Catalytic asymmetric epoxidation of α-methyl α,β- unsaturated anilides as ester surrogates

Article abstract of DOI:10.1055/s-2006-956491

Catalytic asymmetric epoxidation of α-methyl α,β- unsaturated carboxylic acid derivatives was achieved using anilide as a template. The Pr(Oi-Pr)₃-6,6?-Ph-BINOL complex (10 mol%) with a Ph₃P(O) (30 mol%) additive promoted the epoxida

Full text of DOI:10.1055/s-2006-956491

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3529
Catalytic Asymmetric Epoxidation of a-Methyl a,b-Unsaturated Anilides as
Ester Surrogates
Catalytic
Asymhi
h
of
a
-Methyl
u
a
,
b
-Unsatur
a
a
tedAnilides Chen, Hiroyuki Morimoto, Shigeki Matsunaga,* Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)56845206; E-mail: mshibasa@mol.f.u-tokyo.ac.jp; E-mail: smatsuna@ mol.f.u-tokyo.ac.jp
Received 29 August 2006
rotamers (Figure 2, a). To avoid repulsion, the carbon–
Abstract: Catalytic asymmetric epoxidation of a-methyl a,b-unsat-
carbon bond of the enoyl group twists, thereby breaking
the conjugation. Therefore, electrophilicity at the b-car-
bon in a-substituted a,b-unsaturated carbonyl compounds
urated carboxylic acid derivatives was achieved using anilide as a
template. The Pr(Oi-Pr)3–6,6¢-Ph-BINOL complex (10 mol%) with
a Ph3P(O) (30 mol%) additive promoted the epoxidation of anilides
in up to 99% yield and 88% ee. For a-methyl-b-Ph a,b-unsaturated is thought to be lower than that in a-non-substituted a,b-
unsaturated carbonyl compounds.8 We hypothesized that
anilide, the Gd(Oi-Pr)3–6,6¢-I-BINOL complex (10 mol%) with
Ar3P(O) (30 mol%, Ar = 4-methoxyphenyl) was suitable, giving
epoxide in 87% yield and 78% ee.
anilide 2 would be a suitable template9 to overcome the
problem, because repulsion between the a-substituent and
the N–H moiety should be rather small. Thus, the electro-
philicity at b-carbon is thought to be good even with an a-
substituent. When considering monodentate complex-
Key words: asymmetric catalysis, epoxide, anilide, BINOL, rare-
earth metal
ation with Lewis acidic rare-earth metals, an s-cis rotamer
should be preferred over an s-trans rotamer for the
addition of rare-earth-metal peroxide (Figure 2, b).
Catalytic asymmetric epoxidation of a,b-unsaturated car-
boxylic acid derivatives provides useful chiral building
blocks.1–5 We2,3 and others4 recently achieved efficient
catalytic asymmetric epoxidation of a,b-unsaturated
carboxylic acid derivatives, such as esters and amides. We
mainly used rare-earth-metal–BINOL (1a) (Figure 1)
complexes,6 and the epoxidation reactions proceeded via
nucleophilic 1,4-addition of rare-earth-metal peroxide.
High yield and ee were realized in our system, but the use
of a-substituted a,b-unsaturated carboxylic acid deriva-
tives remained problematic7 due to their low electrophilic-
ity at the b-carbon. Herein, we report the utility of anilide
2 (Figure 1) as a template to realize catalytic asymmetric
epoxidation of a-methyl-substituted compounds.
O
O
O
O
Me
(a)
(b)
O
N
R
O
N
Me
RE
R
t-Bu
t-Bu
O
O
O
O
RE
O
O
Ar
Ar
Me
R
N
R
N
H
H
Me
Figure 2
X
On the basis of our previous report on asymmetric epoxi-
dation of a-non-substituted anilide,3e we initiated our
study using 10 mol% of a Sm(Oi-Pr)3–BINOL (1a) com-
plex, a Ph3P(O) additive, TBHP (tert-butyl hydroperox-
ide), and a,b-dimethyl a,b-unsaturated anilides (Table 1).
Epoxidation of anilide 2a proceeded, and 3a was obtained
in 89% ee, albeit in low conversion (entry 1, 9%). To
improve reactivity, the electronic effects of anilide were
examined. As shown in entries 1–5, electron-donating
substituents resulted in a better conversion yield, which
matched well with our previous observation that Lewis
basicity of substrates is important for good complexation
with rare-earth-metal catalysts.3e Among 2a–e, anilide 2e
with a dimethylamino group showed the best reactivity
(entry 5, 59% yield). To further improve the reactivity, we
screened several BINOL derivatives and found that 6,6¢-
Ph-BINOL (1b, Figure 1) was suitable (entry 6, 91% con-
version, 84% ee). Further rare-earth-metal screening re-
vealed that Pr(Oi-Pr)3 gave the best reactivity and
enantioselectivity. With the Pr(Oi-Pr)3–6,6¢-Ph-BINOL
(1b) complex, the reaction completed within six hours,
O
Y
OH
OH
N
R
H
Me
2
X
: (S)-BINOL (1a)
X = H
X = Ph
: (S)-6,6'-Ph-BINOL (1b)
X = I : (S)-6,6'-I-BINOL (1c)
Figure 1 Structures of (S)-BINOL (1a), (S)-6,6¢-Ph-BINOL (1b),
(S)-6,6¢-I-BINOL (1c), and a-methyl a,b-unsaturated anilide 2
Asymmetric 1,4-addition to acyclic a-substituted a,b-un-
saturated carbonyl compounds is difficult due to steric re-
pulsion and rotamer control issues. a-Substituted enones
and conventional templates such as oxazolidinones have
poor reactivity, probably due to steric repulsion in both
SYNLETT 2006, No. 20, pp 3529–3532
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956491; Art ID: Y00906ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.1
2
.2
0
06

3530
Z. Chen et al.
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Table 1 Optimization of Reaction Conditionsa
RE(Oi-Pr)3 (10 mol%)
ligand (10 mol%)
Ph3P(O) (30 mol%)
TBHP (1.2 equiv)
X
X
O
O
O
MS 4 Å, THF, r.t.
N
Me
N
Me
H
H
Me
Me
2a–e
3a–e
Entry
Anilide: X
H- (2a)
Cl- (2b)
Me- (2c)
MeO- (2d)
Me2N- (2e)
2e
Ligand
1a
RE
Time (h)
Conv. (%)b
ee (%)c
1
2
3
4
5
6
7
8d
Sm
Sm
Sm
Sm
Sm
Sm
Pr
36
30
30
30
30
30
6
8
9
89
85
85
83
82
84
86
87
1a
1a
21
32
59
91
98
95
1a
1a
1b
2e
1b
2e
1b
Pr
4
a Reaction was performed at r.t. with anilide 2, RE(Oi-Pr)3 (10 mol%), ligand 1 (10 mol%), Ph3P(O) (30 mol%), and TBHP (1.2 equiv) in THF
(0.1 M), unless otherwise noted.
b Conversion yield determined by 1H NMR analysis of crude reaction mixture.
c Determined by chiral HPLC analysis using DAICEL CHIRALPAK AD-H or CHIRALCEL OJ-H.
d THF–toluene = 1:1 was used as solvent.
Table 2 Catalytic Asymmetric Epoxidation of a-Methyl a,b-Unsaturated Anilides 2e–la
RE(Oi-Pr)3 (10 mol%)
ligand (10 mol%)
Ph3P(O) (30 mol%)
TBHP (1.2 equiv)
X
X
O
O
O
MS 4 Å
THF–toluene, r.t.
N
R
N
R
H
H
Me
Me
(X = NMe2)
2e–l
(X = NMe2)
3e–l
Entry
Anilide: R
Me
RE
Pr
Ligand
1b
Time (h)
Yield (%)b
ee (%)c
87
1
2
2e
2f
2g
2h
2i
4
3.5
3.5
5
92
Et
Pr
1b
97
83
3
n-Pr
Pr
1b
95
86
4
i-Bu-
Pr
1b
99
88
5
PhCH2CH2-
Pr
1b
2
95
79
6
CH2=CH(CH2)8-
2j
2k
2l
Pr
1b
3
90
88
7
BnO(CH2)3-
Pr
1b
3
97
84
8d
9d
10e
Ph
Ph
Ph
Pr
1b
12
17
12
Trace
29
–
2l
Gd
Gd
1b
66
2l
1c
87
78
a Reaction was performed at r.t. with anilide 2, RE(Oi-Pr)3 (10 mol%), ligand 1 (10 mol%), Ph3P(O) (30 mol%), and TBHP (1.2 equiv) in THF–
toluene = 1:1 (0.1 M), unless otherwise noted.
b Isolated yield of analytically pure compound after silica gel column chromatography.
c Determined by chiral HPLC analysis using DAICEL CHIRALPAK AD-H or CHIRALCEL OJ-H.
d THF was used as solvent.
e Ar3P(O) (Ar = 4-Me-C6H4, 30 mol%) was used as an additive.
Synlett 2006, No. 20, 3529–3532 © Thieme Stuttgart · New York

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Catalytic Asymmetric Epoxidation of a-Methyl a,b-Unsaturated Anilides
3531
O
O
and epoxide 3e was obtained in 86% ee and 98% con-
version (entry 7). THF–toluene mixed solvent slightly
improved the reaction rate and enantioselectivity (entry 8,
4 h, 87% ee).10
O
O
a
Ar
Ar
N
R
N
R
Ar = 4-Me2N-C6H4
H
Me
Boc Me
4e: R = Me, 86%
3e: R = Me
3i: R = CH2CH2Ph
3l: R = Ph
4i: R = CH2CH2Ph, 84%
4l: R = Ph, 91%
The substrate scope of the present reaction is summarized
in Table 2. The optimized reaction conditions were appli-
cable to a-methyl-b-alkyl a,b-unsaturated anilides 2e–k,
giving epoxides 3e–k in good yield and enantioselectivity
(entry 1–7). Because the present epoxidation proceeds via
1,4-addition of praseodymium peroxide, epoxidation pro-
ceeded chemoselectively when using anilide 2j with a
simple carbon–carbon double bond (entry 6). Anilide 2k
with a BnO moiety was also applicable (entry 7). With a-
methyl-b-Ph a,b-unsaturated anilide 2l, however, the re-
action did not proceed well with the Pr(Oi-Pr)3–6,6¢-Ph-
BINOL (1b) complex (entry 8). Re-screening of rare-
earth-metal sources revealed that Gd(Oi-Pr)3, which is
more Lewis acidic than Pr(Oi-Pr)3, was suitable for b-Ph
anilide 2l (entry 9). By changing the ligand from 1b to
6,6¢-I-BINOL (1c) and the additive from Ph3P(O) to
Ar3P(O) (Ar = 4-methoxyphenyl),11 epoxide 3l was ob-
tained in 87% yield and 78% ee (entry 10).
O
O
b
N
Me
4e
Me
5e, 85%
O
O
O
c
d
4l
EtO
Ph
EtO
O
Ph
HO Me
Me
6l, 87%
7l, 96%
e
HO
Ph
4i
Me
8i, 87%
Scheme 1 Transformation of anilide moiety. Reagents and conditi-
ons: a) Boc2O (3 equiv), DMAP (0.4 equiv), MeCN, r.t., 12 h; b) pyr-
rolidine, THF, 0 °C to r.t., 6 h; c) NaOEt (2 equiv), EtOH, r.t., 12 h;
d)Pd/C (0.05 equiv), H2 (1 atm), EtOH, r.t., 2 h; e) NaBH4 (3 equiv),
MeOH, 0 °C to r.t., 1.5 h.
The utility of anilide as an ester surrogate was demonstrat-
ed by the transformation shown in Scheme 1. The anilide
moiety was readily converted into amide 5e and ester 6l in
two steps under mild conditions.12 Activation of anilides
2e and 2l with a Boc group, followed by treatment with ei-
ther amine or alkoxide, afforded amide 5e and ester 6l in
85% and 87% yield, respectively. The epoxide remained
intact through the above-mentioned transformation. Ep-
oxide ring opening of 6l using Pd/C under H2 proceeded
regioselectively to afford chiral tert-alcohol 7l in 96%
yield. No regioisomer was observed in the hydrogenation.
Reduction of 4i proceeded smoothly with NaBH4, afford-
ing epoxy alcohol 8i in 87% yield.
References and Notes
(1) Recent general reviews for catalytic asymmetric
epoxidation, see: (a) Bonini, C.; Righi, G. Tetrahedron
2002, 58, 4981. (b) Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-
M.; Su, K.-X. Chem. Rev. 2005, 105, 1603. (c) McGarrigle,
E. M.; Gilheany, D. G. Chem. Rev. 2005, 105, 1563; and
references therein . Reviews on asymmetric epoxidation of
electron deficient C–C double bonds: (d) Porter, M. J.;
Skidmore, J. Chem. Commun. 2000, 1215. (e) Nemoto, T.;
Ohshima, T.; Shibasaki, M. J. Synth. Org. Chem. Jpn. 2002,
60, 94 . Chiral ketone catalysis: (f) Shi, Y. Acc. Chem. Res.
2004, 37, 488; and references therein. (g) Yang, D. Acc.
Chem. Res. 2004, 3, 497 . Polyamino acid catalysis:
(h) Lauret, C.; Roberts, S. M. Aldrichimica Acta 2002, 35,
47. (i) Kelly, D. R.; Roberts, S. M. Biopolymers 2006, 84,
74.
(2) a,b-Unsaturated ester: Kakei, H.; Tsuji, R.; Ohshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 8962.
(3) a,b-Unsaturated N-acylimidazole: (a) Nemoto, T.;
Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
9474. Amide: (b) Nemoto, T.; Kakei, H.; Gnanadesikan, V.;
Tosaki, S.-y.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc.
2002, 124, 14544. N-Acylpyrrole: (c) Kinoshita, T.; Okada,
S.; Park, S.-R.; Matsunaga, S.; Shibasaki, M. Angew. Chem.
Int. Ed. 2003, 42, 4680. (d) Matsunaga, S.; Kinoshita, T.;
Okada, S.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 7559. Amide and anilide: (e) Tosaki, S.-y.;
Tsuji, R.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 2147.
In summary, we demonstrated the utility of anilide as a
template to realize catalytic asymmetric epoxidation of
a-methyl a,b-unsaturated carboxylic acid derivatives. The
Pr(Oi-Pr)3–6,6¢-Ph-BINOL (1b) complex was suitable for
b-alkyl substrates, while the Gd(Oi-Pr)3–6,6¢-I-BINOL
(1c) complex was suitable for b-Ph anilide 2l. Epoxides
were obtained in 87–99% yield and 78–88% ee.13,14
Further trials to improve substrate scope15 as well as enan-
tioselectivity of the present reaction are in progress.
Acknowledgment
This work was supported by Grant-in-Aid for Specially Promoted
Research and Grant-in-Aid for Encouragements for Young
Scientists (B) (for SM) from JSPS and MEXT. H.M. thanks JSPS
Research Fellowships for Young Scientists.
(4) For selected examples of highly enantioselective catalytic
epoxidation of a,b-unsaturated ester by other groups:
(a) Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124,
8792; and references therein. (b) Seki, M.; Furutani, T.;
Imashiro, R.; Kuroda, T.; Yamanaka, T.; Harada, N.;
Arakawa, H.; Kusama, M.; Hashiyama, T. Tetrahedron Lett.
2001, 42, 8201. (c) Jacobsen, E. N.; Deng, L.; Furukawa, Y.;
Synlett 2006, No. 20, 3529–3532 © Thieme Stuttgart · New York

3532
Z. Chen et al.
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Martinez, L. E. Tetrahedron 1994, 50, 4323; and references
therein. (d) For other examples, see the reviews in ref. 1 and
references therein.
(11) For catalyst tuning of rare-earth-metal–BINOL complexes
by various phosphine oxides, see: (a) Yamagiwa, N.; Tian,
J.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2005,
127, 3413; and references therein. (b) See also ref. 6c.
(12) (a) Grehn, L.; Gunnarsson, K.; Ragnarsson, U. J. Chem.
Soc., Chem. Commun. 1985, 1317. (b) For a different
strategy to convert anilides into carboxylic acids, see ref. 9.
(13) General Procedure of Catalytic Asymmetric
Epoxidation of Anilide 2.
(5) For examples of highly enantioselective asymmetric
epoxidation of a,b-unsaturated aldehydes, see: (a) Marigo,
M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K.
A. J. Am. Chem. Soc. 2005, 127, 6964. (b) Sundén, H.;
Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2006, 47, 99.
(6) Rare-earth-metal–BINOL complex for asymmetric
epoxidation of enones: (a) Bougauchi, M.; Watanabe, T.;
Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1997,
119, 2329. (b) Nemoto, T.; Ohshima, T.; Yamaguchi, K.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2725. (c) See
also: Daikai, K.; Kamaura, M.; Inanaga, J. Tetrahedron Lett.
1998, 39, 7321.
(7) Shi and co-workers realized highly enantioselective catalytic
epoxidation of an acyclic (Z)-a-methyl a,b-unsaturated ester
using chiral ketone catalyst. Use of (E)-a-substituted a,b-
unsaturated ester was limited to a cyclic substrate. See, ref.
5a. We also succeeded in asymmetric epoxidation of cyclic
a-substituted a,b-unsaturated amides (two examples). See
ref. 3e.
(8) (a) For an elegant catalytic asymmetric 1,4-addition of
amine nucleophile to a,b-disubstituted a,b-unsaturated
carboxylic acid derivatives using imide as a template, see:
Sibi, M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P.
J. Am. Chem. Soc. 2003, 125, 11796. (b) For use of imides
in asymmetric catalysis, see also: Goodman, S. N.; Jacobsen,
E. N. Adv. Synth. Catal. 2002, 344, 953; and references
therein.
MS 4 Å (300 mg, powdered) in a flask was flame-dried prior
to use under vacuum (0.7 kPa) for 5 min. To a stirred
suspension of Ph3P(O) (25.0 mg, 0.09 mmol), (S)-6,6¢-Ph-
BINOL (13.2 mg, 0.03 mmol) and MS 4 Å in dry THF (1.5
mL) and toluene (1.5 mL) at 25 °C was added Pr(Oi-Pr)3
(0.15 mL, 0.03 mmol, 0.2 M in THF). The mixture was
stirred for 10 min at 25 °C and tert-butyl hydroperoxide
(TBHP; 90 mL, 0.36 mmol, 4 M in toluene) was added. After
10 min, 2e (65.5 mg, 0.3 mmol) was added. After 4 h, the
reaction was quenched with 2% aq citric acid. The mixture
was extracted with CH2Cl2 (3×). Then, the combined organic
layers were washed with brine and dried over MgSO4. The
solvent was evaporated under reduced pressure and the
resulting crude residue was purified by flash silica gel
column chromatography (acetone–hexane = 1:20 to 1:5) to
afford 3e (92% yield, 87% ee).
(14) (a) Relative configurations of epoxide 3e, 3f, and 3k were
confirmed to be trans by NOE. Absloute configuration of
epoxide 3i was determined to be 2R,3S after conversion into
known compound 8i by comparing sign of optical rotation.
Absolute configuration of epoxide 3l was determined to be
2R,3S by comparing sign of optical rotation of 7l with
reported data. (b) Compound 8i: Jung, M. E.; D’Amico, D.
C. J. Am. Chem. Soc. 1995, 117, 7379. (c) Compound 7l:
Lee, M.; Kim, D. H. Bioorg. Med. Chem. 2000, 8, 815.
(d) Relative and absolute configurations of other products
were tentatively assigned by analogy.
(9) For use of anilide activated with Boc group as a template,
see: Saito, S.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128,
8704.
(10) THF–toluene mixed solvent gave better results than THF
alone in related asymmetric epoxidation. Matsunaga, S.;
Qin, H.; Sugita, M.; Okada, S.; Kinoshita, T.; Yamagiwa, N.;
Shibasaki, M. Tetrahedron 2006, 62, 6630.
(15) a-Substituents other than methyl are still problematic at
present. For example, a-ethyl b-methyl a,b-unsaturated
anilide gave epoxide in 39% yield and 73% ee. Studies to
improve reactivity and enantioselectivity are in progress.
Synlett 2006, No. 20, 3529–3532 © Thieme Stuttgart · New York