LETTER
1227
Facile Synthesis of b-Amino Disulfides, Cystines, and Their Direct
Incorporation into Peptides
Synthesi ofb-AminoDisulfides Baig R. B.,a Catherine K. Kanimozhi,a V. Sai Sudhir,a Srinivasan Chandrasekaran*b
Nasir
a
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
Received 26 January 2009
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
methodology has also been extended to serine and threonine derived
sulfamidates to furnish cystine and 3,3¢-dimethyl cystine derivatives.
Key words: benzyltriethylammonium tetrathiomolybdate, b-amino
disulfides, sulfamidates, cystine, peptides
Sulfamidates are versatile intermediates in organic synthesis because of their very high reactivity, ability to function as carbon electrophiles, and utility in the synthesis of
biologically active compounds.1 The most straightforward route for the synthesis of b-amino sulfides involves
the ring opening of sulfamidates or aziridines with thiols.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 disulfide 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
Ts
N
S
S
MeCN, r.t., 10 h
2
Scheme 1
80%
NHTs
3
Reaction of N-tosyl aziridine 2 with [BnNEt3]2MoS4 (1)
Recently, we reported the nucleophilic ring opening of
various N-tosyl aziridines with benzyltriethylammoniumtetrathiomolybdate [BnNEt3]2MoS4 (1) and demonstrated the utility of this methodology for the synthesis of
b-sulfonamidodisulfides 3 (Scheme 1).6 The most important 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 removSYNLETT 2009, No. 8, pp 1227–1232xx. 209
Advanced online publication: 08.04.2009
DOI: 10.1055/s-0028-1088133; Art ID: D03109ST
© Georg Thieme Verlag Stuttgart · New York
O
O
R3N
R1
S
O
R2
Scheme 2
1) [BnNEt3]2MoS4,
MeCN, r.t., 0.5–18 h
2) H+/H2O, r.t., 2–12 h
3) NH4OH, r.t., 10 min
NHR3
R2
S
R1
R2
S
R1
NHR3
Reaction of a sulfamidates with tetrathiomolybdate 1
We began our study by synthesizing the sulfamidite 8 and
sulfamidate 9a starting from L-phenylalanine 4
(Scheme 3).11
NHTs
[BnNEt3]2MoS4 (1 equiv)
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 improved levels of enantioselectivity.7 Thus, N-alkyl b-amino
disulfides are very important ligands for asymmetric nucleophilic addition of organometallic reagents to the carbonyl group.4a,7 Our earlier method leads to N-tosyl-bamino 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 organic synthesis.9,10 We disclose here a general methodology 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
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 activated 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 nucleophilic 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).
Using a structurally representative set of cyclic sulfamidates 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
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b
1228
LETTER
N. Baig R. B. et al.
Ph
Ph
SOCl2, MeOH
OH
H2N
O
O
ClH⋅H2N
0 °C, 6 h
quantitative
Ph
1) PhCHO, Et3N
MeOH, 0 °C, 3 h
2) NaBH4, 0 °C, 5 h
95%
O
4
5
Ph
O
N
H
O
6
LiAlH4, CH2Cl2
–78 °C, 1 h
90%
O
O
O
S
BnN
O
CH2Cl2, 0 °C, 2 h
MeCN–H2O (1:1)
0 °C, 2 h
Ph
quantitative
Ph
9a
1
Ph
SOCl2, Et3N
imidazole
S
NaIO4, RuCl3
O
BnN
Ph
84%
7
1
8
OH
N
H
NHBn
Ph
S
S
NHBn
Ph
S
Ph
NHBn
Ph
NHBn
10a
10a
Scheme 3
S
Synthesis and reactivity of sulfamidite 8 and sulfamidate 9a with 1
SO3
O
S
BnN
O
NHBn
NBn
[BnNEt3]2MoS4 (1)
O
Bn
Bn
9a
hydrolysis
S
S
MeCN, 28 °C, 0.75 h
Bn
S
Bn
S
Bn
NHBn
NBn
10a
SO3
MoS2
Bn
Bn
S
S
Mo
BnN
NBn
S
S
NBn
X
S
BnN SO3
S
BnN SO3
Mo
O3S
S
Bn
Scheme 4
S
SO3
Mo
O3S
S
S
S
S
Bn
Bn
Mechanism for the formation of b-amino disulfide 10a
OH
O
R
OH
OH
NH2
O
1) PhCHO, Et3N, MeOH
0 °C, 3 h
SOCl2, MeOH
R
0 °C to r.t., 6 h
100%
OMe
NH2
2) NaBH4, 0 °C , 6 h
O
R
OMe
NHBn
R = H, 13a, 90%
R = Me, 13b, 88%
R = H, 12a
R = Me, 12b
R = H, 11a
R = Me, 11b
OH
1) SOCl2, Py, CH2Cl2
–78°C to r.t., 2 h
2) NaIO4, RuCl3
MeCN–H2O
0 °C to r.t., 2 h
BnHN
R
O
MeO
S
S
OMe
O
R
R = H, 15a, 75%
R = Me, 15b, 84%
Scheme 5
NHBn
O
1) [BnNEt3]2MOS4
MeCN, r.t., 2 h
2) 2 N HCl, r.t., 12 h
3) NH4OH, 10 min
O
O
Bn
N
OMe
S
O
R
R = H, 14a, 80%
R = Me, 14b, 89%
Synthesis of cystine derivative 15a and 3,3¢-dimethyl cystine derivative 15b using tetrathiomolybdate 1
Synlett 2009, No. 8, 1227–1232
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90%
LETTER
Synthesis of b-Amino Disulfides
enantiopure N-benzyl b-amino disulfides 10a–i in good to
excellent yields (Table 1). The monosubstitution at bcarbon 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 towards 1, and there was no reaction to provide the corresponding 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 substituted sulfamidate 9h derived from (1S,2R)-1-amino-2,3dihydro-1H-indan-2-ol reacted very slowly (18 h) with
Entry
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 procedure.13 The reaction of these sulfamidates 9j–m with
tetrathiomolybdate 1 followed by hydrolysis with saturated citric acid solution gave the corresponding b-aminodi-
Synthesis of N-Benzyl b-Amino Disulfides via Ring Opening of Sulfamidates 9a–i with Tetrathiomolybdate 1a
Time (h)b
Sulfamidates
O
1
tetrathiomolybdate 1 to furnish disulfide 10h in 73%
yield.
O
BnN
Yield (%)
Ph
S
9a
Product
0.75
O
NHBn
10a
S
NHBn
Ph
O
2
9b
90
S
Ph
O
NHBn
S
BnN
0.5
O
10b
70
S
S
NHBn
O
O
3
9c
NHBn
S
0.5
O
BnN
10c
79
S
S
NHBn
O
O
NHBn
S
4
BnN
9d
O
0.75
10d
S
89
S
NHBn
O
O
NHBn
S
5
9e
O
BnN
1.5
10e
S
84
S
NHBn
O
O
NHBn
S
6
BnN
9f
O
1.5
10f
S
87
S
NHBn
O
O
7
9g
NHBn
S
1.5
O
BnN
10g
Ph
S
S
Ph
95
NHBn
Ph
NHBn
8
Bn O
N
S O
9h
18
S
10h
O
73
S
BnHN
O
O
9
a
b
9i
S
BnN
O
48
n.r.
–
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.
Time required for the reaction of sulfamidates with tetrathiomolybdate 1.
Synlett 2009, No. 8, 1227–1232
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Table 1
1229
1230
Table 2
Entry
LETTER
N. Baig R. B. et al.
Reaction of Sulfamidates 9j–m with Tetrathiomolybdate 1a
Sulfamidates
O
1
Products
0.5
10j
Yield (%)
O
NHPMB
S
9j
Time (h)a
PMBN
O
S
83b
S
NHPMB
O
2
O
NHBoc
S
9k
BocN
0.5
O
10k
S
69c
S
NHBoc
O
3
O
NHCbz
S
9l
CbzN
0.5
O
10l
S
85c
S
4
O
NHFmoc
S
9m
FmocN
0.5
O
10m
S
71c
S
NHFmoc
a
Time required for the reaction of sulfamidates with tetrathiomolybdate 1.
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.
b
sufides 10j–m in very good yields (Table 2). These results
show that our method is general and it overcomes all the
limitations of the earlier method reported for the synthesis
of b-amino disulfides which was limited only to N-tosylactivated aziridines.6 Here we have demonstrated the reactivity and stability of Boc, Cbz, Fmoc, Bn, and PMB
groups under the reaction conditions with tetrathiomolybdate 1 to give the corresponding N-protected b-amino disulfides.
nine (Scheme 5). L-Serine (11a) and threonine (11b) were
converted to the corresponding methyl ester amine hydrochlorides 12a and 12b, which were further converted to
the corresponding benzyl amine derivatives 13a and 13b
by reductive amination with benzaldehyde and NaBH4 in
methanol. The reaction of 13a and 13b with SOCl2 followed by oxidation with NaIO4 in acetonitrile–water (1:1)
furnished the sulfamidates 14a and 14b, respectively, in
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 independent 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 peptideO
O
OH
O
1) SOCl2, Py, MeCN
–78 °C to r.t., 2 h
O
Ph
NHBoc
16
O
2) NaIO4, RuCl3
0 °C to r.t., 2 h
Boc
N
S
O
Boc
N
O
O
Ph
H2, Pd/C, MeOH
3 h, 0 °C to r.t.
quantitative
O
17
85%
OH
S
O
O
18
OMe
ClH⋅H2N
O
DCC, NMM, EtOAc
0 °C to r.t., 12 h
60%
O
MeO
NHBoc
H
N
O
O
20
Scheme 6
S
S
[BnNEt3]2MoS4
MeCN, r.t., 8 h
O
N
H
BocHN
OMe
O
sat. citric acid, r.t., 2 h
76%
O
O
Boc
N
S
N
H
O
OMe
O
19
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
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NHCbz
O
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-LeuOMe) 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 opening of sulfamidates with tetrathiomolybdate 1. The versatility of this reaction has been shown by preparing a
number of b-amino disulfides having different N-protecting groups, and the stability of these protecting groups under the reaction conditions have been evaluated. This
methodology was also extended to serine- and threoninederived sulfamidates to furnish the corresponding cystine
and 3,3¢-dimethyl cystine derivatives which are biologically important amino acids. Further studies of the reactivity of structurally diverse sulfamidates with tetrathiomolybdate
are in progress.
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)-1hydroxybutan-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 sulfamidite. This was used without further purification in the next step.
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 combined 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
chromatography; yield 84% (1.05 g); white solid; mp 70 °C; [a]D25
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. 1H NMR (400 MHz,
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.
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-
Synthesis of b-Amino Disulfides
1231
tion (25 mL). Ethyl acetate was removed under vacuum and the sulfamidate 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.
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 extract was washed with brine, dried over anhyd Na2SO4, and concentrated under vacuum. The crude product was purified by SiO2 (100–
200 mesh) column chromatography.
Yield 90% (0.115 g); oily liquid; [a]D25 +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.
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.
1
H 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.
Acknowledgment
Nasir Baig R. B. thanks CSIR New Delhi for a Senior Research Fellowship and IISc for financial assistance.
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LETTER
N. Baig R. B. et al.
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(15) The nucleophilic ring opening of cyclic sulfamidates occur
exclusively by SN2 substitution resulting in inversion of
configuration as demonstrated by other groups.1–3
(16) In order to rule out the intervention of an elimination–
addition mechanism in the formation of 15a,b and 20, the
dehydro amino acid [Boc-DAbu-OMe] derived from BocThreo-OMe was treated with tetrathiomolybdate 1 and there
was no reaction. This rules out the intermediacy of a dehydro
amino acid in the formation of the product.
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