Allylic selenosulfide rearrangement: A method for chemical ligation to cysteine and other thiols

Article abstract of DOI:10.1021/ja057521c

Alkylation of potassium selenosulfate with allylic halides gives Se-allyl seleno Bunte salts. On reaction with thiols at room temperature, these afford mixed dialkyl selenosulfides, which undergo 2,3-sigmatropic rearrangement with loss of selenium, either spontaneously or with assistance by triphenylphosphine, thereby providing mixed dialkyl sulfides and a new permanent chemical ligation method. The process is illustrated through the lipidation of cysteine-containing tripeptides and by the allylation of 1-thioglucose tetraacetate. Copyright

Full text of DOI:10.1021/ja057521c

Published on Web 02/03/2006
Allylic Selenosulfide Rearrangement: A Method for Chemical Ligation to
Cysteine and Other Thiols
David Crich,* Venkataramanan Krishnamurthy, and Thomas K. Hutton
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061
Received November 3, 2005; E-mail: dcrich@uic.edu
Scheme 1. Chemical Ligation via Se-Allyl Selenosulfides
The development of methods for the chemical ligation of small
molecules to peptides and proteins, for conjoining two proteins,
and for the attachment of oligosaccharides to peptides and proteins
is a current frontier in chemical biology.1 One established ligation
method involves the formation of mixed disulfide linkages,2 various
modifications of which have recently been applied to the synthesis
of glycopeptides and proteins.3 The disulfide ligation is especially
attractive in conjunction with native peptide ligation; however, the
ease of disulfide exchange renders the method impermanent.4 We
report preliminary results on the development of a new method of
chemical ligation based on the facile formation of mixed seleno-
sulfides, which are then rendered permanent by a sigmatropic
rearrangement with loss of selenium.
Scheme 2 . Allylation of Simple Thiols
Allylic disulfides are in equilibrium with allylic thiosulfoxides,
by virtue of a 2,3-sigmatropic rearrangement.5 The equilibrium very
strongly favors the allylic disulfide and is only revealed when the
reaction is driven in the forward direction, either by a further
rearrangement or by the addition of a thiophilic reagent, typically
a phosphine. At 60 °C in benzene, rate constants for the rearrange-
ment with transfer of sulfur to triphenyl phosphine were found to
range from 0.7 to 190 × 10-4 s-1, depending on the substituent
pattern.5a Allylic diselenides, on the other hand, undergo the
analogous rearrangement at room temperature in a matter of hours.6
We hypothesized that Se-allyl selenosulfides 2 would undergo a
similar 2,3-sigmatropic rearrangement at room temperature and that
the weakness of the Se-S bond in the selenosulfoxide product 3
would result in the facile loss of selenium, thereby driving the
reaction even in the absence of a phosphine. We further hypoth-
esized that the requisite Se-allylic selenosulfides could be readily
accessed at room temperature from simple Se-allyl seleno Bunte
salts 1, as was known for Se-alkyl seleno Bunte salts,7,8 and that
the combination of these two processes would provide a convenient
new chemical ligation process (Scheme 1).
Reaction of K2SO3 with Se powder and then allyl bromide gave
potassium Se-allyl selenosulfate 5 as an orange solid.8b,9 Reaction
of this Se-Bunte salt with primary aliphatic thiols in methanol at
room temperature resulted in transfer of the allyl group to sulfur,
with loss of selenium (Scheme 2), establishing the validity of the
initial hypothesis.
We next examined the attachment of allyl and substituted allyl
groups to cysteine derivatives (Table 1). These reactions were
conducted in two stages, with formation of the selenosulfide in
methanol and, following filtration on silica gel, triphenylphosphine-
promoted deselenylative rearrangement in CDCl3, all at room
temperature. The 2,3-sigmatropic nature of the rearrangement step
is unmasked with the formation of the S-linalyl cysteine 14 starting
from the Se-geranyl Se-Bunte salt 13.10
Table 1. Application to Cysteine Derivativesa,b
a With Se-Bunte salt 13, the first step was conducted in a methanol/
CH2Cl2 mixture. b Compound 14 was formed as an approximately 1:1
unassigned mixture of diastereomers.
at room temperature with filtration of the excess Bunte salt before
addition of the phosphine. It is noteworthy that this new cysteine
functionalization method is compatible with the indole in tryptophan
and enables the incorporation of the geranyl and farnesyl chains as
the transposed linalyl and nerolidyl groups. We have also demon-
strated application to a carbohydrate-based thiol 24 (Scheme 3).
This rearrangement, which proceeded spontaneously over a period
of several days at room temperature or in a matter of hours on
addition of triphenyl phosphine, took place with complete retention
of the anomeric stereochemistry.
In summary, we describe a new, permanent chemical ligation
method. The method has potential for the attachment of lipids to
protein-based thiols, an area of considerable current interest.11
Applications in combinatorial chemistry and for the attachment of
a wide variety of groups, including poly(ethylene glycol)12 and
Functionalization of small cysteine-containing peptides was
explored with Boc-(R-OMe)-γ-L-Glu-L-Cys-Gly-OMe, 15, and with
Boc-L-Cys-L-Ala-L-Trp-OMe 16 using a selection of allylic Se-
Bunte salts (Table 2). These reactions were conducted in methanol
9
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J. AM. CHEM. SOC. 2006, 128, 2544-2545
10.1021/ja057521c CCC: $33.50 © 2006 American Chemical Society

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Acknowledgment. We thank the NIH (AI 56575) for partial
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Supporting Information Available: Full experimental details and
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