High pressure activation in the asymmetric Michael addition of chiral imines to alkyl and aryl crotonates

Article abstract of DOI:10.1016/S0040-4039(02)00054-0

High pressure-mediated Michael addition of chiral imines derived from 2-methylcyclopentanone, 2-methylcyclohexanone and optically active 1-phenylethylamine, to methyl and phenyl crotonates was investigated. The corresponding adducts were obtained in fair yields and with a high degree of regio-, diastereo- and enantioselectivity.

Full text of DOI:10.1016/S0040-4039(02)00054-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1445–1448
High pressure activation in the asymmetric Michael addition of
chiral imines to alkyl and aryl crotonates
Cheikhou Camara,a Delphine Joseph,a Franc¸oise Dumas,a,* Jean d’Angeloa and Ange`le Chiaronib
aUnite´ de Chimie Organique associe´e au CNRS, Universite´ Paris-Sud, Centre d’Etudes Pharmaceutiques, 5, rue J.-B. Cle´ment,
92296 Chaˆtenay-Malabry, France
bInstitut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette, France
Received 28 November 2001; revised 21 December 2001; accepted 3 January 2002
Abstract—High pressure-mediated Michael addition of chiral imines derived from 2-methylcyclopentanone, 2-methylcyclohexa-
none and optically active 1-phenylethylamine, to methyl and phenyl crotonates was investigated. The corresponding adducts were
obtained in fair yields and with a high degree of regio-, diastereo- and enantioselectivity. © 2002 Elsevier Science Ltd. All rights
reserved.
Owing to the widespread presence of quaternary carbon
centers (QCCs) in natural products (e.g. terpenes,
steroids, alkaloids), their elaboration remains a central
challenge of contemporary organic synthesis.1 How-
ever, several difficulties are encountered in constructing
QCCs, particularly a severe steric hindrance, source of
repulsion in the transition states which substantially
increases their energy levels. Another peculiar aspect of
QCCs is that their configurations are in most cases
definitively secured by the mechanism-based stereo-
selectivity (kinetic control), racemization/epimerization
at a QCC requiring the transient breaking of a CꢀC
bond, of high dissociation energy values.2 A conven-
tional strategy for controlling sterically a QCC takes
advantage of preexisting stereocenters in the starting
substrate (substrate control principle). In the past two
decades, several methods have been developed for the
enantioselective generation of individual QCC, which
involve the use of a chiral auxiliary or a chiral reagent/
chiral catalyst (reagent control principle) to create a
temporary chiral environment. In this respect, the
asymmetric Michael reaction using chiral imines under
neutral conditions we disclosed in 1985 has emerged as
a simple and efficient tool for the stereocontrolled
construction of individual QCC.3 Thus, condensation
of chiral imines 1, derived from racemic 2-substituted
cyclanones and enantiopure 1-phenylethylamine, to
electron-deficient alkenes 2 furnished after hydrolytic
workup 2,2-disubstituted cyclanones 3, obtained in fair
yields and with a high degree of regio- and stereoselec-
tivity (Scheme 1).
Scheme 1.
A great variety of substrates have been used success-
fully in this Michael reaction, without alteration of its
remarkable features. Regarding the electrophilic part-
ner, not only a wide range of electron-withdrawing
groups (COR, CO2R, CN, SO2Ph, NO2), but also of
a-substituents (alkyl groups, OAc, NHAc, SPh, Cl) can
be employed. In contrast, b-substituted electrophilic
alkenes turned out to be strongly deactivated acceptors,
compared to their unsubstituted counterparts. Thus, for
example, all attempts at condensing imine 4b with
methyl crotonate under standard thermal conditions
failed.4 To circumvent this vexing drawback, an alter-
native was found, which utilizes very reactive acceptors,
such as crotonyl cyanide,5 maleic anhydride,6a–e citra-
conic anhydride,6b,c,e phenyl crotonate7 and 1-nitro-
propene.8 However, although generally highly regio-
and stereoselective, these additions were in most cases
complicated by a subsequent N-heterocyclization of the
primary adducts. Another striking feature of the croto-
Keywords: diastereoselection; enantioselection; imines; Michael reac-
tion; pressure, reactions under.
* Corresponding
author.
Fax:
+33(0)146835752;
e-mail:
francoise.dumas@cep.u-psud.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00054-0

1446
C. Camara et al. / Tetrahedron Letters 43 (2002) 1445–1448
nate-type acceptors is that their reactivity was restored
in the intramolecular variants of this conjugate addition:
spiroannulation,9 carbocyclization10 and bridging annu-
lation.11 In such processes, a favorable entropic factor
clearly counterbalances the steric hindrance.
As a part of our program directed at exploring the scope
of this asymmetric Michael addition, and in connection
with synthetic applications, we recently envisioned to
reinvestigate the reactivity of alkyl and aryl crotonates,
with the assistance of high pressure (HP)12 to overcome
the steric inhibition. The effect of pressure on reaction
rates is given by the Evans–Polanyi equation:
(# ln k/#P)T=−DV"/RT
where DV" is the difference in partial molar volumes
between reagents and transition states. This equation
predicts an increase in rate if the transition state occupies
a smaller volume than the total volume of reagents. Since
steric crowding is usually associated with lower partial
volumes, the application of HP sometimes permits the
reactions to occur which are otherwise prevented by
steric factors. In this respect, we have demonstrated in
a series of preliminary experiments that the addition of
imine (R)-4b to methyl acrylate benefits from HP assis-
tance. The expected Michael adduct (S)-5 was actually
obtained with the same yield (80–85%), the same degree
of regio- (>95%) and of stereoselectivity (93%) at 20°C,
in 8 days at atmospheric pressure or in only 5 h under
1.4 GPa (Scheme 2).13,14 Moreover, in the case of the
related chiral b-enaminoesters, which generally require
the use of Lewis acids to react with electrophilic alkenes,
the application of the sole HP activation allows the
formation of the Michael adducts, in the same range of
regio- and stereoselectivity.15
Scheme 3. Reagents and conditions: (a) 1 equiv. methyl croto-
nate, THF, 1.2 GPa, 20 h, 20°C; (b) 20% aqueous AcOH.
from which adduct (3S,1%S,1%%R)-6a was isolated by flash
chromatography on silica gel with a 34% yield, a 72% de
and a 90% ee.
Condensation of known imine 4b [derived from 2-
methylcyclohexanone and (R)-1-phenylethylamine] with
methyl crotonate (1 equiv., THF, 1.2 GPa, 20 h at 20°C)
paralleled completely the conversion (4a“7a): ketoester
(3S,1%S)-7b18 was obtained with a 78% yield, a de ]98%,
and an ee of 94% (Scheme 3). Based on mechanistic
considerations, the stereochemical course of these conju-
gate additions was vouchsafed by means of the X-ray
diffraction analysis of lactam derivative 9b (vide infra).
The reactivity of imines 4a,b towards phenyl crotonate
was investigated next. However, these condensations
afforded invariably enantiopure bicyclic lactams
(4R,4aS,1%R)-9a19 and (4R,4aS,1%R)-9b20 under HP (1
equiv. phenyl crotonate, THF, 0.7 GPa, 20°C, 22 h, 80%
yield) or thermal conditions (1.6 equiv. phenyl crotonate,
120°C, 5 days, 55–60% yield) (Scheme 4). The formation
The reactivity of methyl crotonate was investigated
first.14 Condensation of known imine (R)-4a [prepared
from 2-methylcyclopentanone and (R)-1-phenylethyl-
amine] with methyl crotonate (1 equiv., THF, 1.2 GPa,
20 h at 20°C) gave adduct (3S,1%S,1%%R)-6a, which turned
out to be nearly homogeneous by 1H and 13C NMR
spectroscopy.16 Hydrolysis of crude 6a (20% aqueous
AcOH, THF, 4 h at 20°C) next afforded ketoester
(3S,1%S)-7a17 with a 70% yield. The de and ee in 7a were
respectively ]98 and 96%, determined by 1H NMR
spectroscopy, having added Eu(fod) and Eu(hfc)3 as shift
reagents (Scheme 3). By way of comparison, condensa-
tion of imine (R)-4a with methyl crotonate was investi-
gated at atmospheric pressure. Under forced conditions
(THF, 4 times addition of methyl crotonate of 2 equiv.
each, 30 days at 67°C), a 9/1 mixture of quaternary/ter-
tiary regioisomers was obtained after hydrolytic workup,
Scheme 4. Reagents and conditions: 1 equiv. phenyl crotonate,
THF, 0.7 GPa, 22 h, 20°C or 1.6 equiv. phenyl crotonate,
neat, 1 atm, 120 h, 120°C.
Scheme 2.

C. Camara et al. / Tetrahedron Letters 43 (2002) 1445–1448
1447
of lactams 9a,b clearly involves a N-heterocyclization of
the transient Michael adducts 8a,b, a side reaction
which reflects the marked nucleofugal ability of the
phenoxy group.
The syn relationship between the two vicinal methyl
groups at C-4 and C-4a in lactam 9a was determined by
1H NMR spectroscopy. The equatorial orientation of
the C-4 methyl, syn to the C-4a axial angular methyl,
was first revealed by inspection of the coupling con-
stants between axial H-4 and the two adjacent protons
at C-3 (JH4ax–H3ax=12.8 Hz, JH4ax–H3eq=5.7 Hz). This
stereochemical assignment was further reinforced by
NOESY experiments. However, because of the overlap-
ping of the vicinal methyls signals in the NOESY chart,
direct through-space interaction between these two
groups was not analyzed. Finally, the syn arrangement
of methyls was proved, exploiting a quartet of correla-
tions: H-4 with a-H7 and equatorial a-H3, and C-4a
methyl protons with b-H7 and axial b-H3 (Fig. 1).
Scheme 5.
According to such a model, the alkylation takes place
anti to the bulky phenyl group of the chiral amine
moiety, portrayed in its energetically preferred confor-
mation, minimizing the A1,3-type strain (C1%ꢀH bond
more or less eclipsing the cyclopentene/cyclohexene
ring). This accounts for the absolute configuration at
C-1% in adducts 12. On the other hand, to rationalize
the stereochemical relationship of the two newly created
stereogenic carbon centers of these adducts, crotonates
need to be arranged as depicted in approach 11, namely
with the ester group oriented ‘endo’ relative to the
enamine part of the nucleophilic partners (Scheme 5).
On the other hand, the syn relationship between the
two methyl groups, as well as the absolute configura-
tion of the two newly created C-4 and C-4a stereocen-
ters in homolog 9b, were unequivocally assigned by
X-ray diffraction analysis (Fig. 2).21
The remarkable stereochemical outcome observed in
these conjugate additions can be interpreted by evoking
that the reaction proceeds through the pseudo cyclic
‘aza-ene-synthesis-like’ transition state 10, which
involves as nucleophilic partners the more substituted
secondary enamines, in tautomeric equilibrium with the
starting imines 4a,b.22 In accordance with this mecha-
nism, the proton borne by the nitrogen atom of enam-
ines is transferred to the a-carbon atom of the
crotonate partners, concertedly with the creation of the
CꢀC bond. This requires a synclinal approach of the
reactants, as shown in the Newman projection 11.
To conclude, we have set up a reliable method for
achieving our original objective, namely the construc-
tion of a sterically congested pattern consisting of a
QCC adjacent to a tertiary carbon center, frequently
encountered in natural products. Since highly regio-,
diastereo- and enantioselective, the HP-activated addi-
tion of chiral imines to alkyl/aryl crotonates reported in
this paper indeed offers a direct, efficient solution to
this complex synthetic problem.
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Figure 1. NOESY correlations in lactam 9a.
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Figure 2. X-Ray crystal structure of lactam 9b.

1448
C. Camara et al. / Tetrahedron Letters 43 (2002) 1445–1448
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3H) 0.88 (dd, J=6.7, 0.6 Hz, 3H); 13C NMR (CDCl3, 50
MHz) l: 221.9 (C), 173.0 (C), 50.9 (CH3), 50.3 (CH), 37.9
(CH2), 36.0 (CH2), 33.9 (CH), 32.5 (CH2), 19.0 (CH3),
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18. Ketone 7b: colorless oil; [h]2D0 −91.2 (c 1.25, EtOHabs).
Lit.7 (ent-7b): [h]2D0 +96 (c 3, EtOH).
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EtOHabs); IR (neat, cm−1): w 1665, 1629; 1H NMR
(CDCl3, 400 MHz) l: 7.30–7.70 (m, 5H), 6.20 (q, J=7.1
Hz, 1H), 4.40 (t, J=2.0 Hz 1H), 2.63 (dd, J=18.3, 5.7
Hz, 1H), 2.32 (dd, J=18.3, 12.8 Hz, 1H), 2.30 (m, 1H),
2.10 (ddd, J=15.6, 9.0, 3.1 Hz, 1H), 1.92 (ddq, J=12.8,
6.7, 5.7 Hz, 1H), 1.74 (dd, J=12.2, 7.3 Hz, 1H), 1.61 (d,
J=7.1 Hz, 3H), 1.52 (m, 1H), 0.95 (s, 3H), 0.90 (d,
J=6.7 Hz, 3H); 13C NMR (CDCl3, 50 MHz) l: 169.1
(C), 144.4 (C), 141.0 (C), 128.0 (2 CH), 126.3 (CH) 125.9
(2 CH), 105.0 (CH), 49.6 (CH), 46.8 (C), 37.7 (CH2), 36.5
(CH2), 36.5 (CH), 28.0 (CH2), 14.8 (CH3), 14.6 (CH3),
14.4 (CH3). Anal. calcd for C18H23NO: C, 80.26; H, 8.61;
N, 5.20. Found: C, 80.04; H, 8.56; N, 5.05.
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20. Lactam 9b: white solid; mp 70–71°C (pentane); [h]D20
1
−77.3 (c 2.2, EtOHabs); IR (neat, cm−1): w 1665, 1640; H
NMR (CDCl3, 250 MHz) l: 7.15–7.35 (m, 5H), 6.28 (q,
J=7.1 Hz, 1H), 4.84 (dd, J=5.6, 2.7 Hz 1H), 2.66 (dd,
J=18.5, 6.4 Hz, 1H), 2.26 (dd, J=18.5, 12.3 Hz, 1H),
1.72–2.10 (m, 5H), 1.59 (d, J=7.1 Hz, 3H), 1.40–1.55 (m,
1H), 1.30 (ddd, J=12.5, 3.0, 2.8 Hz, 1H), 0.98 (s, 3H),
0.91 (d, J=6.7 Hz, 3H); 13C NMR (CDCl3, 50 MHz) l:
168.9 (C), 142.3 (C), 140.5 (C), 128.2 (2 CH), 126.1 (CH)
125.4 (2 CH), 110.1 (CH), 50.4 (CH), 42.0 (C), 37.8
(CH2), 36.4 (CH), 36.2 (CH2), 24.9 (CH2), 18.0 (CH2),
15.8 (CH3), 15.2 (CH3), 14.3 (CH3); MS m/z (EI, 70 eV):
283 (M+, 13), 255 (3), 213 (6), 198 (4), 179 (76), 171 (14),
169 (48), 164 (53) 151 (14) 136 (17) 110 (35) 105 (100).
21. Crystal data for lactam 9b: colorless crystal of 0.18×0.32×
0.44 mm, C19H25NO, Mw=283.40; orthorhombic, space
group P21212, Z=4, a=10.878 (5), b=17.438 (7), c=
3
−3
,
,
8.809 (4) A, i=94.00 (2)°, V=1671 A , dc=1.127 g cm
,
;
−1
,
F(000)=616, u=0.71073 A (Mo Ka), v=0.07 mm
18 750 reflections measured (−145h514, −255k525,
−135l513) on a Nonius Kappa CCD area-detector dif-
fractometer. The structure was solved with SHELXL-8623
and refined with SHELXL-93.24 Hydrogen atoms riding.
Refinement converged to R(F)=0.0556 for the 4276
observed reflections having I]2|(I), and wR2=0.1381
for all the 5560 unique data, goodness-of-fit S=1.055.
15. Guingant, A.; Hammami, H. Tetrahedron: Asymmetry
1991, 2, 411–414 (in this respect, see Ref. 3g).
16. Imine 6a: pale yellow oil; IR (neat, cm−1): w 1738, 1673,
Residual electron density: −0.14 and 0.17 e A−3. Full
1
,
1603; H NMR (CDCl3, 200 MHz) l: 7.13–7.40 (m, 5H),
crystallographic results have been deposited as Supple-
mentary Material (CIF file) at the Cambridge Crystallo-
graphic Data Centre, UK (CCDC 147894).
4.45 (q, J=6.5 Hz, 1H), 3.96 (s, 3H), 2.95 (dd, J=14.5,
3.0 Hz, 1H), 2.05–2.48 (m, 4H), 2.02 (dd, J=14.5, 10.8
Hz, 1H), 1.30–1.92 (m, 3H), 1.41 (d, J=6.5 Hz, 3H), 1.04
(s, 3H), 0.91 (d, J=6.5 Hz, 3H); 13C NMR (CDCl3, 50
MHz) l: 180.4 (C), 174.1 (C), 146.0 (C), 127.9 (2 CH),
126.1 (2 CH) 125.4 (CH), 60.9 (CH), 51.0 (CH3), 48.5
(C), 36.5 (CH2), 35.2 (CH), 33.7 (CH2), 28.7 (CH2), 24.5
(CH3), 21.5 (CH3), 20.3 (CH2), 15.0 (CH3).
22. For an overview of this mechanism, see: Tran Huu Dau,
M.-E.; Riche, C.; Dumas, F.; d’Angelo, J. Tetrahedron:
Asymmetry 1998, 9, 1059–1064 and references cited
therein.
23. Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, 46,
467–473.
17. Ketone 7a: colorless oil; [h]2D0 −30.9 (c 2.7, EtOHabs); IR
(neat, cm−1): w 1738; 1H NMR (CDCl3, 200 MHz) l: 3.68
(s, 3H), 2.67 (dd, J=15.1, 3.7 Hz, 1H), 2.25–2.38 (m,
24. Sheldrick, G. M. Program for the refinement of Crystal
Structures, University of Go¨ttingen, Germany, 1993.