Silver-mediated allylic disulfide rearrangement for conjugation of thiols in protic media

Article abstract of DOI:10.1021/jo902012m

(Chemical Equation Presented) Alkyl and aryl allyl disulfides are induced to undergo the desulfurative allylic rearrangement by silver nitrate in protic solvents at room temperature, thereby removing the necessity for the use of phosphines as thiophilic r

Full text of DOI:10.1021/jo902012m

pubs.acs.org/joc
Silver-Mediated Allylic Disulfide Rearrangement for Conjugation
of Thiols in Protic Media
David Crich,*,†,‡ Venkataraman Subramanian,‡ and Maheswaran Karatholuvhu‡
†Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS,
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France and ‡Department of Chemistry,
Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202
dcrich@icsn.cnrs-gif.fr
Received September 17, 2009
Alkyl and aryl allyl disulfides are induced to undergo the desulfurative allylic rearrangement by silver
nitrate in protic solvents at room temperature, thereby removing the necessity for the use of
phosphines as thiophilic reagents. The silver-mediated reaction functions at ambient temperature
in protic solvents and in the absence of protecting groups
SCHEME 1. Phosphine-Mediated Allylic Disulfide
Rearrangement
Introduction
Allylic disulfides, readily formed by the well-known reac-
tion between a thiol and a sulfenyl transfer reagent,1 may be
converted into the more permanent alkyl allyl thioethers by
the desulfurative allylic disulfide rearrangement. We have
studied this reaction extensively over the past several years,
during the course of which we have demonstrated that it is
accelerated in polar solvents and that it may be applied to the
functionalization of peptidyl thiols in protic media at room
temperature.2 This reaction proceeds through an unfavor-
able equilibrium, the result of a reversible 2,3-sigmatropic
rearrangement, with a transient allylic thiosulfoxide from
which an atom of sulfur is excised by triphenylphosphine and
which drives the equilibrium in the forward direction
(Scheme 1).3 Recent computational work has provided
strong support for this mechanism, in particular for the
rate-determining step being the desulfurization of the tran-
sient thiosulfoxide by the phosphine and, in line with our
initial postulate, for the acceleration in protic media being
due to the stabilization of the thiosulfoxide.4
Although in this reaction the phosphine can be replaced by
morpholine in some instances, typically with a reduction in
the E/Z selectivity of the final product, and can be dispensed
with altogether in methanol at reflux, the optimum condi-
tions, which result in excellent E/Z selectivity for disubsti-
tuted olefin formation, require the use of stoichiometric
(1) (a) Chalker, J. M.; Bernardes, G. J. L.; Lin, Y. A.; Davis, B. G. Chem.
Asian J. 2009, 4, 630–640. (b) Hackenberger, C. P. R.; Schwarzer, D. Angew.
Chem., Int. Ed. 2008, 47, 10030–10047. (c) Hermanson, G. T. Bioconjugate
Techniques; Academic Press: San Diego, 1996. (d) Lundblad, R. L. Chemical
Reagents for Protein Modification, 3rd ed.; CRC Press: Boca Raton, 2005.
(2) (a) Crich, D.; Krishnamurthy, V.; Hutton, T. K. J. Am. Chem. Soc.
2006, 128, 2544–2545. (b) Crich, D.; Brebion, F.; Krishnamurthy, V. Org.
Lett. 2006, 8, 3593–3596. (c) Crich, D.; Krishnamurthy, V.; Brebion, F.;
Karatholuvhu, M.; Subramanian, V.; Hutton, T. K. J. Am. Chem. Soc. 2007,
129, 10282–10294. (d) Crich, D.; Yang, F. J. Org. Chem. 2008, 73, 7017–7027.
€
(3) For the early work on this rearrangement, see: (a) Hofle, G.; Baldwin,
J. E. J. Am. Chem. Soc. 1971, 93, 6307–6308. (b) Baechler, R. D.; Hummel, J.
D.; Mislow, K. J. Am. Chem. Soc. 1973, 95, 4442–4444. (c) Moore, C. G.;
Trego, G. R. Tetrahedron 1962, 18, 205–218. (d) Evans, M. B.; Higgins, G.
M. C.; Moore, C. G.; Porter, M.; Saville, B.; Smith, J. F.; Trego, B. R.;
Watson, A. A. Chem. Ind. 1960, 897. (e) Pilgram, K.; Phillips, D. D.; Korte,
F. J. Org. Chem. 1964, 29, 1844–1847. (f) Block, E.; Iyer, R.; Grisoni, S.;
Saha, C.; Belman, S.; Lossing, F. P. J. Am. Chem. Soc. 1988, 110, 7813–7827.
(g) Braverman, S.; Cherkinsky, M. Top. Curr. Chem. 2007, 275, 67–102.
(4) Li, Z.; Wang, C.; Fu, Y.; Guo, Q.-X.; Liu, L. J. Org. Chem. 2008, 73,
6127–6136.
9422 J. Org. Chem. 2009, 74, 9422–9427
Published on Web 11/13/2009
DOI: 10.1021/jo902012m
r
2009 American Chemical Society

Crich et al.
JOCArticle
SCHEME 2. Proposed Metal-Mediated Allylic Disulfide
Rearrangement
SCHEME 3. Preparation of a Model System
phosphine,2 a common feature with the Staudinger ligation.5
In our continuing study of this desulfurative allylic rearran-
gement, we have investigated alternative means of promot-
ing the desulfurization step, retaining the high E/Z selectivity
featured by the original variant. We initially considered the
development of water-soluble phosphines, as has been
achieved for the traceless Staudinger ligation,6 so as to be
able to accelerate the reaction in aqueous media but ulti-
mately opted to search for a completely phosphine-free
system. Along these lines we conceived that thiophilic metal
species would bind preferentially to and excise sulfur from the
more nucleophilic thiosulfoxide rather than from the allylic
disulfide (Scheme 2), and we report here on the reduction of
this concept to practice.7
TABLE 1. Screening of Potentially Thiophilic Metal Salts
MX
CD3CN (%)a,b
CD3OD (%)a,b
CoCl2
NiCl2
CuCl
<5
<5
25
<5
<5
55
<5
72
Fe(NH4)2(SO4)2
AgNO3
<5
38
c
aYields refer to isolated material. bAs determined by 1H NMR
spectroscopy, the balance of the material is largely made up of unreacted
substrate; cThe AgNO3-mediated reaction was also conducted in DMF
and in ethanol, resulting in isolated yields of 70% and 68%, respectively,
of 6 after 12 h.
Results and Discussion
We set out to screen a number of commonly available,
potentially thiophilic salts for the rearrangement of a model
system under protic conditions at room temperature. To this
end a model diallyl disulfide 5 was prepared as outlined in
Scheme 3 beginning from 3,4-dihydroxybutene.8 Thus, the
diol was readily converted to the cyclic thiocarbonate 1 with
thiophosgene, and this latter was subjected to the New-
man-Kwart9 rearrangement to give the thiolcarbonate 2
in excellent yield. In contrast to the somewhat complex
purely thermal process, the tetrakis(triphenylphosphino)-
palladium(0) catalyzed rearrangement took place efficiently
and in high yield in ethanol at reflux.10-13 Cleavage of the
cyclic thiolcarbonate 2 was best achieved by reduction with
lithium aluminum hydride and was followed by immediate
conversion of the resulting mercapto alcohol to the requisite
pyridyl disulfide 3 by exposure to 2,20-dipyridyl disulfide.
Finally, the sulfenyl donor 3 was allowed to react with a
protected L-cysteine derivative 4 to give the model disulfide 5
in 55% yield (Scheme 3).
With a model system in hand, screening experiments were
conducted in both deuterioacetonitrile and deuteriometha-
nol at room temperature with monitoring by NMR spec-
troscopy and final chromatographic isolation of the
products, leading to the results outlined in Table 1.
Among the salts screened, silver nitrate was the clear
favorite, bringing about the desired rearrangement of the
model system in high yield, with excellent trans-selectivity, in
a matter of hours at room temperature. Silver salts were
therefore adopted as the reagents of choice and applied to the
conjugation of a number of systems as set out in Table 2.14
Where available the yields for the same reactions previously
obtained by the phosphine-mediated rearrangement are also
presented in Table 2 for ease of comparison. Although the
yields presented in Table 2 for the rearrangement mediated
by silver nitrate are, with one exception, slightly lower than
their counterparts for the phosphine-mediated rearrange-
ment, it must be realized that the latter, for the most part,
required more forcing conditions. Thus, entries 1 and 2 of
(5) (a) Lin, F. L.; Hoyt, H. M.; van Halbeek, H.; Bergman, R. G.;
Bertozzi, C. R. J. Am. Chem. Soc. 2005, 127, 2686–2695. (b) Soellner, M.
B.; Nilsson, B. L.; Raines, R. T. J. Am. Chem. Soc. 2006, 128, 8820–8828.
€
(c) Kohn, M.; Breinbauer, R. Angew. Chem., Int. Ed. 2004, 43, 3106–3116.
(6) Tam, A.; Soellner, M. B.; Raines, R. T. J. Am. Chem. Soc. 2007, 129,
11421–11430.
(7) We note that the analogous deselenative allylic selenosulfide rearran-
gement of S-alkyl Se-allyl seleno sulfides proceeds in some cases in the
absence of phosphine2 and has been recently applied to the allylation of a
protein. Chaulker, J. M.; Lin, Y. A.; Boutureira, O.; Davis, B. G. Chem.
Commun. 2009, 3714–3716.
(8) Although 3,4-dihydroxybutene is available commercially, it may be
obtained more economically by hydrolysis of the much cheaper 4-vinyl-1,3-
dioxolan-2-one.
(9) Zonta, C.; De Lucchi, O.; Vollicelli, R.; Cotarca, L. Top. Curr. Chem.
2007, 275, 131–162.
(10) Metal-catalyzed [3,3]-sigmatropic rearrangements of a variety of
allylic thionoesters have been described in the literature previously. See,
for example: (a) Overman, L. E.; Roberts, S. W.; Sneddon, H. F. Org. Lett.
€
2008, 10, 1485–1488. (b) Gais, H.-J.; Bohme, A. J. Org. Chem. 2002, 67,
1153–1161, and references therein.
(11) No attempt was made to develop an asymmetric version of this
reaction in view of the destruction of the stereogenic center in the subsequent
application.
(12) The photochemical [1,3]-rearrangement of allylic thiocarbamates is
also a known reaction: Sakamoto, M.; Yoshiaki, M.; Takahashi, M.; Fujita,
T.; Watanabe, S. J. Chem. Soc., Perkin Trans. 1 1995, 373–377.
(13) For a recent palladium-catalyzed variant on the aromatic New-
man-Kwart reaction, see: Harvey, J. N.; Jover, J.; Lloyd-Jones, G. C.;
Moseley, J. D.; Murray, P.; Renny, J. S. Angew. Chem., Int. Ed. 2009, 48,
7612–7615.
(14) For a collection of reviews on reactions promoted and/or catalyzed
by the coinage metals, see: Lipshutz, B., H.; Yamamoto, Y. Chem. Rev. 2008,
108, 2793–2795, and the reviews immediately following this editorial.
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TABLE 2. Silver-Promoted Desulfurative Allylic Disulfide Rearrangement in Methanol
aAr1 = 2-pyridyl, Ar2 = 2-benzothiazolyl. bUnless otherwise stated, all reactions were conducted for 16 h at room temperature in MeOH with 0.05 M
thiol and 2.2 equiv of AgNO3. cConducted with 0.05 M substrate and 3 equiv of PPh3 in benzene at reflux. dEt3N (1.2 equiv) was added to accelerate
e
f
disulfide formation, and rearrangement was complete in 2 days. Rearrangement complete in 24 h. In the attempted reaction with PPh3 a complex
reaction mixture was obtained that did not contain a significant quantity of the anticipated product. gPh2P(4-C6H4NMe2) was used as the thiophile.
hThe lower yield observed here as compared to that reported in Table 1 reflects the incorporation of the sulfenyl transfer step in Table 2.
Table 2 report yields for reactions conducted with triphenyl-
phosphine in benzene at reflux, as no rearrangement was
observed at room temperature. In distinct contrast, the same
rearrangements were effected at room temperature with
silver nitrate. With the siloxylated allylic disulfide 12,14,15
sulfenyl transfer to the anomeric thiol 7 with subsequent
silver-mediated desulfurative rearrangement was again suc-
cessful, albeit with concomitant cleavage of the silyl ether
group (Table 2, entry 3). When this same reaction was
attempted in methanol at room temperature in the presence
of triphenylphosphine rather than silver nitrate, a complex
mixture was observed that did not contain the anticipated
product (Table 2, entry 3). The failure of Table 2, entry 3
under the phosphine-mediated conditions is likely due to
reduced nucleophilicity of the sulfur bound to the anomeric
carbon, on which we have previously remarked,2 and the
electron-withdrawing silyl ether moiety that destabilizes
the partial positive charge on the allylic framework in the
thiosulfoxide. Both of these factors reduce the equilibrium
concentration of the thiosulfoxide, thereby retarding the
desulfurization step, and so permit the onset of other dele-
terious processes including disulfide scrambling. Clearly, in
view of Table 2, entry 3, silver nitrate is a more effective
desulfurization reagent than triphenylphosphine and enables
the combination of these factors to be overcome. This same
retarding effect of the homoallylic oxygen on the phosphine-
mediated rearrangement is apparent from a comparison of
the yields in entries 4 and 6 of Table 2 when both reactions
were conducted in methanol at room temperature.
Entry 7 of Table 2 is particularly interesting as we had
previously found that allyl aryl disulfides do not undergo the
phosphine-mediated desulfurative allylic rearrangement ow-
ing to the more facile nature of the direct attack of the
phosphine on the disulfide bond itself. Indeed, the simple
heating of the disulfide formed from 3 and 18 with triphenyl
phosphine resulted in none of the desired product 19.
Clearly, the silver-mediated protocol reported here over-
comes this problem and results in a good yield of the rear-
ranged allylic sulfide 19. As noted previously, the allyl aryl
disulfides can also be inducted to undergo desulfurative
allylic rearrangement by simple heating to reflux in metha-
nol, but the yields in such cases are only modest.2 Finally,
Table 2, entry 8, is the preparative-scale run of the initial
screening reaction. The somewhat lower yield reported for
the preparative-scale reaction reflects the two-step nature of
the process as opposed to the use of an isolated disulfide in
(15) Obtained by silylation of 3 under standard conditions with tert-
butyldimethylsilyl chloride in 80% yield.
(16) For all disubstituted alkenes, only the E-isomers were observed and
isolated.
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TABLE 3. Silver-Promoted Desulfurative Allylic Disulfide Rearrangement in Aqueous Buffera
aDisulfide formation: Tris buffer (0.2 M, pH 8), MeCN, and THF (2:1:1), 12-16 h. Rearrangement: AgNO3 (2.2 equiv), Tris buffer, and acetonitrile,
24 h.
the screening reactions. In general and with the exception of
0.78 mmol). The reaction mixture was stirred at 75 °C for 1 h,
after which the dark brown mixture was cooled to room
temperature, solvents were evaporated, and the product was
purified by column chromatography using EtOAc/hexanes as
eluent to give 4-vinyl-1,3-oxathiolan-2-one (2) as a colorless oil
(4.0 g, 80%). IR (neat): 1738 cm-1. 1H NMR (500 MHz): δ 5.89
(ddd, J = 17.0, J = 10.0, J = 7.0 Hz, 1H), 5.41 (d, J = 17.0 Hz,
entries 2 and 5 in which trisubstituted olefins were formed,
the silver-mediated reaction presented in Table 2 took place
with excellent E-selectivity on a par with that obtained in the
phosphine-mediated reactions.16
The applicability of the silver-mediated reaction under
aqueous conditions is demonstrated by the examples of Table
3. In particular, entry 2 of Table 3 shows how this chemistry
may be applied to the formation of glycoconjugates in the
complete absence of protecting groups. Once again, excellent
E-selectivity was observed under these conditions.16
1H), 5.29 (d, J = 10.0 Hz, 1H), 4.55 (m, 2H), 4.20 (m, 1H). 13
C
NMR (125 MHz): δ 172.8, 133.2, 120.4, 72.7, 51.6. HREIMS:
calcd for C5H6O2S [M]þ 130.0089, found 130.0089.
2-(Pyridin-2-yldisulfanyl)-but-3-en-1-ol (3). To a stirred solu-
tion of 4-vinyl-1,3-oxathiolan-2-one (2) (2.0 g, 15.4 mmol) in dry
ether (15 mL) cooled to 0 °C was added LiAlH4 (584 mg,
15.4 mmol). The reaction mixture was stirred at the same
temperature for 30 min and then at room temperature for 2 h
before ethyl acetate (5 mL) was added, followed by the sequen-
tial addition of 1.0 M HCl (10.0 mL) and MeOH (10.0 mL). The
reaction mixture was stirred at room temperature for 30 min and
then filtered through a pad of Celite with washing of the filter
pad with MeOH (10.0 mL) and 1.0 M HCl (5.0 mL). The filtrate
and washings were transferred to a solution of 2,20-dipyridyl
disulfide (3.0 g, 13.6 mmol) in MeOH (10.0 mL). The reaction
mixture was stirred at room temperature under a nitrogen
atmosphere for 1 h before the solvents were evaporated and
the crude reaction mixture was dissolved in EtOAc (100 mL) and
washed with saturated bicarbonate solution (50 mL). The ethyl
acetate portion was further washed with brine solution (50 mL),
dried over sodium sulfate, filtered, and evaporated to dryness.
The crude product was purified by column chromatography on
silica gel using EtOAc/toluene as eluent to give 2-(pyridin-2-
yldisulfanyl)-but-3-en-1-ol (3) as a colorless liquid (1.47 g, 45%
for two steps). 1H NMR (400 MHz): δ 8.48 (dd, J = 1.5 Hz, J =
4.8 Hz, 1H), 7.56 (m, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.14 (dd, J =
7.2 Hz, J = 4.8 Hz, 1H), 5.94 (m, 1H), 5.88 (m, 1H), 5.24 (dd,
Conclusion
We demonstrate a new variant on the desulfurative allylic
disulfide rearrangement in which the key desulfurization of
the transient thiosulfoxide intermediate is achieved through
the use of silver nitrate rather than a triarylphosphine. This
metal-mediated process enables the desulfurative allylic re-
arrangement of aryl allyl disulfides, something that could not
be achieved with phosphines owing to the more facile
disulfide cleavage reaction. Reactions take place at room
temperature, give excellent E-selectivity for the formation of
disubstituted alkenes, and are conducted in protic media,
including aqueous mixtures with organic solvents.
Experimental Section
4-Vinyl-1,3-dioxolane-2-thione (1). To a stirred solution of
but-3-ene-1,2-diol (10.0 g, 113.5 mmol) in dichloromethane
(200 mL) under a nitrogen atmosphere was added pyridine
(19.8 g, 250 mmol) followed by DMAP (1.39 g, 11.4 mmol) at
0 °C. Thiophosgene (14.4 g, 124.8 mmol) dissolved in dichlor-
omethane (100 mL) then was added dropwise over a period of
2 h. The reaction mixture was stirred at room temperature for 3 h
and then diluted with 1.0 M HCl (100 mL). The organic part was
separated and washed with saturated NaCl (100 mL), dried over
sodium sulfate, and evaporated to dryness. The crude product
was purified by column chromatography using EtOAc/hexanes
as eluent to give 4-vinyl-1,3-dioxolane-2-thione (1) as a dark
J = 16.5 Hz, J = 9.3 Hz, 2H), 3.79 (m, 1H), 3.62 (m, 2H). 13
C
NMR (125 MHz): δ 159.2, 150.0, 137.1, 134.3, 122.2, 121.8,
118.6, 61.4, 56.6. ESIHRMS: calcd for C9H11NOS2Na [M þ
Na]þ 236.0180, found 236.0191.
Methyl 2-tert-Butoxycarbonylamino-3-(1-hydroxymethylally-
ldisulfanyl)propionate (5). To a stirred solution of 2-(pyridin-2-
yldisulfanyl)-but-3-en-1-ol (3) (160 mg, 0.75 mmol) in methanol
(6.0 mL) was added a solution of N-Boc-L-Cys-OMe (4) (176
mg, 0.75 mmol) in methanol (1.5 mL). The reaction mixture was
stirred at room temperature under N2 atmosphere for 4 h before
the solvents were removed and the crude product was purified
by column chromatography on silica gel using EtOAc/hexanes
as eluent to give methyl 2-tert-butoxycarbonylamino-3-(1-
hydroxymethylallyldisulfanyl)propionate (5) as a thick oil
1
yellow liquid (12.5 g, 85%). IR (neat): 1709 cm-1. H NMR
(500 MHz): 5.95 (ddd, J = 17.0, J = 10.5, J = 7.0 Hz, 1H), 5.56
(d, J = 17.0 Hz, 1H), 5.51 (d, J = 10.5 Hz, 1H), 5.34 (m, 1H),
4.78 (t, J = 8.5 Hz, 1H), 4.36 (t, J = 8.5 Hz, 1H). 13C NMR
(125 MHz): δ 191.7, 131.2, 122.8, 82.7, 73.1. HREIMS: calcd for
C5H6O2S [M]þ 130.0089, found 130.0064.
4-Vinyl-1,3-oxathiolan-2-one (2). To a stirred solution of
4-vinyl-1,3-dioxolane-2-thione (1) (5.08 g, 39.1 mmol) in de-
gassed ethanol (150 mL) (0.26 M) was added Pd(PPh3)4 (904 mg,
1
(139 mg, 55%). H NMR (500 MHz): δ 5.81-5.78 (m, 1H),
5.38 (d, J = 8.0 Hz, 1H), 5.35-5.26 (m, 2H), 4.64-4.62 (m, 1H),
3.94 (d, J = 6.5 Hz, 2H), 3.80 (s, 3H), 3.57-3.49 (m, 1H),
J. Org. Chem. Vol. 74, No. 24, 2009 9425

Crich et al.
JOCArticle
3.22-3.11 (m, 2H), 2.23 (br s, 1H), 1.42 (s, 9H), 13C NMR (125
MHz): δ 171.7, 155.6, 134.8, 134.7, 119.7, 119.6, 80.9, 63.6, 57.2,
56.7, 53.5, 53.2, 42.0, 41.8, 28.8. ESIHRMS: calcd for
C13H23NO5S2Na [M þ Na]þ 360.0915, found 360.0933.
General Procedure for Silver Nitrate Promoted Rearrange-
ment of Allylic Disulfides. Thiol (1.0 equiv) was added to a stirred
solution of disulfide in methanol (0.05 M) at room temperature.
The reaction mixture was stirred at room temperature under a
nitrogen atmosphere until complete disulfide exchange was
visible on TLC (usually less than 1 h). The reaction mixture
was then treated with silver nitrate (2.0 equiv) and stirred in the
dark for 16 h. After completion of the reaction (monitored by
ESI mass spectrometry), NaCl (10 equiv) was added, and the
reaction mixture was stirred for 3-4 h. The reaction mixture was
diluted with methanol and centrifuged to remove the black
precipitate. The solvent was then concentrated to afford the
crude product, which was purified by column chromatography
on silica gel to give the rearranged product.
S-4-Hydroxybut-2-enyl 2,3,4,6-Tetra-O-acetyl-1-thio-β-D-
glucopyranoside (13). To a stirred solution of 1-tert-butyldi-
methylsilyloxy-2-(pyridin-2-yldisulfanyl)-but-3-ene (12) (115 mg,
0.35 mmol) in MeOH (2.0 mL) was added 1-thio-β-D-glucose
tetraacetate (100 mg, 0.29 mmol) under a nitrogen atmosphere.
The yellow-colored solution was stirred at room temperature for
1 h before the solvents were removed, and the crude reaction
mixture was purified by column chromatography on silica gel to
give the mixed disulfide. The mixed disulfide (78 mg, 0.13 mmol)
was dissolved in MeOH (2.0 mL), and silver nitrate (46 mg,
0.27 mmol) was added. The reaction mixture was stirred at room
temperature under a N2 atmosphere in the dark for 16 h
before NaCl (75 mg, 1.3 mmol) was added, and the solution
was stirred for 3-4 h, diluted with MeOH (10.0 mL),
and centrifuged. The supernatant were evaporated to give the
crude product, which was purified by column chromatography
on silica gel using EtOAc/hexanes as eluent to give 13 (45 mg,
67%). [R]23D -49.5 (c = 1.0). 1H NMR (500 MHz): δ 5.78 (dt,
J = 15.5, J = 5.0, 1H), 5.71 (dtd, J = 15.5, J = 6.5, J = 1.0 Hz,
1H), 5.22 (t, J = 9.6 Hz, 1H), 5.07 (t, J = 9.6, 1H), 5.06 (t, J =
9.6 Hz, 1H), 4.50 (d, J = 10.0 Hz, 1H), 4.24 (dd, J = 12.0, J =
5.0 Hz, 1H), 4.18-4.10 (m, 2H), 4.15 (dd, J = 12.0, J = 2.0 Hz,
1H), 3.68 (ddd, J = 9.5, J = 5.0, J = 2.0, 1H), 3.38 (dd, J = 13.5,
J = 7.5, 1H), 3.26 (ddd, J = 13.5, J = 6.0, J = 1.0 Hz, 1H), 2.09
(E)-N-tert-Butoxycarbonyl-S-(4-hydroxybut-2-enyl)-L-cysteine
Methyl Ester (6). Following the general procedure for the silver
nitrate promoted rearrangement of allylic disulfides compound 6
1
was prepared in 72% yield as an oil. [R]23 23.5 (c = 1.0). H
D
NMR (500 MHz):δ 5.80 (dd, J = 15.0, J = 5.0 Hz, 1H), 5.68(dd,
J = 15.0, J = 6.0 Hz, 1H), 5.28 (d, J = 7.5 Hz, 1H), 4.51 (d, J =
8.0 Hz, 1H), 4.15 (d, J = 5.5 Hz, 2H), 3.78 (s, 3H), 3.17 (d, J =
7.0 Hz, 2H), 2.84 (dd, J = 14.0, J = 5.5 Hz, 2H), 1.90 (br s, 1H),
1.46 (s, 9H). 13C NMR (125 MHz): δ 172.0, 156.0, 133.3, 127.7,
80.7, 63.2, 53.6, 52.8, 34.3, 33.3, 28.5. ESIHRMS: calcd for
C13H23NO5SNa [M þ Na]þ 328.1195, found 328.1183.
(s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.77 (br s, 1H). 13
C
NMR (125 MHz): δ 170.9, 170.5, 169.7, 169.6, 133.0, 127.2, 82.2,
76.0, 74.1, 70.2, 68.6, 63.0, 62.4, 31.6, 20.9, 20.9, 20.8, 20.8.
ESIHRMS: calcd for C18H26O10SNa [M þ Na]þ 457.1144, found
457.1138.
N-tert-Butoxycarbonyl-S-(tridec-2-enyl)glutathione Dimethyl
Ester (15)2b. Following the general procedure for the silver
nitrate promoted rearrangement of allylic disulfides, compound
15 was prepared in 61% yield. Its spectral data were consistent
with that reported in the literature.2b
2-(2-(Tridec-1-en-3-yl)disulfanyl)pyridine (8). Compound 8
was prepared according to literature procedure and had spectral
data in agreement with the literature.2c
Tridec-2-enyl-(tetra-O-acetyl-1-thio-β-D-glucopyranoside) (9).
Following the general procedure for the silver nitrate promoted
rearrangement of allylic disulfides, compound 9 was prepared in
62% yield. Its spectral data was consistent with that reported in
the literature.2c
N-tert-Butoxycarbonyl-S-(3,7,11-trimethyldodeca-2,6,10-trienyl)-
glutathione Dimethyl Ester (16). To a stirred solution of 2-(1,5,9-
trimethyl-1-vinyl-deca-4,8-dienyldisulfanyl)-benzothiazole (10)
(120 mg, 0.30 mmol) in methanol (5.0 mL) was added triethy-
lamine (38 μL, 0.27 mmol) followed by Boc-(R-OMe)-γ-L-Glu-
L-Cys-Gly-OMe2a (14) (100 mg, 0.23 mmol). After 1 h, silver
nitrate (78 mg, 0.46 mmol) was added, and the reaction mixture
was stirred under a N2 atmosphere in the dark for 16 h. After
following the general workup procedure, the crude product was
purified by column chromatography on silica gel to give the title
product in 60% yield with spectral data consistent with the
literature.2b
N-tert-Butoxycarbonyl-S-(4-hydroxybut-2-enyl)glutathione
Dimethyl Ester (17). Following the general procedure for the
silver nitrate promoted rearrangement of allylic disulfides, a
stirred solution of 2-(pyridin-2-yldisulfanyl)-but-3-en-1-ol (3)
(70 mg, 0.25 mmol) in methanol (5.0 mL) was treated with
Boc-(R-OMe)-γ-L-Glu-L-Cys-Gly-OMe2a (14) (108 mg, 0.25
mmol). The reaction mixture was stirred under a N2 atmosphere
for 12 h before silver nitrate (85 mg, 0.50 mmol) was added, and
the mixture was stirred in the dark for 16 h before the general
workup procedure was applied. The crude product was purified
by column chromatography on silica gel using CHCl3/MeOH as
eluent to give the title product (17) in 65% yield. [R]23D -2.0 (c
0.85). 1H NMR (400 MHz): δ 7.16 (br s, 1H), 6.92 (d, J = 7.6 Hz,
1H), 5.87-5.80 (m, 1H), 5.72-5.65 (m, 1H), 5.38 (d, J = 7.6 Hz,
1H), 4.64-4.59 (m, 1H), 4.37 (br s, 1H), 4.12 (br s, 2H), 4.03 (d,
J = 5.6 Hz, 2H), 3.74 (s, 3H), 3.73 (s, 3H), 3.27 (br s, 1H), 3.19
(d, J = 7.2 Hz, 2H), 2.90-2.86 (m, 1H), 2.80-2.76 (m, 1H),
2.36-2.33 (m, 2H), 2.18 (m, 1H), 1.95-1.89 (m, 1H), 1.42 (s,
9H). 13C NMR (100 MHz): δ 173.1, 172.6, 170.9, 170.3, 156.1,
133.4, 128.4, 80.6, 63.1, 53.0, 52.9, 52.7, 41.5, 34.5, 33.0, 32.4,
29.0, 28.6. ESIHRMS: calcd for C21H35N3O9SNa [M þ Na]þ
528.19920, found 528.2016.
3,7,11-Trimethyl-dodeca-2,6,10-trienyl Tetra-O-acetyl-1-thio-
β-D-glucopyranoside (11). To a stirred solution of 2-(1,5,9-
trimethyl-1-vinyldeca-4,8-dienyldisulfanyl)benzothiazole2b (10)
(78 mg, 0.19 mmol) in methanol (3.0 mL) was added triethyla-
mine (27 μL, 0.19 mmol) followed by 1-thio-β-D-glucose tetra-
acetate (7) (54 mg, 0.16 mmol). After 1 h, silver nitrate (58 mg,
0.34 mmol) was added, andthe reactionmixture was stirredunder
a N2 atmosphere in the dark for 36 h. After following the general
workup procedure the crude product was purified by column
chromatography to give the title product (11) in 50% yield with
spectral data consistent with that reported in the literature.2b
1-tert-Butyldimethylsilyloxy-2-(pyridin-2-yldisulfanyl)but-3-ene
(12). To a stirred solution of 2-(pyridin-2-yldisulfanyl)but-3-en-
1-ol (3) (1.0 g, 4.69 mmol) in DMF (10.0 mL) under a nitrogen
atmosphere was added imidazole (319 mg, 4.69 mmol) followed
by tert-butyldimethylsilyl chloride (716 mg, 4.69 mmol) at 0 °C.
The reaction mixture was stirred at room temperature for 10 h.
The reaction mixture was diluted with ethyl acetate (100 mL)
and washed with water (100 mL). The organic part was washed
with saturated NaCl solution (50 mL), dried over sodium
sulfate, and evaporated to dryness. The crude product was
purified by column chromatography on silica gel using
EtOAc/hexanes as eluent to give the title product (12) as an
1
oil (1.20 g, 80%). H NMR (500 MHz): δ 8.44 (ddd, J = 5.0,
J = 2.0, J = 1.0 Hz, 1H), 7.56 (m, 1H), 7.38 (d, J = 7.8 Hz, 1H),
7.14 (dd, J = 7.2, J = 4.8 Hz, 1H), 5.94 (m, 1H), 5.88 (m, 1H),
5.24 (dd, J = 16.5, J = 9.3 Hz, 2H), 3.79 (m, 1H), 3.62 (m, 2H),
0.90 (s, 9H), 0.06 (s, 6H). 13C NMR (125 MHz): δ 161.2, 149.5,
137.1, 134.5, 120.6, 119.8, 119.2, 64.7, 57.1, 26.1, 18.6, -5.1.
ESIHRMS: calcd for C15H25NOS2SiNa [M þ Na]þ 350.1045,
found 350.1042.
9426 J. Org. Chem. Vol. 74, No. 24, 2009

Crich et al.
JOCArticle
(E)-4-(4-Chlorophenylsulfanyl)but-2-en-1-ol (19). Following
the general procedure for the silver nitrate promoted rearrange-
ment of allylic disulfides, compound 19 was prepared in 51%
yield. Its spectral data were consistent with that reported in the
literature.2c
CD3OD): δ 173.9, 172.7, 172.4, 170.4, 132.8, 126.9, 61.8, 54.2, 53.2,
40.7, 33.2, 32.1, 31.7, 26.6. ESIHRMS: calcd for C14H23N3O7SNa
[M þ Na]þ 400.1154, found 400.1150.
S-[4-(β-D-Galactopyranosyloxy)but-2-enyl]glutathione (23).
Glutathione (11 mg, 0.03 mmol) was dissolved in 0.5 mL of
Tris buffer (0.2M, pH 8) to which 2-(2-pyridyldisulfanyl)-3-enyl
β-D-galactopyranoside2d (22) (37.5 mg, 0.10 mmol) dissolved in
0.5 mL of CH3CN was added. The reaction mixture was stirred
at room temperature for 16 h before the excess disulfide and
liberated pyridinethiol were removed by washing with tert-butyl
methyl ether (5 mL). The residue was dissolved in water
(3 mL) and treated with silver nitrate (2.2 equiv). The yellow
suspension was allowed to stir for 24 h and then was treated with
3 mL of 5% diluted HCl and centrifuged. The supernatant was
injected into a reversed-phase HPLC system for purification to
give the product in 65% yield, whose spectral data were con-
sistent with the literature.2d
(E)-S-(4-Hydroxybut-2-enyl)glutathione (21). Glutathione
(20) (29 mg, 0.09 mmol) was dissolved in 2 mL of Tris buffer
(0.2 M, pH 8), and the resulting solution was treated with
2-(pyridin-2-yldisulfanyl)but-3-en-1-ol (3) (75 mg, 0.28 mmol)
dissolved in 2.0 mL of CH3CN/THF (1:1). The reaction mixture
was stirred at room temperature for 12 h, after which excess
disulfide and liberated pyridinethiol were removed by washing
with tert-butyl methyl ether (5 mL). The residue was dissolved
in water (3 mL) and treated with silver nitrate (2.2 equiv).
The yellow suspension was allowed to stir for 24 h and then
treated with 3 mL of 5% diluted HCl and centrifuged. The
supernatant was injected into a reversed-phase HPLC system
for purification using a gradient of 100% B to 50% B developed
over 50 min (A, 0.1% TFA/CH3CN; B, 0.1% TFA/H2O; column,
Varian Microsorb C18 250 mm ꢀ 21.4 mm; flow rate, 10 mL/min;
UV detection, 215 nm). Lyophilization of the fraction eluting at
19 min afforded the rearranged glutathione 21 in 85% yield as a
white foam. [R]23D -23.2 (c 0.8, CH3OH). 1H NMR (500 MHz,
CD3OD): δ 5.80-5.74 (m, 1H), 5.69-5.64 (m, 1H), 4.53 (dd, J =
11.5, J = 6.0 Hz, 1H), 4.06 (d, J = 5.0 Hz, 2H), 3.97 (d, J = 8.0 Hz,
2H), 3.61 (t, J = 8.5 Hz, 1H), 3.18 (d, J = 8.0 Hz, 2H), 2.99 (dd,
J = 17.5, J = 6.0 Hz, 1H), 2.70 (dd, J = 17.0, J = 11.5 Hz, 1H),
2.57-2.50 (m, 2H), 2.48-2.03 (m, 2H). 13C NMR (125 MHz,
Acknowledgment. We thank Wayne State University and
the NIH (GM62160) for partial support of this work and an
anonymous reviewer for helpful suggestions regarding the
mechanism of the reaction.
Supporting Information Available: Copies of the 1H and 13
C
NMR spectra of compounds 1-3, 5, 6, 9, 11-13, 15-17, 19, 21,
and 23. This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 24, 2009 9427