Chiral enamide. Part 1: Epoxidations of chiral enamides. A viable approach to chiral nitrogen stabilized oxyallyl cations in [4+3] cycloadditions

Article abstract of DOI:10.1016/S0040-4039(02)00849-3

The first study of stereoselective epoxidations of chiral enamides is described here. Its potential in the synthesis of chiral α-keto aminals as a viable approach to nitrogen stabilized oxyallyl cations in stereoselective [4+3] cycloadditions is also illustrated.

Full text of DOI:10.1016/S0040-4039(02)00849-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4449–4453
Chiral enamide. Part 1: Epoxidations of chiral enamides.
A viable approach to chiral nitrogen stabilized oxyallyl cations
in [4+3] cycloadditions
Hui Xiong, Richard P. Hsung,*,† Lichun Shen and Juliet M. Hahn
Department of Chemistry, University of Minnesota, 207 Pleasant Street S.E., Minneapolis, MN 55455-0431, USA
Received 15 March 2002; revised 29 April 2002; accepted 30 April 2002
Abstract—The first study of stereoselective epoxidations of chiral enamides is described here. Its potential in the synthesis of chiral
a-keto aminals as a viable approach to nitrogen stabilized oxyallyl cations in stereoselective [4+3] cycloadditions is also illustrated.
© 2002 Elsevier Science Ltd. All rights reserved.
Allenamides and ynamides have attracted much atten-
tion in recent literature because they offer superior
thermal stability and comparable reactivity relative to
traditional ynamines and allenamines.1–6 They present
invaluable opportunities for developing new stereoselec-
tive methodologies.3–6 Our investigations involving chi-
ral allenamides5 (1) and ynamides6 (2) have frequently
led us to products that contain the enamide functional-
ity shown in 3 (Fig. 1). Comments suggesting that the
fate of enamides is no more than a simple hydrolysis to
ketones provoked us to examine this functional group
carefully. The fate of enamides is clearly much more
than the suggested less-fruitful hydrolysis.7–9 However,
in comparison with its celebrated structural relatives,
enol ethers and enamines, reactivity of enamides is
actually vastly under appreciated or non-systematically
explored. This prompted us to launch a program exam-
ining reactivity of enamides. Specifically, we studied
epoxidations9 of chiral enamides 3 leading to a-keto
aminals 6. To the best of our knowledge, this is the first
epoxidation study involving chiral enamides.9 We envi-
sioned that 6 can serve as an alternative approach to
chiral nitrogen stabilized oxyallyl cations 7,5a,12,13
thereby providing a significant application of chiral
enamides in stereoselective [4+3] cycloaddition chem-
istry.10–14 We communicate here our preliminary
findings along these efforts.
Representative examples of acyclic or of cyclic enam-
ides, prepared from condensation of aldehydes or
ketones with oxazolidinones via standard dehydrative
conditions,15 were chosen to indicate scopes and gener-
ality of this study. As shown in Scheme 1, m-CPBA
epoxidation of the enamide 8 in MeOH and in the
presence of NaHCO3 led to aminals 9 and 10,16 and
subsequent acidic methanolysis of the mixture led
exclusively to the aminal 10 in 44% overall yield. Subse-
quent oxidation led to the a-keto aminal 11 in 88%
yield, thereby completing the proposed synthetic
sequence for 6 shown in Fig. 1. Cyclic enamides 12 and
1417 could also be readily transformed using the same
sequence to the a-keto aminals 13 and 15, respectively
Figure 1.
* Corresponding author. E-mail: hsung@chem.umn.edu
† A recipient of 2001 Camille Dreyfus Teacher–Scholar Award.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00849-3

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H. Xiong et al. / Tetrahedron Letters 43 (2002) 4449–4453
Scheme 1.
(Scheme 2). The a-keto aminal 15 was converted to the
desired silyl enol ether 16 in 89% yield using KHMDS
and TESCl.
Scheme 3.
Having established the feasibility in epoxidizing achiral
enamides, epoxidiations of chiral enamides were exam-
ined for the level of diastereoselectivity. Epoxidation of
17 using m-CPBA in MeOH under buffered conditions
led to the aminal 18 as two distinct diastereomers in a
1:1 ratio with a sporadic yield range (Scheme 3). Subse-
quent TPAP oxidation led to the a-keto aminal 19 but
remained as two diastereomers. This led us to speculate
that the diastereomeric ratio comes from the C2 aminal
carbon and not C1.18 An oxidative fragmentation was
also observed when the epoxidation conditions involved
MeOH and NaHCO3, although only with chiral enam-
ides, to give the keto aldehyde 239a presumably via 22,
thereby leading to sporadic yields for 18.
assertion that this epoxidation is highly stereoselective
and that the diastereomeric ratio represents indiscrimi-
nant ring-opening of the epoxide at the aminal carbon.
Based on the stereochemical assignment of 28a via
X-ray, epoxidation appears to favor the face away from
the phenyl group (see insert) analogous to our findings
in allenamide epoxidations.5a
Preparations of enol ethers from 30 and 31 appear not
to be as forthright as with 15 in Scheme 2. The a-keto
This fragmentation could be avoided if the epoxidation
was carried with MeOH or NaHCO3 buffer leading to
a-keto aminals 30a/b and 31a/b in excellent yields from
enamides 24 and 25, respectively (Scheme 4). Aminals
28a/b and 29a/b were obtained as a mixture of
diastereomers [1.3:1], and oxidation of 28a/b and 29a/b
either as a mixture or as individual diastereomers led to
30a/b and 31a/b, respectively, either as a mixture with
equal ratio or one isomer. This confirms the earlier
Scheme 4.
Scheme 2.

H. Xiong et al. / Tetrahedron Letters 43 (2002) 4449–4453
4451
aminals 30a/b provided either the TES (32a/b) or TIPS
enol ethers or (33a/b) regioselectively if the ketone
substrate was added to KHMDS in the presence of silyl
chlorides (Scheme 5). On the other hand, while the
a-keto aminal 31b was not regioselective in this
endeavor leading to a mixture of 34 and 35b (the
C1-OMe group is b) under several conditions, a-keto
aminal 31a (the C1-OMe group is a) was suitable to
regioselectively provide the enol ether 35a. We are not
certain at this point why this contrast took place.
Syntheses of these silyl enol ethers allowed us to
explore their potential in stereoselective oxyallyl cation
[4+3] cycloadditions. However, thus far, the TES enol
ether 35a from the a-keto aminal 31a was most success-
ful in establishing the viability of this approach to
stereoselective [4+3] cycloadditions. In the presence of
10–20 mol% of TMSOTf, 35a reacted with furan to
give the desired cycloadducts 36a/b in 30% overall yield
after hydrogenation with a ratio of ]90:10 in favor of
36a as assigned using NOE experiments (Scheme 6).
Scheme 6.
An equal amount of the hemi-cycloadduct 37 was
isolated during many of these preliminary explorations,
and conditions using other Lewis acids such as SnCl4,
TiCl4 and BF3–Et2O did not improve the ratio of 36:37.
This preliminary result suggests that the desired N-acyl
iminium salt 38 can be generated via a selective Lewis
acid activation of the MeO group of 35a, and that an
ensuing 1,4-addition of the furan did occur to give the
oxocarbenium intermediate 39. However, the second
bond formation did not compete well with the elimina-
tion leading to furan. This arrested second bond forma-
tion was not seen in analogous sulfur or oxygen
stabilized oxyallyl cation.11,14
close details of this endeavor in due course. However,
we are able to demonstrate here the first study of
stereoselective epoxidation of chiral enamides, and its
potential in generating chiral a-keto aminals as a viable
source of chiral nitrogen stabilized oxyallyls in stereose-
lective [4+3] cycloadditions.
Acknowledgements
The authors thank NSF [CHE-0094005] for financial
support and Mr. William B. Brennessel for providing
the X-ray structural analysis. H.X. thanks UMN for a
Dissertation Fellowship.
We are currently searching for other experimental pro-
tocols to resolve this particular challenge and will dis-
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Scheme 5.

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1
16. All new compounds are characterized by H NMR, 13C
NMR, FTIR, and mass spectroscopy. Please see Ref. 19
for characterizations of selected key compounds.
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18. Stereochemistry shown at C1 of 18a/b was assigned later
via NMR correlation with 28b. The speculation of a
stereoselective epoxidation of 17 was also supported by
DMDO epoxidation of chiral enamide 25 (see Scheme 4)
using DMDO-d6 that generated from Oxone™ and
acteone-d6. This study led to the observation of a single
1-amido epoxide that was not stable but could be quickly
characterized by 1H NMR. 1H NMR (500 MHz, acetone-
d6) l 0.79 (t, 3H, J=7.0 Hz), 1.00–1.25 (m, 8H), 2.87 (t,
1H, J=6.0 Hz), 4.05 (dd, 1H, J=6.0, 9.0 Hz), 4.56 (s,
1H), 4.72 (t, 1H, J=9.0 Hz), 4.94 (dd, 1H, J=6.0, 9.0
Hz), 7.36–7.47 (m, 5H). This represents the first observa-
tion of a chiral 1-amido epoxide, although Adam had
reported an account of achiral 1-amido epoxide (Ref. 9a).
19. Selected characterizations: 11: Rf=0.53 (50% EtOAc/hex-
9. For the only study of epoxidation of achiral enamides,
see: (a) Adam, W.; Reinhardt, D.; Reissig, H.-U.; Paulini,
K. Tetrahedron 1995, 51, 12257, and references cited
therein; (b) Also see, Koseki, Y.; Kusano, S.; Ichi, D.;
Yoshida, K.; Nagasaka, T. Tetrahedron 2000, 56, 8855.
10. For reviews on oxyallyl and [4+3] cycloaddition reac-
tions, see: (a) Harmata, M. In Advances in Cycloaddition;
Lautens, M., Ed.; JAI: Grennwich, 1997; Vol. 4, pp.
1
ane); H NMR (300 MHz, CDCl3) l 0.86 (t, 3H, J=6.8
Hz), 1.27 (m, 4H), 1.56 (quintet, 2H, J=7.2 Hz), 2.54 (m,
2H), 3.42 (s, 3H), 3.51 (m, 2H), 4.39 (t, 2H, J=8.3 Hz),
5.26 (s, 1H); 13C NMR (125 MHz, CDCl3) l 13.8, 22.3,

H. Xiong et al. / Tetrahedron Letters 43 (2002) 4449–4453
4453
22.7, 31.1, 39.1, 39.5, 56.8, 62.6, 86.6, 158.7, 203.5; IR
(thin film) cm−1 2957s, 2928s, 2872s, 1755s, 1524w,
1483w, 1467m, 1415s, 1381m, 1239s, 1199s; mass spectra
(CI) m/e (% relative abundance) 230 (70) M++H, 198(42),
130(15), 128(33), 105(100), 88(38), 75(19); m/e Calcd for
C11H20NO4 230.1392, found 230.1398. 18a/b: Rf=0.29
2.16 (m, 2H), 3.42 (s, 3H), 4.34 (dd, 1H, J=7.5, 9.0 Hz),
4.71 (t, 1H, J=9.0 Hz), 4.87 (dd, 1H, J=7.5, 9.0 Hz),
5.15 (s, 1H), 7.27–7.37 (m, 5H); 13C (500 MHz, CDCl3) l
13.9, 22.2, 22.3, 31.0, 39.0, 56.7, 56.8, 70.4, 86.5, 128.4,
128.98, 129.40, 136.7, 158.8, 204.3; IR (thin film) cm−1
2954m, 1758s, 1374m, 1037w; mass spectrum (EI): m/e
(% relative intensity) 274 (1) (M+−OMe), 206(100),
162(8), 135(14), 86(14). 35a: Rf=0.53 (50% ether in hex-
1
(50% EtOAc in hexane); [h]2D0 −75.2 (c 0.5 in CH2Cl2); H
NMR (500 MHz, CDCl3) major l 1.20–2.20 (m, 8H),
3.15 (s, 3H), 4.01–4.04 (m, 1H), 4.17 (dd, 1H, J=2.5, 8.0
Hz), 4.60 (t, 1H, J=8.0 Hz), 4.95 (dd, 1H, J=2.5, 8.0
Hz), 7.27–7.41 (m, 5H); 13C (300 MHz, CDCl3) major l
21.9, 22.0, 30.2, 30.9, 50.3, 58.2, 58.3, 70.5, 91.5, 126.2,
128.4, 129.0, 142.2, 158.1; IR (thin film) cm−1 2943m,
1748s, 1334m, 1045w; mass spectrum (GC MS): m/e (%
relative intensity) 259 (3) (M+−MeOH), 162 (65), 104
(100), 91 (23). 23: Rf=0.40 (50% EtOAc in hexane); [h]D20
−72.8 (c 0.50 in CH2Cl2); 1H NMR (500 MHz, CDCl3)
l 1.55–1.68 (m, 4H), 2.42–2.45 (m, 2H), 2.95–2.98 (m,
2H), 4.30 (dd, 1H, J=3.5, 8.5 Hz), 4.70 (t, 1H, J=8.5
Hz), 5.43 (dd, 1H, J=3.5, 8.5 Hz), 7.41–7.27 (m, 5H),
9.73 (t, 1H, J=1.5 Hz); 13C (500 MHz, CDCl3) l 21.4,
23.5, 35.2, 43.5, 57.6, 70.0, 125.9, 128.7, 129.2, 139.1,
153.8, 172.2, 202.2; IR (thin film) cm−1 3034m, 2944m,
1717s, 1435w, 1041m; mass spectrum (LC MS): m/e (%
relative intensity) 276 (6) (M+H+), 230 (45), 186 (67), 164
(66), 120 (100). 30a: Rf=0.41 (50% EtOAc in hexane);
[h]2D0 −52.2 (c 0.54 in CH2Cl2); 1H NMR (500 MHz,
CDCl3) l 2.18 (s, 3H), 3.21 (s, 3H), 4.29 (dd, 1H, J=7.0,
9.0 Hz), 4.71 (t, 1H, J=9.0 Hz), 4.93 (dd, 1H, J=7.0, 9.0
Hz), 5.05 (s, 1H), 7.26–7.40 (m, 5H); 13C (500 MHz,
CDCl3) l 27.0, 57.0, 57.9, 70.7, 88.2, 127.4, 129.0, 129.1,
138.4, 153.8, 202.6; IR (thin film) cm−1 2932m, 1756s,
1459m, 1002w; mass spectrum (GC MS): m/e (% relative
intensity) 218 (2) (M+−OMe), 206(100), 162(13), 135(23),
104(22), 103(35), 86(37), 77(12). 30b: Rf=0.25 (50%
EtOAc in hexane); [h]2D0 −153.9 (c 0.69 in CH2Cl2); 1H
NMR (500 MHz, CDCl3) l 1.73 (s, 3H), 3.43 (s, 3H),
4.37 (dd, 1H, J=7.5, 9.0 Hz), 4.72 (t, 1H, J=9.0 Hz),
4.88 (dd, 1H, J=7.5, 9.0 Hz), 5.12 (s, 1H), 7.27–7.38 (m,
5H); 13C (500 MHz, CDCl3) l 26.1, 56.8, 57.0, 70.3, 86.8,
128.5, 129.0, 129.7, 136.4, 158.6, 202.2; IR (thin film)
cm−1 2932m, 1756s, 1459m, 1002w; mass spectrum (GC
MS): m/e (% relative intensity) 218 (2) (M+−OMe),
206(100), 162(13), 135(28), 104(25), 103(35), 86(36),
77(12). 31a: Rf=0.68 (50% EtOAc in hexane); [h]2D0 −61.1
1
ane); [h]2D0 41.3 (c 0.45 in CHCl3); H NMR (500 MHz,
CDCl3) l 0.70 (q, 6H, J=8.0 Hz), 0.92 (t, 3H, J=7.0
Hz), 0.99 (t, 9H, J=8.0 Hz), 1.30–1.33 (m, 4H), 1.95–2.00
(m, 1H), 2.11–2.18 (m, 1H), 3.19 (s, 3H), 4.19 (dd, 1H,
J=6.0, 9.0 Hz), 4.58 (t, 1H, J=9.0 Hz), 4.78 (dd, 1H,
J=6.0, 9.0 Hz), 4.85 (dt, 1H, J=1.0, 8.0 Hz), 5.21 (d,
1H, J=1.0 Hz), 7.26–7.33 (m, 5H); 13C (500 MHz,
CDCl3) l 5.3, 6.7, 13.9, 22.6, 24.6, 31.7, 55.6, 57.3, 70.7,
85.9, 112.2, 126.9, 128.3, 128.4, 140.6, 142.8, 159.2; IR
(thin film) cm−1 2969m, 2879m, 1774s, 1404m, 1239m,
1171m; mass spectrum (LC MS): m/e (% relative inten-
sity) 420(78) (M+H+), 388(100), 274(8). 36a: Rf=0.48
(50% EtOAc in hexane); [h]2D0 −137.5 (c 0.40 in CHCl3);
1H NMR (500 MHz, CDCl3) l 0.90 (t, 3H, J=7.0 Hz),
1.05–1.75 (m, 10H), 2.68 (ddd, 1H, J=6.0, 6.0, 6.0 Hz),
4.08 (dd, 1H, J=5.0, 9.0 Hz), 4.40 (dd, 1H, J=4.0, 7.0
Hz), 4.51 (ddd, 1H, J=2.0, 6.0, 6.0 Hz), 4.74 (t, 1H,
J=9.0 Hz), 4,83 (d, 1H, J=4.0 Hz), 5.04 (dd, 1H, J=5.0,
9.0 Hz), 7.25–7.41 (m, 5H); 13C (500 MHz, CDCl3) l
13.9, 22.7, 24.4, 25.7, 27.0, 29.5, 55.7, 58.3, 65.5, 71.2,
77.8, 79.9, 126.2, 128.8, 129.3, 140.5, 159.1, 204.4. IR
(thin film) cm−1 2957m, 2929m, 1761s, 1718s, 1457m,
1412m, 1399m, 1074m, 704m; mass spectrum (LC MS):
m/e (% relative intensity) 344(38) (M+H+), 326(64),
276(27), 232(29), 202(23), 176(78), 163(100), 132(30),
120(42). 37 (mixed with some pre-hydrogenated cycload-
duct): Rf=0.55 (50% EtOAc in hexane); 1H NMR (500
MHz, CDCl3) pre-hydrogenated cycloadduct: l 0.85 (t,
3H, J=7.0 Hz), 1.00–1.95 (m, 6H), 2.78 (dt, 1H, J=7.5,
6.0 Hz), 4.06 (dd, 1H, J=4.0, 9.0 Hz), 4.70 (m, 1H), 4.75
(dd, 1H, J=2.0, 6.0 Hz), 4.80 (t, 1H, J=9.0 Hz), 4.87
(dd, 1H, J=2.0, 4.5 Hz), 5.01 (d, 1H, J=4.5 Hz), 5.14
(dd, 1H, J=2.0, 6.0 Hz), 6.14 (dd, 1H, J=2.0, 6.0 Hz),
7.23–7.44 (m, 5H); 37: l 0.91 (t, 3H, J=7.5 Hz), 1.00–
1.95 (m, 6H), 3.44 (d, 1H, J=18.0 Hz), 3.64 (dd, 1H,
J=7.0, 8.0 Hz), 4.14 (t, 1H, J=8.0 Hz), 4.30 (d, 1H,
J=18.0 Hz), 4.73 (t, 1H, J=8.0 Hz), 4.90 (t, 1H, J=8.0
Hz), 6.06 (d, 1H, J=3.5 Hz), 6.24 (dd, 1H, J=2.0, 3.5
Hz), 7.13–7.44 (m, 6H); 13C (500 MHz, CDCl3) l as a
mixture 13.77, 13.83, 22.3, 22.7, 24.7, 28.8, 29.2, 29.5,
49.2, 49.8, 55.6, 57.6, 59.7, 66.0, 70.1, 71.1, 80.4, 81.5,
107.7, 110.6, 126.1, 127.2, 129.0, 129.1, 129.2, 129.5,
132.9, 133.7, 136.7, 140.7, 142.2, 150.9, 158.5, 159.6,
202.2, 202.8; IR (thin film) cm−1 2958m, 2928m, 1762s,
1723m, 1410m, 1399m, 1077m, 706m; mass spectrum
(GC MS): m/e (% relative intensity) Peak 1: 341(30)
(M+), 281(5), 176(95), 150(60), 132(65), 91(78), 81(100);
Peak 2: 341(5) (M+), 281(7), 207(100), 176(10).
1
(c 0.73 in CH2Cl2); H NMR (500 MHz, CDCl3) l 0.88
(t, 3H, J=6.0 Hz), 1.21–1.32 (m, 4H), 1.51–1.56 (m, 2H),
2.47 (t, 2H, J=7.5 Hz), 3.19 (s, 3H), 4.29 (dd, 1H,
J=5.5, 9.0 Hz), 4.70 (t, 1H, J=9.0 Hz), 4.92 (dd, 1H,
J=5.5, 9.0 Hz), 5.09 (s, 1 H), 7.27–7.40 (m, 5H); 13C (500
MHz, CDCl3) l 13.9, 22.4, 22.7, 31.2, 39.3, 57.0, 57.9,
70.7, 88.2, 127.4, 128.9, 129.0, 138.5, 158.6, 204.8; IR
(thin film) cm−1 2932m, 1758s, 1362m, 986w; mass spec-
trum (EI): m/e (% relative intensity) 274 (2) (M+−OMe),
207(13), 206(100), 162(9), 135(15), 104(14), 86(15). 31b:
Rf=0.58 (50% EtOAc in hexane); [h]2D0 −123.5 (c 0.70 in
CH2Cl2); 1H NMR (500 MHz, CDCl3) l 0.81 (t, 3H,
J=7.5 Hz), 0.98–1.04 (m, 3H), 1.06–1.18 (m, 3H), 2.03–