Novel polymer-bound chiral selenium electrophiles

Article abstract of DOI:10.1021/ol0164435

(equation presented) Polymer-bound chiral electrophilic selenium reagents have been developed and applied to stereoselective selenenylation reactions of various alkenes. Different cleavage protocols allow further functionalization of the addition products

Full text of DOI:10.1021/ol0164435

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2931-2933
Novel Polymer-Bound Chiral Selenium
Electrophiles
Lars Uehlin and Thomas Wirth*
Department of Chemistry, Cardiff UniVersity, PO Box 912,
Cardiff CF10 3TB, United Kingdom
wirth@cf.ac.uk
Received July 16, 2001
ABSTRACT
Polymer-bound chiral electrophilic selenium reagents have been developed and applied to stereoselective selenenylation reactions of various
alkenes. Different cleavage protocols allow further functionalization of the addition products leading to improvements in selenium-based
solid-phase chemistry.
Polymer-supported reagents have attracted growing interest
because they can provide attractive and practical methods
for combinatorial chemistry and solid-phase synthesis.1 The
demand of a fast access to complex structures has led to a
large improvement of this methodology during the past years.
Although polymers with selenium functionalities have been
known for a long time,2 there is a high interest in this kind
of solid-phase organic chemistry. Recently, selenium-based
approaches for solid-phase chemistry have been reported
from different research groups.3 New linking strategies with
various loading and cleavage protocols now make use of the
selenium moiety for further functionalizations of the product
molecules. The development of chiral selenium electrophiles
has already established a very efficient tool for the highly
stereoselective synthesis of various molecules.4 We have
already reported first applications of this chemistry to solid-
phase synthesis3l and describe herein more efficient polymer-
bound reagents leading to further improvements in selenium-
based solid-phase chemistry.
It is known that the counterion of the selenium electrophile
plays an important but still not well understood role in the
addition reactions. Our solution-phase studies revealed that
chiral selenenyltriflates lead to highest selectivities and
yields.5 Their preparation is, however, accompanied with the
formation of colloidal silverbromide, and if applied to the
polymer-bound reagents, they were found to be no longer
reactive in subsequent reactions with alkenes. Therefore, it
(3) (a) Ruhland, T.; Andersen, K.; Pedersen, H. J. Org. Chem. 1998,
63, 9204-9211. (b) Yanada, K.; Fujita, T.; Yanada, R. Synlett 1998, 971-
972. (c) Nicolaou, K. C.; Pastor, J.; Barluenga, S.; Winssinger, N. Chem.
Commun. 1998, 1947-1948. (d) Fujita, K.; Watanabe, K.; Oishi, A.; Ikeda,
Y.; Taguchi, Y. Synlett 1999, 1760-1762. (e) Nicolaou, K. C.; Pfefferkorn,
J. A.; Cao, G.; Kim, S.; Kessabi, J. Org. Lett. 1999, 1, 807-810. (f)
Nicolaou, K. C.; Roecker, A. J.; Pfefferkorn, J. A.; Cao, G. J. Am. Chem.
Soc. 2000, 122, 2966-2967. (g) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao,
G. Angew. Chem. 2000, 112, 750-755; Angew. Chem., Int. Ed. 2000, 39,
734-739. (h) Nicolaou, K. C.; Cao, G.; Pfefferkorn, J. A. Angew. Chem.
2000, 112, 755-759; Angew. Chem., Int. Ed. 2000, 39, 739-743. (i)
Nicolaou, K. C.; Winssinger, N.; Hughes, R.; Smethurst, C.; Cho, S. Y.
Angew. Chem. 2000, 112, 1126-1130; Angew. Chem., Int. Ed. 2000, 39,
1084-1088. (j) Zaragoza, F. Angew. Chem. 2000, 112, 2158-2159; Angew.
Chem., Int. Ed. 2000, 39, 2077-2079. (k) Fujita, K.; Taka, H.; Oishi, A.;
Ikeda, Y.; Taguchi, Y.; Fujie, K.; Saeki, T.; Sakuma, M. Synlett 2000, 1509-
1511. (l) Uehlin, L.; Wirth, T. Chimia 2001, 55, 65-67.
(4) (a) Wirth, T. Liebigs Ann./Recueil 1997, 2189-2196. (b) Wirth, T.
Tetrahedron 1999, 55, 1-28. (c) Tiecco, M. Top. Curr. Chem. 2000, 208,
7-54. (d) Wirth, T. Angew. Chem. 2000, 112, 3890-3900; Angew. Chem.,
Int. Ed. 2000, 39, 3742-3751.
(5) (a) Wirth, T. Angew. Chem. 1995, 107, 1872-1873; Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1726-1728. (b) Wirth, T.; Fragale, G. Chem. Eur.
J. 1997, 3, 1894-1902.
(1) (a) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18-26.
(b) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A.
G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J.
Chem. Soc., Perkin Trans. 1 2000, 3815-4195.
(2) (a) Zundel, G. Angew. Chem. 1969, 81, 507-518; Angew. Chem.,
Int. Ed. Engl. 1969, 8, 499-510. (b) Kato, M.; Michels, R.; Heitz, W. J.
Polym. Sci., Polym. Lett. Ed. 1976, 14, 413-415. (c) Michels, R.; Kato,
M.; Heitz, W. Makromol. Chem. 1976, 177, 2311-2320. (d) Taylor, R. T.;
Flood, L. A. J. Org. Chem. 1983, 48, 5160-5164.
10.1021/ol0164435 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/10/2001

was first necessary to optimize the conditions for additions
with selenenylbromides in solution-phase reactions. The
unsaturated alcohol 1 has been cyclized with selenenyl-
bromides 2 leading to the products with 57% de (3a, R )
H) and 75% de (3b, R ) MOM), respectively, showing again
the advantage of a protected chiral side chain with a MOM
substituent.3l
TentaGel as a solid support was much less successful in the
subsequent selenenylation reactions. All following reactions
have been carried out with polystyrene (loading about 2
mmol/g) or with mesoporous silica (loading 0.12-0.3 mmol/
g) as the solid support. Because of the low loading of the
reagents bound to mesoporous silica, yields have not been
determined in selenenylation reactions with this reagent,
although the selectivities were found to be a little bit more
efficient than with the polystyrene-based reagent. By treating
6 with bromine at 0 °C, 7 is obtained quantitatively.
Scheme 1. Solution-Phase Selenenylations with Chiral
Various addition reactions to alkenes with the polymer-
bound selenium electrophile 7 have been performed. The
products 9 obtained after subsequent cleavage from the solid
support are summarized in Table 1. Up to 80% ee in the
Selenenyl Bromides
Table 1. Selenenylation of Different Alkenes with Reagent 7
and Subsequent Cleavage from the Solid Support Using
Different Methods
After these promising results, we prepared the correspond-
ing selenenylbromide on solid support as shown in Scheme
2. Because the cleavage of selenomethyl ethers to the
Scheme 2. Synthesis of Reagent 7 on Solid Support
corresponding selenenylbromides failed,3c,l,6 we again took
advantage of the mixed acetal moiety, which was recently
introduced by us as a very versatile precursor to generate
selenenyl bromides on solid support under mild reaction
conditions.3l Phenol 5 was prepared from 47 and attached to
either polystyrene, TentaGel, or mesoporous silica8 as a solid
support, yielding compounds of type 6. Although the
handling of mesoporous silica is simple because the material
has a rigid structure, does not swell in solvents, and can be
used at low temperatures, the loading achieved was quite
low (between 0.12 mmol/g and 0.3 mmol/g as determined
by elemental analysis).
a Major enantiomer is shown. b Yields determined by GC with an internal
standard (naphthalene); n.d., not determined. c Reaction carried out using
mesoporous silica bound reagent 7 (Et2O, -100 °C). d Reaction carried out
using polystyrene-bound reagent 7 (Et2O, -78 °C). e Allyltributyltin used
instead of tributyltin hydride for the radical cleavage reaction. f Cleavage
by oxidative elimination with hydrogen peroxide.
products can be obtained in the selenenylation reactions,
making the reagent 7 on solid support almost equally
attractive for organic synthesis as their soluble counterparts
with respect to the stereoselectivities. For ease of handling,
they are much more convenient because the workup of these
reactions is only filtration and washing of the resin. Usually
the radical cleavage of the product is performed by treating
the resin with 5 equiv of tributyltin hydride and AIBN in
refluxing benzene for 3 h (Table 1, entries 1, 3-6). Other
reactions such as radical cyclizations3f or elimination
It was shown that the reagents bound to mesoporous silica
are little superior to polystyrene, whereas the reagent with
(6) Laitem, L.; Thibaut, P.; Christians, L. J. Heterocycl. Chem. 1976,
13, 469-473.
(7) Bolton, R. E.; Moody, C. J.; Pass, M.; Rees, C. W.; Tojo, G. J. Chem.
Soc., Perkin Trans. 1 1988, 2491-2499.
(8) Several chiral reagents or catalysts have already been successfully
bound to this almost inert material: (a) Bae, S. J.; Kim, S.; Hyeon, T.;
Kim, B. M. Chem. Commun. 2000, 31-32. (b) Heckel, A.; Seebach, D.
Angew. Chem. 2000, 112, 165-167; Angew. Chem., Int. Ed. 2000, 39, 163-
165.
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Org. Lett., Vol. 3, No. 18, 2001

reactions3d,g-i can be used as alternative cleavage methods
to simultaneously functionalize the products. Using 10 equiv
of allyltributyltin instead of tributyltin hydride transfers an
allyl moiety to the product as shown in Table 1 (entry 2).
Because the tin reagents are very difficult to separate from
the quite volatile product molecules 9, a product purity was
not determined for these reactions. Cleavage by oxidative
elimination via the selenoxide leads to chiral allylic ethers
(Table 1, entry 7). The selenoxide is generated by adding
10 equiv of hydrogen peroxide in THF to the polymer and
stirring for 3 h at room temperature. The purity in this case
was determined to be >95%.
Although selenenylation of enolethers has been known for
a long time9 and is an established concept for glycosylation
in carbohydrate chemistry,10 we employed (E)-â-ethoxy-
styrene in the methoxyselenenylation, and after radical
cleavage the acetal (Table 1, entry 6), with the acetal-carbon
being the only chiral atom in the molecule, was obtained.11
The absolute stereochemistry of this compound was assigned
by reduction of an addition product obtained in a homoge-
neous reaction and comparison to a known compound as
described in the Supporting Information.
with CsF and MOMCl via the MOM-derivative 6.12 This
procedure was, however, applied successfully only for the
TentaGel-based polymer 6.
In conclusion, we have synthesized efficient chiral sele-
nium electrophiles on solid support. These reagents have
successfully been used to add to various alkenes with
reasonable stereoselectivities. They should find useful ap-
plications in solid-phase synthesis and probably also in
combinatorial chemistry as a result of their versatility and
ease of handling. In the future we would like to extend these
polymer-bound selenium-containing reagents toward natural
product synthesis, as well as toward catalytic applications
for various reactions.13
Acknowledgment. Funding was provided by the
Schweizer Nationalfonds. We thank the companies Rapp
Polymere GmbH, Tu¨bingen, and Schuller GmbH, Wertheim,
for generous donations of chemicals and the EPSRC National
Mass Spectrometry Service Centre, Swansea, for some of
the mass spectrometric data.
Supporting Information Available: Representative pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
The selenium-containing molecule is removed completely
by filtration, and the reagent can be regenerated by treatment
OL0164435
(9) Petrzilka, M. HelV. Chim. Acta 1978, 61, 2286-2289.
(10) Jaurand, G.; Beau, J.; Sinay¨, P. J. Chem. Soc.; Chem. Commun.
1981, 572-573.
(11) Uchiyama, M.; Satoh, S.; Ohta, A. Tetrahedron Lett. 2001, 42,
1559-1662.
(12) Harpp, D. N.; Gingras, M. J. Am. Chem. Soc. 1988, 110, 7737-
7745.
(13) (a) Wirth, T.; Ha¨uptli, S.; Leuenberger, M. Tetrahedron: Asymmetry
1998, 9, 547-550. (b) Nishibayashi, Y.; Uemura, S. Top. Curr. Chem. 2000,
208, 235-255.
Org. Lett., Vol. 3, No. 18, 2001
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