Dechalcogenative allylic selenosulfide and disulfide rearrangements: Complementary methods for the formation of allylic sulfides in the absence of electrophiles. Scope, limitations, and application to the functionalization of unprotected peptides in aqueous media

Article abstract of DOI:10.1021/ja072969u

Primary allylic selenosulfates (seleno Bunte salts) and selenocyanates transfer the allylic selenide moiety to thiols giving primary allylic selenosulfides, which undergo rearrangement in the presence of PPh₃ with the loss of selenium to give allylically rearranged allyl alkyl sulfides. This rearrangement may be conducted with prenyl-type selenosulfides to give isoprenyl alkyl sulfides. Alkyl secondary and tertiary allylic disulfides, formed by sulfide transfer from allylic heteroaryl disulfides to thiols, undergo desulfurative allylic rearrangement on treatment with PPh₃ in methanolic acetonitrile at room temperature. With nerolidyl alkyl disulfides this rearrangement provides an electrophile-free method for the introduction of the farnesyl chain onto thiols. Both rearrangements are compatible with the full range of functionality found in the proteinogenic amino acids, and it is demonstrated that the desulfurative rearrangement functions in aqueous media, enabling the derivatization of unprotected peptides. It is also demonstrated that the allylic disulfide rearrangement can be induced in the absence of phosphine at room temperature by treatment with piperidine, or simply by refluxing in methanol. Under these latter conditions the reaction is also applicable to allyl aryl disulfides, providing allylically rearranged allyl aryl sulfides in good yields.

Full text of DOI:10.1021/ja072969u

Published on Web 07/27/2007
Dechalcogenative Allylic Selenosulfide and Disulfide
Rearrangements: Complementary Methods for the Formation
of Allylic Sulfides in the Absence of Electrophiles. Scope,
Limitations, and Application to the Functionalization of
Unprotected Peptides in Aqueous Media
David Crich,*,† Venkataramanan Krishnamurthy, Franck Brebion,
Maheswaran Karatholuvhu,† Venkataraman Subramanian,† and Thomas K. Hutton
Contribution from the Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
Received April 27, 2007; E-mail: dcrich@chem.wayne.edu
Abstract: Primary allylic selenosulfates (seleno Bunte salts) and selenocyanates transfer the allylic selenide
moiety to thiols giving primary allylic selenosulfides, which undergo rearrangement in the presence of PPh3
with the loss of selenium to give allylically rearranged allyl alkyl sulfides. This rearrangement may be
conducted with prenyl-type selenosulfides to give isoprenyl alkyl sulfides. Alkyl secondary and tertiary allylic
disulfides, formed by sulfide transfer from allylic heteroaryl disulfides to thiols, undergo desulfurative allylic
rearrangement on treatment with PPh3 in methanolic acetonitrile at room temperature. With nerolidyl alkyl
disulfides this rearrangement provides an electrophile-free method for the introduction of the farnesyl chain
onto thiols. Both rearrangements are compatible with the full range of functionality found in the proteinogenic
amino acids, and it is demonstrated that the desulfurative rearrangement functions in aqueous media,
enabling the derivatization of unprotected peptides. It is also demonstrated that the allylic disulfide
rearrangement can be induced in the absence of phosphine at room temperature by treatment with
piperidine, or simply by refluxing in methanol. Under these latter conditions the reaction is also applicable
to allyl aryl disulfides, providing allylically rearranged allyl aryl sulfides in good yields.
The development of methods for the functionalization of
biopolymers, especially peptides and proteins, under the mildest
possible conditions, dubbed ligation, is a current frontier in
organic chemistry.1-16 High chemoselectivity, stability, and
compatibility with protic solvents, and even aqueous media, are
requirements for such ligations.
ligation (NCL) for the synthesis of peptides and proteins, and
its enzyme-promoted biochemical equivalent, expressed protein
ligation,18-21 is one such reaction that takes advantage of the
sulfhydryl group and which uses it to great advantage in the
highly chemoselective formation of amide bonds in aqueous
solution.10,21-31 Another thiol-based method, the selective
formation of mixed disulfides, is both one of the oldest and
most enduring of ligation methods.1,2,32-38 The mildness of the
Thiols, and in particular cysteine residues, have proven
popular targets for chemoselective ligation.1,2,17 Native chemical
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† Current address: Department of Chemistry, Wayne State University,
5101 Cass Avenue, Detroit, Michigan 48202.
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10.1021/ja072969u CCC: $37.00 © 2007 American Chemical Society

Allylic Selenosulfide and Disulfide Rearrangements
A R T I C L E S
Scheme 1. Rearrangement of Diallyl Disulfides58
disulfide ligation and its established chemoselectivity for the
cysteine thiol in the presence of all the proteinogenic amino
acids stands in stark contrast to the various other methods for
cysteine functionalization, most of which involve the capture
of the cysteine thiol by electrophilic species, and which
consequently have obvious potential chemoselectivity issues.1,2,39
The practicality of the disulfide ligation, with its direct ap-
plicability to cysteine-containing peptides, also contrasts with
the various ingenious indirect methods that have been developed
for the preparation of S-functionalized cysteine derivatives,17
including, for example, the Michael addition of thiols to
dehydroalanine units,40 the alkylation of thiolates with peptide-
based â-halo-alanine units,41-43 and other electrophiles,44,45 the
opening of peptide-based aziridines by thiolates,46,47 and the
synthesis of peptides with previously functionalized cysteine
building blocks,48-50 each of which requires the synthesis of
modified peptides. The many advantages of the disulfide ligation
are offset, however, by its impermanence, which results from
the lability of the disulfide bond in the presence of thiols and
other reducing agents.
Scheme 2. Pseudo-First-Order Rate Constants for
Phosphine-Mediated Rearrangement in Benzene58
to the well-known Evans-Mislow rearrangement of allylic
sulfoxides.60 This dechalcogenative rearrangement, which may
also be induced to operate in the reverse direction on treatment
of allyl sulfides with elemental sulfur,61 and which is potentially
important in the chemistry of essential oils derived from garlic,62
appeared to us to hold promise as a means of rendering
disulfides permanent if it could be caused to function at ambient
temperatures in protic solvents. The seminal work of Ho¨fle and
Baldwin revealed that the reaction is rapid in benzene at room-
temperature provided that the thiosulfoxide is removed from
the equilibrium. Thus, the diallyl disulfides 1 and 2 rearrange
via the thiosulfoxides 3 and 4 to the thermodynamically more
stable disulfides 5 and 6 via two sequential sigmatropic
rearrangements with half-lives of 79 and 14 min, respectively,
at 24 °C (Scheme 1).58
In the absence of a thiophile, simple alkyl allyl sulfides 7
and 8 were found by Ho¨fle and Baldwin to be stable at room
temperature and could be purified by vacuum distillation,
whereas 10 and 11 were reported to lose sulfur spontaneously
at room temperature, albeit without mention of a time scale for
this process.58 A comparable dependence of rearrangement rate
on substituent pattern was observed by Moore and Trego in
their early work on the reaction.53 Pseudo first-order rate
constants were measured by Ho¨fle and Baldwin for the reaction
of the alkyl allyl disulfides 7-11 with PPh3 in benzene at 60
°C, leading to the conclusion that increased bulk around the
thiosulfoxide reduces its concentration in the equilibrium and
so retards reduction.58 While this remains possible, we consider
it more likely that the equilibrium is shifted more toward the
thiosulfoxide when a more highly substituted alkene is formed
at the expense of a less substituted one, and when a more highly
substituted C-S bond is replaced by a less substituted one
(Scheme 2).58
Consideration of the practical advantages of the disulfide
ligation, and the disadvantages of its impermanence, led us to
investigate methods for rendering it permanent. The result of
our search was the dechalcogenative allylic seleneosulfide and
disulfide ligations, whose scope we describe in full in this
article.51,52
Results and Discussion
Background. The phosphine-promoted desulfurative allylic
rearrangement of diallyl disulfides to give allyl sulfides53-57
proceeds by way of a [2,3]-sigmatropic rearrangement via a
diallyl thiosulfoxide intermediate58,59 and, thus, is closely related
(35) Macindoe, W. M.; van Oijen, A. H.; Boons, G.-J. Chem. Commun. 1998,
847-848.
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Batsanov, A. S.; Davis, B. G. J. Org. Chem. 2005, 70, 9740-9754.
(37) Gamblin, D. P.; Garnier, P.; van Kasteren, S.; Oldham, N. J.; Fairbanks,
A. J.; Davis, B. G. Angew. Chem., Int. Ed. 2004, 43, 828-833.
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J.; Davis, B. G. Org. Biomol. Chem. 2003, 1, 3642-3644.
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5955.
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Ed. 2005, 44, 4596-4599.
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3723.
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126, 12712-12713.
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Soc. 2005, 127, 7359-7369.
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2006, 45, 477-481.
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2544-2545.
A single example of the corresponding deselenative rear-
rangement of a diallyl diselenide, that of di(geranyl) diselenide
to geranyl linalyl selenide, was reported to proceed with a half-
life of approximately 2.5 h at 25 °C on exposure to excess PPh3
(52) Crich, D.; Brebion, F.; Krishnamurthy, V. Org. Lett. 2006, 8, 3593-3596.
(53) Moore, C. G.; Trego, G. R. Tetrahedron 1962, 18, 205-218.
(54) 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.
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1262.
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Commun. 1969, 371-372.
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4442-4444.
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Chem. Soc. 1988, 110, 7813-7827.
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1847.
(58) Ho¨fle, G.; Baldwin, J. E. J. Am. Chem. Soc. 1971, 93, 6307-6308.
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9
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A R T I C L E S
Crich et al.
Table 1. Preliminary Survey of Disulfides and Phosphines
Scheme 3. Formation and Rearrangement of Se-Allylic
Selenosulfides
in chloroform, thereby indicating the selenium version of this
reaction to be considerably faster than the original sulfur
protocol.63 Guillemin and co-workers subsequently were able
to obtain crude preparations (∼80% pure) of diallyl diselenide,
dicrotyl diselenide, and diprenyl diselenide, characterize them
spectroscopically, and study their reactions with tributylstannane,
indicating such diselenides to have at least moderate stability
at room temperature.64
presumably accounts for the differences in reaction times and
temperatures observed. Under the same conditions, the phenyl
geranyl disulfide 20, however, gave the unrearranged phenyl
geranyl sulfide 21 (Table 1, entry 2), thereby drawing attention
to the relatively fine dividing line between the desired dechal-
cogenative allylic rearrangement and the better known nucleo-
philic removal of a sulfur atom from a disulfide.68 As is evident
from the comparison of entries 1 and 2 in Table 1, the
replacement of an alkylthiyl moiety by an arylthiyl group is
sufficient to tip the balance in favor of nucleophilic attack by
the phosphine on the native disulfide. Entry 3 of Table 1
illustrates how the replacement of PPh3 by the more nucleophilic
hexaethylphosphoramine enabled the reaction temperature to be
reduced to the ambient but, unfortunately, with continued
formation of the simple desulfurization product. Finally, Table
1, entry 4, ruled out any future use of hexaethylphosphoramine,
at least in the context of amino acid and peptide-based systems,
owing to both transesterification and racemization evidenced
by incorporation of deuterium from the solvent at the R-center.
Allylic Selenosulfide Rearrangement. The somewhat in-
auspicious results reported in Table 1 led us to consider the
possibility of the deselenative rearrangement of Se-allylic
Preliminary Studies. We initiated our investigations with a
brief survey of methods of mixed disulfide formation, of
solvents, and of phosphines for the allylic disulfide rearrange-
ment. As shown in Table 1, allylic pyridyl sulfides,1,2,65 allylic
thiosulfonates,38 and allylic Bunte salts (S-allyl thiosulfates)66,67
all proved adept at the transfer of allylic sulfides to a range of
simple thiols. The phosphine-promoted rearrangement, however,
was not so simple. Thus, it was necessary to heat the alkyl
geranyl disulfide 18 with PPh3 in toluene at reflux in order to
achieve efficient conversion to the rearranged linalyl sulfide 19
(Table 1, entry 1). It is important to note that, consistent with
our aim of developing a practical process suitable for application
to biologically relevant systems, our reactions were carried out
with a minimal excess of phosphine, unlike the work of Ho¨fle
and Baldwin.58 The difference in the amount of phosphine
(63) Sharpless, K. B.; Lauer, K. B. J. Org. Chem. 1972, 37, 3973-3974.
(64) Riague, E. H.; Guillemin, J.-C. Organometallics 2002, 21, 68-73.
(65) Stoner, E. J.; Negro´n, G.; Gavin˜o, R. In Handbook of Reagents for Organic
Synthesis: Reagents for Glycoside, Nucleotide, and Peptide Synthesis;
Crich, D., Ed.; Wiley: Chichester, 2005; pp 330-338.
(66) Klayman, D. L.; White, J. D.; Sweeney, T. R. J. Org. Chem. 1964, 29,
3737-3738.
(67) Milligan, B.; Swan, J. M. J. Chem. Soc. 1963, 6008-6012.
(68) Harpp, D. N.; Gleason, J. G. J. Am. Chem. Soc. 1971, 93, 2437-2445.
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Allylic Selenosulfide and Disulfide Rearrangements
A R T I C L E S
Table 2. Formation and Rearrangement of Selenosulfides
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A R T I C L E S
Crich et al.
Table 2 (Continued)
a Unless otherwise stated all reactions were conducted in MeOH. b At room temperature. c T ) 65 °C. d CDCl3 was used as a solvent at T ) 65 °C.
selenosulfides, which should be more facile than the desulfur-
ative rearrangement of the allylic disulfides.69 The clean
formation of simple mixed alkyl selenosulfides can be realized
at room temperature by the reaction of Se-alkyl seleno-Bunte
salts with thiols.70,71 Accordingly, a number of Se-allyl seleno
Bunte salts were prepared by the reaction of potassium seleno
sulfate, prepared in situ from potassium sulfite and selenium
powder, with allyl halides. These compounds were typically
orange crystalline solids that, while not indefinitely stable, could
be handled in air at room temperature. Reaction with a range
of aliphatic thiols then resulted in the formation of a series of
selenosulfides, that could be readily detected by thin layer
chromatography and/or NMR spectroscopy, but which were
allowed to undergo the subsequent deselenative rearrangement,
either with or without the addition of phosphine as required
(Scheme 3, Table 2).
We have also prepared the Se-allyl selenosulfides by the
reaction of allyl selenocyanates64 with thiols, a process that also
takes place readily at room temperature (Scheme 3), and which
had been reported for the formation of simple diaryl seleno-
sulfides.72 The formation of allyl selenosulfides from the reaction
of allylselenols with disulfides was not investigated because of
anticipated difficulties in the preparation and handling of the
allylic selenols.64 Overall, it is clear from Table 2 that allyl
selenocyanates may generally be prepared in higher yields than
the corresponding Se-allyl seleno Bunte salts, but that in most
cases both selenenylation systems perform the transfer of the
Se-allyl group to the thiol comparably well, as evidenced by
the yield of the subsequent rearrangement products.
(69) The use of the deselenative allylic diselenide rearrangement was excluded
from consideration on the grounds that selenocysteine is too uncommon in
Nature to form the basis for a broad general methodology.
(70) Patarasakulchai, N.; Southwell-Keely, P. T. Phosphorus Sulfur 1985, 22,
277-282.
(71) Klayman, D. L.; Gu¨nther, W. H. H., Eds. Organic selenium compounds:
their chemistry and biology; Wiley-Interscience: New York, 1973.
It is of some interest to note that the primary allylic
selenocyanates prepared and employed in this study were readily
(72) Clark, E. R.; Al-Turaihi, M. A. S. J. Organomet. Chem. 1977, 134, 181-
187.
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Allylic Selenosulfide and Disulfide Rearrangements
A R T I C L E S
handled at room temperature and showed no tendency to
undergo rapid rearrangement. This observation parallels that of
Riague and Guillemin, who had earlier prepared several of the
same allylic selenocyanates and reported their purification by
vacuum distillation,73 but it stands in contrast to the reported
chemistry of simple allylic thiocyanates which are reported to
undergo [2,3]-sigmatropic rearrangement to the corresponding
allylic isothiocyanates in a matter of hours at room tempera-
ture.74,75 On the basis of the work of Sharpless with 2-methyl-
3-selenocyanato-1-heptene, secondary and presumably tertiary
selenocyanates can be expected to undergo a [1,3]-sigmatropic
rearrangement to their primary regioisomers.63
farnesyl group to a sulfide, failed. This result, which is not
surprising in view of the instability of secondary allylic
selenocyanates and even phenylselenides noted by Sharpless,63
forced us to return to the allylic disulfides.
Allylic Disulfide Rearrangement. The early work on the
allylic disulfide rearrangement (Scheme 2)53,58 indicated the
considerable effect of substituents in the allylic moiety on
reaction rate with the secondary and tertiary allylic disulfides
undergoing rearrangement several orders of magnitude more
rapidly than their primary counterparts in hot benzene, thereby
providing grounds for hope that the rearrangement could be
induced to function as required at room temperature with the
correct substituent pattern. In addition, consideration of the
mechanism of the allylic disulfide rearrangement leads to the
hypothesis that the reaction should be facilitated in polar solvents
capable of stabilizing the dipolar thiosulfoxide intermediate.76,77
Indeed, the early workers in the field noted a 6-10 fold increase
in the rate of desulfurative rearrangement of 1,3-dimethylbut-
2-enyl tert-butyl disulfide with PPh3 on going from benzene to
ethanol/benzene (9/2) at 80 °C,53 and Ho¨fle and Baldwin
commented on the instability of methanolic solutions of 10 and
11 with respect to rearrangement, as compared to the neat
samples.58
A series of secondary and tertiary allylic thiols were prepared
by the [3,3]-sigmatropic rearrangement of a variety of primary
allylic thiocarbonyl derivatives (Scheme 4, Table 3).78-83 While
this chemistry was straightforward, caution was necessary in
the conversion of the rearrangement products to the thiols, as
these were found to undergo a known80 1,3-shift to the isomeric
primary allylic thiols under basic conditions. The optimum
conditions for this cleavage involved the reduction of the thiol
carbamates with lithium aluminum hydride,80 and the cleavage
of the dithiocarbonates with ethanolamine. The thiols were then
allowed to react with either 2,2′-dipyridyl disulfide, 2,2′-di(5-
nitropyridyl) disulfide, or 2,2′-di(1,3-benzothiazolyl) disul-
fide1,2,32-34,65,84-87 for conversion to the corresponding allyl
heteroaryl disulfides and ultimate transfer to the target thiols
(Scheme 4, Table 3). It is noteworthy that sulfenylating agents
derived from hindered allylic thiols have drawn little attention
so far, with only a limited number of allylic benzothiazolyl
disulfides being described in the literature.88,89 In addition to
these allylic heteroaryl disulfides, we also prepared a single
example 75 of an S-allyl Se-phenyl selenosulfide, by reaction
The transfer of a simple allyl or methallyl group did not
necessitate the addition of phosphine and proceeded spontane-
ously over a 2 h period at room temperature. In the case of
geranyl and farnesyl Se-Bunte salts and selenocyanates, pro-
ceeding with allylic rearrangement to the linalyl and nerolidyl
sulfides, respectively, it was necessary to add PPh3 to provoke
the loss of selenium. The more difficult rearrangement of the
geranyl and farnesyl systems corresponds to the pattern observed
originally with the allylic disulfides (Scheme 2), with the prenyl
system 9 undergoing the phosphine-promoted rearrangement
least rapidly. This is clearly the consequence of the formation
of the less stable isoprenyl substitution pattern. The anomeric
thiol 38 rearranged slowly over a period of several days at room
temperature in the presence of PPh3, and much more rapidly at
65 °C. The fluorous-substituted methallyl system 53, unlike the
simple methallyl transfer reactions, necessitated the addition of
PPh3 in order to proceed at room temperature. These latter two
observations are understood in terms of the mechanism of
Scheme 3, with the formation of the intermediate selenosulfoxide
disfavored by either an electron-withdrawing substituent on the
allyl group or by the involvement of the sulfur atom in an exo-
anomeric type interaction that serves to remove electron density
from sulfur. When the reaction takes place with the formation
of a new stereogenic center, this was typically obtained as an
almost equimolar mixture of two diastereomers and, accordingly,
no attempt was made to distinguish the isomers.
The range of examples presented in Table 2, which were all
conducted at room temperature with the exception of the
carbohydrate-based example, displays the broad functional group
compatibility of the method. A series of further experiments in
which the reaction of cysteine derivative 25 with the Se-
methallyl seleno Bunte salt 42 and PPh3 was conducted in
methanol at room temperature in the presence of equimolar
amounts of N-benzyloxycarbonyl tyrosine benzyl ester, N-
benzyloxycarbonyl methionine, NR-benzyloxycarbonyl lysine
methyl ester, N-benzyloxycarbonyl arginine methyl ester, and
N-benzyloxycarbonyl aspartic acid R-methyl ester, with no loss
of yield and with recovery of the spectator amino acid, further
confirmed the applicability of the reaction in the presence of
most standard functional groups.
(76) We assign the dipolar structure to the thiosulfoxides, a class of compounds,
which have not been isolated or characterized spectroscopically, by
reasonable analogy with the sulfoxides. Thiosulfinates (ROS(S)OR) have
been isolated and studied crystallographically, spectroscopically, and
computationally, with the evidence pointing to the polar structure.77
(77) Zysman-Colman, E.; Nevins, N.; Eghbali, N.; Snyder, J. P.; Harpp, D. N.
J. Am. Chem. Soc. 2005, 128, 291-304.
(78) Garmaise, D. l.; Uchiyama, A.; McKay, A. F. J. Org. Chem. 1962, 27,
4509-4512.
(79) Ferrier, R. J.; Vethaviyasar, N. J. Chem. Soc., Chem. Commun. 1970, 1385-
1387.
(80) Hackler, R. E.; Balko, T. W. J. Org. Chem. 1973, 38, 2106-2110.
(81) Ueno, Y.; Sano, H.; Okawara, M. Tetrahedron Lett. 1980, 21, 1767-1770.
(82) Eto, M.; Tajiri, O.; Nakagawa, H.; Harano, K. Tetrahedron 1998, 54, 8009-
8014.
Unfortunately, all attempts at the preparation of tertiary allylic
seleno Bunte salts or the equivalent selenocyanates, such as
would be necessary for the introduction of a simple geranyl or
(83) Nakai, T.; Ari-Izumi, A. Tetrahedron Lett. 1976, 17, 2335-2338.
(84) Talgoy, M. M.; Bell, A. W.; Duckworth, H. W. Can. J. Biochem. 1979,
57, 822-833.
(85) Kimura, T.; Matsueda, R.; Nakagawa, Y.; Kaiser, E. T. Anal. Biochem.
1982, 122, 274-282.
(73) Guillemin, J. C.; Bouayad, A.; Vijaykumar, D. Chem. Commun. (Cam-
bridge, U. K.) 2000, 13, 1163-1164.
(74) Emerson, D. W.; Booth, J. K. J. Org. Chem. 1965, 30, 2480-2481.
(75) Carbohydrate-based allylic thiocyanates, however, require higher temper-
atures for rearrangement. Ferrier, R. J.; Vethaviyaser, N. J. Chem. Soc.
(C) 1971, 1907-1913.
(86) Brzezinska, E.; Ternay, A. L. J. Org. Chem. 1994, 59, 8239-8244.
(87) Rabanal, F.; DeGrado, W. F.; Dutton, P. L. Tetrahedron Lett. 1996, 37,
1347-1350.
(88) Watson, A. A. J. Chem. Soc. (C) 1964, 2100-2107.
(89) Morrison, N. J. J. Chem. Soc., Perkin Trans. 1 1984, 101-106.
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A R T I C L E S
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Table 3. Preparation of Allylic Thiols and the Corresponding Allyl Heteroaryl Disulfides
Scheme 4. Preparation of Secondary and Tertiary Allylic Thiols
and Heteroaryl Disulfides
the addition of triethylamine. Interestingly, sulfenyl transfer from
the selenosulfide 75 was also slow but was accelerated in the
presence of triethylamine, and we conclude that there is no
practical advantage to the use of the selenosulfide transfer
protocol.90 No obvious consequence in terms of reactivity was
observed when the sulfenyl transfer group was changed from
5-nitro-2-pyridyl, to 2-pyridyl, to 2-benzothiazolyl, but the
differing polarities of the corresponding heteroaryl sulfides
formed as byproducts can be used to advantage in the case of
otherwise difficult purifications. Similarly, no significant dif-
ference in the rate of the desulfurative rearrangement was
observed on changing from PPh3 to (4-dimethylaminophenyl)-
diphenylphosphine 84, but the latter did afford a practical
advantage in terms of purification of the final products.
of the thiol with N-phenylselenophthalimide, as it had been
reported that the selenosulfides were more effective at sulfenyl
transfer than the corresponding disulfides.37
The desulfurative rearrangement of the secondary allylic
disulfides takes place with high E-selectivity as anticipated on
the basis of related [2,3]-sigmatropic rearrangements such as
the Evans-Mislow rearrangement60 or the [2,3]-Wittig rear-
rangement.91 With the tertiary allylic disulfides, E/Z mixtures
of the rearranged products are formed that slightly favor the
E-isomer. Interestingly, in the case of the nerolidyl selenosulfide
75, the product 86 was obtained as a more complex mixture of
isomers, presumably because of isomerization of the central
alkene in the resulting farnesyl chain by the selenide byproducts
As anticipated these allylic heteroaryl disulfides enabled
smooth sulfenyl transfer to a selection of primary thiols in either
benzene or methanol/acetonitrile mixtures at room temperature
(Table 4). Addition of either PPh3 or (4-dimethylaminophenyl)-
diphenylphosphine then provoked the desired desulfurative
allylic rearrangement. For those reactions that were carried out
in benzene, the sulfenyl transfer was affected at room temper-
ature, after which the phosphine was added and the reaction
mixture heated to reflux to bring about the rearrangement. On
the other hand, as expected from mechanistic considerations,
when reactions were conducted in methanol and acetonitrile,
no heating was required for the entire sequence. With the more
highly substituted allyl heteroaryl disulfides, sulfenyl transfer
was relatively slow but was accelerated very significantly by
(90) The accelerated reactions reported in the literature37 for sulfenyl transfer
from selenosulfides, as compared to disulfides, also appear to be the result
of the inclusion of triethylamine.
(91) Nakai, T.; Mikami, K. In Organic Reactions; Paquette, L. A., Ed.; John
Wiley & Sons: New York, 1994; Vol. 46, pp 105-209.
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Allylic Selenosulfide and Disulfide Rearrangements
A R T I C L E S
Table 4. Formation and Rearrangement of Secondary and Tertiary Allylic Disulfide
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A R T I C L E S
Crich et al.
Table 4 (Continued)
Scheme 5. Functionalization of Glutathione
in combination with light.92 When the reaction of the cysteine
derivative 83 with the sulfenyl transfer agent 66 and PPh3 was
carried out in a mixture of deuteriomethanol and deuterioac-
etonitrile, no incorporation of deuterium at the amino acid
R-center was observed, indicating that the reaction conditions
do not provoke racemization.
The examples presented in Table 4 attest to the broad
functional group compatibility of the formation and desulfurative
rearrangement of secondary and tertiary allylic disulfides and
draw attention to the complementary nature of the process with
the deselenative allylic selenosulfide protocol, with all classes
of primary, secondary, and tertiary allylic sulfides accessible
by one of the two reaction sequences at room temperature and
without the need for electrophilic reagents.
(92) Barrett, A. G. M.; Barton, D. H. R.; Johnson, G.; Nagubandi, S. Synthesis
1978, 741.
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Allylic Selenosulfide and Disulfide Rearrangements
A R T I C L E S
Scheme 6. Functionalization of a Fibronectin Fragment
Peptide Functionalization in Aqueous Media. The ap-
plicability of the desulfurative allylic rearrangement to unpro-
tected peptides in aqueous media was first probed with
glutathione 93 and sulfenylating agent 64. In the event, reaction
of disulfide 64 with glutathione 93 in a 2/1/1 mixture of tris
buffer/MeCN/THF, with a substrate concentration of 0.02 M
at room temperature, followed by addition of PPh3 smoothly
yielded the lipidated glutathione 94 in 70% yield (Scheme 5).
The chemoselectivity of the rearrangement was further
explored with the commercial decapeptide fibronectin fragment
95.93,94 This decapeptide was selected as a proving ground
because of the dense array of the more challenging amino acid
side chains that it presents. As with glutathione 93, sulfenylation
of the cysteine moiety of the decapeptide 95, followed by
phosphine-promoted rearrangement, was accomplished at room
temperature in aqueous buffer, with the aid of organic cosol-
vents, and resulted in the isolation of the lipidated decapeptide
96 in 70% yield (Scheme 6). The location of the tridecene chain
on the cysteine group in 96 was established by MS/MS
experiments.
As a second demonstration of the protocol in aqueous media,
we prepared an octapeptide 101 in which the cysteine residue
was located four residues from a C-terminal methionine unit,
so as to mimic the Cys-AA1-AA2-Met sequence targeted by the
farnesyl transferase enzymes.95-97 The other amino acids in this
synthetic peptide were selected so as to provide a measure of
steric hindrance to the cysteine moiety. Two tetrapeptides were
assembled routinely,98,99 and 97, which was destined to become
the N-terminal fragment of the target, was saponified, converted
to the ethylthio ester 98 with HATU and ethanethiol,100,101 and
finally released from the carbamate protecting group (Scheme
7). This sequence resulted in an inseparable mixture of two
diastereomers 99 at the C-terminal alanine, a problem known
to plague thioester synthesis for NCL.102 Coupling of thioester
99 with tetrapeptide 100 under conditions of NCL afforded the
target octapeptide 101 in 51% yield as a 1.3/1 mixture of two
diastereomers, which was separated by preparative RP-HPLC.
The major diastereoisomer, presumed to be the all L-octapeptide,
was then allowed to react with the nerolidyl benzothiazolyl
disulfide 74 under buffered aqueous conditions at room tem-
perature, followed by addition of PPh3, leading overall to the
farnesylated octapeptide 102 in 66% isolated yield (Scheme 7).
This farnesylation reaction occurred with the formation of E/Z-
isomers mixtures in approximately equal ratio in line with the
model experiments in organic solution (Table 4).
The examples of Schemes 5-7 are distinct from other recent
functionalizations of sulfur in cysteine-containing peptides,17
as they require neither the use of electrophilic reagents,1,2,39 nor
the incorporation of modified amino acid residues into the
peptide backbone prior to functionalization,40-47 nor the syn-
thesis of peptides with previously functionalized amino acid
building blocks.48-50 These factors combine to render this
chemistry both highly chemoselective, and highly efficient in
terms of steps required on the actual peptide target. In contrast
to other methods involving the addition of nucleophilic thiols
to dehydroalanine groups inserted into peptides,40 the products
are obtained as single diastereomers with the sole exception
being the formation of E/Z-mixtures when the allylic sulfide
(98) Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis; 2nd ed.;
Springer-Verlag: Heidelberg, 1994.
(99) Goodman, M.; Mahwah, A. F.; Moroder, L.; Toniolo, C., Eds. Houben-
Weyl. Methods in Organic Chemistry. Synthesis of Peptides and Peptido-
mimetics; Thieme: Stuttgart, 2002-2003; Vol. E22a-e.
(100) Schnolzer, M.; Alewood, P.; Jones, A.; Alewood, D.; Kent, S. B. H. Int.
J. Pept. Protein Res. 1992, 40, 180-193.
(93) Boucaut, J.-C.; Darribe`re, T.; Poole, T. J.; Aoyama, H.; Yamada, K. M.;
Thierry, J. P. J. Cell. Biol. 1984, 99, 1822-1830.
(94) Yamada, K. M.; Kennedy, D. W. J. Cell. Biol. 1984, 99, 29-36.
(95) Casey, P. J. Science 1995, 266, 221-.
(96) Kale, T. A.; Hsieh, S.-a. J.; W., R. M.; Distefano, M. D. Curr. Top. Med.
Chem. 2003, 3, 1043-1074.
(101) Clippingdale, A. B.; Barrow, C. J.; Wade, J. D. J. Pept. Sci. 2000, 6,
225.
(97) Brunsveld, L.; Kuhlmann, J.; Alexandrov, K.; Wittinghofer, A.; Goody,
R. S.; Waldmann, H. Angew. Chem., Int. Ed. 2006, 45, 6622-6646.
(102) Kajihara, Y.; Yoshihara, A.; Hirano, K.; Yamamoto, N. Carbohydr. Res.
2006, 341, 1333-1340.
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A R T I C L E S
Crich et al.
Scheme 7. Synthesis of an Octapeptide by Native Chemical Ligation and Subsequent Farnesylation
contains a trisubstituted alkene. We anticipate that the use of a
water-soluble phosphine should be possible in the above
experiments, with the proviso that it not be sufficiently
nucleophile and/or basic to lead to the type of problems outlined
for hexaethylphosphoramine encountered in our preliminary
survey of conditions.
the rearrangement can be achieved by stirring with 2 equiv of
piperidine at room temperature in methanol, or simply by heating
to reflux in methanol with no added thiophile for a period of
several hours. Examples of rearrangements so-conducted are
presented in Table 5 using a sulfenyl transfer reagent 104
derived by removal of the silyl group from sulfenyl donor 79.
Appropriate control experiments conducted with PPh3 at room
temperature are also reported in Table 5.
Rearrangement in the Absence of Phosphines. Finally, we
turn to the question of the requirement for a phosphine to
promote the desulfurative rearrangement of the allylic disulfides.
Several factors indicated that conditions may be found under
which the reaction would function in the absence of the
phosphine. For example, the attempted purification of disulfide
103 by chromatography over silica gel resulted in the isolation
of 13% of the allylically rearranged thioether 85 along with
the disulfide itself (Scheme 8).52 Second, on standing in
deuteriochloroform that had not been treated to remove acidic
impurities, the same disulfide 103 underwent partial rearrange-
ment to 85 with loss of sulfur.52 More tangentially related are
the reported use of morpholine or piperidine to drive the related
allylic sulfoxide/sulfenate rearrangement,60 and the uptake of
molecular sulfur by allylic sulfides leading to rearranged allylic
disulfides.56
Scheme 8. Rearrangement in the Absence of Phosphines
It is of some interest that both the piperidine and the refluxing
methanol conditions enable the desulfurative rearrangement of
allyl aryl disulfides for the first time, thereby opening up new
avenues for the synthesis of allyl aryl sulfides and extending
the overall scope of the reaction. The rearrangements of the
allyl aryl disulfides presented in Table 5, and conducted in the
absence of phosphine but with the aid of either piperidine or
hot methanol, are to be contrasted with the attempted promotion
The apparent acid-catalyzed rearrangement of 103 to 85 with
loss of sulfur could not be developed into a satisfactory general
method. However, after some investigation, we have found that
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Allylic Selenosulfide and Disulfide Rearrangements
A R T I C L E S
Table 5. Desulfurative Rearrangement of Allylic Disulfides in the Absence of Phosphine
of such a rearrangement set out in Table 1, when the excision
of sulfur was observed without the allylic rearrangement. We
also note the application of the overall process to a tertiary thiol
and draw attention to the absence of racemization in the case
of the cysteine derivative as determined in the usual manner
by the use of deuteriomethanol as solvent.
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A R T I C L E S
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Conclusions
Acknowledgment. We thank the NIH (AI 56575 and GM
62160) for partial support of this work, and the Ministe`re des
Affaires EÄ trange`res, France, for the award of a Lavoisier
Fellowship to F.B. D.C. thanks Professor Yasuhiro Kajihara,
Yokoyama City University, for a helpful discussion regarding
native chemical ligation.
The deselenative allylic rearrangement of primary allyl
selenosulfides and the desulfurative rearrangement of secondary
and tertiary allylic are powerful and complementary techniques
for the synthesis of primary, secondary, and tertiary allylic
sulfides at room temperature. The preparation of the seleno-
sulfides and disulfides requires no electrophilic reagent, leading
to highly chemoselective methods for the permanent modifica-
tion of thiols. The chemoselectivity of the two reactions enables
their application to unprotected peptides in aqueous media in
the presence of all types of standard amino acid side chains,
thereby providing a powerful means for the direct and permanent
modification of cysteine-containing peptides.
Supporting Information Available: Full experimental pro-
tocols and copies of spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA072969U
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