Stereocontrol in solid-phase radical reactions: Radical addition to oxime ether anchored to polymer support

Article abstract of DOI:10.1021/ol005771m

(Matrix presented) A high degree of stereocontrol in solid-phase radical reactions was achieved by using triethylborane and diethylzinc as a radical initiator at low reaction temperature. Alkyl radical addition to Oppolzer's camphorsultam derivatives of o

Full text of DOI:10.1021/ol005771m

ORGANIC
LETTERS
2000
Vol. 2, No. 10
1443-1445
Stereocontrol in Solid-Phase Radical
Reactions: Radical Addition to Oxime
Ether Anchored to Polymer Support
Hideto Miyabe, Chihiro Konishi, and Takeaki Naito*
Kobe Pharmaceutical UniVersity, Motoyamakita, Higashinada, Kobe 658-8558, Japan
taknaito@kobepharma-u.ac.jp
Received March 7, 2000
ABSTRACT
A high degree of stereocontrol in solid-phase radical reactions was achieved by using triethylborane and diethylzinc as a radical initiator at
low reaction temperature. Alkyl radical addition to Oppolzer’s camphorsultam derivatives of oxime ether anchored to polymer support proceeded
smoothly to give the r-amino acid derivatives with excellent diastereoselectivities.
Stereocontrol in free radical-mediated carbon-carbon bond-
forming reactions has been of great importance in organic
synthesis. In recent years, a high degree of stereocontrol in
solution-phase radical reactions has been achieved at low
reaction temperature mainly by using triethylborane as a
radical initiator.1 We have recently demonstrated that tri-
ethylborane has the potential to induce radical reactions on
solid support at below room temperature.2,3 Thus, employ-
ment of triethylborane and its related radical initiators would
facilitate the control of stereochemistry in solid-phase
reactions and allow further progress in the fields of combi-
natorial chemistry and drug discovery.4 As a part of our
program directed toward the development of solid-phase
radical reactions, we now report the results of experiments
to probe the utility of triethylborane and diethylzinc in
stereoselective solid-phase radical reactions. As shown
below, the radical addition to the chiral oxime ethers
anchored to a polymer support proceeded smoothly even at
-78 °C to give an R-amino acid derivative with excellent
diastereoselectivity.
Our recent studies showed that triethylborane has the
potential to induce solid-phase radical reactions on solid
support even at -78 °C and acts multiply as a radical
initiator, a Lewis acid, and a radical terminator.2a,5 Recently,
Ryu and Komatsu reported that diethylzinc-air system can
serve as an initiator of tin hydride-mediated radical reaction
as well as triethylborane.6-8 To test the viability of diethyl-
zinc, we first investigated the simple addition of an ethyl
(1) For reviews, see: (a) Sibi, M. P.; Porter, N. A. Acc. Chem. Res.
1999, 32, 163. (b) Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. Engl.
1998, 37, 2562. (c) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J.; Thoma,
G.; Kulicke, K. J.; Trach, F. Org. React. (N.Y.) 1996, 48, 301. (d) Curran,
D. P.; Porter, N. A.; Giese, B. In Stereochemistry of Radical Reactions:
Concepts, Guidelines, and Synthetic Applications; VCH: Weinheim, 1996.
(2) (a) Miyabe, H.; Fujishima, Y.; Naito, T. J. Org. Chem. 1999, 64,
2174. (b) Miyabe, H.; Tanaka, H.; Naito, T. Tetrahedron Lett. 1999, 40,
8387.
(3) The solid-phase radical reactions using AIBN or SmI2 as a radical
initiator have been reported. See: (a) Routledge, A.; Abell, C.; Balasubra-
manian, S. Synlett 1997, 61. (b) Du, X.; Armstrong, R. W. J. Org. Chem.
1997, 62, 5678. (c) Sibi, M. P.; Chandramouli, S. V. Tetrahedron Lett.
1997, 38, 8929. (d) Du, X.; Armstrong, R. W. Tetrahedron Lett. 1998, 39,
2281. (e) Berteina, S.; De Mesmaeker, A. Tetrahedron Lett. 1998, 39, 5759.
(f) Berteina, S.; Wendeborn, S.; De Mesmaeker, A. Synlett 1998, 1231. (g)
Watanabe, Y.; Ishikawa, S.; Takao, G.; Tour, T. Tetrahedron Lett. 1999,
40, 3411. (h) Yim, A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J. Tetrahedron
Lett. 1999, 40, 4535. (i) Caddick, S.; Hamza, D.; Wadman, S. N.
Tetrahedron Lett. 1999, 40, 7285. (j) Zhu, X.; Ganesan, A. J. Comb. Chem.
1999, 1, 157.
(4) For reviews, see: (a) Brown, R. C. D. J. Chem. Soc., Perkin Trans.
1 1998, 3293. (b) Chem. ReV. 1997, 97, 347-510 (whole issue of No. 2).
(c) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron
1997, 53, 5643.
(5) (a) Miyabe, H.; Ueda, M.; Yoshioka, N.; Naito, T. Synlett 1999, 465.
(b) Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1, 569.
(6) Ryu, I.; Araki, F.; Minakata, S.; Komatsu, M. Tetrahedron Lett. 1998,
39, 6335.
(7) For related examples, see: (a) Bertrand, M. P.; Feray, L.; Nouguier,
R.; Perfetti, P. Synlett 1999, 1148. (b) Bertrand, M. P.; Feray, L.; Nouguier,
R.; Perfetti, P. J. Org. Chem. 1999, 64, 9189. (c) Bertrand, M. P.; Feray,
L.; Nouguier, R.; Stella, L. Synlett 1998, 780.
10.1021/ol005771m CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/21/2000

radical, generated from diethylzinc and O2, to achiral oxime
ether 1 anchored to Wang resin (Scheme 1).9 To a flask
Scheme 2
Scheme 1
containing oxime ether 1 and undegassed CH2Cl2 was added
a commercially available 1.0 M solution of diethylzinc in
hexane (5.1 equiv) at -78 °C, and then the reaction mixture
was stirred at the same temperature for 15 min. As expected,
the ethylated product 3 was obtained in 89% yield after
cleavage of the resin by using TFA followed by purifica-
tion.10 Changing the temperature from -78 to 20 °C and
the replacement of CH2Cl2 with toluene as a solvent were
also effective for the reaction. It is noteworthy that diethyl-
zinc works well as an effective radical initiator for the solid-
phase radical reaction without interference of polystyrene
skeleton of the resin, and good chemical yield was observed
even at low reaction temperature.
On the basis of these results, we next investigated the
control of stereochemistry in solid-phase reactions by using
triethylborane and diethylzinc at low reaction temperature.
The auxiliary of choice was Oppolzer’s camphorsultam since
it had shown good characteristics in our previous work on
solution-phase radical reactions.5b,8 Additionally, we also
expected that the direct comparison of the solid-phase radical
reactions with the solution-phase radical reactions would lead
to informative and instructive suggestions regarding stereo-
selection in solid-phase radical reaction. Preparation of chiral
oxime ethers 8 and 9 anchored to a polymer support is shown
in Scheme 2. Mesylation of the tert-butyldimethylsilylated
p-xylylene glycol derivative 4 in the presence of triethyl-
amine in CH2Cl2 followed by treatment with N-hydroxy-
phthalimide in one pot afforded the desired imide 5 in 79%
yield.11 One-pot preparation of oxime ether 6 was achieved
by treatment of imide 5 with hydrazine monohydrate in
MeOH and subsequent condensation with 2-hydroxy-2-
methoxyacetic acid methyl ester.12 Treatment of oxime ether
6 with (1R)-(+)-2,10-camphorsultam in the presence of
trimethyl aluminum in boiling dichloroethane gave oxime
ether having sultam as a single E isomer, which was then
treated with pyridinium p-toluenesulfonate in EtOH at 60
°C to give deprotected alcohol 7 in 89% yield from 6. The
alcohol 7 could be attached to carboxypolystyrene resin by
the treatment with DCC in the presence of DMAP in CH2Cl2
at 20 °C for 12 h to give the resin-bound oxime ether 8.13
The loading level of the resin-bound glyoxylic oxime ether
8 was determined to be 0.77 mmol/g by quantification of
nitrogen by elemental analysis. Treatment of alcohol 7 with
glutaric anhydride gave carboxylic acid in 99% yield, which
was then attached to Wang resin according to the similar
reaction method to give the resin-bound glyoxylic oxime
ether 9 in 0.83 mmol/g loading level.
(8) For our related example, see: (a) Miyabe, H.; Ushiro, C.; Naito, T.
Chem. Commun. 1997, 1789. (b) Miyabe, H.; Ushiro, C.; Ueda, M.;
Yamakawa, K.; Naito, T. J. Org. Chem. 2000, 65, 176.
(9) Oxime ether 1 was readily prepared from glyoxylic oxime ether
(HO2CCHdNOBn) and Wang resin. See ref 2a.
(10) Purification was accomplished by a combination of Amberlite IR-
120B (eluting with MeOH) and the preparative TLC (MeOH/CHCl3, 1:10,
v/v).
(11) Diether, R. K.; Datar, R. Can. J. Chem. 1993, 71, 814.
(12) Moody, C. J.; Gallagher, P. T.; Lightfoot, A. P.; Slawin, A. M. Z.
J. Org. Chem. 1999, 64, 4419.
(13) Carboxypolystyrene and Wang resins purchased from Novabiochem
were used in all experiments.
We first investigated the simple addition of an ethyl
radical, generated from triethylborane and O2, to the car-
boxypolystyrene resin-bound oxime ether 8 in CH2Cl2 at -78
°C (Scheme 3). Although the radical reaction might proceed
smoothly, the difficulty in achieving the subsequent cleavage
1444
Org. Lett., Vol. 2, No. 10, 2000

support.8 The absolute configuration of the major product
1
was assigned to be R since their H NMR data showed
Scheme 3
similarity with that of major product in the solution-phase
radical reaction showed in our recent report.8 Purification
of the resulting R-amino acid derivative was accomplished
by preparative TLC (hexane/AcOEt 2:3, v/v) to afford the
free amino acid derivative 11a in 74% isolated yield (entry
1). Diethylzinc could also be utilized to achieve a high degree
of stereocontrol in solid-phase radical reaction of 9 to afford
the ethylated product 11a in 67% isolated yield with excellent
diastereoselectivity (entry 2).
To test the generality of the solid-phase radical reaction
of 9, we next investigated the reaction using different radical
precursors under the iodine atom-transfer reaction condi-
tions.16 However, the reactivity of oxime ether anchored to
polymer support was quite different from that of oxime ethers
in solution-phase reactions. General reaction procedures
established in the solution-phase radical reactions did not
give the good results.8b In the case of the solid-phase addition
of isopropyl radical to 9 using triethylborane, the addition
of ethyl radical, generated from triethylborane, competed
with the iodine atom-transfer process to give a large amount
of the ethylated product 11a and a small amount of the
isopropylated product 11b.5a,7b Selective formation of the
desired isopropylated product 11b was observed in the
reaction using triethylborane in i-PrI/toluene (4:1, v/v) at 0
°C (entry 3). After purification by preparative TLC, the
isopropylated product 11b was obtained in 69% isolated yield
with good diastereoselectivity. Additionally, in the solid-
phase reactions, the often tedious workup to remove excess
reagents from reaction mixture was eliminated by washing
the resin with solvents. The addition of a bulky cyclohexyl
radical proceeded in slightly lower chemical efficiency under
the same reaction conditions to give the cyclohexylated
product 11c, obtained in 58% isolated yield (entry 4).
Diethylzinc worked well under similar reaction conditions
to give the alkylated products with good selectivity (entries
5 and 6).
of the resin has remained unresolved; thus, a trace amount
of the ethylated product 10 was only isolated.14 We next
investigated the ethyl radical addition to Wang resin-bound
oxime ether 9 in CH2Cl2 (Table 1). Triethylborane and
Table 1. Solid-Phase Radical Addition to 9
entry
initiator
R
product
% yielda
selectivity
1b
2b
3c
4c
5c
6c
Et3B
Et2Zn
Et3B
Et3B
Et2Zn
Et2Zn
Et
Et
i-Pr
c-Hexyl
i-Pr
c-Hexyl
11a
11a
11b
11c
11b
11c
74
67
69
58
53
41
>95% de
>95% de
92% de
92% de
90% de
90% de
a Isolated yields of major diastereomer 11a-c. b Reactions were carried
out with Et3B or Et2Zn (5.0 equiv) in CH2Cl2 at -78 °C. c Reactions were
carried out with Et3B or Et2Zn (10 equiv) in i-PrI/toluene (4:1, v/v) at 0
°C.
In conclusion, we have demonstrated that triethylborane
and diethylzinc can be applied to the stereoselective solid-
phase radical reactions.
diethylzinc worked well as an effective radical initiator at
-78 °C for the solid-phase radical reaction of oxime ether
9. To a flask containing oxime ether 9 and undegassed
CH2Cl2 was added a commercially available 1.0 M solution
of triethylborane in hexane, and then the reaction mixture
was stirred at -78 °C for 30 min. The resin was then filtered
and washed successively with CH2Cl2 and AcOEt, and the
subsequent cleavage of the resin with TFA/CH2Cl2 (1:5, v/v)
gave the crude ethylated R-amino acid derivative as a TFA
salt. The diastereomeric purity was found to be not less than
95% de.15 The diastereoselectivity of solid-phase radical
reaction was better than that obtained by solution-phase
radical reaction shown in our recent report, probably due to
lower reactivity of oxime ether anchored to a polymer
Acknowledgment. We thank the Ministry of Education,
Science, Sports and Culture of Japan and the Science
Research Promotion Fund of the Japan Private School
Promotion Foundation for research grants. Partial support
for this work was also provided to H.M. by the Nissan
Chemical Industries Award in Synthetic Organic Chemistry,
Japan. H.M. gratefully acknowledges the financial support
from Takeda Science Foundation, Japan.
Supporting Information Available: General experimen-
tal procedures and characterization data for all obtained
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL005771M
(14) The screening of several methods for the cleavage of the resin under
the basic reaction conditions did not show good results because of the
competitive reactions such as removal of the sultam and the formation of
unidentified products.
(16) Bertrand’s group and our group have reported that the solution-
phase radical addition to imino groups proceeded in the absence of Bu3SnH
by using Et3B or Et2Zn. In this reaction, Et3B and Et2Zn act multiply as a
Lewis acid, a radical initiator, and a terminator. See refs 5, 7, and 8.
1
(15) Diastereoselectivities were determined by H NMR analysis.
Org. Lett., Vol. 2, No. 10, 2000
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