Polymer-supported selenium reagents for organic synthesis

Article abstract of DOI:10.1039/a804795b

Organoselenium resins 1-4 were prepared from polystyrene via lithiation and quenching with MeSeSeMe, and shown to react with a variety of substrates, aiding in useful functionalizations.

Full text of DOI:10.1039/a804795b

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Polymer-supported selenium reagents for organic synthesis
K. C. Nicolaou,*† Joaquín Pastor, Sofia Barluenga and Nicolas Winssinger
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey
Pines Road, La Jolla, California 92037, USA
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093,
USA
Organoselenium resins 1–4 were prepared from polystyrene
via lithiation and quenching with MeSeSeMe, and shown to
react with a variety of substrates, aiding in useful func-
tionalizations.
O
Se
O
i
Br
OEt
OEt
6
6
5
6
Combinatorial chemistry and solid phase synthesis have
recently emerged as powerful tools for the drug discovery
process.1 The latter technique is particularly useful for combi-
natorial library construction due to its adaptability to the
powerful and elegant split-pool methods2 and because of the
well recognized purification advantages associated with it. The
utilization of polymer-bound reagents,3 in particular, has gained
popularity due to the non-requirement for tethering the substrate
to the polymer. Here we describe the preparation of a series of
solid-supported selenium resins4,5 2–4 (Scheme 1) and their
application as linkers and reagents for solid phase synthesis. A
distinct advantage of the new reagents is the convenience of
handling and their totally odorless nature as compared to the
non-bound reagents, whose toxicity and foul smell is often
problematic.
ii
H
CO2Me
iii
O
OH
CO2Me
HO
HO
OH
OH
7
8
OH
O
Scheme 1 summarizes the preparation of the new resins 2–4
from readily available starting materials. Thus, polystyrene
beads suspended in cyclohexane were treated with BunLi–
TMEDA6 and the lithiated species was quenched with MeSe-
SeMe,7 furnishing selenium reagent 1 as a pale yellow resin (the
loading of selenium was controlled by addition of MeSeSeMe
in substoichiometric amounts to the lithiated polystyrene).
Exposure of 1 to bromine resulted in quantitative conversion8 to
the polymer-supported selenenyl bromide 2, which was isolated
after filtration and washing as a deep red resin. The selenium
OEt
OEt
O
6
10
iv,v
OEt
+
6
O
9
6
11
OH
OH
vi,vii
12
13
i
SeMe
viii
1
OTBDPS
I
OTBDPS
Se
Polystyrene
15
14
ii
ix
iv
OTBDPS
OTBDPS
SeLi
SeBr
16
4
2
O
x
iii
17
Se
N
Scheme 2 Reagents and conditions: i, 2 (1 equiv.), CH2Cl2, 23 °C, 30 min;
ii, Bun3SnH (4 equiv.), AIBN (0.01 equiv.), PhMe, 110 °C, 6 h, 92% (2
steps); iii, 2 (1.5 equiv), THF, 278 °C, 30 min, then H2O2 (30%, 2 equiv.),
278 ? 23 °C, 20 h, 94% (2 steps); iv, 3 (0.5 equiv.), H2O (1 equiv.), CSA
(0.05 equiv.), CH2Cl2, 24 h; v, Bun3SnH (2 equiv.), AIBN (0.005 equiv.),
PhMe, 110 °C, 6 h, 82% (2 steps), 10:11 = 2:1; vi, 3 (0.5 equiv.), H2O (1
equiv.), CSA (0.05 equiv.), CH2Cl2, 24 h; vii, Bun3SnH (2 equiv.), AIBN
(0.005 equiv.), PhMe, 110 °C, 6 h, 80% (two steps); viii, 4 (0.5 equiv.),
THF, 23 °C, 12 h; ix, Bun3SnH (2 equiv.), AIBN (0.005 equiv.), PhMe,
110 °C, 6 h, 89% (2 steps); x, H2O2 (30%, 1 equiv), THF, 23 °C, 12 h, 78%
(2 steps)
O
3
Scheme 1 Reagents and conditions: i, BunLi (2.5
M in hexanes, 24 equiv.),
TMEDA, cyclohexane, 65 °C, 4 h, then filtration and washing with THF,
then dimethyl diselenide (2.0 mmol g21 of polystyrene), THF, 0 °C, 30 min,
100%; ii, Br2 (0.9 equiv.), CHCl3, 0 °C, 10 min, 100% (based on
consumption of Br2), then filtration and washing, then EtOH, 70 °C, 1 h,
> 95%; iii, potassium phthalimide (1.5 equiv.), 18-crown-6 (1.5 equiv.),
benzene, 23 °C, 5 h, > 95% yield; iv, LiBH4 (2.0
THF, 23 °C, 1 h, > 95%
M in THF, 2.0 equiv.),
Chem. Commun., 1998
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Table 1 Polymer-bound selenium promoted synthesis of 2-deoxyglyco-
Table 1 summarizes applications of polymer-bound selenium
bromide 2 and selenium phthalimide11 3 to the synthesis of
2-deoxyglycosides.12 Most noteworthy is the inverse glycosida-
tion stereoselectivity obtained under different reaction condi-
tions. Thus, glycosidation of tri-O-benzylglucal 18 with BnOH
using the polymer-bound selenenyl bromide reagent 2 (X = Br)
sidesa
O
O
OR
(i)
SeX, ROH
BnO
BnO
BnO
BnO
(ii) Bun3SnH, AlBN
OBn
OBn
followed by Bun SnH–AIBN (cat.) cleavage of the newly
3
formed selenium–carbon bond released the 2-deoxy glycosyl-
ated product 19 in 86% yield with 5:1 selectivity in favor of the
a-anomer (entry 3), whereas the same transformation carried
out with the polymer-bound selenenyl phthalimide reagent 2
yielded the product in 72% with a 5:1 selectivity in favor of the
b-anomer (entry 5).
18
19
Ratio
t/h Yield (%) a:b
Entry
ROH
Reagent Solvent
1
2
3
BnOH
BnOH
BnOH
2
2
2
CH2Cl2
PhMe
24 87
24 96
MeCN–CH2Cl2 24 86
(2:1)
48 68
48 72
MeCN–CH2Cl2 48 23
(2:1)
2 :1
2:1
5:1
In conclusion, we have successfully prepared a series of
polymer-bound selenium reagents/linkers and demonstrated a
number of their uses in organic synthesis. These reagents should
find useful applications in solid phase and combinatorial
synthesis due to their versatility and ease of handling.
We thank Drs Dee H. Huang and Gary Siuzdak for NMR and
mass spectroscopic assistance, respectively. This work was
financially supported by the Skaggs Institute for Chemical
Biology, the National Institutes of Health, USA, and grants
from Novartis, Amgen, Pfizer, Merck, DuPont-Merck, Hoff-
mann LaRoche and Schering-Plough.
4
5
6
BnOH
BnOH
BnOH
3
3
3
CH2Cl2
PhMe
1:5
1:5
1:1
O
OMe
HO
7
2
MeCN–CH2Cl2 24 61
(2:1)
8:1
BnO
OBn
OMe
OBn
OBn
O
HO
8
3
2
PhMe
48 45
1:1
BnO
OBn
O
Notes and References
O
O
O
9
MeCN–CH2Cl2 96 50
(2:1)
20:1
† E-mail: kcn@scripps.edu
O
HO
1 For selected reviews, see: F. Balkenhohl, C. von dem Brussche-
Hünnefleld, A. Lansky and C. Zechel, Angew. Chem., Int. Ed. Engl,,
1996, 35, 2288; L. A. Thompson and J. A. Ellman, Chem. Rev., 1996,
96, 555; M. A. Gallop, R. W. Barret, W. J. Dower, S. P. Foder and E. M.
Gorden, J. Med. Chem., 1994, 37, 1233; E. M. Gorden, R. W. Barret,
W. J. Dower, S. P. Foder and M. A. Gallop, J. Med. Chem., 1994, 37,
1385; W. H. Moos, G. D. Green and M. R. Pavia, Annu. Rep. Med.
Chem., 1993, 28, 315.
a
All reactions were carried out under an atmosphere of argon in the
presence of 4 Å molecular sieves. Reagents and conditions: i, (for reagent
2) ROH (1 equiv.), 2,6-di-tert-butyl-4-methylpyridine (1 equiv.), 2 (0.5
equiv.); (for reagent 3) ROH (1 equiv.), CSA (1 equiv.) and 3 (0.5 equiv.);
solvent and time as shown in Table; ii, Bun3SnH (2 equiv.), AIBN (0.005
equiv.), PhMe, 110 °C, 8 h.
2 For general references, see: J. J. Baldwin and I. Henderson, in Synthesis
of Encoded Small Molecule Combinatorial Libraries, ed. J. P. Delvin,
Dekker, New York, NY, 1997; A. W. Czarnick, Curr. Opin. Chem.
Biol., 1997, 1, 60; X. Y. Xiao, C. Zhao, H. Potash and M. P. Nova,
Angew. Chem., Int. Ed. Engl., 1997, 37, 780; P. A. Tempest and R. W.
Armstrong, J Am. Chem. Soc., 1997, 119, 7607.
3 S. W. Kaldor and M. G. Siegel, Curr. Opin. Chem. Biol., 1997, 1,
101.
4 For reviews of the use of organoselenium reagents in organic synthesis
see: K. C. Nicolaou and N. A. Petasis, Selenium in Natural Product
Synthesis, CIS Inc, Philadelphia, PA, 1984; D. Liotta, Organoselenium
Chemistry, Wiley, NY, 1986.
5 To the best of our knowledge, this constitutes the first report of the
polymer-bound reagents presented herein. For previous preparation of
polymer bound selenophenol, phenylselenium chloride and diphenyl
selenoxide by copolymerization of 4-vinylselenophenol with div-
inylbenzene, see: R. Michels, M. Kato and W. Heitz, Makromol. Chem.,
1976, 177, 2311.
6 M. J. Farrall and M. J. Fréchet, J. Org. Chem., 1976, 41, 3877.
7 For an example of a related reaction, see: C. Lambert, M. Hilbert, L.
Christiaens and N. Dereu, Synth. Commun., 1991, 21, 85.
8 L. Laitem, P. Thibaut and L. Christians, J. Heterocycl. Chem., 1976, 13,
469.
9 K. C. Nicolaou, D. A. Claremon, W. E. Barnette and S. P. Seitz, J. Am.
Chem. Soc., 1979, 101, 3704.
10 K. C. Nicolaou, W. E. Barnette and R. L. Magolda, J. Am. Chem. Soc.,
1981, 103, 3480.
11 To the best of our knowledge, this is the first example of selenium
phthalimide promoted glycosidation.
12 For previous examples of selenium mediated glycosidations, see: G.
Jaurand, J.-M. Beau and P. Sinay, Chem. Commun., 1981, 572; M. Peres
and J.-M. Beau, Tetrahedron Lett., 1989, 30, 75; F. Calvani, P. Crotti,
C. Gardelli and M. Pineschi, Tetrahedron Lett., 1994, 50, 12 999; W. R.
Roush and X.-F. Lin, J. Am. Chem. Soc., 1995, 117, 2236.
phthalimide reagent 3 was obtained as a yellow resin from 2 by
displacement with potassium phthalimide in the presence of
18-crown-6 ( > 95% yield),9 while the lithium selenide 4 (a pale
yellow resin) was prepared by LiBH4 reduction of 2 (95%
yield). All new reagents appeared to be quite stable in the air at
ambient temperature (inert atmosphere is recommended, how-
ever, for their storage and use).
Scheme 2 displays chemistry demonstrating the use of resins
2–4 both as solid phase linkers and polymer-bound reagents.
Thus, olefin 5 was quantitatively loaded onto the polymer by
treatment with the polymer-bound selenium bromide resin 2
and, subsequently, released reductively under the influence of
Bun SnH–AIBN (cat.) to recover the starting olefin 5 in 92%
3
overall yield. The polymer-bound selenium bromide 2 was also
shown to be as effective as phenylselenium bromide for the
known two-step transformation10 of PGF2a methyl ester 7 to the
PGI2 analogues 8 (94% yield, ca. 2:1 ratio of C-6 epimers,
Scheme 2). Hydration of an olefin was demonstrated to proceed
smoothly with the selenium phthalimide resin 3.9 Thus, terminal
olefin 9 was converted to the regioisomeric alcohols 10 and 11
in 82% overall yield (10:11 ca. 2:1 ratio) by the action of
reagent 3 and CSA in the presence of H2O, followed by
reductive cleavage from the solid support with Bun SnH–
3
AIBN. Furthermore, cyclic olefin 12 was converted to alcohol
13 in 80% overall yield by the same two-step procedure. The
use of the resin 4 was demonstrated as follows. Alkyl iodide 14
was efficiently loaded onto the polymer through mild alkylation
conditions in THF. The substrate was then released from the
polymer (15) by either free radical chemistry to obtain the
corresponding alkyl compound 16 (89% overall yield) or
oxidative conditions leading to olefinic product 17 (78% overall
yield).
Received in Corvallis, OR, USA, 23rd June 1998; 8/04795B
1948
Chem. Commun., 1998