The first direct oxidative conversion of a selenol to a stable selenenic acid: Experimental demonstration of three processes included in the catalytic cycle of glutathione peroxidase

Article abstract of DOI:10.1021/ol016682s

(matrix presented) A stable selenenic acid was synthesized by direct oxidation of a selenol bearing a novel bowl-type substituent with H₂O₂, and its structure was established by X-ray crystallographic analysis. Selenenyl sulfides obt

Full text of DOI:10.1021/ol016682s

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3569-3572
The First Direct Oxidative Conversion of
a Selenol to a Stable Selenenic Acid:
Experimental Demonstration of Three
Processes Included in the Catalytic
Cycle of Glutathione Peroxidase
Kei Goto,* Michiko Nagahama, Tadashi Mizushima, Keiichi Shimada,
,†
Takayuki Kawashima, and Renji Okazaki*
Department of Chemistry, Graduate School of Science, The UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
goto@chem.s.u-tokyo.ac.jp
Received September 1, 2001
ABSTRACT
A stable selenenic acid was synthesized by direct oxidation of a selenol bearing a novel bowl-type substituent with H O , and its structure was
2
2
established by X-ray crystallographic analysis. Selenenyl sulfides obtained by the reaction of the selenenic acid with 1,4-dithiols were reduced
to the corresponding selenol by treatment with a tertiary amine, thus achieving the experimental demonstration of three processes included
in the catalytic cycle of glutathione peroxidase.
Selenenic acids (RSeOH) have been well-recognized as
important intermediates in organic1 and biochemical2 reac-
Scheme 1
tions of selenium compounds. In the catalytic cycle of
glutathione peroxidase (GPx) shown in Scheme 1, a selenenic
acid intermediate is considered to be formed by oxidation
† Present address: Department of Chemical and Biological Sciences,
Faculty of Science, Japan Women’s University, 2-8-1 Mejirodai, Bunkyo-
ku, Tokyo 112-8681, Japan. E-mail: okazaki@jwu.ac.jp. Fax: +81-3-5981-
3664.
(1) For reviews, see: (a) The Chemistry of Organic Selenium and
Tellurium Compounds; Patai, S., Rappoport, Z., Eds.; John Wiley & Sons:
New York, 1986, 1987; Vols. 1, 2. (b) Organoselenium Chemistry; Liotta,
D., Ed.; John Wiley & Sons: New York, 1987. (c) Magnus, P. D. In
ComprehensiVe Organic Chemistry; Jones, D. N., Ed.; Pergamon Press:
Oxford, 1979; Vol. 3, p 491-538.
(2) (a) Ganter, H. E. Chem. Scripta 1975, 8a, 79. (b) Flohe´, L. In Free
Radicals in Biology; Pryor, W. A., Ed.; Academic Press: New York, 1982;
Vol. V, Chapter 7, pp 223-254. (c) Ganter, H. E.; Kraus, R. J. In Methods
in Enzymology; Colowick, S. P., Kaplan, N. O. Eds.; Academic Press: New
York, 1984; Vol. 107, pp 593-602.
of a selenol with peroxides.2 This process, which detoxifies
the peroxides, has also been postulated to be included in the
catalytic cycle of many synthetic GPx mimics.3 However,
the evidence for this process is very circumstantial; usually
oxidation of a selenol rapidly affords the corresponding
10.1021/ol016682s CCC: $20.00 © 2001 American Chemical Society
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diselenide as a result of ready reaction of the intermediary
selenenic acid with a selenol. Furthermore, selenenic acids
are notoriously unstable because they undergo very rapid
self-condensation to form the corresponding selenoseleni-
nates. Although several selenenic acids have been observed
so far,3d,f,4-6 most of them were generated by selenoxide syn
elimination, hydrolysis of selenenates, or oxidation of
selenenyl sulfides and diselenides. Recently, we5 and others6
reported the isolation of stable selenenic acids, but they were
also prepared by thermolysis of the corresponding butyl
selenoxides. In this communication, we report the first direct
oxidative conversion of a selenol to a stable selenenic acid
and the experimental demonstration of three processes that
are considered to compose the catalytic cycle of GPx by
taking advantage of a novel bowl-type substituent 1 (denoted
as Bmt)7 developed by us (Figure 1).8
Scheme 2
treatment with elemental selenium afforded tetraselenide 3
as the main product, which was reduced to selenol 4 by
LiAlH4. When selenol 4 was treated with an equimolar
amount of H2O2 in THF, selenenic acid 5 was obtained as a
major product (Scheme 3). In this reaction, only a small
Scheme 3
amount of diselenide 6 was formed. Selenenic acid 5 was
isolated by silica gel chromatography in 77% yield as stable
1
pale yellow crystals.9 The H NMR spectrum (CDCl3) of 5
showed the signal of the hydroxyl proton at δ 1.25 (readily
exchangeable with D2O), and in the 77Se NMR (CDCl3) a
signal was observed at δ 1079. The structure of 5 was finally
established by X-ray crystallographic analysis.10 It was
revealed that there are two discrete molecules of 5 and two
hexane molecules in the unit cell. Figure 2 shows the ORTEP
drawing of one fragment of these selenenic acids. The Se-O
Figure 1. Novel bowl-type substituent.
We previously reported the synthesis of a stable sulfenic
acid (RSOH) by direct oxidation of a thiol bearing the Bmt
group.7b The bowl-shaped structure of the Bmt group was
found to effectively prevent the disulfide formation as well
as the self-condensation of the sulfenic acid. Similar steric
effects are also expected for the selenium derivatives. Selenol
4 bearing a Bmt group was readily prepared by the reactions
shown in Scheme 2. Lithiation of bromide 2 followed by
(3) For examples, see: (a) House, K. L.; Dunlap, R. B.; Odom, J. D.;
Wu, Z.-P.; Hilvert, D. J. Am. Chem. Soc. 1992, 114, 8573-8579. (b)
Engman, L.; Stern, D.; Cotgreave, I. A.; Andersson, C. M. J. Am. Chem.
Soc. 1992, 114, 9737-9743. (c) Engman, L.; Andersson, C.; Morgenstern,
R.; Cotgreave, I. A.; Andersson, C.-M.; Hallberg, A. Tetrahedron 1994,
50, 2929-2938. (d) Iwaoka, M.; Tomoda, S. J. Am. Chem. Soc. 1994, 116,
2557-2561. (e) Back, T. G.; Dyck, B. P. J. Am. Chem. Soc. 1997, 119,
2079-2083. (f) Mugesh, G.; Panda, A.; Singh, H. B.; Punekar, N. S.;
Butcher, R. J. J. Am. Chem. Soc. 2001, 123, 839-850.
(4) (a) Reich, H. J.; Hoeger, C. A.; Willis, W. W., Jr. J. Am. Chem. Soc.
1982, 104, 2936-2937. (b) Reich, H. J.; Hoeger, C. A.; Willis, W. W., Jr.
Tetrahedron 1985, 41, 4771-4779 and references therein. (c) Reich, H. J.;
Jasperse, C. P. J. Org. Chem. 1988, 53, 2389-2390.
(5) Saiki, T.; Goto, K.; Okazaki, R. Angew. Chem., Int. Ed. Engl. 1997,
36, 2223-2224.
(6) Ishii, A.; Matsubayashi, S.; Takahashi, T.; Nakayama J. J. Org. Chem.
1999, 64, 1084-1085.
(7) (a) Goto, K.; Holler, M.; Okazaki, R. Tetrahedron Lett. 1996, 37,
3141-3144. (b) Goto, K.; Holler, M.; Okazaki, R. J. Am. Chem. Soc. 1997,
119, 1460-1461. (c) Goto, K.; Okazaki, R. Liebigs Ann./Recueil 1997,
2393-2407. (d) Goto, K.; Holler, M.; Okazaki, R. Chem. Commun. 1998,
1915-1916. (e) Tan, B.; Goto, K.; Kobayashi, J.; Okazaki, R. Chem. Lett.
1998, 981-982. (f) Goto, K.; Kobayashi, J.; Okazaki, R. Organometallics
1999, 18, 1357-1359.
(8) A part of this work has been presented in the 8th International
Conference on the Chemistry of Selenium and Tellurium, Sa˜o Paulo, Brazil,
Aug 6-11, 2000 (PS-59).
Figure 2. ORTEP drawing of BmtSeOH (5) with thermal ellipsoid
plot (30% probability). Selected bond lengths (Å), bond angle (deg),
and torsion angle (deg): Se(1)-O(1), 1.808(3); Se(1)-C(1),
1.914(3); O(1)-Se(1)-C(1), 96.80(12); O(1)-Se(1)-C(1)-C(2),
61.8(2).
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Org. Lett., Vol. 3, No. 22, 2001

bond length of this fragment is 1.808(3) Å, clearly indicating
the single-bond character of this bond. As for the other
fragment, unfortunately, the disordering of the oxygen atom
has made it difficult to discuss the detailed structural
parameters of the SeOH moiety. In both fragments, two rigid
m-terphenyl units surround the SeOH group like a brim of a
bowl, thus preventing the self-condensation of the selenenic
acid. During oxidation of selenol 4, this bowl-shaped
framework is considered to suppress the reaction of the
initially formed selenenic acid 5 with the second molecule
of 4 to yield diselenide 6. Selenenic acid 5 showed
remarkable stability, and no decomposition was observed
even after heating at 80 °C for 1 d in toluene-d8.
In fact, when the mixture of selenol 4 and dibutyl disulfide
was allowed to stand in the presence of triethylamine for 8
d in CDCl3, selenol 4 disappeared completely and selenenyl
sulfide 8a was obtained (Scheme 6). For enhancement of
Scheme 6
the selenol formation, 1,4-butanedithiol was employed, which
affords a thermodynamically stable cyclic disulfide upon
oxidation. Reaction of selenenic acid 5 with an excess of
1,4-butanedithiol afforded selenenyl sulfide 8d (Scheme 7).
Selenenic acid 5 was further oxidized to seleninic acid 7
quantitatively by treatment with m-CPBA (Scheme 4). The
Scheme 4
Scheme 7
reactions of 5 with several kinds of thiols proceeded at room
temperature to afford the corresponding selenenyl sulfides
8a-c (Scheme 4). Reduction of selenenyl sulfides 8a-c to
selenol 4 by treatment with a thiol was then examined.
Treatment of 8a-c with an excess amount of thiols in the
presence of triethylamine, however, resulted in the thiol
exchange on the selenium atom almost exclusively with the
formation of a trace amount of selenol 4 (Scheme 5). These
When 8d was treated with triethylamine, elimination of 1,2-
dithiane took place and selenol 4 was obtained in a good
yield. Use of dithiothreitol (DTT) as a 1,4-dithiol similarly
reduced 5 to 4. In the reaction of 5 with an excess of DTT,
the quantitative formation of selenenyl sulfide 8e was
Scheme 5
1
confirmed by H NMR, which was further treated with
triethylamine without isolation to give selenol 4. These results
are consistent with the report that the peroxidase activity of
ebselen was improved when dithiols were used as a substrate
instead of glutathione.12
In summary, the synthesis of a stable selenenic acid by
direct oxidation of a selenol was achieved for the first time
(10) Crystal data for 5‚C6H14: C62H72OSe, FW ) 912.16, triclinic, space
group P-1, a ) 15.3560(6) Å, b ) 18.9830(5) Å, c ) 19.3350(8) Å, R )
87.445(2)°, â ) 78.993(2)°, γ ) 66.908(2)°, V ) 5086.4(3) Å3, Z ) 4,
Dcalcd ) 1.191 g/cm3, µ ) 7.79 cm-1. The intensity data were collected at
150 K on a MAC Science DIP-2030 imaging plate area detector with Mo
KR radiation (λ ) 0.71069 Å); 17779 independent reflections. The structure
was solved by direct methods and refined by a full-matrix least-squares on
F2 using SHELXL 97.11 R1 (I > 2σ(I)) ) 0.0545, wR2 ) 0.1552 (all data)
for 1330 parameters.
(11) Sheldrick, G. M. SHELXL 97: Program for Crystal Structure
Refinement; University of Go¨ttingen: Germany, 1997.
(12) (a) Haenen, G. R. M. M.; De Rooij, B. M.; Vermeulen, N. P. E.;
Bast, A. Mol. Pharmacol. 1990, 37, 412-422. (b) Biewenga, G. Ph.; Bast.
A. Methods Enzymol. 1995, 251, 303-314.
results suggest that the equilibrium lies to the selenenyl
sulfide and the thiol rather than the selenol and the disulfide.
(9) Data for 5: pale yellow crystals, mp 198-202 °C; 1H NMR (500
MHz, CDCl3) δ 1.00 (s, 9H), 1.25 (s, 1H), 1.94 (s, 24H), 3.82 (s, 4H), 6.55
(s, 2H), 6.79 (br, 8H), 6.94 (t, J ) 7.5 Hz, 4H), 7.03 (d, J ) 7.5 Hz, 4H),
7.32 (t, J ) 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.0 (q), 31.0 (q),
34.6 (s), 37.2 (t), 123.9 (d), 126.5 (d), 126.8 (d), 127.1 (d), 129.0 (d), 136.4
(s), 138.5 (s), 138.8 (s), 141.0 (s), 141.6 (s), 143.6 (s), 150.8 (s); 77Se NMR
(95 MHz, CDCl3, Me2Se) δ 1079; IR (CH2Cl2) 3502 cm-1 (νOH); HRMS-
(FAB) m/z obsd 826.3682, calcd for C56H58OSe 826. 3653. Anal. Calcd
for C56H58OSe: C, 81.43; H, 7.08; Se, 9.56. Found: C, 81.39; H, 7.08; Se,
9.14.
Org. Lett., Vol. 3, No. 22, 2001
3571

by taking advantage of a novel bowl-type substituent. The
selenenic acid was reduced to the parent selenol via the
selenenyl sulfides by the reaction with 1,4-dithiols and
subsequent treatment with amine. These results present the
conclusive experimental demonstration of the interconversion
among the three species.
Technology, Japan, and the Sumitomo Foundation (K.G.).
We also thank Tosoh Finechem Corporation for a generous
gift of alkyllithiums.
Supporting Information Available: Experimental pro-
cedure for the preparation of 5, physical and analytical data
for 4-7 and 8a,d, and crystallographic data for 5. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research (no. 10740297 (K.G.))
from the Ministry of Education, Culture, Sports, Science and
OL016682S
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Org. Lett., Vol. 3, No. 22, 2001