Unprecedented effects of achiral oxazolidinones on enantioselective radical-mediated conjugate additions using a chiral zinc triflate

Article abstract of DOI:10.1021/ol006927l

equation presented A role of achiral oxazolidinones to enhance the enantioselectivity in reactions of N-cinnamoyloxazolidinones with alkyl radicals promoted by a chiral Lewis acid is described. Efficient enantioselective radical-mediated conjugate additio

Full text of DOI:10.1021/ol006927l

ORGANIC
LETTERS
2001
Vol. 3, No. 2
299-302
Unprecedented Effects of Achiral
Oxazolidinones on Enantioselective
Radical-Mediated Conjugate Additions
Using a Chiral Zinc Triflate
Masatoshi Murakata,* Hideyuki Tsutsui, and Osamu Hoshino*
Faculty of Pharmaceutical Sciences, Science UniVersity of Tokyo,
Shinjuku-ku, Tokyo 162-0826, Japan
murakata@ps.kagu.sut.ac.jp
Received November 28, 2000
ABSTRACT
A role of achiral oxazolidinones to enhance the enantioselectivity in reactions of N-cinnamoyloxazolidinones with alkyl radicals promoted by
a chiral Lewis acid is described. Efficient enantioselective radical-mediated conjugate additions of N-cinnamoyloxazolidinone can be realized
by use of a chiral zinc triflate generated from a readily prepared chiral bisoxazoline and an achiral oxazolidinone. The NH moiety of achiral
oxazolidinones is found to be necessary to enhance the enantioselectivity.
Asymmetric induction in enantioselective radical reactions
by use of chiral Lewis acids has been the focus of current
investigation in synthetic organic chemistry.1 Recently,
reports on enantioselective radical-mediated conjugate ad-
ditions to N-enoyloxazolidinones catalyzed by chiral Lewis
acids generated from chiral bisoxazolines have appeared.2
Despite this impressive progress, there is no report on an
external achiral ligand to increase the enantioselectivity in
radical-mediated conjugate additions.3 We describe here the
effects of achiral oxazolidinones on the enantioselectivity
in the reactions of N-cinnamoyloxazolidinones with alkyl
radicals promoted by a chiral Lewis acid.
At first, we examined the reactions of a tert-butyl radical
to N-cinnamoyloxazolidinones 1 and 2 (Scheme 1 and Figure
Scheme 1. Enantioselective Radical-Mediated Conjugate
Additions of 1 and 2 in the Presence of Additives
(1) For recent reviews including enantioselective radical reactions, see:
(a) Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. 1998, 37, 2562-2579.
(b) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163-171.
(2) (a) Wu, J. H.; Radinov, R.; Porter, N. A. J. Am. Chem. Soc. 1995,
117, 11029-11030. (b) Sibi, M. P.; Ji, J.; Wu, J. H.; Gu¨rtler, S.; Porter, N.
A. J. Am. Chem. Soc. 1996, 118, 9200-9201. (c) Wu, J. H.; Zhang, G.;
Porter, N. A. Tetrahedron Lett. 1997, 38, 2067-2070. (d) Sibi, M. P.; Ji,
J. J. Org. Chem. 1997, 62, 3800-3801. (e) Iserloh, U.; Curran, D. P.;
Kanemasa, S. Tetrahedron: Asymmetry 1999, 10, 2417-2428. (f) Mero,
C. L.; Porter, N. A. J. Org. Chem. 2000, 65, 775-781. Other enantiose-
lective radical-mediated conjugate additions, see: (g) Urabe, H.; Yamashita,
K.; Suzuki, K.; Kobayashi, K.; Sato, F. J. Org. Chem. 1995, 60, 3576-
3577. (h) Nishida, M.; Hayashi, H.; Nishida, A.; Kawahara, N. Chem.
Commun. 1996, 579-580. (i) Sibi, M. P.; Shay, J. J.; Ji, J. Tetrahedron
Lett. 1997, 38, 5955-5958.
1). The results are shown in Table 1.4 The reaction of 1 with
tert-butyl iodide and tributyltin hydride promoted by a chiral
10.1021/ol006927l CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/16/2000

52% ee, respectively, by adding 1a and 2a at the beginning
of the reaction (entries 2 and 3). When N-cinnamoyldiphen-
yloxazolidinone (2) was used as a substrate,6 the effects of
2a were outstanding. Surprisingly, the degree of asymmetric
induction in the reaction with assistance by 2a dramatically
reached 88% ee with the opposite facial selectivity
(R configuration) (entry 5), while the reaction without 2a
gave 5 with S configuration in only 3% ee (entry 4).7
The effects of achiral oxazolidinones mentioned above are
of interest, because the zinc without external ligands has a
satisfactory coordination sphere (a six-coordination: biden-
tate ligands 2 and 3 and two OTf ligands). Thus, the influence
of various additives on the reaction of 2 were examined. The
reactions were performed using isopropyl iodide, because
the ee of the product 6 could be determined directly by HPLC
using a chiral column.8 As shown in Table 2, the reaction
Figure 1. Ligands.
Lewis acid generated from Zn(OTf)2 and 3 by use of
triethylborane as a radical initiator at -78 °C gave 4 in 88%
chemical yield,5 but the enantiomeric excess (ee) was only
9% with S configuration predominating (entry 1). After
Table 1. Enantioselective Radical-Mediated Conjugate
Additions of tert-Butyl Radical to 1 or 2 in the Presence of
Zn(OTf)2 and 3a
Table 2. Enantioselective Radical-Mediated Conjugate
Additions of Isopropyl Radical to 2 in the Presence of 3 and
Zn(OTf)2
a
entry
substrate
additive
yield (%)b
ee (%)4
config4
entry
additive
yield (%)b
ee (%)8
config8
1
2
3
4
5
1
1
1
2
2
none
1a
2a
none
2a
88
86
78
80
96
9
41
52
3
S
S
S
S
R
1
2
3
4
5
6
none
2a
9
10
11
12
72
86
74
89
95
98
32
82
13
14
28
29
S
R
S
S
S
S
88
a Stoichiometric amounts of catalysts were used (catalyst:substrate )
1:1). Zn(OTf)2:3:additive ) 1:1:1. All reactions were carried out by use of
2 equiv each of t-BuI, Bu3SnH, and Et3B for a substrate in CH2Cl2 at -78
°C. b Isolated yield.
a Stoichiometric amounts of catalysts were used (catalyst: 2 ) 1:1).
Zn(OTf)2:3:additive ) 1:1:1. All reactions were carried out by use of 2
equiv each of i-PrI, Bu3SnH, and Et3B for 2 in CH2Cl2 at -78 °C. b Isolated
yield.
several attempts, we discovered that achiral oxazolidinones
1a and 2a, which are the intermediates in the synthesis of 1
or 2, played a significant role in inducing high enantio-
selectivity. The enantioselectivities were increased to 41 and
using 2a as an additive gave the best result (entry 2: 82%
ee, R). Other additives, 9-12, did not increase the degree
of ee (13-29% ee, S). It is noted that N-methyldiphenyloxa-
zolidinone (12) as a structural analogue of 2a was not
effective (29% ee, S). These results demonstrate that the NH
moiety of oxazolidinone is responsible for high asymmetric
induction.
The difference in function between 2a and 12 in a solution
of Zn(OTf)2 led us to study the complexes spectroscopically
[1H NMR (500 MHz) spectra at -30 °C]9 (Figure 2).10 When
2 equiv of 2 was added to a CD2Cl2 solution of a 1:1:1
mixture of 3, Zn(OTf)2, and 12, the pattern of the CH2 signal
(3) For a recent review on nonchiral additives in the enantioselective
reactions, see: (a) Vogl, E. M.; Gro¨ger, H.; Shibasaki, M. Angew. Chem.,
Int. Ed. 1999, 38, 1570-1577 and references therein. For selected recent
reports on the use of achiral ligands in the enantioselective reactions
catalyzed by chiral Lewis acids, see: (b) Kobayashi, S.; Hachiya, I.; Ishitani,
H.; Araki, M. Tetrahedron Lett. 1993, 34, 4535-4538. (c) Kobayashi, S.;
Ishitani, H. J. Am. Chem. Soc. 1994, 116, 4083-4084. (d) Desimoni, G.;
Faita, G.; Righetti, P. P. Tetrahedron Lett. 1996, 37, 3027-3030. (e)
Desimoni, G.; Faita, G.; Invernizzi, A. G.; Righetti, P. Tetrahedron 1997,
53, 7671-7688. We recently reported the enantioselective radical-mediated
allylations catalyzed by chiral aluminum reagents and high enantioselec-
tivities were also obtained by use of a chiral aluminum containing Et2O,
see: (f) Murakata, M.; Jono, T.; Mizuno, Y.; Hoshino, O. J. Am. Chem.
Soc. 1997, 119, 11713-11714. (g) Murakata, M.; Jono, T.; Hoshino, O.
Tetrahedron: Asymmetry 1998, 9, 2087-2092.
(6) For substituted N-enoyloxazolidinones as substrates in enantioselective
radical reactions, N-enoyldimethyloxazolidinones are known, see ref 2b.
(7) The reaction of 2 assisted by an achiral ligand was initially carried
out by use of 2a, because employment of 2a in the reaction of 1 gave a
slightly higher ee than that of 1a (entry 2 vs 3 in Table 1) However, an
unsubstituted achiral oxazolidinone 1a was also effective: the reaction of
2 with isopropyl iodide using 1a as an additive gave 6 in 84% ee (R) with
91% yield. Although clarification of the role of C-4 substituent on achiral
(4) The ee of 4 was determined directly by HPLC using a chiral column
(Chiralcel OD). The ee of 5 was determined by a chiral HPLC analysis of
benzyl 4,4-dimethyl-3-phenylpentanoate, which was obtained by hydolysis
of 5 followed by esterification [LiOH-H2O2, 93%; (COCl)2, DMF, then
Et3N, PhCH2OH, 96%] (Chiralcel OJ). The absolute configurations of 4
and 5 were determined by chemical correlation with (S)-4,4-dimethyl-3-
phenylpentanoic acid, see: Imajo, S.; Kuritani, H.; Shingu, K.; Nakagawa,
M. J. Org. Chem. 1979, 44, 3587-3589. See the Supporting Information
for details.
1
oxazolidinone remains, the use of 2a was expected to facilitate H NMR
analysis of the zinc complexes since the CH2 signals of 2a would be simpler
than those of 1a (Figure 2).
(8) A chiral column (Chiralcel OD) was used. The absolute configuration
of 6 was determined by chemical correlation with (S)-4-methyl-3-phenyl-
pentanoic acid, see: Lardicci, L.; Salvadori, P.; Caporusso, A. M.;
Menicagli, R.; Belgodere, E. Gazz. Chim. Ital. 1972, 102, 64-84, and also
ref 2b. See the Supporting Information for details.
(5) The chiral ligand 3 {[R]25 -180.4 (c 1.1, EtOH), mp 63-64 °C
D
(Et2O-petroleum ether)} was prepared by a similar method to that described
in the literature, see: (a) Evans, D. A.; Peterson, G. S.; Johnson, J. S.;
Barnes, D. M.; Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63,
4541-4544. (b) Corey, E. J.; Imai, N.; Zhang, H.-Y. J. Am. Chem. Soc.
1991, 113, 728-729.
(9) When the measurements were carried out at -78 °C, these signals
became too broad to allow the spectra to be analyzed.
300
Org. Lett., Vol. 3, No. 2, 2001

The tight coordination of 2a to the chiral zinc triflate in
the presence of 2 permitted an efficient substoichiometric
reactions, and the ternary complex containing 2a was found
to afford radical adducts 5-8 in higher ee’s generally than
the complex without 2a.13 The results are shown in Table
3.14 The ee values were similar to those attained with a
Table 3. Enantioselective Radical-Mediated Conjugate
Additions of Radicals to 2 in the Presence of Zn(OTf) and 3a
2
chiral LA
(equiv)
yield
ee
entry R-I
additive (%)b (%)4,8,14 config4,8,14
1
2
3
4
5
6
7
8
9
i-Pr
i-Pr
i-Pr
t-Bu
c-Hex
c-Hex
c-Hex
Et
0.5
0.5
0.25
0.25
1.0
1.0
0.25
1.0
1.0
0.25
none
2a
2a
2a
none
2a
2a
none
2a
85
87
92
72
80
83
86
73
92
91
24
84
80
83
4
81
84
5
S
R
R
R
R
R
R
R
S
Figure 2. 1H NMR (500 MHz) spectra: (a) 12; (b) Zn(OTf)2-3
and 12; (c) Zn(OTf)2-3 and 12 with 2 equiv of 2; (d) 2a; (e) Zn-
(OTf)2-3 and 2a; (f) Zn(OTf)2-3 and 2a with 2.5 equiv of 2. b:
12 or 2a. O: 3. 0: 2. 4: water (contamination).
Et
Et
71
72
10
2a
S
a Stoichiometric (catalyst: 2 ) 1:1) and substoichiometric (catalyst:2 )
1:2 or 1:4) amounts of catalyst were used. Zn(OTf)2:3:2a ) 1:1:1. All
reactions were carried out by use of 2 equiv each of alkyl iodide and Bu3SnH
for 2, and Et3B (2-4 equiv for catalyst) in CH2Cl2 at -78 °C. See ref 13.
b Isolated yield.
of 12 became nearly identical to that of the free 12.11 This
finding and the results from asymmetric reactions (entries 1
and 6 in Table 2) indicate that the coordination of 12 to a
zinc center is weak enough to allow competition between
12 and 2; therefore, the asymmetric reaction mainly pro-
ceeded by way of the complex dissociated with 12, so that
the sense and degree of asymmetric induction in the presence
of 12 were similar to those in the absence of an additive.
On the other hand, the CH2 signals of 2a became broad, but
the chemical shifts were almost unchanged, even when 2.5
equiv of 2 was added to a solution of the chiral zinc complex
containing 2a, indicating that 2a could coordinate tightly to
the zinc center in the presence of 2. Thus, it is reasonable to
assume that addition of 2a and 2 gives rise to a newly formed
ternary chiral zinc complex.12
stoichiometric amount. Although a slight loss of selectivity
was observed in the reactions of a primary radical, acceptable
ee’s were obtained (entries 9 and 10).15 It is also noted that
the sense of asymmetric induction of all reactions with 2a
was identical. Apparently, employment of the ternary
complex provides a reliable method, which allows the
synthesis of radical adducts in good to high ee’s with
predictable absolute configuration.16
In conclusion, efficient enantioselective conjugate addi-
tions by use of a chiral zinc complex containing an achiral
oxazolidinone have been developed. Moreover, our finding
that an achiral oxazolidinone having an NH moiety can
coordinate to a chiral zinc triflate in the presence of a
substrate so that enantioselectivity of the radical addition is
enhanced dramatically is unprecedented. Although effects
of achiral ligands on the enantioselectivity are known in other
areas of asymmetric catalysis, the results mentioned here
(10) Chemical shifts are referenced to methylene chloride. Zn(OTf)2 was
obtained from Aldrich Chemical Co. and used without further purification.
CD2Cl2 was distilled under argon from CaH2 prior to use. Solutions for the
measurements were prepared under an argon atmosphere. [2a] ) [12] )
[Zn(OTf)2] ) [3] ) 50 mM, which is identical to the concentration of a
solution used in the present asymmetric reactions. Chemical shift of the
CH2 signal of 12: (a) δ 4.63 as a singlet; (b) δ 4.57 and 4.61, two sets of
a doublet, J ) 9.2 Hz; (c) δ 4.64 as a singlet. Chemical shift of the CH2
signal of 2a: (d) δ 4.89 as a singlet; (e) δ 3.82 and 4.35, two sets of a
doublet, J ) 8.9 Hz; (f) δ 3.91 and 4.39, two sets of a doublet, J ) 8.6 Hz.
See the Supporting Information for details.
(11) By addition of 2, the chemical shift of the NCH3 signal of 12 in a
solution containing Zn(OTf)2 and 3 also came close to that of free 12.
Chemical shift of the NCH3 signal of 12: δ 2.58 (free 12), δ 2.38 (a chiral
zinc complex containing 12), δ 2.51 (a chiral zinc complex containing 12
and 2).
(12) Although the precise structures of the complexes are not interpreted
at this time, at least one OTf counteranion might dissociate in the complex
combined both with 2a and 2. For reports of OTf as a dissociate anion or
an auxiliary ligand in the chiral Lewis acids, see: (a) Evans, D. A.;
Kozlowski, M. C.; Tedrow, J. S. Tetrahedron Lett. 1996, 37, 7481-7484.
(b) Yao, S.; Johannsen, M.; Jorgensen, K. A. J. Chem. Soc., Perkin Trans.
1 1997, 2345-2349. (c) Crosignani, S.; Desimoni, G.; Faita, G.; Righetti,
P. P. Tetrahedron 1998, 54, 15721-15730. (d) Evans, D. A.; Tregay, S.
W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am. Chem. Soc. 2000,
122, 7936-7943 and references therein. Also see refs 2a-c, 2e,f, and 2i.
(13) In some cases 2a enhances chemical yields; however, it is not
excluded that operations of the isolation and purification of the products
cause a loss to chemical yields, especially workup (MeCN-hexane) to
remove organotin compounds.
(14) The ee’s of 7 and 8 were determined directly by HPLC using a
chiral column (Chiralcel OD). The absolute configuration of 7 was
determined by converting it to (R)-3-cyclohexyl-3-phenyl-1-propanal. For
the antipode, see: Ahlbrecht, H.; Enders, D.; Santowski, L.; Zimmermann,
G. Chem. Ber. 1989, 122, 1995-2004. The absolute configuration of 8
was determined by chemical correlation with (R)-3-phenylpentanoic acid,
see: Lardicci, L.; Menicagli, R.; Salvadori, P. Gazz. Chim. Ital. 1968, 98,
738-759, and also ref 2i. For the antipode, see: Soai, K.; Machida, H.;
Yokota, N. J. Chem. Soc. Perkin Trans. 1 1987, 1909-1914. See the
Supporting Information for details.
(15) As the pioneering work, one example of the enantioselective radical-
mediated conjugate addition of ethyl radical has been known to give 39%
ee, see: ref 2i.
Org. Lett., Vol. 3, No. 2, 2001
301

should provide new insights into the formation of a chiral
zinc triflate. Studies to elucidate the precise mechanism of
the asymmetric induction and further improve the enanti-
oselectivity are in progress.
Acknowledgment. M.M. is grateful for partial financial
support provided by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science and Culture of
Japan.
(16) General procedure of the substoichiometric enantioselective
conjugate additions: A mixture of 98% Zn(OTf)2 (0.2 mmol), 3 (0.2 mmol),
and 2a (0.2 mmol) in CH2Cl2 (2 mL) was stirred for 1 h at rt to become a
clear solution. The resulting clear solution was cooled to -78 °C. A solution
of 2 (0.4 or 0.8 mmol) in CH2Cl2 (2 mL) was added, and the mixture was
stirred for 30 min at -78 °C. Alkyl iodide (0.8 or 1.6 mmol), Bu3SnH (0.8
or 1.6 mmol), and a solution of triethylborane in hexane (1 N, 0.4 mmol)
were added successively, and the mixture was allowed to stand for 12 h at
the same temperature. The reactions were monitored by analytical thin-
layer chromatographic (TLC) methods (silica gel). When TLC analysis
showed the starting material, an additional portion of a solution of
triethylborane (0.4 mmol) was added, and the mixture was stirred for an
additional 12 h at -78 °C. After the reaction was complete (TLC, benzene),
AcOH (0.4-0.8 mL) was added at -78 °C and the mixture was stirred for
1 h. H2O was added, and the mixture was extracted with CH2Cl2 (20 mL
× 2). The organic layer was washed with saturated aqueous NaHCO3 and
Supporting Information Available: Experimental pro-
cedures, spectral data for the compounds, determination of
1
the absolute configurations, and H NMR spectral data for
the chiral zinc complexes. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL006927L
brine successively and dried over MgSO4. After filtration, the solvent was
removed under reduced pressure. The residue was taken up in MeCN. The
mixture was washed with hexane. Concentration followed by purification
through column chromatography (hexane-AcOEt) gave 5-8.
302
Org. Lett., Vol. 3, No. 2, 2001