An efficient synthesis of cis- and trans-methyl-3-hydroxy-2-pyrrolidone-5-carboxylates, key intermediates for the synthesis of γ-substituted glutamic acid analogs

Full text of DOI:10.1021/jo960241i

4838
J . Org. Chem. 1996, 61, 4838-4841
An Efficien t Syn th esis of cis- a n d
tr a n s-Meth yl-3-h yd r oxy-2-p yr r olid on e-
5-ca r boxyla tes, Key In ter m ed ia tes for th e
Syn th esis of γ-Su bstitu ted Glu ta m ic Acid
An a logs
F igu r e 1.
Sch em e 1
Lawrence J . Heinz,* W. H. W. Lunn, R. E. Murff,
J onathan W. Paschal, and Larry A. Spangle
Lilly Research Laboratories, A Division Of
Eli Lilly And Company, Lilly Corporate Center,
Indianapolis, Indiana 46285
Received February 6, 1996
Glutamic acid is the principle excitatory neurotrans-
mitter in the mammalian central nervous system.1
Receptors which modulate both the presynaptic release
of glutamate and postsynaptic sensitivity to glutamate
excitation are known as excitatory amino acid (EAA)
receptors.2 These can be subdivided into two classes,
ionotropic glutamate receptors (iGluR) and metabotropic
glutamate receptors (mGluR). Ionotropic glutamate
receptors mediate fast synaptic transmission through
ligand-gated ion channels while metabotropic glutamate
receptors modulate intracellular second messengers
through G protein-coupled processes. Excessive stimula-
tion of these receptors by glutamic acid, a phenomenon
known as excitotoxicity, can lead to neuronal cell damage
or cell death.3 Therefore, EAA receptor antagonists may
be useful in the treatment of acute or chronic neurode-
generative disorders such as global or focal cerebral
ischemia and Alzheimer’s disease.4
Recently (2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)pen-
tane-1,5-dioic acid (Figure 1), a glutamic acid analog, has
been disclosed as a potent mGluR antagonist.5 This
observation prompted us to develop an efficient, multi-
gram, stereochemically controlled synthesis of racemic
methyl trans-3-hydroxy-2-pyrrolidone-5-carboxylate (1)
(Scheme 1), thereby providing us with a key intermediate
for preparing γ-substituted glutamic acid analogs. The
preparation of the corresponding ethyl derivative of 1 has
been described via a five step synthesis starting from
ethyl 2,3-dibromopropionate and diethyl acetamido ma-
lonate.6 This procedure suffers from divergent synthetic
pathways and poor overall yield (3%). Recent papers7
prompted us to explore the possibility of using acyl
nitroso dienophiles in the synthesis of 1. Following a
modified procedure,8 commercially available benzyl N-
hydroxycarbamate was oxidized in situ with tetrabutyl-
ammonium periodate forming the transient acyl nitroso
dienophile. This intermediate readily underwent [4 +
2] cycloaddition to cyclopentadiene, affording the hetero
Diels-Alder adduct 2 in 93% yield on a large (1 mol)
scale. Our modification of this procedure led to a modest
22% increase in yield of 2 with respect to the published
procedure.8 Subjecting 2 to potassium permanganate9
gave the diacid 3 which was readily converted to the
diester 4 (65%) by treatment with trimethyloxonium
tetrafluoroborate. Initial attempts to reductively cleave
the N-O bond of 4 with aluminum amalgam10 failed.
Attempts to cleave the N-O bond, employing molybde-
num hexacarbonyl11 proved successful, albeit with major
drawbacks, such as formation of multiple byproducts and
low overall yields. Finally, we found that when the
diester 4 was subjected to catalytic hydrogenation in the
presence of palladium on carbon, both the N-O bond and
the resulting benzyl carbamate were cleaved. This
intermediate readily underwent intramolecular cycliza-
tion in situ, in a highly stereocontrolled fashion, affording
methyl trans-3-hydroxy-2-pyrrolidone-5-carboxylate (1)
(77%). The overall yield of 1 over four steps was 40%.
Assignment of 1 as the trans isomer was made through
1H NMR coupling constant measurements and NOE
studies. The proton H5 (4.29 δ) in Figure 2 displays
coupling constants of 9.3 and 2.6 Hz to H4b (2.37 δ), and
H4a (2.61 δ), respectively. The larger coupling is indica-
tive of cis stereochemistry. The coupling constants of H3
* Author to whom correspondance should be addressed.
(1) (a) McDonald, J . W.; J ohnston, M. V. Brain Res. Rev. 1990, 15,
41. (b) Collingridge, G. L.; Lester, R. A. Pharmacol. Rev. 1989, 41, 143.
(2) Hollman, M.; Heinemann, S. Annu. Rev. Neurosci. 1994, 17, 31.
(3) (a) Pin, J .-P.; Duvoisin, R. Neuropharmacology 1995, 34, 1. (b)
Schoepp, D. D.; Conn, P. J . Trends Pharmacol. Sci. 1993, 14, 13. (c)
Nakanishi, S.; Masu M. Annu. Rev. Biophys. Biomol. Struct. 1994, 23,
319. (d) Meldrum, B.; Garthwaite, J . Trends Pharmacol. Sci. 1990,
11, 379. (e) Beal, M. F. FASEB J . 1992, 6, 3338. (f) Choi, D. W.;
Rothman, S. M. Annu. Rev. Neurol. 1990, 13, 171. (g) Lipton, S. A.;
Rosenburg, P. A. N. Engl. J . Med. 1994, 330, 613.
(4) (a) Ulas, J .; Weihmuller, F. B.; Brunner, L. C.; J oyce, J . N.;
Marshall, J . F.; Cotman, C. W. J . Neurosci. 1994, 14, 6317. (b) Francis,
P. T.; Sims, N. R.; Procter, A. W.; Bowen, D. M. J . Neurochem. 1993,
60, 1589.
(5) Wermuth, C. G.; Mann, A.; Schoenfelder, A.; Wright, R. A.;
J ohnson, B. G.; Burnett, J . P.; Mayne, N. G.; Schoepp, D. D. J . Med.
Chem., in press.
(6) (a) Lee, Y. K.; Kaneko, T.; Hanafusa, T. Bull. Chem. Soc. J pn.
1962, 35, 875. (b) Lee, Y. K.; Kaneko, T. Bull. Chem. Soc. J pn. 1973,
46, 3494.
(8) Kirby, G. W.; McGuigan, H.; Mackinnon, J . W. M.; McLean, D.;
Sharma, R. P. J . Chem. Soc., Perkin. Trans. 1 1985, 1437.
(9) Starks, C. M. J . Am. Chem. Soc. 1971, 93, 195.
(10) Keck, G. E.; Fleming, S.; Nickell, D.; Weider, P. Synth.
Commun. 1979, 281.
(7) (a) Ritter, A. R.; Miller, M. J . J . Org. Chem. 1994, 59, 4602. (b)
Ritter, A. R.; Miller, M. J . Tetrahedron Lett. 1994, 50, 9379.
(11) Nitta, M.; Kobayashi, T. J . Chem. Soc., Perkin Trans. 1 1985,
1401.
S0022-3263(96)00241-1 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 14, 1996 4839
a solid. Combining the isolated lots of 5 afforded a 53%
yield of this product from 6.
The stereochemistry at the C3 position of 5 could not
be determined using 1H NMR coupling constant mea-
surements because of similarities in the couplings be-
tween H5 to H4 and H3 to H4. The proton H5 (4.19 δ) in
Figure 2 displayed coupling constants of 7.5 Hz to H4b
(2.85 δ) and 8.5 Hz to H4a (2.08 δ). The coupling
constants of H3 (4.38 δ) were 7.8 Hz to H4b (2.85 δ) and
8.5 Hz to H4a (2.08 δ). With this, the stereochemistry at
C-3 was assigned by a 2-D ROESY13 experiment. ROEs
between H5 and H4b as well as H3 and H4b were found.
Protons H3, H4b, and H5 are situated on the same face of
the pyrrolidone ring system thus inferring cis stereo-
chemistry between the C3-hydroxyl group and C5-ester
functionality (Figure 2).
F igu r e 2. Observed NOEs for 1 and ROEs for 5.
Sch em e 2
Additional supporting data for the stereochemical
assignments of isomers 1, 5, 6, and 7 can be drawn by
1
comparison of their H NMR spectra. Close examination
of protons H4a and H4b reveal clear differences in chemical
shifts when these protons are influenced by highly
shielded or deshielded electronic environments. The H4a
proton in trans isomer 1 resonates at 2.61ppm. When
H4a is situated on the same face of the pyrrolidone ring
as the C3-hydroxy and C5-ester functionality, as in 5,
the resulting highly shielded electronic environment
causes an upfield shift of 0.53 ppm for this proton
compared to 1. Analogously, when H4b is no longer
situated on the same face of the ring system as the C3-
hydroxy and C5-ester functionality, as in 5, the resulting
deshielded electronic environment causes a downfield
shift of 0.48 ppm for this proton compared to H4b in 1.
The same phenomenon was observed for the benzoyl
isomers 6 and 7 (see Experimental Section for peak
positions and the Supporting information for the NMR
spectra).
(4.41 δ) are 8.1 Hz to both H4a and H4b, which cannot be
used to determine stereochemistry at the C-3 position.
However, results of the NOE experiments shown in
Figure 2 were used to determine stereochemistry at the
C-3 position. There are NOEs between H4b and H5 and
between H3 and H4a. The observed NOEs indicate that
the C3 hydroxyl functionality and H4a are situated on
opposite faces of the pyrrolidone ring system. Similarly,
H4a and H5 are also situated on opposite faces of the
pyrrolidone ring system. Therefore, the C3-hydroxyl
functionality is deduced to be trans to the C5-car-
bomethoxy group.
The corresponding cis isomer 5 was readily synthesized
from 1 in two steps (Scheme 2). Employing standard
Mitsunobu conditions,12 treatment of 1 with benzoic acid
afforded the cis benzoate 6 in 69% yield with inversion
of configuration. The corresponding trans benzoate 7
(64%) was prepared from 1 with benzoyl chloride in
pyridine. Examination of the cis and trans benzoates by
1H NMR revealed clear differences between the C4
methylene protons (see Experimental Section for peak
positions and the supporting information for the NMR
spectra). Next, the cis benzoate 6 was subjected to
methanolysis to yield methyl cis-3-hydroxy-2-pyrrolidone-
5-carboxylate (5). Examination of the crude cis isomer
5 by 1HNMR indicated no epimerization had resulted
during methanolysis of the benzoate 6. Pure 5 was
isolated by crystallization followed by purification using
Florisil column chromotography. The mother liquor was
subjected to silica gel column chromotography. In the
latter process, epimerization occurred affording a 87:13
mixture of cis and trans isomers. We were able to
separate 5 from the mixture by exploiting the differences
in solubility between the two diastereomers. The cis
isomer 5 was water soluble and relatively insoluble in
organic solvents, while the trans isomer 1 exhibited
opposite solubilities to that of 5. Trituration of the
mixture in THF followed by filtration afforded pure 5 as
In conclusion, we have been able to selectively prepare
methyl trans-3-hydroxy-2-pyrrolidone-5-carboxylate (1) in
a concise, stereochemically controlled manner from cy-
clopentadiene. As demonstrated, our approach is ame-
nable to large scale synthesis and is a 13 fold improve-
ment in yield over a previously described procedure for
the corresponding ethyl ester derivative.6 The corre-
sponding cis isomer 5 was also synthesized in a stereo-
chemically controlled fashion from 1 in two steps, a 2 fold
improvement in yield from a previously described pro-
cedure.6 Both isomers serve as useful synthetic inter-
mediates for synthesizing γ-substituted glutamic acid
analogs. Subsequent application of these intermediates
to our EAA antagonist structure activity studies are
ongoing and will be reported elsewhere.
Exp er im en ta l Section
Melting points are uncorrected. THF was distilled from
sodium benzophenone ketyl prior to use. All other reagents were
purchased from commercial sources and used as obtained. 1H
NMR spectra were obtained at 300 MHz. 13C NMR spectra were
obtained at 75 MHz. The COESY and ROESY experiments were
obtained at 500 MHz. Field desorption mass spectral data was
recorded on
a VG 70se instrument. Separations by flash
chromatography were performed on silica gel (230-400 mesh).
Flash silica gel filtration refers to Harwood’s technique.14
(13) (a) Bothner-By, A. A.; Stephens, R. L.; Lee, J . M.; Warren, C.
D.; J eanloz, R. W. J . Am. Chem. Soc. 1984, 106, 811. (b) Bax, A. J .
Magn. Reson. 1988, 77, 134.
(12) Mitsunobu O. Synthesis 1981, 1.
(14) Harwood, L. M. Aldrichim. Acta 1985, 18, 25.

4840 J . Org. Chem., Vol. 61, No. 14, 1996
Notes
N-(Ben zyloxyca r bon yl)-2-oxa -3-a za bicyclo[2.2.1]h ep t-5-
en e (2). To a suspension of benzyl N-hydroxycarbamate (166.5
g, 1.0 mol) in CH2Cl2 (1000 mL) cooled to -10 °C was added
freshly distilled cyclopentadiene (59.6 g, 0.9 mol). The solution
was then treated with a suspension of tetrabutylammonium
periodate (429 g, 1.0 mol) in CH2Cl2 (900 mL) at a rate such
that the temperature remained below 3 °C. After the addition
of the periodate was complete (ca. 20 min), the resulting mixture
was stirred at -5 °C for 2 h. A solution of NaHSO3 (340.5 g,
3.3 mol) in water (1350 mL) was carefully added (cautionshighly
exothermic reaction!) at such a rate to maintain the reaction
temperature between -2 °C and 6 °C. Once the addition of the
NaHSO3 was complete (ca. 50 min), the organic phase was
removed. The aqueous phase was treated with water (1600 mL),
causing further separation of the organic and aqeuous phases.
The combined organic phases were washed with water (3 × 1600
mL), saturated NaHCO3 solution (1050 mL), water (1600 mL),
and 1 N HCl solution (1200 mL). The organic phase was dried
over NaCl and then MgSO4 and concentrated in vacuo to afford
547 g of a brown residue. This residue was treated with Et2O
(1400 mL) and the resulting mixture filtered. The filtrate was
evaporated to a solid (206.0 g). The solid was subjected to flash
silica gel filtration, eluting with hexane:EtOAc (4:1, 4 × 3 L)
and then hexane:EtOAc (2:1, 6 × 3 L). The fractions containing
the title compound were combined and concentrated in vacuo
to afford a yellow oil. The title compound crystallized from the
oil yielding 194.9 g (93%) of a solid: mp 34-36 °C. 1H (CDCl3)
δ 7.31 (m, 5H), 6.38 (s, 2H), 5.24 (s, 1H), 5.19 (d, J ) 12.2 Hz,
1H), 5.12 (d, J ) 12.2 Hz, 1H), 5.05 (s, 1H), 2.01 (d, J ) 8.7 Hz,
1H), 1.75 (d, J ) 8.7 Hz, 1H); APT 13C (DMSO-d6) δ up: 158.6,
136.0, 66.8, 47.9; down: 134.5, 133.2, 128.4,128.1, 127.8, 83.1,
64.8; FDMS m/ z (relative intensity) 231 (100, M+). Anal. Calcd
for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.25; H,
5.69; N, 5.96.
N-(Ben zyloxyca r bon yl)-3,5-d ica r boxy-1,2-oxa zolin e (3).
A biphasic solution of 2 (69.4 g, 0.30 mol) in toluene (694 mL)
and water (150 mL) was treated with tetrabutylammonium
hydrogen sulfate (10.2 g, 0.03 mol). The resulting mixture was
cooled to approximately 2 °C, and a solution of KMnO4 (123.2 g,
0.78 mol) in water (800 mL) was added at a rate such that the
temperature was kept below 6 °C. After the addition of the
permanganate was complete (ca. 50 min), the resulting mixture
was mechanically stirred at 0 °C for 2.2 h. The reaction mixture
was then treated with Celite 521 (348 g) and filtered through a
dry Celite pad. The insolubles were washed with MeOH:H2O
(3600 mL, 4:1). The filtrate was concentrated in vacuo to a
volume of about 400 mL. This concentrate was treated with H2O
(100 mL) and EtOAc (600 mL). The pH of this mixture was
adjusted to 0.81 by the addition of 18 N H2SO4 (110 mL). The
phases were separated and the aqueous phases extracted with
EtOAc (2 × 500 mL). The combined organics were dried over
NaCl and MgSO4, filtered, and concentrated in vacuo to afford
81.3 g of the crude title compound. This material was used in
the next reaction without further purification. 1H (CDCl3) δ 7.32
(m, 5H), 5.19 (s, 2H), 4.83 (t, J ) 6.3 Hz, 1H), 4.68 (t, J ) 6.9
Hz, 1H), 2.85 (dd, J ) 6.9, 6.3 Hz, 2H); FDMS m/ z (relative
intensity) 296 (100, M+).
intensity) 323 (100, M+); Anal. Calcd for C15H17NO7: C, 55.73;
H, 5.30; N, 4.33. Found: C,55.63; H, 5.34; N, 4.38.
Meth yl tr a n s-3-Hydr oxy-2-pyr r olidon e-5-car boxylate (1).
A mixture of 4 (100.5 g, 0.31 mol) and 5% palladium on carbon
(40.0 g) in THF (1.2 L) was hydrogenated at 50 psi and at rt.
After 18 h the reaction mixture was filtered and the filtrate
concentrated in vacuo to a solid. Recrystallization from EtOAc
gave 38.3 g (77%) of the title compound: mp 86 °C. 1H (CDCl3)
δ 7.03 (s, CD3OD exchangeable), 4.41 (dd, J ) 8.3, 8.2 Hz, 1H),
4.29 (ddd, J ) 9.3, 2.5, 1.1 Hz, 1H), 3.77 (s,3H), 2.61 (ddd, J )
13.5, 8.2, 2.5 Hz, 1H), 2.37 (ddd, J ) 13.5, 9.3, 8.3 Hz, 1H); APT
13C NMR (DMSO-d6) δ up: 176.6, 173.1, 34.0; down: 67.0, 52.1,
51.5; FDMS m/ z (relative intensity) 160 (100, M+). Anal. Calcd
for C6H9NO4: C, 45.28; H, 5.70; N, 8.80. Found: C, 45.54; H,
5.70; N, 8.54.
Meth yl cis-3-Ben zoyl-2-p yr r olid on e-5-ca r boxyla te (6). A
mixture consisting of 1 (1.56 g, 9.8 mmol), triphenylphosphine
(3.08 g, 11.8 mmol), and benzoic acid (1.44 g, 11.8 mmol), in THF
(36 mL) at -5 °C was treated with DEAD (2.05 g, 11.8 mmol),
while maintaining the reaction temperature below 7 °C. After
stirring 4 h at rt, the reaction was concentrated in vacuo to an
oil. The oil was treated with CHCl3 (5 mL), resulting in the
precipitation of dicarbethoxyhydrazine. The crystalline dicarb-
ethoxyhydrazine was collected by filtration and washed with 1:1
CHCl3:hexane (5 mL). The filtrate was concentrated in vacuo
and purified on a flash silica gel column (5.5 × 8.5 cm), eluting
with acetone to afford the title compound. Recrystallization from
acetone:diisopropyl ether afforded 1.78 g (69%): mp 108-109
°C. 1H (CDCl3) δ 8.07 (d, J ) 8.3 Hz, 2H), 7.58 (m, 1H), 7.44
(m, 2H), 6.41 (bs, 1H), 5.54 (dd, J ) 8.3, 8.2 Hz, 1H), 4.30 (dd,
J ) 7.8, 7.8 Hz, 1H), 3.80 (s,3H), 3.10 (ddd, J ) 13.6, 8.2, 8.2 Hz
1H), 2.29 (ddd, J ) 13.5, 7.8, 7.8 Hz, 1H); APT 13C NMR (DMSO-
d6) δ up: 172.9, 172.5, 165.8, 130.1, 32.0; down: 134.6, 130.2,
129.8, 71.1, 53.1, 52.5; FDMS m/ z (relative intensity) 263 (100,
M), 204 (10). Anal. Calcd for C13H13NO5: C, 59.31; H, 4.98; N,
5.32. Found: C,59.45; H, 5.01; N, 5.49.
Meth yl cis-3-Hyd r oxy-2-p yr r olid on e-5-ca r boxyla te (5).
A solution of sodium methoxide (0.08 g, 1.5 mmol) in MeOH (11
mL) was treated with 6 (1.34 g, 5.1 mmol). The reaction was
stirred at 22 °C for 3.2 h, treated with 1 N HCl (1.5 mL, 1.5
mmol), and then concentrated in vacuo to afford an oil. 1H NMR
of this material indicates no epimerization has occurred. The
oil was cooled to -20 °C, resulting in crystal formation. The
crystals were collected by filtration, washed with CHCl3, taken
up into methanol, purified on a Florisil column (3 × 7 cm),
eluting with CHCl3:MeOH (9:1), to afford 354 mg of the title
compound. The filtrate was concentrated in vacuo, taken up
into MeOH, and subjected to silica gel chromtography (3 × 7
cm, 90:10:1 CHCl3:MeOH:NH4OH). The product eluted as a
mixture of 6.7:1 cis:trans methyl 3-hydroxy-2-pyrrolidone-5-
carboxylate. This mixture was triturated in THF (4 mL), filtered
and washed with THF (1 mL) to afford 75 mg of the title
compound. Combining both lots of 6 afforded 429 mg (53%) of
pure methyl cis-3-hydroxy-2-pyrrolidone-5-carboxylate: mp 71-
72 °C. 1H (CDCl3) δ 6.62 (bs, 1H), 4.38 (dd, J ) 8.5, 7.8 Hz,
1H), 4.19 (ddd, J ) 8.5, 7.8, 7.6 Hz, 1H), 3.80 (s, 3H), 2.85 (ddd,
J ) 13.0, 7.8, 7.6 Hz, 1H), 2.08 (ddd, J ) 12.9, 8.9, 8.9 Hz, 1H);
APT 13C (DMSO-d6) δ up: 175.8, 172.2, 34.0; down: 67.7, 51.8,
50.9; FDMS m/ z (relative intensity) 159 (100, M). Anal. Calcd
for C6H9NO4: C, 45.28; H, 5.70; N, 8.80. Found: C,45.52; H,
5.70; N, 8.57.
Meth yl tr a n s-3-Ben zoyl-2-p yr r olid on e-5-ca r boxyla te (7).
To a solution of 1 (0.56 g, 3.5 mmol) in pyridine (7 mL) at 22 °C
was added benzoyl chloride (0.49 g, 3.5 mmol). The reaction was
stirred at 22 °C for 6 h and then concentrated in vacuo to afford
a solid. The solid was treated with CH2Cl2 (30 mL) and H2O
(30 mL), phases were separated, and the aqueous phases were
extracted with additional CH2Cl2 (2 × 10 mL). The combined
organic phases were dried over Na2SO4 and then filtered. The
filtrate was boiled down to approximately 10 mL and cooled to
22 °C, and the resulting crystals were collected by filtration to
afford 450 mg (64%) of the title compound: mp 187-189 °C. 1H
(CDCl3) δ 8.08 (d, J ) 7.4 Hz, 2H), 7.59 (m, 1H), 7.45 (m, 2H),
6.89 (bs, 1H), 5.58 (dd, J ) 8.2, 8.2 Hz, 1H), 4.39 (dd, J ) 9.1,
2.8, Hz, 1H), 3.82 (s, 3H), 2.88 (ddd, J ) 13.8, 8.2, 2.8 Hz, 1H),
2.53 (ddd, J ) 13.9, 9.1, 7.8 Hz, 1H); APT 13C NMR (DMSO-d6)
δ up: 172.6, 172.0, 164.9, 128.9, 30.9; down: 133.7, 129.3, 128.8,
69.6, 52.4, 51.8; FDMS m/ z (relative intensity) 264 (100, M+),
N-(Ben zyloxyca r b on yl)-3,5-b is(m et h oxyca r b on yl)-1,2-
oxa zolin e (4). A solution of crude 3 (69.7 g, 0.27 mol) in CH2-
Cl2 (1000 mL) was cooled to -40 °C with an CH3CN/dry ice bath.
The solution was then treated with diisopropylethylamine (68.7
g, 0.53 mol) over a 5 min period. The solution was treated with
trimethyloxonium tetrafluoroborate (78.5 g, 0.53 mol) while
maintaining the reaction temperature below -37 °C. After 3
h, the reaction was allowed to warm to -25 °C for 1 h, and then
the cooling bath was removed. The reaction was treated with
H2O (500 mL) and the phases were separated. The organic
phase was washed with NaHSO4 solution (3 × 400 mL). The
organic phase was dried over NaCl and concentrated in vacuo
to give 81.2 g of crude product. The material was subjected to
flash silica gel filtration, eluting with hexane:EtOAc (4:1, 8 L)
and then hexane:EtOAc (2:1, 19 L). The fractions containing
the desired product were combined and concentrated in vacuo
to afford 49.4 g (65%) of a yellow oil. 1H (CDCl3) δ 7.33 (m, 5H),
5.22 (s, 2H), 4.85 (t, J ) 6.3 Hz, 1H), 4.60 (t, J ) 6.3 Hz, 1H),
3.77 (s, 3H), 3.74 (s, 3H), 2.82 (dd, J ) 6.3, 6.3 Hz, 2H); APT 13C
(DMSO-d6) δ up: 169.8, 168.3, 156.1, 135.6, 67.6, 35.2; down:
128.4, 128.2, 128.0, 77.0, 60.0, 52.5, 52.3; FDMS m/ z (relative

Notes
J . Org. Chem., Vol. 61, No. 14, 1996 4841
204 (24). Anal. Calcd for C13H13NO5: C, 59.31; H, 4.98; N, 5.32.
Found: C,59.36; H, 5.03; N, 5.51.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
1, 5, 6, and 7 (4 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Ack n ow led gm en t. We thank J . Gilliam for as-
sistance with the mass spectral data along with the
Physical Chemistry Department of Lilly Research Labo-
ratories for providing analytical and spectral data.
J O960241I