Magnesium-coordinated chelation control in 1,3-dipolar cycloaddition of chiral α-alkoxymethyl ether nitrile oxide: Application to the synthesis of (-)/(-)- cis -clausenamide

Article abstract of DOI:10.1055/s-0034-1379485

A facile regio- and diastereoselective nitrile oxide cycloaddition method using magnesium-coordinated chelation control of chiral α-alkoxymethyl ether nitrile oxide is reported. This reaction could be successfully applied as a key step in both the formal total synthesis of (-)-clausenamide and the total synthesis of (-)-cis-clausenamide.

Full text of DOI:10.1055/s-0034-1379485

LETTER
▌2953
lMettear gnesium-Coordinated Chelation Control in 1,3-Dipolar Cycloaddition of
Chiral α-Alkoxymethyl Ether Nitrile Oxide: Application to the Synthesis of
(–)/(–)-cis-Clausenamide
Synthesis of (–)/(–)-cis-Clausenamide
Kazuhiro Tanda,* Atsushi Toyao, Akiko Watanabe, Masanori Sakamoto, Tetsuo Yamasaki*
Department of Pharmaceutical Chemistry, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki 882-8508, Japan
Fax +81(982)235711; E-mail: tanda@phoenix.ac.jp; E-mail: tetsuyam@phoenix.ac.jp
Received: 29.08.2014; Accepted after revision: 30.09.2014
OH
OH
Ph
Ph
Abstract: A facile regio- and diastereoselective nitrile oxide cyc-
loaddition method using magnesium-coordinated chelation control
of chiral α-alkoxymethyl ether nitrile oxide is reported. This reac-
tion could be successfully applied as a key step in both the formal
total synthesis of (–)-clausenamide and the total synthesis of (–)-cis-
clausenamide.
3
3
Ph
Ph
O
O
N
N
H
H
HO
HO
Me
Me
(–)-clausenamide (1)
(–)-cis-clausenamide (2)
Figure 1 Structure of (–)-clausenamide (1) and (–)-cis-clausen-
amide (2)
Key words: cycloaddition, magnesium, nitrile oxide, diastereo-
selectivity, natural products
thetic route toward the stereocontrolled synthesis of 3,4,5-
trisubstituted 2-isoxazolines, including an improvement
in cycloaddition diastereoselectivity by use of a combina-
tion of alkoxymethyl ether nitrile oxides with magnesium
alkoxide. This facile approach to the synthesis of substi-
tuted 2-isoxazolines was applied to both a formal total
synthesis of 1 and a total synthesis of 2.
The 1,3-dipolar cycloaddition of nitrile oxides has attract-
ed considerable attention in synthetic organic chemistry
because of its application in the synthesis of complex nat-
ural products.1 Thus, numerous examples of regio- and/or
diastereoselective nitrile oxide cycloaddition reactions
have been developed and intensely studied.2 One of the
major advances in this field is the metal-coordinated 1,3-
dipolar cycloaddition of benzonitrile oxide with allylic al-
cohols in the presence of magnesium alkoxides, which in-
troduce a high reaction rate enhancement and absolute
regiocontrol, as reported by Kanemasa et al.3 Recently,
Carreira et al. have developed convenient and broadly ap-
plicable (i.e., including aliphatic nitrile oxides) reaction
conditions for highly diastereoselective cycloaddition re-
actions by improving upon Kanemasa’s methods.4 In this
contribution, we describe the regio- and diastereoselective
1,3-dipolar cycloaddition of α-alkoxy aliphatic nitrile ox-
ides to 3-substituted allylic alcohols.
The outline of our synthesis strategy toward the clau-
senamides is illustrated in Scheme 1. The clausenamides
may be synthesized from 2-isoxazoline A, by
(a) oxidation and esterification, (b) selective reduction,
and (c) N–O bond cleavage and subsequent recyclization
to construct the pyrrolidinone rings. 2-Isoxazoline A may
be obtained by a putative 1,3-dipolar cycloaddition of ni-
trile oxide B with cinnamyl alcohol 3 from the less hin-
dered face in an exo fashion.
a) oxidation
esterification
Racemic clausenamide was first isolated from Clausena
lansium (Lours.) Skeels, a Chinese folk medicine;
(–)-clausenamide (1) has shown potent nootropic activi-
ties in many behavioral experiments, and is currently be-
ing developed as a promising antidementia drug.5
Moreover, (–)-cis-clausenamide (2), the C3 isomer of 1, is
demonstrated to be nearly twice as active as 1 (Figure 1).6
Given the important pharmacological activity and inter-
esting molecular structure — namely, a densely substitut-
ed pyrrolidinone ring with four contiguous stereocenters
— it is clear why the clausenamides are widely studied by
synthetic chemists as important synthetic targets.7
OH
Ph
clausenamides
Ph
O
N
RO
b) selective reduction
A
c) N–O bond cleavage
and recyclization
1,3-dipolar
cycloaddition
O–
Ph
N
Ph
OH
RO
B
3
Scheme 1 Retrosynthetic analysis of clausenamides
In the context of our study on 1,3-dipolar cycloaddition
reactions, we succeeded in the development of a new syn-
On the basis of our strategy, various chiral nitrile oxide
precursors, hydroximoyl chlorides 4a–e, were readily pre-
pared from known ester L-methyl mandelate (Table 1).8
When compound 4a was treated with (E)-cinnamyl alco-
SYNLETT 2014, 25, 2953–2956
Advanced online publication: 06.11.2014
DOI: 10.1055/s-0034-1379485; Art ID: st-2014-u0725-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2954
K. Tanda et al.
LETTER
hol (3)9 in the presence of i-PrOH and EtMgBr in CH2Cl2
at room temperature, the cycloaddition proceeded to give
a 62:38 separable mixture of cycloadduct 5a and its dias-
tereomer 5a' in 69% combined yield (entry 1). Treatment
of 4b with 3 under similar conditions resulted in a de-
crease in diastereoselectivity to give a 54:46 mixture of 5b
and 5b' in 80% yield (entry 2). However, when a similar
reaction was carried out with 4c, with an α-hydroxy hy-
droximoyl chloride and a MOM protecting group, the
starting material was smoothly consumed to give a 75:25
separable mixture of 5c and its diastereomer 5c' in 85%
yield (entry 3). When 4d, possessing MEM substitution,
was treated under similar conditions, the diastereoselec-
tivity of the cycloaddition was slightly increased to 78:22
(entry 4). Finally, the use of toluene as a solvent with 4d
gave more satisfactory results, affording the correspond-
ing cycloadducts in 64% yield with 87:13 diastereoselec-
tivity (entry 5). Treatment of 4e with 3, to verify that the
method preserves the stereochemical configuration at the
benzyl position, gave the corresponding cycloadducts in
56% yield, similar to the result obtained using 4d, without
racemization (entry 6).
Ph
O
Ph
O
MgXn
O
N
O
N
O
MgXn
O
XnMg
XnMg
Ph
H
H
O
R
O
R
Ph
favored
unfavored
Figure 2 Stereochemical model
The significant increase in diastereoselectivity in the reac-
tions of nitrile oxides 4c and 4d with cinnamyl alcohol (3)
might be explained by considering the chelation effect be-
tween magnesium alkoxides and the MOM and MEM Scheme 2 Reagents and conditions: (a) Dess–Martin periodinane,
CH2Cl2, r.t.; (b) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH–
H2O, r.t.; (c) TMSCHN2, benzene–MeOH, 91% from 5c; (d) HCl aq,
THF, r.t., (e) 4-nitrobenzoyl chloride, Et3N, CH2Cl2, r.t., 90% from 6.
group of the nitrile oxide. This chelation effect, which
causes a steric interaction with the phenyl group of 3 in the
cycloaddition transition state, results in the cycloadduct
being obtained by reaction in the less hindered exo mode
(Figure 2).
ment of 5c with Dess–Martin periodinane, followed by
This effect between magnesium alkoxides and α-
alkoxymethyl ether nitrile oxide might be supported by an
experiment in which replacing the MEM group of the ni-
trile oxide with an alkyl group would result in a change in
diastereoselectivity. The structure of major cycloadduct
5c was established by X-ray crystallographic analysis af-
ter further elaboration to 7, as shown in Scheme 2. Treat-
oxidation with sodium chlorite, yielded the corresponding
carboxylic acid. Subsequent methyl ester formation with
TMS-diazomethane gave methyl ester 6 in 91% yield over
three steps. Deprotection of 6 with acid produced the cor-
responding alcohol, which was esterified with 4-nitroben-
zoyl chloride to give a crystalline product, ester 7, in 90%
yield.11
Table 1 1,3-Dipolar Cycloaddition of Cinnamyl Alcohol 3 with α-Hydroxy-Protected Nitrile Oxides 4a–e10
Ph
OH
Ph
OH
3 (1.1 equiv)
EtMgBr (3.0 equiv)
i-PrOH (3.3 equiv)
Cl
Ph
Ph
R1O
Ph
R1O
O
O
OH
N
N
N
R1O
solvent, 0 °C to r.t., 12 h
4a–e
5a–e
5a'–e'
Entry
4
R1 (4)
Solvent
Cycloadducts
Yield (%)a
Ratiob
1
2
3
4
5
6
4a
4b
4c
4d
4d
4e
TBDMS
n-propyl
MOM
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
5a/5a'
5b/5b'
5c/5c'
5d/5d'
5d/5d'
5e/5e'
69
80
85
56
64
56
62:38
54:46
75:25
78:22
87:13
77:23
MEM
MEM
(+)-menthoxymethyl
a Isolated yield after column chromatography.
b Determined by 1H NMR spectroscopic analysis after purification.
Synlett 2014, 25, 2953–2956
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (–)/(–)-cis-Clausenamide
2955
We then examined the elaboration of 8 to intermediate 9
en route to (–)-clausenamide (1) (Scheme 3). 2-Isoxazo-
line 8, which was available from MOM-group cleavage of
6, was subjected to trimethyloxonium tetrafluoroborate to
give N-methylisoxazolinium salt C.12 In our trials using
several hydride-delivering reagents (data not shown) for
the conversion of C into 9, treatment with zinc borohy-
dride successfully afforded 9 as a single stereoisomer in
63% yield from 8. To our knowledge, this is the first ex-
ample of a stereoselective reduction of the C=N bond of a
3,4,5-trisubstituted isoxazolinium salt.13
Ph
OH
a
Ph
HO
9
O
N
H
Me
2
Scheme 4 Reagents and conditions: (a) Zn, AcOH–H2O, 90 °C,
66%.
In conclusion, we have revealed that magnesium alkox-
ides influence not only the regioselectivity, but also the di-
astereoselectivity of the 1,3-dipolar cycloaddition of α-
alkoxymethyl ether nitrile oxide and cinnamyl alcohol;
we have used this mode of reactivity to develop a new
route for the synthesis of clausenamide and derivatives.
We believe that our results constitute a valuable contribu-
tion toward asymmetric 1,3-dipolar cycloaddition reac-
tions without chiral catalysts and/or auxiliaries. The
elucidation of the mechanism for the diastereoselectivity
of the cycloaddition and further applications of this meth-
od to the synthesis of additional natural products are under
intense investigation.
The hydroxyl group of 9 was protected as the acetate by
using acetic anhydride, then reduction of 10 with zinc dust
and acetic acid effected cleavage of the N–O bond fol-
lowed by concomitant cyclization of the resulting amino
ester to pyrrolidinone 11 in 73% yield. By using the Bar-
ton–McCombie deoxygenation protocol,14 11 was trans-
formed into thionocarbonate 12, which was then treated
with tributyltin hydride and a stoichiometric amount of
triethylborane to afford the deoxygenated intermediate.
Subsequent treatment with LiOH gave deoxypyrrolidi-
none 13 in 63% yield over two steps; the latter compound
is a known intermediate of (–)-clausenamide (1).7a,15 Fi-
nally, reductive cleavage of 9 with zinc dust and acetic
acid gave (–)-cis-clausenamide (2) in 66% yield (Scheme
4).16
Acknowledgment
This work was financially supported by The Science Research Pro-
motion Fund. We also thank Dr. Osamu Tamura and Dr. Tamiko
Kiyotani at Showa Pharmaceutical University for X-ray analysis of
7.
Ph
CO2Me
Ph
CO2Me
a
b
Ph
HO
Ph
HO
O
O
N
N
References and Notes
Me
8
(1) (a) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410.
(b) Kanemasa, S.; Tsuge, O. Heterocycles 1990, 30, 719.
(c) Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry toward Heterocycles and
Natural Products; John Wiley and Sons: New York, 2002.
(d) Pellissier, H. Tetrahedron 2007, 63, 3235.
(2) (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863. For chiral catalysis and/or auxiliaries in nitrile oxide
cycloadditions, see: (b) Ukaji, Y.; Inomata, K. Synlett 2003,
1075. (c) Sibi, M. P.; Itoh, K.; Jasperse, C. P. J. Am. Chem.
Soc. 2004, 126, 5366. (d) Sibi, M. P.; Ma, Z.; Itoh, K.;
Prabagran, N.; Jasperse, C. P. Org. Lett. 2005, 7, 2349.
(e) Yamamoto, H.; Hayashi, S.; Kubo, M.; Harada, M.;
Hasegawa, M.; Noguchi, M.; Sumitomo, M.; Hori, K. Eur.
J. Org. Chem. 2007, 2859. (f) Brinkmann, Y.; Madhushaw,
R. J.; Jazzar, R.; Bernardinelli, G.; Kündig, E. P.
C
Ph
CO2Me
Ph
CO2Me
c
d
Ph
HO
Ph
O
O
N
N
H
H
AcO
Me
Me
9
10
S
PhS
Ph
OH
O
Ph
e
f, g
Ph
Ph
O
O
N
N
H
H
AcO
AcO
Me
Me
11
12
Tetrahedron 2007, 63, 8413. (g) Suga, H.; Adachi, Y.;
Fujimoto, K.; Furihata, Y.; Tsuchida, T.; Kakehi, A.; Baba,
T. J. Org. Chem. 2009, 74, 1099.
OH
Ph
Ph
ref. 7a
Ph
Ph
(3) (a) Kanemasa, S.; Nishiuchi, M.; Kamimura, A.; Hori, K. J.
Am. Chem. Soc. 1994, 116, 2324. (b) Kanemasa, S.; Okuda,
K.; Yamamoto, H.; Kaga, S. Tetrahedron Lett. 1997, 38,
4095. (c) Kanemasa, S. Synlett 2003, 1371.
O
O
N
N
(3 steps)
H
H
HO
HO
Me
13
Me
1
(4) (a) Bode, J. W.; Fraefel, N.; Muri, D.; Carreira, E. M.
Angew. Chem. Int. Ed. 2001, 40, 2082. (b) Bode, J. W.;
Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611. (c) Bode,
J. W.; Carreira, E. M. J. Org. Chem. 2001, 66, 6410.
(d) Fader, L. D.; Carreira, E. M. Org. Lett. 2004, 6, 2485.
(e) Muri, D.; Lohse, N.; Carreira, E. M. Angew. Chem. Int.
Ed. 2005, 44, 4036. (f) Becker, N.; Carreira, E. M. Org. Lett.
2007, 9, 3857.
Scheme 3 Reagents and conditions: (a) (CH3)3BF4, CH2Cl2, r.t.; (b)
Zn(BH4)2, THF, –78 °C, 63% from 8; (c) Ac2O, DMAP, pyridine,
CH2Cl2, r.t.; (d) Zn, AcOH–H2O, 90 °C, 73% from 9; (e) O-phenyl
chlorothionoformate, pyridine, DMAP, CH2Cl2, 40%; (f) Bu3SnH,
cat. Et3B, toluene, r.t.; (g) aq LiOH, MeOH, r.t. 63% from 11.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2953–2956

2956
K. Tanda et al.
LETTER
(film): 3113, 3067, 3031, 2970, 2947, 2847, 1742, 1732,
(5) (a) Chen, Y. R.; Yang, M. H.; Huang, L.; Liu, G.; Benz, U.
Ger. Offen. DE3431257 Appl. Aug 24, 1984; Chem. Abstr.
1986, 105, 72689r. (b) Feng, Z.; Li, X.; Zheng, G.; Huang,
L. Bioorg. Med. Chem. Lett. 2009, 19, 2112.
(6) Li, X.; Zhu, C.; Li, C.; Wu, K.; Huang, D.; Huang, L. Eur. J.
Med. Chem. 2010, 45, 5531.
(7) For previous syntheses of these compounds, see:
(a) Hartwig, W.; Born, L. J. Org. Chem. 1987, 52, 4352.
(b) Huang, D. F.; Huang, L. Tetrahedron 1990, 46, 3135.
(c) Yakura, T.; Matsumura, Y.; Ikeda, M. Synlett 1991, 343.
(d) Cappi, M. W.; Chen, W.-P.; Flood, R. W.; Liao, Y.-W.;
Roberts, S. M.; Skidmore, J.; Smith, J. A.; Williamson, N.
M. Chem. Commun. 1998, 1159. (e) Yang, L.; Wang, D.-X.;
Zheng, Q.-Y.; Pan, J.; Huang, Z.-T.; Wang, M.-X. Org.
Biomol. Chem. 2009, 7, 2628. (f) Zhang, L.; Zhou, Y.; Yu,
X. Synlett 2012, 1217. (g) Xuan, Y.-N.; Lin, H.-S.; Yan, M.
Org. Biomol. Chem. 2013, 11, 1815.
1601, 1523, 1517, 1351, 1264, 1235, 1105, 1012, 851 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 8.4 Hz, 2 H),
7.62 (d, J = 9.2 Hz, 2 H), 7.42–7.17 (m, 10 H), 6.95 (s, 1 H),
4.95 (d, J = 4.8 Hz, 1 H), 4.48 (d, J = 4.4 Hz, 1 H), 3.72 (s,
3 H). 13C NMR (100 MHz, CDCl3): δ = 169.5, 162.7, 158.1,
150.6, 137.3, 135.1, 134.2, 130.8, 129.5, 129.1, 129.0,
128.3, 127.7, 126.0, 123.3, 86.7, 71.2, 57.1, 52.9. HRMS
(FAB): m/z [M + Na]+ calcd for C25H20N2O7Na: 483.1168;
found: 483.1181.
(12) For the preparation of N-methylisoxazolinium
tetrafluoroborates, see: Cerri, A.; De Micheli, C.; Gandolfi,
R. Synthesis 1974, 710.
(13) For reduction of isoxazolimium salts, see: (a) Henneböhle,
M.; LeRoy, P.-Y.; Hein, M.; Ehrler, R.; Jäger, V. Z.
Naturforsch., B: J. Chem. Sci. 2004, 59, 451. (b) Jäger, V.;
Frey, W.; Bathich, Y.; Shiva, S.; Ibrahim, M.; Henneböhle,
M.; LeRoy, P.-Y.; Imerhasan, M. Z. Naturforsch., B:
J. Chem. Sci. 2010, 65, 821.
(8) All hydroximoyl chlorides expect for 4d are stable under
prolonged storage.
(9) We obtained (E)-cinnamyl alcohol 3 by the Luche reduction
of (E)-cinnamaldehyde, see: Gemal, A. L.; Luche, J.-L.
J. Am. Chem. Soc. 1981, 103, 5454.
(14) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc.,
Perkin Trans. 1 1975, 1574. For reviews, see: (b) Hartwig,
W. Tetrahedron 1983, 39, 2609. (c) Crich, D.; Quintero, L.
Chem. Rev. 1989, 89, 1413.
(10) 1,3-Dipolar Cycloaddition of Cinnamyl Alcohol (3) with
α-Hydroxy-Protected Nitrile Oxides; Typical Procedure
for 4c: To a solution of the (E)-cinnamyl alcohol (3) (796
mg, 5.94 mmol) and i-PrOH (1.50 mL, 17.8 mmol) in
CH2Cl2 (187 mL) was added EtMgBr (1.0 mol/L in THF,
17.8 mL, 17.8 mmol) at 0 °C. The resulting mixture was
stirred for 30 min at 0 °C. At this time, hydroximoyl chloride
4c (1.50 g, 6.53 mmol) in CH2Cl2 (100 mL) was added to the
reaction dropwise by using a dropping funnel over 20 min,
followed by two rinses with CH2Cl2 (5 mL each). The
reaction mixture was stirred for 12 h and gently warmed to
r.t., then the reaction was quenched with sat. aq NH4Cl
solution. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3 × 40 mL). The combined
organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified
by silica gel column flash chromatography (hexane–EtOAc,
1:1) to give cycloadducts 5c/5c' (1.81 g, 85%) as a yellow
oil. d.r. = 75:25 [integration of signals at δ = 5.40 (major)
and 5.28 (minor) ppm in the 1H NMR spectrum].
(15) Spectroscopic Data for 13: [α]D27 –184.1 (c 0.50, CHCl3);
mp 122–124 °C. IR (film) 3362, 3088, 3056, 3030, 2923,
2243, 1670, 1492, 1454, 1401, 1259, 1042, 911, 760 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.28–7.06 (m, 8 H),
6.71–6.69 (m, 2 H), 5.34 (d, J = 3.6 Hz, 1 H), 4.64 (dd,
J = 2.8, 3.2 Hz, 1 H), 4.28 (dd, J = 3.2, 5.2 Hz, 1 H), 3.82
(dt, J = 8.4, 12.4 Hz, 1 H), 2.91 (s, 3 H), 2.08–1.96 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 173.4, 141.2, 137.7, 128.4,
127.7, 127.3, 127.0, 126.8, 126.3, 72.1, 67.8, 40.7, 33.1,
30.1. HRMS (FAB): m/z [M + H]+ calcd for C18H20NO2:
282.1494; found: 282.1522.
(16) Synthesis of (–)-cis-Clausenamide (2): A mixture of 9 (350
mg, 1.07 mmol) and zinc dust (1.05 g, 16.0 mmol) was
heated at 90 °C in AcOH–H2O (10:1, 18 mL) for 3 h. The
reaction mixture was concentrated in vacuo, diluted with
EtOAc, neutralized with sat. aq NaHCO3 solution and
washed with brine. The organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified
by silica gel column flash chromatography (CHCl3–MeOH,
15:1) to give (–)-cis-clausenamide (2) (272 mg, 86%).
[α]D26 –6.78 (c 1.00, CHCl3); mp 194–196 °C. IR (film):
3299, 3209, 3181, 2919, 2852, 1684, 1661, 1454, 1404,
1239, 1214, 1103, 1023, 953, 910 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.29–7.19 (m, 10 H), 4.81 (d, J = 4.8 Hz, 1 H),
4.53 (d, J = 6.8 Hz, 1 H), 4.17 (dd, J = 6.0, 0.8 Hz, 1 H), 3.84
(dd, J = 6.0 Hz, 0.8 Hz, 1 H), 3.30 (br. s, 1 H), 2.61 (s, 3 H),
2.23 (br. s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 175.8,
140.6, 134.2, 130.0, 128.6, 128.2, 127.8, 126.7, 71.9, 71.8,
65.8, 47.5, 29.6. HRMS (FAB): m/z [M + H]+ calcd for
C18H20NO3: 298.1443; found: 298.1473.
Major Cycloadduct 5c: [α]D27 –160.7 (c 1.00, CHCl3). IR
(film): 3428, 3060, 3028, 2945, 2889, 2825, 1604, 1494,
1455, 1151, 1094, 1035, 902, 753 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.36–7.27 (m, 8 H), 7.17 (d, J = 6.8 Hz, 2 H),
5.40 (s, 1 H), 4.58 (dd, J = 5.6, 3.6 Hz, 1 H), 4.32 (dd,
J = 60.4, 6.8 Hz, 2 H), 4.19 (d, J = 6.0 Hz, 1 H), 3.73–3.68
(m, 1 H), 3.59–3.53 (m, 1 H), 3.11 (s, 3 H), 1.94 (t,
J = 6.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 161.5,
138.4, 137.3, 129.0, 128.5, 128.3, 127.9, 127.8, 127.1, 93.8,
89.9, 72.2, 63.1, 55.7, 55.4, 53.4. HRMS (FAB): m/z [M +
H]+ calcd for C19H22NO4: 328.1549; found: 328.1533.
(11) Spectroscopic Data for 7: Colorless crystals; mp 131–
133 °C (from MeOH). [α]D28 –212.9 (c 1.00, CHCl3). IR
Synlett 2014, 25, 2953–2956
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