Enantioselective Michael reactions of chiral secondary enaminoesters with 2-substituted nitroethylenes. Syntheses of trans,trans-2,4-disubstituted pyrrolidine-3-carboxylates

Article abstract of DOI:10.1021/jo000206i

The Michael reaction of chiral 3-substituted secondary enaminoesters with 2-substituted nitroethylenes leads to (Z)-adducts, with good to excellent diastereoselectivity. The nitro group of these adducts was catalytically reduced to give, after cyclization and chiral amine elimination, pyrrolines or pyrrolidines after further reduction. In particular, the syntheses of ethyl (2R,3S,4S)-2,4-dimethylpyrrolidine-3-carboxylate and ethyl (2R,3R,4S)-2-(4-methoxyphenyl)-4-(3,4-(methylenedioxy)phenyl)pyrrolidine-3-ca rboxylate are described.

Full text of DOI:10.1021/jo000206i

J . Org. Chem. 2000, 65, 4593-4600
4593
En a n tioselective Mich a el Rea ction s of Ch ir a l Secon d a r y
En a m in oester s w ith 2-Su bstitu ted Nitr oeth ylen es. Syn th eses of
tr a n s,tr a n s-2,4-Disu bstitu ted P yr r olid in e-3-ca r boxyla tes
Gilbert Revial, Sethy Lim, Bernard Viossat,† Pascale Lemoine,† Alain Tomas,†
Arthur F. Duprat, and Michel Pfau*
Laboratoire de Chimie Organique, CNRS (ESA 7084), ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05,
France, and Laboratoire de Physique, Universite´ Paris 5, 4 Avenue de l’Observatoire,
75270 Paris Cedex 06, France
Received February 14, 2000
The Michael reaction of chiral 3-substituted secondary enaminoesters with 2-substituted nitro-
ethylenes leads to (Z)-adducts, with good to excellent diastereoselectivity. The nitro group of these
adducts was catalytically reduced to give, after cyclization and chiral amine elimination, pyrrolines
or pyrrolidines after further reduction. In particular, the syntheses of ethyl (2R,3S,4S)-2,4-
dimethylpyrrolidine-3-carboxylate and ethyl (2R,3R,4S)-2-(4-methoxyphenyl)-4-(3,4-(methylene-
dioxy)phenyl)pyrrolidine-3-carboxylate are described.
The Michael-type addition of imines reacting via their
secondary enamines tautomers was first described 30
years ago.1 Theoretical studies2b,c have shown that in the
general case of a secondary enamine and an electrophilic
olefin bearing a carbonyl as the electron-withdrawing
group, a compact syn approach of the reactants leads to
chairlike and boatlike complexes in which the N-atom of
the secondary enamine and the C-atom of the carbonyl
group (endo position) are included. If an imine derived
from a 2-substituted cyclanone is reacted with a substi-
tuted electrophilic olefin, and as the chair complex lies
at about 4 kcal/mol below the boat one (which would lead
to an adduct with the opposite stereochemical relation-
ship of the substituents), the implication is that a high
diastereoselectivity should be observed for the reaction
and also that the relationship of the substituents could
be anticipated (Figure 1). These predictions have been
confirmed experimentally.2d,3
F igu r e 1. Diastereoselectivity in the syn approach of the
reactants.
enamine undergoes enantioselective Michael reactions,
allowing the preparation of a variety of building blocks
bearing a quaternary stereogenic center, and many
synthetic applications have been reported.2
Almost 50 years ago, Grob and Camenisch reported
that secondary enaminoester 1 reacted with 1-nitropro-
pene to give pyrrole 6 in 70% yield.4 In a second article,
a mechanism was suggested for this reaction in which
the E isomer 3 of the Z adduct 2 is in equilibrium with
its aci-nitro tautomer 4 which is cyclized to the hydrated
nitroso compound 5, affording pyrrole 6 through water
and hyponitrous acid eliminations5,6 (Scheme 1).
Grob and Schad had also shown that the N-benzyl
analogue of uncyclized Z intermediate 2 could actually
be isolated when the reaction was performed in acetoni-
trile5 rather than in ethanol. One can suppose that in
this case the formation of a stabilizing intramolecular
hydrogen bond is allowed, impeding tautomerization to
the imine form which can lead to the E isomer 3 and
pyrrole 6. In view of this very interesting observation it
occurred to us that an enantioselective reaction could be
possible for enaminoesters of type 1, derived from a chiral
amine, leading to adducts of type 2 which involve a
When a chiral nonracemic amine is used with a
racemic 2-substituted carbonyl compound, the secondary
† Universite´ Paris 5, 4 Avenue de l’Observatoire.
(1) Pfau, M.; Ribie`re, C. J . Chem. Soc. Chem. Commun. 1970, 66-
67. Pfau, M.; Ribie`re, C. Bull Soc. Chim. Fr. 1971, 2584-2590.
(2) (a) Pfau, M.; Revial, G.; Guingant, A.; d’Angelo, J . J . Am. Chem.
Soc. 1985, 107, 273-274. Pfau, M.; Revial, G. (KIREX), PCT WO 85
04873, 1985. Mech a n ism s: (b) Sevin, A.; Tortajada, J .; Pfau, M. J .
Org. Chem. 1986, 51, 2671-2675. (c) Sevin, A.; Masure, D.; Giessner-
Prettre, C.; Pfau, M. Helv. Chim. Acta 1990, 73, 552-573. (d) Pfau,
M.; Tomas, A.; Lim, S.; Revial, G. J . Org. Chem. 1995, 60, 1143-1147.
(e) J abin, I.; Revial, G.; Tomas, A.; Lemoine, P.; Pfau, M. Tetrahe-
dron: Asymmetry 1995, 6, 1795-1812. (f) Lucero, M. J .; Houk, K. N.
J . Am. Chem. Soc. 1997, 119, 826-827. Review s: Revial, G.; Pfau,
M. Org. Synth. 1991, 70, 35-46. Oare, D. A.; Heathcock, C. H. Topics
Stereochem. 1991, 20, 87-170 (see p 114). D’Angelo, J .; Desmae¨le, D.;
Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459-505.
D’Angelo, J .; Cave´, C.; Desmae¨le, D.; Dumas, F. Trends Org. Chem.
1993, 4, 555-616. Guingant, A. Advances in Asymmetric Synthesis;
J AI Press Inc.: Greenwich, CT, 1997; Vol. 2, pp 159-174. Develop -
m en ts a n d a p p lica tion s: J abin, I.; Revial, G.; Melloul, K.; Pfau, M.
Tetrahedron: Asymmetry 1997, 8, 1101-1109 and references included.
(3) That the expected relationship was in fact the reverse one in an
example reported (Cave´, C.; Daley, V.; d’Angelo, J . Tetrahedron:
Asymmetry 1995, 6, 79-82) led the authors to claim that the carbonyl
group is in exo rather than in endo position (the boat complex possibility
was not invoked). However, in a later article (Cave´, C.; Desmae¨le, D.;
d’Angelo, J . J . Org. Chem. 1996, 61, 4361-4368) the authors explained
that in the original paper the relevant structures “have been permuted
by inadvertence,” thus implicitly confirming the generality of the
theoretical prediction.2b
(4) Grob, C. A.; Camenisch, K. Helv. Chim. Acta 1953, 36, 49-58.
(5) Grob, C. A.; Schad, H. P. Helv. Chim. Acta 1955, 38, 1121-1127.
(6) Recently, the reaction displayed in Scheme 1 was extended to
the reaction of cyclohexanones imines with 2-substituted nitroethyl-
enes, affording tetrahydroindoles: Lim. S.; J abin, I.; Revial, G.
Tetrahedron Lett. 1999, 40, 4177-4180.
10.1021/jo000206i CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/21/2000

4594 J . Org. Chem., Vol. 65, No. 15, 2000
Revial et al.
1
Sch em e 1
Only noncyclized adducts were detected by H NMR
of the crude mixtures in all examples, with the exception
of the reactions of enaminoester 17 with nitroolefins 8
and 11 in which the adducts 18 and 20 are significantly
cyclized to afford pyrroles 19 and 21, respectively. In
these cases where a long reaction time was required, we
tried to accelerate the reaction by using a Lewis acid
catalyst; thus, in one example dealing with enaminoester
17 and nitroolefin 14, the reaction performed in the
presence of MgCl2 was indeed accelerated, but under
these conditions a mixture of nitroenaminoester 22 and
pyrrole 23 was obtained; moreover, the diastereoselec-
tivity was lowered. Pyrrole 23 was isolated and charac-
terized in this case.
After purification by recrystallization and/or flash
chromatography (FC), the structures of adducts 9, 12,
15, 22, and 26 were determined by 1H and 13C NMR
spectrography.
Sch em e 2
Adduct 20 was inseparable by FC, and in these
conditions the proportion of the corresponding cyclized
compound 21 increased. In the other example of pyrrole
formation, FC purification of adduct 18 was therefore not
attempted. In this case, the reaction of enaminoester 17
with nitroolefin 8 was also carried out without solvent,
and the reaction time was much reduced. More interest-
ingly, less pyrrole 19 was formed, and the unpurified
mixture was used directly for the next step (vide infra).
The structures of compounds 18 and 20 (as well as
those of the corresponding pyrroles 19 and 21) were
determined by NMR, using in each case the mixture of
the two reaction products.
The diastereoselectivities were determined by 1H NMR
of the crude reaction mixtures and are good to excellent
(93:7 to >99:1) when the nitroolefin bears an alkyl
substituent. The diastereoselectivity was much reduced
(83:17 to 90:10) when the substituent is an aryl group.
Moreover, separation of the major diastereoisomer could
not be achieved in any instance.
Molecular modeling7 of enaminoesters 7 and 17 (Figure
2) shows that their two diastereotopic faces are subject
to very different steric hindrance as is the case with the
usual chiral secondary enamines of 2-substituted cyclo-
hexanone imines,2b although in the present instance the
phenyl substituent (R1) in compound 17 is very different
in size by comparison with the corresponding methylene
group in an 1-amino-2-substituted cyclohexene.
The absolute configuration of adduct 9 was determined
by single-crystal X-ray diffraction and those of the other
tertiary stereogenic center. These adducts in turn could
be used in particular for the syntheses of pyrrolines and
pyrrolidines. In fact it had already been shown that when
a chiral secondary enamine (derived from 2-methyl-
cyclohexanone) reacts with â- (or R-)substituted acrylates,
a controlled tertiary stereogenic center is created along
the usual quaternary one2e (Scheme 2). The reaction
proceeds with an excellent diastereoselectivity in ac-
cordance again with the theoretical predictions2b (vide
supra) and with a high enantioselectivity,2c,f which in
turn is in accordance with the heuristic rule2b allowing
the prediction of the favored diastereofacial selectivity,
i.e., the absolute configuration of the adduct.
Resu lts a n d Discu ssion
Ch ir a l Ad d u cts fr om th e Mich a el Rea ction . Ex-
periments with various substituents on both the enami-
noester and the nitroolefin were performed under mild
conditions to limit the cyclization of the adducts. The first
and the last example were chosen for synthetic applica-
tions (vide infra) (Scheme 3, Table 1).
Sch em e 3

Michael Reactions of Chiral Secondary Enaminoesters
J . Org. Chem., Vol. 65, No. 15, 2000 4595
F igu r e 2. Modeling of the R enantiomers of enaminoesters 7 and 17.
F igu r e 3. Rule for predicting the absolute configuration of Michael adducts.
Ta ble 1. Ch ir a l Ad d u cts fr om Mich a el Rea ction s of
En a m in oester s w ith Nitr oolefin sa
the syn approach leading to a chairlike complex is still
prevalent, meaning that attractive MO interactions aris-
ing from frontier orbitals should operate between the
N-atoms of the amino and nitro groups as they usually
do between the N-atom of the amino group and the
C-atom of a carbonyl group.2b
enamino- nitroolefin conditions product, yield, diastereo-
ester
(1 equiv) (MeCN, rt)
%
%
selectivity
7
8
11
14
8
1.2 M, 3 h
9 >99 95b
10 <1
>99:1
2.5 M, 24 h 12 >99 87c
13 <1
6.5 M, 3 d
>99:1
85:15
94:6
Although all the adducts which are obtained involve a
1
15 >99 80c
stabilizing H-bond (in H NMR, the NH hydrogen atom
16 <1
is typically shifted downfield at ca. 10 ppm) which
restricts the isomerization of the double bond, cyclized
compounds are nonetheless produced in the reaction of
enaminoester 17 with nitroolefin 8 or 11 (Table 1). In
these cases, the R1 substituent is a phenyl group, and
one can suppose that for the corresponding Z adducts 18
and 20, there is more crowding than in adducts 9, 12,
and 15 where R1 is a methyl group, allowing a slight
displacement of the ZHE equilibrium to the right, with
increased formation of pyrroles 19 and 21 compared to
10, 13, and 16. When enaminoester 17 is reacted with
nitroolefin 14, and enaminoester 24 with nitroolefin 25,
however, pyrrole formation is not observed. In this
instance it is possible that in the E form of the corre-
sponding adducts 22 and 26, the bulky aryl substituent
in the R-position of the aci-nitro group (analogous to
structure 4 in Scheme 1) lowers the efficiency of attack
of this group by the enamino nitrogen atom.
d
17
2.5 M, 6 d
18 70
19 30
-
-
-
d,e
g
no solvent, 18 91
23 h
2.5 M, 6 d
93:7
19 9
11
14
25
20 70f
21 30
96:4
7 M, 6 d
22 >99 95c
23 <1
90:10
83:17
24
1 M, 18 dh
26 >99 93c
27 <1
a
See Scheme 3 for structures and see text for notes e and f.
Washed crystalline compound. c FC purification. Not purified.
b
d
e Used directly for the next step. f 20/21: 75:25 before FC. In-
g
h
separable mixture of 20 and 21. Time required for total solubi-
lization of compound 25.
adducts are assumed by analogy (Scheme 3). The abso-
lute configurations are as predicted2b (vide supra) (Figure
3; see also Figure 2).
The results above show that the replacement of a
carbonyl by a nitro group in the electrophilic olefin does
not alter the mechanism of the Michael reaction, i.e., that
In one example we have confirmed that stirring adduct
9 at room temperature in a protic solvent (ethanol)
suppresses the hydrogen bonding, since it leads to the
corresponding Grob’s type product, i.e., pyrrole 10. We
have also cyclized the adduct 26 to pyrrole 27.
(7) Optimized molecular structures were generated using the com-
bination of CS Chemdraw Pro 5.0 (1998) and CS Chem3D Pro 5.0
(1999), Cambridge Soft (Cambridge, MA). The resulting MM2 geom-
etries were refined with the semiempirical molecular orbital PM3
algorithm available in CS Mopac Pro.
Cycliza tion of th e Red u ced Ad d u cts Lea d in g to
Ch ir al P yr r olidin es. Syn th esis of P yr r olidin e (R,S,S)-

4596 J . Org. Chem., Vol. 65, No. 15, 2000
Revial et al.
Sch em e 4
Sch em e 5
phenyl)nitroethylene followed by hydrogenation over Ra-
Ni, was reduced with sodium cyanoborohydride to afford
three pyrrolidine isomers, the trans-trans (racemic equiva-
lent of compound 39, Scheme 6), the cis-trans, and the
cis-cis (equiv 40). The cis-cis isomer was separated and
through basic treatment gave the trans-trans compound
(12% yield from ethyl (4-methoxybenzoyl)acetate) which
was then N-substituted. Resolution of the most efficient
compound A127722 (N-substituted with CH2NBu2) led
to the active enantiomer corresponding to (R,R,S)-39.9
As the trans-trans pyrrolidine derivative can lead to a
variety of interesting compounds, in particular to com-
pound A127722, we decided to attempt the synthesis of
pyrrolidine (R,R,S)-39 (Scheme 6). Before using adduct
26 involving two bulky aryl substituents, we first tried
the reduction-cyclization reaction with the two adducts
18 and 22 bearing, respectively, phenyl/methyl and
phenyl/phenyl substituents (Scheme 5). Thus the unpu-
rified mixture of adducts 18 (93:7) and pyrrole 19 (18/
19, 91:9) (Scheme 3, Table 1) was catalytically reduced
under similar conditions to those used for adduct 9
(Scheme 4). In this case, 1H NMR of the filtered and
evaporated reaction mixture showed that compound 18
had totally reacted but that the cyclization was not
complete. It was thus necessary to heat an ethanolic
solution of the mixture at reflux for 14 h to end the
cyclization leading to compound (S,S)-34 and its diaste-
reomer (R,S)-34 (85:15) in 48% global yield from enami-
noester 17 and both with 86% ee. In these conditions,
the amount of pyrrole 19 increased slightly and it was
also isolated and characterized. When adducts 22 (90:
10) were treated under similar conditions (a 24 h ethanol
reflux was necessary in this case to complete the cycliza-
tion), compound (S,R)-35 and its diastereomer (R,R)-35
(89:11) were obtained in 76% global yield from adduct
22, both with 80% ee. In the two experiments, no trace
of dihydrogenated products corresponding to compounds
34 and 35 were observed, in contrast with the example
(Scheme 4) where the cyclized compounds bear methyl/
methyl substituents.
The projected synthesis of pyrrolidine (R,R,S)-39 was
achieved, starting from adduct 26 (Scheme 3, Table 1).
Thus, the inseparable mixture of diastereomers 26
(83:17) when treated identically to adduct 22, gave (R,S)-
36 and its diastereomer (S,S)-38 (94:6) in 84% global
yield (Scheme 6).
Reduction of the double bond in compound 36 was
achieved with H2 over Ra-Ni (50 °C for 40 h) rather than
by cyanoborohydride reduction as performed by Winn et
al., yielding a mixture of pyrrolidines (R,R,S)-39 and its
diastereoisomer (R,S,S)-40 (86:14) and only a trace of a
cis-trans isomer. If the formation of compound (R,R,S)-
39 can be readily accounted for from imine 36, that of
compound (R,S,S)-40 occurs most probably from the cis
pyrroline 38 and from the enamine tautomer 37, even if
it is present in undetectable proportion, assuming that
30. From 2,4-dialkylpyrrolidine-3-carboxylates, Ohki et
al. have prepared a number of racemic 1,2,4-trisubsti-
tuted 3-(diphenylmethylidene)pyrrolidinium salts show-
ing anticholinergic activities.8 In particular they synthe-
sized iodides of a cis-2,4-dimethylpyrrolidinium derivative.
The Michael adducts of ethyl acetoacetate with 1-nitro-
propene were reduced (H2,160 atm; Ra-Ni; 90 °C, 8 h) to
afford a mixture of cis-cis and trans-trans 3-(ethoxycar-
bonyl)-2,4-dimethylpyrrolidine (the racemic equivalents
of compounds 29 and 30, respectively, Scheme 4) follow-
ing cyclization and subsequent reduction of the imine
double bond thus formed (57% global yield from ethyl
acetoacetate). These adducts then yielded the racemic
targets.
Our goal was to arbitrarily obtain chiral intermediate
(R,S,S)-30 [and/or (R,R,S)-29] starting from adduct 9
(Scheme 3, Table 1). The reduction of nitro compound 9
occurred smoothly at room temperature after 24 h under
only 6 atm pressure of hydrogen with Ra-Ni catalysis,
leading directly to chiral pyrrolidines (R,R,S)-29 and
(R,S,S)-30 (Scheme 4). Substituting the H-atom of amine
28 and pyrrolidines 29 and 30 by the Boc group allowed
the separation of compound 31 from pyrrolidines 32 and
33, by FC. Basic epimerization of the pyrrolidine mixture
then led to the thermodynamically more stable trans-
trans compound 33 in 61% yield from adduct 9 (58%
global yield from ethyl acetoacetate). Pyrrolidine 33 was
deprotected (75% yield) to give the pure target compound
(R,S,S)-30 (ee > 98%).
Syn th esis of P yr r olin es (S,S)-34, (S,R)-35, a n d
P yr r olid in e (R,R,S)-39. Winn et al. for their part have
prepared a number of racemic N-substituted 2,4-diaryl-
pyrrolidine-3-carboxylic acids which represent a novel
class of endothelin receptor antagonists.9,10
The pyrroline (racemic equivalent of compound 36,
Scheme 6) obtained by Michael reaction of ethyl (4-
methoxybenzoyl)acetate with 2-(3,4-(methylenedioxy)-
(8) Ohki, S.; Nagasaka, T.; Matsuda, H.; Ozawa, N.; Hamaguchi,
F. Chem Pharm. Bull. 1986, 34, 3606-3613.
(9) Winn, M.; von Geldern, T. W.; Opgenorth, T. J .; J ae, H.-S.;
Tasker, A. S.; Boyd, S. A.; Kester, J . A.; Mantei, R. A.; Bal, R.; Sorensen,
B. K.; Wu-Wong, J . R.; Chiou, W. J .; Dixon, D. B.; Novosad, E. I.;
Hernandez, L.; Marsh, K. C. J . Med. Chem. 1996, 39, 1039-1048.
(10) Tasker, A. S.; Sorensen, B. K.; J ae, H.-S.; Winn, M.; von
Geldern, T. W.; Dixon, D. B.; Chiou, W. J .; Dayton, B. D.; Calzadila,
S.; Hernandez, L.; Marsh, K. C.; Wu-Wong, J . R.; Opgenorth, T. J . J .
Med. Chem. 1997, 40, 322-330.

Michael Reactions of Chiral Secondary Enaminoesters
J . Org. Chem., Vol. 65, No. 15, 2000 4597
Sch em e 6
mmol) of the ketoester, 4 mL (31 mmol) of (S)-1-phenyleth-
ylamine, and 20 mL of a 10% solution of AcOH in ethanol,
was heated at reflux for 24 h. The cooled mixture was then
concentrated under reduced pressure and diluted with EtOAc.
The usual workup followed by FC (20:80) afforded 3.99 g (80%
yield) of 24: EIMS m/z (rel int) 325 (M+, 47), 252 (34), 237
(77), 134 (46), 105 (base); IR (film) 1730, 1645, 1610 cm-1; 1H
NMR δ 1.32 (t, J ) 7.1 Hz, 3H), 1.49 (d, J ) 6.6 Hz, 3H), 3.83
(s, 3H), 4.15-4.24 (m, 2H), 4.51 (dq, J ) 9.2, 6.6 Hz, 1H), 4.65
(s, H) 6.81-6.87 (m, 2H), 7.11-7.33 (m, 7H), 8.93 (d, J ) 9.2
Hz, 1H); 13C NMR δ 14.62, 24.65, 53.90, 55.27, 58.74, 86.53,
113.56 (2C), 125.66 (2C), 126.84, 128.51 (2C), 128.73, 129.16
(2C), 144.92, 160.29, 164.24, 170.45.
(E)-1-Nitr op r op en e (8). Intermediate 2-hydroxy-1-nitro-
propane was obtained in 72% yield by a method describing
the preparation of analogous compounds:13 bp 90 °C/125 Torr;
EIMS m/z (rel int) 104 (M+ - 1, 1), 90 (27), 62 (70), 59 (base);
IR (film) 3400 cm-1; 1H NMR in agreement with lit.;14 13C NMR
δ 19.76, 64.91, 81.50. Dehydration of the nitro alcohol was
achieved according to lit.15 but in the presence of a few
hydroquinone crystals allowing the formation of 8 in 79% yield
rather than 30%:15 EIMS m/z (rel int) 87 (M+, base); IR and
1H NMR in agreement with lit.;15 13C NMR δ 13.74, 138.12,
140.35.
its hydrogenation is faster than that of its imines
counterparts 36 and 38. Basic treatment afforded then
the target trans-trans pyrrolidine (R,R,S)-39 (ee 66%) in
67% yield from pyrrolines 36 and 38. An optically pure
sample of the compound was obtained by N-Boc protec-
tion, subsequent ester saponification, and recrystalliza-
tion of the salt derived from (S)-2-phenylethylamine
followed by deprotection and reesterification.
Exp er im en ta l Section
Gen er a l. TLC was performed with glass plates (0.25 mm)
precoated with silica gel, and flash chromatography (FC) was
carried out with silica gel (200-450 mesh), using EtOAc/
hexanes as eluents (proportions given). GC-MS was performed
with a HP 5890 GC apparatus (equipped with a 12 m × 0.20
mm dimethylpolysiloxane capillary column) linked to a HP
5971 EIMS. 1H and 13C NMR spectra of CDCl3 solutions were
recorded respectively at 300 and 75.5 MHz. Anhydrous sol-
vents were freshly distilled under argon, CH2Cl2 over CaCl2,
ether and THF over Na/benzophenone. Commercial (R)- and
(S)-1-phenylethylamine, ee ) 96% and 99%, respectively, were
used without further purification. Unless otherwise indicated,
organic phases were washed with a saturated NaCl aqueous
solution, dried over MgSO4, filtered, and evaporated under
reduced pressure. All Michael reactions were performed under
a nitrogen atmosphere in the presence of a few hydroquinone
crystals.
(E)-1-Nitr obu ten e (11). The 2-hydroxy-1-nitrobutane in-
termediate was obtained as above13 in 76.5% yield: bp 100-
103 °C/120 Torr; EIMS m/z (rel int) 90 (M+ - 29, 81), 72 (30),
1
62 (base), 55 (95); IR (film) 3400 cm-1, H NMR δ 1.00 (t, J )
7.0 Hz, 3H), 1.54 (dq, J ) 7.0, 7.0 Hz, 2H), 2.98 (br s, 1H),
4.14-4.28 (m, 1H), 4.30-4.46 (m, 2H); 13C NMR δ 9.40, 26.75,
69.87, 80.31. Dehydration was achieved as above,15 giving 11
in 88% yield: bp 60-63 °C/15 Torr; EIMS m/z (rel int) 101
(M+, 1), 86 (13), 55 (33), 39 (base); IR and 1H NMR in
agreement with lit.;16 13C NMR δ 11.63, 21.74, 139.02, 143.91.
2-(3,4-(Meth ylen edioxy)ph en yl)-1-n itr oeth en e (25). This
compound was prepared according to lit.,17 in 72% yield: mp
166 °C (CH3NO2-CHCl3) [lit.:17 160.5-161 °C (EtOH-PhH)];
EIMS m/z (rel int) 193 (M+, base), 146 (91); IR (Nujol) 1630,
Eth yl 3-[(1R)-(1-P h en yleth yl)a m in o]bu t-2-en oa te (7).
A 2 mL (15.5 mmol) amount of (R)-1-phenylethylamine were
slowly added at room temperature under nitrogen to 2 mL
(15.7 mmol) of ethyl acetoacetate and stirred for 2 h. Toluene
was then added and, after the usual workup, 3.50 g (97 %
yield) of known oily 7 was obtained: [R]20 -618 (c 1.44,
D
EtOH); EIMS, IR, 1H and 13C NMR in agreement with lit.11
Eth yl 3-P h en yl-3-[(1R)-(1-p h en yleth yl)a m in o]p r op -2-
en oa te (17). A solution of 4.2 mL (24.3 mmol) of ethyl benzoyl
acetate, 4.3 mL (34.7 mmol) of (R)-1-phenylethylamine, and 2
mL of acetic acid in 25 mL of ethanol was heated at reflux
under nitrogen for 4 h. After cooling, the usual workup
followed by FC (30:70) afforded 5.2 g (73% yield) of known 17:
1
1600 cm-1; H NMR δ 6.07 (s, 2H), 6.88 (d, J ) 8.1 Hz, 1H)
7.00 (d, J ) 1.8 Hz, 1H), 7.09 (dd, J ) 8.1, 1.8 Hz, 1H), 7.48
(d, J ) 13.6 Hz, 1H), 7.93 (d, J ) 13.6 Hz, 1H); 13C NMR δ
102.08, 107.02, 109.09, 124.22, 126.63, 135.42, 139.10, 148.79,
151.40.
[R]20 -335 (c 1.43, EtOH); EIMS, IR, 1H and 13C NMR in
D
agreement with lit.11
Eth yl 2-[(1S)-1-(Nitr om eth yl)eth yl]-3-[(1R)-(1-p h en yl-
eth yl)a m in o]bu t-2-en oa te (9). A solution of 1.74 g (20 mmol)
of 8 in 7 mL of CH3CN was added dropwise to a solution of
4.0 g (17.2 mmol) of 7 in 7 mL of CH3CN, in an ice bath. The
Eth yl 3-(4-Meth oxyp h en yl)-3-[(1S)-(1-p h en yleth yl)a m i-
n o]p r op -2-en oa te (24). Ethyl 3-(4-methoxyphenyl)-3-oxopro-
panoate was prepared according to lit.,12 in 93% yield: bp 120
°C/0.2 Torr; EIMS m/z (rel int) 222 (M+, 14), 135 (base); IR
(film) 1740, 1675, 1600 cm-1; 1H NMR in agreement with lit.;12
13C NMR δ 13.91, 45.60, 55.34, 61.17, 113.72 (2C), 128.94,
130.70 (2C), 163.82, 167.58, 190.84. A solution of 3.40 g (15.3
(13) Wollenberg, R. H.; Miller, S. J . Tetrahedron Lett. 1978, 3219-
3222.
(14) Baer, H. H.; Chiu, S.-H. L.; Shields, D. C. Can. J . Chem. 1973,
2828-2835.
(11) Bartoli, G.; Cimarelli, C.; Dalpozzo, R.; Palmieri, G. Tetrahedron
1995, 51, 8613-8622.
(12) Clay, R. J .; Collom, T. A.; Karrick, G. L.; Wemple, J . Synthesis
1993, 290-292.
(15) Melton, J .; McMurry, J . E. J . Org. Chem. 1975, 40, 2138-2139.
(16) Ballini, R.; Castagnani, R.; Petrini, M. J . Org. Chem. 1992, 57,
2160-2162.
(17) Kamlet, M. J . J . Am. Chem. Soc. 1955, 77, 4896-4898.

4598 J . Org. Chem., Vol. 65, No. 15, 2000
Revial et al.
Ta ble 2. Rea ction of 17 w ith 14 in P r esen ce of MgCl2
latter was removed and the mixture kept at room temperature
for 3 h. After solvent evaporation at room temperature under
reduced pressure, the crystalline 9 was washed with ether-
hexane (5:95) (5.22 g, 95% yield). An analytical sample was
obtained by recrystallization: mp 88-89 °C (ether-hexane);
time
conversion %
22:23
diastereoselectivity
4 h
44 h
10 d
91
100
100
69:31
67:33
59:41
66:34
66:34
54:46
[R]20 -485 (c 0.97, EtOH); calcd for C17H24N2O4, C 63.73, H
D
7.55, N 8.74; found C 63.6, H 7.60, N 8.86; IR (CDCl3) 1635,
1
1590, 1545 cm-1; H NMR δ 1.21 (d, J ) 7.0 Hz, 3H), 1.34 (t,
1.37 (t, J ) 7.0 Hz, 3H), 1.39 (d, J ) 6.6 Hz, 3H), 2.67-2.80
(m, 1H), 3.93-4.06 (m, 1H), 4.20-4.35 (m, 3H), 4.61 + 4.69
(each, dd, J ) 11.0, 8.5 Hz) (1H), 6.58-7.50 (m, 10H), 9.85 (d,
J ) 7.0 Hz, 3H), 1.50 (d, J ) 6.6 Hz, 3H), 1.87 (s, 3H), 3.36-
3.49 (m, 1H), 4.22 (dq, J ) 11.0, 7.0 Hz, 2H), 4.50 (dd, J )
11.4, 7.0 Hz, 1H), 4.64 (dq, J ) 7.0, 6.6 Hz, 1H), 4.73 (dd, J )
11.4, 8.0 Hz, 1H), 7.20-7.37 (m, 5H), 10.07 (d, J ) 6.6 Hz,
1H); 13C NMR δ 14.55, 15.72, 17.93, 25.16, 32.60, 53.56, 58.86,
80.80, 91.99, 125.46 (2C), 127.09, 128.84 (2C), 145.23, 161.07,
170.24. A monocrystal of compound 9 was used for an X-ray
structure determination (see the end of the Experimental
Section).
J ) 8.8 Hz, 1H);
13C NMR δ 14.52, 18.14, 24.63, 33.90, 54.16,
59.18, 80.43, 93.24, 125.65-128.73 (9C), 130.63, 134.66,
144.99, 163.85, 170.30.
The same reaction was also carried out in CH3CN (2.5 M
solution) at room temperature for 6 d, followed by solvent
evaporation. In this case, the 1H NMR spectrum of the reaction
mixture showed adduct 18 and its diastereomer (94:6) as well
as pyrrole 19 (70:30).
Cycliza tion of Ad d u ct 9 in to Eth yl 2,4-Dim eth yl-1-
[(1R)-1-p h en yleth yl]-1H-p yr r ole-3-ca r boxyla te (10). A so-
lution of 1.50 g (4.69 mmol) of 9 in 40 mL of ethanol was
allowed to stand at room temperature for 24 h. After evapora-
tion, a FC (10:90) of the residue afforded 0.370 g (29% yield)
of 10 and 0.570 g of starting 9. Pyrrole 10 was recrystallized
in EtOAc-hexane: mp 105 °C; [R]20D 23.9 (c 8.86, CHCl3); calcd
for C17H21NO2, C 75.25, H 7.80, N 5.16; found C 75.3, H 7.82,
N 5.05; EIMS m/z (rel int) 271 (M+, 45), 105 (base); IR (CDCl3)
1690 cm-1; 1H NMR δ 1.33 (t, J ) 7.0 Hz, 3H), 1.76 (d, J ) 7.0
Hz, 3H), 2.25 (d, J ) 1.1 Hz, 3H), 2.41 (s, 3H), 4.26 (q, J ) 7.0
Hz, 2H), 5.29 (q, J ) 7.0 Hz, 1H), 6.47 (br s, 1H), 6.99-7.05
(m, 2H), 7.19-7.33 (m, 3H). 13C NMR δ 11.49, 12.95, 14.52,
21.99, 54.59, 59.01, 111.46, 115.79, 120.33, 125.78 (2C), 127.40,
128.74 (2C), 136.27, 142.48, 166.46.
Eth yl 2-[(1S)-1-(Nitr om eth yl)p r op yl]-3-p h en yl-3-[(1R)-
(1-ph en yleth yl)am in o]pr op-2-en oate (20) an d Eth yl 4-Eth -
yl-2-p h en yl-1-[(1R)-1-p h en yleth yl]-1H-p yr r ole-3-ca r box-
yla te (21) Mixtu r e. A 273 mg (2.70 mmol) amount of 11 and
737 mg (2.50 mmol) of 17 in 1.0 mL of CH3CN were stirred at
room temperature for 6 days. The 1H NMR spectrum of the
crude residue showed the presence of adduct 20 and its
diastereomer (96:4, CHCH2CH3 at 0.67 and 0.73 ppm, respec-
tively) as well as pyrrole 21 (20/21, 75:25, CHCH2CH3/
OCH2CH3 at 0.67 + 0.73 and 0.98 ppm, respectively). After
FC (10:90), 794 mg of an inseparable oily mixture of 20 and
21 (70:30) was obtained. Com p ou n d s 20: 1H NMR δ 0.67 +
0.73 (each, t, J ) 7.3 Hz) (3H), 1.35 (t, J ) 7.0 Hz, 3H), 1.37
(d, J ) 7.0 Hz, 3H), 1.31-1.45 (m, 1H), 1.60-1.70 (m, 1H),
2.47-2.59 (m, 1H), 3.93-4.08 (m, 1H), 4.28 (q, J ) 7.0 Hz,
2H), 4.30-4.38 (m, 1H), 4.61 + 4.69 (each, dd, J ) 11.0, 8.5
Hz)(1H), 6.90-7.50 (m, 10H), 9.98 (d, J ) 9.2 Hz, 1H); 13C
NMR δ 12.10, 14.41, 24.89, 24.96, 40.48, 54.00, 59.01, 79.70,
91.46, 125.49-130.47 (10C), 134.37, 145.00, 164.44, 170.18.
Com p ou n d 21: EIMS m/z (rel int) 347 (M+, 66), 302 (6), 244
(12), 243 (66), 198 (16), 197 (19), 196 (25), 105 (base); 1H NMR
δ 0.98 (t, J ) 7.0 Hz, 3H), 1.23 (t, J ) 7.5 Hz, 3H), 1.71 (d, J
) 7.0 Hz, 3H), 2.75-2.85 (m, 2H), 4.02 (q, J ) 7.0 Hz, 2H),
5.10 (q, J ) 7.0 Hz, 1H), 6.54 (br s, 1H), 6.95-7.38 (m, 10H);
13C NMR δ 13.88, 14.60, 20.19, 21.74, 54.54, 58.89, 111.71,
115.34, 126.00 (2C), 127.32, 127.76 (2C), 128.16, 128.51 (2C),
128.66, 130.61 (2C), 132.97, 139.19, 142.47, 165.45.
Eth yl 2-[(1S)-1-(Nitr om eth yl)p r op yl]-3-[(1R)-(1-p h en yl-
eth yl)a m in o]bu t-2-en oa te (12). A solution of 1.30 g (12.9
mmol) of 11 and 2.98 g (12.8 mmol) of 7 in 5 mL of CH3CN
was stirred at room temperature for 24 h. After removal of
the solvent under reduced pressure at room temperature, a
FC (10:90) of the residue afforded 3.74 g (87.5% yield) of solid
adduct 12: mp 78-80 °C (ether-hexane, 5:95); [R]20D -510 (c
3.03, EtOH); calcd for C18H26N2O4, C 64.65, H 7.84, N 8.37;
found C 64.7, H 7.84, N 8.22; IR (CDCl3) 1630, 1590, 1545 cm-1
;
1H NMR δ 0.77 (t, J ) 7.3 Hz, 3H), 1.33 (t, J ) 7.0 Hz, 3H),
1.50 (d, J ) 6.6 Hz, 3H), 1.46-1.55 (m, 1H), 1.72-1.80 (m,
1H), 1.84 (s, 3H), 3.11-3.27 (m, 1H), 4.15-4.27 (m, 2H), 4.49
(dd, J ) 11.8, 6.6 Hz, 1H), 4.60-4.72 (m, 1H), 4.78 (dd, J )
11.8, 8.8 Hz, 1H), 7.18-7.36 (m, 5H), 10.17 (d, J ) 6.6 Hz,
1H); 13C NMR δ 11.88, 14.38, 15.99, 24.59, 24.98, 39.40, 53.38,
58.68, 79.90, 89.62, 125.19 (2C), 126.88, 128.66 (2C), 145.22,
162.27, 170.02.
Eth yl 2-[(1S)-2-Nitr o-1-p h en yleth yl]-3-p h en yl-3-[(1R)-
(1-p h en yleth yl)a m in o]p r op -2-en oa te (22). A 2.20 g (14.8
mmol) amount of 14 and 4.20 g (14.2 mmol) of 17 in 2.0 mL of
CH3CN were stirred at room temperature for 6 days. After
FC (10:90) of the crude residue of the reaction, 5.90 g (94%
yield) of oily adduct 22 and its diastereomer (90:10, one
aromatic H at 6.63-6.67 and 6.73-6.76 ppm, respectively)
were obtained: [R]20D -325 (c 0.84, EtOH); EIMS (direct intro)
m/z (rel int) 444 (M+, 4), 384 (5), 149 (35), 105 (62), 44 (base);
Eth yl 2-[(1S)-2-Nitr o-1-p h en yleth yl]-3-[(1R)-(1-p h en yl-
eth yl)a m in o]bu t-2-en oa te (15). A solution of 1.10 g (7.38
mmol) of 14 and 1.68 g (7.21 mmol) of 7 in 1.1 mL of CH3CN
was stirred at room temperature for 3 days. The solvent was
removed under reduced pressure, and 1H NMR of the crude
residue showed the presence of 15 and its diastereomer (85:
15, NHPhCHCH3 at 1.51 and 1.52 ppm, respectively). A FC
(10:90) of the residue afforded 2.20 g (80% yield) of an
inseparable oily mixture of these diastereomers: IR (film)
1
IR (film) 1740, 1645, 1550 cm-1; H NMR δ 1.22 (t, J ) 7.0
Hz, 3H), 1.47 (d, J ) 6.6 Hz, 3H), 4.05-4.15 (m, 2H), 4.16-
4.28 (m, 2H), 4.95 (dd, J ) 11.7, 7.0 Hz, 1H), 5.09 (dd, J )
11.7, 8.4 Hz, 1H), 6.63-6.67 + 6.73-6.76 (m, 1H), 7.00-7.60
(m, 14H), 10.04 + 10.14 (m, 1H); 13C NMR δ 14.14, 24.59,
42.63, 54.22, 59.16, 78.88, 92.35, 125.21-129.05 (15C), 134.08,
141.07, 144.77, 164.51, 170.03. HRMS m/z calcd for C27H28N2O4
444.2049, found 444.2047.
1
1740, 1645, 1600, 1555 cm-1; H NMR δ 1.10 (t, J ) 7.0 Hz,
3H), 1.51 + 1.52 (each, d, J ) 7.0 Hz) (3H), 1.95 (s, 3H), 3.95-
4.20 (m, 2H), 4.60-4.75 (m, 2H), 4.95-5.15 (m, 2H), 7.00-
7.40 (m, 10H), 10.20 (d, J ) 6.6 Hz, 1H); 13C NMR δ 14.20,
16.04, 25.11, 41.22, 53.65, 58.93, 78.91, 91.85, 125.43 (2C),
126.25, 126.76 (2C), 127.17, 128.22 (2C), 128.94 (2C), 141.45,
145.17, 162.06, 169.92.
Rea ction in th e P r esen ce of MgCl2. A 253 mg (1.70
mmol) amount of 14, 500 mg (1.70 mmol) of 17, and 16 mg
(0.170 mmol) of MgCl2 in 0.25 mL of acetonitrile were stirred
1
Eth yl 2-[(1S)-1-(Nitr om eth yl)eth yl]-3-p h en yl-3-[(1S)-1-
(p h en yleth yl)a m in o]p r op -2-en oa te (18) a n d P yr r ole 19
Mixtu r e. A 0.219 g (2.52 mmol) amount of 8 and 0.670 g (2.27
mmol) of 17 were stirred without solvent at room temperature
at room temperature. Samples were analyzed by H NMR at
different reaction times. Proportions 22:23 and diastereo-
selectivities were respectively determined using OCH2CH3 at
1.22 and 0.82 ppm, and one aromatic H at 6.63-6.67 and
6.73-6.76 ppm (Table 2). After 10 days, filtration of the
catalyst and evaporation of the solvent was followed by a FC
(10:90) of the residue, affording 282 mg (42% yield) of 23.
Eth yl 2,4-d ip h en yl-1-[(1S)-1-p h en yleth yl]-1H-p yr r ole-
3-ca r boxyla te (23): EIMS m/z (rel int) 395 (M+, 90), 291
(base), 246 (43), 105 (84); IR (film) 1710, 1700 cm-1; 1H NMR
1
for 23 h. The H NMR spectrum of the crude reaction mixture
showed the presence of adduct 18 and its diastereomer (93:7,
CHHNO2 at 4.69 and 4.61 ppm, respectively) as well as pyrrole
19 (vide infra, 91:9, CHCH3/OCH2CH3 at 1.07 and 0.99 ppm,
respectively). This mixture was used directly for the synthesis
of 34. Com p ou n d s 18: 1H NMR δ 1.07 (d, J ) 7.0 Hz, 3H),

Michael Reactions of Chiral Secondary Enaminoesters
J . Org. Chem., Vol. 65, No. 15, 2000 4599
δ 0.82 (t, J ) 7.0 Hz, 3H), 1.74 (d, J ) 7.0 Hz, 3H), 3.95 (q, J
dioxane, and 1.0 mL of 4 N HCl was stirred at room temper-
ature for 1 h. After ether extraction followed by the usual
workup, a molecular distillation (60 °C/15 Torr) afforded 189
) 7.0 Hz, 2H), 5.18 (q, J ) 7.0 Hz, 1H), 6.8-7.5 (m, 16H); 13
C
NMR δ 13.52, 21.78, 54.82, 59.26, 111.87, 117.39, 125.97 (2C),
126.20, 126.31, 126.99, 127.07 (2C), 127.44 (2C), 128.24, 128.39
(2C), 129.24 (2C), 130.61 (2C), 132.21, 135.36, 139.04, 141.95,
165.08.
mg of 30 (75% yield): [R]20 -31 (c 4.90, EtOH); EIMS m/z
D
(rel int) 171 (M+, 7), 142 (67), 57 (base); IR (film) 1725 cm-1
;
1H NMR δ 1.10 (d, J ) 7.0 Hz, 3H), 1.23 (d, J ) 6.3 Hz, 3H),
1.27 (t, J ) 7.0 Hz, 3H), 1.97 (dd, J ) 8.5, 8.5 Hz, 1H), 2.17 (s,
1H), 2.39-2.54 (m, 1H), 2.63 (dd, J ) 11.0, 7.0 Hz, 1H), 3.18
(dd, J ) 11.0, 8.1 Hz, 1H), 3.35 (dq, J ) 8.5, 6.3 Hz, 1H), 4.16
(q, J ) 7.0 Hz, 2H); 13C NMR δ 14.33, 18.89, 20.72, 40.24,
53.96, 59.36, 60.45, 60.51, 174.45; HRMS (CI, NH3) calcd for
C9H18O2N (M+ + 1) m/z 172.1338, found m/z 172.1333.
Eth yl 2-[(1R)-1-(3,4-(Meth ylen ed ioxy)p h en yl)-2-n itr o-
eth yl]-3-(4-m eth oxyp h en yl)-3-[(1S)-(1-p h en yleth yl)a m i-
n o]p r op -2-en oa te (26). A 4.63 g (24.0 mmol) of 25, 7.81 g
(24.0 mmol) of 24, and 24 mL of CH3CN were stirred at room
temperature for 18 days; a FC (20:80) of the crude residue of
the reaction afforded 11.6 g (93.5%) of oily adduct 26 and its
inseparable diastereomer (83:17, OCH2O at 5.87 and 5.90 ppm
respectively): IR (film) 3220, 1745, 1640, 1610 cm-1; 1H NMR
δ 1.23 (t, J ) 7.0 Hz, 3H), 1.39 (d, J ) 7.0 Hz, 3H), 3.59 (s,
3H), 4.00-4.26 (m, 4H), 4.82 (dd, J ) 11.7, 7.3 Hz, 1H), 5.00
(dd, J ) 11.7, 8.5 Hz, 1H), 5.87 + 5.90 (each, s) (2H), 6.40-
7.40 (m, 12H), 9.98 + 10.02 (each, d, J ) 8.8 Hz) (1H); 13C
NMR δ 14.35, 24.62, 42.73, 54.29, 55.21, 59.27, 79.29, 92.71,
100.85, 107.91, 107.96, 113.71, 114.01, 120.15, 125.65 (2C),
126.43, 126.63, 128.49 (2C), 129.07, 129.12, 135.15, 144.88,
145.85, 147.40, 159.91, 164.71, 170.10.
Eth yl (3S,4S)-3-Meth yl-5-p h en yl-3,4-d ih yd r o-2H-p yr -
r ole-4-ca r boxyla te (34) a n d Eth yl 4-Meth yl-2-p h en yl-1-
[(1R)-1-p h en yleth yl]-1H-p yr r ole-3-ca r boxyla te (19) Mix-
tu r e. A 2.4 g amount of ethanol washed Ra-Ni was added to
a solution of the mixture of 18 and 19 (91:9) (vide supra) in
10 mL of ethanol. After stirring at room temperature under
hydrogen (7 atm) for 3 h, the catalyst was filtered on Celite
and the filtrate diluted in 20 mL of ethanol was heated at
reflux for 14 h. The cooled solution was evaporated under
reduced pressure and a FC (20:80) of the residue afforded 134
mg of 19 and 252 mg (48% global yield from 17) of 34 and its
diastereomer (85:15, GC-MS, tR 3.72 and 4.00 min, respec-
tively). Com p ou n d s 34: EIMS m/z (rel int) 231 (M+, 14), 157
(30), 117 (base) (d ia ster eom er : identical spectrum pattern,
typical for a diastereomer2d,e); IR (film) 1730 cm-1; 1H NMR δ
1.11-1.22 (m, 6H), 2.70-2.88 (m, 1H), 3.66-3.80 (m, 2H),
4.04-4.20 (m, 2H), 4.33 (ddd, J ) 16.2, 7.4, 2.2 Hz, 1H), 7.35-
7.45 (m, 3H), 7.78-7.87 (m, 2H); 13C NMR δ 14.02, 20.24,
38.45, 61.11, 61.71, 68.44, 128.06 (2C), 128.48 (2C), 130.62,
133.64, 168.86, 171.82. Com p ou n d 19: EIMS m/z (rel int)
333 (M+, 93), 229 (98), 105 (base); IR (film) 1700 cm-1; 1H NMR
δ 0.99 (t, J ) 7.0 Hz, 3H), 1.69 (d, J ) 7.0 Hz, 3H), 2.31 (d, J
) 1.1 Hz, 3H), 4.03 (q, J ) 7.0 Hz, 2H), 5.10 (q, J ) 7.0 Hz,
1H), 6.52 (d, J ) 1.1 Hz, 1H), 6.96-7.45 (m, 10H); 13C NMR δ
12.48, 13.87, 21.62, 54.37, 58.82, 112.32, 116.61, 121.23, 125.97
(2C), 127.30, 127.72 (2C), 128.00, 128.46 (2C), 130.56 (2C),
132.83, 138.98, 142.27, 165.45.
Cycliza t ion of Ad d u ct 26 in t o E t h yl 2-(4-m et h oxy-
ph en yl)-4-(3,4-(m eth ylen edioxy)ph en yl)-1-[(1S)-1-ph en yl-
eth yl]-1H-p yr r ole-3-ca r boxyla te (27). A solution of 5.98 g
(11.5 mmol) of 26 in 60 mL of EtOH was heated at reflux for
24 h. After evaporation of the mixture at reduced pressure, a
FC (30:70) of the residue afforded 2.73 g (51% yield) of 27
which was recrystallized: mp 112 °C (AcOEt/hexane); [R]20
D
-34.5 (c 6.42, CHCl3); calcd for C29H27NO5, C 74.18, H 5.80,
N 2.98; found C 74.1, H 5.78, N 2.94; EIMS m/z (rel int) 469
(M+, 58), 364 (base), 105 (54); IR (CHCl3) 1710, 1695, 1610
cm-1; 1H NMR δ 0.92 (t, J ) 7.0 Hz, 3H), 1.73 (d, J ) 7.0 Hz,
3H), 3.82 (s, 3H), 3.98 (q, J ) 7.0 Hz, 2H), 5.18 (q, J ) 7.0 Hz,
1H), 5.93 (s, 2H), 6.72-7.30 (m, 13H); 13C NMR δ 13.79, 21.86,
54.74, 55.25, 59.32, 100.79, 107.66, 110.06, 111.88, 113.40 (2C),
117.11, 122.17, 124.34, 126.09 (2C), 127.50, 128.61 (2C),
129.57, 131.89 (2C), 138.88, 142.14, 146.13, 146.98, 159.62,
165.20 (one quaternary C not found).
Eth yl (2R,3S,4S)-1-(ter t-Bu toxyca r bon yl)-2,4-d im eth -
ylp yr r olid in e-3-ca r boxyla te (33). A 5.00 g amount of etha-
nol washed Ra-Ni was added to a solution of 1.51 g (4.72
mmol) of 9 in 35 mL of ethanol. The mixture was stirred at
room temperature under hydrogen (6 atm) for 24 h. The
catalyst was then filtered on Celite and the filtrate concen-
trated under reduced pressure. A GC-MS analysis showed the
Eth yl (3R,4S)-3,5-Dip h en yl-3,4-d ih yd r o-2H-p yr r ole-4-
ca r boxyla te (35). The same procedure as performed above
for obtaining 34 was used with 7.0 g of Ra-Ni, 3.00 g (6.75
mmol) of 22, and 40 mL of ethanol. The filtered solution was
then heated at reflux for 24 h. After cooling and evaporation,
a FC (20:80) of the residue afforded 1.51 g (76% yield) of 35
and its diastereomer (89:11, GC-MS, tR 10.48 and 10.79 min,
respectively): EIMS m/z (rel int) 293 (M+, 8), 220 (36), 117
(base) (d ia ster eom er : identical spectrum pattern, typical for
presence of 28 as well as two compounds (ca. 2:1, each M+
)
171) with tR 4.08 and 4.16 min, respectively, corresponding to
30 (cf EIMS, next experiment) and 29 (identical mass spectrum
pattern with slightly different relative intensities, typical for
a diastereomer2d,e). The oily residue was diluted in 5 mL of
CH2Cl2 and 1.5 g (6.87 mmol) of di-tert-butyl dicarbonate was
added. After stirring the mixture for 4 h, the solvent was
evaporated; a FC (AcOEt/CH2Cl2, 5:95) afforded a mixture of
diastereomers which was diluted in 10 mL of a 0.1 M NaOEt
ethanol solution and heated at reflux for 1.5 h. The epimer-
ization was followed by GC-MS (100 °C for 1 min, then 18 °C/
min up to 280 °C) until complete disappearance of the minor
signal (tR 5.49 min) in favor of the major signal (tR 5.29 min).
Extraction with CH2Cl2 was followed by the usual workup
giving a residue which was purified by FC (10:90), affording
0.78 g of 33 (61% yield). An analytical sample was obtained
1
a diastereomer2d,e); IR (film) 1725 cm-1; H NMR δ 1.15 (t, J
) 7.0 Hz, 3H), 3.88 (ddd, J ) 8.1, 4.4, 4.4 Hz, 1H), 4.10 (dq, J
) 11.0, 7.0 Hz, 1H), 4.15 (dq, J ) 11.0, 7.0 Hz, 1H), 4.25 (ddd,
J ) 16.9, 4.4, 1.1 Hz, 1H), 4.26 (ddd, J ) 4.4, 2.2, 1.1 Hz, 1H),
4.65 (ddd, J ) 16.9, 8.1, 2.2 Hz, 1H), 7.10-7.50 (m, 8H), 7.86-
7.92 (m, 2H); 13C NMR δ 13.90, 49.08, 61.23, 62.59, 68.91,
126.91 (2C), 127.04, 127.86 (2C), 128.24 (2C), 128.83 (2C),
130.66. 133.20, 143.35, 168.60, 171.32.
Eth yl (3S,4R)-5-(4-Meth oxyp h en yl)-3-(3,4-(m eth ylen e-
dioxy)ph en yl)-3,4-dih ydr o-2H-pyr r ole-4-car boxylate (36).
The same procedure as performed above for obtaining 34 was
used with 8.0 g of Ra-Ni, 4.43 g (8.55 mmol) of 26 and its
diastereomer (83:17), and 60 mL of ethanol, under hydrogen
(6 atm) for 2 h. The filtrate was heated at reflux for 24 h. After
evaporation of the cooled solution, a FC (20:80) of the residue
afforded 2.64 g (84% yield) of 36 and its diastereomer 38 (94:
6, 2 aromatic H at 8.06 and 8.20 ppm, respectively; GC-MS,
no separation): EIMS m/z (rel int) 367 (M+, 20), 294 (21), 147
by molecular distillation (70-75 °C/15 Torr): [R]20 -38 (c
D
6.41, EtOH); EIMS m/z (rel int) 214 (M+ - 57, 33), 170 (60),
142 (40), 57 (base); IR (film) 1735, 1690 cm-1; 1H NMR (C6D5-
CD3, 90 °C) δ 0.87 (d, J ) 6.3 Hz, 3H), 1.02 (t, J ) 7.0 Hz,
3H), 1.33 (d, J ) 6.3 Hz, 3H), 1.41 (s, 9H), 2.07 (dd, J ) 10.3,
8.1 Hz, 1H), 2.09-2.27 (m, 1H), 2.70 (dd, J ) 10.3, 10.7 Hz,
1H), 3.77 (dd, J ) 10.7, 7.0, 1H), 3.96 (q, J ) 7.0 Hz, 2H),
3.98-4.08 (m, 1H); 13C NMR (CDCl3) δ 14.28, 16.12, 20.43 +
21.14, 28.51 (3C), 36.41, 53.00 + 53.23, 56.92, 59.45 + 59.94,
60.82, 79.40, 154.13, 172.76; HRMS (CI, NH3) calcd for
1
(base); IR (film) 1725 cm-1; H NMR (C6D6) δ 0.82 (t, J ) 7.0
Hz, 3H), 3.25 (s, 3H), 3.77 (ddd, J ) 8.1, 4.6, 4.6, 1H), 3.83
(dq, J ) 11.0, 7.0 Hz, 1H), 3.90 (dq, J ) 11.0, 7.0 Hz, 1H),
4.15 (ddd, J ) 16.5, 4.6, 1.0 Hz, 1H), 4.21 (br d, J ) 4.6 Hz,
1H), 4.59 (ddd, J ) 16.5, 8.1, 1.8 Hz, 1H), 5.34 (s, 2H), 6.43
(dd, J ) 8.1, 1.8 Hz, 1H), 6.53 (d, J ) 8.1 Hz, 1H), 6.58 (d, J
) 1.8 Hz, 1H), 6.72 (br d, J ) 9.0 Hz, 2H), 8.06 + 8.20 (each,
br d, J ) 9.0 Hz) (2H); 13C NMR (CDCl3) δ 14.07, 49.09, 55.33,
C
14H24O4N (M++1) m/z 272.1862, found m/z 272.1860.
Eth yl (2R,3S,4S)-2,4-Dim eth ylp yr r olid in e-3-ca r boxy-
la te (30). A mixture of 397 mg (1.47 mmol) of 33, 0.4 mL of

4600 J . Org. Chem., Vol. 65, No. 15, 2000
Revial et al.
61.31, 62.87, 68.92, 101.02, 106.91, 108.39, 113.85 (2C), 119.82,
126.03, 129.66 (2C), 137.56, 146.49, 148.07, 161.68, 167.91,
171.50.
(2C), 120.39, 127.77 (2C), 134.16, 136.37, 146.28, 147.86,
158.97, 173.66. HRMS calcd for C21H23NO5 m/z 369.1576, found
m/z 369.1576.
X-r a y Str u ctu r e Deter m in a tion of Com p ou n d 9. C17H24
-
Eth yl (2R,3R,4S)-2-(4-Meth oxyp h en yl)-4-(3,4-(m eth yl-
en ed ioxy)p h en yl)p yr r olid in e-3-ca r boxyla te (39). A 11.0
g amount of ethanol washed Ra-Ni was added to a solution
of 2.49 g (6.80 mmol) of 36 in 60 mL of ethanol, and the
mixture was heated at 50 °C under hydrogen (6 atm) for 40 h.
The cooled solution was filtered on Celite and concentrated.
A 1H NMR spectrum of a sample showed a mixture of 39 and
40 (86:14, OCH2CH3 at 1.10 and 0.82 ppm, respectively). A 68
mg (1.0 mmol) amount of NaOEt in 25 mL of ethanol was
added to the residue which was heated at reflux for 1 h. The
solvent was then evaporated, and a FC (80:20) of the residue
N2O4, M ) 320.38. A suitable crystal of size 0.30 mm × 0.35
mm × 0.42 mm was investigated on a Syntex P21 diffracto-
meter (Mo KR radiation, λ ) 0.71069 Å, graphite monochro-
mator). Cell dimensions were determined by a least-squares
fit to the setting angles of 20 reflections with 6.17 e 2θ e
11.43°, orthorhombic, space group P212121, Z ) 8, a
)
)
7.565(4), b ) 17.59(2), c ) 27.12(3) Å, V ) 3609(6) Å3, dx
1.18 g.cm-3, µ ) 0.084 mm-1. 8338 reflections were measured
up to 2θ ) 55° of which 1941 with I > 2σ(I) were kept in
refinement calculations. The structure was solved by direct
methods using SHELXS8619 and refined by full matrix least-
squares with SHELXL93.20 Non hydrogen atoms were refined
with anisotropic temperature factors; hydrogen atoms were
located. Convergence was reached at R ) 0.11. The poor
quality of the crystal has not allowed a best refinement. The
residual electron density in the final difference Fourier map
does not show any features up to 0.22 e. Å-3 and down to -0.15
e. Å-3. The asymmetric unit consists of two independent
molecules.
afforded 1.70 g (68% yield) of 39: [R]20 35.5 (c 11.52, EtOH).
D
A 66% ee value for 39 is given by the diastereomeric ratio (83:
17) of (S,R)-26 and (S,S)-26 determined by 1H NMR. This value
is further estimated by LISR 1H NMR determinations with
Eu(hfc)3, following the chemical shift of the methyl group of
the ester function in 39 (ee ) 70%).
Enantiopure 39 was obtained by the following procedure:
to a solution of 1.0 g (2.71 mmol) of 39 in 3 mL of CH2Cl2 was
added 0.70 g (3.20 mmol) of di-t-butyl dicarbonate. After
stirring the mixture at room temperature for 4 h followed by
evaporation of the solvent, a FC (30:70) yielded 1.20 g of the
N-Boc protected compound which was saponified with 6 mL
of a 2 M aqueous KOH solution diluted in 5 mL of ethanol, at
room temperature for 2 h. The mixture was then acidified with
HCl to pH ) 1, and the resulting carboxylic acid derivative
was extracted with AcOEt. After the usual workup, the
compound was dissolved in 4 mL of AcOEt, and 0.326 g (2.70
mmol) of (S)-1-phenylethylamine was added to yield the
corresponding salt which crystallized. Four recrystallizations
in THF-ether afforded the pure salt which was deprotected
and esterified through dissolution in 30 mL of a saturated
solution of dry HCl in ethanol and heating at 60 °C overnight.
After evaporation, a FC (80:20) of the residue afforded 0.550
Lists of the fractional atomic coordinates, thermal param-
eters, and bond distances and angles have been deposited at
the Cambridge Crystallographic Data Centre, U.K., as Sup-
porting Information.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 9, 10, 12, 15, 18, 19, 22, 24, 26, 27, 30,
33, 34, 35, 36, 39, as well as X-ray structure of compound 9.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O000206I
(18) We thank Dr. Martin Winn (Abbott Laboratories) for a copy of
the 1H NMR spectrum of compound 43.
(19) Sheldrick, G. M. SHELXS86. Program for solution of crystal
structures. University of Go¨ttingen. Germany (1985).
(20) Sheldrick, G. M. SHELXL93. Program for refining crystal
structures. University of Go¨ttingen. Germany (1993).
g (55% yield) of 39: [R]20 57.7 (c 7.68, EtOH); EIMS m/z (rel
D
int) 369 (M+, 2), 148 (base); IR (film) 3335, 1725, 1610 cm-1
;
1H NMR in agreement with lit.;10,18 13C NMR δ 14.19, 50.58,
54.53, 55.20, 60.56, 61.34, 66.68, 100.90, 107.49, 108.17, 113.87