the dehydroaminoacid 4 could be isolated in 15% yield and the
starting material (80%) was recovered (Scheme 1). Since the
attempt to prepare 5a from 3a was unsuccessful, we decided to
convert tosylate 3a to the corresponding thiocyanate 6a (Scheme
2) via an SN2 substitution reaction, which in turn can be converted
* Corresponding author. Tel.: +91 080 2293 2404; fax: +91 80 2360 2423.
E-mail address: scn@orgchem.iisc.ernet.in (S. Chandrasekaran).
Honorary Professor, Jawaharlal Nehru Centre for Advanced Scientific Research,
Bangalore, India.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.001

1426
R. B. Nasir Baig et al. / Tetrahedron: Asymmetry 19 (2008) 1425–1429
O
O
NHCbz
4 (15%)
OH
O
OTs O
TsCl, Py,
60h, 85%
[BnNEt3]2MoS4,1
NHCbz
O
O
O
CH3CN, 24h, rt
NHCbz
NHCbz
O
S
S
O
2a
3a
O
NHCbz
5a (0%)
Scheme 1. Reaction of 3a with 1.
yield without a loss in enantiomeric purity. This methodology
could be extended to the synthesis of Boc- and Fmoc-protected
3,30-dimethylcystine derivatives 5b and 5c with the same effi-
ciency (Scheme 3). This demonstrates that the methodology can
be used successfully when Boc or Fmoc are used for the protection
of the amino group. With the successful synthesis of 5a–c, we ex-
tended this methodology to the synthesis of threo-3,30-dimethyl-
cystine derivatives 9a–c, where the configuration of the C3
OTs O
SCN O
KSCN
O
O
NHCbz
NHCbz
3a
6a
Scheme 2. Reaction of 3a with KSCN.
carbon atom is same as in L-threonine. The SN2 displacement of
to the corresponding disulfide 5a using tetrathiomolybdate 1.13
Accordingly, the reaction of 3a with excess KSCN (5 equiv) in dif-
ferent solvent systems was studied. The results of these studies
are summarized in Table 1. The reaction of tosylate 3a with KSCN
in anhydrous acetone was unsuccessful as it did not furnish thiocy-
anate 6a even after 30 h at reflux, whereas the reaction in metha-
nol and THF gave the thiocyanate 6a in very poor yields. In ethanol,
compound 6a was isolated in 40% yield. Acetonitrile and 1,4-diox-
ane were found to be the best solvents for this reaction as the thio-
cyanate 6a was obtained in 60% and 58% yield, respectively.14 The
reactions of 3a in DMF or DMSO (90 °C, 12 h) furnished 6a in 52%
and 48 % yield, respectively. After the successful isolation of thio-
cyanate 6a in moderate yield, it was treated with tetrathiomolyb-
date 1 (1.2 equiv, CH3CN, 28 °C, 10 h), and underwent reductive
dimerization13 to give 3,30-dimethylcystine derivative 5a in 92%
the hydroxy group of 2a with CBr4/PPh315 gave 7a in 67% yield. Fur-
ther treatment of 7a with tetrathiomolybdate 1 (1.2 equiv CH3CN,
28 °C, 24 h) gave the dehydroamino acid 4 instead of threo-3,30-
dimethylcystine derivative 9a (Scheme 4). An alternate strategy
was worked out to obtain the desired result. Compound 7a was
treated with an excess of KSCN which resulted in the formation
of 8a in 54% yield. Reductive dimerization of 8a with tetrathiomo-
lybdate 1 (1.2 equiv, CH3CN, 28 °C, 10 h) gave the threo-3,30-di-
methylcystine derivative 9a in excellent yield (90%) (Scheme 5).
This methodology was extended further for the synthesis of Boc-
and Fmoc-protected threo-3,30-dimethylcystine derivatives 9b–c.
3. Conclusion
We have developed a simple and efficient methodology for the
synthesis of allo-3,30-dimethylcystine 5a–c and threo-3,30-dimeth-
ylcystine derivatives 9a–c in enantiomerically pure form using L-
threonine from the chiral pool and benzyltriethylammonium tetra-
Table 1
Reaction of 3a with KSCN in different solvents
thiomolybdate 1 as the key reagent.
Entry
Solvents
Temperature
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
Acetone
Methanol
Ethanol
THF
Acetonitrile
1,4-Dioxane
DMF
Reflux
Reflux
Reflux
Reflux
Reflux
90 °C
30
30
24
30
15
15
12
12
—
5
40
8
60
58
52
48
4. Experimental
4.1. General
All reactions were performed in oven-dried apparatus and stir-
red magnetically. The melting points and optical rotation values
(recorded at 25 °C) reported are uncorrected. Infrared spectra were
recorded using an FTIR instrument and the frequencies are
90 °C
90 °C
DMSO
a
Isolated yields.
NHR
O
OH
O
OTs O
SCN O
KSCN, CH3CN
15 h, reflux
[BnNEt3]2MoS4
Py, TsCl
O
S
O
O
O
S
O
0º C, 60 h
CH3CN, 10 h , rt
NHR
NHR
NHR
O
NHR
3a R = Cbz, 85%
3b R = Boc, 81%
3c R = Fmoc, 77%
6a R = Cbz, 60%
6b R = Boc, 57%
6c R = Fmoc ,65%
5a R = Cbz, 92%
5b R = Boc, 90%
5c R = Fmoc, 94%
2a R = Cbz
2b R = Boc
2c R = Fmoc
Scheme 3. Synthesis of allo-3,30-dimethylcystine derivatives.

R. B. Nasir Baig et al. / Tetrahedron: Asymmetry 19 (2008) 1425–1429
1427
O
O
Br
O
NHCbz
OH
O
[BnNEt3]2MoS4 1
4 (50%)
CBr4, PPh3
O
O
NHCbz
C6H6, 3 h, rt, 67%
CH3CN, 24 h, rt
NHCbz
NHCbz
O
7a
2a
O
S
S
O
O
NHCbz
9a ( 0%)
Scheme 4. Reaction of 7a with 1.
NHR
O
SCN O
OH
O
Br
O
O
S
S
[BnNEt3]2MoS4
1
CBr4, PPh3
C6H6, rt, 3 h
KSCN, CH3CN
O
O
O
O
CH3CN, 10 h, rt
15 h, reflux
NHR
O
NHR
NHR
NHR
2a R=Cbz
2b R=Boc
2c R=Fmoc
7a R = Cbz, 67%
7b R = Boc, 60%
7c R = Fmoc, 75%
8a R = Cbz ,54%
8b R = Boc, 50%
8c R = Fmoc, 61%
9a R = Cbz, 90%
9b R = Boc, 91%
9c R = Fmoc, 96%
Scheme 5. Synthesis of threo-3,30-dimethylcystine derivatives.
reported in wave number (cmꢁ1), and intensities of the peak are
denoted as s (strong), w (weak), and m (medium). 1H and 13C spec-
tra were recorded at 300 MHz at 75 MHz, respectively. Chemical
shifts are reported in parts per million downfield from the internal
reference, tetramethylsilane (TMS). Multiplicity is indicated using
the following abbreviations: s (singlet), d (doublet), dd (double
doublet) t (triplet), m (multiplet), br s (broad singlet). Mass spectra
were recorded on Q-TOF electro-spray instrument. References for
the compound reported previously are indicated against each of
them along with the characterization data.
J = 7.8 Hz, 1H), 4.54 (dd, J = 8.4, 3.6 Hz, 1H), 4.39–4.31 (m, 1H),
3.8 (s, 3H), 1.79 (d, J = 6.9 Hz, 3H), 1.45 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 169.3, 154.8, 80.3, 59.2, 52.4, 49.5, 28.1, 22.7;
m/z (HRMS) calcd for C10H18BrNO4 + Na 318.0317; found 318.0315.
4.2.3. Fmoc-Thr(Br)-OMe, 7c
White solid; mp = 111 °C; Purified by column chromatography:
EtOAc/hexane (1:9); yield 75%; IR (Neat) 3338 (br), 2951(w), 1734
(s), 1720 (s), 1508 (m), 1212 (m), 759 (m) cmꢁ1; 1H NMR (300 MHz,
CDCl3) d 7.76 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 7.2 Hz, 2H), 7.42–7.29
(m, 4H), 5.73 (d, J = 8.1 Hz, 1H), 4.61 (dd, J = 8.4 Hz, 3.9 Hz, 1H),
4.43–4.36 (m, 3H), 4.23 (t, J = 6.9 Hz, 1H), 3.87–3.81 (m, 1H), 3.81
(s, 3H), 1.80 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 169.0,
155.5, 143.5, 141.2, 127.7, 127.0, 125.0, 119.9, 67.3, 59.30, 52.7,
49.1, 7.0, 2.7; m/z (HRMS) calcd for C21H20N2O4S + Na 419.1041;
found 419.1030.
4.2. General procedure for the synthesis of bromoderivatives
7a–c
4.2.1. Synthesis of 7a
To a stirred solution of PPh3 (0.393 g, 1.5 mmol) in anhydrous
benzene (15 mL), CBr4 (0.497 g, 1.5 mmol) was added and the reac-
tion mixture was stirred for 1 h at room temperature. To this, com-
pound 2a (0.267 g, 1 mmol) was added and the reaction mixture
was stirred for further 2 h. The reaction mixture was filtered
through Celite, and washed with benzene (2 ꢂ 10 mL), after which
the solvent was evaporated and the crude product was purified by
silica gel (100–200 mesh) column chromatography EtOAc/hexane
(1:9); Gummy liquid; yield 67%; IR (Neat) 3347 (br), 1727 (s),
4.3. General procedure for the synthesis of thiocyanates (6a–c
and 8a–c)
4.3.1. Synthesis of 6a
To a solution of tosyl derivative 3a (0.421 g, 1 mmol) in anhy-
drous acetonitrile, KSCN (0.486 g, 5 mmol) was added and the solu-
tion was refluxed for 15 h. The reaction mixture was allowed to
come to room temperature and acetonitrile was removed under
vacuum. The residue was extracted with DCM (3 ꢂ 20 mL) and fil-
tered through Na2SO4. The crude thiocyanate 6a was then purified
by silica gel (100–200 mesh) column chromatography EtOAc/hex-
1516 (m), 1213 (m) cmꢁ1 1H NMR (300 MHz, CDCl3) d 7.33 (s,
;
5H), 5.81 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 4.61 (dd, J = 8.4, 3.6 Hz,
1H), 4.39–4.31 (m, 1H) 3.76 (s, 3H), 1.76 (d, J = 7.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 169.0, 155.5, 135.8, 128.5, 128.2, 128.1,
67.3, 59.6, 52.7, 49.2, 22.7; m/z (HRMS) calcd for C13H16BrNO4 + Na
352.0160; found 352.0158.
ane (3:7); Gummy liquid; yield 60%; [
a]
D = +70 (c 1, CHCl3); IR
;
(Neat) 3342 (br), 2154 (m), 1727 (s) cmꢁ1
1H NMR (300 MHz,
CDCl3) d 7.35 (s, 5H), 5.76 (d, J = 7.5 Hz, 1H), 5.13 (s, 2H), 4.71(dd,
J = 3.6 Hz, 7.5 Hz, 1H), 3.81 (s, 3H), 3.75–3.73 (m, 1H), 1.56 (d,
J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 168.8, 155.6, 135.6,
128.5, 128.3, 128.1, 110.1, 67.5, 57.7, 53.0, 46.6, 17.6; m/z (HRMS)
calcd for C14H16N2O4S + Na 331.0728; found 331.0714.
4.2.2. Boc-Thr(Br)-OMe, 7b
Gummy liquid; Purified by column chromatography EtOAc/hex-
ane (1:9); yield 60%; IR (Neat) 3362 (br), 1747 (s), 1715 (s), 1506
(m), 1165 (m) cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 5.48 (d,

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R. B. Nasir Baig et al. / Tetrahedron: Asymmetry 19 (2008) 1425–1429
4.3.2. (allo) Boc-Thr(SCN)-OMe, 6b
centrated. The crude product was purified by silica gel (100–
200 mesh) column chromatography EtOAc/hexane (3:7); Gummy
Gummy liquid; Purified by column chromatography: EtOAc/
hexane (2:8); yield 57%; [ D = +97 (c 1, CHCl3); IR (Neat) 3361
(br), 2960 (w), 2155 (m), 1741 (s), 1513 (m), 1163 (m) cmꢁ1 1H
NMR (300 MHz, CDCl3) 5.45 (d, J = 6.9 Hz, 1H), 4.66 (dd,
a
]
liquid: yield 92%; [
a]
D = ꢁ98.4 (c 1, CHCl3); IR (Neat) 3350 (br)
;
1724 (s), 1526 (m), 1216 (m) cmꢁ1
;
1H NMR (300 MHz, CDCl3) d
d
7.35 (s, 5H), 5,45 (d, J = 8.7 Hz, 1H), 5.11 (s, 2H), 4.79 (dd,
J = 9 Hz, 3.6 Hz, 1H), 3.75 (s, 3H), 3.37–3.35 (m, 1H), 1.25 (d,
J = 3.3 Hz, 7.5 Hz, 1H), 3.83 (s, 3H), 3.79–3.73 (m, 1H), 1.57 (d,
J = 6.9 Hz, 3H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3) d 169.1,
154.9, 110.3, 81.0, 57.3, 53.0, 46.9, 28.1, 17.7; m/z (HRMS) calcd
for C11H18N2O4S + Na 297.0885; found 297.0884.
J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
170.85, 155.98,
136.01, 128.5, 128.19, 128.13, 67.25, 56.80, 52.64, 48.08, 15.68;
m/z (HRMS) calcd for
C26H32N2O8S2 + Na 587.1498; found
587.1490.
4.3.3. (allo) Fmoc-Thr(SCN)-OMe, 6c
White solid; mp = 106 °C; Purified by column chromatography:
4.4.2. N,N0-Bis(tert-butoxycarbonyl)-allo-3,30-dimethyl-
L-
EtOAc/hexane (2:8); yield 65%; [
3339 (br), 2953 (w), 2154 (m), 1724 (s), 1513 (m), 1221 (m), 740
(m) cmꢁ1 1H NMR (300 MHz, CDCl3) d 7.76 (d, J = 7.6 Hz, 2H), 7.5
a
]
D = +56.0 (c 1, CHCl3); IR (Neat)
cystine dimethyl ester 5b
Gummy liquid; Purified by column chromatography: EtOAc/hex-
,
ane (3:7); yield 90%; [
a
]
D = ꢁ54.9 (c 4.38, CHCl3); lit.7b = +52.9 for
(d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H),
5.72 (d, J = 7.6 Hz, 1H), 4.69 (dd, J = 8 Hz, 3.6 Hz, 1H), 4.5 (dd,
J = 10.4 Hz, 7.2 Hz, 1H), 4.40 (dd, J = 10.4 Hz 7.2 Hz, 1H), 4.2 (t,
J = 6.8 Hz, 6.4 Hz, 1H), 3.83 (s, 3H), 3.76–3.72 (m, 1H), 1.57 (d,
J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 168.8, 155.7, 143.5,
141.3, 127.8, 127.1, 124.9, 120.0, 110.0, 67.4, 57.8, 53.0, 47.1,
46.6, 17.7; m/z (HRMS) calcd for C21H20N2O4S + Na 419.1041;
found 419.1030.
the enantiomer of 5b at 17 °C (c 1.14, CHCl3); IR (Neat) 3366 (br),
2977, 1741, 1715, 1508, 1367, 1163 cmꢁ1 1H NMR (300 MHz,
;
CDCl3) d 5.15 (d, J = 7.2 Hz 1H), 5.70 (br s, 1H), 3.77 (s, 3H), 3.36
(br s, 1H), 1.45 (s, 9H), 1.27 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 171.7, 155.1, 80.2, 56.4, 52.5, 48.2, 28.2, 15.9; m/z (HRMS)
calcd for C20H36N2O8S2 + Na 519.1811; found 519.1808.
4.4.3. N,N0-Bis(9-fluorenylmethoxycarbonyl)-allo-3,30-
dimethyl-
White solid; mp = 172 °C; Purified by column chromatography:
EtOAc/hexane (3:7); yield 94%; [
D = ꢁ44.0 (c 1, CHCl3); IR (Neat)
3346 (br), 1723 (s), 1513 (m), 1216 (m), 758 (m), 740 (m) cmꢁ1
NMR (300 MHz, CDCl3) 7.75 (d, J = 7.2 Hz, 2H), 7.59 (d,
L-cystine dimethyl ester 5c
4.3.4. (threo) Cbz-Thr(SCN)-OMe, 8a
Gummy liquid; Purified by column chromatography: EtOAc/
a]
hexane (3:7); yield 54%; [
a]
D = +25.6 (c 1, CHCl3); IR (Neat) 3332
;
(br), 2956 (w), 2155 (m), 1725 (s), 1520 (m), 1216 (m) cmꢁ1
;
1H
d
NMR (300 MHz, CDCl3) d 7.27 (s, 5H), 5.68 (d, J = 8.4 Hz, 1H),
5.059 (s, 2H), 4.68 (dd, J = 9 Hz, 3.3 Hz, 1H), 3.84–3.79 (m, 1H),
3.78 (s, 3H), 1.46 (d, J = 6.9 Hz, 3H), 13C NMR (75 MHz, CDCl3) d
169.2, 156.1, 135.6, 128.4, 128.2, 128.0, 110.1, 67.2, 58.1, 53.0,
47.0, 18.5; m/z (HRMS) calcd for C14H16N2O4S + Na 331.0728;
found 331.0714.
J = 7.2 Hz, 2H), 7.47–7.26 (m, 4H), 5.48 (d, J = 9.3 Hz, 1H), 4.82
(dd, J = 9.3 Hz, 3.6 Hz, 1H), 4.59 (d, J = 7.5 Hz, 2H), 4.22 (t,
J = 7.2 Hz, 1H), 3.77 (s, 3H), 3.40 (br s, 1H), 1.29 (d, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 170.9, 156.0, 143.6, 141.2,
127.7, 127.0, 125.0, 119.9, 67.3, 56.8, 52.7, 48.1, 47.0, 15.83; m/z
(HRMS) calcd for C40H40N2O8S2 + Na 763.2124; found 763.2126.
4.3.5. (threo) Boc-Thr(SCN)-OMe, 8b
4.4.4. N,N0-Bis(benzyloxycarbonyl)-threo-3,30-dimethyl-
L-
Gummy liquid; Purified by column chromatography: EtOAc/
cystine dimethyl ester 9a
hexane (3:7); yield 50%; [
a
]
D = +15.1 (c 1, CHCl3); IR (Neat) 3338
;
White solid; mp = 107 °C; Purified by column chromatography:
(br), 2155 (m), 1728 (s) cmꢁ1
1H NMR (300 MHz, CDCl3) d 5.34
EtOAc/hexane (3:7); yield 90%; [
a]
D = +172.1 (c 0.44, CHCl3); lit.7a
(d, J = 6.9 Hz, 1H), 4.69 (dd, J = 2.7, 9.3 Hz, 1H), 3.92–3.89 (m, 1H),
3.83 (s, 3H), 1.55 (d, J = 6.9, 3H), 1.54 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 169.5, 155.4, 110.2, 80.8, 57.70, 52.9, 47.4, 28.1, 18.6;
m/z (HRMS) calcd for C11H18N2O4S + Na 297.0885; found 297.0883.
ꢁ167 for the enantiomer of 9a at 18 °C (c 1, CHCl3); IR (Neat)
3336 (br), 1724 (s), 1521 (m), 1216 (m) cmꢁ1; NMR (300 MHz,
CDCl3) d 7.31 (s, 5H); 5.62 (d, J = 8.7 Hz, 1H), 5.12 (s, 2H), 4.59
(dd, J = 8.7 Hz, 3.3 Hz, 1H), 3.73 (s, 3H), 3.57–3.48 (br s, 1H), 1.3
(d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.7, 156.2,
136.0, 128.5, 128.2, 128.0, 67.25, 57.4, 52.5, 48.6, 17.8; m/z (HRMS)
calcd for C26H32N2O8S2 + Na 587.1498; found 587.1478.
4.3.6. (threo) Fmoc-Thr(SCN)-OMe, 8c
White solid; mp = 127 °C; Purified by column chromatography:
EtOAc/hexane (2:8); yield 61%; [
3337 (br), 2953 (w), 2154 (m), 1718 (s), 1521 (m), 1521 (m),
1220, 759, 741 cmꢁ1 1H NMR (300 MHz, CDCl3)
7.75 (d,
a]D = +13.7 (c 1, CHCl3); IR (Neat)
4.4.5. N,N0-Bis(tert-butoxycarbonyl)-threo-3,30-dimethyl-
L-
cystine dimethyl ester 9b
;
d
J = 7.2 Hz, 2H), 7.59 (d, J = 6.3, 2H), 7.42–7.72 (m, 4H), 5.73 (d,
J = 8.1, 1H), 4.75 (dd, J = 3 Hz, 8.1 Hz, 1H), 4.51–4.35 (m, 2H) 4.22
(t, J = 6.9 Hz, 1H), 3.87–3.81 (m, 1H), 3.75 (s, 3H), 1.52 (d,
J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 169.2, 156.1, 143.3,
141.2, 127.7, 127.0, 124.9, 119.9, 110.9, 67.4, 58.2, 53.0, 47.0,
46.8, 18.5; m/z (HRMS) calcd for C21H20N2O4S + Na 419.1041;
found 419.1030.
Gummy liquid; Purified by column chromatography: EtOAc/
hexane (3:7); yield 91%; [ D = +145 (c 1, CHCl3); IR (Neat) 3368
(br), 2978 (w), 1746 (s), 1718 (s), 1502 (m), 1164 (m) cmꢁ1 1H
NMR (300 MHz, CDCl3) d 5.35 (d, J = 9 Hz 1H), 4.51 (dd, J = 9 Hz,
2.7 Hz, 1H), 3.76 (s, 3H), 3.54–3.46 (m, 1H), 1.45 (s, 9H), 1.33 (d,
J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 177.0, 155.5, 80.2,
57.0, 52.3, 49.1, 28.2, 18.0; m/z (HRMS) calcd for C20H36N2O8S2 +
Na 519.1811; found 519.1807.
a]
;
4.4. General procedure for the synthesis of 3,30-dimethylcystine
derivatives: 5a–c and 9a–c
4.4.6. N,N0-Bis(9-fluorenylmethoxycarbonyl)-threo-3,30-
dimethyl-
White solid; mp = 181 °C; Purified by column chromatography:
EtOAc/hexane (3:7); yield 94%; [ D = +75.6 (c 1, CHCl3); IR (Neat)
3342 (br), 2952 (w), 1723 (s), 1513 (m), 1215 (m), 756 (m) cmꢁ1
NMR (300 MHz, CDCl3) d 7.76 (d, J = 7.5 Hz, 2H), 7.6 (d, J = 6.9 Hz,
2H), 7.42–7.25 (m, 4H), 5.6 (d, J = 9 Hz, 1H), 4.62 (dd, J = 8.7 Hz,
3.3 Hz, 1H), 4.43–4.38 (m, 2H), 4.23 (t, J = 6.9 Hz, 1H), 3.75 (s,
L-cystine dimethyl ester 9c
4.4.1. Synthesis of 5a
To the solution of thiocyanate 6a (0.308 g, 1 mmol,) in acetoni-
trile (5 mL), tetrathiomolybdate 1 (0.730 g, 1.2 mmol) was added
and the reaction mixture was stirred for 10 h. The solvent was re-
moved under vacuum, after which the solid residue was extracted
with (3:7) DCM/Et2O (5 ꢂ 10 mL), filtered through Celite and con-
a]
;

R. B. Nasir Baig et al. / Tetrahedron: Asymmetry 19 (2008) 1425–1429
1429
3H), 3.59–3.50 (m, 1H), 1.32 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 170.8, 156.3, 143.7, 141.4, 127.8, 127.1, 125.1, 120.0, 67.3,
57.6, 52.6, 48.8, 47.2, 17.9; m/z (HRMS) calcd for C40H40N2O8S2 +
Na 763.2124; found 763.2136.
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Acknowledgements
R.B.N.B. Thanks CSIR, New Delhi, for a Senior Research Fellow-
ship and IISc, for financial assistance.
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