Regio- and stereospecific synthesis of β-sulfonamidodisulfides and β-sulfonamidosulfides from aziridines using tetrathiomolybdate as a sulfur transfer reagent

Article abstract of DOI:10.1021/jo0624389

A comprehensive study of a general and effective one-step procedure for the synthesis of β-sulfonamidodisulfides directly from N-tosyl aziridines in a regio- and stereospecific manner under neutral conditions without the use of any Lewis acid or base has been reported. This methodology is extended to the synthesis of an optically pure cyclic seven-membered disulfide 29. Synthesis of a variety of β-sulfonamidosulfides involving tandem, multistep reactions in one pot is also reported.

Full text of DOI:10.1021/jo0624389

Regio- and Stereospecific Synthesis of â-Sulfonamidodisulfides and
â-Sulfonamidosulfides from Aziridines using Tetrathiomolybdate as
a Sulfur Transfer Reagent‡
Devarajulu Sureshkumar, Thanikachalam Gunasundari, Venkataraman Ganesh,
and Srinivasan Chandrasekaran*,†
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India
scn@orgchem.iisc.ernet.in
ReceiVed NoVember 27, 2006
A comprehensive study of a general and effective one-step procedure for the synthesis of â-sulfonami-
dodisulfides directly from N-tosyl aziridines in a regio- and stereospecific manner under neutral conditions
without the use of any Lewis acid or base has been reported. This methodology is extended to the synthesis
of an optically pure cyclic seven-membered disulfide 29. Synthesis of a variety of â-sulfonamidosulfides
involving tandem, multistep reactions in one pot is also reported.
Introduction
protocols used in the ring opening of aziridines with thiols are
in the presence of Lewis acids such as BF3‚OEt2, ZnCl2, Cu-
(OTf)2, Yb(OTf)3, Ti(OiPr)4, etc. and other Bronsted acids or
bases. However, to the best of our knowledge there are not many
reports for the synthesis of â-sulfonamidodisulfides from
aziridines in a single-step process.3 â-Sulfonamidodisulfide,
which has disulfide bridge, is the most important structural motif
in a wide range of biologically active peptides and proteins and
plays an unique role in the conformation and formation of
tertiary structure of peptides.4 In a recent communication, we
reported our results on the nucleophilic ring opening of various
aziridines with benzyltriethylammonium tetrathiomolybdate5
[BnEt3N]2MoS4 (1) and demonstrated the utility of this meth-
odology for the synthesis of a number of interesting sulfur
heterocycles with high regio- and stereocontrol.6 In continuation
of our investigation into the utility of 1 in organic synthesis,
herein we present details of a comprehensive study of a general
Aziridines 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
natural products.1 The most straightforward route for the
synthesis of â-sulfonamidosulfides involves the regioselective
ring-opening reaction of aziridines with thiols, and several other
procedures have appeared in the literature.2 The most common
* To whom correspondence should be addressed. Tel: +91-80-2293 2404.
Fax: +91-80-2360 2423.
† Honorary Professor, Jawaharlal Nehru Center for Advanced Scientific
Research, Jakkur, Bangalore.
‡ Dedicated to Professor K. Venkatesan on the occasion of his 75th birthday.
(1) (a) Tanner, D. Angew. Chem., Int. Ed. 1994, 33, 599-619. (b) Hu,
X. E. Tetrahedron 2004, 60, 2701-2743. (c) McCoull, W.; Davis, F. A.
Synthesis 2000, 10, 1347-1365.
(2) Wu, J.; Hou, X. L.; Dai, L. X. J. Chem. Soc., Perkin Trans. 1 2001,
1314-1317 and references therein.
(3) (a) Fulton, D. A.; Gibson, C. L. Tetrahedron Lett. 1997, 38, 2019-
2022. (b) Hata, Y.; Watanabe, M. Tetrahedron 1987, 43, 3881-3888. (c)
Poelert, M. A.; Hof, R. P.; Peper, N. C. M. W.; Kellogg, R. M. Heterocycles
1994, 37, 461-475.
(5) Prabhu, K. R.; Devan, N.; Chandrasekaran, S. Synlett 2002, 1762-
1778.
(6) Sureshkumar, D.; Koutha, S.; Chandrasekaran, S. J. Am. Chem. Soc.
2005, 127, 12760-12761.
(4) Thornton, J. M. J. Mol. Biol. 1981, 151, 261-287.
10.1021/jo0624389 CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/23/2007
2106
J. Org. Chem. 2007, 72, 2106-2117

â-Sulfonamidodisulfides and â-Sulfonamidosulfides
TABLE 1. Solvent Effect on the Ring Opening of N-Tosyl
Aziridine 3a
SCHEME 3. Mechanism for Formation of
â-Sulfonamidosulfide 5a
entry
solvent
temp
time (h)
ratio 4a:5a
yield (%)
1
2
3
4
5
6
7
THF
rt
rt
48
0.5
5
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
DMF
7:3
8:2
9:1
9:1
10:0
7:3
80
83
84
84
86
81
-10 °C
-20 °C
-30 °C
rt
SCHEME 4. Regiospecific Ring Opening of
Monosubstituted Aziridines 3
3
0.25
rt
SCHEME 1. Nucleophilic Ring Opening of Aziridines
Using 1
SCHEME 5. Regiospecific Ring Opening of
D-Glucose-Derived Aziridine 3o with 1
SCHEME 2. Mechanism for Formation of
â-Sulfonamidodisulfide 4
SCHEME 6. Regiospecific Ring Opening of
Carbohydrate-Derived Aziridine 3p with 1
and effective one-step procedure for the synthesis of â-sulfona-
midodisulfides 4 directly from N-tosyl aziridines 3 in a regio-
and stereospecific manner under neutral conditions without the
use of any Lewis acid or base. This methodology is extended
to the synthesis of a cyclic seven-membered disulfide 29 and a
variety of sulfonamidosulfides involving multistep, tandem
reactions.
using different solvent systems and reaction temperatures (Table
1). When the reaction was carried out in acetonitrile at
-30 °C, 4a and 5a (9:1) were obtained in 84% yield. By
switching the solvent from acetonitrile to dichloromethane
(28 °C, 3 h), 4a was obtained as the exclusive product in 86%
yield.
It is reasonable to visualize the nucleophilic attack of reagent
1 on the aziridine 3a at the less-substituted carbon center in a
regiospecific manner followed by opening of the second
aziridine ring to form an intermediate X. The intermediate X
can then undergo an internal redox process5,9,10 to form the
â-sulfonamidodisulfide 4a (Scheme 2). A tentative mechanism
for the formation of â-sulfonamidosulfide 5a is depicted in
Scheme 3. Use of coordinating solvents such as acetonitrile
accelerates the formation of â-sulfonamidodisulfide 4a as well
as reductive cleavage of the disulfide bond10 by 1, leading to
the formation of thiolate intermediate Y, which further attacks
aziridine 3a in a regiospecific manner to furnish â-sulfonami-
dosulfide 5a.
Results and Discussion
Reaction of Enantiopure N-Tosyl Aziridines with Tetrathi-
omolybdate 1. Whereas treatment of unactivated aziridines7 2a
and 2b with 1 (1.1 equiv, CH3CN, 28 °C, 48 h) failed to effect
ring opening even under refluxing conditions, the activated
N-tosyl aziridine8 3a on reaction with 1 (1.1 equiv, CH3CN,
28 °C, 0.5 h) underwent smooth and clean ring opening in a
regiospecific manner to afford â-sulfonamidodisulfide 4a and
â-sulfonamidosulfide 5a (7:3) in 80% yield (Scheme 1). To
avoid the formation of 5a, reaction conditions were optimized
(7) (a) Bates, G. S.; Varelas, M. A. Can. J. Chem. 1980, 58, 2562-
2566. (b) Lohray, B. B.; Gao, Y.; Sharpless, K. B. Tetrahedron Lett. 1989,
30, 2623-2626. (c) Berry, M. B.; Craig, D. Synlett 1992, 41-44. (d) Bieber,
L. W.; De Araujo, M. C. F. Molecules 2002, 7, 902-906.
(8) It has been tested with other protecting groups (activating groups)
such as Boc and Cbz, but the reaction took more time (20 h) in the case of
Boc and in the case of Cbz the reaction was incomplete even after 88 h.
The N-Boc-protected 2,3-disubstituted aziridines failed to undergo ring
opening with 1.
(9) (a) Kruhlak, N. L.; Wang, M.; Boorman, P. M.; Parvez, M. Inorg.
Chem. 2001, 40, 3141-3148. (b) Boorman, P. M.; Wang, M.; Parvez, M.
J. Chem. Soc., Chem. Commun. 1995, 999-1000.
(10) (a) Pan, W. H.; Harmer, M. A.; Halbert, T. R.; Stiefel, E. I. J. Am.
Chem. Soc. 1984, 106, 459-460. (b) Coyle, C. L.; Harmer, M. A.; George,
G. N. Daage, M.; Stiefel, E. I. Inorg. Chem. 1990, 29, 14-19. and references
therein. (c) Prabhu, K. R.; Sivanand, P.; Chandrasekaran, S. Angew. Chem.,
Int. Ed. 2000, 39, 4316-4319.
J. Org. Chem, Vol. 72, No. 6, 2007 2107

Sureshkumar et al.
TABLE 2. Synthesis of Enantiopure â-Sulfonamidodisulfides
N-tosyl group12 in the presence of disulfide bond, but the results
have not been satisfactory.
SCHEME 7. Regiospecific Ring Opening of
2,2-Disubstituted Aziridines
Synthesis of Carbohydrate-Derived â-Sulfonamidodisul-
fides. To expand the scope of this methodology to the study of
other aziridines having different functionality and complexity,
D-glucose-derived aziridine 3o was synthesized from the epoxide
3l13a in three steps (Scheme 5). D-Glucose- and D-mannitol-
derived aziridines13 3o and 3p were treated with 1 (1.1 equiv,
CH2Cl2, 28 °C) to afford the corresponding disulfides 4l and
4m, respectively, in good yields (Schemes 5 and 6). These
The mildness of reaction conditions and the excellent yields
of products obtained encouraged us to examine the scope and
generality of the present methodology. The results are sum-
marized in Table 2. Starting from optically active aziridines7c
(3c-k) enantiopure â-sulfonamidodisulfides (4c-k) were ob-
tained in good to excellent yields (Scheme 4). In the reaction
of 3d with 1, although 4d was the major product, a small amount
of monosulfide 5d was also formed. The structure of mono-
sulfide 5d was confirmed by X-ray analysis.11
(11) CCDC 631951 (5d), CCDC 631952 (7a), CCDC 631953 (7c),
CCDC 631954 (9a), CCDC 631955 (9b), CCDC 288572 (9c), CCDC
631956 (11a), CCDC 631957 (14), CCDC 631958 (32), CCDC 631959
(36), and CCDC 631960 (44) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallography Data Centre via www.ccdc.cam.ac.uk/data
request/cif.
In order to use these N-tosyl-â-sulfonamidodisulfides for
further transformations, attempts were made to deprotect the
2108 J. Org. Chem., Vol. 72, No. 6, 2007

â-Sulfonamidodisulfides and â-Sulfonamidosulfides
TABLE 3. Synthesis of â-Substituted â-Sulfonamidodisulfides
SCHEME 9. Stereospecific Ring Opening of Aziridines 10
SCHEME 10. Stereospecific Ring Opening of Cyclic
Aziridine 14
a Isolated as a mixture (1:1) of diastereomers except in the case of 7a.
8a17 was treated with 1 (1.1 equiv, CH3CN, 28 °C, 8 h) to afford
exclusively the anti-â-sulfonamidodisulfides 9a and 9a′ as a
diastereomeric mixture (dr ) 1:1) in 79% yield. (Scheme 8).
In the case of (()-trans-N-tosyl-2,3-diethylaziridine 8b,17 syn-
â-sulfonamidodisulfides 9b and 9b′ were obtained as a diaster-
eomeric mixture (dr ) 1:1) in 82% yield under the same reaction
conditions (Table 4). Stereospecificity of this reaction was
confirmed by single-crystal X-ray analysis of 9a and 9b.11
To assess the regio- and stereospecificity together in the same
substrate, (()-cis-N-tosyl-2-isopropyl-3-methylaziridine 8c was
treated with 1 (1.1 equiv, CH3CN, 28 °C, 11 h) to afford
exclusively the anti-â-sulfonamidodisulfides 9c11 and 9c′ as a
diastereomeric mixture (dr ) 1:1) in 80% yield.6 In the case of
(()-trans-N-tosyl-2-isopropyl-3-methylaziridine 8d, the syn-â-
sulfonamidodisulfides6 9d and 9d′ were obtained as a diaster-
eomeric mixture (dr ) 1:1) in 85% yield under the same reaction
conditions. Here, tetrathiomolybdate 1 attacks the aziridines 8c
and 8d at the less-hindered C2 carbon site in a SN2 fashion with
regio- and stereocontrol and with complete inversion (Table 4,
entries 3 and 4).
Reaction of Cyclic Aziridines with 1. This methodology
was then extended to study the reaction of aziridines derived
from cyclic systems. Reaction of aziridines 10 with 1 (1.1 equiv,
CH3CN, 28 °C, 0.5-48 h, room temperature) led to facile ring
opening in a stereospecific manner to afford trans-â-sulfona-
midodisulfides 11 and 11′ as a diastereomeric mixture (dr )
1:1) in very good yields (Scheme 9). Although the reaction of
aziridine 10a was very fast (0.5 h), in the case of aziridines
10b and 10c the reaction was much slower (2 and 12 h,
respectively). Interestingly, treatment of 1 with bicyclic aziridine
10d derived from cyclooctene did not yield any product even
after 48 h. This reactivity trend may be attributed to the puckered
nature of bicyclic aziridine 10d; with increasing size of the
bicyclic aziridine ring, the nucleophilic attack at the aziridine
ring becomes more difficult. To demonstrate selective opening
of aziridine ring in the presence of epoxide, aziridino-epoxides18
10f-10h were synthesized from the corresponding 1,4-cyclic
dienes using a Sharpless aziridination16 (1,4-diene, 3 mmol;
CAT, 3.3 mmol; PTAB, 0.3 mmol; 15 mL CH3CN, room
temperature, 12 h) followed by epoxidation using m-CPBA as
an epoxidation reagent.17 Treatment of aziridino-epoxides
10f-10h with 1 (1.1 equiv, CH3CN, room temperature), re-
SCHEME 8. Regio- and Stereospecific Ring Opening of
2,3-Disubstituted Aziridines 8
enantiopure disulfide derivatives have the potential to be used
as chiral ligands in diethyl zinc addition to aldehydes.14
Reaction of Disubstituted N-Tosyl Aziridines with Tetrathi-
omolybdate 1. When this methodology was applied to the
reaction of 2,2-disubstituted aziridines 6, nucleophilic attack15
occurred exclusively at the unsubstituted carbon atom to form
â-sulfonamidodisulfides 7 (dr ) 1:1) as expected (Scheme 7).
As depicted in Table 3, a series of â-substituted â-sulfonami-
dodisulfides 7 could be synthesized in a straightforward manner,
allowing some interesting structural diversity. Using this strategy
we have demonstrated the synthesis of R-methyl cystinol
derivative 7c and R-methyl homo cystinol derivative 7d in a
single step from the corresponding aziridines16 6c and 6d,
respectively, in good yields (Table 3, entries 3 and 4). The
structures of compound 7a and 7c were confirmed by single-
crystal X-ray analysis.11
Reaction of 2,3-Disubstituted Aziridines with 1. To dem-
onstrate the stereospecificity in the ring opening of 2,3-
disubstituted aziridines with 1, meso-N-tosyl-2,3-diethylaziridine
(12) (a) Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1988, 53, 2367-
2371. (b) Opalka, C. J.; D’Ambra, T. E.; Faccone, J. J.; Bodson, G.;
Cossement, E. Synthesis 1995, 766-768. (c) Kudav, D. P.; Samant, S. P.;
Hosangadi, B. D. Synth. Commun. 1987, 17, 1185-1187.
(13) (a) Epoxide 3l was prepared from D-glucose in five steps through
a known procedure: Methods in Carbohydrate Chemistry; Academic
Press: New York, 1963; Vol. II, p 190. (b) Atsushi, E.; Toshiyuki, K.;
Tohru, F. Synlett 1999, 7, 1103-1105. (c) Mao, H.; Joly, G. J.; Peters, K.;
Hoornaert, G. J.; Compernolle, F. Tetrahedron 2001, 57, 6955-6967.
(14) (a) Kang, J.; Kim, D. S.; Kim, J. I. Synlett 1994, 10, 842-4. (b)
Braga, L. B.; Milani, P.; Paixao, M. W.; Zeni, G.; Rodrigues, O. E. D.;
Alves, E. F. Chem. Commun. 2004, 2488-2489. (c) Braga, A. L.; Luedtke,
D. S.; Wessjohann, L. A.; Paixao, M. W.; Schneider, P. H. J. Mol. Catal.
A: Chem. 2005, 229, 47-50.
(15) Stamm, H.; Assithianakis, P.; Buchholz, B.; Weiss, R. Tetrahedron
Lett. 1982, 23, 5021-5024.
(16) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 6844-6845.
(17) Iwamoto, K.; Kajima, M.; Chatani, N.; Murai, S. J. Org. Chem.
2001, 66, 169-174.
J. Org. Chem, Vol. 72, No. 6, 2007 2109

Sureshkumar et al.
TABLE 4. Synthesis of Disubstituted â-Sulfonamidodisulfides by Regio- and Stereospecific Ring Opening of 2,3-Disubstituted Aziridines 8
SCHEME 11. Tandem Aziridine Opening-Disulfide Formation-Reduction-Cyclization in One Pot
SCHEME 12. Regio- and Stereospecific Ring Opening of Trisubstituted Aziridines
sulting in the exclusive formation of products 11f-11h,
respectively, in good yields (Table 5). The epoxide ring was
left untouched under the reaction conditions. In continuation
of these studies, aziridine 1411 was synthesized starting from
1,4-cyclohexadiene by aziridination followed by dihydroxyla-
tion19 and subsequent acetylation (Scheme 10). Reaction of 14
with 1 (1.1 equiv, CH3CN, room temperature, 3 h) furnished
hydroxy-protected trans-â-sulfonamidodisulfide 15 as a dia-
stereomeric mixture (dr ) 1:1) in 70% yield (Scheme 10).
These studies could be further extended to the ring opening
of both the aziridine and epoxide rings with 1 in the same
molecule in a tandem, one-pot operation. Accordingly, (()-
aziridino-epoxide 16a was synthesized from allyl glycidyl ether
by Sharpless aziridination.16 Treatment of 16a with 1 (2.2 equiv,
CH3CN/EtOH; 1:1, room temperature, 10 h) resulted in the
formation of 17a and 17b (1:1 ratio) in 72% yield. A tentative
mechanism for the tandem aziridine and epoxide ring opening20
(18) Sureshkumar, D.; Maity, S.; Chandrasekaran, S. J. Org. Chem. 2006,
71, 1653-1657.
2110 J. Org. Chem., Vol. 72, No. 6, 2007

â-Sulfonamidodisulfides and â-Sulfonamidosulfides
TABLE 5. Synthesis of trans-â-Sulfonamidodisulfides
with 1 followed by cyclization to form 17a and 17b is presented
in Scheme 11. In the first stage, the reaction of 16a with 1 leads
to 16b resulting from the aziridine ring opening. The intermedi-
ate disulfide 16b undergoes reductive cleavage with 110 to form
the thiolate N, which then undergoes 8-exo-tet-cyclization to
give the products.
Reaction of 2,2,3-Trisubstituted Aziridines with 1. Next,
we studied the ring opening of 2,2,3-trisubstituted aziridines
18 with 1. The reaction of aziridine 18a with 1 (1.1 equiv,
CH3CN, room temperature, 4 h) gave a diastereomeric mixture
of 19a in 74% yield (Scheme 12). This product resulted from
aziridine ring opening with 1 at the more hindered site21 to form
a quaternary carbon center. The structure of this product is
1
supported by the H NMR where the -NH proton appears as a
doublet. In order to extend this methodology, we synthesized
an optically pure trisubstituted aziridine22 18b from ∆3-carene
using the Sharpless procedure (Scheme 12). Since formation
of bromonium ion is the first step in the Sharpless aziridina-
tion procedure,16 in the case of ∆3-carene the formation of
bromonium ion I occurs selectively in a trans-fashion and
Chloramine-T opens up the bromonium ion I from the R-face
followed by Br-Cl elimination to generate intermediate IV,
(19) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 23, 1973-1976. (b) VanRheenen, V.; Cha, D. Y.; Hartley, W. M.
Organic Syntheses; Wiley: New York, 1988; Collect. Vol. VI, p 342. (c)
Maras, A.; H. Secen, H.; Sutbeyaz, Y.; Balci, M. J. Org. Chem. 1998, 63,
2039-2041. (d) Mehta, G.; Ramesh, S. S.; Bera, M. K. Chem. Eur. J. 2003,
9, 2264-2272.
(21) (a) Li, P.; Forbeck, E. M.; Evans, C. D.; Joullie, M. M. Org. Lett.
2006, 8, 5105-5107. (b) Lin, P.; Bellos, K.; Stamm, H.; Onistschenko, A.
Tetrahedron 1992, 48, 2359-2372.
(20) Devan, N.; Sridhar, P. R.; Prabhu, K. R.; Chandrasekaran, S.
J. Org. Chem. 2002, 6, 9417-9420.
J. Org. Chem, Vol. 72, No. 6, 2007 2111

Sureshkumar et al.
SCHEME 13. Tentative Mechanism for Formation of cis-Aziridino-carene by Sharpless Aziridination
SCHEME 14. Synthesis of Seven-Membered Cyclic Disulfide from L-Glutamic Acid
SCHEME 15. Tentative Mechanism for Formation of 29
which upon intramolecular substitution forms cis-aziridino-
carene 18b. In the catalytic cycle, formation of trans-bromonium
ion I is 3.5 kcal/mol more stable than the corresponding cis-
bromonium ion, which then leads to the formation of 18b
(Scheme 13).23 Treatment of 18b with 1 (1.1 equiv, CH3CN,
room temperature, 4 h) led to the formation of disulfide 19b in
68% yield via regio- and stereospecific ring opening from the
more hindered site as in the case of 18a. A detailed study of
the mechanism of ring opening of trisubstituted aziridines with
1 is under investigation.
Synthesis of Seven-Membered Cyclic Disulfide 29 from
L-Glutamic Acid 20. This methodology was then extended to
(22) Handy, S. T.; Ivanow, A.; Czopp, M. Tetrahedron Lett. 2006, 47,
1821-1823.
(23) DFT calculations were carried out on intermediates I and II using
B3LYP method and the 6-31.G(d) level basis set using Guassian 98.
2112 J. Org. Chem., Vol. 72, No. 6, 2007

â-Sulfonamidodisulfides and â-Sulfonamidosulfides
SCHEME 16. Synthesis of â-Sulfonamidosulfide Involving Tandem, Multistep Reactions
using TBDPSCl furnished the protected amino alcohol 24,26
TABLE 6. Synthesis of â-Sulfonamidosulfides by Tandem,
Multistep Reaction Mediated by 1
which upon mesylation followed by cyclization afforded aziri-
dine 25 in good yield. Aziridine 25 was converted into
â-sulfonamidodisulfide 26 in 65% yield using 1 as sulfur transfer
reagent. Deprotection of 26 using TBAF gave diol 27, which
was further converted into ditosylate 28. Treatment of ditosylate
28 with 1 (2.2 equiv, CH3CN, 28 °C, 5 h) afforded (-)-(S)-
1,2-dithiepane-4-amino derivative 29 in 55% yield (Scheme 14).
A tentative mechanism for the reaction ditosylate 28 with 1 to
form dithiepane derivative 29 is presented in Scheme 15.
Synthesis of â-Sulfonamidosulfides: Tandem Disulfide
Cleavage-Aziridine Ring Opening. Finally, we have dem-
onstrated cleavage of disulfide bonds assisted by 1 and the use
of masked thiolate for the synthesis of â-sulfonamidosulfides
involving multistep reactions in a one-pot operation (Scheme
16). It has been shown earlier that disulfide bonds are cleaved
in the presence of 1, involving an induced redox reaction.10 The
results of tandem cleavage of disulfide bonds assisted by 1
followed by aziridine ring opening to provide â-sulfonami-
dosulfides are summarized in Table 6. Thus, in the reaction of
disulfide 30 with 1 (2.2 equiv, CH3CN, 28 °C, 3 h) followed
by the addition of aziridine 3a, the corresponding â-sulfona-
midosulfide 31 was obtained as the only product in good yield.
Treatment of trans-aziridino-epoxide 10f with p-chloro diphenyl
disulfide 30 with 1 under similar conditions gave selectively
aziridine-opened trans-â-sulfonamidosulfide 34 without affect-
ing the epoxide ring. Finally, to assess the regio- and ste-
reospecificity together in the same substrate, cis-aziridine 8c
was treated with disulfide 30 in the presence of 1 to afford
exclusively the anti-â-sulfonamidosulfide 39 in 68% yield. In
the case of trans-aziridine 8d, the syn-â-sulfonamidosulfide 40
was obtained in 72% yield under the same reaction condition.
Solid-state structure and stereochemistry of compounds 32, 36,
and 44 were confirmed by X-ray crystallography.11
Conclusion
In summary, tetrathiomolybdate 1 provides an easy access
to â-sulfonamidodisulfides from aziridines in regio- and ste-
reospecific ring-opening processes under neutral conditions
without the use of any Lewis acid or base. Selective aziridine
ring opening in the presence of epoxide has also been
demonstrated to provide epoxy-â-sulfonamidodisulfides from
the aziridino-epoxides. We have achieved the construction of
eight-membered ring system 17 from aziridino-epoxide 16a by
the synthesis of disulfide 29, a potential radiation-protection
drug24 starting from (+)-(S)-glutamic acid using tetrathiomo-
lybdate 1 as sulfur transfer reagent (Scheme 14). L-Glutamic
acid 20 was converted into dimethyl glutamate amine hydro-
chloride 21, which was further converted into tosylamino
derivative 22 followed by reduction using LiBH4 in THF for
12 h to furnish (S)-2-tosylamino-1,5-pentanediol 23.25 Selective
protection of the hydroxyl group at C-5 of the amino diol 23
(25) (a) Grabowski, S.; Armbruster, J.; Prinzbach, H. Tetrahedron Lett.
1997, 38, 5485-5488. (b) Kang, S. H.; Hwang, Y. S.; Youn, J. H.
Tetrahedron Lett. 2001, 42, 7599-7603.
(24) Herbrandson, H. F.; Wood, R. H. J. Med. Chem. 1969, 12, 620-
624.
(26) Wipf, P.; Graham, T. H. J. Org. Chem. 2001, 66, 3242-3245.
J. Org. Chem, Vol. 72, No. 6, 2007 2113

Sureshkumar et al.
2H), 5.10 (d, J ) 9.9 Hz, 1H), 4.31 (d, J ) 7.8 Hz, 1H), 4.10-
4.06 (m, 1H), 3.98 (dd, J ) 13.2, 7.5 Hz, 1H), 3.86-3.76 (m, 1H),
3.71 (dd, J ) 8.7, 6.0 Hz, 1H), 3.59 (t, J ) 7.8 Hz, 1H), 2.60 (d,
J ) 7.8 Hz, 1H), 2.43 (s, 3H), 1.41 (s, 3H), 1.38 (s, 3H), 1.33 (s,
1H), 1.31 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 143.6, 137.9,
129.8, 127.1, 109.8, 109.7, 77.8, 77.4, 76.8, 67.7, 51.9, 39.5, 27.0,
26.9, 26.2, 25.2, 21.5. HRMS m/z: calcd for C38H56N2O12S4K+
[M + K+] 899.2353, found 899.2336.
performing both aziridine and epoxide ring opening in one pot
and also the synthesis of optically pure cyclic seven-membered
disulfide 29 from L-glutamic acid. Additionally, a number of
â-sulfonamidosulfides were synthesized in a tandem, multistep
process in a one-pot operation.
Experimental Section
â-Sulfonamidodisulfide 7c. Rf ) 0.30 (EtOAc/hexanes, 1:1).
Yield: 0.102 g, 74%. Mp: 156 °C. IR (neat) νmax: 3456, 3289,
Synthesis of D-Glucose-Derived Aziridine 3o. The mesylate
3n13b (0.271 g, 0.5 mmol) was dissolved in dry THF and cooled to
0 °C, followed by the addition of a suspension of freshly washed
(hexanes) sodium hydride (60% dispersion in mineral oil, 0.160 g,
4.0 mmol) in THF (3 mL). After 22 h, the reaction mixture was
evaporated onto SiO2, and chromatography on SiO2 (ethyl acetate/
hexanes, 1:9) yielded 3o as a colorless oil. Rf ) 0.50 (EtOAc/
1
1512, 1443, 1312, 1223, 1212, 1165, 667 cm-1. H NMR (300
MHz, CDCl3/DMSO-d6, 1:1 mixture of diastereomers): δ 7.79 (d,
J ) 8.1 Hz, 4H), 7.31 (d, J ) 8.1 Hz, 4H), 5.54 (s, 1H), 5.52 (s,
1H), 3.61-3.57 (m, 4H), 3.12 (dd, J ) 27.6, 13.5 Hz, 4H), 2.78
(bs, 2H), 2.43 (s, 6H), 1.12 (s, 3H), 1.11 (s, 3H). 13C NMR (75
MHz, CDCl3/DMSO-d6, 1:1 mixture of diastereomers): δ 142.2,
140.1, 128.9, 126.1, 66.4, 59.8, 59.7, 47.3, 20.8, 19.5, 19.4. HRMS
m/z: calcd for C22H32N2O6S4Na+ [M + Na+] 571.1041, found
571.1038. Anal. Calcd for C22H32N2O6S4: C, 48.15; H, 5.88; N,
5.10; S, 23.37. Found: C, 48.24; H, 5.81; N, 5.28; S, 23.42.
General Procedure for the Synthesis of Aziridines.16 To a
mixture of an appropriate olefin (3 mmol) and TsNClNa.3H2O
(CAT) (0.930 g, 3.3 mmol) in CH3CN (15 mL) was added
phenyltrimethylammonium tribromide (PTAB) (0.113 g, 0.3 mmol)
at 28 °C. After 12 h of vigorous stirring, the reaction mixture was
concentrated, filtered through a short column of silica gel, and eluted
with 10% EtOAc in hexanes. After evaporation of solvent, the
resultant solid was purified by flash column chromatography to
yield the corresponding aziridine.
cis-2,3-Diethyl-N-tosyl Aziridine 8a. Rf ) 0.7 (EtOAc/hexanes,
3:7). Yield: 0.486 g, 64%. Mp: 78 °C. IR (neat) νmax: 1334, 1162,
948, 716, 682 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.83 (d, J )
8.1 Hz, 2H), 7.32 (d, J ) 8.1 Hz, 2H), 2.78-2.71 (m, 2H), 2.44 (s,
1H), 1.58-1.32 (m, 4H), 0.87 (t, J ) 7.2 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 144.2, 135.4, 129.5, 128.0, 46.7, 21.6, 20.0, 11.6.
HRMS m/z: calcd for C13H19NO2SNa+ [M + Na+] 276.1034, found
276.1036. Anal. Calcd for C13H19NO2S: C, 61.63; H, 7.56; N, 5.53;
S, 12.66. Found: C, 61.75; H, 7.59; N, 5.66; S, 12.78.
hexanes, 1:1). Yield: 0.178 g, 80%. [R]27 ) -60.00 (c ) 1.0,
D
CHCl3). IR (neat) νmax: 1520, 1451, 1329, 1171, 1041, 670 cm-1
.
1H NMR (400 MHz, CDCl3): δ 7.83 (d, J ) 8.1 Hz, 2H), 7.37-
7.29 (m, 7H), 5.91 (d, J ) 3.9 Hz, 1H), 4.70 (d, J ) 12.2 Hz, 1H),
4.57 (d, J ) 3.9 Hz, 1H), 4.46 (d, J ) 12.2 Hz, 1H), 3.87 (d, J )
3.7 Hz, 1H), 3.74 (dd, J ) 7.4, 3.7 Hz, 1H), 3.18-3.17 (m, 1H),
2.60 (d, J ) 7.3 Hz, 1H), 2.42 (s, 3H), 2.03 (d, J ) 4.6 Hz, 1H),
1.39 (s, 3H), 1.28 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 144.4,
136.9, 134.7, 129.5, 128.5, 128.2, 128.0, 127.9, 111.8, 105.4, 82.2,
81.8, 80.6, 71.8, 38.9, 28.9, 26.7, 26.1, 21.6. HRMS m/z: calcd
for C23H27NO6SNa+ [M + Na+] 468.1457, found 468.1461.
General Procedure for Ring Opening of Mono- and 2,2-
Disubstituted Aziridines with Benzyltriethylammonium Tetrathi-
omolybdate 1. To a stirred solution of appropriate aziridine (0.50
mmol) in CH2Cl2 (3 mL) was added benzyltriethylammonium
tetrathiomolybdate 1 (0.335 g, 0.55 mmol) at room temperature
(28 °C). After completion of the reaction (TLC, 2-6 h) the solvent
was removed in vacuo, and the black residue was extracted with
CH2Cl2/Et2O (1:4, 5 × 20 mL) and filtered through Celite pad.
The filtrate was concentrated, and the crude product was purified
by flash column chromatography on silica gel (230-400 mesh,
eluting with hexanes/ethyl acetate 9:1) to obtain the corresponding
â-sulfonamidodisulfides in good yield.
trans-2,3-Diethyl-N-tosyl Aziridine 8b. Rf ) 0.8 (EtOAc/
â-Sulfonamidodisulfide 4a. Rf ) 0.60 (EtOAc/hexanes, 3:7).
hexanes, 3:7). Yield: 0.516 g, 68%. Mp: 122 °C. IR (neat) νmax
:
Yield: 0.138 g, 86%. [R]27 ) -80.32 (c ) 12.6, CH2Cl2). IR
1321, 1159, 937, 711, 696 cm-1. 1H NMR (300 MHz, CDCl3): δ
7.84 (d, J ) 8.1 Hz, 2H), 7.30 (d, J ) 8.1 Hz, 2H), 2.64-2.58 (m,
2H), 2.43 (s, 3H), 1.79-1.69 (m, 4H), 0.93 (t, J ) 7.2 Hz, 6H).
13C NMR (75 MHz, CDCl3): δ 143.7, 137.9, 129.4, 127.4, 50.9,
23.2, 21.5, 11.7. HRMS m/z: calcd for C13H19NO2SNa+ [M + Na+]
276.1034, found 276.1031. Anal. Calcd for C13H19NO2S: C, 61.63;
H, 7.56; N, 5.53; S, 12.66. Found: C, 61.82; H, 7.61; N, 5.71; S,
12.62.
D
(neat) νmax: 3263, 1329, 1158, 815, 666 cm-1. 1H NMR (300 MHz,
CDCl3): δ 7.58 (d, J ) 8.1 Hz, 2H), 7.21-7.16 (m, 5H), 6.99-
6.96 (m, 2H), 5.11 (d, J ) 7.8 Hz, 1H), 3.76-3.66 (m, 1H), 2.99
(dd, J ) 13.8, 4.8 Hz, 1H), 2.90 (dd, J ) 13.8, 6.3 Hz, 1H), 2.75-
2.66 (m, 2H), 2.39 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 143.2,
136.9, 136.4, 129.6, 129.3, 128.6, 126.9, 126.7, 54.3, 43.2, 39.2,
21.5. HRMS m/z: calcd for C32H36N2O4S4Na+ [M + Na+]
663.1456, found 663.1466. Anal. Calcd for C32H36N2O4S4: C,
59.97; H, 5.66; N, 4.39; S, 20.01. Found: C, 60.12; H, 5.84; N,
4.58; S, 20.32.
cis-N-Tosyl-aziridino-carene 18b. Rf ) 0.60 (EtOAc/hexanes,
3:7). Yield: 0.586 g, 64%. [R]27D ) +36.00 (c ) 1.0, CHCl3). IR
(neat) νmax: 1450, 1321, 1157, 1091, 923, 815 cm-1. 1H NMR (300
MHz, CDCl3): δ 7.77 (d, J ) 8.1 Hz, 2H), 7.29 (d, J ) 8.1 Hz,
2H), 3.03 (dd, J ) 7.8, 3.9 Hz, 1H), 2.42 (s, 3H), 2.28 (q, J ) 8.7
Hz, 1H), 2.11 (dd, J ) 15.6, 8.6 Hz, 1H), 1.76 (s, 3H), 1.19 (dd,
J ) 15.6, 6.4 Hz, 1H), 0.98 (s, 3H), 0.85-0.79 (m, 1H), 0.78 (s,
3H), 0.66-0.57 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 143.3,
138.3, 129.3, 126.9, 51.2, 46.9, 28.3, 27.7, 21.5, 20.5, 19.1, 19.0,
18.9, 18.8, 15.6. HRMS m/z: calcd for C17H23NO2SNa+ [M + Na+]
328.1347, found 328.1348.
General Procedure for Ring Opening of 2,3-Disubstituted
Aziridines with 1. To a well-stirred solution of appropriate aziridine
(0.50 mmol) in CH3CN (6 mL) was added 1 (0.335 g, 0.55 mmol)
at once, and the mixture was stirred at room temperature (28 °C)
for 5-11 h. The solvent was evaporated under reduced pressure,
and the black residue was extracted with CH2Cl2/Et2O (1:5, 3 ×
10 mL) and filtered through a Celite pad. The filtrate was
concentrated, and the residue was purified by flash column
chromatography on silica gel to give â-sulfonamidodisulfides in
good yields.
â-Sulfonamidodisulfide 4l. Rf ) 0.60 (EtOAc/hexanes, 1:1).
Yield: 0.179 g, 75%. [R]27D ) +16.00 (c ) 1.0, CHCl3). IR (neat)
1
ν
max: 3280, 1513, 1455, 1324, 1160, 1074, 1029, 665 cm-1. H
NMR (300 MHz, CDCl3): δ 7.69 (d, J ) 8.1 Hz, 2H), 7.41-7.30
(m, 3H), 7.26-7.20 (m, 4H), 5.71 (d, J ) 3.6 Hz, 1H), 5.22 (d,
J ) 5.4 Hz, 1H), 4.56 (d, J ) 12.0 Hz, 1H), 4.51 (d, J ) 3.9 Hz,
1H), 4.40 (d, J ) 12.0 Hz, 1H), 4.31 (dd, J ) 7.2, 3.3 Hz, 1H),
3.95 (d, J ) 3.3 Hz, 1H), 3.87 (q, J ) 6.0 Hz, 1H), 3.02 (dd,
J ) 14.4, 6.3 Hz, 1H), 2.83 (dd, J ) 14.4, 4.5 Hz, 1H), 2.38 (s,
3H), 1.43 (s, 1H), 1.27 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
143.2, 137.1, 136.7, 129.4, 128.7, 128.2, 127.8, 127.4, 116.1, 111.9,
104.5, 81.9, 81.5, 78.6, 71.4, 52.3, 40.7, 26.7, 26.2, 21.5. HRMS
m/z: calcd for C46H56N2O12S4K+ [M + K+] 995.2353, found
995.2373.
â-Sulfonamidodisulfide 4m. Rf ) 0.70 (EtOAc/hexanes, 1:1).
Yield: 0.153 g, 71%. [R]27D ) +36.00 (c ) 1.0, CHCl3). IR (neat)
ν
max: 3278, 1373, 1336, 1159, 1070, 846, 669 cm-1. 1H NMR (300
MHz, CDCl3): δ 7.76 (d, J ) 8.1 Hz, 2H), 7.29 (d, J ) 8.1 Hz,
2114 J. Org. Chem., Vol. 72, No. 6, 2007

â-Sulfonamidodisulfides and â-Sulfonamidosulfides
anti-â-Sulfonamidodisulfide 9c and 9c′. Rf ) 0.30 (EtOAc/
the mixture was stirred at room temperature (28 °C) for 3 h. The
solvent was evaporated under reduced pressure, and the black
residue was extracted with CH2Cl2/Et2O (1:5, 3 × 10 mL) and
filtered through a Celite pad. The filtrate was concentrated, and
the residue was purified by flash column chromatography on silica
gel to give â-sulfonamidodisulfide 15 as colorless oil in good yield.
hexanes, 3:7). Yield: 0.090 g, 80%. Mp: 157 °C. IR (neat) νmax
:
3285, 1507, 1456, 1323, 1238, 1201, 1157, 899, 826, 753, 667 cm-1
.
1H NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers): δ 7.78
(d, J ) 8.4 Hz, 2H), 7.76 (d, J ) 8.4 Hz, 2H), 7.28 (d, J ) 8.4 Hz,
4H), 5.09 (d, J ) 9.3 Hz, 1H), 4.72 (d, J ) 9.3 Hz, 1H), 3.25 (m,
2H), 3.16 (m, 2H), 2.41 (s, 6H), 1.92 (m, 2H), 1.31 (d, J ) 6.6 Hz,
3H), 1.19 (d, J ) 7.8 Hz, 3H), 0.83 (d, J ) 7.8 Hz, 3H), 0.78 (d,
J ) 6.6 Hz, 6H), 0.71 (d, J ) 6.6 Hz, 3H). 13C NMR (75 MHz,
CDCl3, 1:1 mixture of diastereomers): δ 143.1, 143.0, 138.7, 138.6,
129.4, 126.9, 63.8, 63.7, 49.7, 30.2, 21.5, 20.9, 18.9, 18.3. HRMS
m/z: calcd for C26H40 N2O4S4Na+ [M + Na+] 595.1769, found
595.1776. Anal. Calcd for C26H40N2O4S4: C, 54.51; H, 7.04; N,
4.89; S, 22.39. Found: C, 54.71; H, 7.27; N, 5.18; S, 22.13.
syn-â-Sulfonamidodisulfide 9d and 9d′. Rf ) 0.45 (EtOAc/
Rf ) 0.70 (EtOAc/hexanes, 1:1). Yield: 0.140 g, 70%. IR (neat)
1
ν
max: 3281, 1743, 1446, 1369, 1246, 1159, 1041, 663 cm-1. H
NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers): δ 7.78
(d, J ) 8.1 Hz, 4H), 7.34 (d, J ) 8.1 Hz, 4H), 5.58 (d, J ) 7.2 Hz,
1H), 5.43 (d, J ) 6.9 Hz, 1H), 5.18 (bs, 2H), 4.95-4.88 (m, 2H),
3.51 (bs, 2H), 3.38 (bs, 2H), 2.44 (s, 6H), 2.30-2.07 (m, 2H), 2.08-
2.02 (m, 16H), 1.79-1.62 (m, 6H). 13C NMR (75 MHz, CDCl3,
1:1 mixture of diastereomers): δ 170.1, 170.0, 169.7, 169.6, 143.8,
137.8, 129.9, 126.9, 69.0, 67.6, 67.5, 49.9, 31.8, 21.6, 21.5, 20.9,
20.8. HRMS m/z: calcd for C34H44N2O12S4Na+ [M + Na+]
823.1675, found 823.1675.
hexanes, 3:7). Yield: 0.096 g, 85%. Mp: 142 °C. IR (neat) νmax
:
.
3288, 1512, 1463, 1323, 1239, 1207, 1159, 905, 828, 754, 668 cm-1
1H NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers): δ 7.76
(d, J ) 8.4 Hz, 4H), 7.28 (d, J ) 8.4 Hz, 4H), 4.61 (d, J ) 9.9 Hz,
1H), 4.57 (d, J ) 9.6 Hz, 1H), 3.37 (m, 2H), 2.89 (m, 2H), 2.41 (s,
6H), 1.97 (m, 2H), 1.20 (d, J ) 6.9 Hz, 6H), 0.86 (d, J ) 6.9 Hz,
6H), 0.77 (d, J ) 5.7 Hz, 6H). 13C NMR (75 MHz, CDCl3, 1:1
mixture of diastereomers): δ 143.1, 138.6, 129.4, 127.1, 127.0,
62.4, 62.3, 50.5, 50.4, 30.0, 29.9, 21.5, 20.6, 20.5, 17.9, 17.8, 17.7,
17.6. HRMS m/z: calcd for C26H40 N2O4S4Na+ [M + Na+]
595.1769, found 595.1780. Anal. Calcd for C26H40N2O4S4: C,
54.51; H, 7.04; N, 4.89; S, 22.39. Found: C, 54.62; H, 7.24; N,
5.03; S, 22.23.
Synthesis of 3-(Tosylamino)-1,5-oxathiocan-7-ol 17. To a
stirred solution of aziridino-epoxide 16a (0.141 g, 0.50 mmol) in
CH3CN/EtOH (1:1; 5 mL) was added tetrathiomolybdate 1 (0.669
g, 1.1 mmol) at room temperature (28 °C). After completion of the
reaction (TLC, 10 h) the solvent was removed in vacuo, and the
black residue was extracted with CH2Cl2/Et2O (1:4, 5 × 20 mL)
and filtered through a Celite pad. The filtrate was concentrated,
and the crude product was purified by flash column chromatography
on silica gel (230-400 mesh, eluting with hexanes/ethyl acetate
8:2) to obtain compounds 17a and 17b as a diastereomeric mixture
(1:1). Rf ) 0.70 (EtOAc/hexanes, 1:1). Yield: 0.114 g, 72%. IR
(neat) νmax: 3466, 3273, 1415, 1326, 1158, 1091, 1033, 814, 664
cm-1. 1H NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers):
δ 7.77-7.73 (m, 4H), 7.31 (d, J ) 8.1 Hz, 4H), 5.71 (d, J ) 9.6
Hz, 1H), 5.17 (d, J ) 9.6 Hz, 1H), 3.98 (dd, J ) 12.3, 3.3 Hz,
4H), 3.89-3.81 (m, 2H), 3.77 (dd, J ) 11.1, 4.5 Hz, 2H), 3.66-
3.61 (m, 2H), 3.56-3.41 (m, 4H), 3.03 (dd, J ) 15.3, 6.6 Hz, 2H),
2.91-2.59 (m, 8H), 2.43 (s, 6H). 13C NMR (75 MHz, CDCl3, 1:1
mixture of diastereomers): δ 143.7, 143.6, 138.1, 137.8, 129.9,
129.8, 126.9, 126.8, 75.9, 74.6, 74.1, 72.2, 70.3, 67.9, 52.7, 51.7,
40.2, 40.0, 39.1, 38.5, 21.5. HRMS m/z: calcd for C13H19NO4S2-
Na+ [M + Na+] 340.0653, found 340.0658.
â-Sulfonamidodisulfide 11a and 11a′. Rf ) 0.30 (EtOAc/
hexanes, 1:1). Yield: 0.110 g, 81%. Mp: 156 °C. IR (neat) νmax
:
3268, 1447, 1323, 1159, 1092, 813, 667 cm-1. 1H NMR (300 MHz,
CDCl3, 1:1 mixture of diastereomers): δ 7.81 (d, J ) 8.1 Hz, 4H),
7.31 (d, J ) 8.1 Hz, 4H), 5.32 (d, J ) 6.6 Hz, 1H), 5.11 (d, J )
6.0 Hz, 1H), 3.59-3.50 (m, 2H), 3.17-3.08 (m, 2H), 2.43 (s, 6H),
2.21-2.05 (m, 2H), 1.99-1.85 (m, 2H), 1.67-1.26 (m, 8H). 13C
NMR (75 MHz, CDCl3, 1:1 mixture of diastereomers): δ 143.5,
143.4, 137.6, 137.4, 129.7, 129.6, 127.3, 127.2, 60.5, 59.4, 56.5,
55.4, 31.9, 31.8, 30.6, 30.3, 21.8, 21.7, 21.5. HRMS m/z: calcd
for C24H32N2O4S4Na+ [M + Na+] 563.1143, found 563.1158. Anal.
Calcd for C24H32N2O4S4: C, 53.30; H, 5.96; N, 5.18; S, 23.72.
Found: C, 53.51; H, 5.86; N, 5.33; S, 23.89.
Synthesis of ∆3-Carene Derived â-Sulfonamidodisulfide 19b.
To a well-stirred solution of cis-∆3-carene derived aziridine 18b
(0.50 mmol) in CH3CN (6 mL) was added 1 (0.335 g, 0.55 mmol)
at once, and the mixture was stirred at room temperature (28 °C)
for 4 h. The solvent was evaporated under reduced pressure, and
the black residue was extracted with CH2Cl2/Et2O (1:5, 3 × 10
mL) and filtered through a Celite pad. The filtrate was concentrated,
and the residue was purified by flash column chromatography on
silica gel to give â-sulfonamidodisulfide 19b as colorless oil in
good yield. Rf ) 0.60 (EtOAc/hexanes, 3:7). Yield: 0.115 g, 68%.
Synthesis of Aziridine Derivative 14. OsO4 (4 mg, 1 mol %)
and 50% aqueous solution of N-methylmorpholine N-oxide (NMMO)
(260 µL, 0.56 mmol) were added to a solution of aziridine 1316
(272 mg, 1.09 mmol) in acetone/water (4:1, 5 mL) at 0 °C, and the
resulting pale yellow reaction mixture was stirred at room temper-
ature for 4 h, before quenching with solid NaHSO3. The resulting
mixture was diluted with ethyl acetate (10 mL) and filtered through
Celite, and the filtrate was concentrated under reduced pressure.
The crude residue was dissolved in pyridine (5 mL), and acetic
anhydride (246 µL, 2.61 mmol) was added slowly at 0 °C. After
the reaction mixture stirred for 3 h at room temperature, pyridine
was removed under reduced pressure, diluted with diethyl ether
(25 mL), and washed with 1 N cold hydrochloric acid. The residue
was subjected to column chromatography over silica gel (20% ethyl
acetate/hexanes) to afford the aziridine 14 as colorless crystals. Rf
) 0.60 (EtOAc/hexanes, 3:7). Yield: 0.287 g, 72%. Mp: 122 °C.
IR (neat) νmax: 1749, 1246, 1168, 1048, 666 cm-1. 1H NMR (300
MHz, CDCl3): δ 7.81 (d, J ) 8.1 Hz, 2H), 7.34 (d, J ) 8.1 Hz,
2H), 4.90 (t, J ) 5.4 Hz, 2H), 2.98 (s, 2H), 2.45 (s, 3H), 2.17 (d,
J ) 5.1 Hz, 4H), 2.0 (s, 6H). 13C NMR (75 MHz, CDCl3, 1:1
mixture of diastereomers): δ 170.2, 144.4, 135.5, 129.6, 127.5,
67.5, 36.7, 25.4, 21.6, 20.9. HRMS m/z: calcd for C17H21NO6SNa+
[M + Na+] 390.0987, found 390.0998. Anal. Calcd for C17H21-
NO6S: C, 55.57; H, 5.76; N, 3.81; S, 8.73. Found: C, 55.62; H,
5.83; N, 3.96; S, 8.97.
[R]27 ) +46.00 (c ) 1.0, CHCl3). IR (neat) νmax: 3280, 1455,
D
1321, 1159, 813, 669 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.77
(d, J ) 8.1 Hz, 2H), 7.32 (d, J ) 8.1 Hz, 2H), 4.49 (d, J ) 8.7 Hz,
1H), 3.39 (dd, J ) 14.7, 8.7 Hz, 1H), 2.44 (s, 3H), 2.25 (dd, J )
14.7, 7.5 Hz, 1H), 2.05-1.96 (m, 1H), 1.18 (s, 3H), 1.06-0.86
(m, 2H), 0.98 (s, 3H), 0.93 (s, 3H), 0.70-0.54 (m, 2H). 13C NMR
(75 MHz, CDCl3): δ 143.4, 137.4, 129.7, 127.3, 55.6, 54.7, 30.6,
28.1, 25.8, 24.6, 21.6, 20.9, 18.6, 18.5, 15.3. HRMS m/z: calcd
for C34H48N2O4S4Na+ [M + Na+] 699.2395, found 699.2382.
N1-[(1S)-4-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-1-(hydroxy-
methyl)butyl]-4-methyl-1-benzene Sulfonamide 24. To a solution
of amino diol25 23 (1 g, 3.7 mmol) in DMF (25 mL) held at 0 °C
under argon were successively added imidazole (0.548 g, 8.0 mmol)
and tert-butyldiphenylsilyl chloride (1.1 mL, 4.1 mmol). After 30
min of stirring at 0 °C, the mixture was warmed to room
temperature and stirred for additional 3 h. The reaction solution
was diluted with ethyl acetate (30 mL) and water (30 mL). The
layers were separated, and the aqueous phase was extracted with
ethyl acetate (2 × 30 mL). The organic extracts were combined
and washed with water (2 × 30 mL). The resulting residue was
Synthesis of â-Sulfonamidodisulfide 15. To a well-stirred
solution of aziridine 14 (0.184 g, 0.50 mmol) in CH3CN (6 mL)
was added tetrathiomolybdate 1 (0.335 g, 0.55 mmol) at once, and
J. Org. Chem, Vol. 72, No. 6, 2007 2115

Sureshkumar et al.
purified by flash chromatography on silica gel (ethyl acetate/hexanes
The resultant oily residue was purified by flash chromatography
on silica gel (EtOAc/hexanes, 3:7) to afford the diol 27 as a color-
less oil. Rf ) 0.50 (EtOAc/hexanes, 1:1). Yield: 0.118 g, 86%.
2:8) to afford compound 24 as a colorless oil. Rf ) 0.40 (EtOAc/
hexanes, 1:9). Yield: 1.51 g, 80%. [R]27 ) - 16.00 (c ) 2.0,
D
[R]27 ) -49.00 (c ) 1.0, CHCl3). IR (neat) νmax: 3513, 3272,
CHCl3). IR (neat) νmax: 3502, 3262, 1328, 1162, 672 cm-1. H
1
D
1321, 1153, 663 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J
) 8.1 Hz, 2H), 7.30 (d, J ) 8.1 Hz, 2H), 5.83 (bs, 1H), 3.53-3.46
(m, 3H), 2.91 (dd, J ) 15.0, 4.2 Hz, 1H), 2.71 (dd, J ) 15.0, 6.6
Hz, 1H), 2.42 (s, 3H), 2.33 (bs, 1H), 1.75-1.67 (m, 1H), 1.56-
1.40 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 143.5, 137.6, 129.7,
127.1, 62.1, 53.2, 44.2, 29.9, 27.9, 21.6. HRMS m/z: calcd for
C24H36N2O6S4Na+ [M + Na+] 599.1354, found 599.1368.
NMR (300 MHz, CDCl3): δ 7.73 (d, J ) 8.1 Hz, 2H), 7.62-7.59
(m, 5H), 7.43-7.35 (m, 7H), 4.83 (d, J ) 7.8 Hz, 1H), 3.57-3.45
(m, 4H), 3.25-3.19 (m, 1H), 2.38 (s, 3H), 1.77 (bs, 3H), 1.55-
1.22 (m, 4H), 1.02 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 143.5,
137.5, 135.5, 133.6, 130.8, 129.7, 127.7, 127.1, 64.9, 63.1, 55.4,
28.3, 28.1, 26.8, 21.5, 19.1. HRMS m/z: calcd for C28H37NO4-
SSiNa+ [M + Na+] 534.2110, found 534.2126.
(4S)-4-[(4-Methylphenyl)sulfonyl]amino-5-[((2S)-2-[(4-meth-
ylphenyl)sulfonyl]amino-5-[(4-methyl phenyl)sulfonyl]oxypen-
tyl)disulfanyl]pentyl-4-methyl-1-benzenesulfonate 28. To a so-
lution of diol 27 (0.115 g, 0.20 mmol) in pyridine (2 mL) cooled
to 0 °C was added DMAP (5 mg, 0.04 mmol) and p-toluenesulfonyl
chloride (0.084 g, 0.44 mmol). After stirring for 15 min at 0 °C
and 3 h at room temperature, the solution was diluted with diethyl
ether (50 mL) and washed with water (5 mL), cold 1 M HCl (2 ×
5 mL), saturated NaHCO3 (5 mL), and water (5 mL). The organic
phase was dried over MgSO4 and concentrated in vacuo. Chroma-
tography on silica gel (10% EtOAc/hexanes) gave the ditosylate
28 as a colorless oil in high purity. Rf ) 0.60 (EtOAc/hexanes,
3:7). Yield: 0.133 g, 75%. [R]27D ) -41.00 (c ) 1.0, CHCl3). IR
(2S)-2-(3-[1-(tert-Butyl)-1,1-diphenylsilyl]oxypropyl)-1-[(4-me-
thylphenyl)sulfonyl]azirane 25. To a solution of amido alcohol
24 (1 g, 1.96 mmol) in dry CH2Cl2 (15 mL) were slowly added
pyridine (0.48 mL, 5.9 mmol) followed by mesyl chloride (0.23
mL, 2.9 mmol) at 0 °C. The mixture was stirred at 20 °C for 3 h.
The reaction mixture was diluted with 30 mL of diethyl ether
followed by washing with cold HCl (1 N, 2 × 20). The aqueous
layer was extracted with Et2O (3 × 15 mL). The combined organic
layers were dried (Na2SO4) and evaporated to afford a crude residue.
It was dissolved in dry THF and cooled to 0 °C followed by the
addition of a suspension of freshly washed (hexanes) sodium
hydride (60% dispersion in mineral oil, 0.157 g, 4.0 mmol) in THF
(3 mL). After 3 h, the reaction mixture was evaporated onto SiO2,
and chromatography on SiO2 (ethyl acetate/hexanes, 1:9) yielded
25 as a colorless oil. Rf ) 0.70 (EtOAc/hexanes, 2:8). Yield: 0.739
g, 76%. [R]27D ) -152.00 (c ) 1.0, CHCl3). IR (neat) νmax: 1324,
1162, 1110, 819, 703 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.80
(d, J ) 8.1 Hz, 2H), 7.63-7.60 (m, 2H), 7.42-7.29 (m, 8H), 3.58
(t, J ) 6.0 Hz, 2H), 2.76-2.68 (m, 1H), 2.63 (d, J ) 7.2 Hz, 1H),
2.42 (s, 3H), 2.06 (d, J ) 4.5 Hz, 1H), 1.75-1.64 (m, 1H), 1.58-
1.32 (m, 3H), 1.02 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 144.4,
135.5, 135.2, 133.8, 129.6, 127.9, 127.6, 62.9, 40.2, 33.8, 29.6,
27.8, 26.8, 21.6, 19.2. HRMS m/z: calcd for C28H35NO3SSiNa+
[M + Na+] 516.2005, found 516.2032.
N1-((1S)-4-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-1-[((2S)-5-[1-
(tert-butyl)-1,1-diphenylsilyl]oxy-2-[(4-methylphenyl)sulfonyl]-
aminopentyl)disulfanyl]methylbutyl)-4-methyl-1-benzenesulfona-
mide 26. To a stirred solution of aziridine 25 (0.247 g, 0.50 mmol)
in CH2Cl2 (3 mL) was added benzyltriethylammonium tetrathio-
molybdate 1 (0.335 g, 0.55 mmol) at room temperature (28 °C).
After completion of the reaction (TLC, 2 h) the solvent was
removed in vacuo, and the black residue was extracted with CH2-
Cl2/Et2O (1:4, 5 × 20 mL) and filtered through a Celite pad. The
filtrate was concentrated, and the crude product was purified by
flash column chromatography on silica gel (230-400 mesh, eluting
with hexanes/ethyl acetate 9:1) to obtain the corresponding â-sul-
fonamidodisulfide 26 as a colorless oil. Rf ) 0.50 (EtOAc/hexanes,
2:8). Yield: 0.171 g, 65%. [R]27D ) -50.00 (c ) 1.0, CHCl3). IR
(neat) νmax: 3276, 1532, 1093, 853, 775, 663 cm-1. 1H NMR (300
MHz, CDCl3): δ 7.73 (d, J ) 8.1 Hz, 2H), 7.61 (d, J ) 8.1 Hz,
4H), 7.43-7.35 (m, 6H), 7.25-7.21 (m, 2H), 5.08 (d, J ) 8.1 Hz,
1H), 3.48 (t, J ) 6.0 Hz, 1H), 2.97 (dd, J ) 13.5, 3.9 Hz, 1H),
2.69 (dd, J ) 13.5, 6.6 Hz, 1H), 2.36 (s, 3H), 1.73-1.14 (m, 5H),
1.02 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 143.3, 137.8, 135.5,
133.7, 129.7, 127.7, 127.1, 63.1, 53.1, 44.3, 29.7, 28.2, 26.9, 21.5,
19.2. HRMS m/z: calcd for C56H72N2O6S4Si2Na+ [M + Na+]
1075.3709, found 1075.3736.
1
(neat) νmax: 3278, 1311, 1156, 669 cm-1. H NMR (300 MHz,
CDCl3): δ 7.75 (d, J ) 8.1 Hz, 2H), 7.73 (d, J ) 8.1 Hz, 2H),
7.34 (d, J ) 8.1 Hz, 2H), 7.29 (d, J ) 8.1 Hz, 2H), 5.17 (d, J )
7.8 Hz, 1H), 3.88 (dd, J ) 11.1, 5.4 Hz, 2H), 3.42 (m, 1H), 2.81
(dd, J ) 14.1, 4.5 Hz, 1H), 2.58 (dd, J ) 14.1, 6.6 Hz, 1H), 2.45
(s, 3H), 2.42 (s, 3H), 1.68-1.58 (m, 2H), 1.47-1.36 (m, 2H). 13
C
NMR (75 MHz, CDCl3): δ 144.9, 143.7, 137.6, 132.8, 129.9, 129.8,
127.8, 127.0, 69.8, 52.7, 44.2, 29.4, 24.6, 21.6, 21.5. HRMS m/z:
calcd for C38H48N2O10S6Na+ [M + Na+] 907.1531, found 907.1572.
Synthesis of (S)-1,2-Dithiepane-4-amino Derivative 29. To a
well-stirred solution of ditosylate 28 (0.13 g, 0.15 mmol) in CH3-
CN (6 mL) was added 1 (0.2 g, 0.33 mmol) at once, and the mixture
was stirred at room temperature (28 °C) for 5 h. The solvent was
evaporated under reduced pressure, and the black residue was
extracted with CH2Cl2/Et2O (1:5, 3 × 10 mL) and filtered through
a Celite pad. The filtrate was concentrated, and the residue was
purified by flash column chromatography on silica gel to give 29
as colorless oil. Rf ) 0.70 (EtOAc/hexanes, 3:7). Yield: 0.025 g,
55%. [R]27 ) -16.00 (c ) 1.0, CHCl3). IR (neat) νmax: 3268,
D
1331, 1136, 659 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.76 (d, J
) 8.1 Hz, 2H), 7.31 (d, J ) 8.1 Hz, 2H), 4.86 (d, J ) 9.6 Hz, 1H),
3.85-3.75 (m, 1H), 2.91 (dd, J ) 14.1, 4.2 Hz, 1H), 2.83-2.69
(m, 3H), 2.44 (s, 3H), 2.16-2.04 (m, 1H), 2.16-1.75 (m, 3H). 13
C
NMR (75 MHz, CDCl3): δ 143.6, 137.9, 129.8, 126.9, 54.2, 47.5,
36.3, 32.9, 22.9, 21.5. HRMS m/z: calcd for C12H17NO2S3Na+
[M + Na+] 326.0319, found 326.0310.
Synthesis of â-Sulfonamidosulfide 34. To a well-stirred solution
of appropriate disulfide 30 (0.5 mmol) in CH3CN (8 mL) was added
1 (0.609 g, 1.0 mmol) at once, the mixture was stirred at room
temperature (28 °C) for 2 h, and to this was added aziridine 10f
(0.133 g, 0.5 mmol). After completion of the reaction (TLC, 3 h)
the solvent was evaporated under reduced pressure, and the black
residue was extracted with CH2Cl2/Et2O (1:5, 3 × 10 mL) and
filtered through a Celite pad. The filtrate was concentrated, and
the residue was purified by flash column chromatography on silica
gel to give â-sulfonamidosulfide 34 as colorless oil in good yield.
N1-((1S)-4-Hydroxy-1-[((2S)-5-hydroxy-2-[(4-methylphenyl)-
sulfonyl]aminopentyl)disulfanyl] methylbutyl)-4-methyl-1-ben-
zenesulfonamide 27. To a solution of 26 (0.250 g, 0.24 mmol) in
THF (3 mL) kept at 0 °C under argon was added a solution of
tetra-n-butylammonium fluoride (1.0 M) in THF (0.25 mL, 1 equiv).
After stirring for 15 min at 0 °C, the reaction mixture was gradually
allowed to attain room temperature over 3 h. It was then diluted
with EtOAc (0.56 mL) and washed with water (2 × 10 mL). The
organic phase was dried over MgSO4 and evaporated to dryness.
Rf ) 0.50 (EtOAc/hexanes, 3:7). Yield: 0.135 g, 66%. IR (neat)
1
ν
max: 3248, 1336, 1145, 642 cm-1. H NMR (300 MHz, CDCl3/
DMSO-d6): δ 7.72 (d, J ) 8.4 Hz, 2H), 7.31 (d, J ) 8.4 Hz, 2H),
7.27-7.22 (m, 4H), 6.39 (d, J ) 6.0 Hz, 1H), 3.57 (bs, 1H), 3.23-
3.20 (m, 1H), 3.03-2.94 (m, 1H), 2.78-2.58 (m, 2H), 2.45 (s,
3H), 2.42-2.40 (m, 1H), 2.36 (td, J ) 13.2, 4.2 Hz, 1H), 1.41-
1.18 (m, 2H). 13C NMR (75 MHz, CDCl3/DMSO-d6): δ 143.0,
138.2, 135.5, 135.1, 134.2, 129.9, 129.3, 128.8, 69.9, 54.9, 52.3,
2116 J. Org. Chem., Vol. 72, No. 6, 2007

â-Sulfonamidodisulfides and â-Sulfonamidosulfides
48.8, 39.8, 38.4, 21.4. HRMS m/z: calcd for C19H20ClNO3S2Na+
[M + Na+] 432.0471, found 432.0483.
Acknowledgment. D.S. thanks CSIR, New Delhi for a senior
research fellowship, and S.C.N. thanks DST, New Delhi for a
JC Bose National Fellowship and for CCD X-ray facility.
â-Sulfonamidosulfide 38. Rf ) 0.60 (EtOAc/hexanes, 3:7).
Yield: 0.127 g, 70%. IR (neat) νmax: 3256, 1462, 1382, 1133, 818,
1
755, 664 cm-1. H NMR (300 MHz, CDCl3): δ 7.66 (d, J ) 8.4
Supporting Information Available: Experimental procedures;
1H, 13C, and DEPT spectra for all new compounds; and X-ray
structures of compounds 5d, 7a, 7c, 9a, 9b, 9c, 11a, 14, 32, 36,
and 44 in CIF format. This material is available free of charge via
the Internet at http://pubs.acs.org.
Hz, 2H), 7.29-7.18 (m, 7H), 4.97 (d, J ) 9.9 Hz, 1H), 3.48-3.39
(m, 1H), 2.85 (td, J ) 7.8, 3.3 Hz, 1H), 1.61 (t, J ) 7.2 Hz, 3H),
1.57-1.26 (m, 4H), 0.90 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 143.1, 138.3, 135.6, 131.2, 129.6, 129.0, 128.3, 126.9,
58.3, 57.8, 27.2, 22.9, 21.5, 12.3, 10.7. HRMS m/z: calcd for
C19H25NO2S2Na+ [M + Na+] 386.1224, found 386.1213.
JO0624389
J. Org. Chem, Vol. 72, No. 6, 2007 2117