Facile synthesis of β-amino disulfides, cystines, and their direct incorporation into peptides

Article abstract of DOI:10.1055/s-0028-1088133

Herein, we report a simple and efficient methodology for the synthesis of β-amino disulfides by regioselective ring opening of sulfamidates with benzyltriethylammonium tetrathiomolybdate [BnNEt₃] ₂MoS₄. Stability and reactivity of different protecting groups under the reaction conditions have been discussed. This methodology has also been extended to serine and threonine derived sulfamidates to furnish cystine and 3,3′-dimethyl cystine derivatives. Georg Thieme Verlag.

Full text of DOI:10.1055/s-0028-1088133

LETTER
1227
Facile Synthesis of b-Amino Disulfides, Cystines, and Their Direct
Incorporation into Peptides
S
a
ynthesis of
b-Am
a
ino Disulfi
s
des ir Baig R. B.,a Catherine K. Kanimozhi,a V. Sai Sudhir,a Srinivasan Chandrasekaran*b
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India
Honorary Professor, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India
Fax +91(80)23602423; E-mail: scn@orgchem.iisc.ernet.in
b
Received 26 January 2009
al of the tosyl group from the product to obtain the free
amine is nontrivial. The presence of a sulfur chelation site
in catalysts for enantioselective transition-metal-mediated
C–C bond formation has been found to give rise to im-
Abstract: Herein, we report a simple and efficient methodology for
the synthesis of b-amino disulfides by regioselective ring opening
of sulfamidates with benzyltriethylammonium tetrathiomolybdate
[BnNEt3]2MoS4. Stability and reactivity of different protecting
groups under the reaction conditions have been discussed. This proved levels of enantioselectivity.7 Thus, N-alkyl b-amino
methodology has also been extended to serine and threonine derived
disulfides are very important ligands for asymmetric nu-
sulfamidates to furnish cystine and 3,3¢-dimethyl cystine deriva-
tives.
cleophilic addition of organometallic reagents to the car-
bonyl group.4a,7 Our earlier method leads to N-tosyl-b-
Key words: benzyltriethylammonium tetrathiomolybdate, b-amino
disulfides, sulfamidates, cystine, peptides
amino disulfides which are not good ligands for these
reactions.8 Hence, there is a need for an efficient method
for the direct synthesis of N-alkyl b-amino disulfides. In
continuation of our investigation into the utility of 1 in or-
ganic synthesis.9,10 We disclose here a general methodol-
ogy for the direct synthesis of N-alkyl b-amino disulfides
starting from sulfamidates under neutral conditions
(Scheme 2). This methodology was also extended to
serine- and threonine-derived sulfamidates to give cystine
and 3,3¢-dimethyl cystine derivatives, respectively
Sulfamidates are versatile intermediates in organic syn-
thesis because of their very high reactivity, ability to func-
tion as carbon electrophiles, and utility in the synthesis of
biologically active compounds.1 The most straightfor-
ward route for the synthesis of b-amino sulfides involves
the ring opening of sulfamidates or aziridines with thi-
ols.2,3 The common protocol used in the ring opening of
sulfamidates with thiols is in the presence of a base.2a,3
However, there are not many reports for the synthesis of
b-amino disulfides in a single-step process.4 b-Amino di-
sulfide is the most important structural motif in a wide
range of biologically active peptides and proteins and
plays a unique role in the conformation and formation of
tertiary structure of peptides.5
O
O
NHR3
R2
R2
1) [BnNEt3]2MoS4,
MeCN, r.t., 0.5–18 h
S
R3N
O
S
R1
R1
S
2) H+/H2O, r.t., 2–12 h
3) NH4OH, r.t., 10 min
NHR3
R2
R1
Scheme 2 Reaction of a sulfamidates with tetrathiomolybdate 1
We began our study by synthesizing the sulfamidite 8 and
NHTs
sulfamidate 9a starting from L-phenylalanine
4
Ts
N
(Scheme 3).11
S
[BnNEt3]2MoS4 (1 equiv)
S
MeCN, r.t., 10 h
80%
Treatment of sulfamidite 8 with 1 (1.2 equiv, MeCN,
28 °C) failed to effect ring opening even after stirring at
room temperature for 48 hours. However, the more acti-
vated sulfamidate 9a on reaction with 1 (1.2 equiv,
MeCN, 28 °C, 0.75 h) underwent smooth and facile ring
opening to afford N-benzyl b-amino disulfide 10a in 90%
yield (Scheme 3). It is reasonable to visualize nucleo-
philic attack of 1 exclusively at the C–O bond of 9a in a
highly stereo specific (SN2) manner followed by opening
of the second sulfamidate ring to form an intermediate X.
The intermediate X then undergoes an internal redox
process12 to give b-amino disulfide 10a after hydrolysis
(Scheme 4).
NHTs
2
3
Scheme 1 Reaction of N-tosyl aziridine 2 with [BnNEt3]2MoS4 (1)
Recently, we reported the nucleophilic ring opening of
various N-tosyl aziridines with benzyltriethylammoni-
umtetrathiomolybdate [BnNEt3]2MoS4 (1) and demon-
strated the utility of this methodology for the synthesis of
b-sulfonamidodisulfides 3 (Scheme 1).6 The most impor-
tant limitations of this method are that (a) the reaction
works only in the case of activated aziridines like 2 and
the ring opening with tetrathiomolybdate 1 is dependent
on the substituents on the aziridine ring and (b) the remov-
Using a structurally representative set of cyclic sulfami-
dates 9a–i synthesized from the corresponding L-amino
acids employing the route outlined in Scheme 3 we have
been able to generate the corresponding substituted and
SYNLETT 2009, No. 8, pp 1227–1232
Advanced online publication: 08.04.2009
DOI: 10.1055/s-0028-1088133; Art ID: D03109ST
x
x.
x
x.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

1228
N. Baig R. B. et al.
LETTER
Ph
Ph
O
Ph
O
1) PhCHO, Et3N
MeOH, 0 °C, 3 h
SOCl2, MeOH
OH
O
O
H2N
ClH⋅H2N
Ph
N
0 °C, 6 h
quantitative
2) NaBH4, 0 °C, 5 h
95%
H
O
4
5
6
LiAlH4, CH2Cl2
–78 °C, 1 h
90%
O
S
O
O
Ph
SOCl2, Et3N
imidazole
S
NaIO4, RuCl3
O
BnN
BnN
O
OH
CH2Cl2, 0 °C, 2 h
84%
MeCN–H2O (1:1)
0 °C, 2 h
quantitative
Ph
N
H
Ph
Ph
9a
7
1
1
8
90%
NHBn
NHBn
Ph
S
Ph
S
Ph
S
Ph
S
NHBn
10a
NHBn
10a
Scheme 3 Synthesis and reactivity of sulfamidite 8 and sulfamidate 9a with 1
SO3
NBn
O
NHBn
Bn
O
S
Bn
S
S
BnN
[BnNEt3]2MoS4 (1)
hydrolysis
Bn
S
O
S
Bn
MeCN, 28 °C, 0.75 h
NHBn
Bn
9a
NBn
SO3
10a
MoS2
Bn
BnN
Bn
S
S
S
S
S
S
S
S
BnN SO3
SO3
Mo
Mo
O3S
Mo
S
O3S
NBn
Bn
S
S
S
NBn
Bn
BnN SO3
Bn
X
Scheme 4 Mechanism for the formation of b-amino disulfide 10a
OH
O
OH
O
1) PhCHO, Et3N, MeOH
0 °C, 3 h
OH
O
SOCl2, MeOH
R
OH
R
OMe
R
OMe
2) NaBH4, 0 °C , 6 h
0 °C to r.t., 6 h
100%
NH2
NH2
NHBn
R = H, 13a, 90%
R = Me, 13b, 88%
R = H, 11a
R = Me, 11b
R = H, 12a
R = Me, 12b
1) SOCl2, Py, CH2Cl2
–78°C to r.t., 2 h
2) NaIO4, RuCl3
MeCN–H2O
0 °C to r.t., 2 h
BnHN
MeO
R
O
1) [BnNEt3]2MOS4
MeCN, r.t., 2 h
O
Bn
N
S
S
R
OMe
NHBn
O
OMe
R
O
2) 2 N HCl, r.t., 12 h
3) NH4OH, 10 min
S
O
O
R = H, 14a, 80%
R = Me, 14b, 89%
R = H, 15a, 75%
R = Me, 15b, 84%
Scheme 5 Synthesis of cystine derivative 15a and 3,3¢-dimethyl cystine derivative 15b using tetrathiomolybdate 1
Synlett 2009, No. 8, 1227–1232 © Thieme Stuttgart · New York

LETTER
Synthesis of b-Amino Disulfides
1229
enantiopure N-benzyl b-amino disulfides 10a–i in good to tetrathiomolybdate 1 to furnish disulfide 10h in 73%
excellent yields (Table 1). The monosubstitution at b- yield.
carbon does not have dramatic effect on the reactivity of
sulfamidates 9a–g with tetrathiomolybdate 1. However,
b,b¢-disubstituted sulfamidate 9i was found to be inert to-
wards 1, and there was no reaction to provide the corre-
sponding b-amino disulfide even after stirring the reaction
mixture for 48 hours. This may be due to overcrowding of
two methyl groups at the b-carbon atom. A highly substi-
tuted sulfamidate 9h derived from (1S,2R)-1-amino-2,3-
dihydro-1H-indan-2-ol reacted very slowly (18 h) with
The mildness of reaction conditions and the excellent
yields obtained encouraged us to study the generality of
this methodology with various protecting groups used for
the protection of amino groups in sulfamidates.With this
in mind we synthesized the sulfamidates 9j–m starting
from (S)-2-aminobutanol following the literature proce-
dure.13 The reaction of these sulfamidates 9j–m with
tetrathiomolybdate 1 followed by hydrolysis with saturat-
ed citric acid solution gave the corresponding b-aminodi-
Table 1 Synthesis of N-Benzyl b-Amino Disulfides via Ring Opening of Sulfamidates 9a–i with Tetrathiomolybdate 1a
Entry
Sulfamidates
Time (h)b
Product
Yield (%)
90
O
O
O
Ph
NHBn
S
1
9a
0.75
10a
S
BnN
S
NHBn
Ph
Ph
O
O
NHBn
S
2
3
9b
9c
0.5
0.5
10b
10c
70
79
S
BnN
O
S
NHBn
NHBn
O
O
NHBn
S
S
O
BnN
S
O
O
O
NHBn
S
BnN
4
5
9d
9e
0.75
1.5
10d
10e
89
84
S
S
S
S
S
S
NHBn
NHBn
NHBn
O
O
NHBn
NHBn
S
O
BnN
O
O
S
BnN
O
6
7
9f
1.5
1.5
10f
87
95
O
O
NHBn
Ph
S
9g
10g
Ph
S
O
BnN
Ph
S
NHBn
NHBn
O
Bn
N
S
O
S
8
9
9h
9i
18
48
10h
73
–
O
S
BnHN
O
O
S
n.r.
O
BnN
a Reagents and conditions: i) [BnNEt3]2MoS4 (1.2 equiv, MeCN, 28 °C, 0.5–18 h; ii) 2 N HCl, r.t., 12 h; iii) NH4OH, r.t., 10 min.
b Time required for the reaction of sulfamidates with tetrathiomolybdate 1.
Synlett 2009, No. 8, 1227–1232 © Thieme Stuttgart · New York

1230
N. Baig R. B. et al.
LETTER
Table 2 Reaction of Sulfamidates 9j–m with Tetrathiomolybdate 1a
Entry
1
Sulfamidates
Time (h)a
0.5
Products
Yield (%)
O
O
O
NHPMB
NHBoc
S
9j
10j
83b
69c
85c
71c
S
S
S
S
PMBN
S
NHPMB
O
O
O
S
2
3
4
9k
9l
0.5
0.5
0.5
10k
10l
BocN
S
NHBoc
O
O
O
NHCbz
NHFmoc
S
CbzN
S
NHCbz
O
O
S
9m
10m
FmocN
O
S
NHFmoc
a Time required for the reaction of sulfamidates with tetrathiomolybdate 1.
b Reagents and conditions: i) [BnNEt3]2MoS4 (1.2 equiv, MeCN, 28 °C, 30 min; ii) 2 N HCl, r.t., 12 h; iii) NH4OH, r.t., 10 min.
c Reagents and conditions: i) [BnNEt3]2MoS4 (1.2 equiv, MeCN, 28 °C, 30 min; ii) sat. citric acid soln, r.t., 2 h.
sufides 10j–m in very good yields (Table 2). These results nine (Scheme 5). L-Serine (11a) and threonine (11b) were
show that our method is general and it overcomes all the converted to the corresponding methyl ester amine hydro-
limitations of the earlier method reported for the synthesis chlorides 12a and 12b, which were further converted to
of b-amino disulfides which was limited only to N-tosyl- the corresponding benzyl amine derivatives 13a and 13b
activated aziridines.6 Here we have demonstrated the re- by reductive amination with benzaldehyde and NaBH4 in
activity and stability of Boc, Cbz, Fmoc, Bn, and PMB methanol. The reaction of 13a and 13b with SOCl2 fol-
groups under the reaction conditions with tetrathiomolyb- lowed by oxidation with NaIO4 in acetonitrile–water (1:1)
date 1 to give the corresponding N-protected b-amino di- furnished the sulfamidates 14a and 14b, respectively, in
sulfides.
excellent yields. The reaction of sulfamidates 14a and 14b
with tetrathiomolybdate 1 furnished the cystine and 3,3¢-
dimethyl cystine derivatives 15a and 15b, respectively, in
75% and 84% yield (Scheme 5). The compounds 15a and
15b were found to be diastereomerically pure by 1H NMR
spectroscopy.15
The reactivity of sulfamidates with 1 was found to be in-
dependent of the nature of the protecting groups used
(Table 2).
The methodology was then extended to the synthesis of
biologically important cystine and 3,3¢-dimethyl cystine
derivatives 15a and 15b,14 starting from serine and threo-
Since, the amino acids 15a and 15b have free N-terminal
nitrogen they could be utilized further for peptide-
O
O
Boc
N
OH
O
Boc
N
1) SOCl2, Py, MeCN
–78 °C to r.t., 2 h
O
OH
S
H2, Pd/C, MeOH
O
O
Ph
S
O
O
Ph
O
3 h, 0 °C to r.t.
quantitative
2) NaIO4, RuCl3
0 °C to r.t., 2 h
O
O
NHBoc
16
17
18
85%
OMe
ClH⋅H2N
O
DCC, NMM, EtOAc
0 °C to r.t., 12 h
60%
NHBoc
O
H
N
MeO
O
Boc
N
[BnNEt3]2MoS4
MeCN, r.t., 8 h
S
O
OMe
O
S
O
N
H
O
S
OMe
sat. citric acid, r.t., 2 h
76%
O
N
O
H
20
19
O
BocHN
Scheme 6 Synthesis of dipeptide disulfide 20, incorporating a 3,3¢-dimethyl cystine via ring opening of sulfamidate 19 with 1
Synlett 2009, No. 8, 1227–1232 © Thieme Stuttgart · New York

LETTER
Synthesis of b-Amino Disulfides
1231
tion (25 mL). Ethyl acetate was removed under vacuum and the sul-
famidate peptide 19 was purified by SiO2 (100–200 mesh) column
chromatography; yield 60% (0.869 g); white solid; mp 117 °C;
[a]D25 –19.33 (c 1, CHCl3). IR (neat): 3373 (br), 2959 (m), 1744 (s),
1708 (s), 1549 (w), 1390 (m), 1326 (m), 1197 (m), 1151 (m), 1052
(w), 885 (w), 831 (m) cm–1. 1H NMR (300 MHz, CDCl3): d = 6.81
(1 H, d, J = 7.8 Hz), 5.06–4.98 (1 H, m), 4.66–4.61 (1 H, m), 3.73
(3 H, s), 1.72–1.45 (15 H, m), 0.93 (3 H, d, J = 6.0 Hz). 13C NMR
(75 MHz, CDCl3): d = 172.4, 165.8, 148.6, 86.7, 78.8, 64.6, 52.3,
51.0, 41.1, 27.7, 24.7, 22.7, 21.6, 18.9. HRMS: m/z calcd for
C16H28N2O8S [M + Na]+: 431.1464; found: 431.1446.
coupling reactions. To demonstrate the utility of this
method for direct incorporation of unnatural amino acid
containing disulfide bond into a peptide, we synthesized a
peptide 19 by coupling sulfamidate 18 with (NH2-Leu-
OMe) leucine methyl ester (Scheme 6). The reaction of 19
with tetrathiomolybdate 1 gave the peptide 20 as a single
diastereomer16 containing 3,3¢-dimethyl cystine in good
yield (76%).
In summary we have disclosed an easy method for direct
access to b-amino disulfides by regioselective ring open-
ing of sulfamidates with tetrathiomolybdate 1. The versa-
tility of this reaction has been shown by preparing a
number of b-amino disulfides having different N-protect-
ing groups, and the stability of these protecting groups un-
der the reaction conditions have been evaluated. This
methodology was also extended to serine- and threonine-
derived sulfamidates to furnish the corresponding cystine
and 3,3¢-dimethyl cystine derivatives which are biologi-
cally important amino acids. Further studies of the reactiv-
ityofstructurallydiversesulfamidateswithtetrathiomolybdate
are in progress.
b-Amino Disulfides; Typical Procedure
Synthesis of 10a
To a well-stirred solution of sulfamidate 9a (0.151g, 0.50 mmol) in
MeCN (6 mL) was added [BnNEt3]2MoS4 (1, 0.365g, 0.6 mmol) in
portions over a period of 5 min. The reaction mixture was stirred for
further 45 min at r.t. To this solution 2 N HCl (3 mL) was added,
and the stirring was continued for further 12 h at r.t. Finally, the
reaction mixture was neutralized by addition of NH4OH solution
and extracted with EtOAc (4 × 20 mL). The combined organic ex-
tract was washed with brine, dried over anhyd Na2SO4, and concen-
trated under vacuum. The crude product was purified by SiO2 (100–
200 mesh) column chromatography.
25
Yield 90% (0.115 g); oily liquid; [a]D +73.61 (c 1, CHCl3). IR
(neat): 3324 (br), 3058 (m), 3024 (s), 2919 (s), 2846 (m), 1601 (w),
1493 (s), 1453 (s), 1110 (m), 741 (s), 698 (s) cm–1. 1H NMR (300
MHz, CDCl3): d = 7.29–7.11 (10 H, m), 3.77 (2 H, d, J = 3.0 Hz),
3.06 (1 H, m), 2.81–2.66 (4 H, m), 1.90 (1 H, br s). 13C NMR (75
MHz, CDCl3): d = 140.0, 138.4, 129.3, 128.4, 128.0, 126.9, 126.3,
57.4, 51.1, 43.4, 39.8. HRMS: m/z calcd for C32H32N2S2 [M + H]+:
513.2398; found: 513.2396.
N-Boc-, N-Cbz-, and N-Fmoc-Protected Sulfamidates; Typical
Procedure
Synthesis of 9k
Step I: A solution of SOCl2 (0.47 mL, 6.5 mmol) in dry MeCN (15
mL) under nitrogen was cooled to –40 °C, and then tert-butyl (S)-1-
hydroxybutan-2-ylcarbamate (0.945g, 5 mmol) in dry MeCN (10
mL) was added dropwise over 10 min, stirring was continued for
further 45 min at the same temperature. Dry pyridine (1.9 mL, 25
mmol) was then added. The reaction mixture was further stirred for
1 h and was allowed to warm to r.t. The reaction mixture was
quenched with H2O and extracted with EtOAc (3 × 20 mL). The
combined organic portions were then washed with H2O, dried over
anhyd Na2SO4 and concentrated in vacuum to afford the crude sulf-
amidite. This was used without further purification in the next step.
Compound 20
Yield 76% (0.137 g); gummy solid; [a]D25 –12.00 (c 1, CHCl3). IR
(neat): 3327 (br), 2961 (m), 2932 (w), 1748 (m), 1687 (m), 1651 (s),
1550 (m), 1522 (m), 1367 (w), 1250 (w), 1162 (m), 1008 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.52 (1 H, d, J = 9.0 Hz), 5.34 (1
H, d, J = 9.0 Hz), 4.62–4.55 (1 H, m), 4.16 (1 H, dd, J = 6.0, 9.0
Hz), 3.73 (3 H, s), 3.20 (1 H, m), 1.77–1.59 (3 H, m), 1.56 (9 H, s),
1.40 (3 H, d, J = 6.0 Hz), 0.92 (6 H, d, J = 4.5 Hz). 13C NMR (75
MHz, CDCl3): d = 172.9, 169.9, 155.5, 80.4, 60.0, 52.3, 50.8, 41.2,
36.7, 28.2, 24.7, 22.7, 21.7, 21.0. HRMS: m/z calcd for
C32H58N4O10S2 [M + Na]+: 745.3492; found: 745.3476.
Step II: To a cooled (ice bath) solution of crude (step I) sulfamidite
(5 mmol) in MeCN (30 mL) was added RhCl3 (20 mg), followed by
NaIO4 (1.60 g, 7.50 mmol) and then H2O (30 mL). The mixture was
stirred at 0 °C for 2 h, then diluted with Et2O, and the phases were
separated. The aqueous phase was extracted with Et2O. The com-
bined organic portions were washed with NaHCO3 soln and then
brine. The solution was dried over anhyd Na2SO4 and concentrated.
The crude product was purified by SiO2 (100–200 mesh) column
Acknowledgment
Nasir Baig R. B. thanks CSIR New Delhi for a Senior Research Fel-
lowship and IISc for financial assistance.
25
chromatography; yield 84% (1.05 g); white solid; mp 70 °C; [a]D
3.18 (c 1, CHCl3). IR (neat): 2978 (m), 1734 (s), 1372 (s), 1321 (s),
1193 (s), 1150 (s), 928 (m), 655 (m) cm–1. H NMR (400 MHz,
1
References and Notes
CDCl3): d = 4.64 (1 H, dd, J = 6.4, 8.0 Hz), 4.33 (1 H, dd, J = 1.6,
9.4 Hz), 4.27 (1 H, m), 1.90 (2 H, m), 1.55 (9 H, s), 0.97 (3 H, t,
J = 8.0 Hz). 13C NMR (75 MHz, CDCl3): d = 148.6, 85.2, 69.2, 58.4,
27.8, 25.1, 8.7. HRMS: m/z calcd for C9H17NO5S [M + Na]+:
274.0725; found: 274.0732.
(1) (a) Cohen, S. C.; Halcomb, R. L. J. Am. Chem. Soc. 2002,
124, 2534. (b) Bower, J. F.; Szeto, P.; Gallagher, T. Org.
Biomol. Chem. 2007, 5, 143. (c) Bower, J. F.; Szeto, P.;
Gallagher, T. Org. Lett. 2007, 9, 4901. (d) Avenoza, A.;
Busto, J. H.; Jimenez-Oses, G.; Peregrina, J. M. Org. Lett.
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Synthesis of 19
A solution of 18 (1.0 g, 3.55 mmol), HCl·NH2-Leu-OMe (0.618 g,
4.2 mmol, 1.2 equiv), N-methyl morpholine (1.16 mL, 10.6 mmol,
3 equiv) in EtOAc (50 mL) was cooled to 0 °C and DCC (1.09 g,
5.32 mmol, 1.5 equiv) was added in small portions. The reaction
mixture was brought to r.t. (28 °C) and stirred for 12 h. The reaction
mixture was cooled and filtered. The filtrate was washed with sat.
citric acid solution (25 mL), sat. Na2CO3 (25 mL), and brine solu-
(g) Avenoza, A.; Busto, J. H.; Corzana, F.; Jimenez-Oses,
G.; Peregrina, J. M. Chem. Commun. 2004, 980. (h) Attani,
M.; Wei, L.; Lubell, W. D. Org. Lett. 2001, 3, 2965.
Synlett 2009, No. 8, 1227–1232 © Thieme Stuttgart · New York

1232
N. Baig R. B. et al.
LETTER
(10) (a) Nasir Baig, R. B.; Sai Sudhir, V.; Chandrasekaran, S.
(2) (a) Menendez, R. E.; Lubell, W. D. Tetrahedron 2003, 59,
2581. (b) Wu, J.; Hou, X. L.; Dai, L. X. J. Chem. Soc.,
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Synlett 2009, No. 8, 1227–1232 © Thieme Stuttgart · New York

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