2-Acetoxyacrylonitrile: Use as electrophile equivalent to acetaldehyde in the asymmetric Michael reaction using chiral imines

Article abstract of DOI:10.1016/S0040-4039(00)01971-7

The asymmetric Michael addition reaction between a variety of chiral imines and 2-acetoxyacrylonitrile gave after hydrolysis, the adducts in fair yields and with de and ee ≥95%.

Full text of DOI:10.1016/S0040-4039(00)01971-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 381–383
2-Acetoxyacrylonitrile: use as electrophile equivalent to
acetaldehyde in the asymmetric Michael reaction using
chiral imines
Laurent Keller, Cheikhou Camara, Antonio Pinheiro, Franc¸oise Dumas* and Jean d’Angelo*
Unite´ Associe´e au CNRS, Centre d’Etudes Pharmaceutiques, Universite´ de Paris Sud, 5, rue J.-B. Cle´ment,
92296 Chaˆtenay-Malabry, France
Received 8 October 2000; accepted 30 October 2000
Abstract—The asymmetric Michael addition reaction between a variety of chiral imines and 2-acetoxyacrylonitrile, an electrophile
equivalent to acetaldehyde, was reported. The resulting adducts were obtained in fair yields and with de and ee ]95%. © 2001
Elsevier Science Ltd. All rights reserved.
The asymmetric Michael reaction using chiral imines
under neutral conditions constitutes one of the most
potent methodologies for the enantioselective elabora-
tion of quaternary carbon centers.1 As a part of our
effort at synthesizing the side-chains of Cephalotaxus
alkaloids,2 we recently envisioned to extend the scope
of the above reaction by the use, as an electrophilic
partner, of a synthon equivalent to acetaldehyde. Re-
ported herein is the utilization, for such a purpose, of
2-acetoxyacrylonitrile (2).
bicyclic derivatives 5 and 11; the absolute configuration
at C-1% in 3 and 4 rests on a heuristic stereochemical
rule we have proposed in this series (vide infra)
(Scheme 1).
The reactivity of 2 towards chiral imine 1, an adequate
nucleophilic partner for the synthesis of the aforemen-
tioned targets,2 was examined first. Addition of known
imine 1 [prepared from 2-benzyloxycyclohexanone and
(R)-1-phenylethylamine]3 to 2-acetoxyacrylonitrile (2)4
(neat, 40 h at 20°C) gave adduct (2R,1%R,1¦R)-3, which
turned out to be stereochemically homogeneous by 1H
and 13C NMR spectroscopy.5 Hydrolysis of crude 3
(AcOH, H2O, THF, 4 h at 20°C) next afforded cyclo-
hexanone (2R,1%R)-46 (72% overall yield, calculated
from the starting 2-benzyloxycyclohexanone). The de
Scheme 1.
1
Regeneration of an aldehyde function at C-2 in 4 was
next attempted. This requires a desacetylation step,
followed by dehydrocyanation of the resulting cyanohy-
drin. While basic treatments of 4 furnished invariably
undefined compounds, the bicyclic hemiacetal
(2R,1aS,3aR)-57 was formed with a 77% yield when the
reaction was conducted under acidic conditions (2N
HCl, THF, 30 h at 50°C). However, all efforts at
generating the aldehyde 7 through dehydrocyanation of
5 (a process which, in fact, would implicate the open
form of this hemiacetal) were fruitless. In contrast,
and ee in 4 were both ]95% (determined by H NMR
spectroscopy, having added Eu(fod) and Eu(hfc)3 as
shift reagents). The relative configuration of the two
stereogenic centers in 4 was assigned by NMR spec-
troscopy including NOE experiments at level of the
Keywords: chiral imines; Michael reactions; 2-acetoxyacrylonitrile;
stereocontrol.
* Corresponding authors. E-mail: francoise.dumas@cep.u-psud.fr;
jean.dangelo@cep.u-psud.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01971-7

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L. Keller et al. / Tetrahedron Letters 42 (2001) 381–383
sequential exposure of 5 to NaOMe (0.95 equiv.,
MeOH, −20°C) and NaO2Cl (NaH2PO4, H2O, 20°C)8
gave the sensitive bicyclic lactone (1aS,3aR)-6,9 albeit
with a modest yield (ca. 35%). Formation of 6 clearly
involves the transient aldehyde 7, in equilibrium
through the addition of a molecule of water with the
bis-hemiacetal 8, the in situ oxidation of the latter
furnishing ultimately the lactone 6 (Scheme 2).
tolerates substantial variations on the starting cy-
clanone, both of the size of the ring and of the nature
of the a-substituent. Thus, condensation of imines
derived from cyclanones 12, 14a, 14b and (R)-1-
phenylethylamine with electrophilic alkene 2 paralleled
completely the conversion (1“4): adducts (2R,1%R)-13,
(2R,1%S)-15a and (2R,1%S)-15b were indeed, respec-
tively, obtained in fair yields and with de and ee
]95%.13
The nucleophilic species involved in the present
Michael addition are in fact the more substituted sec-
ondary enamines 16, in tautomeric equilibrium with the
starting imines.14 The above remarkable stereochemical
outcomes can be rationalized by evoking the synclinal
approach (17) of the two reactants [16+2]. According
to this model, the alkylation process takes place prefer-
entially on the less hindered p-face of the enamine (anti
to the bulky phenyl group), portrayed in its energeti-
cally preferred conformation. This accounts for the
absolute configuration at C-1% in resulting adducts 18.
Control of the stereogenic center at C-2 in 18 originates
from a concerted transfer of the NH proton of enamine
16 to the a-vinylic center of electrophile 2, the electron-
withdrawing group of this acceptor facing the nitrogen
atom of the enamine (‘endo-arrangement’). It is note-
worthy that the present stereochemical pattern is in all
respects identical to the one evoked when methyl 2-ace-
toxyacrylate was used as an electrophilic partner
(Scheme 4).14a,c
Scheme 2.
Incidentally, another interesting observation was made
when compound 5 was subjected to the Swern reagent
[DMSO, (COCl)2, CH2Cl2, then Et3N, 20°C]: the
olefinic derivative (2R,3aR)-1110 was isolated in a 55%
yield. This apparently unprecedented dehydration pro-
cess can be interpreted by assuming the original forma-
tion of a dimethylalkoxysulfonium ion11 at C-1a, 9,
which collapses to olefin 11, a fragmentation assisted by
the neighboring oxygen atom and which likely impli-
cated the intermediary oxonium ion 10. An alternative
route for converting 5 into 11 was also investigated,
that employed the Burgess’ inner salt (Et3N+SO2N−
COOMe)12 as a dehydration reagent (toluene, 48 h at
60°C, 60% yield) (Scheme 3).
Finally, the versatility of the present conjugate addition
was examined. Interestingly, we found that this reaction
Scheme 3.
Scheme 4.

L. Keller et al. / Tetrahedron Letters 42 (2001) 381–383
383
Work on the utilization of adduct 4 and analogs as
starting materials for the enantioselective synthesis of
the side-chains of Cephalotaxus alkaloids is in progress
in our laboratory.
(C), 211.0 (C) ppm; anal. calcd: C, 68.54; H, 6.71; N,
4.44; found: C, 68.66; H, 6.81; N, 4.36.
7. Compound 5: colorless solid; mp 105°C (CH2Cl2);
[h]D20= +17 (c=3, CHCl3); IR (KBr): 3545, 2235 cm−1
;
1H NMR (CDCl3, 200 MHz): 1.31–1.74 (m, 5H), 1.80
(m, 2H), 2.01 (m, 1H), 2.39 (dd, J=8.6, 12.6 Hz, 1H),
2.64 (dd, J=5.2, 12.6 Hz, 1H), 3.73 (s, 1H, OH), 4.47 (d,
J=10.6 Hz, 1H), 4.57 (d, J=10.6 Hz, 1H), 4.71 (dd,
J=5.2, 8.6 Hz, 1H), 7.28–7.39 (m, 5H) ppm; 13C NMR
(50 MHz, CDCl3): 21.0 (CH2), 22.3 (CH2), 29.9 (CH2),
33.5 (CH2), 36.8 (CH2), 62.0 (CH), 66.1 (CH2), 81.3 (C),
105.0 (C), 119.4 (C), 127.9 (2 CH), 128.4 (3 CH), 137.3
(C) ppm; anal. calcd: C, 70.31: H, 7.01: N, 5.12; found:
C, 70.25; H, 7.03; N, 5.02.
Acknowledgements
We are grateful to Dr. Jacqueline Mahuteau for valu-
able assistance with NMR studies and Mrs. Sophie
Mairesse-Lebrun for performing elemental analyses
(Centre d’Etudes Pharmaceutiques Chaˆtenay-Malabry).
8. Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45,
1175–1176.
References
9. Compound 6: sensitive white solid; IR (KBr): 3383, 1769
1. For recent references, see: (a) Thominiaux, C.; Rousse´,
S.; Desmae¨le, D.; d’Angelo, J.; Riche, C. Tetrahedron:
Asymmetry 1999, 10, 2015–2021; (b) Nour, M.; Tan, K.;
Cave´, C.; Villeneuve, D.; Desmae¨le, D.; d’Angelo, J.;
Riche, C. Tetrahedron: Asymmetry 2000, 11, 995–1002;
(c) Gassama, A.; d’Angelo, J.; Cave´, C.; Mahuteau, J.;
Riche, C. Eur. J. Org. Chem. 2000, 3165–3169.
2. de Oliveira, E. R.; Dumas, F.; d’Angelo, J. Tetrahedron
Lett. 1997, 38, 3723–3726.
1
cm−1; H NMR (CDCl3, 200 MHz): 1.09–1.95 (m, 5H),
2.01–2.47 (m, 3H), 2.68 (d, J=17.1 Hz, 1H), 2.85 (d,
J=17.1 Hz, 1H), 4.38 (d, J=10.1 Hz, 1H), 4.50 (d,
J=10.1 Hz, 1H), 4.71 (s, 1H, OH), 7.18–7.42 (m, 5H)
ppm; 13C NMR (50 MHz, CDCl3): 21.6 (CH2), 22.0
(CH2), 29.4 (CH2), 34.9 (CH2), 36.9 (CH2), 65.1 (CH2),
81.2 (C), 106.7 (C), 127.7 (2 CH), 128.2 (CH), 129.0 (2
CH), 136.9 (C), 171.8 (C) ppm.
10. Compound 11: colorless solid; mp 107°C (EtOH); [h]D20
=
3. Desmae¨le, D.; d’Angelo, J. Tetrahedron Lett. 1989, 30,
345–348.
−147 (c=0.7, CHCl3); IR (KBr): 3038, 2233 cm−1
;
1H
NMR (CDCl3, 400 MHz): 1.34 (dt, J=3.5, 13.8 Hz, 1H),
1.72 (m, 1H), 1.84 (m, 1H), 2.02–2.13 (m, 2H), 2.23 (m,
1H), 2.51 (dt, J=3.5, 13.8 Hz, 1H), 2.85 (d, J=13.6 Hz,
1H), 4.49 (d, J=10.3 Hz, 1H), 4.58 (d, J=10.3 Hz, 1H),
4.99 (d, J=8.2 Hz, 1H), 5.12 (t, J=3.8 Hz, 1H), 7.27–
7.46 (m, 5H) ppm; 13C NMR (50 MHz, CDCl3): l ppm
17.3 (CH2), 22.9 (CH2), 30.1 (CH2), 39.4 (CH2), 64.7
(CH), 66.3 (CH2), 77.5 (C), 99.8 (CH), 118.3 (C), 127.6 (2
CH), 128.4 (3 CH), 137.5 (C), 154.1 (C) ppm.
4. Nowak, R. M. J. Org. Chem. 1963, 28, 1182–1187.
5. Compound 3: colorless oil; IR (neat): 2233, 1752, 1658
1
cm−1; H NMR (CDCl3, 200 MHz): 1.39 (d, J=6.5 Hz,
3H), 1.32–2.48 (m, 8H), 1.98 (s, 3H), 2.45 (dd, J=6.2,
15.4 Hz, 1H), 2.79 (dd, J=5.4, 15.4 Hz, 1H); 4.00 (d,
J=11.7 Hz, 1H), 4.36 (d, J=11.7 Hz, 1H), 4.74 (q,
J=6.5 Hz, 1H), 5.55 (dd, J=5.4, 6.2 Hz, 1H), 7.07–7.45
(m, 10H) ppm; 13C NMR (50 MHz, CDCl3): 20.1 (CH3),
20.6 (CH2), 25.3 (CH3), 25.8 (CH2), 27.0 (CH2), 36.2
(CH2), 37.1 (CH2), 58.2 (CH), 58.4 (CH), 63.9 (CH2),
79.6 (C), 118.1 (C), 126.4 (2 CH), 126.6 (CH), 126.7 (2
CH), 127.2 (CH), 128.1 (2 CH), 128.3 (2 CH), 138.0 (C),
145.8 (C), 168.8 (C), 169.7 (C) ppm.
11. Omura, K.; Swern, D. Tetrahedron 1978, 1651–1660.
12. Burgess, E. M.; Penton, Jr., H. R.; Taylor, E. A. J. Org.
Chem. 1973, 38, 26–31.
13. Compound 13: 55% yield, [h]2D0= +46 (c=0.8, EtOH);
compound 15a: 60% yield, [h]2D0= +31 (c=5.5, EtOH);
compound 15b: 74% yield, [h]2D0= +65 (c=4.5, EtOH).
14. For the mechanistic aspects, see: (a) Ambroise, L.; Des-
mae¨le, D.; Mahuteau, J.; d’Angelo, J. Tetrahedron Lett.
1994, 35, 9705–9708; (b) Cave´, C.; Desmae¨le, D.; d’An-
gelo, J.; Riche, C.; Chiaroni, A. J. Org. Chem. 1996, 61,
4361–4368; (c) Cave´, C.; Le Porhiel-Castellon, Y.; Daley,
V.; Riche, C.; Chiaroni, A.; d’Angelo, J. Tetrahedron
Lett. 1997, 38, 8703–8706; (d) Tran Huu Dau, M. E.;
Riche, C.; Dumas, F.; d’Angelo, J. Tetrahedron: Asym-
metry 1998, 9, 1059–1064.
6. Compound 4: colorless solid; mp 62°C (EtOH); [h]2D0= +
1
75 (c=2, EtOH); IR (KBr): 2240, 1740 cm−1; H NMR
(CDCl3, 400 MHz): 1.51–1.64 (m, 4H), 1.99 (s, 3H), 2.12
(m, 1H), 2.21 (dd, J=7.1, 15.7 Hz, 1H), 2.27–2.40 (m,
2H), 2.67 (dd, J=5.4, 15.7 Hz, 1H), 2.77 (ddd, J=4.9,
12.2, 12.8 Hz, 1H), 4.17 (d, J=11.1 Hz, 1H), 4.53 (d,
J=11.1 Hz, 1H), 5.43 (dd, J=5.4, 7.1 Hz, 1H), 7.28–
7.44 (m, 5H) ppm; 13C NMR (50 MHz, CDCl3): 20.2
(CH3), 20.4 (CH2), 27.7 (CH2), 34.3 (CH2), 37.5 (CH2),
39.1 (CH2), 57.3 (CH), 65.4 (CH2), 81.3 (C), 117.1 (C),
127.1 (2 CH), 127.7 (CH), 128.5 (2 CH), 136.8 (C), 169.0
.
.