Efficient asymmetric selenomethoxylation and selenohydroxylation of alkenes with a new sulfur containing chiral diselenide

Article abstract of DOI:10.1016/S0040-4039(00)00358-0

The synthesis of a new chiral non-racemic sulfur containing diselenide is described. The electrophilic selenium reagent, produced from this diselenide by treatment with bromine and silver triflate, has been used to effect the selenomethoxylation and the selenohydroxylation of alkenes. These addition reactions occurred with good chemical yield and with high diastereoselectivities. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00358-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3241–3245
Efficient asymmetric selenomethoxylation and
selenohydroxylation of alkenes with a new sulfur containing
chiral diselenide
Marcello Tiecco,∗ Lorenzo Testaferri, Luana Bagnoli, Francesca Marini, Andrea Temperini,
Cristina Tomassini and Claudio Santi
Istituto di Chimica Organica, Facoltà di Farmacia, Università di Perugia, I-06123-Perugia, Italy
Received 20 January 2000; accepted 28 February 2000
Abstract
The synthesis of a new chiral non-racemic sulfur containing diselenide is described. The electrophilic selenium
reagent, produced from this diselenide by treatment with bromine and silver triflate, has been used to effect
the selenomethoxylation and the selenohydroxylation of alkenes. These addition reactions occurred with good
chemical yield and with high diastereoselectivities. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; chiral diselenides; selenomethoxylation; selenohydroxylation.
Chiral non-racemic selenium compounds have been recently employed to effect successful asymmetric
syntheses. Several research groups have been deeply involved in the preparation of different types of
optically active diselenides1,2 since these are commonly used as starting materials to produce organo-
selenium reagents. Chiral electrophilic selenium reagents, which can be simply prepared in situ from
diselenides, were allowed to react with alkenes in the presence of external or internal nucleophiles
and afforded the corresponding addition or cyclization products, respectively, with moderate to high
asymmetric induction.2,3
A common characteristic of all the various chiral diselenides described in the literature is the close
proximity of an oxygen or a nitrogen atom to the selenium atom. This is exemplified in Scheme 1 by
the diselenide 1, which is one of the products prepared and investigated by Wirth.1 It has been reported
on several occasions that selenium can interact with nearby heteroatoms. In some cases, the existence
of this intramolecular interaction has been demonstrated by theoretical calculations as well as by crystal
structure determinations and by NMR spectroscopy.4,5 This interaction, which is depicted by structure
2 in Scheme 1, and which is suggested to be due to an orbital interaction between the heteroatom lone
pair and the low-lying antibonding orbital of the SeY (n-σ*SeY) will force the chiral center to come close
∗
Corresponding author. Tel: +39 075 5855100; fax: +39 075 5855116; e-mail: tiecco@unipg.it (M. Tiecco)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00358-0
tetl 16638

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to the reaction center during the addition of the selenenylating agent to the alkene and this will result
in asymmetric induction. Moreover, the same interaction should also dictate the structure of the active
selenium reagent, thus playing a fundamental role in the formation of the preferred diastereomer of the
addition products.
Scheme 1.
In all the diselenides described so far the heteroatom was either oxygen or nitrogen. We now report
the synthesis of the first sulfur containing chiral diselenide and the asymmetric addition reactions of
the corresponding electrophilic reagent to several kinds of alkenes. The structure of this diselenide 6
(Scheme 2) is very similar to those of the corresponding oxygen or nitrogen containing diselenides 1.
Diselenide 6 was synthesized from the optically active alcohol 4 (Scheme 2) which was obtained by chiral
reduction of 20-bromoacetophenone 3 with (+)-B-chlorodiisopinocampheylborane.6 The alcohol (98%
ee) was transformed into the tosylate and then treated with sodium methanethiolate to afford the sulfide
5. Metal–halogen exchange reaction with n-BuLi gave the lithiated intermediate which was treated with
selenium metal. Successive oxidative work-up gave the di-2-[(1S)-1-(methylthio)ethyl]phenyl diselenide
6, which was purified by column chromatography. Compound 6 was enantiomerically pure when it was
analyzed by proton NMR spectra in CDCl3 in the presence of (S)-(+)-1-(9-antryl)-2,2,2-trifluorethanol.
Compound 6 was transformed in situ into the selenenyl triflate 7, by treatment with bromine and AgOTf.
Scheme 2.
The efficiency of the electrophilic reagent 7 in stereoselective syntheses was tested by determining
the diastereomeric ratios obtained in the asymmetric selenomethoxylation and selenohydroxylation of
alkenes (Scheme 3) which afforded compounds 9 and 10, respectively, as a mixture of the two possible
diastereomers. These reactions occur through the intermediate formation of the seleniranium ions 8 and,
in the case of (E)-alkenes, it is the facial selectivity during the initial formation of these intermediates
that determines the diastereoselectivity of the addition process.7
Scheme 3.

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In the case of the selenomethoxylation reactions, 7 was prepared by adding bromine and then AgOTf
to the solution of 6 in methylene chloride at −78°C. An excess of the alkene dissolved in methanol was
then added and the mixture was stirred at the same temperature for the time indicated in Table 1. The
reactions of selenohydroxylation were instead carried out by preparing 7, at −78°C, in THF. An excess of
the alkene and 1 ml of water were added and the mixture was left to reach room temperature. The progress
of the reactions was monitored by TLC and/or proton NMR spectroscopy. Reaction times are indicated
in Table 1. Reaction mixtures were worked-up in the usual way and compounds 9 and 10 were purified
by column chromatography. In no case could the two diastereomers be separated. The diastereomeric
ratios were determined by proton NMR spectroscopy and, in the case of compound 10, also by GC–MS.
Chemical yields and diastereomeric ratios (d.r.) are reported in Table 1.
The results of these experiments indicate that good diastereoselectivity was obtained in every case
with the only exception being that of the selenomethoxylation of cyclohexene. The diastereomeric ratios
obtained in the selenomethoxylation of alkenes are considerably better than those obtained starting from
the diselenides of type 1 and are more or less similar to those observed with the most efficient diselenides
which have been described so far in the literature.1,2 Of particular relevance are the good results obtained
in the asymmetric selenohydroxylation reactions. The only previous example of these reactions was
reported by us8 using the camphorselenenyl sulfate, produced by oxidation of the diselenide, described by
Back et al.,9 with ammonium persulfate. The diastereomeric ratios obtained with the electrophilic reagent
7 and reported in Table 1 are considerably higher than those observed with the camphor derivative. It is
noteworthy that in these selenohydroxylation reactions a good facial selectivity is obtained by working
at room temperature. In fact, in all the other types of addition of chiral electrophilic selenium reagents to
alkenes, efficient asymmetric inductions are obtained only by working at very low temperatures.
The absolute configurations of the major isomers were established in some cases and were effected
by deselenenylation and comparison of the enantiomers thus obtained with commercial products or
with compounds described in the literature (Scheme 4). Reductive deselenenylation of 9a and 10a with
triphenyltin hydride and AIBN in refluxing benzene afforded the (−)-(S)-1110 (90%) and the (−)-(S)-
128 (78%), respectively. Oxidative elimination of 9b and 10b with hydrogen peroxide in methanol
afforded (+)-(S)-1311 (85%) and (−)-(S)-1412 (75%), respectively. Finally, the reaction of 9f with
ammonium persulfate in methanol8 gave (−)-(S)-1513 (68%). In every case the enantiomeric excess of
the deselenenylation product was in good agreement with the diastereomeric ratios reported in Table 1.
Scheme 4.
Selenocyclization reactions can also be promoted by the sulfur containing electrophilic reagent 7.
Thus, as indicated in Scheme 4, compound 16 gave the selenoetherification product 17 in 88% yield and
with a diastereomeric ratio of 93:7 and compound 18 gave the selenolactonization product 19 in 75%
yield and with a diastereomeric ratio of 89:11. In both cases 7 was prepared at −78°C and the reaction
mixture was then left to reach room temperature and stirred for 6 h.

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Table 1
Reactions of alkenes with the diselenide 6 in CH2Cl2 and MEOH at −78°C (selenomethoxylation)
and in THF and H2O at room temperature (selenohydroxylation)
The results reported in this paper greatly support the suggestion that the intramolecular non-bonded
interaction between selenium and a close heteroatom is a very important factor which is responsible for
the efficiency of the various chiral electrophilic selenium reagents in asymmetric syntheses. The present
data also suggest that the interaction of selenium with sulfur is probably more important than those with
oxygen or with nitrogen. Moreover, as already shown by Wirth et al. in the case of oxygen containing

3245
diselenides,14 a more efficient transfer of chirality can probably be obtained by introducing an appropriate
substituent in the 3 position of the diselenide 6.
Acknowledgements
Financial support from MURST, National Project ‘Stereoselezione in Sintesi Organica. Metodologie
ed Applicazioni’, the University of Perugia, Progetti di Ateneo, and CNR, Rome is gratefully acknowled-
ged.
References
1. Wirth, T. Liebigs Ann./Recueil 1997, 2189–2196.
2. Wirth, T. Tetrahedron 1999, 55, 1–28.
3. Tiecco, M. In Topics in Current Chemistry: Organoselenium Chemistry: Modern Developments in Organic Synthesis; Wirth,
T., Ed. Electrophilic selenium, selenocyclizations. Springer-Verlag: Heidelberg, 2000; pp 7–54.
4. Iwaoka, M.; Tomoda, S. J. Am. Chem. Soc. 1996, 118, 8077–8084.
5. Komatsu, H.; Iwaoka, M.; Tomoda, S. Chem. Commun. 1999, 205–206.
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