A short, facile synthesis of 5-substituted 3-amino-1H-pyrrole-2- carboxylates

Full text of DOI:10.1021/jo9917902

J . Org. Chem. 2000, 65, 2603-2605
2603
Sch em e 1
A Sh or t, F a cile Syn th esis of 5-Su bstitu ted
3-Am in o-1H-p yr r ole-2-ca r boxyla tes
Ning Chen, Yuelie Lu, Kumar Gadamasetti,†
Clarence R. Hurt, Mark H. Norman, and
Christopher Fotsch*
Department of Small Molecule Drug Discovery,
Amgen Inc., One Amgen Center Drive,
Thousand Oaks, California 91320-1789
Received November 18, 1999
Derivatives of 3-amino pyrroles have been shown to
exhibit antibacterial, antiviral, anticonvulsant, antiin-
flammatory, analgesic, and antipyretic activities.1 In
addition, many azo dyes are derived directly from 3-ami-
nopyrroles.2 In the midst of our research efforts, we found
ethyl 3-amino-5-phenyl-1H-pyrrole-2-carboxylate (1) to be
a useful intermediate in the synthesis of other nitrogen
heterocycles.3 Therefore, we needed a rapid synthesis of
pyrrole 1 and its analogues.
Sch em e 2
Initially, we investigated an approach toward the
synthesis of pyrrole 1 similar to the one described by
Elliott and co-workers4,5 for the preparation of 3-amino-
4-benzyl-1H-pyrrole-2-carboxylate (2). In their synthesis,
condensation with aldehyde 3 and diethyl aminomalonate
(4) gave 3-substituted enamine 5, which was cyclized in
the presence of sodium methoxide to give pyrrole 2
(Scheme 1). However, using a similar approach toward
the synthesis of pyrrole 1, we were unable to synthesize
the 2-substituted enamine 7 from benzoyl acetonitrile (6)
and diethyl aminomalonate (4) using standard conditions
such as azeotropic removal of water,6 dehydration with
molecular sieves, or Lewis acid catalysis (TiCl4,7 BF3‚
OEt2).
Considering the lower electrophilicity of the aryl ketone
6 compared to the aldehyde 3, an alternative strategy
for preparing enamine 7 was examined. Since amines are
known to undergo substitution reactions with chloro- and
alkylthio-substituted olefins to yield enamines,8 we took
a similar approach and investigated the reaction of
p-toluenesulfonyl enol ester of R-cyano ketone 8 with
diethyl aminomalonate (4) (Scheme 2). Tosylate 8 was
prepared by reacting benzoyl acetonitrile with p-toluene-
sulfonic anhydride (1.2 equiv) in dichloromethane and
triethylamine (1.5 equiv) in 99% yield. Initial attempts
to obtain enamine 7 from the addition of diethyl amino-
malonate to 8 using K2CO3 in THF failed. However, when
a mixture of tosylate 8 and diethyl aminomalonate
hydrochloride (1.2 equiv) were treated with an ethanolic
solution of sodium ethoxide (0.2 M, 3.5 equiv),9 the
pyrrole 1 was directly obtained without isolation of
enamine 7. Addition of the amine, cyclization and decar-
boxylation occurred in one pot at room temperature to
give a 46% overall yield of 1 from benzoyl acetonitrile.
Upon further investigation we found that the initial use
of tosylate 8 and diethyl aminomalonate was fortuitous.
Attempts to improve the synthesis by substituting the
† Current address: Axys Pharmaceuticals, Inc., 180 Kimball Way,
South San Francisco, CA 94080.
(1) (a) Tarzia, G.; Panzone, G.; Leali, M.; Burdisso, M.; Schiatti, P.;
Selva, D. Farmaco, Ed. Sci. 1984, 39, 538-558. (b) Tarzia, Giorgio;
Panzone, Gianbattista U.S. Patent 4,140,696, 1988. (c) Panzone,
Gianbattista; Tarzia, Giorgio U.S. Patent 4,104,969, 1988. (d) Mezent-
seva, M. V.; Nesterova, I. N.; Nikolaeva, I. S.; Golovanova, E. A.;
Baklanova, O. V.; Filitis, L. N. Khim.-Farm. Zh. 1991, 25, 21-23. (e)
Unverferth, K.; Engel, J .; Hoefgen, N.; Rostock, A.; Guenther, R.;
Lankau, H.-J .; Menzer, M.; Rolfs, A.; Liebscher, J .; Mueller, B. and
Hofmann, H.-J . J . Med. Chem. 1998, 41, 63-73.
(2) (a) Gewald, K.; Schaefer, H.; Bellmann, P. Ger. (East), 265143,
1988. (b) Yagihara, T.; Matsui, N.; Hamamoto, I. PCT Int. Appl. WO
9002734, 1990.
(3) Literature examples of 3-amino-1H-pyrrole-2-carboxylates being
used as precursors to heterocycles: (a) Niitsuma, S.; Kato, K.; Takita,
T.; Umezawa, H. Tetrahedron Lett. 1985, 26, 5785-5786. (b) Geies,
A. A.; El-Dean, A. M. K.; Moustafa, O. S. Monatsh. Chem. 1996, 127,
1263-1272. (c) Monge, A.; Palop, J . A.; Parrado, P.; Perez-Ilzarbe, C.;
Fernandez-Alvarez, E. J . Heterocycl. Chem. 1987, 24, 437-439. (d)
Monge, A.; Palop, J . A.; Goni, T.; Martinez-Crespo, F.; Recalde, I.;
Fernandez-Alvarez, E. J . Heterocycl. Chem. 1986, 23, 647-649. (e)
Monge, A.; Aldana, I.; Font, M.; Arraras, J . A.; Santiago, E.; Lopez-
Unzu, M. J .; Martinez de Irujo, J . J .; Alberdi, E.; Fernandez-Alvarez,
E. Arch. Pharm. (Weinheim, Ger.) 1992, 325, 439-452.
(4) Elliott, A. J .; Morris, P. E., J r.; Petty, S. L.; Williams, C. H. J .
Org. Chem. 1997, 62, 8071-8075.
(5) Other similar approaches are: (a) Lim, M.-I.; Klein, R. S. and
Fox, J . J . J . Org. Chem. 1979, 44, 3826-3829. (b) Lim, M. I.; Ren, W.
Y.; Otter, B. A. and Klein, R. S. J . Org. Chem. 1983, 48, 780-788.
(6) (a) Furukawa, M., Okawara, T., Noguchi, Y. and Terawaki, Y.
Chem. Pharm. Bull. 1979, 27, 2223-2226. (b) Birnberg, G. H.,
Fanshawe, W. J ., Francisco, G. D. and Epstein, J . W. J . Heterocycl.
Chem. 1995, 32, 1293-1298.
(8) (a) Erdmann, B.; Knoll, A. and Liebscher, J . J . Prakt. Chem.
1988, 330, 1015-1021. (b) Gewald, K.; Schaefer, H.; Bellmann, P.;
Hain, U. J . Prakt. Chem. 1992, 334, 491-496.
(9) In
a similar process, Elliott and co-workers also reported
(7) (a) Carlson, R., Nilsson, A. and Stroemqvist, M. Acta Chem.
Scand. 1983, B37, 7-13. (b) Selva, M., Tundo, P. and Marques, C. A.
Synth. Commun. 1995, 25, 369-378.
obtaining a pyrrole directly from the addition of diethyl aminomalonate
to ethyl (ethoxymethylene)cyanoacetate. See: Elliott, A. J .; Montgom-
ery, J . A.; Walsh, D. A. Tetrahedron Lett. 1996, 37, 4339-4340.
10.1021/jo9917902 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/22/2000

2604 J . Org. Chem., Vol. 65, No. 8, 2000
Notes
Ta ble 1. 5-Su bstitu ted
3-Am in o-1H-p yr r ole-2-ca r boxyla tes
1-p h en ylvin yl p-Tolu en esu lfon a te (8). To a 100-mL, round-
bottomed flask were added benzoyl acetonitrile (0.73 g, 5.0
mmol), p-toluenesulfonic anhydride (2.02 g, 6.0 mmol), and CH2-
Cl2 (25 mL). To the above solution was then added Et3N (1.05
mL, 7.5 mmol) dropwise. After 16 h stirring at ambient tem-
perature, the reaction mixture was partitioned between H2O and
CH2Cl2. The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (3×). The combined organic layers
were dried (Na2SO4) and concentrated in vacuo to give an orange
solid. This material was purified by flash chromatography on
silica gel with 1:6 EtOAc-hexanes as eluant to give 1.47 g (99%)
of the title compound as an off-white solid. This material was a
3:1 mixture of the Z and E isomers10 as determined by integra-
tion of the corresponding methyl singlets at 2.47 and 2.44 ppm,
R1
R2
product
overall yield
4-methoxyphenyl
3-trifluoromethylphenyl
3,4-dichlorophenyl
4-trifluoromethoxyphenyl
3-methylphenyl
2-chlorophenyl
2-furanyl
H
H
H
H
H
H
H
H
H
10
11
12
13
14
15
16
17
18
19
30
37
31
38
37
31
61
43
30
21
1
respectively. H NMR (CDCl3; 500 MHz) (chemical shifts of the
E-isomer are given parenthetically): δ 2.47 (2.45) (s, 3H), 5.57
(5.56) (s, 1H), 7.35-7.60 (7.31-7.50) (m, 5H) 7.58 (7.65) (d, 2H,
J ) 8.0), 7.90 (7.76) (d, 2H, J ) 8.0); 13C NMR (CDCl3; 100 MHz)
δ 21.07 (24.25), 89.50 (91.91), 113.56 (118.19), 126.36 (130.81),
128.20 (131.20), 128.36 (131.40), 129.61 (132.94), 131.04 (134.47),
131.57 (134.52), 131.74 (134.75), 146.25 (149.56), 162.02 (166.18);
2-thienyl
tert-butyl
methyl
phenyl
MS (ESI) m/z: 300 (M + 1), 298 (M - 1). Anal. Calcd for C16H13
-
NO3S: C, 64.20; H, 4.38; N, 4.68; S, 10.71. Found: C, 64.29; H,
4.41; N, 4.68; S, 10.88.
tosylate for a mesylate, or by using ethyl glycinate
instead of diethyl aminomalonate, led to an intractable
mixture of products. With sodium methoxide as the base
a major byproduct 9 formed as a result of the addition of
methoxide to the tosylate 8 (Scheme 2). Use of the
stronger nonnucleophilic base potassium tert-butoxide led
to unisolable mixture of products.
Eth yl 3-Am in o-5-p h en yl-1H-p yr r ole-2-ca r boxyla te (1).
Sodium ethoxide was prepared freshly from Na (0.37 g, 16.2
mmol) and absolute ethanol (10 mL) in a 100-mL, round-
bottomed flask equipped with a positive flow of N2 gas. To the
above solution was then added a solution of 2-cyano-1-phenyl-
vinyl p-toluenesulfonate 8 (1.38 g, 4.6 mmol) and diethyl
aminomalonate hydrochloride (1.20 g, 5.5 mmol) in ethanol (15
mL) and THF (7 mL) dropwise through an addition funnel. After
the addition was completed, the reaction mixture was stirred
at ambient temperature for 2 h and concentrated in vacuo to
give an orange solid. Water and EtOAc were added, and the
aqueous layer was back-extracted with EtOAc (3×). The com-
bined EtOAc layers were dried (Na2SO4) and concentrated in
vacuo to give an orange solid. This material was purified by flash
chromatography on silica gel with 1:6 EtOAc-hexanes as eluant
to give 0.50 g (47%) of the title compound as an off-white solid.
Mp: 155.0-155.5 °C. 1H NMR (DMSO-d6; 500 MHz) δ 1.30 (t,
3H, J ) 7.1), 4.23 (q, 2H, J ) 7.1), 5.75 (br s, 2H), 6.00 (d, 1H,
J ) 2.8), 7.24-7.44 (m, 3H), 7.75 (d, 2H, J ) 8.0), 10.73 (br s,
1H); MS (ESI) m/z: 231 (M + 1), 229 (M - 1); IR (Nujol, cm-1):
3433, 3340, 1666. Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13;
N, 12.17. Found: C, 67.96; H, 6.03; N, 12.07.
Ten other examples of 5-substituted 3-amino-1H-
pyrrole-2-carboxylates were prepared using the method
described above (10-19, Table 1). While tosylate 8 was
used after being purified by column chromatography, for
analogue preparation we found it more convenient to use
tosylates simply after aqueous workup. Examples 10-
14 illustrate that the electronic nature of the phenyl ring
has little affect on the overall yields. The electron-rich
4-methoxyphenyl (10) and 3-methylphenyl (14) deriva-
tives had comparable yields to the electron-poor 3-trif-
luoromethylphenyl (11), 3,4-dichlorophenyl (12), and
4-trifluoromethoxyphenyl (13) derivatives. The reaction
process was not sensitive to the steric effects of the
2-chlorophenyl (15) or the tert-butyl (18) groups since
yields were comparable to products containing less steri-
cally demanding groups. However, attempts to form the
product with a 2-nitro group on the aryl ring led to
decomposition of the starting material. Heteroaromatics
such as furanyl (16, 61% yield) and thienyl (17, 43%
yield) behaved similarly to phenyl (1, 46% yield). Finally,
a tetrasubstituted pyrrole (19) was also formed using this
method.
Com p ou n d s 10-19: P r ep a r ed Usin g th e Meth od s De-
scr ibed Above for Tosyla te 8 a n d P yr r ole 1. Only the
amounts of R-cyano ketones are given below. All other reagents
were used in the same molar ratio as detailed in the experi-
mental methods above.
Eth yl 3-Am in o-5-(4-m eth oxyp h en yl)-1H-p yr r ole-2-ca r -
boxyla te (10). The title compound (0.78 g, 30%) was prepared
using 4-methoxybenzoyl acetonitrile (1.75 g, 10 mmol) and was
recrystallized from toluene. Mp: 173.0-174.5 °C. 1H NMR
(DMSO-d6; 500 MHz) δ 1.29 (t, 3H, J ) 7.0), 3.77 (s, 3H), 4.21
(q, 2H, J ) 7.0), 5.07 (br s, 2H), 5.89 (d, 1H, J ) 1.2), 6.93 (d,
2H, J ) 8.4), 7.69 (d, 2H, J ) 8.4), 10.58 (br s, 1H); MS (ESI)
m/z: 261 (M + 1); IR (Nujol, cm-1): 3432, 3340, 1667. Anal.
Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C,
64.86; H, 6.21; N, 10.57.
In summary, we have developed an extremely facile,
two-step synthesis for 5-substituted 3-amino-1H-pyrrole-
2-carboxylates. The key step in this synthesis is the one-
pot formation of the pyrrole ring from diethyl amino-
malonate and p-toluenesulfonyl enol esters of R-cyano
ketones. Other applications of this process are currently
being explored and will be reported in due course.
(10) In an independent experiment, the Z and E isomers were
separated by flash chromatography on silica gel with 1:9 EtOAc-
hexanes as the eluant. The ortho-protons (Hb) of the major isomer ((Z)-
8) showed a strong NOE when the vinyl proton (Ha) was irradiated.
However, irradiation of the vinyl proton (Ha) on the minor isomer ((E)-
8) led to no enhancement of the ortho-protons (Hb).
Exp er im en ta l Section
Gen er a l. All chemicals were commercially available and
reagent grade unless otherwise specified. All solvents were
anhydrous grade and were used without further purification.
High-resolution mass spectra (HRMS) were performed by Mass
Consortium, La J olla, CA. Elemental analyses were performed
by Atlantic Microlab, Inc., Norcross, GA. Melting points were
determined with a capillary melting point apparatus and are
uncorrected.
Rep r esen ta tive Exa m p le for th e P r ep a r a tion of Eth yl
3-Am in o-5-su bstitu ted-1H-pyr r ole-2-car boxylates. 2-Cyan o-

Notes
Eth yl 3-Am in o-5-[3-(tr iflu or om eth yl)ph en yl]-1H-pyr r ole-
J . Org. Chem., Vol. 65, No. 8, 2000 2605
7.51 (d, 1H, J ) 7.5), 7.59 (d, 1H, J ) 7.5), 10.74 (br s, 1H); MS
(ESI) m/z: 265 (M + 1); IR (Nujol, cm-1): 3466, 3378, 1678. Anal.
Calcd for C13H13ClN2O2: C, 58.99; H, 4.95; N, 10.58; Cl, 13.39.
Found: C, 58.80; H, 5.08; N, 10.40; Cl, 13.17.
2-ca r boxyla te (11). The title compound (5.22 g, 37%) was
prepared using [3-(trifluoromethyl)benzoyl]acetonitrile (10 g,
46.9 mmol) and was recrystallized from toluene. Mp: 181.5-
1
182.0 °C. H NMR (DMSO-d6; 500 MHz) δ 1.31 (t, 3H, J ) 7.0),
E t h yl 3-Am in o-5-(2-fu r a n yl)-1H -p yr r ole-2-ca r b oxyla t e
(16). The title compound (1.28 g, 61%) was prepared using
2-furoylacetonitrile (1.35 g, 10 mmol) and was recrystallized from
4.25 (q, 2H, J ) 7.0), 5.12 (br s, 2H), 6.15 (d, 1H, J ) 2.6), 7.58
(d, 2H, J ) 8.1), 8.00-8.01 (m, 1H), 8.22 (s, 1H), 11.06 (br s,
1H); MS (ESI) m/z: 299 (M + 1); IR (Nujol, cm-1): 3441, 3356,
1641. Anal. Calcd for C14H13F3N2O2: C, 56.38; H, 4.39; N, 9.39.
Found: C, 56.10; H, 4.48; N, 9.14.
1
toluene. Mp: 124.0-125.0 °C. H NMR (DMSO-d6; 500 MHz) δ
1.29 (t, 3H, J ) 7.0), 4.22 (q, 2H, J ) 7.0), 5.11 (br s, 2H), 5.84
(d, 1H, J ) 2.7), 6.53-6.54 (m, 1H), 6.95 (d, 1H, J ) 3.4), 7.65
(d, 1H, J ) 1.4), 10.85 (br s, 1H); MS (ESI) m/z: 221 (M + 1); IR
(Nujol, cm-1): 3425, 3338, 1667. Anal. Calcd for C11H12N2O3:
C, 59.99; H, 5.49; N, 12.72. Found: C, 59.95; H, 5.55; N, 12.79.
E t h yl 3-Am in o-5-(2-t h ien yl)-1H -p yr r ole-2-ca r b oxyla t e
(17). The title compound (0.97 g, 43%) was prepared using
2-thenoylacetonitrile (1.51 g, 10 mmol) and was recrystallized
from toluene. Mp: 149.0-151.0 °C. 1H NMR (DMSO-d6; 500
MHz) δ 1.29 (t, 3H, J ) 7.0), 4.22 (q, 2H, J ) 7.0), 5.10 (br s,
2H), 5.79 (d, 1H, J ) 2.6), 7.05-7.07 (m, 1H), 7.44 (d, 1H, J )
4.0), 7.58 (d, 1H, J ) 4.0), 10.90 (br s, 1H); MS (ESI) m/z: 237
(M + 1); IR (Nujol, cm-1): 3425, 3337, 1662. Anal. Calcd for
Eth yl 3-Am in o-5-(3,4-d ich lor op h en yl)-1H-p yr r ole-2-ca r -
boxyla te (12). The title compound (2.43 g, 31%) was prepared
using 3,4-dichlorobenzoyl acetonitrile (5.57 g, 26.0 mmol) and
1
was recrystallized from toluene. Mp: 184.0-185.0 °C. H NMR
(DMSO-d6; 500 MHz) δ 1.30 (t, 3H, J ) 7.0), 4.24 (q, 2H, J )
7.0), 5.12 (br s, 2H), 6.11 (s, 1H), 7.60 (d, 1H, J ) 8.5), 7.72 (d,
1H, J ) 8.5), 8.14 (s, 1H), 10.95 (br s, 1H); MS (ESI) m/z: 299
(M + 1); IR (Nujol, cm-1): 3440, 3337, 1638. Anal. Calcd for
C
13H12Cl2N2O2: C, 52.19; H, 4.04; N, 9.36; Cl, 23.70. Found: C,
52.20; H, 4.12; N, 9.23; Cl, 23.53.
Eth yl 3-Am in o-5-[4-(tr iflu or om eth oxy)p h en yl]-1H-p yr -
r ole-2-ca r boxyla te (13). The title compound (2.58 g, 38%) was
prepared using [4-(trifluoromethoxy)benzoyl]acetonitrile (5.00 g,
21.8 mmol) and was recrystallized from toluene. Mp: 175.0-
C
11H12N2O2S: C, 55.92; H, 5.12; N, 11.86; S, 13.57. Found: C,
56.04; H, 5.04; N, 11.75; S, 13.60.
E t h yl 3-Am in o-5-(ter t-b u t yl)-1H -p yr r ole-2-ca r b oxyla t e
(18). The title compound (0.63 g, 30%) was prepared using 4,4-
dimethyl-3-oxopentane nitrile (1.25 g, 10 mmol). 1H NMR
(DMSO-d6; 500 MHz) δ 1.20 (s, 9H), 1.26 (t, 3H, J ) 7.0), 4.19
(q, 2H, J ) 7.0), 4.93 (br s, 2H), 5.32 (d, 1H, J ) 2.9), 9.98 (br s,
1H); 13C NMR (DMSO-d6; 100 MHz) δ 15.70, 30.50, 32.32, 58.92,
95.12, 104.56, 126.72, 148.72, 161.90; MS (HRMS) m/z: 211.1446
(expected), 211.1443 (observed); IR (neat, cm-1): 3477, 3329,
1659.
Eth yl 3-Am in o-5-m eth yl-4-p h en yl-1H-p yr r ole-2-ca r boxy-
la te (19). The title compound (0.51 g, 21%) was prepared using
(R-acetylphenyl)acetonitrile (1.59 g, 10 mmol) and was recrystal-
lized from toluene. Mp: 157.0-158.5 °C. 1H NMR (DMSO-d6;
500 MHz) δ 1.26 (t, 3H, J ) 7.0), 2.21 (s, 3H), 4.16 (q, 2H, J )
7.0), 4.90 (br s, 2H), 7.17-7.42 (m, 5H), 10.18 (br s, 1H); MS
(ESI) m/z: 245 (M + 1); IR (Nujol, cm-1): 3449, 3352, 1655. Anal.
Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C,
69.06; H, 6.47; N, 11.54.
1
178.0 °C. H NMR (DMSO-d6; 500 MHz) δ 1.30 (t, 3H, J ) 7.0),
4.24 (q, 2H, J ) 7.0), 5.12 (br s, 2H), 6.04 (d, 1H, J ) 2.3), 7.35
(d, 2H, J ) 8.6), 7.88 (d, 2H, J ) 8.6), 10.86 (br s, 1H); MS (ESI)
m/z: 315 (M + 1); IR (Nujol, cm-1): 3446, 3313, 1669. Anal.
Calcd for C14H13F3N2O3: C, 53.51; H, 4.17; N, 8.91. Found: C,
53.24; H, 4.28; N, 8.81.
Eth yl 3-Am in o-5-(3-m eth ylp h en yl)-1H-p yr r ole-2-ca r box-
yla te (14). The title compound (2.86 g, 37%) was prepared using
(3-methylbenzoyl)acetonitrile (5.00 g, 31.4 mmol) and was
recrystallized from toluene. Mp: 121.0-123.0 °C. 1H NMR
(DMSO-d6; 500 MHz) δ 1.30 (t, 3H, J ) 7.0), 2.32 (s, 3H), 4.22
(q, 2H, J ) 7.0), 5.08 (br s, 2H), 5.98 (d, 1H, J ) 2.8), 7.07 (d,
1H, J ) 7.7), 7.23-7.26 (m, 1H), 7.53 (d, 1H, J ) 7.7), 7.61 (s,
1H), 10.67 (br s, 1H); MS (ESI) m/z: 245 (M + 1); IR (Nujol,
cm-1): 3422, 3336, 1668. Anal. Calcd for C14H16N2O2: C, 68.83;
H, 6.60; N, 11.47. Found: C, 68.74; H, 6.72; N, 11.29.
Eth yl 3-Am in o-5-(2-ch lor op h en yl)-1H-p yr r ole-2-ca r box-
yla te (15). The title compound (0.82 g, 31%) was prepared using
2-chlorobenzoyl acetonitrile (1.80 g, 10 mmol) and was recrystal-
lized from toluene/cyclohexane. Mp: 90.0-91.5 °C. 1H NMR
(DMSO-d6; 500 MHz) δ 1.28 (t, 3H, J ) 7.0), 4.22 (q, 2H, J )
7.0), 5.12 (br s, 2H), 5.98 (d, 1H, J ) 2.2), 7.32-7.38 (m, 2H),
Ack n ow led gm en t. We thank Dr. Ying Luo for
providing us with the NOE data for compound 8.
J O9917902