Enantioselective protonation and alkylation of non-covalent mixed aggregates of chiral 3-aminopyrrolidine lithium amides

Article abstract of DOI:10.1016/S0040-4020(02)00377-0

Non-covalent aggregates of highly polar entities assemble, on a temporary basis, a chiral moiety to a reagent. Attempts to take advantage of this phenomenon with chiral 3-aminopyrrolidine (3-AP) lithium amides are described. The enantioselective protonation of a complex involving these amides and the lithium enolate of 2-methyltetralone by an achiral proton source gives products in which the ee does not exceed 40%. The same class of chiral amides is then applied to the asymmetric nucleophilic alkylation of aldehydes using alkyllithiums and phenyllithium. In this case, a mixed aggregate made up of the lithium amide and the alkyllithium, a structure that has been detailed previously in comparable situations, seems to be directly involved in the reaction. Thus, higher asymmetric inductions are obtained, affording the alkylation products in ee of up to 70%.

Full text of DOI:10.1016/S0040-4020(02)00377-0

TETRAHEDRON
Pergamon
Tetrahedron 58 -2002) 4707±4716
Enantioselective protonation and alkylation of non-covalent
mixed aggregates of chiral 3-aminopyrrolidine lithium amides
Karine Flinois, Yi Yuan, Christophe Bastide, Anne Harrison-Marchand and Jacques Maddalunop
   Â
Laboratoire des Fonctions Azotees and Oxygenees Complexes de l'IRCOF, UMR 6014 CNRS, Universite de Rouen,
76821 Mont St Aignan Cedex, France
Received 4 January 2002; accepted 27 February 2002
AbstractÐNon-covalent aggregates of highly polar entities assemble, on a temporary basis, a chiral moiety to a reagent. Attempts to take
advantage of this phenomenon with chiral 3-aminopyrrolidine -3-AP) lithium amides are described. The enantioselective protonation of a
complex involving these amides and the lithium enolate of 2-methyltetralone by an achiral proton source gives products in which the ee does
not exceed 40%. The same class of chiral amides is then applied to the asymmetric nucleophilic alkylation of aldehydes using alkyllithiums
and phenyllithium. In this case, a mixed aggregate made up of the lithium amide and the alkyllithium, a structure that has been detailed
previously in comparable situations, seems to be directly involved in the reaction. Thus, higher asymmetric inductions are obtained, affording
the alkylation products in ee of up to 70%. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Since the pioneering work of Whitesell1 and Duhamel,2 chiral
lithium amides -CLA) have become versatile tools in asym-
metric synthesis. Excellent reviews have detailed their numer-
ous uses,3 especially as chiral bases in enantioselective
deprotonation reactions. Applications of CLAs to natural
products synthesis, in particular owing to their capacity to
desymmetrize meso compounds, have also been described.4
But CLAs are more than just bases. Davies and colleagues
have for instance elegantly taken advantage of the nucleo-
philic character of these reagents in a diastereoselective
version of the hetero-Michael addition of amides to a,b-
unsaturated esters.5 Interestingly, the well-known tendency
of these highly polar entities to gather into homogeneous
oligomers -ladder type) and to form mixed aggregates with
other organolithium compounds has been studied in depth, in
particular by Snaith, Mulvey and colleagues,6 but has received
only scarce synthetic interest. We present in this paper two
applications -enantioselective protonation -EP) and alkylation
reactions) for such chiral non-covalent entities that we have
studied recently. We have focused our research on chiral 3-
aminopyrrolidine -3-AP) lithium amides that behave as potent
auxiliaries in the alkylation reaction.7 The low-temperature
formation of a non-covalent complex involving one lithium
amide and one alkyllithium in THF has been established by
multinuclear NMR spectroscopy8 and ab initio calculations,9
providing a strong molecular basis to this investigation.
2.1. Synthetic access to chiral 3-aminopyrrolidines
Only a few routes to diamines 1 have been described to
date.10 The four syntheses we have considered are
summarized in Scheme 1. Three approaches are based
on the transformation of natural amino acids, namely
Keywords: lithium; amines; enantioselective alkylation; enantioselective
protonation; aggregation.
p
Corresponding author. Tel.: 133-235-522-446; fax: 133-235-522-971;
e-mail: jmaddalu@crihan.fr
Scheme 1. Synthetic routes to 3-aminopyrrolidines 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020-02)00 377-0

4708
K. Flinois et al. / Tetrahedron 58 12002) 4707±4716
-l)-glutamine 2, -l)-glutamic acid 3 or 4-hydroxy--l)-
proline 4. These routes require ®ve to seven steps and
provide 1 in 30±60% yield.11 The ee of the ®nal 3-AP is
somewhat eroded when starting from 2 and 3 while 4 can be
transformed into enantiomerically pure 1. The simplest and
most ef®cient access to 1 utilizes 3-amino-N-benzylpyrroli-
dine 5, commercially available in both enantiomeric forms,
the primary amino group being easily transformed in two
steps -imination/reduction) into a secondary one. On the
other hand, 5 is the only aminopyrrolidine available, limit-
ing this route to R2ˆBn. Actually, this substituent is well
suited to most of the applications we have considered to
date, as described below.
2.2. Application of 3-AP lithium amides to the
enantioselective protonation of lithium enolates
The EP of a prochiral intermediate is a deracemisation
method that can offer an ef®cient access to asymmetric car-
bonyl compounds.12 In particular, the EP of ketone and ester
enolates has proved ef®cient in access to complex targets
such as -R)-a--1)-damascone and other fragrances, as
elegantly demonstrated by Fehr and co-workers.13 In most
cases studied to date, the source of chirality in the key
protonation step is also the source of the proton. Thus,
tartaric acid derivatives, ephedrine-based aminoalcohols,
chiral alcohols, aminoboranes, imides or amine hydro-
chlorides and a few other sources have been used for an
asymmetric delivery of their most acidic proton.14a Recent
results have shown that a catalytic amount of the chiral
proton donor can be suf®cient.13d,e,14b±e Vedejs has enlarged
this classical `chiral-proton pool' to chiral aniline-Lewis
acids couples for which he described the Internal Proton
Return -IPR) phenomenon,15a particularly ef®cient for the
EP of amide enolates.15 Another important development has
been proposed by Koga who ®rst showed that protonation of
2-methyl-1-tetralone lithium enolate by such simple acids as
AcOH can take place in ee of up to 91% provided that the
intermediate enolate, generated in the presence of 1 equiv.
LiBr, is complexed by a chiral piperidine-derived tri-
amine.16a,b Eames has also made a similar observation
using a C2 symmetrical cyclohexyldiamine.16c Recently,
Tomioka has nicely taken advantage of a comparable
enolate±chiral amine complex that undergoes EP using a
thiophenol.16d
Scheme 2.
metal -Li or K) of the enolate, the substituents R1, R2 and
R3 of the 3-AP, the presence of lithium salts -LiBr or
t-BuOLi), the temperature -between 220and 2788C), the
solvent -THF or toluene) and the protonating agent -AcOH
or t-BuOH) were all varied. These data are not presented
here since no signi®cant ee could be measured -by chiral GC
on the crude medium) in such conditions. We thus switched
to mixtures involving 3-AP lithium amides and ketone
lithium enolates -Scheme 2) in the hope that stronger inter-
actions between the partners could lead to higher asym-
metric inductions.
The results we are presenting here are limited, for the sake
of clarity, to the 2-methyltetralone lithium enolate 7. The
experimental conditions we have retained were inspired
from those described by Koga.16a The enolate was prepared
in toluene or THF by reacting the corresponding trimethyl-
silyl enol ether 6 with 2.2 equiv. of a commercial MeLi/
LiBr -1:1) solution -in ether) at 408C during 5 min. The
medium was then cooled to 2788C before 1.1 equiv. of
dissolved 3-AP 1 was added. The resulting mixture was
kept at 2788C for 1 h and the proton donor -1 or 2 equiv.)
then introduced. The reaction was ®nally quenched after a
further 40min by an excess of acetic anhydride or of an
aqueous solution of citric acid, and the temperature raised
to room temperature. The ee were then determined from the
pentane extracts of the crude neutralized medium by chiral
We thought it could be interesting to push forward this
concept by aggregating a lithium enolate to a CLA before
exposing the chiral complex thus obtained to an achiral
proton source -Scheme 2). This would extend the scope of
the 3-AP lithium amide aggregates to the large ®eld of
lithium enolate chemistry. The formation of hetero-
aggregates between LDA or tetramethylpiperidine lithium
amide and lithium cyclohexenolate in THF has been clearly
established by NMR spectroscopy by Collum and
colleagues and they have also studied the in¯uence on
these complexes of salts or additives such as LiBr or
HMPA.17 Before starting our investigations on the lithiated
species, it was necessary to ®rst evaluate the eventual
induction potential of the amine itself. This has been
achieved through a set of EP experiments involving
different lithium enolates -derived from 2-alkylcyclohexa-
nones and 2-methyltetralone) in conditions in which the
Table 1. Protonation of mixtures of 2-methyltetralone lithium enolate 7 and
3-AP lithium amides 1a-Li -R1ˆR2ˆBn) or 1b-Li -R1ˆBn, R2ˆn-Pr,
Scheme 2)
Entry Amine Solvent LiBr -Equiv.)
HY
Yield -%) ee -%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1a
1a
1a
1a
Tol
Tol
Tol
Tol
0TFA
0HCl
2
2
2
0TFA
0HCl
2
95
89
,3
,3
HCl
79
47
91
,3
,3
,3
,3
,3
,3
,3
AcOH
AcOH
81
93
HCl
AcOH
Tol
THF
THF
THF
THF
93
90
2

K. Flinois et al. / Tetrahedron 58 12002) 4707±4716
4709
Table 2. Protonation of mixtures of 2-methyltetralone lithium enolate 7 and
various 3-AP lithium amides 1-Li at 2788C in toluene -Scheme 2)
Entry Amine
R1 R2
LiBr -equiv.) ee -%)
1
2
3
4
5
6
7
8
1c
1d
1e
1f
1g
1h
5
5
1i
1j
1k
H
H
H
H
H
H
H
H
Ph
Ph
n-Pr
MeOC2H4
a--S)-Methylbenzyl
a--R)-Methylbenzyl
CH2-a-Napht.
CH2-b-Napht.
Bn
Bn
Bn
Ph
2
2
2
2
2
2
2
0
2
2
2
7 -S)
6 -S)
,3
15 -S)
15 -S)
15 -S)
40- S)
,3
9
10
11
5 -S)
,3
,3
SiPh2t-Bu Ph
GC. The data in Table 1 indicate that the induction remains
almost null in all cases.
These disappointing results prompted us to turn to a new
family of CLAs derived this time from primary amines 1
Scheme 3. Stepwise vs. synchronous protonation of a possible 1:1 mixed
aggregate between 3-AP lithium amide 1-Li and 2-methyltetralone
enolate 7.
1
Â
-R ˆH). To our knowledge, only Muzart, Henin and
colleagues have resorted to a primary amine in an EP
experiment.18 Since no speci®c protocol has been described
for primary lithium amides, we left our procedure
unchanged. However, and to keep the experimental explora-
tion of such a large domain within reasonable limits, we
chose to ®rst restrict the protonating agent to AcOH
-2 equiv.). The structure of the 3-AP was then varied to
some extent and the results are gathered in Table 2. The
chemical yields have not been measured but the conversions
-as determined by GC) are very high -.90%) while the ee,
albeit more encouraging than those of Table 1, remained
very low. The `best' result -40% ee) was obtained with
amide 5-Li that bears a benzyl appendage on the ring nitro-
gen -entry 7). Interestingly, the introduction of a second
asymmetric centre on the benzylic position -entries 3 and
4) or enlargement of the aromatic ring -entries 5 and 6) had a
signi®cantly negative effect. The central role of LiBr in
these aggregation phenomena can be appreciated from
entry 8 where the ee dropped to insigni®cant values when
no salt was present in the reaction medium. The importance
of the primary character of the 3-AP to preserve the modest
induction potential of these compounds is ®nally con®rmed
by the results obtained with the anilines 1i and 1j -entries 9
and 10) or silylamine 1k -entry 11).
To our knowledge, the aggregates between CLAs and
lithium enolates have not found any application in EP
yet,19 and the study presented here suggests that 3-AP
lithium amides will hardly be ef®cient auxiliaries for this
class of reaction. Actually, controlling the stepwise proton
transfer towards a `dianionic' complex raises the crucial
issue of the priority order between two competing sites.15f,20
If the lithium amide is the ®rst to intercept the incoming
proton, as expected on simple grounds of thermodynamical
basicity, the complex is likely to evolve into an enolate/
amine aggregate resembling that studied above
-Scheme 3). By contrast, if the enolate is sterically more
accessible to the proton, it can become the kinetically
most basic site, providing a different chiral environment to
the EP key-step. Since our attempts to avoid this possible
problem by a double -more or less synchronous) protonation
of the putative non-covalent complex by diacids -such as
malic or maleic acids) remained unsuccessful -see above),
we had to check the induction potential of amine 5 itself.
Complexing the usual 2-methyltetralone lithium enolate 7
-prepared this time using only 1.1 equiv. MeLi/LiBr) with
1.1 equiv. 5 according to the procedure described above,
followed by the addition of 1.1 equiv. AcOH, ®nally led
to tetralone 8 in quantitative yield and 34% ee. Thus it
seems that the simple formation of an enolate±amine
complex can almost fully account for the results we
obtained and seems to indicate that achieving the selective
protonation of an enolate in the presence of a -chiral)
lithium amide is dif®cult to master.
Starting from these data, many variations have been under-
taken to improve the ef®ciency of 1 in the EP reaction.
Variations of the experimental parameters have included
the temperature -of the synthesis and/or mixing of the
enolate or of the protonation), the introduction of ageing
phases for the complexes, a lithium/potassium exchange,
the addition of various salts or additives -LiF, LiCl, LiI,
LiOTf, HMPA or TMEDA), the changes in the proportions
of the partners -excess or default of methyllithium), the
solvent -THF, Et2O, DMM or tBuOMe), the structure of
the enolate -from methyl and phenylcyclohexanones,
2-chlorotetralone or 2,2,6-trimethylcyclohexanone) and
the proton donor -water, tri¯uoro and trichloroacetic acids,
malic and maleic acids, phtalimide or BHT). For the sake of
brevity, the corresponding results are not shown here, but in
none of these cases could the ee be signi®cantly improved
for our test reaction.
This disappointing observation should not discourage future
developments of these non-covalent systems, of which
chemistry is already well documented,21 to other classes
of reactions involving enolates. In addition, one should
keep in mind that the rational design of the partners will
certainly improve thanks to the constant accumulation of
data regarding the solution structures of comparable species
by spectroscopic techniques such as multinuclear NMR or
in situ infrared recordings.

4710
K. Flinois et al. / Tetrahedron 58 12002) 4707±4716
Scheme 4.
Scheme 5. Sketches of the three experimental protocols compared in this
work.
2.3. Application of 3-AP lithium amides to the
enantioselective alkylation of aldehydes
describe the condensation of the same alkyllithium in the
presence of 1.5 equiv. of 3-AP lithium amide 1l, m onto
o-tolualdehyde 12, yielding alcohol 13 in 80% ee at
2788C -Scheme 4 -bottom)).7 Our results have been asso-
ciated to the NMR8 and theoretical9 descriptions of a 1:1
complex between 1m and butyllithium -represented in
Scheme 5).
The second application to non-covalent asymmetric aggre-
gates we have considered is the enantioselective alkylation
of aldehydes. If the condensation of chiral complexes of
organozinc compounds onto carbonyl groups is currently
the object of considerable efforts,22 the organolithium
reagents have been relatively unstudied. They are indeed
generally regarded as being too reactive toward aldehydes
to be channeled through an asymmetric pathway. However,
and as early as 1984, Hogeveen and Eleveld have shown
that advantage could be taken of the association between the
aminoether-derived CLA 10 and butyllithium in the conden-
sation on benzaldehyde 9, providing benzylic alcohol 11 in
90% ee -Scheme 4 -top)).23 Since then very interesting
developments have been brought to this original system,
following the breakthrough by Davidsson and Hilmersson
who have established, from NMR spectroscopic data, that a
1:1 non-covalent complex was formed between 10 and
butyllithium.24 Our own research in this ®eld led us to
We decided to investigate in greater detail this last reaction.
We were particularly interested in getting a better understand-
ing of the conditions for the formation of such aggregates and
in trying to extend the scope of organolithium reagents
compatible with these chiral auxiliaries. We thus focused
our work on the model reaction of Scheme 4 -bottom), resort-
ing to one of the best chiral inductor we had in hand. The 3-
benzhydrylamino-N-benzylpyrrolidine 1m seemed perfectly
appropriate since: -i) it gives ee up to 73% in the alkylation
with o-tolualdehyde;7 -ii) it is readily prepared from commer-
cial 3-amino-N-benzylpyrrolidine 5 in 79% yield and 100%
ee; -iii) it is very stable and can be kept over long periods.
Table 3. Experimental variations of the reaction of Scheme 4 following three different protocols -as sketched on Scheme 5)
Entry
Amine
Protocol
Solvent
BuLi -equiv.)
3-AP -equiv.)
T -8C)
t -h)
Yielda -%)
ee -%)
1
2
3
4
5
6
7
8
1m
1m
1m
1m
1m
1m
1m
1m
1m
1m
1m
1m
17
A
A
A
A
B
C
A
B
C
A
A
A
A
B
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Tol
2.5
5.01.0
1.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
1.5
.52100
.52100
2101.0
.52100
.52200
2201.0
278
278
278
.52200
220
77
97
73
81
97
83
1.5
1.5
1.092
96
73
28
23
70
57
66
69
72
58
50
100
3
0.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
63
53
9
10
11
12
13
14
0.5
92
55
30
21
DME±Et2O -1:1)
THF
THF
.52200
.52200
.52200
37
17
15
a
Based on integrations of NMR spectra.

K. Flinois et al. / Tetrahedron 58 12002) 4707±4716
4711
Our ®rst studies focused on modi®cations of our `standard'
experimental procedure7 -Table 3, entry 1) to put into
evidence an eventual in¯uence of the aggregation condi-
tions on the selectivity of the reaction in Scheme 4 -bottom).
Three different protocols have been designed, as sum-
marized in Scheme 5. In the ®rst one -A), the whole butyl-
lithium was directly added to the 3-AP in solution in THF at
temperature -T, 220or 2788C) and the putative complex let
for ageing during time -t). In the second protocol -B), the
3-AP lithium amide was prepared in a ®rst separate step by
addition of 1.1 equiv. of butyllithium at the same tempera-
ture -T). After 30min, the second equivalent of butyl-
lithium was added and the mixture aged during time -t)
before adding into the reaction. The third protocol -C)
was reversed in the sense that the amine in THF was
added to 2 equiv. of butyllithium in THF at the same
temperature -T ), and the mixture left for time -t). In all
cases, 1 equiv. of aldehyde also in THF was ®nally intro-
duced into the medium at 2788C and the reaction quenched
after 1 h by aqueous HCl. After the usual work-up, the ee of
1
the alcohols were determined by H NMR spectroscopy in
CDCl3 in the presence of [Eu-hfc)3].
Scheme 6. Possible homo and hetero-aggregation schemes of 3-AP lithium
amide 1m-Li.
The results are presented in Table 3. The asymmetric induc-
tions we have observed for this system are consistently in
favor of alcohol -R)-13. The ®rst four entries summarize our
attempts to use sub-stoichiometric amounts of chiral ligands
in the reaction. Entries 2 and 3 clearly indicate that in the
presence of a large excess of BuLi or of a sub-stoichiometric
-20%) amount of 3-AP, the ee drops, while entry 4 -in which
exactly one equivalent of diamine is used) exhibits an ee
comparable to the ®rst entry, the reference experiment
involving 1.5 equiv. of 3-AP. This observation suggests
that if the 1:1 complex we have observed is the reactive
entity responsible for the asymmetric induction, it is more
ef®cient than the pure BuLi aggregates -tetramer1dimer)
present in THF -see entry 1) but the difference of reactivity
between these competing species is not suf®cient to
warranty a catalytic version of the reaction. In entries 4±9
are compared the results of the three protocols presented
above, at two different temperatures -210/220and
2788C) and with 1 equiv. of 3-AP. In the two series, the
ee decreases from protocol A to B, the results of C lying in
between the two others. It is somewhat risky to draw any
conclusion from these very limited variations. However, the
relatively good reproducibility of the data suggests that the
organization of the reaction medium be consistently altered
by the experimental procedure. In particular, we are aware
of a possible competition between mixed and homogeneous
aggregation processes -Scheme 6). It has indeed been calcu-
lated that the stabilization of the lithium dimethylamide±
methyllithium complex with respect to the corresponding
homogeneous entities [ie -Me2NLi)2 and -MeLi)2] is
extremely small -<0.2 kcal/mol).9 The presence of an
homogenous CLA dimer on one hand and of an alkyllithium
dimer -or higher oligomers) on the other, is expected to
result in a drop in the enantioselectivity of the alkylation
reaction. Therefore, protocol B -that allows the dimerisation
of the lithium amide) should be associated with lower ee
than protocol A, as observed experimentally. By contrast,
protocol C should favor the mixed aggregation, the lithium
amide being generated in the presence of an excess of butyl-
lithium, and thus be associated with higher ee than those
obtained following A. Table 3 shows this is not the case,
maybe because of the participation of `higher order'
oligomers in which BuLi/3-AP.1.
As a complement, we examined the in¯uence of typical
solvents for this same reaction. Entries 10±12 show that
THF is de®nitely the best solvent for our system since the
ee value drops in the three cases we have considered. This is
probably to be considered in relation with the strong
in¯uence of the medium polarity on these complexes
computed recently.25
The possible in¯uence of the protocol on the ee has also
been evaluated on 4-aminopiperidine 17. In these diamines,
the only asymmetric center is borne by the lateral amino
chain. They have been simply prepared following Scheme 7.
The starting N-Boc-4-hydroxypiperidine 14 is com-
mercially available and can be transformed into the corre-
sponding mesylate 15 -or tosylate) and substituted by
a-methylbenzylamine, affording 16 in 30% yield. The
®nal LAH reduction of the carbamate provides diamine 17
in 73% yield.
Scheme 7.

4712
K. Flinois et al. / Tetrahedron 58 12002) 4707±4716
Scheme 8. Possible homo and hetero-aggregation schemes of lithium amide 17-Li.
The results in Table 3 show that the ee associated with
amine 17 are much lower than those derived from 1m,
whatever the experimental conditions. This can be due to
the eventual absence of folding of 17-Li -as suggested by
preliminary NMR spectroscopic data)26 that would favor the
dimerization of this species -Scheme 8). The amide dimer
18 would then be in equilibrium with: -i) a mixed aggregate
with BuLi -19) that can, in turn, react with tolualdehyde to
give the expected alcohol 13; -ii) the a-aminoalcoholate 20
due to the direct alkylation of the amide on the aldehyde.27
The drop of the yield can thus be explained by the presence
of 20 in the medium, that does not react with BuLi and gives
back tolualdehyde upon aqueous work up. The low ee can
be due to either a weak induction by the mixed aggregate 19
or to the equilibrium between homogeneous and hetero-
geneous dimers/aggregates 18/19. In support of this scheme
are the results of entry 11, which show that pre-forming the
lithium amide -protocol B) decreases both the yield and ee
-Scheme 8).
almost zero, indicating that, as in the ®rst section of this
work, LiBr has a dramatic effect on these heteroaggregation
phenomena, as reported previously by Scolastico et al.28
A
comparable drop in enantioselectivity is observed when
using t-BuLi -entry 5), probably because this bulky reagent
does not aggregate with the 3-AP lithium amide. Finally, we
examined the case of phenyllithium -entry 6). Interestingly,
this organometallic gives signi®cant ee -58%) and a reversal
of the enantioselectivity, the -S)-a-tolyl benzylic alcohol
being obtained in this case.29 The origin of this change in
the induction is dif®cult to explain with our model and calls
for molecular modeling on the aldehyde docking and
rotation steps.
3. Conclusion
Non-covalent mixed aggregates of 3-AP lithium amides can
Table 4. Extension of the reaction of Scheme 4 to four different organo-
lithium compounds
We ®nally decided to vary the organolithium compounds
used in conjunction with the 3-AP 1m. In Table 4 are
gathered the results concerning methyllithium, n-butyl-
lithium, t-butyllithium and phenyllithium. Entry 1 indicates
that switching from butyl to methyllitium decreases the ee
-compare entries 1 and 2). It takes an increase in the chiral
complex to aldehyde ratio to get back to a comparable
induction level -entry 3). By contrast, resorting to the equi-
molar complex MeLi/LiBr -in ether) reduces the ee to
Entry
RLi
1m/RLi/TolCHO Yield -%) ee -%)
1
2
3
4
5
6
MeLi
BuLi
MeLi
1:2.2:1
1:2.2:1
1.5:2.5:1
100
81
8068 -
100
77
58 -R)
70- R)
R)
5 -R)
0
58 -S)
MeLi1LiBr -1:1) 1:2.2:1
1:2.2:1
1:2.2:1
t-BuLi
PhLi
75

K. Flinois et al. / Tetrahedron 58 12002) 4707±4716
4713
help to develop enantioselective versions of reactions
involving organolithium reagents. The results we present
in this paper provide an evaluation of their applicability to
two families of reaction, the EP and the asymmetric nucleo-
philic alkylation of aldehydes. In the ®rst category, the
putative 3-AP complexes turned out to behave as relatively
modest inductors -ee #40%), probably because of the
competition between the amide and the enolate for the
incoming proton. In the second class, the aggregates seem
to react ef®ciently with the o-tolualdehyde and give access
to the expected alcohols with ee in <70%. The conditions
tested led us to the conclusion that the rapid formation of the
amide-alkyllithium complex should be favored by direct
addition of the whole butyllithium to the amine -protocol
A). Further synthetic developments need to be brought to
this chemistry of non-covalent aggregates that has already
found very promising applications21 and seems to be extend-
ible to bimetallic systems such as lithium amide/organozinc
complexes.30 Developments to new reagents such as func-
tionalized vinyllithium compounds as well as the theoretical
analysis of the ultimate condensation step taking place after
the aggregate-aldehyde docking are currently under investi-
gation.
The spectroscopic characteristics of this intermediate are as
follows: 1H NMR -300 MHz, CDCl3) 0.78 -t, 3H,
Jˆ6.1 Hz), 1.58±1.36 -hex, 2H, Jˆ5.7 Hz), 1.70±1.55 -m,
1H), 2.70±1.95 -m, 4H), 2.84±2.72 -m, 1H), 3.11 -m, 2H,
Jˆ9.8 Hz), 4.12 -m, 1H), 5.04 -s, 2H), 5.29 -broad d, NH,
Jˆ7.5 Hz), 7.28 -s, 5H); 13C NMR: 11.5, 23.2, 23.8, 40.6,
41.7, 45.4, 58.3, 66.9, 126.2, 128.3, 128.9, 137.0, 156.1.
CIMS -CH4) m/z -relative intensity): 291 -M1C2H51; 23);
263 -MH1; 100%). Anal. calcd for C15H23N2O2: C, 68.67;
H, 8.45; N, 10.68. Found: C, 68.18; H, 8.48; N, 11.67.
25
[a]D ˆ24.1 -cˆ0.02; dioxane).
The Z-protecting group was removed by hydrogenolysis:
palladium hydroxide -20% on carbon, 0.4 g, 2.8 mmol)
was stirred in absolute ethanol -70mL) for 30min. A
solution of the above carbamate -2.0g, 7.6 mmol in 5 mL
ethanol) was then introduced and the stirring continued for
4 h. The catalyst was ®ltered over a celite pad and the
solvent evaporated at 08C. A chromatography was then
performed over silica gel -eluting with CH2Cl2/MeOH,
85:15). Aminopyrrolidine 1c was recovered as a colorless
oil -Ydˆ99.5%).
1H NMR -300 MHz, CDCl3) d 0.93 -t, Jˆ9.0Hz, 3H), 1.21
-hex, Jˆ8.0Hz, 2H), 1.57 -m, 1H), 2.11±2.31 -m, 1H), 2.39
-m, 1H), 2.29±2.48 -m, 1H), 2.66±2.81 -m, 3H), 3.06 -dd,
Jˆ9.0, 8.1 Hz, 1H), 3.39±3.48 -m, 1H), 4.60 -bs, 2H); 13C
NMR -75 MHz, CDCl3) d 12.4, 22.1, 35.3, 51.2, 53.6, 58.8,
64.1; EIMS m/z -relative intensity) 128 -M1, 21), 99 -74),
84 -100), 57 -48); IR -®lm, NaCl) nmax -cm21) 3350, 3280,
2968. Anal. calcd for C7H16N2: C, 65.57; H, 12.58; N, 21.85.
Found: C, 65.22; H, 12.61; N, 22.17.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a Bruker
DPX300 spectrometer operating at 300 and 75 MHz,
respectively, or on a Bruker Avance DMX 500 spectrometer
operating at 500 MHz -1H) and 125 MHz -13C). IR spectra
were obtained on a Perkin±Elmer 16PC FTIR spectrometer.
The mass spectra were recorded on a Jeol AX500 apparatus,
under electron impact conditions -EIMS) at 70eV ionizing
potential; isobutane -t-BuH) was used for chemical ioniza-
tion -CIMS). Melting points were taken on a Reichert
microscope apparatus. Optical rotations, [a]D, were
measured on a Perkin±Elmer polarimeter 341 spectrometer
in quartz cells -dˆ1 dm), using Na and Hg beams.
4.1.3. 1-Propyl-3-.S)-benzylaminopyrrolidine 1b. To the
primary aminopyrrolidine 1c -1.28 g, 10mmol) in solution
in dry ether -25 mL) was added freshly distilled benzalde-
hyde -1.38 g, 13 mmol) and the mixture stirred overnight at
Ê
room temperature over activated 4 A molecular sieves. The
reaction was followed by GC and, upon completion, the
solution was ®ltered and directly added, under argon, over
a suspension of LiAlH4 -722 mg, 19 mmol) in THF at 08C.
The reaction was stirred at room temperature for 4 h and
then quenched successively with water -0.6 mL), 4 M
NaOH -0.6 mL) and ®nally water -1.9 mL). The solids
were ®ltered over a celite pad that was then washed with
CH2Cl2 and AcOEt. The solvents were evaporated, and the
oily residue redissolved in ether and washed with hydro-
chloric acid -1 M, 100 mL). This aqueous phase was
extracted with AcOEt before being neutralized -NaOH 4N
until pH gets basic) and reextracted by AcOEt then
CH2Cl2. A ¯ash chromatography was then run on silica
gel -eluant: petroleum ether/AcOEt/NEt3, 98.5:1.0:0.5) to
4.1.1. 3-Aminopyrrolidines 1. Only 3-AP 1b, c, e, f are
new compounds and were prepared following procedures
adapted from Ogura10f and Moon.10g The ee of these
diamines have been checked by 19F NMR spectroscopy
after derivatisation11 with chiral a-¯uoro-a-phenylacetic
acid.31
4.1.2. 1-Propyl-3-.S)-aminopyrrolidine 1c. This primary
amine has been obtained from -S)-2-benzyloxycarbonyl-
amino-1,4-dimethanesulfonyloxybutane, prepared from
dimethyl Z-asparaginate as described in Ref. 10f,g. This
dimesylate -3.95 g, 10mmol) was added to neat n-propyl-
amine -5.9 g, 100 mmol), the mixture warmed to 458C and
stirred for 3 h. The excess propylamine was then evaporated
under vacuum and the oily residue dissolved in ethyl acetate
-100 mL). The solution was washed with water -50 mL),
dried -MgSO4) then evaporated. The N-propyl-3-benzyl-
oxycarbonylaminopyrrolidine thus obtained was puri®ed
by ¯ash chromatography on silica gel -eluting with
CH2Cl2/MeOH, 90:10) and obtained as a yellow oil
-Ydˆ53%).
provide aminopyrrolidine 1b as
-Ydˆ88%).
a pale yellow oil
1H NMR -300 MHz, CDCl3) d 1.06 -t, Jˆ7.1 Hz, 3H),
1.49±1.65 -m, 1H), 2.01±2.19 -m, 2H), 2.32±2.68 -m,
7H), 2.73 -dd, Jˆ9.8, 6.2 Hz, 1H), 3.25±3.40-m, 1H),
3.72 -s, 2H), 7.27±7.49 -m, 5H); 13C NMR -75 MHz,
CDCl3) d 14.8, 26.0, 32.9, 53.8, 54.8, 57.5, 60.6, 61.3,
126.6±128.6, 141.1; CIMS -t-BuH) m/z 219 -MH1). Anal.
calcd for C14H22N2: C, 77.01; H, 10.16; N, 12.83. Found: C,
76.82; H, 10.06; N, 13.12.

4714
K. Flinois et al. / Tetrahedron 58 12002) 4707±4716
4.1.4. 1-.R)-a-Methyl-benzyl-3-.S)-aminopyrrolidine 1e.
This primary amine has been obtained from -S)-2-benzyl-
oxycarbonylamino-1,4-dimethanesulfonyloxybutane, pre-
pared from dimethyl Z-asparaginate as described in Ref.
10f,g. To a sonicated solution of this dimesylate -3.00 g,
7.6 mmol) in dioxane -16 mL) was added neat commercial
-R)-a-methylbenzylamine -1 g, 1.07 mL, 8.3 mmol). A
light precipitate formed that slowly redissolved at room
temperature. When the solution cleared off, the temperature
was raised to 408C and the solution stirred for 4 days. The
dioxane was then evaporated and the oily residue
redissolved in ether -90mL), dried -MgSO 4) and
evaporated before being chromatographed over silica gel
-eluant CH2Cl2/MeOH, 90:10) providing 1--R)-a-methyl-
benzyl-3--S)-benzyloxycarbonylaminopyrrolidine in 54%
yield.
calcd for C20H24N2O2: C, 74.05; H, 7.46; N, 8.63. Found: C,
73.76; H, 7.47; N, 8.86. [a]D ˆ26.3 -cˆ0.02; dioxane).
1
1--S)-a-methyl-benzyl-3--S)-aminopyrrolidine 1f H NMR
-300 MHz, CDCl3) d 1.23 -d, Jˆ6.4 Hz, 3H), 1.44 -m, 1H),
2.00±2.16 -m, 2H), 2.49 -m, 3H), 3.00 -q, Jˆ6.4 Hz, 1H),
4.08 -m, 1H), 4.43 -bs, 2H), 7.18 -s, 5H); 13C NMR
-75 MHz, CDCl3) d 24.0, 32.5, 50.6, 51.3, 65.7, 67.0,
127.5, 128.5, 128.9, 156.4. Anal. calcd for C12H18N2: C,
75.74; H, 9.53; N, 14.72. Found: C, 74.62; H, 9.51; N, 15.89.
25
4.1.6.
N-.tert-Butoxycarbonyl)-4-methylsulfonyloxy-
piperidine 15. To a solution of N--tert-butoxycarbonyl)-4-
hydroxypiperidine -2.0g, 9.94 mmol) in dichloromethane
-20mL), pyridine -3.84 mL, 48 mmol, 4.8 equiv.),
methanesulfonyl chloride -1.80g, 15.65 mmol, 1.6 equiv.)
and catalytic amount of 4-dimethylaminopyridine were
added at 08C. After being stirred for 86 h at room tempera-
ture, the solution was concentrated and ethyl acetate
-40mL) were added. An insoluble salt precipitated and
was ®ltered. The remaining solution was concentrated
then puri®ed by chromatography on silica gel -heptane/
ether, 50:50) to give 15 as a white solid: -2.57 g, 93%):
1H NMR -500 MHz, CDCl3) d 1.49 -s, 9H), 1.83 -m, 2H),
1.99 -m, 2H), 3.06 -s, 3H), 3.33 -m, 2H), 3.73 -m, 2H), 4.91
-m, 1H); 13C NMR -125 MHz, CDCl3) d 27.4, 30.6, 37.8,
39.5, 76.6, 79.0, 153.6; IR -®lm, NaCl) nmax -cm21) 1700,
1180; EIMS m/z -relative intensity) 201 -4), 127 -17), 110
-9), 84 -42).
The spectroscopic characteristics of this intermediate are as
follows: 1H NMR -300 MHz, CDCl3) d 1.33 -d, 3H,
Jˆ6.8 Hz), 1.54±1.45 -m, 1H), 2.26±2.11 -m, 2H), 2.76±
2.45 -m, 2H), 3.05 -m, 1H), 3.35 -q, 1H, Jˆ6.7 Hz), 4.33 -m,
1H), 5.19 -s, 2H), 5.63 -broad d, NH, Jˆ8.5 Hz), 7.42±7.14
-m, 10H); 13C NMR -75 MHz, CDCl3) d 23.3, 32.5, 50.9,
52.5, 59.7, 65.8, 67.4, 127.1, 127.3, 127.5, 128.5, 128.8,
128.9, 140.4, 145.3, 156.4. CIMS -t-BuH) m/z -relative
intensity): 367 -M1C3H71; 5%); 325 -MH1; 100%). Anal.
calcd for C20H24N2O2: C, 74.05; H, 7.46; N, 8.63. Found: C,
25
73.92; H, 7.38; N, 7.54. [a]D ˆ16.4 -cˆ0.02; dioxane).
In this case, the presence of the a-methylbenzyl substituent
required a selective hydrogenolysis of the Z-protecting
group which can be achieved using the Pd/cyclohexadiene
method.32 Thus, the above carbamate -324 mg, 1 mmol) was
disolved in absolute ethanol -10mL) before palladium -10%
on carbon, 324 mg), then commercial cyclohexadiene
-800 mg, 10 mmol) were added. This mixture was stirred
for 1±24 h at room temperature -depending on catalyst
batch) under argon and completion of the reaction checked
by TLC. Aminopyrrolidine 1e was ®nally obtained after a
¯ash chromatography on silica gel -eluant CH2Cl2/MeOH,
90:10) as a light-yellow oil -Ydˆ95%).
1H NMR -300 MHz, CDCl3) d 1.40-d, Jˆ6.5 Hz, 3H), 1.51
-m, 1H), 2.04±2.50 -m, 3H), 2.67±2.97 -m, 2H), 3.41 -q,
Jˆ6.5 Hz, 1H), 4.04 -m, 3H), 7.21±7.40 -s, 5H); 13C NMR
-75 MHz, CDCl3) d 22.8, 33.2, 50.9, 51.9, 66.5, 68.1, 128.5,
129.6, 130.0, 157.5; CIMS -t-BuH) m/z -relative intensity)
233 -M1C3H71, 12); 191 -MH1; 100). Anal. calcd for
C12H18N2: C, 75.74; H, 9.53; N, 14.72. Found: C, 75.56;
H, 9.33; N, 15.12.
4.1.7. N-.tert-Butoxycarbonyl)-4-.10-.R)-phenylethyl)-
aminopiperidine 16. A mixture of N--tert-butoxycar-
bonyl)-4-methylsulfonyloxypiperidine
5.63 mmol) and -S)-a-methylbenzylamine
15
-1.58 g,
-5 mL,
38.8 mmol, 6.9 equiv.) was heated at 1158C for 24 h.
After cooling to room temperature, ethyl acetate -60mL)
and 4 M NaOH -10mL) were added and stirred vigorously.
The aqueous phase was extracted with ethyl acetate
-2£30mL) and the organic phases were combined and
washed with water. The concentrated residue was diluted
with methanol -5 mL) and a solution of l--1)-tartaric acid
-0.95 g, 6.27 mmol) in methanol -25 mL) was added. The
solution was kept at room temperature for one day and
®ltrated. The ®ltrate was concentrated and ether -10mL)
and 1N HCl -10mL) were added and stirred vigorously
for 15 min. The organic phase was extracted with water
-15 mL) and the aqueous phases were combined and washed
with ethyl acetate -3£5 mL). Sodium hydrogen carbonate
was slowly introduced followed by a few drops of 4N
aqueous sodium hydroxide. The aqueous solution was
extracted with dichloromethane -3£10mL). The organic
layer was collected, dried -MgSO4), ®ltered and concen-
4.1.5. 1-.S)-a-methyl-benzyl-3-.S)-aminopyrrolidine 1f.
The same above two-step procedure was followed.
1
trated to give 16 as a pale yellow oil -0.52 g, 30%): H
NMR -500 MHz, CDCl3) d 1.32 -d, Jˆ6.6 Hz, 3H), 1.41
-s, 9H), 1.64 -m, 2H), 1.89 -m, 2H), 2.42 -m, 1H), 2.63 -m,
2H), 3.94 -q, Jˆ6.6 Hz, 1H), 3.95 -m, 2H), 7.30-m, 5H);
13C NMR -125 MHz, CDCl3) d 23.8, 27.4, 30.9, 32.1, 41.7,
51.1, 53.6, 78.3, 125.5, 126.0, 127.5, 153.7; IR -®lm, NaCl)
nmax -cm21) 3317, 1694; EIMS m/z -relative intensity) 247
-19), 143 -18), 105 -100).
1--S)-a-methylbenzyl-3--S)-benzyloxycarbonylaminopyrro-
lidine -Ydˆ53%, yellow solid): 1H NMR -300 MHz,
CDCl3), d 1.35 -m, 4H), 1.95 -m, 1H), 2.65±2.18 -m,
3H), 3.01±2.99 -m, 1H), 4.02 -q, 1H, Jˆ6.3 Hz), 4.34 -m,
1H), 5.11 -broad d, NH, Jˆ8.3 Hz), 5.22 -s, 2H), 7.42±7.14
-m, 10H); 13C NMR -75 MHz, CDCl3) d 23.6, 32.7, 50.7,
51.0, 60.0, 66.3, 67.0, 127.1, 127.3, 127.5, 128.5, 128.8,
128.9, 137.9, 146.1, 156.1. CIMS -t-BuH) m/z -relative
intensity) 367 -M1C3H71; 7%); 325 -MH1; 100%). Anal.
4.1.8. N-Methyl-4-.10-.R)-phenylethyl)aminopiperidine
17. A solution of N--tert-butoxycarbonyl)-4--10--R)-phenyl-

K. Flinois et al. / Tetrahedron 58 12002) 4707±4716
4715
ethyl)aminopiperidine 16 -0.62 g, 2.04 mmol) in dry THF
-30mL) was added over 20min to a suspension of lithium
aluminum hydride -0.39 g, 10.18 mmol, 5 equiv.) in freshly
distilled THF -20mL), placed under nitrogen atmosphere at
08C. The solution was stirred at room temperature for 4 h
then heated at 608C for 1 h. After cooling at 08C, the excess
of LAH was hydrolyzed by successive addition of cold
water -0.8 mL), 4N aqueous sodium hydroxide -0.8 mL)
and cold water -1.0mL). The white precipitate was ®ltered
on celite and washed with dichloromethane -10mL). The
®ltrate was concentrated and the residue was dissolved in
ether -10mL). 1N aqueous hydrochloric acid -10mL) was
added and the solution was stirred at room temperature for
15 min. The acidic aqueous layer was extracted and sodium
hydrogen carbonate was slowly added until pH 9. The
medium was then extracted with dichloromethane
-3£10mL). The organic layer was collected, dried
-MgSO4), ®ltered and concentrated to give 17 as a colorless
butyllithium complex -0.2 mmol in 3 mL solution) was
prepared following one of the three protocols A, B or C
described in the results and discussion section, freshly
distilled o-tolualdehyde in 0.5 mL dry THF solution was
added slowly at 2788C. After stirring 1 h at the same
temperature the reaction was quenched by 1N HCl and
extracted with Et2O -3£10mL). The extracts were dried
and concentrated under reduced pressure. Flash chromato-
graphy -heptane/Et2O, 80:20) of the residue on silica gel
gave pure sec-alcohol. The benzylic alcohols obtained are
all described in the literature.7b,35 Their enantiomeric
excesses were determined by Eu-hfc)3 chiral-shift NMR
experiments and con®gurations were determined by
comparing the optical rotation with the literature data.
Acknowledgements
1
oil -0.33 g, 73%): H NMR -500 MHz, CDCl3) d 1.34 -d,
Y. Y. acknowledges the Haute and Basse-Normandie inter-
regional funds -PUNCH program) for a post-doctoral grant.
We also wish to thank Professor Marie-Claire Lasne and Dr
Jacques Rouden -ISMRA, Caen) for providing us with
samples of diamine 1i, j, as well as Dr Claude Giessner-
Jˆ6.6 Hz, 3H), 1.37±1.44 -m, 2H), 1.70-m, 1H), 1.88 -m,
2H), 1.94 -m, 1H), 2.22 -s, 3H), 2.30-m, 1H), 2.77 -m, 2H),
3.96 -q, Jˆ6.6 Hz, 1H), 7.32 -m, 5H); 13C NMR -125 MHz,
CDCl3) d 23.8, 27.4, 30.9, 32.1, 41.7, 51.0, 53.0, 78.3, 125.5,
126.0, 127.5, 153.7; IR -®lm, NaCl) nmax -cm21) 3317; EIMS
m/z -relative intensity) 218 -M1, 20), 91 -100).
Â
Prettre -Universite Paris VI), Dr Catherine Fressigne, Dr
Hassan Oulyadi and Stephanie Desjardins -Universite de
Â
Â
Â
Rouen) for very helpful discussions.
4.2. General procedure for the enantioselective
protonation of 2-methyltetralone lithium enolate by
acetic acid
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8
following the methodology
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A typical run was as follows. After the 3-AP lithium amide/

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K. Flinois et al. / Tetrahedron 58 12002) 4707±4716
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