Enantioselective conjugate addition of a lithium ester enolate catalyzed by chiral lithium amides

Article abstract of DOI:10.1021/ol062270d

(Diagram presented) Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on α,β-unsaturated esters. Michael adducts were obtained in ee's up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction was found to be determined by both the relative configuration of the stereogenic centers borne by the amide and the solvent in which the reaction was conducted.

Full text of DOI:10.1021/ol062270d

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5745-5748
Enantioselective Conjugate Addition of
a Lithium Ester Enolate Catalyzed by
Chiral Lithium Amides
Nicolas Duguet,† Anne Harrison-Marchand,† Jacques Maddaluno,*,† and
Kiyoshi Tomioka*,‡
Laboratoire des Fonctions Azote´es & Oxyge´ne´es Complexes de l’IRCOF, UMR CNRS
6014, UniVersite´ et INSA de Rouen, 76821 Mont Saint-Aignan Cedex, France, and
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-Ku,
Kyoto 606-8501, Japan
jmaddalu@crihan.fr; tomioka@mail.pharm.kyoto-u.ac.jp
Received September 14, 2006
ABSTRACT
Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on
r,â-
unsaturated esters. Michael adducts were obtained in ee’s up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium
amide. The sense of the induction was found to be determined by both the relative configuration of the stereogenic centers borne by the
amide and the solvent in which the reaction was conducted.
The stereoselective formation of carbon-carbon bonds by
conjugate addition of carbonucleophiles to R,â-unsaturated
systems has been studied intensively over the past few years.1
Among the useful nucleophiles used in this process, lithium
enolates derived from ketones or esters, which have found
countless applications in aldolisation reactions,2 remain
relatively underemployed.3,4 Most reported examples are
limited to the addition of stabilized enolates such as those
derived from malonates, cyanoacetates, and acetoacetates.5
Indeed, the reactions with simple, unstabilized enolates are
often complicated by side reactions, which include proton
transfers, undesired condensations between reacting species,
and concomitant 1,2-additions.
Nevertheless, a few diastereo-6 and enantioselective7
versions of the conjugate addition were successfully devel-
oped. In the latter case, the lithium enolates have been closely
associated to chiral diethers,7c amines,7a-c lithium alkoxides,7e
or lithium amides.7a Thus, Tomioka’s group has been
studying the influence of chiral diethers (such as 2, Scheme
1), on the 1,4-addition of lithium ester enolates onto cyclic
† University of Rouen.
‡ Kyoto University.
(1) For reviews on the asymmetric Michael addition, see for instance:
(a) Sibi, P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061. (b) Krause,
N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171-196. (c) Berner, O. M.;
Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877-1894. (d)
Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688-1690.
(2) Valnot, J.-Y.; Maddaluno, J. In The Chemistry of Organolithium
Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley and Sons Ltd.:
Chichester, U.K., 2006; Vol. 2, pp 525-646.
(5) RajanBabu, T. V. J. Org. Chem. 1984, 49, 2083-2089.
(6) (a) Corey, E. J.; Peterson, R. T. Tetrahedron Lett. 1985, 26, 5025-
5028. (b) Bernardi, A.; Marchionni, C.; Novo, B.; Karamfilova, K.; Potenza,
D.; Scolastico, C.; Roversi, P. Tetrahedron 1996, 52, 3497-3508. (c)
Davies, S. G.; Diez, D.; Dominguez, S. H.; Garrido, N. M.; Kruchinin, D.;
Price, P. D.; Smith, A. D. Org. Biomol. Chem. 2005, 3, 1284-1301.
(7) (a) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay,
T.; Simson, M.; Seebach, D. Synthesis 1993, 1271-1290. (b) Yasuda, K.;
Shindo, M.; Koga, K. Tetrahedron Lett. 1996, 37, 6343-6346. (c) Iguchi,
M.; Doi, H.; Hata, S.; Tomioka, K. Chem. Pharm. Bull. 2004, 52, 125-
129. (d) Tomioka, K. Yakugaku Zasshi 2004, 124, 43-53. (e) Kumamoto,
T.; Aoki, S.; Nakajima, M.; Koga, K. Tetrahedron: Asymmetry 1994, 5,
1431-1432.
(3) (a) Yamaguchi, M.; Tsukamoto, M.; Hirao, I. Chem. Lett. 1984, 375-
376. (b) Yamaguchi, M.; Tsukamoto, M.; Hirao, I. Tetrahedron Lett. 1985,
26, 1723-1726.
(4) Yamataka, H.; Yamada, K.; Tomioka, K. In The Chemistry of
Organolithium Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley and
Sons Ltd.: Chichester, U.K., 2004; Vol. 1, pp 901-939.
10.1021/ol062270d CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/08/2006

Scheme 1. Putative Ternary Complex Formed between a
Scheme 3. Protocol to Generate an Enolate:Amide Aggregate
Chiral Diether, LDA. and a Lithium Enolate7c
and acyclic enones.7c Interestingly, the best ee (74%) was
obtained when adding one equiv of LDA to the stoichio-
metric mixture of enolate and chiral ligand (1:1:1). More
generally, the reaction of putative ternary complexes (such
as 3, Scheme 1) was found to give adducts in higher ee’s
than the corresponding binary complexes working without
the assistance of a lithium amide.8,9
The formation of mixed aggregates of ketone or ester
enolates and chiral or achiral lithium amides has also been
evidenced, both in the solid state10 and in solution.8,11 These
entities have been proposed to be decisive actors controlling
the kinetics, the regioselectivity and the enantioselectivity
of the reaction in which they are involved.
3-Aminopyrrolidines (3APLi) are known to form 1:1
noncovalent aggregates, 3APLi:RLi, the structure of which
was established by NMR12 and supported by DFT calcula-
tions.12,13 These aggregates have been used as chiral auxil-
iaries for the enantioselective 1,2-addition of alkyl-,14
aryl-,15 and vinyllithiums16 on aldehydes. We present here
results suggesting that 3APLi can also form aggregates with
lithium enolates of ester (Scheme 2), to be used in enanti-
oselective Michael additions on R,â-unsaturated esters.
the enolate double bond configuration and leads to the
creation of a single asymmetric center.17 The protocol
retained to run these experiments was designed to avoid, in
a first set of experiments, any interference of the amine used
to deprotonate the ester with the putative complex of enolate
and amide. Therefore, the enolate was generated by adding
3APLi to the ester (30 min at -20 °C; see Supporting
Information). The resulting 3APH (5 or 6) was then
deprotonated in situ by 1 equiv of n-BuLi added atop
(Scheme 3).
The first experiments were optimized using (E)-tert-butyl
crotonate. Parameters to be considered included the solvent,
the temperature, and the ratio between the enolate, the amide,
and the substrate (Table 1). Preparing the enolate 1 with LDA
and leaving the residual i-Pr2NH in the medium led to a poor
13% yield after 6 h (entry 1). A similar result was obtained
replacing LDA with 5-Li (yield ) 11%). In contrast, the
presence of 1 equiv of lithium amide enhanced the yield of
the transformation up to 86% (entry 2), as previoulsy noted
in the enantioselective 1,2-addition of comparable lithium
enolates on imines.18 We next substituted LDA with the
chiral 5-Li and were delighted to note that the resulting ester
(+)-7 was obtained in 68% yield and 72% ee (entry 3).
Increasing the chiral amide to enolate ratio improved slightly
the yields but left the ee almost unaltered (entries 4 and 5).
This observation supports the hypothesis of the formation
of a 1:1 enolate:amide aggregate (Scheme 2). The best results
(yield ) 82%, ee ) 76%) were obtained when increasing
both the amide and enolate concentrations (entry 6). Interest-
ingly, swapping from THF to toluene reversed the sense of
the induction, albeit the performances of the reaction were
somewhat decreased (entry 7). This inversion was also
observed with the diastereomeric amide 6-Li (entry 8), as
noted previously during the 1,2-addition of alkyllithiums on
Scheme 2. Hypothesis of a Mixed Aggregate between a
Lithium Enolate and 3APLi
The study was conducted with the lithium enolate 1
derived from 2,4-dimethylpentan-3-yl iso-butyrate 4 (Scheme
3). This choice circumvents the problem of the control of
(8) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am.
Chem. Soc. 1997, 119, 2060-2061.
(9) Iguchi, M.; Tomioka, K. Org. Lett. 2002, 4, 4329-4331.
(10) Williard, P. G.; Hintze, M. J. J. Am. Chem. Soc. 1990, 112, 8602-
8604.
(11) (a) Galiano-Roth, A. S.; Kim, Y. J.; Gilchrist, J. H.; Harrison, A.
T.; Fuller, D. J.; Collum, D. B. J. Am. Chem. Soc. 1991, 113, 5053-5055.
(b) Sun, C.; Williard, P. G. J. Am. Chem. Soc. 2000, 122, 7829-7830. (c)
Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 2459-2463. (d)
Ramirez, A.; Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2006, 128, 10326-
10336.
(12) Corruble, A.; Valnot, J. Y.; Maddaluno, J.; Prigent, Y.; Davoust,
D.; Duhamel, P. J. Am. Chem. Soc. 1997, 119, 10042-10048.
(13) (a) Fressigne´, C.; Maddaluno, J.; Marquez, A.; Giessner-Prettre, C.
J. Org. Chem. 2000, 65, 8899-8907. (b) Fressigne´, C.; Lautrette, A.;
Maddaluno, J. J. Org. Chem. 2005, 70, 7816-7828.
(14) (a) Corruble, A.; Valnot, J. Y.; Maddaluno, J.; Duhamel, P. J. Org.
Chem. 1998, 63, 8266-8275. (b) Corruble, A.; Davoust, D.; Desjardins,
S.; Fressigne´, C.; Giessner-Prettre, C.; Harrison-Marchand, A.; Houte, H.;
Lasne, M.-C.; Maddaluno, J.; Oulyadi, H.; Valnot, J.-Y. J. Am. Chem. Soc.
2002, 124, 15267-15279.
(15) Flinois, K.; Yuan, Y.; Bastide, C.; Harrison-Marchand, A.; Madd-
aluno, J. Tetrahedron 2002, 58, 4707-4716.
(16) Yuan, Y.; Harrison-Marchand, A.; Maddaluno, J. Synlett 2005,
1555-1558.
(17) Kambara, T.; Hussein, M. A.; Fujieda, H.; Iida, A.; Tomioka, K.
Tetrahedron Lett. 1998, 39, 9055-9058.
(18) Hussein, M. A.; Iida, A.; Tomioka, K. Tetrahedron 1999, 55,
11219-11228.
5746
Org. Lett., Vol. 8, No. 25, 2006

The congested product resulting from the addition of our
bulky enolate to cumbersome (E)-tert-butyl 4-methylpent-
2-enoate (R ) i-Pr) resulted in surprisingly good chemical
yields; however, the associated ee’s remained very low
(entries 5 and 6). Overall, this reaction seems highly substrate
sensitive and requires a re-optimization of its conditions in
every new case.
Table 1. Conjugate Addition of Lithium Enolate 1 on
(E)-tert-Butyl Crotonate (R ) Me)
In a last section, we ran complementary experiments to
probe the possible formation of ternary enolate:amide:amine
complexes, closer to the enolate:amide:chiral ether studied
previously by Tomioka et al.7c Thus, two new protocols were
designed. The first (protocol A) was identical to that
described above (Scheme 3), except that it was followed by
the addition of an extra equivalent of an amine atop of the
enolate-amide mixture. The second protocol (B) implied the
deprotonation of the ester by a given lithium amide, resulting
in an enolate-amine mixture, before a second equivalent of
another lithium amide was added (Table 3). In all cases, the
entry amide
ratioa
solvent temp (°C) 7 (%)b ee (%)c
1
2
LDA 0.0:1.3:1.0 THF
LDA 1.3:1.3:1.0 THF
-78
-78
-78
-78
-78
-78
-78
-78
-78
-20
-78
-20
13d
86
68
83
81
82
52
95
91
76
45
61
3
4
5
6
7
8
9
10
11
12
5-Li
5-Li
5-Li
5-Li
5-Li
6-Li
6-Li
6-Li
6-Li
6-Li
1.3:1.3:1.0 THF
1.7:1.3:1.0 THF
2.6:1.3:1.0 THF
2.4:2.0:1.0 THF
1.7:1.3:1.0 toluene
1.7:1.3:1.0 THF
2.4:2.0:1.0 THF
2.4:2.0:1.0 THF
2.4:2.0:1.0 toluene
2.4:2.0:1.0 toluene
72 (+)
74 (+)
71 (+)
76 (+)
62 (-)
55 (-)
54 (-)
53 (-)
45 (+)
30 (+)
Table 3. Conjugate Addition of Lithium Enolate 1 on
tert-Butyl Crotonate in the Presence of Amide and Amine
a Ratio between amide:enolate:(E)-tert-butyl crotonate. b Isolated yields
in 7. c Measured by HPLC on a Daicel Chiralpak AD-H column (see
Supporting Information). The absolute configuration of 7 remains to be
determined. d Isolated yield after 6 h.
o-tolualdehyde.14b However, the associated ee’s are lower
(entries 8-10). Finally, a “double inversion” was noticed
when employing 6-Li in toluene; the (+)-7 enantiomer was
recovered, but in a mediocre 30% ee (entry 12).
We next probed the influence of the structure of the
substrate on the enantioselectivity of the reaction (Table 2).
Table 2. Conjugate Addition of Lithium Enolate 1 on
(E)-tert-Butyl Cinnamate (R ) Ph) and (E)-tert-Butyl
4-methylpent-2-enoate (R ) i-Pr) in the Presence of Chiral
3APLi in THF
first
second
entry protocola amine/amide amine/amide 7 (%)b ee (%)c
1
2
3
4
5
A
B
A
A
B
5-Li
5
5-Li
LDA
i-Pr2NH
i-Pr2NH
LDA
5
5
5-Li
79
72
94
60
47
71
67
62
19
66
entry Ra amide temp (°C) time (h) yield (%)b ee (%)c
1
2
3
4
5
6
Ph
Ph
Ph
Ph
i-Pr
i-Pr
5-Li
5-Li
6-Li
6-Li
5-Li
6-Li
-78
-20
-78
-20
-78
-78
6
2
6
2
3
3
8 (52)
8 (94)
8 (52)
8 (96)
9 (75)
9 (79)
12 (+)
2 (+)
50 (-)
6 (-)
11 (+)
15 (+)
a See text for the definition of the protocols. b Isolated yields. c Measured
by HPLC on a Daicel Chiralpak AD-H column (see Supporting Information).
The (+) enantiomer was recovered in all of these experiments.
a R refers to the Scheme in Table 1. b Isolated yields in 8 or 9. c Measured
by HPLC on a Daicel Chiralpak AD-H column (see Supporting Information).
The absolute configurations of 8 and 9 remain to be determined.
ratio amine/amide/enolate/tert-butyl crotonate was kept equal
to 1.3:1.3:1.3:1.0, figures adapted from the above results.
The data are presented in Table 3. Its entry 1 suggests that
the addition of i-Pr2NH to the enolate:5-Li complex is
meaningless, the results being similar to those obtained in
Table 1, entry 3. When the order of introduction of the
additives is reversed (entry 2), the output is hardly altered.
This suggests that LDA is more basic than 5-Li and that a
similar enolate:5-Li aggregate is obtained in entries 1 and
2. The latter seems to be poorly affected by the chiral amine
Applying the previous protocol to 5-Li and tert-butyl
cinnamate (R ) Ph) required longer reaction times and led
to very disapointing results inductionwise (entry 1). Raising
the temperature increased significantly the reaction rate while
the ee plummeted (entry 2). A similar observation was made
with amide 6-Li (entries 3 and 4).
Org. Lett., Vol. 8, No. 25, 2006
5747

5, which exerts a slightly unfavorable effect on the ee (entry
3), suggesting a “mismatch” relationship between the amine
and its corresponding amide. If the enolate is first aggregated
with LDA and the free chiral amine 5 added atop of this
complex (entry 4), the ee drops to 19%. This observation
probably translates the mediocre induction power of the
amine itself, which would hardly interact with the robust
enolate:achiral amide mixed aggregate. Entry 5 finally
supports the above assumptions, since the addition of 5-Li
to the enolate:i-Pr2NH mixture once more affords the enolate:
5-Li complex associated with a 66% ee.
Inspired by Seebach’s pionnering works,7a we finally
attempted to form a ternary complex between LiBr, enolate
1, and 5-Li. However, generating the enolate with 5-Li and
then deprotonating the resulting amine with MeLi:LiBr (1:
1) led to disapointing figures (yield ) 15%, ee ) 11%).
In conclusion, the above results show that 3APLi lithium
amides act as chiral auxiliaries in the enantioselective
conjugate addition of lithium enolate to R,â-unsaturated
esters. Values for ee’s of up to 76% were reached after
optimization of the experimental conditions. The sense of
the induction appears to be controlled both by the relative
configuration of the stereogenic centers borne by the amide
and by the solvent. The analysis of the data suggests that, at
low temperature, mixed aggregates form between the two
lithiated entities. Within the limits of the Curtin-Hammett
postulate, this complex can be held responsible for the
observed inductions. Detailed NMR and theoretical studies
will be necessary to describe the structure of this putative
species and its interaction with the electrophiles.12,14b
Acknowledgment. N.D. acknowledges the Ministe`re de
la Recherche et de la Technologie for a Ph.D. grant and the
Japan Society for the Promotion of Science 2005 Summer
Program for a scientific exchange grant. The interregional
program Poˆle Universitaire Normand de Chimie Organique
(PUNCHorga) is thanked for supporting this research.
Supporting Information Available: Detailed experi-
1
mental procedures and H and 13C NMR spectra of the
synthesized new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL062270D
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Org. Lett., Vol. 8, No. 25, 2006