Organocatalytic enantioselective synthesis of highly functionalized polysubstituted pyrrolidines

Article abstract of DOI:10.1002/chem.200800788

The organocatalytic conjugate addition of different aldehydes to α-nitroacrolein dimethyl acetal, generating the corresponding highly functionalized nitroaldehydes in high yields and with high stereoselectivities, has been studied in detail. These transformations have been achieved by using both readily available starting materials in a 1:1 ratio as well as commercially available catalysts at a 10 mol % catalyst loading. Furthermore, a very short and efficient protocol has been devised for the preparation of highly enantioenriched pyrrolidines containing two or three contiguous stereocenters starting from the obtained Michael adducts. 3,4-Disubstituted pyrrolidines have been obtained in a single step by Znmediated chemoselective reduction of the nitro group followed by intramolecular reductive amination, and trisubstituted homoproline derivatives have been prepared by means of an olefination reaction and a cascade process involving chemoselective reduction of the nitro group followed by a fully diastereoselective intramolecular azaMichael reaction.

Full text of DOI:10.1002/chem.200800788

FULL PAPER
DOI: 10.1002/chem.200800788
Organocatalytic Enantioselective Synthesis of Highly Functionalized
Polysubstituted Pyrrolidines
Nerea Ruiz, Efraím Reyes, Jose L. Vicario,* Dolores Badía,* Luisa Carrillo, and
Uxue Uria[a]
Abstract: The organocatalytic conju-
gate addition of different aldehydes to
b-nitroacrolein dimethyl acetal, gener-
ating the corresponding highly func-
tionalized nitroaldehydes in high yields
and with high stereoselectivities, has
been studied in detail. These transfor-
mations have been achieved by using
both readily available starting materials
in a 1:1 ratio as well as commercially
available catalysts at a 10 mol% cata-
lyst loading. Furthermore, a very short
and efficient protocol has been devised
for the preparation of highly enan-
tioenriched pyrrolidines containing two
or three contiguous stereocenters start-
ing from the obtained Michael adducts.
3,4-Disubstituted pyrrolidines have
been obtained in a single step by Zn-
mediated chemoselective reduction of
the nitro group followed by intramolec-
ular reductive amination, and trisubsti-
tuted homoproline derivatives have
been prepared by means of an olefina-
tion reaction and a cascade process in-
volving chemoselective reduction of
the nitro group followed by a fully dia-
stereoselective intramolecular aza-
Michael reaction.
Keywords: asymmetric synthesis ·
Michael addition · organocatalysis ·
pyrrolidines
catalysis
·
stereoselective
Introduction
gether with the commercial availability of many of the cata-
lysts employed, has contributed to the rapid growth of this
methodology in the field of organic synthesis.
In recent years, organocatalysis has emerged as an excellent
tool for the asymmetric synthesis of optically active com-
pounds through operationally simple and environmentally
friendly methodologies.[1] Many research groups worldwide
have shown that one of the main advantages of this method-
ology is that relatively complex molecules can be easily pre-
pared starting from readily available starting materials
under efficient stereochemical control. The fact that most of
the organocatalytic reactions reported tolerate the presence
of water and oxygen, which allows them to be performed
without having to use dried solvents or inert atmosphere, to-
Aparticular approach in this area involves the use of sec-
ondary amines as chiral catalysts. In this context, many
methodologies have appeared for carrying out the a-func-
tionalization, b-functionalization, and g-functionalization of
carbonyl compounds (aldehydes and/or ketones). As has
been demonstrated, the catalytic systems necessary for the
aforementioned transformations are generated through the
activation of carbonyl compounds by the formation of an
enamine,[2] iminium ion,[3] dienamine,[4] or iminium radical[5]
intermediate. In these transformations, various types of new
bonds can be formed, depending on both the nucleophile
and electrophile components involved in the reaction. Thus,
many successful methodologies have been reported for the
À
À
À
À
À
stereocontrolled formation of C C, C N, C O, C S, C Se,
[a] N. Ruiz, Dr. E. Reyes, Prof. J. L. Vicario, Prof. Dr. D. Badía,
Prof. L. Carrillo, U. Uria
À
and C halogen bonds. Furthermore, the possibility of utiliz-
ing differently substituted or conveniently functionalized
starting materials has led to the synthesis of many optically
active compounds with broad spectra of substitution pat-
terns, increasing the interest of these adducts for further
modification in so-called diversity-oriented synthesis
(DOS).[6] Surprisingly, despite the already mentioned evi-
dent practical advantages of asymmetric organocatalysis,
there have been relatively few literature reports concerning
Departamento de Química Orgµnica II
Facultad de Ciencia y Tecnología
Universidad del País Vasco/
Euskal Herriko Unibertsitatea
P.O. Box 644, 48080 Bilbao (Spain)
Fax : (+34)94-601-5454
E-mail: joseluis.vicario@ehu.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800xxx.
Chem. Eur. J. 2008, 14, 9357 – 9367
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9357

the direct application of this methodology to the synthesis
of natural or pharmaceutically active products.[7]
the literature a large excess of the aldehyde along with a
20–30 mol% catalyst loading were necessary in order to
obtain complete conversion in this type of transformation.[14]
In this context, the organocatalytic Michael reaction has
become a powerful tool for the stereocontrolled synthesis of
chiral compounds containing two or more stereogenic cen-
ters.[8] Aparticularly interesting variant of this transforma-
tion is the chiral amine-catalyzed conjugate addition of alde-
hydes to nitroalkenes,[9,10] in which the obtained adducts
constitute versatile molecules that can be transformed into
many useful chiral compounds by exploiting the intrinsic re-
activity of the formyl moiety and, more especially, the nitro
group.[11] However, although this transformation has been
extensively studied by a number of research groups, the use
of functionalized starting materials suitably predisposed for
the preparation of polyfunctionalized compounds as inter-
mediates for the synthesis of biologically relevant molecules
still remains rather unexplored.[12]
Related to this topic, previous results obtained by our re-
search group (Scheme 1) have demonstrated that commer-
cially available l-prolinol can be used as an excellent orga-
nocatalyst in the conjugate addition of structurally diverse
aldehydes to b-nitroacrolein dimethyl acetal (a functional-
ized nitroalkene).[13] The reactions proceed with good yields
and enantioselectivities with a wide range of different alde-
hyde donors and, remarkably, require a 1:1 molar ratio of
nucleophile/electrophile and a rather low substrate/catalyst
ratio (up to 1 mol%). In this context, the use of b-nitroacro-
lein dimethyl acetal as a Michael acceptor represents a real
advantage in this reaction because its high electrophilicity
allows complete consumption of the starting aldehyde donor
reagent in the presence of a small amount of catalyst. It has
to be pointed out that in many of the examples described in
Scheme 1. l-Prolinol-catalyzed Michael reaction of aldehydes and b-ni-
troacrolein dimethyl acetal developed by our group.
On the other hand, several limitations were reported in
the preliminary studies, such as the long reaction times re-
quired to achieve synthetically useful yields and, more sig-
nificantly, the low diastereoselectivity provided by the cata-
lyst, which resulted in the final adducts being isolated as
mixtures of syn/anti diastereoisomers in variable propor-
tions. In this paper, we wish to present a detailed study
aimed at improving this transformation, which has been es-
pecially directed towards overcoming the aforementioned
limitations found in our first study. Furthermore, we have
also explored the synthetic possibilities of the obtained poly-
functionalized adducts, which has led to a direct and effi-
cient synthetic protocol for the stereocontrolled preparation
of substituted pyrrolidines containing two or three contigu-
ous stereogenic centers.
Results and Discussion
We started by trying to improve our recently reported con-
ditions for the Michael addition of aldehydes to b-nitroacro-
lein dimethyl acetal (2) using the reaction between propanal
(1a) and 2 as a model system (Scheme 2). In our previous
report, we had observed that prolinol (3a) was a very effi-
cient catalyst for the reaction, but other simple amino alco-
hols such as a,a-diphenylprolinol (3b) and indolinemetha-
nol (3c) as well as the a-amino acid 2-indolinecarboxylic
acid (3d) were also able to promote the reaction, leading to
higher enantioselectivities compared to those furnished by
other commercially available chiral amines tested. We there-
fore decided to reinvestigate the use of these catalysts under
different reaction conditions (Table 1), comparing the results
with those obtained under the optimal conditions found in
our preliminary report, which involved stirring a solution of
the requisite aldehyde and b-nitroacrolein dimethyl acetal in
iPrOH at RT using 3a (10 mol%) as catalyst (entry 1). In all
cases, we carried out the reaction using equimolar amounts
of nitroalkene acceptor and aldehyde donor.
Abstract in Spanish: Se ha estudiado detalladamente la reac-
ción de adición conjugada organocatalítica enantioselectiva
de distintos aldehídos con el dimetil acetal de b-nitroacrolei-
na, obteniØndose los aductos correspondientes con excelente
rendimiento y diastereo- y enantioselectividad. Esta transfor-
mación se lleva a cabo empleando cantidades equimolares de
aldehído y nitroalqueno así como aminas secundarias quira-
les disponibles comercialmente como catalizadores en canti-
dad de 10% molar. Ademµs, se ha puesto a punto un proto-
colo sencillo y eficaz para la síntesis de pirrolidinas enan-
tioenriquecidas conteniendo dos o tres estereocentros contí-
guos partiendo de los aductos Michael obtenidos. Así, se han
preparado pirrolidinas 3,4-disustituidas desde sus precursores
nitroaldehídicos a travØs de un proceso en cascada consisten-
te en la reducción quemoselectiva del grupo nitro seguido de
una reacción de aminación reductora intramolecular. Del
mismo modo, partiendo de los mismos precursores, se han
preparado derivados de homoprolina con tres centros este-
reogØnicos mediante una reacción de Wittig seguida de un
proceso en cascada de reducción/reacción aza-Michael intra-
molecular, cursando esta fflltima con total diastereoselectivi-
dad.
As can be seen in Table 1, when a-amino acid 3d was em-
ployed as catalyst, a strong solvent effect was found. Thus,
no reaction occurred in a protic solvent such as iPrOH
(entry 2), while the use of THF furnished the Michael
adduct 4a in higher yield, and with higher diastereo- and
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Organocatalytic Michael Additions
FULL PAPER
as well as an improvement in the diastereoselectivity (syn/
anti 9:1). As was observed with catalyst 3c, the inclusion of
2 equiv of water as an additive (entry 15) resulted in a sig-
nificant enhancement in the yield of the reaction (62% in
just 24 h). In all cases, catalyst 3b provided an excellent
degree of enantioselection.
As a remarkable feature, it has to be pointed out that the
use of indoline-containing catalysts 3c and 3d furnished the
final adduct 4a with opposite absolute configuration com-
pared to the reaction catalyzed by 3a or 3b. This can be
seen as another advantageous aspect of this methodology
because all the catalysts employed in this study belong to
the l-series of the corresponding a-amino acids from which
they are obtained, which is the more abundant enantiomer
usually present in natural sources.
We anticipated that, as previously mentioned, the forma-
tion of inactive oxazolidine by-products could account for
the lower activity and might therefore explain the long reac-
tion times required to attain high yields of the Michael
adduct, even in the presence of water as an additive. The
possibility of oxazolidine formation no longer exists when
the alcohol moiety is modified in the form of a silyl or alkyl
ether and, moreover, the introduction of bulky trialkylsilyl
substituents would result in additional steric requirements
during the formation of the new stereocenters and therefore
lead to an improvement in diastereo- and enantioselectivity.
In addition, O-silylated derivatives would be expected to ex-
hibit enhanced solubility in organic solvents as compared to
their amino alcohol counterparts, which would also result in
an improved catalyst performance. For these reasons, we de-
cided to evaluate the use of prolinol ether derivatives 3e
and 3 f as potentially more active catalysts than the parent
amino alcohol 3a (Table 2). We also extended our study to
diphenylprolinol silyl ether 3g, which has been successfully
Scheme 2. Catalysts tested in the Michael reaction of propanal and b-ni-
troacrolein dimethyl acetal.
enantioselectivity, than was observed for the parent proli-
nol-catalyzed reaction (cf. entries 3 and 1), although a very
long reaction time was required. Changing to the more
polar solvent DMF (entry 4) resulted in a significant de-
crease in the enantioselectivity. No improvement was ob-
served when we employed acid additives in the reaction,
which are known to help in the formation of the intermedi-
ate enamine nucleophile in the catalytic cycle (entries 5 and
6). We next proceeded to evaluate indolinemethanol 3c as
catalyst, observing that this catalyst generally provided
better yields and stereoselectivities than 3d. The reaction in
iPrOH afforded 4a in modest yield (entry 7), and when
THF was employed as solvent a very long time was required
to attain a similar yield of the adduct (entry 8). Carrying out
the reaction in DMF led to a moderate yield of the Michael
adduct with good diastereo- and enantioselectivity (entry 9),
and a noticeable increase in the yield was observed when
the reaction was carried out in the presence of excess alde-
hyde (entry 10) or when a Brønsted acid additive was incor-
porated into the reaction design (entry 11). Interestingly, the
addition of 2 equiv of water to the reaction mixture also re-
sulted in a slight increase in the yield, without having any
negative effect on the stereoselectivity (entry 12).[15] This
might be attributed to the
action of water in preventing
the formation of stable oxazo-
lidine by-products between
either of the aldehydes present
in the reaction medium (the
starting material or the final
adduct) and the amino alcohol
catalyst that would eventually
lead to catalyst consumption.
Finally, we evaluated the use
of a,a-diphenylprolinol 3b as
catalyst for this transformation,
and again observed that very
long reaction times were re-
quired in THF in order to ach-
Table 1. Screening of the organocatalytic Michael reaction of propionaldehyde with nitroacrolein dimethyl
acetal in the presence of amino acid 3d or amino alcohols 3a–c.[a]
Entry
Solvent
Catalyst
Additive
t [h]
Yield [%][b]
syn/anti[c]
ee [%][d]
1
2
3
4
5
6
7
8
iPrOH
iPrOH
THF
DMF
DMF
DMF
iPrOH
THF
DMF
DMF[g]
DMF
DMF
THF
3a
3d
3d
3d
3d
3d
3c
3c
3c
3c
3c
3c
3b
3b
3b
–
–
–
–
12
168
312
72
168
72
72
312
72
72
72
72
240
168
24
74
<5
76
19
<5
18
20
21
55
64
66
62
16
35
62
1.7:1
–
3.5:1
2.2:1
–
3.6:1
20:1
3.3:1
9.8:1
7.4:1
8.2:1
9.6:1
2.1:1
9.0:1
10:1
80
–
À85[e]
À57[e]
–
p-TsOH[f]
Ph2CHCO2H[f]
À52[e]
À96[e]
À88[e]
À91[e]
À93[e]
À96[e]
À98[e]
92
–
–
–
–
9
10
11
12
13
14
15
Ph2CHCO2H[f]
H2O[h]
–
–
DMF
DMF
98
98
H2O[h]
ieve
a modest yield of 4a
[a] Reaction carried out on a 1.00 mmol scale using 1 equiv each of 1a and 2 with 10 mol% of catalyst in the
specified solvent and at RT. [b] Isolated yield after flash column chromatography. [c] Determined by NMR
analysis of the reaction mixture. [d] Calculated from chiral GC data after transformation to the corresponding
acetal derived from propane-1,3-diol. [e] The opposite enantiomer was obtained. [f] 10 mol% of the additive
was added to the reaction mixture. [g] Reaction carried out with 5 equiv of aldehyde. [h] Reaction carried out
in the presence of 2 equiv of water.
(entry 13), while the use of
DMF as solvent (entry 14) al-
lowed a similar yield of the Mi-
chael adduct to be obtained in
a much shorter reaction time,
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J. L. Vicario, D. Badía, et al.
Table 2. Screening of the organocatalytic Michael reaction of propionaldehyde with nitroacrolein dimethyl
should release the Michael
adduct 4a and the free catalyst
3g, which would be ready to
participate in a subsequent cat-
alytic cycle. The key to the suc-
cess of catalyst 3g is the effect
exerted by the bulky diphe-
nyl(trimethylsilyloxy)methyl
acetal in the presence of catalysts 3e–g.[a]
substituent at the pyrrolidine
ring, which results in very effi-
cient geometry control of the
enamine intermediate together
with an excellent ability to dis-
criminate between its diaste-
reotopic faces. The observed
syn-diastereoselectivity may be
rationalized in terms of an acy-
clic synclinal transition state,
as proposed by Seebach and
Entry
Solvent
Catalyst
Additive
t [h]
Yield [%][b]
syn/anti[c]
ee [%][d]
1
2
3
4
5
THF
THF
THF
DMF
DMF
3e
3 f
3g
3g
3g
–
–
–
–
24
24
72
72
24
81
75
75
79
86
1.2:1
1:1.4
4.5:1
5.8:1
6.0:1
68
64
97
98
>99
H2O[e]
[a] Reaction performed on a 1.00 mmol scale using 1 equiv each of 1a and 2 with 10 mol% of catalyst in the
specified solvent and at RT. [b] Isolated yield after FC. [c] Determined by NMR spectrometric analysis of the
reaction mixture. [d] Calculated from chiral GC data after transformation to the corresponding acetal derived
from propane-1,3-diol. [e] Reaction performed in the presence of 2 equiv of water.
employed as a very efficient organocatalyst in other trans-
formations.[16]
As can be seen in Table 2, modification of the free hy-
droxyl group in prolinol with a methyl or silyl ether led to a
more active catalyst, as was expected, providing better
yields of the Michael adduct in shorter reaction times (en-
tries 1 and 2), although key parameters such as the diaster-
eo- and enantioselectivity were adversely affected by these
structural changes in the catalyst. On the other hand, the
3g-catalyzed reaction (entry 3) proceeded much more rapid-
ly than the parent reaction catalyzed by amino alcohol 3b
(cf. entry 3 in Table 2 with entry 13 in Table 1), while main-
taining a high level of stereoselectivity, although the results
were not much better than those obtained with simple l-
prolinol 3a in our preliminary study (see entry 1 in Table 1).
Changing the solvent to DMF did not significantly improve
the performance of this catalyst (entry 4 in Table 2), but, to
our delight, when we carried out the reaction in the pres-
ence of 2 equivalents of water, a good yield of the desired
Michael adduct 4a was obtained in a much shorter time
(24 h), while maintaining high diastereoselectivity and excel-
lent enantioselectivity.
Scheme 3. Optimal conditions found for the organocatalytic enantioselec-
tive Michael reaction between propanal and b-nitroacrolein dimethyl
acetal. a) 3g (10 mol%), H2O (2 equiv), DMF, RT, 24 h. b) 3c
(10 mol%), H2O (2 equiv), DMF, RT, 72 h.
Therefore, after analyzing all of the results obtained
during the catalyst screening process, it can be stated that
we have found a suitable and improved synthetic protocol
for carrying out the Michael reaction of propanal and b-ni-
troacrolein dimethyl acetal using small chiral organic mole-
cules as catalysts. The optimal reaction conditions found for
the synthesis of both enantiomers of Michael adduct 4a are
summarized in Scheme 3.
The observed absolute configuration of adduct 4a ob-
tained in the reaction catalyzed by the O-silyldiarylprolinol
3g can be explained in terms of a mechanistic pathway such
as that depicted in Scheme 4. In a first step, propanal and
catalyst 3g would condense to form a stereodefined nucleo-
philic enamine intermediate. This enamine would then react
with the nitroalkene electrophile, and a final hydrolysis step
Scheme 4. Proposed catalytic cycle and transition state for the 3g-cata-
lyzed Michael reaction of propanal and 2.
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Organocatalytic Michael Additions
FULL PAPER
Golinski,[17] in which electro-
static interactions between the
partially positive nitrogen of
the enamine and the negative-
ly charged oxygen atoms of
the nitro group are invoked.
The difference in the sense
of enantiodiscrimination exert-
ed by indoline-derived cata-
lysts 3c and 3d and the other
proline-derived catalysts 3a,
3b, and 3e–g can be easily ex-
plained in terms of the prefer-
ential formation of two differ-
ently arranged enamine inter-
mediates during the activation
of the aldehyde donor by the
catalyst. It is well known that
O-silylated diphenylprolinol-
derived enamines adopt a pref-
erential conformation in which
the substituent at the pyrroli-
dine ring and the enamine sub-
stituent (Me in this case)
remain as far as possible from
each other in order to avoid
steric crowding.[18] On the
other hand, indolinecarboxylic
acid-derived enamines adopt
the opposite conformation in
order to minimize steric inter-
actions between the enamine
substituent and the a-hydrogen
Table 3. Organocatalytic enantioselective Michael reaction of 2 and different aldehydes catalyzed by 3g and
3a.[a]
Entry
Aldehyde
Product
Catalyst
t [h]
Yield [%][b]
syn/anti[c]
ee [%][d]
3g
3a
24
12
86
74
6.0:1
1.7:1
>99
80
1
3g
3a
48
48
63
75
11:1
3.7:1
>99
80
2
3
3g
3a
72
72
85
65
>20:1
1.7:1
>99
80
3g
3a
72
72
61
63
>20:1
92
83
4
5
6
2:1
3g
3a
72
70
75
46
>20:1
>99
88
9:1
3g
3a
72
72
81
63
3:1
1.3:1
>99
82
3g
3a
48
36
85
99
1.5:1
1.3:
>99
40
7
8
3g
3a
72
48
<5
99
n.d.[e]
1.5:1
n.d.[e]
97
of
the
aromatic
ring
(Figure 1).[19]
[a] Reaction performed on a 1.00 mmol scale using 1 equiv each of 1 and 2 with 10 mol% of catalyst in the
specified solvent and at RT. For data concerning the use of catalyst 3a in this reaction, see ref.[13] [b] Isolated
yield after FC. [c] Determined by NMR spectrometric analysis of the reaction mixture. [d] Calculated from
chiral GC or HPLC data (see the Supporting Information). [e] n.d.=Not determined.
Having established an opti-
mized protocol, we then pro-
ceeded to extend this method-
comparison with the previously reported reactions employ-
ing catalyst 3a.
As Table 3 shows, a broad range of differently substituted
aldehydes could be used in the conjugate addition reaction,
affording the desired polyfunctionalized products. As can be
seen, the yields obtained in all the reactions ranged from
good to excellent, and in almost all cases the use of catalyst
3g improved the conversion of the reaction or allowed it to
be carried out in a shorter time compared to when catalyst
Figure 1. Conformations of the most favored enamines formed with cata-
lysts 3g and c, respectively.
ology to other aldehyde donors with different substitution
patterns in order to gain further insight into the scope and
limitations of the method with regard to the aldehyde sub-
strate (Scheme 5). It was envisaged that this would provide
access to a wide range of differently substituted, highly func-
tionalized, enantioenriched nitroalkanes of high synthetic
potential due to the presence of the nitro group together
with two chemically differentiated formyl groups. The re-
sults obtained are summarized in Table 3, together with a
Scheme 5. Organocatalytic enantioselective Michael reaction between al-
dehydes and b-nitroacrolein dimethyl acetal catalyzed by 3g or 3a. a) 3g
(10 mol%), H2O (2 equiv), DMF, RT, or 3a (10 mol%), iPrOH, RT.
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J. L. Vicario, D. Badía, et al.
3a was used. For example, the 3a-catalyzed reaction of 1e
and 2 (R=iPr) furnished 4e in 46% yield, while when cata-
lyst 3g was employed the yield was increased to 75%
(entry 5). However, the most important advantage associat-
ed with the use of catalyst 3g was found in the diastereo-
and enantioselectivities of the reactions, which were signifi-
cantly improved in all cases, with the adducts 4a–g being ob-
tained in syn/anti ratios of up to >20:1 with 92% ee or
higher. The only exceptions were found for the reaction
with phenylacetaldehyde (entry 7), which furnished the Mi-
chael adduct 4g as a 1.5:1 mixture of diastereoisomers,
albeit with excellent enantioselectivity, and in the case of
benzyloxyacetaldehyde (entry 8), in which case the 3g-medi-
ated reaction furnished only traces of the conjugate addition
product 4h whereas the use of l-prolinol 3a allowed the
preparation of functionalized nitroalkane 4g in excellent
yield and with moderate diastereoselectivity.
g-Nitroaldehydes 4b–g were found to be somewhat unsta-
ble compounds and therefore, for better characterization
and handling purposes, we decided to transform these ad-
ducts into the corresponding more stable acetates 5b–g
through a reduction/esterification procedure (Scheme 6).
Thus, nitroaldehydes 4 were subjected to reduction of the
formyl group with NaBH4 in MeOH, and then the obtained
alcohols were directly esterified with acetic anhydride in the
presence of a catalytic amount of DMAP. The obtained
esters could be conveniently characterized, and we also em-
ployed these acetate derivatives to determine the enantiose-
lectivity of the Michael reaction because in this form the
two enantiomers could be easily separated by chiral GC,
which could not be accomplished with their g-nitroaldehyde
precursors 4b–g under all conditions examined.
Scheme 7. Organocatalytic enantioselective Michael reaction of ketones
and b-nitroacrolein dimethyl acetal.[21]
tones to nitroalkenes usually give poor results when the
same reaction is carried out using aldehydes.
In the present case, catalyst 3g proved to be completely
inactive in this transformation when we attempted the reac-
tions of b-nitroacrolein dimethyl acetal 2 with cyclohexa-
none 6a and acetone 6d, but, on the other hand, l-prolinol
(3a) turned out to be an effective catalyst for this transfor-
mation (Table 4).[22] In fact, when we examined the reaction
of cyclohexanone (6a) and 2 catalyzed by 3a under the opti-
mal conditions that we had established when employing al-
dehydes as donors, the Michael adduct 7a was obtained in
moderate yield but with excellent diastereo- and enantiose-
lectivities (entry 1). We also surveyed other solvents with a
view to improving the yield of the reaction (entries 2–5), ob-
serving that it could be improved by using polar aprotic sol-
vents such as THF (entry 2) or DMF (entry 3) without sig-
nificantly affecting the stereoselectivity. We extended these
reaction conditions to other cyclic ketones such as cyclopen-
tanone (6b) (entry 6) and cycloheptanone (6c) (entry 7), ob-
serving that the reactions became very slow and furnished
only low yields of the Michael adducts, which were accom-
panied by large amounts of the starting materials. Acetone
was also tested as a Michael donor but, in this case, the
enantioselectivity of the reaction was significantly lower (en-
tries 8 and 9).
Synthesis of trisubstituted pyrrolidines: The pyrrolidine ring
is a ubiquitous structural feature shared by many natural
products and drugs. As a consequence, the development of
short, versatile, and efficient procedures for the stereocon-
trolled preparation of pyrrolidines represents a very impor-
tant field of research for organic chemists.[23] Enantiomeri-
Scheme 6. Transformation of g-nitroaldehydes 4 into esters 5. a) NaBH4,
MeOH, RT. b) Ac2O, DMAP, CH2Cl2, RT. DMAP=4-dimethylaminopyr-
idine.
We also investigated the pos-
sibility of carrying out the Mi-
Table 4. Screening of the 3a-catalyzed Michael reaction of ketones with 2.[a]
chael reaction using ketones as
Michael donors (Scheme 7). It
has to be pointed out that the
amine-catalyzed enantioselec-
tive Michael reaction of ke-
tones with nitroalkenes is a
rather undeveloped transfor-
mation compared with the
parent reaction using alde-
hydes as donors.[20] Moreover,
it is very often found in this
case that the catalysts that per-
form well in the addition of ke-
Entry
Ketone
Product
Solvent
Yield [%][b]
syn/anti[c]
ee [%][d]
1
2
3
4
5
6
7
8
9
10
6a
6a
6a
6a
6a
6b
6c
6d
6d
6d
7a
7a
7a
7a
7a
7b
7c
7d
7d
7d
iPrOH
THF
DMF
toluene
CHCl3
THF
THF
THF
acetone
iPrOH
27
51
44
16
20
30
10
20
40
56
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
–
96
97
91
95
87
87
n.d.
43
43
70
–
–
[a] Reaction carried out on a 1.00 mmol scale using 1 equiv each of 6 and 2 with 10 mol% of catalyst in the
specified solvent and at RT. [b] Isolated yield after FC. [c] Determined by NMR spectrometric analysis of the
reaction mixture. [d] Calculated from chiral GC data.
9362
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Chem. Eur. J. 2008, 14, 9357 – 9367

Organocatalytic Michael Additions
FULL PAPER
cally pure pyrrolidines and derivatives are compounds of
great interest, which have found application as chiral re-
agents or catalysts for use in the field of organic synthesis,
and are also very important biologically active compounds
with potential therapeutic applications in medicine.
Taking into account the importance of providing new
methodologies for the synthesis of enantioenriched polysub-
stituted pyrrolidines bearing different functional groups, we
decided to prepare a variety of different derivatives with a
homoproline general structure using our newly developed
methodology. Thus, a short retrosynthetic analysis, as shown
in Scheme 8, shows that pyrrolidines can be obtained after
Scheme 9. Olefination of adduct 4a. a) (EtO)2P(O)CH2CO2Et, DBU,
CH2Cl2, RT. b) Ph3P=CHCO2Et, CH2Cl2, RT.
this reason, we decided to switch to a Wittig reaction as an
alternative protocol for the preparation of adduct 8a under
neutral reaction conditions. Thus, when we stirred a solution
of Michael adduct 4a and ethoxycarbonylmethylenetriphe-
nylphosphorane in CH2Cl2 at room temperature, we were
able to isolate the a,b-unsaturated ester 8a in good yield
(88%) and without epimerization at the a-stereocenter.
We next proceeded to carry out chemoselective reduction
of the nitro group in the presence of the a,b-unsaturated
ester moiety, which was accomplished by treating adduct 8a
with Zn in AcOH followed by basification, standard work-
up, and final purification by flash chromatography. To our
delight, the reaction proceeded in a very clean way, directly
furnishing pyrrolidine 9a (Scheme 10). This indicates that a
clean and selective reduction of the nitro group occurred,
followed by an intramolecular aza-Michael reaction, which
most probably occurred after basifying the reaction mixture
and during work-up. In addition, we also found that the cyc-
lization step proceeded with complete diastereoselectivity,
furnishing a single diastereoisomer, as indicated by NMR
analysis of the crude reaction mixture. This also indicates
that the chirality present in the w-amino-a,b-unsaturated
ester precursor was able to exert very effective asymmetric
induction during the aza-Michael reaction step. The configu-
ration of the newly created stereogenic center was deter-
mined by NOE experiments, which showed a 1,2-trans rela-
tionship with the methyl substituent at the adjacent stereo-
center and a 1,3-cis relationship with the dimethoxymethyl
substituent (Scheme 10).
Scheme 8. Retrosynthetic analysis for the synthesis of homoproline deriv-
atives.
an intramolecular aza-Michael reaction of a conveniently
substituted w-amino-a,b-unsaturated ester intermediate, the
amino group in which can be formed from the correspond-
ing nitro derivative by chemoselective reduction. This w-
nitro-a,b-unsaturated ester derivative should be easily acces-
sible from our adducts 4a–g by a simple olefination proce-
dure. It has to be pointed out that a key step in this synthe-
sis relies upon the intramolecular aza-Michael addition, in
which a third new stereogenic center is created. In this con-
text, it is expected that the chiral information already pres-
ent in the aminoenoate precursor should exert effective
asymmetric induction in the formation of this new stereo-
center, although special attention would have to be paid to
the experimental conditions for carrying out this transforma-
tion in order to obtain the final compounds as single diaste-
reoisomers.
We proceeded to carry out the synthesis according to the
proposed synthetic plan using adduct 4a as a model sub-
strate, and therefore we started with the projected olefina-
tion reaction in order to obtain the w-nitro-a,b-unsaturated
ester 8a (Scheme 9). We first explored the use of a Horner–
Wadsworth–Emmons olefination procedure under condi-
tions previously found to be appropriate in a similar con-
text[24] and, in fact, when we carried out the reaction be-
tween 4a and ethyl 2-(diethoxyphosphoryl)acetate in the
presence of DBU, we obtained the expected w-nitro-a,b-un-
saturated ester 8a in excellent yield but as a disappointing
1:1 mixture of diastereoisomers due to epimerization of the
stereocenter at the a-position of the starting aldehyde. This
epimerization process could not be avoided by changing the
solvent, the base, or the temperature. We attributed the epi-
merization of the a-stereocenter of the starting material to
the acidity of the proton at this position, which could under-
go a fast deprotonation/protonation process under the basic
conditions required for the HWE olefination reaction. For
These conditions were extended to the rest of the nitroal-
dehydes 4b–g, showing that this reaction sequence could be
easily performed in all cases, furnishing the target trisubsti-
tuted homoproline products 9b–g in only two steps
(Table 5). The olefination step proceeded in good yield in
each case[25] and without any appreciable epimerization at
the stereogenic centers created during the organocatalytic
enantioselective Michael reaction step. Moreover, the final
reduction/cyclization step also took place with complete dia-
Scheme 10. Synthesis of homoproline derivative 9a. a) Zn, AcOH, RT.
b) NaOH (pH 12)
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J. L. Vicario, D. Badía, et al.
Table 5. Synthesis of the a,b-unsaturated esters 8 and pyrrolidines 9.
Table 6. Synthesis 3,4-disubstituted pyrrolidines 10.
Entry
1
Substrate
Product
Yield [%][a]
Entry Substrate
Product
Yield
[%][a]
Product
Yield
[%][a]
51[b]
1
2
4a
4b
88
85
68
64
2
3
4
5
74
75
81
79
3
4
5
6
7
4c
4d
4e
4 f
4g
78
74
73
45
69
66
44
71
84
51
6
7
75
80
[a] Isolated yield after flash column chromatography. [b] The reaction
was carried out at À158C (see ref. [26]).
[a] Isolated yield after flash column chromatography.
stereoselectivity regarding the generation of the third ste-
reocenter, thus cleanly furnishing the target pyrrolidines
9b–g as single diastereoisomers of high enantiomeric purity.
These conditions were extended to all of the Michael ad-
ducts 4, furnishing pyrrolidines 10a–g in excellent yields and
as single diastereoisomers in all cases.[26]
Synthesis of disubstituted pyrrolidines: Adirect access to
chiral 3,4-disubstituted pyrrolidines using Michael adducts
4a–g was also envisaged by carrying out a cascade process
consisting of chemoselective reduction of the nitro group
followed by intramolecular reductive amination (Table 6).
To our delight, when we treated g-nitroaldehyde 4d with Zn
in AcOH, a clean reaction occurred and we were able to
isolate pyrrolidine 10d in excellent yield as a single diaste-
reoisomer. This shows that the reduction/reductive amina-
tion cascade process also proceeded without epimerization
at the a-stereocenter of the starting material, which was ex-
pected to be fairly prone to racemization during the reduc-
tive amination step through imine/enamine tautomerization.
Conclusion
We have improved our recently developed protocol for car-
rying out the organocatalytic conjugate addition of different-
ly substituted aldehydes to b-nitroacrolein dimethyl acetal
(a functionalized nitroalkene). The use of commercially
available (S)-2-(trimethylsilyloxydiphenylmethyl)pyrrolidine
(3g) as catalyst provided the final adducts in good yields, in
shorter reaction times, and with higher enantio- and diaste-
reoselectivities than those provided by l-prolinol, which was
found to be the most efficient catalyst in our previous study.
Moreover, the corresponding Michael adducts could be
9364
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Chem. Eur. J. 2008, 14, 9357 – 9367

Organocatalytic Michael Additions
FULL PAPER
2808C, constant pressure flow=7 psi, Ti =708C (2 min), Tf1 =1008C
(208CminÀ1, hold 30 min), Tf2 =2108C (0.18CminÀ1): (minor anti-isomer)
major enantiomer: tR =167.85 min; minor enantiomer: tR =169.36 min;
(major syn-isomer) major enantiomer: tR =176.16 min; minor enantio-
mer: tR =178.49 min.
easily transformed into highly functionalized enantioen-
riched pyrrolidines by two different methodologies. Pyrroli-
dines containing three stereogenic centers were obtained by
a new protocol relying on a Wittig olefination reaction fol-
lowed by a cascade process consisting of chemoselective re-
duction of the nitro group followed by a base-promoted
fully diastereoselective intramolecular aza-Michael reaction.
Alternatively, 3,4-disubstituted pyrrolidines were obtained
in a single step from the Michael adducts by another cas-
cade process consisting of chemoselective reduction fol-
lowed by intramolecular reductive amination. The method-
ology presented herein constitutes a very efficient, short
(three steps from nitroacrolein dimethyl acetal for the syn-
thesis of trisubstituted pyrrolidines and only two steps for
the 3,4-disubstituted derivatives), and modular approach for
the construction of differently substituted stereodefined pro-
line derivatives, which are molecules of interest due to their
substitution pattern involving well differentiated functionali-
ties suitable for further modifications.
A
hyde 4b (0.14 g, 0.63 mmol) was obtained according to the general proce-
dure starting from butanal (72 mg, 1.00 mmol) and b-nitroacrolein di-
methyl acetal (0.15 g, 1.00 mmol) in the presence of catalyst 3g (32 mg,
0.10 mmol) and water (36 mg, 2.00 mmol). Yield: 0.14 g, 0.63 mmol, 63%;
[a]2D0 =+12.9 (c=1.0, CH2Cl2); 1H NMR (CDCl3, 300 MHz): d=1.01 (t,
3H, J=7.3 Hz), 1.46 (m, 1H), 1.80 (m, 1H), 2.52 (m, 1H), 3.01 (m, 1H),
3.33 (s, 3H), 3.35 (s, 3H), 4.34 (m, 2H), 4.59 (dd, 1H, J=13.6, 7.1 Hz),
9.61 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=12.4, 19.5, 41.1, 51.3,
55.2, 55.3, 73.3, 104.4, 202.7 ppm; IR: n˜ =1555 (NO2), 1718 cmÀ1 (C=O);
MS (EI): m/z (%) 218 (1) [M+], 141 (38), 127 (21), 113 (78), 97 (33), 81
(60), 75 (100); HRMS: m/z: calcd for [C9H17NO5]+: 219.1107; found:
219.1109. The ee was determined after transformation to 5b (see below).
(2R,3R)-2-Ethyl-4,4-dimethoxy-3-(nitromethyl)butyl acetate (5b): The
ester 5b was obtained by reduction/esterification of 4b (0.14 g,
0.64 mmol) following the general experimental procedure using NaBH4
(0.22 g, 6.00 mmol), Ac2O (0.05 mL, 0.60 mmol), and DMAP (7 mg,
0.06 mmol). Yield: 0.16 g, 0.60 mmol, 90%; [a]2D0 =À2.9 (c=0.45,
CH2Cl2); 1H NMR (CDCl3, 300 MHz): d=0.98 (t, 3H, J=7.1 Hz), 1.42
(m, 2H), 1.91 (m, 1H), 2.06 (s, 3H), 2.86 (m, 1H), 3.35 (s, 6H), 4.08 (d,
2H, J=5.1 Hz), 4.35 (m, 2H), 4.51 ppm (dd, 1H, J=12.9, 6.1 Hz);
13C NMR (CDCl3, 75 MHz): d=11.9, 20.9, 22.0, 38.0, 41.2, 54.2, 55.2,
64.3, 73.7, 104.9, 171.8 ppm; MS (EI): m/z (%): 185 (2) {M+À78], 111
(21), 93 (4), 75 (100), 55 (4); HRMS: m/z: calcd for [C11H21NO6]+:
263.1369; found: 263.1377; IR: n˜ =1555 (NO2), 1740 cmÀ1 (C=O). The ee
(>99%) was determined by chiral GC-MS using a CP-Chirasil-Dex CB
Experimental Section
General procedure for the organocatalytic Michael reaction of aldehydes
1a–h and b-nitroacrolein dimethyl acetal 2; enantioselective synthesis of
nitroaldehydes 4a–g and nitroesters 5b–g: An ordinary vial equipped
with a magnetic stirring bar was charged with catalyst 3g (0.10 mmol,
10 mol%), DMF (2.0 mL), and the appropriate aldehyde 1a–g
(1.0 mmol), and stirring was maintained at RT for 5 min. Nitroalkene 2
(1.0 mmol) and H2O (2.0 mmol) were then added and the mixture was
stirred at RT until completion of the reaction. The crude reaction mixture
was then directly applied to a column of silica gel and subjected to flash
chromatography (n-hexane/AcOEt 8:2), yielding the target g-nitroalde-
hydes 4a–g as colorless oils. For the purposes of better characterization
and ee determination, aldehydes 4b–g were transformed into the corre-
sponding acetates by reduction/esterification. This was carried out by dis-
solving the respective aldehydes 4b–g in MeOH (2 mL), cooling the solu-
tion to 08C, and then adding NaBH4 (10.0 mmol) in small portions. Each
reaction mixture was stirred at RT until full conversion was observed by
TLC, whereupon saturated aqueous NH4Cl solution (2 mL) and CH2Cl2
(10 mL) were carefully added and the resulting mixture was stirred for a
further 30 min. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (3”3 mL). The combined organic layers were
dried over Na2SO4 and the solvent was removed in vacuo. The obtained
yellowish oil was redissolved in CH2Cl2 (2 mL), and then DMAP
(0.1 mmol) and acetic anhydride (1.0 mmol) were added at RT. The reac-
tion mixture was stirred for 30 min and was then directly applied to a
column of silica gel and subjected to flash chromatography (n-hexane/
AcOEt 7:3) to yield the desired esters 5b–g as colorless oils.
column;
T
inj =2508C,
T
det =2808C, constant flow=1.0 mLminÀ1
hold 30 min), Tf2 =2108C
, Ti =
708C (3 min), Tf1 =1008C (308CminÀ1
,
(0.58CminÀ1): minor anti-isomer: first enantiomer: tR =81.17 min; second
enantiomer: tR =81.42 min, major syn-isomer: minor enantiomer: tR =
83.61 min; major enantiomer: tR =86.06 min.
General procedure for the synthesis of a,b-unsaturated esters 8a–g:
(Ethoxycarbonylmethylidene)triphenylphosphorane
(5.0 mmol)
was
added to a solution of the appropriate aldehyde 4 (1.0 mmol) in dry
CH2Cl2 (30 mL) at 08C. Stirring was maintained at this temperature until
completion of the reaction, as monitored by TLC analysis. Asaturated
aqueous solution of NH4Cl (10 mL) and H2O (10 mL) were then added
and the aqueous layer was separated and extracted with CH2Cl2 (3”
10 mL). The combined organic fractions were collected, dried over
Na2SO4, and the solvent was removed in vacuo. The crude reaction mix-
ture was then subjected to purification by flash column chromatography
(n-hexane/AcOEt 7:3).
Ethyl
(4S,5R,2E)-6,6-dimethoxy-4-methyl-5-(nitromethyl)hex-2-enoate
(8a): w-Nitroester 8a (0.17 g, 0.61 mmol) was obtained according to the
general procedure starting from 4a (0.14 g, 0.69 mmol) and Ph3P=
CHCO2Et (1.26 g, 3.45 mmol). Yield: 0.17 g, 0.61 mmol 88%; [a]D20
=
1
À15.2 (c=1.0, CH2Cl2); H NMR (CDCl3, 300 MHz): d=1.12 (d, 3H, J=
6.7 Hz), 1.25 (t, 3H, J=7.1 Hz), 2.66 (m, 2H), 3.33 (s, 3H), 3.34 (s, 3H),
4.22 (m, 4H), 4.52 (dd, 1H, J=12.6, 6.8 Hz), 5.81 (d, 1H, J=15.6 Hz),
6.80 ppm (dd, 1H, J=15.6, 7.8 Hz); 13C NMR (CDCl3, 75 MHz): d=14.2,
16.8, 34.9, 44.4, 54.7, 55.1, 60.4, 73.1, 104.5, 122.4, 149.2, 166.2 ppm; IR:
n˜ =1555 (NO2), 1716 cmÀ1 (C=O); MS (EI): m/z (%) 229 (M+À46), 197
(16), 183 (18), 137 (4), 131 (12), 123 (19), 99 (16), 81 (9), 75 (100), 54 (2);
HRMS: calcd for [C11H17O3]+ (M+À78): 197.1178; found: 197.1168.
(2R,3R)-4,4-Dimethoxy-2-methyl-3-(nitromethyl)butanal (4a): Nitroalde-
hyde 4a (0.17 g, 0.86 mmol) was obtained according to the general proce-
dure starting from propanal (60 mg, 1.00 mmol) and b-nitroacrolein di-
methyl acetal (0.15 g, 1.00 mmol) in the presence of catalyst 3g (32 mg,
0.10 mmol) and water (36 mg, 2.00 mmol). Yield: 0.17 g, 0.86 mmol, 86%;
[a]2D0 =À12.4 (c=1.0, CH2Cl2); 1H NMR (CDCl3, 300 MHz, TMS): d=
1.13 (d, 3H, J=7.3 Hz), 2.55 (m, 1H), 3.11 (m, 1H), 3.32 (s, 3H), 3.34 (s,
3H), 4.30 (d, 1H, J=6.5 Hz), 4.35 (dd, 1H, J=13.5, 7.0 Hz), 4.57 (dd,
1H, J=13.5, 6.2 Hz), 9.56 ppm (s, 1H); 13C NMR (CDCl3, 75 MHz): d=
9.8, 41.4, 44.6, 54.6, 55.7, 73.7, 103.8, 201.7 ppm; IR: n˜ =1558 (NO2),
1724 cmÀ1 (C=O); MS (EI): m/z (%): 204 (2) [M+], 174 (13), 142 (8), 127
(42), 113 (26) 99 (100), 84 (32), 75 (90); HRMS: m/z: calcd for
[C8H14NO5]+: 204.0872; found: 204.0872. The ee (>99%) was determined
by chiral GC-MS using a CP-Chirasil-Dex CB column after transforma-
General procedure for the cascade reduction/cyclization reaction: synthe-
sis of pyrrolidines 9a–g and 10a–g: Zn (25.0 mmol) was added in small
portions over a period of 10 min to a solution of the unsaturated nitroes-
ter 8 (for the synthesis of 9) or the g-nitroaldehyde 4 (for the synthesis of
10) (1.0 mmol) in H2O/AcOH (1:1; 20 mL) at 08C. The reaction mixture
was stirred for 2 h at RT, then filtered, and the filtrate was adjusted to
pH 12 with 4m NaOH. The aqueous layer was extracted with CH2Cl2 (3”
10 mL). The organic fractions were combined, dried over Na2SO4, and
the solvent was removed in vacuo. Pyrrolidines 9a–g and 10a–g were iso-
tion to the acetal derived from propane-1,3-diol;[27]
Tinj =2508C, Tdet =
Chem. Eur. J. 2008, 14, 9357 – 9367
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9365

J. L. Vicario, D. Badía, et al.
lated after purification by flash column chromatography (AcOEt/MeOH
10:3).
[5] For reviews, see: a) S. Bertelsen, M. Nielsen, K. A. Jørgensen,
Angew. Chem. 2007, 119, 7500; Angew. Chem. Int. Ed. 2007, 46,
7356; b) S. Mukherjee, B. List, Nature 2007, 447, 152; see also c) H.
Kim, D. W. C. MacMillan, J. Am. Chem. Soc. 2008, 130, 398; d) M. P.
Sibi, M. Hasegawa, J. Am. Chem. Soc. 2007, 129, 4124; e) T. D.
Beeson, A. Mastracchio, J. Hong, K. Ashton, D. W. C. MacMillan,
Science 2007, 316, 582; f) H.-Y. Jang, J.-B. Hong, D. W. C. MacMil-
lan, J. Am. Chem. Soc. 2007, 129, 7004.
[6] M. D. Burke, S. L. Schreiber, Angew. Chem. 2004, 116, 48; Angew.
Chem. Int. Ed. 2004, 43, 46.
[7] a) M. J. Gaunt, C. C. C. Johansson, A. McNally, N. C. Vo, Drug Dis-
covery Today 2007, 12, 8; b) R. M. de Figueiredo, M. Christmann,
Eur. J. Org. Chem. 2007, 2575.
Ethyl (2S,3R,4R)-[4-(dimethoxymethyl)-3-methylpyrrolidin-2-yl]acetate
(9a): Pyrrolidine 9a (76 mg, 0.31 mmol) was obtained according to the
general procedure starting from 8a (0.12 g, 0.45 mmol) and Zn (0.75 g,
11.32 mmol). Yield: 76 mg, 0.31 mmol, 68%; [a]2D0 =À12.7 (c=0.7,
CH2Cl2); 1H NMR (CDCl3, 300 MHz): d=1.05 (d, 3H, J=6.7 Hz), 1.23
(t, 3H, J=7.1 Hz), 1.51 (m, 1H), 2.01 (m, 1H), 2.33 (m, 2H), 2.59 (dd,
1H, J=15.6, 3.6 Hz), 2.97 (m, 2H), 3.32 (s, 3H), 3.34 (s, 3H), 4.12 (q,
2H, J=7.1 Hz), 4.23 ppm (d, 1H, J=7.1 Hz); 13C NMR (CDCl3,
75 MHz): d=14.2, 17.3, 38.9, 41.6, 46.9, 48.7, 53.7, 54.0, 60.5, 63.0, 107.5,
172.6 ppm; IR: n˜ =1733 (C=O), 3418 cmÀ1 (NH); MS (EI): m/z (%) 246
(1) [M++1], 215 (33), 198 (81), 182 (51), 170 (24), 168 (15), 158 (100),
129 (32), 126 (52), 108 (13), 97 (15), 94 (97), 85 (34), 75 (42), 56 (20);
HRMS: m/z: calcd for [C7H12NO]+: 126.0919; found: 126.0923 [M+
À119].
[8] For some reviews, see: a) J. L. Vicario, D. Badia, L. Carrillo, Synthe-
sis 2007, 2065; b) D. AlmaÅi, D. A. Alonso, C. Najera, Tetrahedron:
Asymmetry 2007, 18, 299; c) S. B. Tsogoeva, Eur. J. Org. Chem.
2007, 1701; d) S. Sulzer-Mosse, A. Alexakis, Chem. Commun. 2007,
3123.
(3R,4R)-3-(Dimethoxymethyl)-4-methylpyrrolidine (10a): Pyrrolidine
10a (72 mg, 0.45 mmol) was obtained according to the general procedure
starting from 4a (184 mg, 0.89 mmol) and Zn (1.45 g, 22.25 mmol) and
carrying out the reaction at À158C (see ref. [26]). The solvents had to be
removed especially carefully because pyrrolidine 10a was found to be
volatile. Yield: 72 mg, 0.45 mmol, 51%; [a]2D0 =+10.0 (c=0.6, CH2Cl2);
1H NMR (CDCl3, 300 MHz): d=1.09 (d, 3H, J=6.5 Hz), 2.11 (m, 1H),
2.53 (m, 1H), 2.97 (m + brs, 3H), 2.04 (m, 1H), 3.19 (m, 1H), 3.33 (s,
3H), 3.35 (s, 3H); 4.31 ppm (d, 1H, J=6.9 Hz); 13C NMR (CDCl3,
75 MHz): d=18.9, 36.6, 49.0, 49.3, 53.5, 53.8, 55.5, 107.3 ppm; IR: n˜ =
3414 cmÀ1 (NH); MS (EI): m/z (%) 129 (M+À30, 14), 127 (17), 112 (21),
96 (72), 85 (100), 75 (38), 71 (19), 67 (18); HRMS: m/z: calcd for
[C6H10]+: 96.0813; found: 96.0814 [M+À63].
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Acknowledgement
This research was supported by the University of the Basque Country
(Subvención General a Grupos de Investigación and UNESCO 06/06)
and the Ministerio de Educación y Ciencia of Spain (CTQ 2005-02131/
BQU). N.R. thanks the Spanish Ministerio de Educacion y Ciencia, E.R.
thanks the University of the Basque Country, and U.U. thanks the
Basque Government for their fellowships. The authors also acknowledge
PETRONOR, S.A., for the generous gift of solvents.
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Chem. Eur. J. 2008, 14, 9357 – 9367

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Received: April 25, 2008
Published online: September 2, 2008
Chem. Eur. J. 2008, 14, 9357 – 9367
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9367