Synthesis of enantiopure 2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridine derivatives

Full text of DOI:10.1021/jo9514376

1890
J . Org. Chem. 1996, 61, 1890-1893
step process. The presence or absence of ester substit-
Syn th esis of En a n tiop u r e 2,3,8,8a -
uents on the unsaturated carbonyl substrate changes the
regiochemistry of the reaction, directing the cyclization
of the oxazolidine moiety to positions 2 or 6 of the
pyridine ring, respectively. Further transformations of
this system have also been accomplished9 in order to
prepare new derivatives, by modification of the substit-
uents in the tetrahydropyridine ring or functionalization
of the oxazolidine ring. These modifications are of
interest in the study of structure-activity relationships
and the mechanism of action of this class of compounds,
which are not calcium antagonists like the parent dihy-
dropyridines.
Tetr a h yd r o-7H-oxa zolo[3,2-a ]p yr id in e
Der iva tives†
Esther Caballero,* Pilar Puebla, Manuel Medarde,*
Mar Sa´nchez, Miguel A. Salvado´,‡
Santiago Garc´ıa-Granda,‡ and Arturo San Feliciano
Departamento de Qu´ımica Orga´nica, Facultad de Farmacia,
Universidad de Salamanca, Avenida del Campo Charro
s.n., 37007 Salamanca, Spain, and Departamento de
Quı´mica Fı´sica, Facultad de Quı´mica, Universidad de
Oviedo, J ulian Claverı´a 8, 33006 Oviedo, Spain
The synthesis of pure enantiomers is necessary to
ascertain the activity of each enantiomer. Different
approaches have been described for asymmetric induction
in the Hantzsch reaction,10 mainly based on the use of
chiral esters, sulfoxides, and other substituents in the
starting enamine or in the Michael acceptor.11 In other
cases, the resolution of racemic mixtures through their
diastereomeric salts or esters12 or by enzymatic resolu-
tion13 has been used to prepare pure enantiomers from
racemic dihydropyridines obtained in the Hantzsch reac-
tion. Asymmetric synthesis of dihydropyridines by other
methodologies has also been described.14 To achieve the
enantioselective synthesis of the 2,3,8,8a-tetrahydro-7H-
oxazolo[3,2-a]pyridine system (2), the use of chiral enam-
ines formed from chiral amino alcohols is another pos-
sibility that could produce high diastereoselectivity, thus
leading to enantiopure representatives of this class of
antihypertensive agents. A related methodology has
been used for the synthesis of dihydropyridines by the
Hantzsch reaction.15
Received August 3, 1995 (Revised Manuscript Received
December 22, 1995)
In tr od u ction
The synthesis of antianginous and antihypertensive
agents has attracted the interest of organic chemists for
a long time.1 In this area, 1,4-dihydropyridines (1)
emerged as very potent calcium antagonists, easy to
synthesize by the Hantzsch methodology in a one-pot
process from keto esters, aldehydes, and ammonia.2
Many derivatives have been obtained by different re-
search groups from universities and industries, mainly
directed to the modification of the substituents on the
basic skeleton of the dihydropyridine3 with the aim of
finding more selective and longer-acting therapeutic
agents. Racemic and enantiopure compounds have been
tested in the search for new compounds with improved
activity and a better pharmacological profile.4 In this
field, we have been working on several kinds of deriva-
tives5 and have finally obtained the very promising long-
lasting antihypertensive tetrahydrooxazolopyridine 2
derivatives.6 This class of compounds is structurally
related to the active dihydropyridines, but with two main
differences: (1) a substitution on the N-atom, which
usually decreases the antihypertensive activity,7 and (2)
an additional oxazolidine ring fused to the a-bond of the
hydropyridine structure.
In this paper, we describe a procedure for the enantio-
selective synthesis of compounds 3 using enamines from
(R)- and (S)-1-amino-2-propanol. In this process, it is
noticeable that the formation of three new stereocenters
in the tetrahydropyridine ring is controlled by the pres-
ence of a single chiral carbon atom in the starting
enamine, placed three, four, and five bonds away from
these newly created stereocenters.
In this research, we studied the regioselectivity of the
reaction between unsaturated keto esters and enamines
of ethanolamine,8 which produced the tetrahydrooxa-
zolopyridine system in approximately 50% yield in a one-
Resu lts a n d Discu ssion
Following the previously described methodology,6,8 we
began the preparation of 2- and 3-substituted 2,3,8,8a-
* To whom correspondence should be addressed. Phone: 34-23-
294528. Fax: 34-23-294515. E-mail: escab@gugu.usal.es.
† This paper is dedicated to the memory of the late Prof. Fe´lix
Serratosa.
(9) Caballero, E.; Puebla, P.; Sa´nchez, M.; Moran del Prado, L.;
Medarde, M.; San Feliciano, A. Unpublished work.
(10) Goldmann, S.; Stoltefuss, J . Angew. Chem., Int. Ed. Engl. 1991,
30, 1559.
(11) Davis, R.; Kern, J . R.; Kurz, L. J .; Pfister, J . R. J . Am. Chem.
Soc. 1988, 110, 7873. Arrowsmith, J . E.; Campbell, S. F.; Cross, P. E.;
Stubbs, J . K.; Burges, R. A.; Gardiner, D. G.; Blackburn, K. J . J . Med.
Chem. 1986, 29, 1696.
(12) Alajarin, R.; Alvarez-Builla, J .; Vaquero, J . J .; Sunkel, C.; Fau
de Casa-J uana, M.; Statkow, P. R.; Sanz-Aparicio, J . Tetrahedron
Asymm. 1993, 4, 617. Satoh, Y.; Okamura, K.; Shiokawa, Y. Chem.
Pharm. Bull. 1994, 42, 950. Wester, R. T.; Mularski, Ch.J .; Magnus-
Ayritey, J . T.; Da Silva J ardine, P.; LaFlamme, J . A.; Berke, H.;
Bussolotti, D. L.; Rauch, A. L.; Hoover, K. W.; Kennedy, Ch.A.;
Burkard, M. R.; Mangiapane, M. L.; Aldinger, Ch.E.; Cooper, K.;
Carpino, Ph.A. BioMed. Chem. Lett. 1994, 4, 133. Ogawa, T.; Matsu-
moto, K.; Yokoo, C.; Hatayama, K.; Kitamura, K. J . Chem. Soc., Perkin
Trans. 1 1993, 525.
(13) Ebiike, H.; Achiwa, K. Tetrahedron Asymm. 1994, 5, 1447.
Hirose, Y; Kariya, K.; Nakanishi, Y.; Kurono, Y.; Achiwa, K. Tetrahe-
dron Lett. 1995, 36, 1063. Yamazaki, Y.; Ebiike, H.; Aciwa, K. Chem.
Pharm. Bull. 1994, 42, 1968.
‡ Departamento de Qu´ımica F´ısica, Universidad de Oviedo.
(1) Bossert, F.; Vater, W. Med. Res. Rev. 1989, 9, 291. Theroux, P.;
Taeymans, Y.; Waters, D. D. Drugs 1983, 25, 178. Bu¨hler, F. R.;
Hulthen, U. L.; Kiowski, W.; Muller, F. B.;Bolli, P. J . Cardiovasc.
Pharmacol. 1982, 4, S350.
(2) Hantzsch, A. Liebigs Ann. Chem. 1882, 215, 1. Sausins, A.;
Duburs, G. Heterocycles 1988, 27, 269.
(3) Rampe, D.; Triggle, D. J . Prog. Drug. Res. 1993, 40, 191 and
references therein.
(4) Hof, R. P.; Ruegg, U. T.; Hof, A.; Vogel, A. J . Cardiovasc.
Pharmacol. 1985, 7, 689. Goldmann, S.; Stoltefuss, J . Angew. Chem.,
Int. Ed. Engl. 1991, 30, 1559. Rovnyak, G. C.; Kimball, S. D.; Beyer,
B.; Cucinotta, G.; DiMarco, J . D.; Gougoutas, J .; Hedberg, A.; Malley,
M.; Mccarthy, J . P.; Zhang, R.; Moreland, S J . Med. Chem. 1995, 38,
119.
(5) San Feliciano, A.; Caballero, E.; Puebla, P.; Pereira, J . A. P.;
Gras, J .; Valenti, C. I. Eur. J . Med. Chem. 1992, 27, 527.
(6) San Feliciano, A.; Caballero, E.; Pereira, J . A. P.; Puebla, P.
Tetrahedron 1991, 47, 6503.
(14) Meyers, A. I., Oppenlaender, T. J . Chem. Soc., Chem. Commun.
1986, 920.
(15) Enders, D.; Mu¨ller, S.; Demir, A. S. Tetrahedron Lett. 1988,
29, 6437. Kosugi, Y.; Hori, M.; Nagasaka, T. Heterocycles 1994, 39,
591.
(7) Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem., Int. Ed. Engl.
1981, 20, 762.
(8) Caballero, E.; Puebla, P.; Medarde, M.; San Feliciano, A.
Tetrahedron 1993, 49, 10079.
0022-3263/96/1961-1890$12.00/0 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 5, 1996 1891
tetrahydro-7H-oxazolo[3,2-a]pyridines (3 and 4) using
conveniently substituted enamines from amino alcohols.
Starting from â-keto esters 5 and racemic 1-amino-2-
propanol (6), the racemic enamine 8 was obtained, and
from racemic 2-amino-1-butanol (7) enamine 9 was
produced.
F igu r e 1. ORTEP drawing of compound 3a r , showing two
conformers present in the unit cell.
Sch em e 1. Syn th esis of En a n tiop u r e
2,3,8,8a -Tetr a h yd r o-7H-oxa zolo[3,2-a ]p yr id in es 3
fr om En a m in es 8
When these enamines were employed in the synthesis
of the 2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridines, 2-
or 3-substituted derivatives were isolated in yields
comparable to those previously described, but from
enamines 8 only one stereoisomer of 3 was produced,
while from enamines 9 two diastereomeric products 4
were obtained. The relative stereochemistry of type 3
compounds at C-8a and C-7 can be easily established as
cis-1,3-diaxial by the shielding of the methyl group at C8a
(0.90 ppm) and that at C-8 as trans-1,2-diaxial by the
coupling constant between H-7 and H-8 (∼0 Hz), which
are the same relative stereochemistries at C-7, C-8, and
C-8a as those produced for the unsubstituted 2.8 Thus,
the reaction is stereospecific, and only the relative
stereochemistry at C-2 was not established at that time.
From the starting material 9, it is possible that the
resulting diastereomers 4 could have different relative
stereochemistries at C-3 or at C-8a. Molecular modeling
studies suggest that the most stable conformations for
C-3 epimers, with the same C-8a configuration, maintain
the same disposition of C-7 and C-8a substituents: cis
1,3-diaxial (Me at C-8 shielded) or trans 1,3-dipseudo-
equatorial (Me at C-8a deshielded). As a consequence
of the observed shielding of Me-C8a, both stereoisomers
of 4 most likely differ in the relative stereochemistry at
C-8a.
any of the pure 3a r , 3a s, 3b r , 3cs, and 3d r products
(detection limit <3%). When pure 3a r containing shift
reagent and 3a s containing an equal amount of the same
shift reagent were mixed, the spectrum of the resulting
mixture was identical to the spectrum of the racemic
mixture containing the same duplicate signals.
Once the enantioselective synthesis of 3 by this meth-
odology was proved, only the stereochemistry of the C7-
C8a moiety relative to that of C2 remained to be
established. The absence of an NOE on Me-C2 or H-2
upon irradiation of the Me-C8a was interpreted as a cis-
relationship between Me-C8a and Me-C2. To confirm
the proposed stereochemistry of type 3 compounds,
substance 3a r was subjected to X-ray diffraction, and an
ORTEP drawing of the structure is shown in Figure 1.
As shown, there are two conformers in the unit cell, but
the differences between them are very small and they
show the same spatial arrangements. These differences
mainly appear in the conformation of the oxazolidine
ring, since the torsion angles are less than 10° in all cases
except for those affecting the oxazolidine ring and the
carboxylate on C8: C8a-O1-C2-C3, C7-C8-C12-O4,
C8a-C8-C12-O5, C8a-O1-C2-C9, C2-O1-C8a-C8,
C7-C8-C12-O5, and C8a-C8-C12-O4, which are in
the 10°-20° range. In both conformations, the spatial
arrangement of the aromatic ring and the Me-C8a are
The above results clearly demonstrated that the ster-
eochemistry of the chiral center of the enamine produces
a total chiral induction in the three new centers C-7, C-8,
and C-8a created in the synthesis of 2-substituted 2,3,8,-
8a-tetrahydro-7H-oxazolo[3,2-a]pyridines 3. In conclu-
sion, it may be possible to accomplish the enantioselective
synthesis of the 2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]-
pyridine system using the diastereospecific reaction of
enantiopure enamines of type 8.
Accordingly, both enantiomers (2′R)-8a r and (2′S)-8a s
of methyl 3-((2-hydroxypropyl)amino)but-2(Z)-enoate were
prepared from pure commercial enantiomers of 1-amino-
2-propanol and methyl acetylacetate. From ethyl, benzyl,
and tert-butyl acetylacetates enantiopure 8br , 8cs, and
8d r were obtained. These enamines were used in the
cyclization reaction, producing the usual yields of the
2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridines 3 (Scheme
1). The enantiomeric purity of these derivatives was
checked using chiral lanthanide shift reagents in 1H-
NMR, which produced a duplicity of representative
signals in the spectra of racemic 3a but no duplicity in
1
those suggested by H-NMR data, and theoretical calcu-
lations obtained by molecular mechanics (Macromodel

1892 J . Org. Chem., Vol. 61, No. 5, 1996
Notes
Sch em e 2. Mech a n istic P r op osa l for th e
Ster eocon tr olled Cycliza tion
by the hydroxyl group to the electron deficient R-position
of the enamine. Moreover, it is proposed that the
favorable approach between the enamine and the unsat-
urated ester would take place with both double bonds,
having opposite polarizations, in a syn relationship and
the remaining substituents avoiding the appearance of
strong interactions. The C-H bonds close to C-Ar and
C-COOMe bonds during the approach allow a reaction
process with low hindrance and good charge stabilization,
thus yielding intermediate 11. The closure of 11 toward
the tetrahydropyridine ring produces the final product
3.
Exp er im en ta l Section
For general experimental details see refs 6 and 8. Optical
rotations were measured at 25 °C on a digital Perkin-Elmer 241
polarimeter in a 1 dm cell.
Gen er a l P r oced u r e. A mixture of the unsaturated keto
ester 10 (20 mmol) and enamines 8 or 9 (20 mmol) in MeOH
(50 mL) was refluxed for 24 h. The solvent was removed, and
the 2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridines were isolated
in 37-48% yield after flash chromatography (Hex/AcOEt) and/
or crystallization.
4.0) and are in agreement with the absence of NOE’s
between Me-C8a and H2 or Me-C2. Consequently, the
proposed cis relative stereochemistry between Me-C8a
and Me-C2 was unequivocally established in this de-
rivative, which has the structure (2R,7S,8R,8aR)-di-
methyl 7-(3-chlorophenyl)-2,5,8a-trimethyl-2,3,8,8a-tet-
rahydro-7H-oxazolo[3,2-a]pyridine-6,8-dicarboxylate(3a r ).
The lack of an appreciable coupling between H-7 and H-8
is also in agreement with their dihedral angles (-88.7°
and -83.5°) measured for the conformers.
(+)-(2R,7S,8R,8a R)-Dim eth yl 7-(3-ch lor op h en yl)-2,5,8a -
tr im eth yl-2,3,8,8a -tetr a h yd r o-7H-oxa zolo[3,2-a ]p yr id in e-
6,8-d ica r boxyla te (3a r ): 48% yield; mp 130-131 °C (MeOH);
[R]D ) +74.4° (c 0.82, CHCl3); IR (KBr) 1750, 1690, 1590; 1H-
NMR (200 MHz, CDCl3) δ 0.90 (3H, s), 1.27 (3H, d, J ) 5.8 Hz),
2.59 (3H, d, J ) 1.3 Hz), 3.25 (1H, m), 3.27 (1H, m), 3.44 (3H,
s), 3.71 (3H, s), 4.08 (1H, m), 4.12 (1H, m), 4.27 (1H, s), 7.0-7.4
(4H, m); 13C-NMR (50.3 MHz, CDCl3) δ 18.7 (q), 20.5 (q), 28.7
(q), 41.0 (d), 50.5 (q), 51.7 (q), 52.7 (t), 53.2 (d), 72.8 (d), 90.4 (s),
92.5 (s), 125.9 (d), 126.3 (d), 127.9 (d), 129.5 (d), 134.3 (s), 147.5
(s), 152.0 (s), 169.3 (s), 171.6 (s). Anal. Calcd for C20H24ClNO5:
C, 60.99; H, 6.14; N, 3.56. Found: C, 60.61; H, 6.33; N, 3.65.
(-)-(2S,7R,8S,8a S)-Dim eth yl 7-(3-ch lor op h en yl)-2,5,8a -
tr im eth yl-2,3,8,8a -tetr a h yd r o-7H-oxa zolo[3,2-a ]p yr id in e-
6,8-d ica r boxyla te (3a s): 40% yield; mp ) 128-129 °C (MeOH);
[R]D ) -70.8° (c 0.82, CHCl3). Anal. Calcd for C20H24ClNO5:
C, 60.99; H, 6.14; N, 3.56. Found: C, 60.75; H, 6.18; N, 3.70.
(+)-(2R,7S,8R,8a R)-Meth yl 7-(3-ch lor op h en yl)-8-(eth oxy-
ca r bon yl)-2,5,8a -tr im eth yl-2,3,8,8a -tetr a h yd r o-7H-oxa zolo-
[3,2-a ]p yr id in e-6-ca r boxyla te (3br ): 40% yield; [R]D ) +26.3°
(c 0.38, CHCl3); IR (film) 1730, 1680, 1600, 1580; 1H-NMR (200
MHz, CDCl3) δ 0.90 (3H, s), 1.27 (3H, d, J ) 5.7 Hz), 1.31 (3H,
t, J ) 7.1 Hz), 2.60 (3H, s), 3.25 (1H, m), 3.27 (1H, m), 3.44 (3H,
s), 4.03 (1H, m), 4.12 (1H, m), 4.18 (2H, c, J ) 7.1 Hz), 4.28 (1H,
s), 7.11-7.29 (4H, m); 13C-NMR (50.3 MHz, CDCl3) δ 14.2 (q),
18.6 (q), 20.3 (q), 28.6 (q), 40.9 (d), 50.5 (q), 52.5 (t), 53.2 (d),
60.4 (t), 72.7 (d), 90.3 (s), 92.5 (s), 125.9 (d), 126.3 (d), 127.7 (d),
129.4 (d), 134.2 (s), 147.5 (s), 151.1 (s), 169.3 (s), 171.2 (s). Anal.
Calcd for C21H26ClNO5: C, 61.84; H, 6.42; N, 3.43. Found: C,
61.46; H, 6.51; N, 3.75.
In a previous paper,8 we included a mechanistic
proposal to account for the formation of different regio-
isomers of the tetrahydrooxazolopyridines and other
reaction products having the cyclohexane skeleton. The
mechanism should also explain the stereospecificity of
the reaction. Our proposal was based on the necessary
formation of the oxazolidine ring prior to the tetra-
hydropyridine ring in the pathway to tetrahydrooxazol-
opyridines because separate experiments demonstrated
that N-hydroxyethyldihydropyridines do not cyclize un-
der the reaction conditions. All the reaction products
with cyclohexane and tetrahydrooxazolopyridine skel-
etons contain a new C-C bond, linking the â-position of
the enamine and the â-position of the unsaturated keto
ester, and its formation is proposed as the first step for
this reaction.16 In this step, the C-7 and C-8 stereo-
centers are generated. The stereochemistry at C-8a is
generated during the formation of the oxazolidine ring
and must be directly governed by the stereochemistry of
the hydroxyalkyl chain attached to the N atom of the
enamine.
During the Michael addition, electron density dimin-
ishes in the enamine and may be compensated by the
electron pairs of the close hydroxylic oxygen. Both steps
could be simultaneous, thus producing the Michael
addition-oxazolidine cyclization intermediate 11 de-
picted in Scheme 2. In this process, all the stereocenters
are generated from the chiral center of the enamine, and
hence, the most favored approach of the reagents must
produce the resulting stereochemistries. As depicted, the
methyl group of the hydroxypropylamine, which governs
the stereochemistry, is maintained distant from the rest
of the molecule in a favorable disposition for the attack
(+)-(2S,7R,8S,8a S)-Meth yl 7-(3-ch lor op h en yl)-8-(ben zyl-
oxyca r bon yl)-2,5,8a -tr im eth yl-2,3,8,8a -tetr a h yd r o-7H-ox-
a zolo[3,2-a ]p yr id in e-6-ca r boxyla te (3cs): 45% yield; mp )
126-127 °C (Et2O); [R]D ) +33.5° (c 0.65, CHCl3); 1H-NMR (200
MHz, CDCl3) δ 0.90 (3H, s), 1.16 (3H, d, J ) 5.8 Hz), 2.54 (3H,
s), 3.27 (1H, m), 3.32 (1H, m), 3.44 (3H, s), 3.69 (1H, m), 3.97
(1H, m), 4.30 (1H, s), 5.07 (1H, d, J ) 12.4 Hz), 5.22 (1H, d, J )
12.4 Hz), 7.12-7.25 (9H, m); 13C-NMR (50.3 MHz, CDCl3) δ 18.7
(q), 20.3 (q), 28.7 (q), 40.9 (d), 50.5 (q), 52.5 (t), 53.5 (d), 66.3 (t),
72.6 (d), 90.4 (s), 92.5 (s), 125.9 (d), 126.3 (d), 127.9 (d), 128.2 ×
2 (d), 128.5 × 3 (d), 129.5 (d), 134.3 (s), 136.1 (d), 147.4 (s), 152.0
(s), 169.3 (s), 171.1 (s). Anal. Calcd for C26H28ClNO5: C, 66.45;
H, 6.01; N, 2.98. Found: C, 66.73; H, 6.23; N, 3.03.
(+)-(2R,7S,8R,8a R)-Met h yl 7-(3-ch lor op h en yl)-8-(ter t-
b u t yloxyca r b on yl)-2,5,8a -t r im et h yl-2,3,8,8a -t et r a h yd r o-
7H-oxa zolo[3,2-a ]p yr id in e-6-ca r boxyla te (3d r ): 37% yield;
mp ) 118-119 °C (MeOH); [R]D ) +71.1° (c 0.98, CHCl3); IR
(KBr) 1740, 1690, 1570; 1H-NMR (200 MHz, CDCl3) δ 0.89 (3H,
s), 1.27 (3H, d, J ) 6.0 Hz), 1.47 (9H, s), 2.59 (3H, s), 3.13 (1H,
m), 3.25 (1H, m), 3.44 (3H, s), 4.05 (1H, m), 4.16 (1H, m), 4.22
(1H, s), 7.09-7.27 (4H, m); 13C-NMR (50.3 MHz, CDCl3) δ 18.7
(q), 20.4 (q), 28.2 × 3 (q), 28.7 (q), 41.0 (d), 50.4 (q), 52.6 (t), 54.4
(16) Katrizky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron
1986, 42, 5729; 1987, 43, 5171. Robinson, J . H.; Brent, L. W.; Chau,
Ch.; Floyd, K. A.; Gillham, S. L.; McHahan, T. L.; Magde, D. J .;
Motycka, T. J .; Pack, H. J .; Roberts, A. L.; Seally, L. A.; Simpson, S.
L.; Smith, R. R.; Zalesny, K. N. J . Org. Chem. 1992, 57, 7352. Ogawa,
T.; Matsumoyo, K.; Yoshimura, M.; Hatayama, K.; Kitamura, K.; Kita,
Y. Tetrahedron Lett. 1993, 34, 1967. Kucklander, U.; Hilgeroth, A.
Arch. Pharm. (Weinheim) 1994, 327, 287.

Notes
J . Org. Chem., Vol. 61, No. 5, 1996 1893
(d), 72.7 (d), 80.5 (s), 90.5 (s), 92.3 (s), 125.9 (d), 126.2 (d), 127.9
(d), 129.4 (d), 134.2 (s), 147.9 (s), 151.2 (s), 169.4 (s), 171.3 (s).
Anal. Calcd for C23H30ClNO5: C, 63.37; H, 6.94; N, 3.21.
Found: C, 63.09; H, 6.98; N, 2.96.
Isotropic least-squares refinement, using a local version of
SHELX76,18 converged to R ) 0.101. At this stage an empirical
absorption correction was applied using DIFABS,19 and further
refinements were carried out on /F/2 using the program
SHELXL93.20 Absolute configuration was checked (Flack pa-
rameter21 ø ) 0.02(7)). Atomic scattering factors were taken
from International Tables for X-ray Crystallography.22 Geo-
metrical calculations were made with PARST.23 The crystal-
lographic plots were made with EUCLID.24 All calculations were
made at the University of Oviedo on the Scientific Computer
Center and X-ray group VAX-computers.
(()-Dim eth yl 7-(3-Ch lor op h en yl)-3-eth yl-5,8a -d im eth yl-
2,3,8,8a -t et r a h yd r o-7H -oxa zolo[3,2-a ]p yr id in e-6,8-d ica r -
boxyla te (4). Following the same methodology previously
described, an unresolved 6:4 mixture of two diastereomers of 4
was obtained from enamine 9 (43%). The spectroscopic data
were observed for each component in the mixture. Major: 1H-
NMR (200 MHz, CDCl3) δ 0.97 (3H, t, J ) 7.2 Hz), 1.32 (3H, s),
1.69 (2H, m), 2.47 (3H, d, J ) 1.1 Hz), 2.52 (1H, d, J ) 12.0 Hz),
3.30 (3H, s), 3.45 (3H, s), 3.83 (1H, m), 3.99 (1H, d, J ) 9.0 Hz),
4.03 (1H, dd, J 1 ) 1.1 Hz, J 2 ) 12.0 Hz), 4.12 (1H, dd, J 1 ) 5.0
Hz, J 2 ) 9.0 Hz), 7.0-7.4 (4H, m); 13C-NMR (50.3 MHz, CDCl3)
δ 10.7 (q), 17.6 (q), 18.6 (q), 26.6 (t), 44.3 (d), 50.0 (q), 51.7 (q),
59.2 (d), 59.7 (d), 68.0 (t), 92.0 (s), 101.6 (s), 125.5 (d), 126.4 (d),
127.0 (d), 129.4 (d), 134.1 (s), 147.0 (s), 150.0 (s), 167.6 (s), 171.6
(s). Minor: 1H-NMR (200 MHz, CDCl3) δ 0.88 (3H, t, J ) 7.2
Hz), 0.90 (3H, s), 1.69 (2H, m), 2.57 (3H, d, J ) 1.1 Hz), 3.33
(1H, s), 3.43 (3H, s), 3.72 (3H, s), 3.83 (1H, m), 3.81 (1H, d, J )
9.0 Hz), 4.12 (1H, dd, J 1 ) 5.0 Hz, J 2 ) 9.0 Hz), 4.33 (1H, br s),
7.0-7.4 (4H, m); 13C-NMR (50.3 MHz, CDCl3) δ 11.2 (q), 18.7
(q), 24.7 (q), 28.1 (t), 41.3 (d), 50.4 (q), 51.7 (q), 53.7 (d), 59.7 (d),
67.5 (t), 90.7 (s), 92.0 (s), 125.8 (d), 126.2 (d), 127.3 (d), 129.4
(d), 134.1 (s), 147.0 (s), 152.0 (s), 167.6 (s), 171.6 (s).
Ack n ow led gm en t. Financial support came from the
Spanish DGICYT (SAF94-310; SAF95-1566) and the
J unta de Castilla y Leo´n (SA 08/93). We thank Dr.
Benigno Macias (Department of Inorganic Chemistry)
for E.A. and Dr. J ose Luis Lo´pez for theoretical calcula-
tions.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H-NMR
spectra of 3a r , 3a s, racemic 3a , and Eu(tfc)3 displacement
experiments and a table of 13C NMR assignments (9 pages).
This material is contained in libraries on microfiche, im-
mediately 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.
J O9514376
Sin gle-Cr ysta l X-r a y Str u ctu r e Deter m in a tion of 3a r .
Colorless crystal, size 0.46 × 0.33 × 0.20 mm. C20H24Cl1N1O5,
Mr ) 393.87, monoclinic, space group P21, a ) 10.497(4) Å, b )
10.504(4) Å, c ) 18.536(5) Å, â ) 100.81(2) V ) 2008(1) Å3, Z )
4, Dx ) 1.30 M g m-3, Mo KR radiation (graphite crystal
monochromator, λ ) 0.710 73 Å), µ ) 0.220 cm-1, F(000) ) 832,
T ) 293 K. Final conventional R ) 0.049 (for 4804 Fo > 4σ(Fo))
and wR2 ) 0.136 (for all reflections), w ) 1.0/[σ2(Fo2) +
(0.0893P)2] where P ) (max(Fo2, 0) + 2*Fc2)/3. Total number of
parameters 488. The intensity data of 7718 reflections in hkl
range (-12, -12, -22) to (12, 12, 22) and θ limits (0 < θ < 25°)
were measured, using the ω - 2θ scan technique. Profile
analysis was performed on all reflections.17 The structure was
solved by Patterson interpretation using the program SHELXS86.
(17) Lehman, M. S.; Larsen, F. K. Acta Crystallogr. 1974, A30, 580.
Grant, D. F.; Gabe, E. J . J . Appl. Crystallogr. 1978, 11, 114.
(18) Sheldrick, G. M. SHELX76, Program for crystal structure
determination. University of Cambridge, England, 1976. Van der
Maelen, J . F. Ph.D. Thesis, University of Oviedo, Spain, 1991.
(19) Walker, N.; Stuart, D. Acta Crystallogr. 1983, A39, 158.
(20) Sheldrick, G. M. SHELXL93. J . Appl. Crystallogr., manuscript
in preparation.
(21) Flack, H. D. Acta Crystallogr. 1983, A39, 876.
(22) International Tables for X-ray Crystallography; Kynoch Press:
Birmingham (Present distributor: Kluwer Academic Publishers, Dor-
drecht), 1974; Vol. IV.
(23) Nardelli, M. Comput. Chem. 1983, 7, 95.
(24) Spek, A. L. The EUCLID package. In Computational Crystal-
lography; Sayre, D., Ed.; Clarendon Press: Oxford, 1982; p 528.