Stereochemical aspects in the asymmetric Michael addition of chiral imines to substituted electrophilic alkenes

Article abstract of DOI:10.1021/jo960140k

The Michael-type addition of chiral imines, derived from racemic α-substituted cyclanones and optically active 1-phenylethylamine, to electrophilic alkenes, in neutral conditions, constitutes one of the most efficient methods for the stereocontrolled construction of quaternary carbon centers. In order to create an additional stereogenic center at the α- or β-position to the quaternary one, the behavior of a variety of α- and β-substituted alkenyl acceptors was examined. In general, these additions are highly regioselective, the alkylation taking place predominantly, if not exclusively, at the more substituted α-side of the imine function; however, in some cases (electrophilic alkenes 28 and 49), significant amounts (10-15%) of regioisomeric adducts were obtained. With the exception of methyl propiolate 52, a remarkable control of the absolute configuration of the adducts were always observed with these Michael acceptors. According to the general rule we have previously proposed, the alkylation process takes place preferentially on the less hindered π-face of the more substituted secondary enamine, in tautomeric equilibrium with the starting imine. An excellent diastereocontrol was always obtained by using the present α- and β-substituted alkenes. These stereochemical outcomes can be interpreted by invoking that the reaction proceeds through a compact approach of the reactants, the hydrogen atom at the nitrogen center of the enamine being transferred to the α-vinylic carbon atom of the acceptor, concertedly with the creation of the C-C bond. In this respect the "endo-approach" 58, in which the electron-withdrawing group of the acceptor faced to the nitrogen atom of the enamine (case of acceptors 10, methyl methacrylate, 24, 28, 43, 47, and 49) largely prevails over the "exo-approach" 59 (case of acceptor 38). This predominant "endo-preference" can be reasonably interpreted in terms of a cooperative effect between steric and stereoelectronic factors.

Full text of DOI:10.1021/jo960140k

J . Org. Chem. 1996, 61, 4361-4368
4361
Ster eoch em ica l Asp ects in th e Asym m etr ic Mich a el Ad d ition of
Ch ir a l Im in es to Su bstitu ted Electr op h ilic Alk en es
Christian Cave´, Didier Desmae¨le, and J ean d’Angelo*
Laboratoire de Chimie Organique associe´ au CNRS, Universite´ Paris-Sud, Centre d’Etudes
Pharmaceutiques, 5 rue J .-B. Cle´ment, 92296 Chaˆtenay-Malabry, France
Claude Riche and Ange`le Chiaroni
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received J anuary 22, 1996X
The Michael-type addition of chiral imines, derived from racemic R-substituted cyclanones and
optically active 1-phenylethylamine, to electrophilic alkenes, in neutral conditions, constitutes one
of the most efficient methods for the stereocontrolled construction of quaternary carbon centers.
In order to create an additional stereogenic center at the R- or â-position to the quaternary one,
the behavior of a variety of R- and â-substituted alkenyl acceptors was examined. In general, these
additions are highly regioselective, the alkylation taking place predominantly, if not exclusively, at
the more substituted R-side of the imine function; however, in some cases (electrophilic alkenes 28
and 49), significant amounts (10-15%) of regioisomeric adducts were obtained. With the exception
of methyl propiolate 52, a remarkable control of the absolute configuration of the adducts were
always observed with these Michael acceptors. According to the general rule we have previously
proposed, the alkylation process takes place preferentially on the less hindered π-face of the more
substituted secondary enamine, in tautomeric equilibrium with the starting imine. An excellent
diastereocontrol was always obtained by using the present R- and â-substituted alkenes. These
stereochemical outcomes can be interpreted by invoking that the reaction proceeds through a
compact approach of the reactants, the hydrogen atom at the nitrogen center of the enamine being
transferred to the R-vinylic carbon atom of the acceptor, concertedly with the creation of the C-C
bond. In this respect the “endo-approach” 58, in which the electron-withdrawing group of the
acceptor faced to the nitrogen atom of the enamine (case of acceptors 10, methyl methacrylate, 24,
28, 43, 47, and 49) largely prevails over the “exo-approach” 59 (case of acceptor 38). This
predominant “endo-preference” can be reasonably interpreted in terms of a cooperative effect
between steric and stereoelectronic factors.
Sch em e 1
In tr od u ction
Owing to the presence, as a key structural feature, of
quaternary carbon centers in many important naturally
occurring products (terpenes, steroids, alkaloids, etc.), the
enantioselective elaboration of such pivotal entities con-
stitutes a major, fascinating area of the asymmetric
synthesis.1 Conceptionally, one of the simplest methods
for the stereocontrolled construction of quaternary carbon
centers is the alkylation, in a suitable chiral environment,
of R-disubstituted ketones (or their equivalents) (eq 1).
Although highly attractive, this methodology however
requires that the regio- and stereoselectivity of the
alkylation process should be controlled simultaneously.
1 and optically active 1-phenylethylamine 2 add, under
neutral conditions, to electrophilic alkenes 4 to furnish,
after acidic hydrolytic workup, R-disubstituted cyclanones
5, in good yields and with a high degree of regio- and
stereoselectivity, along with the recovered unchanged
chiral auxiliary (Scheme 1).
(1)
This reaction, which tolerates a great variation in the
nature of both reagent partners, has been successfully
applied by ourselves and others to the enantioselective
synthesis of various natural compounds.2 The mecha-
nistic aspects of this Michael addition have also been
extensively investigated, from both experimental and
theoretical viewpoints.2 It has thus been proposed that
the nucleophilic partners in the reaction are the more
substituted secondary enamines, in tautomeric equilib-
rium with imines 3, a view strengthened by the fact that
addition of deuterated imine 6 to methyl acrylate led
A decade ago, we proposed a particularly efficient and
simple solution to this challenging problem (at least in
the case of cyclic ketones), based on the Michael-type
alkylation of chiral imines.2 Thus, we have shown that
imines 3, derived from racemic R-substituted cyclanones
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
(1) Review: Fuji, K. Chem. Rev. 1993, 93, 2037-2066.
(2) Reviews: (a) d’Angelo, J .; Desmae¨le, D.; Dumas, F.; Guingant,
A. Tetrahedron: Asymmetry 1992, 3, 459-505. (b) d’Angelo, J .; Cave´,
C.; Desmae¨le, D.; Dumas, F. Trends in Organic Synthesis; Pandalai,
S. G., Ed.; Trivandrum: India, 1993; Vol. 4, pp 555-615.
S0022-3263(96)00140-5 CCC: $12.00 © 1996 American Chemical Society

4362 J . Org. Chem., Vol. 61, No. 13, 1996
Cave´ et al.
Sch em e 2
Ch a r t 1
cleanly to adduct 8, which contains a deuterium atom at
the R-position to the ester group.3 On the other hand,
the complete control of the stereogenic center at C-2
position in adduct 8 supports the hypothesis that the
deuteron borne by the nitrogen atom in the secondary
enamine 7 was transferred to the R-vinylic center of
methyl acrylate concertedly with the creation of the C-C
bond (Scheme 2).
Ch a r t 2
Of peculiar interest from both synthetic and mecha-
nistic viewpoints, was the creation of an additional
stereogenic center at the R- or â-position to the quater-
nary one, by using adequately substituted electrophilic
alkenes. In this paper, we report the stereochemical
results obtained by using a variety of R- and â-substituted
alkenyl acceptors, and of methyl propiolate as electro-
philic alkyne. Excellent stereoselectivities were generally
observed in such additions. These stereochemical out-
comes can be rationalized by evoking that the reaction
proceeds through an “aza-ene-synthesis-like” transition
state, the geometry of which is governed by steric and
stereoelectronic factors.
as chiral shift reagent]. The relative configuration of the
two stereogenic centers in 15 was determined through
its cyclization, by addition of ammonia (NH3 in MeOH,
5 days at 20 °C, then p-TsOH heated to reflux in toluene),
to bicyclic lactam (3R,4aR)-16. The trans relationship
between the two substituents at C-3 and C-4a in 16 was
determined as follows. Addition of keto ester 17 to
methyl methacrylate (Triton B, THF, 12 h at 20 °C)
furnished 18 (as an equimolar mixture of racemic dia-
stereomers), which was cyclized by addition of ammonia,
followed by treatment with p-TsOH heated to reflux in
toluene, to a 1:1 mixture of racemic lactams 16 and 19
(an experiment which, incidentally, established that 16
and 19 did not interconvert in such operating conditions).
Lactams 16 and 19 were easily separated by flash
chromatography over silica gel (Chart 2). Structure of
lactam (()-16 was unequivocally established by an X-ray
diffraction analysis (Figure 1).7
Resu lts a n d Discu ssion
Chiral imine 9, prepared by condensing racemic 2-me-
thylcyclohexanone with (R)-1-phenylethylamine, or its
enantiomer, were used as nucleophilic reagents in all
experiments. Chiral enamino ester 14 and enamino
lactam 35 were also employed in some cases. Consider-
ing the significant propensity of the adducts to equilibrate
(through a retro-Michael-type fragmentation),4 only the
experiments performed under relatively mild operating
conditions were taken into account in the present inves-
tigation.
Determination of the absolute configuration of the
quaternary carbon center in 15 was established by
chemical correlation, starting from keto ester (R)-20, of
known configuration. This was first protected as ketal
derivative 21. Sequential deprotonation of 21 (LDA,
THF, -78 °C) and methylation (MeI, -78 °C, 3 h)
produced a mixture of diasteromers 22 and 23, which
were easily separated by flash chromatography, in the
ratio of 4.5:1. Acidic hydrolysis of the minor isomer 23
finally led to the corresponding keto ester which proved
to be identical in all respects, including the optical
rotation, with 15 (Chart 3).
r-Su bstitu ted Alk en yl Accep tor s. Addition of imine
9 to ethyl 2-deuteroacrylate (10) (neat, 48 h at 20 °C, and
then 20% aqueous AcOH, 2 h at 20 °C) furnished in 75%
yield keto ester (2R,1′S)-11.3 The depicted relative
configuration of the two stereogenic centers in adduct 11
was determined at the level of the bicyclic lactam
derivative 12, obtained by addition of NH3 to 11 (MeOH,
3 days at 20 ° C, then p-TsOH, heated 3 h to reflux in
benzene). A strong NOE (10%) was actually observed
between the angular methyl group and the hydrogen
1
atom in the R-position to the lactam function in the H
NMR spectrum of 12 (Chart 1).
Condensation of imine 9 with methyl methacrylate
produced adduct 13 in very low yield (1%).5 In contrast,
MgBr2-catalyzed addition of chiral enamino ester (R)-14
to this electrophile (7 days at 20 °C and then 10%
aqueous AcOH, 24 h at 20 °C) gave with a 72% yield
adduct (2R,1′R)-15.6 This adduct was found to be homo-
(5) When, in our hands, all attempts at condensing methyl meth-
acrylate or methyl crotonate with imine 9, under thermal conditions,
furnished essentially polymeric materials (see Experimental Section),
the authors claimed that, somewhat paradoxically, the Michael adducts
were formed in good yields and with excellent stereoselectivities, by
using highly forcing conditions (30 days at 120 °C for methyl croto-
nate).12 In any case, considering such very drastic operating conditions,
there is no certainty that the so-called adducts were formed under
kinetic control,4 and therefore the reported stereochemistries do not
necessarily reflect the geometrical arrangement of the reactants in the
corresponding transition states.
1
geneous by H NMR spectroscopy [after adding Eu(hfc)3
(3) Ambroise, L.; Desmae¨le, D.; Mahuteau, J .; d’Angelo, J . Tetra-
hedron Lett. 1994, 35, 9705-9708.
(4) (a) Huffman, J . W.; Rowe, C. D.; Matthews, F. J . J . Org. Chem.
1982, 47, 1438-1445. (b) Desmae¨le, D.; d’Angelo, J .; Bois, C. Tetra-
hedron: Asymmetry 1990, 1, 759-762.
(6) Cave´, C.; Daley, V.; d’Angelo, J .; Guingant, A. Tetrahedron:
Asymmetry 1995, 6, 79-82.
(7) In our original paper, structures 16 and 19 have been permuted
by inadvertence.6

Asymmetric Michael Addition of Chiral Imines
J . Org. Chem., Vol. 61, No. 13, 1996 4363
Ch a r t 4
Ch a r t 5
F igu r e 1. X-ray crystal structure of lactam (()-16.
Ch a r t 3
to reflux in benzene, 90% yield). A strong NOE was
observed between the angular methyl group and H3 in
1
the H NMR spectrum of 32, ascertaining the cis rela-
tionship between these two substituents. The R config-
uration at the quaternary carbon in 29 was determined
as follows.This keto ester was protected as ketal 33. The
acetoxy group in 33 was then cleaved by reduction (SmI2/
HMPA/THF/MeOH) giving, after acidic hydrolytic work-
up, the known, enantiopure keto ester (R)-34 (Chart 5).
Addition of enamino lactam (S)-35 to electrophilic
alkene 28 (THF, 24 h at 20 °C, and then 20% aqueous
AcOH, 12 h at 20 °C) afforded with a 55 % yield adduct
(16S,20R)-36,8 as a single isomer. The relative configu-
ration of the two stereogenic centers in 36 was estab-
Addition of imine ent-9 to R-methylene-γ-butyrolactone
24 (3 days at 40 °C in THF, and then 10% aqueous AcOH,
2 h at 20 °C) furnished adduct (2R,1′R)-25 with a 54%
yield. The relative configuration of the two stereogenic
centers in 25 was established by chemical correlation.
For this purpose 25 was first cyclized to lactam 26 by
addition of ammonia (NH3 in MeOH, 72 h at 20 °C).
Dehydration of 26 (heated 12 h to reflux in benzene, in
the presence of a catalytic amount of p-TsOH) then gave
(3R,4aR)-27 (70% overall yield). The depicted relative
stereochemistry in 27 was assigned by 1H NMR spec-
troscopy, a strong NOE (11%) was indeed observed
between the angular methyl and the H atom at C-3. An
enantiomeric excess of 97% (after correction of the
enantiomeric purity of the starting chiral amine) in
adduct 25 was measured by 1H NMR spectroscopy [after
adding Eu(hfc)3 as chiral shift reagent]. The portrayed
absolute configuration in 25, although not definitively
established, rests on a heuristic rule we have proposed
(vide infra, Figure 3), predicting that the alkylation takes
place predominantly on the less hindered π-face of imine
ent-9, anti to the phenyl group (Chart 4).
Condensation of imine ent-9 with methyl 2-acetoxy-
acrylate (28) (neat, 90 min at 20 °C, then 20% aqueous
AcOH, 1 h at 20 °C) furnished adduct (2S,1′R)-29 (60%
yield), accompanied by 10% of regioisomer 30 (mixture
of not fully characterized stereomers).3 The relative
configuration of the two stereogenic centers in 29 was
determined by converting this compound by addition of
ammonia (NH3 in MeOH, 4 days at 20 °C, 72% yield) to
bicyclic lactam 31 (concomitant cleavage of the acetoxy
group by ammonia took place during this reaction).
Dehydration of 31 then afforded 32 (p-TsOH, heated 2 h
1
lished by H NMR spectroscopy including NOE experi-
ments at the level of the pentacyclic lactone derivative
37 [i: LiAl(Ot-Bu)3,THF, 20 °C; ii: separation of epimers;
iii: Amberlyst R15, heated 24 h to reflux in benzene; iv:
POCl3, heated 12 h to reflux in MeCN, and then 1 atm of
H2, Pd-C, AcOEt, 12 h at 20 °C] (Chart 6).
Addition of imine 9 to methyl R-(phenylthio)acrylate
(38) (THF, 24 h at 20 °C, and then 20% aqueous AcOH,
2 h at 20 °C) produced adduct (2S,1′S)-39 with a 80%
yield.9 The relative configuration of the two stereogenic
centers in 39 was established as follows. Treatment of
adduct 39 with aqueous ammonia led to bicyclic lactam
40 which was converted (DBU) to the thermodynamically
more stable epimer 41; thus the PhS group is axial in
compound 40 and equatorial in isomer 41. Further data
in support of these stereochemical assignments were
obtained from the 1H NMR spectra of these diastereomers
(thus a 18% NOE was observed between the angular
methyl group and H-3 in 41). The S configuration (90%
ee) at the quaternary carbon center in 39 was unam-
(8) Mekouar, K.; Ambroise, L.; Desmae¨le, D.; d’Angelo, J . Synlett
1995, Special Issue May, 529-532.
(9) d’Angelo, J .; Guingant, A.; Riche, C.; Chiaroni, A. Tetrahedron
Lett. 1988, 29, 2667-2670.

4364 J . Org. Chem., Vol. 61, No. 13, 1996
Cave´ et al.
Ch a r t 6
Ch a r t 9
Ch a r t 10
THF) afforded bicyclic lactam 48 with an excellent
stereoselectivity (Chart 9).10
Addition of imine ent-9 to maleic anhydride 49 (THF,
1 h at 0 °C) furnished with a 65% yield adduct (3R,3aR)-
50, accompanied by ca. 15% of regioisomers (as a mixture
of diastereomers), resulting from the alkylation at the
less substituted R-side of imine ent-9.11 These regioiso-
mers (not fully characterized) were separated from 50
by flash chromatography over silica gel. The portrayed
relative configuration of the stereogenic centers at C-3
and C-3a in acid 50 was established through its conver-
tion to alcohol 51 (i: NaHCO3, then drying of the sodium
salt; ii: ClCOCOCl; iii: NaBH4 in THF). The cis relation-
ship of the angular methyl and the appendage at C-3 in
Ch a r t 7
1
51 was assigned through the analysis of the H and 13C
NMR resonances, including 1D and 2D experiments,
1
phase sensitive DFQ COSY, DFQ NOESY, and H-13C
direct and long range correlations (HMQC and HMBC).
The depicted absolute configuration in 50 rests on the
heuristic rule we have proposed (vide infra, Figure 3)
(Chart 10).
Ch a r t 8
Met h yl P r op iola t e a s Alk yn yl Accep t or . The
Michael-type condensation of chiral imines with electro-
philic alkynes would be also of peculiar value, since it
potentially provides the direct access of highly function-
alized adducts, such as 42. Thus addition of imine 9 to
methyl propiolate 52 (heated 14 h to reflux in THF, and
then 20% aqueous AcOH, 2 h at 20 °C) gave with a 70%
yield adducts (S)-(E)-42 and (S)-(Z)-53, in the respective
ratio of 13:1, accompanied by ca. 4% of regioisomers,
resulting from the alkylation at the less substituted
R-side of imine 9. However an important decrease in the
enantioselectivity was observed with this acceptor, com-
pared to previous electrophilic alkenes; thus, the enan-
tiomeric purity of known keto ester ent-34, obtained by
catalytical hydrogenation of the present adduct (S)-(E)-
42 (1 atm of H2, Pd-C), was only 43% (Chart 11).
biguousy determined by converting this compound to the
known keto ester ent-34, through the intermediate 42
(i: m-chloroperbenzoic acid, and then heat; ii: H2/PtO2)
(Chart 7).
â-Su bstitu ted Alk en yl Accep tor s. No definite com-
pound was obtained in the condensation of imine 9 with
methyl crotonate.5 In contrast, this imine reacted
smoothly with the very reactive crotonyl cyanide 43
(cyclohexane, 24 h at 5 °C), giving with a 50% combined
yield a mixture of bicyclic lactams (4R,4aS,8aR)-44 and
(4R,4aR)-45.9 The cis relationship between the methyl
groups at C-4 and C-4a in adducts 44 and 45 was
unequivocally assigned from their 1H NMR spectra;
indeed analysis of the H3-H4 coupling constants estab-
lished that, in both cases, the methyl group at C-4 is
equatorial. Moreover, the absolute configurations of the
three newly created stereogenic centers in 44 were
ascertained by an X-ray diffraction analysis of this
compound (Chart 8).
Discu ssion
We have proposed that the addition of chiral imines
to electrophilic alkenes proceeds through a compact
complex, that involves as nucleophilic partners the
secondary enamines, in tautomeric equilibrium with the
starting imines.2 This view was recently reinforced by
(10) Barta, N. S.; Brode, A.; Stille, J . R. J . Am. Chem. Soc. 1994,
116, 6201-6206.
(11) For the Michael-type reaction of 2-methyl(benzylimino)cyclo-
hexane with maleic anhydride, see: Pfau, M.; Tomas, A.; Lim, S.;
Revial, G. J . Org. Chem. 1995, 60, 1143-1147.
Interestingly, Stille recently reported that addition of
enamino ester (R)-46 to crotonyl chloride 47 (refluxing

Asymmetric Michael Addition of Chiral Imines
J . Org. Chem., Vol. 61, No. 13, 1996 4365
Ch a r t 11
F igu r e 3.
F igu r e 2.
Sch em e 3
F igu r e 4.
chiral enamino ester and methyl acrylate have been
theoretically simulated by using the MOPAC program.2
An excellent agreement was obtained between these
calculations and the experimental findings. In this
regard, a practical, general rule has been developed,
enabling the prediction of the predominant facial selec-
tivity. According to this rule, the alkylation process takes
place preferentially on the less hindered π-face of the
enamine (anti to the bulky phenyl group), depicted in its
energetically preferred conformation (Figure 3).
An excellent diastereocontrol was always obtained by
using the present R- and â-substituted alkenes as Michael
acceptors. In this respect, the “endo-approach” 58, in
which the electron-withdrawing-group of the acceptor
faced the nitrogen atom of the enamine partner (case of
acceptors 10, methyl methacrylate, 24, 28, 43, 47, and
49) largely prevails over the “exo-approach” 59 (case of
acceptor 38). This “endo-preference” has been tentatively
rationalized, invoking that the endo-approach is stabi-
lized by attractive orbital interaction between the nitro-
gen center of the enamine and the electron-withdraw-
ing-group of the Michael acceptor.12,13 However, this
interpretation ignored all steric interactions which are
necessarily engendered in such compact approaches.
Thus, it is manifest that a destabilizing steric interaction
between the R substituent of the enamine and the
electron-withdrawing-group of the acceptor is specifically
developed in the exo-approach 59, a factor which should
be imperatively taken into account in the present inves-
tigation (Figure 4).
the observation that, in conversion 6 f 8 (vide supra),
the deuterium atom in the R-position to the imine group
of 6 was transferred to the R-vinylic center of the
electrophilic alkene concertedly with the creation of the
C-C bond.3 The [3 + 3]-type structure 54, stabilized by
bonding orbital interaction between the N-atom of the
enamine and the electron-withdrawing group of the
electrophile, has been proposed as reactive complex.12
Although supported by theoretical calculations, this
interpretation, however, offers no satisfactory explana-
tion for the above-mentioned crucial, concerted proton
transfer. In this respect, the alternative [4 + 2]-type
“aza-ene-synthesis-like” complex 55, which implicates the
hydrogen atom at the enamine nitrogen center, appears
to be a more realistic model (Figure 2).
In general the addition of chiral imines derived from
2-substituted cyclanones to electrophilic alkenes is highly
regioselective, the alkylation taking place predominantly,
if not exclusively, at the more substituted R-side of the
imine functionality. This can be readily interpreted by
examining the tautomeric equilibrium of chiral imine 3
with the two possible secondary enamines 56 and 57,
portrayed in their energetically preferred conformations,
minimizing the main steric interactions.2 In the more
substituted enamine 56, the N-H bond is syn to the
enamine double bond and consequently the internal,
concerted proton transfer is allowed. In contrast, in the
case of the less substituted regioisomer 57, the crucial,
concerted proton transfer is prevented for obvious geo-
metrical reasons. It should be also noted that, inciden-
tally, the more reactive enamine 56 appears to be also
the energetically preferred one, since it is stabilized by
the additional hyperconjugative interaction of the R
group (Scheme 3).
On this basis, the predominant endo-preference re-
ported here can be reasonably interpreted in terms of a
cooperative effet between steric and stereoelectronic
factors; the endo-approach is, however, disfavored when
the electrophilic alkene is substituted in the R-position
by a bulky group (case of acceptor 38). Finally it should
be pointed out that the largely predominant formation
of (E)-adduct 42 [13:1 over the (Z)-isomer 53], observed
in the addition of imine 9 to methyl propiolate 52,
provides an additional support to the above-mentioned
internal, concerted proton transfer.
With the exception of methyl propiolate 52, all elec-
trophilic partners mentioned in this work led to a high
control of the absolute configuration of the Michael
adducts. To help rationalize this remarkable enantiose-
lectivity, the two diastereotopic approaches involving a
(12) J abin, I.; Revial, G.; Tomas, A.; Lemoine, P.; Pfau, M. Tetra-
hedron: Asymmetry 1995, 6, 1795-1812.
(13) Sevin, A.; Tortajada, J .; Pfau, M. J . Org. Chem. 1986, 51, 2671-
2675.

4366 J . Org. Chem., Vol. 61, No. 13, 1996
Cave´ et al.
quinone (10 mg) was heated at 85 °C under nitrogen for 7 days.
The yellow, sticky jelly obtained was taken up in methanol (8
mL). A 10% aqueous acetic acid solution (10 mL) was added,
and the mixture was stirred for 2 h at 20 °C. Insoluble white
polymeric material (650 mg), identified as poly(methyl meth-
Con clu d in g Rem a r k s
The Michael-type addition of chiral imines, derived
from racemic R-substituted cyclanones and optically
active 1-phenylethylamine, to electrophilic alkenes in
neutral conditions constitutes one of the most efficient
methods for the stereocontrolled construction of quater-
nary carbon centers. Through this work we have shown
that an additional stereogenic center could be created at
the R- or â-position to the quaternary one, by using a
variety of R- and â-substituted alkenyl acceptors. The
regioselectivity of such addition reactions is generally
excellent; however, in some cases (acceptors 28 and 49),
significant amounts (10-15%) of regioisomeric adducts,
resulting from the alkylation at the less substituted
R-side of starting imines, were observed. Very high levels
of enantio- and diastereoselectivity were always obtained.
These stereochemical outcomes can be interpreted by
invoking that the reaction involves an “aza-ene-synthesis-
like” cyclic transition state, the geometry of which is
controlled by steric and stereoelectronic factors. Applica-
tion of the present powerful methodology to the asym-
metric synthesis of various targets is currently under
investigation in our laboratory.
1
acrylate) by H NMR, was removed by filtration. The filtrate
was concentrated, and the residue was taken up in diethyl
ether, washed with 1 N hydrochloric acid and brine, and dried.
Careful chromatography of the crude over silica gel (hexane:
ethyl acetate 4:1) afforded adduct 1312 (30 mg, 1%) and
acetophenone (90 mg, 5%, a compound which probably origi-
nates from the hydrolysis of the imine formed by 1,3-proto-
tropic rearrangement of starting imine 9). No definite com-
pound was isolated when the above experiment was repeated,
by using prolonged reaction times (24 days at 85 °C).12
Attem p ted Ad d ition of Im in e 9 to Meth yl Cr oton a te.12
A mixture of distilled imine 9 (1.07 g, 5 mmol), freshly distilled
methyl crotonate (0.75 g, 7.5 mmol), and hydroquinone (5 mg)
was heated at 120 °C under nitrogen for 6 days. A dark brown
gum was obtained. Workup conditions were as described for
the addition of imine 9 to methyl methacrylate. Chromatog-
raphy over silica gel furnished ca. 50 mg of a complex mixture
of compounds (by TLC and 1H NMR).
[R-(R*,R*)]-r-Meth yl-1-(m eth oxyca r bon yl)-2-oxocyclo-
h exa n ep r op a n oic Acid Meth yl Ester (15). A solution of
enamino ester 146 (4 g, 15.44 mmol) in diethyl ether (20 mL)
and methyl methacrylate (0.5 mL, 4.7 mmol) were added to a
solution of MgBr2 (16.46 mmol) in diethyl ether (60 mL). The
mixture was stirred at 20 °C for 7 days. During this period,
portions of methyl methacrylate (0.5 mL, 4.7 mmol) were
added to this mixture each 12 h. A 10% aqueous acetic acid
(20 mL) was then added, and the resulting mixture was stirred
for 24 h. The solvents were removed under reduced pressure,
and 1 N HCl (5 mL) was added to the residual oil. The mixture
was extracted with ether (3 × 25 mL), and the collected organic
phases were washed with brine, dried, and concentrated in
vacuum. Chromatography over silica gel (hexane:ethyl acetate
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were recorded on a
Kofler bench. Infrared (IR) spectra were obtained as neat films
between NaCl plates or KBr pellets. The 1H NMR spectra and
13C NMR spectra were recorded in CDCl3, unless otherwise
stated. Recognition of methyl, methylene, methine, and
quaternary carbon nuclei in 13C NMR spectra rests on the
J -modulated spin-echo sequence. Optical rotations were mea-
sured at 589 nm in a 1 dm-cell at specified temperature. Mass
spectra were recorded by electron impact at 70 eV. Analytical
thin-layer chromatography was performed on Merck silica gel
60F254 glass precoated plates (0.25 mm layer). All liquid
chromatography separations were performed using Merck
silica gel 60 (230-400 mesh ASTM). Diethyl ether and
tetrahydrofuran (THF) were distilled from Na-benzophenone
ketyl. Methanol was dried over magnesium and distilled.
Benzene and CH2Cl2 were distilled from calcium hydride,
under a nitrogen atmosphere. All reactions involving air- or
water-sensitive compounds were routinely conducted in glass-
ware which was flame-dried under a positive pressure of
nitrogen. Organic layers were dried over anhydrous MgSO4.
Chemicals obtained from commercial suppliers were used
without further purification. Elemental analyses were ob-
tained from the Service de microanalyse, Centre d’Etudes
Pharmaceutiques, Chaˆtenay-Malabry, France. X-ray crystal-
lographic intensity data of (()-16 were measured using
graphite-monochromated Cu KR radiation, and the (θ-2θ)
scan technique up to given θ ) 60°. The structure was solved
by direct methods using SHELXS8614 and refined by full
matrix least-squares with SHELX76,15 minimizing the function
∑w(Fo - |Fc|)2. The hydrogen atoms, located in difference
Fourier maps, were introduced in theoretical position (d(C-
H) ) 1.00 Å) and assigned an isotropic thermal factor
equivalent to that of the bonded carbon atom, plus 10%.
Convergence was reached at given R and Rw (with Rw ) {Sw(Fo
4:1) afforded pure keto ester 15 as a colorless oil (2.85 g, 72%).
1
IR (neat, cm-1) 1740, 1715; [R]20 +56 (c 1.7, CCl4); H NMR
D
(200 MHz, CDCl3) δ 3.70 (s, 3H), 3.60 (s, 3H), 2.50-1.30 (m,
11H), 1.16 (d, J ) 6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ
207.2 (C), 176.7 (C), 172.5 (C), 59.9 (C), 52.3 (CH3), 51.5 (CH3),
40.7 (CH2), 37.8 (CH2), 35.5 (CH2), 35.2 (CH), 27.1 (CH2), 22.2
(CH2), 19.9 (CH3). Anal. Calcd for C13H20O5: C, 60.92; H, 7.86.
Found: C, 60.71; H, 7.94.
(3R-tr a n s)-3-Meth yl-4a -(m eth oxyca r bon yl)-3,4,4a ,5,6,7-
h exa h yd r o-2(1H)-qu in olin on e (16). A stream of ammonia
was bubbled through an ice-cooled solution of keto ester 15
(100 mg, 0.39 mmol), in anhydrous methanol (30 mL). After
standing 12 h at 20 °C, ammonia was again bubbled through
the mixture. This operation was repeated each 12 h, until no
more starting material was detected by TLC. After 2 days,
the solution was evaporated, and the residue was dissolved
in benzene (40 mL), p-toluenesulfonic acid (10 mg, 0.06 mmol)
was added, and the mixture was refluxed 3 h with azeotropic
removal of water. The solution was cooled to 20 °C and
concentrated. Chromatography over silica gel (ethyl acetate:
hexane 4:1) afforded lactam 16 (62 mg, 72%) as a a solid: mp
149-151 °C (diethyl ether); IR (CHCl3, cm-1) 1730, 1662; [R]20
D
+21.4 (c 1.0, MeOH); 1H NMR (200 MHz, CDCl3) δ 8.00 (broad
s, 1H), 5.03 (t, J ) 3.5 Hz, 1H), 3.65 (s, 3H), 2.34-2.24 (m,
3H), 2.18-1.93 (m, 2H), 1.77-1.63 (m, 1H), 1.50-1.27 (m, 3H),
1.15 (d, J ) 6.7 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 175.0
(C), 172.9 (C), 133.8 (C), 106.3 (CH), 52.5 (CH3), 45.9 (C), 39.1
(CH2), 33.9 (CH), 33.7 (CH2), 23.2 (CH2), 19.0 (CH2), 16.1 (CH3).
r-Meth yl-1-(m eth oxyca r bon yl)-2-oxocycloh exa n ep r o-
p a n oic Acid Meth yl Ester (18). To a mixture of 1-(meth-
oxycarbonyl)-2-oxocyclohexane (17) (4 g, 25.64 mmol) and
Triton B (1.04 g, 2.5 mmol) in THF (40 mL) was added methyl
methacrylate (5 mL, 4.68 mmol) at 0 °C. The mixture was
refluxed for 12 h. After cooling, the solvent was removed under
reduced pressure and diethyl ether (15 mL) was added. The
organic phase was washed with brine, dried, and concentrated.
Distillation of the residue afforded 18 as an equimolar mixture
of racemic diastereomers (4.54 g, 69%): bp 130-140 °C (0.03
Torr); IR (CHCl3, cm-1) 1740, 1715; 1H NMR (200 MHz, CDCl3)
2
1/2
- |Fc|)2 / ∑wFo
}
and w ) 1/[σ2(Fo) + 0.001Fo2]).16
Attem p ted Ad d ition of Im in e 9 to Meth yl Meth a cr yl-
a te.12 A mixture of distilled imine 92 (3 g, 14 mmol), freshly
distilled methyl methacrylate (2.1 g, 21 mmol), and hydro-
(14) Scheldrick, G. SHELSX86. Program for crystal structure deter-
mination: University of Go¨ttingen: Germany, 1985.
(15) Scheldrick, G. SHELSX76. Program for crystal structure deter-
mination: University of Cambridge: United Kingdom, 1976.
(16) The authors have deposited atomic coordinates for (()-16 with
the Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

Asymmetric Michael Addition of Chiral Imines
J . Org. Chem., Vol. 61, No. 13, 1996 4367
δ 3.6 (s, 3H), 3.5 (s, 3H), 2.5-1.2 (m, 11H), 1.10 (2 d, 3H); 13
C
in vacuum. The crude mixture (180 mg, 86%) was analyzed
by GC on a BP column of 5.5 m × 0.22 mm, at 180 °C; retention
times: 22: 4620 s (81.7%), 23: 4674 s (18.3%). Chromatog-
raphy over silica gel (cyclohexane:ethyl acetate 2:1) afforded
NMR (50 MHz, CDCl3) δ 207.6 (C), 207.4 (C), 177.1 (C), 176.9
(C), 172.2 (C), 172.0 (C), 60.4 (C), 60.0 (C), 52.5 (CH3), 52.4
(CH3), 51.7 (CH3), 51.6 (CH3), 41.1 (CH2), 41.0 (CH2) 38.3 (CH2),
38.0 (CH2), 36.6 (CH2), 35.8 (CH2), 35.7 (CH), 35.4 (CH), 27.8
(CH2), 27.4 (CH2), 22.6 (CH2), 22.5 (CH2), 20.1 (CH3), 19.8
(CH3). Anal. Calcd for C13H20O5: C, 60.92; H, 7.86. Found:
C, 60.89; H, 7.93.
pure ketals 22 and 23 as colorless oils. 22; IR (neat, cm-1
)
1
1737; [R]20 +27.7 (c 1.4, CCl4); H NMR (200 MHz, CDCl3) δ
D
3.90 (m, 4H), 3.70 (s, 3H), 3.66 (s, 3H), 2.40-1.20 (m, 11H),
1.07 (d, J ) 6.7 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 178.5
(C), 174.8 (C), 111.1 (C), 65.1 (CH2), 64.9 (CH2), 54.7 (C), 52.0
(CH3), 51.9 (CH3), 36.7 (CH), 34.7 (CH2), 32.2 (CH2), 29.6 (CH2),
23.2 (CH2), 20.7 (CH2), 19.6 (CH3). Anal. Calcd for C15H24O6:
C, 59.98; H, 8.05. Found: C, 60.01; H, 8.11. 23; IR (neat,
(tr a n s)-3-Met h yl-4a -(m et h oxyca r b on yl)-3,4,4a ,5,6,7-
h exa h yd r o-2(1H)-qu in olin on e (16) a n d (cis)-3-Meth yl-4a -
(m eth oxyca r bon yl)-3,4,4a ,5,6,7-h exa h yd r o-2(1H)-qu in o-
lin on e (19). The procedure, starting from keto ester 18 (1.0
g, 3.9 mmol), was as described for the addition of ammonia to
keto ester 15. Chromatography over silica gel (ethyl acetate:
hexane 4:1), followed by recrystallization in diethyl ether,
afforded (()-lactam 16 (300 mg, 34%) and (()-lactam 19 (320
cm-1) 1737; [R]20 -1.0 (c 5.8, CCl4); 1H NMR (200 MHz,
D
CDCl3) δ 3.90 (m, 4H), 3.66 (s, 3H), 3.63 (s, 3H), 2.60-1.30
(m, 11H), 1.15 (d, J ) 6.1 Hz, 3H); 13C NMR (50 MHz, CDCl3)
δ 177.0 (C), 174.5 (C), 110.7 (C), 64.8 (CH2), 64.3 (CH2), 53.8
(C), 51.6 (CH3), 51.5 (CH3), 35.6 (CH), 35.5 (CH2), 31.8 (CH2),
30.8 (CH2), 23.0 (CH2), 21.1 (CH2), 19.8 (CH3). Anal. Calcd
for C15H24O6: C, 59.98; H, 8.05. Found: C, 59.79; H, 7.98.
[R-(R*,R*)]-3-[(2-Oxo-1-m eth ylcycloh exyl)m eth yl]-2(5H)-
3,4-d ih yd r ofu r a n on e (25). R-Methylene-γ-butyrolactone 24
(325 mg, 3.3 mmol) and hydroquinone (10 mg) were added to
a solution of imine ent-9 (2.15 g, 10 mmol) in THF (3 mL) at
20 °C, and the mixture was heated at 40 °C for 72 h. During
this period, two other portions of 24 (125 mg, 1.3 mmol) were
added each 24 h. The mixture was cooled to 20 °C and diluted
with THF (20 mL). A 20% aqueous acetic acid solution was
then added (10 mL), and the resulting mixture was stirred
for 3 h. The solvents were removed under reduced pressure,
and 1 N HCl (5 mL) was added to the residual oil. The mixture
was extracted with diethyl ether (5 × 25 mL), and the
combined organic layers were washed with brine, dried, and
concentrated in vacuum. Chromatography over silica gel
(hexane:ethyl acetate 2:1), followed by distillation, afforded
mg, 37%). (()-16: mp 170-172 °C. Anal. Calcd for C12H17
-
1
NO3: C, 60.92; H, 7.86. Found: C, 60.89; H, 7.93; the IR, H
and13C NMR specta were identical with those of (+)-16. Slow
evaporation of a solution of (()-16 in diethyl ether gave small
monocrystals, suitable for an X-ray crystallographic analysis:
C12H17NO3, Mw ) 223.28, crystal of 0.07 × 0.08 × 0.23 mm,
triclinic, space group P-1, Z ) 2, a ) 7.824(8), b ) 8.644(12),
c ) 12.093(13) Å, R ) 75.13(4), â ) 117.49(4), γ ) 125.73(4)°,
V ) 589(1) Å3, dcalc ) 1.26 g cm-3, F(000) ) 240, λ (Cu KR) )
1.5418 Å, µ ) 0.70 mm-1
. Of the 2118 collected reflexions
(-8 e h e 8, -13 e k e 12, -9 e k e 16), 1726 were unique
(Rint ) 0021) and 847 were considered as observed having I g
2σ(I). Cell parameters were refined from 23 well-centered
reflexions with 7.5 e 32.8°. Convergence was reached at
R ) 0.0054 and RW ) 061. The residual electron density in
the final difference map was located between -0.23 and 0.20
eÅ3. In the crystal two molecules of 16 form a centrosymmetric
dimer linked by two hydrogen bonds: N1‚‚‚O11′‚‚‚N1′
(N1‚‚‚O11′: 2.894(5) Å, H1‚‚‚O11′: 2.41 Å, N1-H‚‚‚O11: 163°,
symmetry: -x,1 - y,-z). The eight atoms N1, C2, C3, C5,
C7, C8, C9, C10 are approximately planar (maximum devia-
tions: -0.14, 0.11 Å), C4 and C6 are, respectively, at -0.69
and -0.55 Å of this plane (Figure 1). (()-19; mp 150-155
pure ketolactone 25 (433 mg, 54%): bp 120-130 °C (0.05 Torr);
1
[R]20 +31.0 (c 7.6, EtOH); IR (neat, cm-1) ν: 1771, 1706; H
D
NMR (CDCl3, 400 MHz) δ 4.31 (ddd, J ) 1.7, 8.8, 9.0 Hz, 1H),
4.09 (ddd, J ) 6.2, 9.0, 10.9 Hz, 1H), 2.50-2.44 (m, 3H), 2.40-
2.34 (m, 1H), 2.25 (dddd, J ) 1.7, 8.7, 11.5, 14.4 Hz, 1H), 1.98
(m, 1H), 1.90-1.60 (m, 6H), 1.48 (dd, J ) 8.7, 14.4 Hz, 1H),
1.11 (s, 3H); 13C NMR (CDCl3, 50 MHz) δSPCLN 214.4 (C),
179.1 (C), 65.9 (CH2), 47.9 (C), 39.1 (CH2), 38.3 (2 CH2), 35.8
(CH), 31.1 (CH2), 26.8 (CH2), 23.0 (CH3), 20.5 (CH2); MS, m/z:
210 (M•+, 10), 166 (15), 125 (35), 112 (55), 99 (30), 97 (30), 86
(100). Anal. Calcd for C12H18O3: C, 68.54; H, 8.63. Found:
C, 68.39; H, 8.53.
1
°C; IR (CHCl3, cm-1) 1729, 1657; H NMR (400 MHz, CDCl3)
δ 7.40 (broad s, 1H), 5.08 (t, J ) 3.7 Hz, 1H), 3.71 (s, 3H), 2.64
(ddq, J ) 1.8, 7.1, 7.8 Hz, 1H), 2.30 (m, 2H), 2.23 (dd, J )1.8,
14.0 Hz, 1H), 2.15-2.10 (m, 1H), 1.91 (dd, J ) 7.1, 14.0 Hz,
1H), 1.74-1.71 (m, 1H), 1.50-1.22 (m, 3H), 1.15 (d, J ) 7.8
Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 175.4 (C), 172.9 (C),
133.7 (C), 107.4 (CH), 52.5 (CH3), 44.0 (C), 37.7 (CH2), 35.2
(CH2), 34.2 (CH), 23.5 (CH2), 19.2 (CH2), 18.0 (CH3).
(3R-tr a n s)-3,4,4a,5,6,7-Hexah ydr o-4a-m eth yl-3-(h ydr ox-
yeth yl)-2(1H)-qu in olin on e (27). The procedure, starting
from lactone 25 (150 mg, 0.71 mmol), was as described for the
addition of ammonia to keto ester 15. Chromatography over
silica gel (ethyl acetate) afforded lactam 27 (110 mg, 80%), as
a colorless oil. Because this product readily decomposed in
(R)-(6-Ca r b om et h oxy-1,4-d ioxa sp ir o[4.5]d eca n -6-yl)-
p r op a n oic Acid Meth yl Ester (21). To a solution of TM-
SOTf (22 mg, 0.1 mmol) in CH2Cl2 (1 mL) were successively
added 1,2-bis(trimethylsilyloxy)ethane (2 mL, 5.4 mmol) and
ketone 20 (1.3 g, 5.4 mmol) at -78 °C. The mixture was stirred
for 3 h at -78 °C, quenched by addition of dry pyridine (0.2
mL), poured into a saturated NaHCO3 aqueous solution (15
mL), and extracted with diethyl ether (3 × 15 mL). The
organic layers were dried and concentrated. Chromatography
over silica gel (cyclohexane:ethyl acetate 2:1) afforded pure
ketal 21 as a oil (1.45 g, 94%); IR (neat, cm-1) 1737; [R]20D +9.3
CDCl3, NMR spectra were recorded in C6D6. IR (neat, cm-1
)
3400, 1679, 1652; 1H NMR (400 MHz, C6D6) δ 9.75 (s, 1H), 5.0
(t, J ) 3.5 Hz, 1H), 4.69 (broad s, 1H), 3.85 (m, 1H), 3.71 (dt,
J ) 3.7, 10.1 Hz, 1H), 2.54 (m, 1H), 2.12 (m, 1H), 1.85 (m,
2H), 1.48-1.35 (m, 3H), 1.30 (dt, J ) 13.0, 3.3 Hz, 1H), 1.22
(dd, J ) 6.1, 13.0 Hz, 1H), 1.10 (dd, J ) 3.3, 13.4 Hz, 1H),
1.03 (d, J ) 13.4 Hz, 1H), 0.86 (s, 3H); 13C NMR (50 MHz,
C6D6) δ 173.9 (C), 139.5 (C), 103.9 (CH), 61.3 (CH2), 41.8 (CH2),
37.3 (CH), 36.7 (CH2), 35.2 (CH2), 31.5 (CH2), 23.6 (CH2), 22.8
(CH3), 18.1 (CH2).
1
(c 3.0, CCl4); H NMR (200 MHz, CDCl3) δ 3.80 (m, 4H), 3.57
(s, 3H), 3.53 (s, 3H), 2.30-1.20 (m, 12H); 13C NMR (50 MHz,
CDCl3) δ 173.9 (C), 173.7 (C), 110.6 (C), 64.7 (CH2), 64.4 (CH2),
53.9 (C), 51.7 (CH3), 51.5 (CH3), 31.9 (CH2), 30.4 (CH2), 29.7
(CH2), 26.6 (CH2), 22.8 (CH2), 20.8 (CH2). Anal. Calcd for
C14H22O6: C, 58.72; H, 7.74. Found: C, 58.61; H, 7.81.
[S-(R*,S*)]-(6-Ca r bom eth oxy-1,4-d ioxa sp ir o[4.5]d eca n -
6-yl)-r-m et h ylp r op a n oic a cid m et h yl est er (22) a n d
[R-(R*,R*)]-(6-Ca r b om et h oxy-1,4-d ioxa sp ir o[4.5]d eca n -
6-yl)-r-m eth ylp r op a n oic a cid m eth yl ester (23). Ketal 21
(200 mg, 0.7 mmol) was added to a solution of lithium
diisopropylamide (107 mg, 1 mmol) in THF (2 mL) at -78 °C.
The mixture was stirred at -78 °C for 2 h. Methyl iodide (0.07
mL, 1.12 mmol) was added and the mixture was stirred for 3
[S -(R *,S *)]-r-(Ace t yloxy)-1-m e t h yl-2-oxocycloh e x-
a n ep r op a n oic a cid m eth yl ester (29). A mixture of imine
9 (4.0 g, 18.6 mmol), freshly distilled 2-acetoxyacrylate 28 (2.94
g, 20.4 mmol), and hydroquinone (10 mg) was stirred at 20 °C
for 90 min. THF (20 mL) and a 20% aqueous acetic acid
solution (10 mL) were added. The mixture was stirred for 2 h
at 20 °C. The solvent was removed under reduced pressure,
and 1 N HCl (5 mL) was added to the residual oil. The mixture
was extracted with CH2Cl2 (5 × 20 mL), and the combined
organic layers were washed with brine, dried, and concentrated
in vacuum. Chromatography over silica gel (cyclohexane:ethyl
acetate 9:1), followed by distillation, afforded pure keto ester
h
at -78 °C. The solvent was removed under reduced
pressure, and water was added (2 mL). The mixture was
extracted with diethyl ether (3 × 5 mL), and the combined
organic layers were washed with brine, dried, and concentrated
29 (2.55 g, 53%); bp 100-110 °C (0.02 Torr); [R]20 ) -11.0 (c
D
7.5, EtOH); IR (neat, cm-1) 1748, 1708; H NMR (200 MHz,
1

4368 J . Org. Chem., Vol. 61, No. 13, 1996
Cave´ et al.
CDCl3) δ 4.97 (dd, J ) 3.2, 9.0, Hz, 1H), 3.69 (s, 3H), 2.50-
2.30 (m, 2H), 2.20 (dd, J ) 3.2, 15.0 Hz, 1H), 2.07 (s, 3H), 1.92
(dd, J ) 9.0, 15.0, Hz, 1H), 1.90-1.60 (m, 6H), 1,13 (s, 3H);
13C NMR (CDCl3, 50 MHz) δ 213.9 (C), 170.7 (C), 169.9 (C),
69.6 (CH), 52.2 (CH3), 47.4 (C), 39.1 (CH2), 38.2 (CH2), 37.9
(CH2), 27.0 (CH2), 22.2 (CH3), 20.7 (CH2), 20.4 (CH3); MS,
m/z: 256 (M•+, 0.5), 214 (8), 183 (7), 164 (3), 155 (14), 137 (12),
125 (17), 112 (100).
(d, J ) 11.0 Hz, 1H), 5.89 (d, J ) 11.0 Hz, 1H)] which was
separated by flash chromatography.
[3R-(1S*),3r,3a r]-1-(1-P h en ylet h yl)-2-oxo-3a -m et h yl-
2,3,3a ,4,5,6-h exa h yd r oin d ole Acetic Acid (50). To a solu-
tion of ent-9 (500 mg, 2.32 mmol) in THF (5 mL) was added at
0 °C a solution of maleic anhydride 49 (0.25 g, 2.52 mmol) in
THF (1 mL). The mixture was kept 1 h at 0 °C. The solvent
was removed under vacuum, and the residue was chromato-
graphed over silica gel (ethyl acetate: hexane 1:1.5), giving
50 (472 mg, 65%): mp 163-165 °C (EtOH); [R]20D +16.4 (c 5.3,
MeOH); IR (neat, cm-1) 3427, 1737, 1715; 1H NMR (CDCl3,
200 MHz) δ 9.5 (broad s, 1H), 7.32-7.20 (m, 5H), 5.56 (q, J )
7.0 Hz, 1H), 4.59 (t, J ) 3.6 Hz, 1H), 2.88-2.81 (m, 2H), 2.48-
2.40 (m, 1H), 2.10-1.50 (m, 9 H), 1.03 (s, 3H); 13C NMR (CDCl3,
50 MHz) δ 176.1 (C), 175.4 (C), 141.8 (C), 140.1 (C), 128.5 (2
CH), 127.2 (CH), 126.4 (2 CH), 103.1 (CH), 50.2 (CH), 49.1
(CH), 40.6 (C), 33.4 (CH2), 30.4 (CH2), 23.1 (CH2), 20.2 (CH3),
17.8 (CH2), 15.2 (CH3). Anal. Calcd for C19H23NO3‚1H2O: C,
70.81; H, 7.45; N, 4.35. Found: C, 70.62; H, 7.49; N, 4.35.
[3R-(1S*), 3r,3ar]-1-(1-P h en yleth yl)-2-oxo-3-(2-h ydr oxy-
et h yl)-3a -m et h yl-2,3,3a ,4,5,6-h exa h yd r oin d ole (51). An
aqueous solution of 1 N NaOH (1 mL, 1 mmol) was added to
lactam-acid 50 (100 mg, 0.32 mmol). The mixture was kept
30 min at 20 °C, and the water was removed under vacuum
(50 °C, 0.1 Torr). The anhydrous sodium salt obtained was
suspended in THF (2 mL), and a solution of oxalyl chloride
(0.165 mg, 1.3 mmol) in THF (1 mL) was added dropwise over
a period of 30 min at 20 °C. The mixture was concentrated in
vacuum, and the residue was taken up in THF (1 mL). Sodium
borohydride (0.039 g, 1.13 mmol) was added at once to the
suspension at 10 °C, and the mixture was stirred for 1 h at
this temperature. The reaction mixture was quenched with
water (3 mL), the organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The
combined organic layers were dried, and the solvent was
removed under reduced pressure. The residue was chromato-
graphed over silica gel (ethyl acetate: hexane 1:1), affording
lactam-alcohol 51 (84 mg, 88%): amorphous solid; [R]20D +10.2
[3R-(3â, 4a r, 8a r)]-3,8a -Dih yd r oxy-4a -m eth yl-octa h y-
d r o-2(1H)-qu in olin on e (31). A stream of ammonia was
bubbled through an ice-cooled solution of keto ester 29 (1 g,
3.9 mmol), in anhydrous methanol (30 mL). After standing
12 h at 20 °C, ammonia was again bubbled through the
mixture. The process was repeated each 12 h, until no more
starting material was detected by TLC. After 3 days the
solvent was evaporated. Crude lactam-alcohol was chromato-
graphed over silica gel (ethyl acetate:methanol 9:1) to give 31
(0.57 g, 73%) as an amorphous solid: IR (neat, cm-1) 3400,
1
1660; H NMR (200 MHz, CDCl3) δ 7.34 (broad s, 1H), 6.10
(broad s, 1H), 4.40 (t, J ) 8.6 Hz, 1H), 4.1 (s, 1H), 2.15-1.90
(m, 3H), 1.70-1.25 (m, 7H), 1.10 (s, 3H); 13C NMR (CDCl3, 63
MHz) δ 178.6 (C), 106.7 (C), 75.5 (CH), 44.4 (C), 42.7 (CH2),
35.3 (CH2), 32.4 (CH2), 23.0 (CH3), 21.3 (CH2), 18.7 (CH2); MS,
m/z: 199 (M•+, 2), 181 (4), 155 (100), 137 (25), 125 (14), 112
(16), 111 (16), 95 (18), 75 (55). Anal. Calcd for C12H18O3: C,
60.30; H, 8.54; N, 7.03. Found: C, 60.09; H, 8.69; N, 6.94.
(3R-tr a n s)-3-Hyd r oxy-3,4,4a ,5,6,7-h exa h yd r o-4a -m eth -
yl-2(1H)-qu in olin on e (32). A solution of quinolinone 31 (0.25
g, 1.25 mmol) and p-toluenesulfonic acid (10 mg, 0.06 mmol)
in anhydrous benzene (20 mL) was refluxed 4 h with azeotropic
removal of water. The solution was cooled to 20 °C, and
concentrated in vacuum. Chromatography over silica gel
(ethyl acetate) afforded lactam 27 (110 mg, 48%) as an
1
amorphous solid: IR (neat, cm-1) 3400, 1679, 1652; H NMR
(200 MHz, CDCl3) δ 7.40 (broad s, 1H), 4.80 (t, J ) 3.7 Hz,
1H), 4.35 (dd, J ) 6.3, 12.1 Hz, 1H), 3.40 (s, 1H), 2.20-2.00
(m, 2H), 1.80-1.20 (m, 6H), 1.21 (s, 3H); 13C NMR (CDCl3, 63
MHz) δ 172.3 (C), 138.7 (C), 105.2 (CH), 65.3 (CH), 41.8 (C),
36.7 (CH2), 32.4 (CH2), 23.7 (CH3), 23.2 (CH2), 17.2 (CH2); MS,
m/z: 181 (M•+, 1), 155 (100), 137 (25), 125 (20), 112 (22), 111
(22), 95 (20), 75 (52).
[S-(E)]-1-Meth yl-2-oxocycloh exa n e-2-p r op en oic Acid
Meth yl Ester (42) (fr om im in e 9 a n d m eth yl p r op iola te
52). Methyl propiolate 52 (0.45 g, 5.4 mmol) was added to a
solution of imine 9 (1 g, 4.65 mmol) in THF (5 mL), at 20 °C.
The mixture was refluxed for 14 h. The solution was cooled
to 20 °C and diluted with THF (20 mL). A 10% aqueous acetic
acid solution was added (10 mL), and the resulting mixture
was stirred for 3 h. The solvents were removed under reduced
pressure, and 1 N HCl (5 mL) was added to the residual oil.
The mixture was extracted with diethyl ether (3 × 25 mL),
and the combined organic layers were washed with brine,
dried, and concentrated in vacuum. Chromatography over
silica gel (hexane:ethyl acetate 4:1) followed by distillation,
afforded ketone 42 as a colorless oil (635 mg, 69%): bp 105-
1
(c 5.75, MeOH); H NMR (CDCl3, 200 MHz) δ 7.36-7.20 (m,
5H), 5.58 (q, J ) 7.2 Hz, 1H), 4.70 (br d, 1H, exchangeable
with D2O), 4.55 (t, J ) 4.5 Hz, 1H), 3.90 (m, 1H), 3.69 (ddd, J
) 3.0, 10.4, 11.0 Hz, 1H), 2.39 (dd, J ) 3.3, 10.4 Hz, 1H), 2.1-
1.66 (m, 7H), 1.63 (d, J ) 7.2 Hz, 3H), 1.48 (m, 1 H), 1.04 (s,
3H); 13C NMR (CDCl3, 50 MHz) δ 177.1 (C), 142.5 (C), 140.4
(C), 128.5 (2 CH), 127.1 (CH), 126.3 (2 CH), 102.0 (CH), 62.6
(CH2), 55.0 (CH), 48.7 (CH), 40.7 (C), 33.3 (CH2), 27.6 (CH2),
23.2 (CH2), 20.4 (CH3), 17.8 (CH2), 15.2 (CH3).
Ack n ow led gm en t. The following colleagues and
students of the Centre d’Etudes Pharmaceutiques,
Chaˆtenay-Malabry, are gratefully acknowledged: Dr
J acqueline Mahuteau for valuable assistance with NMR
studies, Mrs. Sophie Mairesse-Lebrun for performing
elemental analyses, M. Vale´rie Daley and Mr. Khalid
Mekouar for the preparation of starting materials, and
Dr. Franc¸oise Dumas for stimulating discussions.
110 °C (0.02 Torr); [R]20D -61.9 (c 20.1, MeOH); IR (neat, cm-1
)
1712, 1649; 1H NMR (CDCl3, 200 MHz) δ 7.12 (d, J ) 16.1
Hz, 1H), 5.75 (d, J ) 16.1 Hz, 1H), 3.72 (s, 3H), 2.40-2.30 (m,
2H), 2.10-1.50 (m, 6 H), 1.21 (s, 3H); 13C NMR (CDCl3, 50
MHz) δ 211.2 (C), 166.6 (C), 151.8 (CH), 120.7 (CH), 51.6 (CH),
51.40 (C), 39.5 (CH2), 39.3 (CH2), 27.3 (CH), 23.2 (CH2), 21.6
(CH3). Anal. Calcd for C11H16O3: C, 67.35; H, 8.16. Found:
C, 67.11; H, 8.01. Compound (E)-42 was accompanied by ca
7% of not fully characterized (Z)-isomer 53 [1H NMR: δ 6.27
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra (15 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 mastehead page for ordering information.
J O960140K