Biomimetic seleninates and selenonates

Article abstract of DOI:10.1021/ja8034448

The synthesis of a variety of pyranose-, nucleoside-, (amino acid)-, and polyhydric-based seleninic and selenonic acids by DMDO oxidation of the corresponding selenoesters is reported, as well as some unusual coupling reactions of the seleninate and selenonate functionality with biological nucleophilic groups (sulfhydryl, indole, phenol, imidazole, carboxamide) that are found in proteins and enzyme active sites. Copyright

Full text of DOI:10.1021/ja8034448

Published on Web 06/25/2008
Biomimetic Seleninates and Selenonates
Mohannad Abdo and Spencer Knapp*
Department of Chemistry & Chemical Biology, RutgerssThe State UniVersity of New Jersey,
Piscataway, New Jersey 08854
Received May 14, 2008; E-mail: spencer.knapp@rutgers.edu
Table 1. Synthesis of Seleninates and Selenonates from
Selenoesters
Aliphatic seleninic (RSeO2H) and selenonic (RSeO3H) acids and
their salts may be viewed as isosteres1 of the biologically ubiquitous
anionic O-phosphate,2 O-sulfate,3 and carboxylate4,5 groups and
can be predicted to resist the action of most enzymes that operate
in the biosynthesis or subsequent processing of those bioanions.
While sometimes considered too unstable6 or too toxic7 for
medicinal chemistry use, seleninates and selenonates nevertheless
exhibit unique reactivity that can potentially be channeled for an
assortment of bioorganic applications, including studies of enzyme
action and inhibition, enzyme structure and mechanism, and
biomimetic chemical ligation. We report a mild and efficient method
for the preparation of pyranose-, nucleoside-, amino acid-, and
polyhydric-based seleninates and selenonates, as well as some
unusual coupling reactions with nucleophilic functionality that is
commonly found in proteins and enzyme active sites.
Selenoesters such as the gluco-pyranoside-based 1 (eq 1) are
readily prepared by displacement reaction of the corresponding
primary iodide with a selenocarboxylate anion generated in situ
from the carboxylic acid and Woollins’ reagent.8 Clean oxidation
of 1 to the seleninic acid occurred in the presence of stoichiometric
amounts of dimethyldioxirane (DMDO);9 the product 2 crystallized
from solution and was characterized by mass spectrometry, 1H, 13C,
and 77Se NMR spectroscopy, and X-ray crystallography. The
acetates were cleaved quantitatively with methoxide to afford triol
3 without affecting the seleninate functionality. Oxidation of 2 with
excess DMDO led to the selenonate, which was conveniently
isolated by chromatography as its triethylammonium salt 4.
Alternatively, 4 was prepared directly from 1 by DMDO oxidation
in 81% yield; deacetylation with methoxide gave selenonate triol
sodium salt 5 quantitatively.10 Fewer than a dozen aliphatic
selenonic acids have been previously reported and very little is
known about their chemistry.
By using comparable transformations, a variety of polyfunctional
selenoesters were converted to seleninates and selenonates (Table
1). The manno-pyranoside (6) and gluco-pyranose (11) systems gave
respective seleninates (8 and 13) and selenonates (10 and 15) that
superficially resemble the corresponding 6-O-phosphates.11 Uridine
(16) and 2′-deoxyuridine (17) substrates gave initially upon
oxidation the cyclic seleninic esters 18 and 19, but these rings were
readily opened during subsequent deacetylation. Nucleoside se-
leninates 20 and 21 and selenonates 22 and 23 may be thought of
as truncated 5′-O-phosphate analogues.12 The mono- and di-O-
acylated butanediol and propanediol seleninates (25, 29, and 30)
and selenonates (26, 31, and 32) resemble lysophospholipids,
although they are monobasic. The selenoglutamate 35 was prepared
9
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2008 American Chemical Society

C O M M U N I C A T I O N S
from a protected homoserine by Mitsunobu substitution followed
by DMDO oxidation; cyclized seleninamide 34 was isolated as the
intermediate.
The stability of many, but not all, of the new seleninates, can be
attributed to the slow rate of selenoxy retro-ene elimination expected
for systems with a ꢀ-oxygen substituent.23 For others (25, 40), the
stability of the resulting alkene would seem to be insufficient to
favor the elimination (compare the selenocysteine systems, which
eliminate readily). The stability of the selenonates may derive from
the ability of their C-Se bonds (1°, electron-poor, beta-branched)
to withstand both SN1 and SN2 pathways for cleavage.
In contrast to the homoserine substrate, serine-derived selenoester
36 gave a seleninic acid that was not isolable, but instead eliminated
H2SeO2 within minutes by retro-ene reaction to give the dehy-
droalanine derivative 38.13 Following treatment of the presumed
seleninic acid intermediate with p-toluenesulfonylhydrazide,14
however, the trapped stable redox product selenolsulfonate 37 was
isolated in good yield. The alaninol-derived system 39, by
comparison, oxidized smoothly to seleninate 40 without elimination,
and further oxidation to selenonate 41 was also uneventful.
Seleninic acids react with mercaptans to give the selenosulfide.15
With seleninate 2, 1.0 equiv of N-Boc-cysteine methyl ester reacted
in CH2Cl2 solution within 1 min at 23 °C to give the coupled
product 42 in good yield.16 A number of enzyme active sites contain
a cysteine sulfhydryl,17 so given the appropriate seleninate-
containing substrate mimic, this reaction is a potential avenue for
Acknowledgment. This paper is dedicated to Prof. E. J. Corey
on the occasion of his 80th birthday. We are thankful to Dr. T. J.
Emge for crystallography and to Rohm and Haas Co. for a graduate
assistantship to M.A.
Supporting Information Available: Experimental details for new
compounds, and the crystal structure of 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
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