Diastereocontrolled synthesis of enantioenriched 3,4-disubstituted β-prolines

Article abstract of DOI:10.1021/jo061603h

Enantioenriched 3,4-disubstituted β-prolines have been prepared with a high diastereocontrol through a carbometalation reaction or through a domino Michael addition/carbometalation reaction.

Full text of DOI:10.1021/jo061603h

Diastereocontrolled Synthesis of Enantioenriched 3,4-Disubstituted
â-Prolines
Fabrice Denes, Alejandro Perez-Luna, and Fabrice Chemla*
Laboratoire de Chimie Organique, UMR 7611, FR2769, UniVersite´ Pierre et Marie Curie,
Tour 44-45, 2e`me e´tage, Case 183, 4 place Jussieu, 75252 Paris Cedex 05, France
fchemla@ccr.jussieu.fr
ReceiVed August 2, 2006
Enantioenriched 3,4-disubstituted â-prolines have been prepared with a high diastereocontrol through a
carbometalation reaction or through a domino Michael addition/carbometalation reaction.
Introduction
to 3,4-disubstituted â-prolines. We would like to report our
results concerning the diastereoselective synthesis of enantiopure
3-substituted and 3,4-disubstituted â-prolines.
Oligo-(â-aminoacids), also known as â-peptides, have raised
considerable interest1 over the past decade. These oligomers
have shown enhanced resistance toward hydrolysis by proteases
and greater conformational stability than the most widely known
R-peptides. These interesting properties have led to numerous
synthetic studies2 toward new and efficient preparations of their
building blocks, â-amino acids. Among the latter, â-proline ((S)-
pyrrolidine-3-carboxylic acid) has been shown to be an interest-
ing synthetic target: oligomers of â-proline have been found
to possess a rigid secondary structure3,4 and endomorphin-1
analogues containing â-proline are µ-opioid receptor agonists
and display an enhanced enzymatic hydrolysis resistance.5
Whereas several enantioselective syntheses of â-proline itself
are reported,3,6 few studies have been devoted to the stereose-
lective and enantioselective synthesis7 of 4-substituted â-prolines
(mainly through enantioselective [2 + 3] azomethine ylide
cycloadditions)8 and, to the best of our knowledge, even fewer9
Results and Discussion
Enantiopure â-Proline through Carbocyclization of â-N-
Allyl Amino Ester Zinc Enolates. We have shown recently10
that 3,4-disubstituted 3-carbomethoxypyrrolidines can be ob-
tained in good yields from zinc enolates derived from â-N-allyl
amino esters 1. The carbometalation reaction observed from
these enolates has been shown to involve a C-centered zinc
(7) (a) Sarmiento, R. M. R.; Wirtz, B.; Iding, H. Tetrahedron: Asymmetry
2003, 14, 1547-1551. (b) Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena,
M.; Rinaldi, S. Tetrahedron: Asymmetry 2003, 14, 3353-3358. (c) Chung,
J. Y. L.; Cvetovich, R.; Amato, J.; McWilliams, J. C.; Reamer, R.;
DiMichele, L. J. Org. Chem. 2005, 70, 3592-3601.
(8) (a) Reed, A. D.; Hegedus, L. S. J. Org. Chem. 1995, 60, 3787-
3794. (b) Fevig, J. M.; Abelman, M. M.; Brittelli, D. R.; Kettner, C. A.;
Knabb, R. M.; Weber, P. C. Bioorg. Med. Chem. Lett. 1996, 6, 295-300.
(c) Ma, Z.; Wang, S.; Cooper, C. S.; Fung, A. K. L.; Lynch, J. K.; Plagge,
F.; Chu, D. T. W. Tetrahedron: Asymmetry 1997, 8, 883-887. (d) Li, Q.;
Wang, W.; Berst, K. B.; Claiborne, A.; Hasvold, L.; Raye, K.; Tufano, M.;
Nilius, A.; Shen, L. L.; Flamm, R.; Alder, J.; Marsh, K.; Crowell, D.; Chu,
D. T. W.; Plattner, J. J. Bioorg. Med. Chem. Lett. 1998, 8, 1953-1958. (e)
Ling, R.; Ekhato, V.; Rubin, J. R.; Wustrow, D. J. Tetrahedron 2001, 57,
6579-6588. (f) Carey, J. S. J. Org. Chem. 2001, 66, 2526-2529. (g) Haight,
A. R.; Bailey, A. E.; Baker, W. S.; Cain, M. H.; Copp, R. R.; DeMattei,
J. A.; Ford, K. L.; Henry, R. F.; Hsu, M. C.; Keyes, R. F.; King, S. A.;
McLaughlin, M. A.; Melcher, L. M.; Nadler, W. R.; Oliver, P. A.; Parekh,
S. I.; Patel, H. H.; Seif, L. S.; Staeger, M. A.; Wayne, G. S.; Wittenberger,
S. J.; Zhang, W. Org. Process Res. DeV. 2004, 8, 897-902. (h) Belyk,
K. M.; Beguin, C. D.; Palucki, M.; Grinberg, N.; DaSilva, J.; Askin, D.;
Yasuda, N. Tetrahedron Lett. 2004, 45, 3265-3268.
(1) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180.
(2) EnantioselectiVe Synthesis of b-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997.
(3) Kim, Y. J.; Kaiser, D. A.; Pollard, T. D.; Ichikawa, Y. Bioorg. Med.
Chem. Lett. 2000, 10, 2417-2419.
(4) Sandvoss, L. M.; Carlson, H. A. J. Am. Chem. Soc. 2003, 125,
15855-15862.
(5) (a) Cardillo, G.; Gentilucci, L.; Qasem, A. R.; Sgarzi, F.; Spampinato,
S. J. Med. Chem. 2002, 45, 2571-2578. (b) Cardillo, G.; Gentilucci, L.;
Tolomelli, A.; Calienni, M.; Qasem, A. R.; Spampinato, S. Org. Biomol.
Chem. 2003, 1, 1498-1502.
(6) (a) Mazzini, C.; Lebreton, J.; Alphand, V.; Furtoss, R. J. Org. Chem.
1997, 62, 5215-5218. (b) Klein, S. I.; Czekaj, M.; Molino, B. F.; Chu, V.
Bioorg. Med. Chem. Lett. 1997, 7, 1773-1778. (c) Thomas, C.; Orecher,
F.; Gmeiner, P. Synthesis 1998, 1491-1496. (d) Huck, B. R.; Langenhan,
J. M.; Gellman, S. H. Org. Lett. 1999, 1, 1717-1720. (e) Felluga, F.;
Pitacco, G.; Prodan, M.; Pricl, S.; Visintin, M.; Valentin, E. Tetrahedron:
Asymmetry 2001, 12, 3241-3249.
(9) (a) Karlsson, S.; Ho¨gberg, H.-E. J. Chem. Soc., Perkin Trans. 1 2002,
1076-1082. (b) Karlsson, S.; Ho¨gberg, H.-E. Eur. J. Org. Chem. 2003,
2782-2791.
(10) Denes, F.; Chemla, F.; Normant, J. F. Synlett 2002, 919-922.
10.1021/jo061603h CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/14/2006
398
J. Org. Chem. 2007, 72, 398-406

Synthesis of 3,4-Disubstituted â-Prolines
SCHEME 1. Diastereoselective Synthesis of
3,3,4-Trisubstituted Pyrrolidines
did not detect the free amine and we obtained the corresponding
pyrrolidines after aqueous workup in good yields and as
diastereo- and enantiomerically pure compounds (eq 1). These
results closely parallel our findings on the benzylamino series
(zinc enolates derived from 1) where â-elimination was only
detected in the case of the unsubstituted zinc enolates (derived
from 1 with R ) H in Scheme 1).10 We attribute this to a higher
reactivity correlated with a higher substitution pattern.14
One of the most interesting features of the carbocyclization
of zinc enolates is the resulting organometallic species that can
be further functionalized with various electrophiles. The pyr-
rolidinylmethylzinc species obtained after the carbocyclization
reaction from â-N-allylamino ester 5b could be quenched with
iodine (eq 2), and the resulting iodide 7 could be isolated in
fair yield and as a diastereomerically pure compound.
enolate (Scheme 1)11 and to lead highly stereoselectively to the
corresponding metalated pyrrolidines 2 that react further with
various electrophiles to give diversely substituted pyrrolidines
3 in good to excellent yields (Scheme 1).
An enantioselective version of this carbometalation reaction
could thus be envisioned by using a chiral auxiliary either on
the ester moiety or on the nitrogen atom. In the related
carbocyclization reaction of R-amino zinc enolates, attempts to
induce stereoselectivity by means of a chiral ester (menthyl or
phenylmenthyl) or chiral amide (camphorsultam) have been
reported12 to be unsuccessful (limited diastereoselectivities or
lack of reactivity). By contrast, very high levels of stereoin-
duction have been achieved using the inexpensive, readily
available (in both enantiomeric forms) R-methylbenzylamino
group as stereoinductor.12,13 We have thus examined the
behavior of enantiopure â-N-allylamino esters 5a-e (Scheme
2) as starting materials for the carbocyclization reaction. 5b-e
were easily prepared, as a mixture of two diastereomers, through
alkylation of the parent unsubstituted â-N-allylamino ester 5a.
We first studied the behavior of the zinc enolate derived from
â-N-allylamino ester 5a which was prepared by deprotonation
with LDA followed by zinc salt addition at -60 °C. Upon
warming, when ZnBr2 was used, â-elimination occurred and
only amine 4 was recovered after aqueous workup. This side
reaction could be partially avoided by performing the trans-
metalation step with ZnI2 (instead of ZnBr2). Under these
conditions, a smooth carbocyclization reaction took place upon
warming, affording after aqueous workup pyrrolidine 6a
(Scheme 3) in fair yield and to our delight in diastereomerically
The sense of the stereoinduction was determined through
chemical correlation in the case of 6b (Scheme 4). Cleavage of
the chiral auxiliary was achieved through hydrogenolysis, and
the amino moiety was benzylated under standard conditions to
afford chiral pyrrolidine 8 in 74% overall yield. This pyrrolidine
was spectroscopically (1H and 13C NMR) identical to the trans
racemic pyrrolidine we reported previously,10 and the trans
relationship between the carbomethoxy group in C-3 and the
C-4 methyl group was thus secured. The ester moiety was
reduced to alcohol 9. Reduction of the corresponding mesylate
into a methyl group proved to be rather difficult but was finally
achieved with triethylborohydride to give (-)-10 in 41% yield.
The enantiomeric compound has been reported15 previously with
a +11.1 optical rotation. We could thus determine the absolute
configuration in C-4 and deduce the sense of the stereoinduction
in 6b. The absolute configurations in 6a and 6c-e were assumed
to be identical to that of 6b.
1
pure form (based on H and 13C NMR of the crude reaction
product).
Having in hand an efficient methodology for the preparation
of enantiopure 3,4-disubstituted â-proline esters, we turned our
attention to the possible stereoselective formation of two
contiguous quaternary carbon centers. Deprotonation of â-N-
methallyl aminoester 11 (Scheme 5) followed by transmetalation
with zinc iodide afforded after carbocyclization and hydrolysis
the corresponding tetrasubstituted pyrrolidine 12 in 63% isolated
yield as a mixture of two diastereomers (dr ) 86:14). Iodolysis
of the pyrrolidinylzinc intermediate gave the corresponding
iodopyrrolidine 13 with a moderate stereoselectivity as a mixture
of four diastereomers (dr ) 70:11:10:9). Unfortunately, the
major diastereomer could not be isolated by flash chromatog-
raphy, and only a mixture of two diastereomers could be
obtained (43%, dr ) 90:10). The absolute configurations of the
two quaternary carbon centers of this major diastereomer could
thus not be determined unambiguously. They are assumed to
be as depicted in Scheme 5 by analogy with the stereochemical
behavior of N-allyl esters reported above.
By contrast, â-elimination was not a problem starting from
the substituted â-N-allylamino esters 5b-e. Using ZnBr2, we
(11) Sliwinski, E.; Denes, F.; Chemla, F.; Normant, J. F. C. R. Chim.
2003, 67-78.
(12) Karoyan, P.; Chassaing, G. Tetrahedron Lett. 1997, 38, 85-88.
(13) (a) Lorthiois, E.; Marek, I.; Normant, J. F. Tetrahedron Lett. 1997,
38, 89-92. (b) Karoyan, P.; Chassaing, G. Tetrahedron: Asymmetry 1997,
8, 2025-2032. (c) Lorthiois, E.; Marek, I.; Normant, J. F. J. Org. Chem.
1998, 63, 2442-2450. (d) Karoyan, P.; Triolo, A.; Nannicini, R.; Giannotti,
D.; Altamura, M.; Chassaing, G.; Perrotta, E. Tetrahedron Lett. 1999, 40,
71-74. (e) Karoyan, P.; Chassaing, G. Tetrahedron Lett. 2002, 43, 253-
255. (f) Karoyan, P.; Quancard, J.; Vaissermann, J.; Chassaing, G. J. Org.
Chem. 2003, 68, 2256-2265. (g) Quancard, J.; Magellan, H.; Lavielle, S.;
Chassaing, G.; Karoyan, P. Tetrahedron Lett. 2004, 45, 2185-2187. (h)
Quancard, J.; Labonne, A.; Jacquot, Y.; Chassaing, G.; Lavielle, S.; Karoyan,
P. J. Org. Chem. 2004, 69, 7940-7948.
(14) It has been already reported that only disubstituted zinc ester enolates
undergo intermolecular carbometalation reaction on cyclopropene deriva-
tives: Nakamura, E.; Kubota, K. J. Org. Chem. 1997, 62, 792-793.
(15) Yamaura, Y.; Hyakutake, M.; Mori, M. J. Am. Chem. Soc. 1997,
119, 7615-7616.
J. Org. Chem, Vol. 72, No. 2, 2007 399

Denes et al.
SCHEME 2. Preparation of â-Amino Esters 5a-e
SCHEME 3. Reaction of Zinc Enolate Derived from
â-N-Allylamino Ester 5a
strong salt effect still remain unclear. Indeed, no zinc salt
addition was necessary in the reaction of sp2 organometallics
(phenyl, cyclohexenyl, and 2-propenyl), and the corresponding
pyrrolidines were obtained with high diastereoselectivity (Table
1, entries 6-8). The compound obtained after n-butyl (respec-
tively, phenyl) group addition was identical to compound 6c
(respectively, 6e) obtained previously (see above) from 5c
(respectively, 5e).
SCHEME 4. Chemical Correlation for Pyrrolidine 6b
Diastereoselectivity in the Carbometalation Reaction. In
the carbometalation of zinc enolates derived from â-aminoesters
1, the diastereoselectivity has been previously explained11 by a
transition state involving a C-metalated zinc enolate 16 (Figure
1). Due to an extra chelation with zinc salts between the nitrogen
atom and the carbomethoxy group, the latter adopts a pseudo-
axial position leading to the trans substituted pyrrolidine. In the
case of zinc enolates 5a-e bearing an R-methylbenzylamino
group, the trans relative configuration between C-3 and C-4
centers tends to prove that here again a N-Zn-O bridge is
being formed in the corresponding transition states.
Enantiopure â-Proline through Domino Michael Addition/
Carbometalation Reaction. We have also shown recently16 that
disubstituted pyrrolidines can be obtained through a domino
Michael addition/carbometalation process starting from the â-N-
allyl amino enoate 14 (Scheme 6). The diastereoselectivity is
excellent, and the resulting metalated carbomethoxypyrrolidine
intermediates can be further functionalized with various elec-
trophiles.
Following our good results in the enantioselective carbocy-
clization of zinc enolates depicted above, we have thus examined
the possible stereocontrol exerted by the R-methylbenzylamino
group in our domino reaction by using acrylic ester 15 (eq 3).
Our first trials were made with n-BuCu(CN)ZnBr. As reported
previously in this type of domino reaction, a strong salt effect
was observed on the relative stereoselectivity between the two
newly formed carbon centers. Moreover, we also noticed a
strong impact of the presence and the nature of salts on the
chirality transfer from the chiral auxiliary (eq 3, Table 1). As a
general trend, we noticed that the conditions leading to a good
stereocontrol in the achiral version also resulted in good chirality
transfer. Our best results were obtained using organocopper/
zinc mixed reagents prepared from 3 equiv of zinc salts and
salt-free organolithium compounds (Table 1, entry 3). To our
delight, these conditions showed to be general and the addition/
cyclization of several alkyl groups was performed with high
stereoselectivity (Table 1, entries 3-5). The reasons for this
However, in this case the nitrogen becomes stereogenic as a
result of complexation to the zinc salt. Such diastereoselective
complexation to nitrogen has already been reported17 and
involved in diastereoselective transformations. A stereodiffer-
entiation (whatever its origin) could be imagined at this stage,
and transition state 17 could be favored over 18 (Figure 1). To
gain further insight in the role played by this chelation and to
determine whether the complexation is diastereoselective or not,
we thus examined spectroscopically the reaction of unsubstituted
starting material 5a (as a model of the lithium enolate) with
zinc salts in various solvents. Addition of ZnI2 (5 equiv) to
â-amino ester 5a in acetone-d6 resulted in a rapid (15 min)
1
formation of a complex that could be observed by H NMR.
However, two sets of signals were detected (in a 58:42 ratio),
attributable to the two possible diastereomers. Addition of ZnI2
(5 equiv) to 5a in ether resulted in the rapid precipitation of a
solid that, after filtration and drying, gave also two sets of signals
in acetone-d6, with a diastereomeric ratio of 55:45. These NMR
experiments show that the formation of a complex indeed takes
(17) (a) Ferey, V.; Vedrenne, P.; Toupet, L.; Le Gall, T.; Mioskowski,
C. J. Org. Chem. 1996, 61, 7244-7245. (b) Ferey, V.; Toupet, L.; Le Gall,
T.; Mioskowski, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 430-432. (c)
Vedejs, E.; Kendall, J. T. J. Am. Chem. Soc. 1997, 119, 6941-6942. (d)
Ebden, M. R.; Simpkins, N. S.; Fox, D. N. A. Tetrahedron 1998, 54, 12923-
12952. (e) Ariffin, A.; Blake, A. J.; Ebden, M. R.; Wan, S.; Simpkins,
M. S.; Fox, D. N. A. J. Chem. Soc., Perkin Trans. 1 1999, 2439-2447. (f)
Vedejs, E.; Bhanu Prasad, A. S.; Kendall, J. T.; Russel, J. S. Tetrahedron
2003, 59, 9849-9856.
(16) Denes, F.; Chemla, F.; Normant, J. F. Eur. J. Org. Chem. 2002,
3536-3542.
400 J. Org. Chem., Vol. 72, No. 2, 2007

Synthesis of 3,4-Disubstituted â-Prolines
SCHEME 5. Formation of Two Consecutive Quaternary Carbon Centers
SCHEME 6. Diastereoselective Domino 1,4-Addition/Carbocyclization Reaction
TABLE 1. Diastereoselectivity in the Domino Michael Addition/Carbocyclization Reaction with Organocopper Zinc Mixed Species
entry
RM
additive
product
dra
yield (%)b
1
2
n-BuCu(CN)ZnBr-LiBrc
n-BuCu(CN)ZnBr-LiBrc
ZnBr2 (1 equiv)
ZnBr2 (2 equiv),
LiBr (1 equiv)
ZnBr2 (3 equiv)
ZnBr2 (3 equiv)
ZnBr2 (3 equiv)
6c
6c
62:22:16
49:29:22
n.d.
n.d.
3
4
5
6
7
8
n-BuCu(CN)ZnBr-LiBrc
6c
6f
6g
6e
6h
6i
>95:5
91:9
>95:5
>95:5
>95:5
>95:5
57
62
54
57
51
58
EtCu(CN)ZnBr-LiBrc
n-HexCu(CN)ZnBr-LiBrc
PhCu(CN)ZnBr-3LiBrd
1-cyclohexenylCu(CN)ZnBr-3LiBrd
1-propenylCu(CN)ZnBr-3LiBrd
a Determined by 1H NMR on the crude reaction mixture. b Isolated yield. c Prepared from salt-free organolithium species, CuCN and ZnBr2. d The
organolithium species was prepared through I-Li exchange with t-BuLi (2 equiv).
SCHEME 7. Carbocyclizations Starting from Aminoesters
19 and 21
FIGURE 1. Possible intermediates in the carbocyclization reaction
from zinc enolates.
place, but that the R-methylbenzyl group is not capable of
inducing diastereoselective complexation of ZnI2 to the adjacent
nitrogen (eq 4). Although these NMR experiments have been
performed on aminoester 5a and not on its lithium enolate, the
excellent diastereoselectivity observed in the carbocyclization
process does not seem compatible with the stereorandom
Starting from â-amino ester 19, the carbocyclization reaction
formation of the complex 5a-ZnI2.
gave the corresponding pyrrolidine 20 with an excellent
diastereoselectivity (>95:5), albeit in moderate yield. This dr,
similar to those reported from 1, shows that the simple
diastereoselection of the carbocyclization step (i.e., the trans
relationship between C-3 and C-4) is not related to the
aromaticity of the nitrogen substituent. This simple diastereo-
selection arises from the intrinsic nature of the transition state
involving a C-centered zinc enolate (16 in Figure 1) which does
not inVolVe the aromatic moiety.
By contrast, the carbocyclization reaction starting from 21
gave the corresponding pyrrolidine 22 in good yield but with
very poor stereoselectivity (dr ) 58:42). It should be noted that,
although the starting material 21 is engaged as a mixture of
two diastereomers, the stereocenter R to the ester moiety is lost
We next turned our attention to the study of the influence of
structural parameters on diastereoselectivity and in particular
to the role played by the aromatic ring. We thus examined the
diastereoselectivity in the reactions starting from the cyclohexyl
and (S)-R-methylcyclohexyl analogues 19 and 21 (Scheme 7).
J. Org. Chem, Vol. 72, No. 2, 2007 401

Denes et al.
SCHEME 8. Radical/Polar Mechanism of the Domino
Reaction
FIGURE 2. Origin of the chirality transfer in the carbocyclization
reaction from zinc enolates.
FIGURE 3. Origin of the chirality transfer for the radical cyclization
in the domino reaction.
SCHEME 9. Domino Reaction on Michael Acceptor 15
during the deprotonation step, and the resulting zinc enolate is
thus enantiomerically pure. Two new stereocenters are created
in this carbocyclization step, and four possible diastereomers
1
can be obtained. Only two were observed by H NMR, but
unfortunately we could not ascertain the relative stereochem-
istries of the two newly formed stereocenters. However, this
result compared to the excellent diastereoselectivity obtained
from 19 strongly suggests that the simple diastereoselection (i.e.,
the trans relationship between C-3 and C-4) is maintained in
the cyclization step, but the enantioselectivity transfer is almost
inexistent when a cyclohexyl is used instead of a phenyl moiety.
The aromaticity thus seems to be strongly involved in the
enantioselectivity transfer between the R-methylbenzyl group
and the two newly formed stereogenic centers C-3 and C-4.
Zinc(II)-Ar interactions have been largely involved13c,18 in
organozinc chemistry and can be invoked to explain the
diastereoselectivity of the carbocyclization reaction. An interac-
tion between the aromatic moiety and the zinc salt chelated by
the carbomethoxy and the nitrogen moieties would lead to
diastereomeric transition states 23 and 24 (Figure 2). The steric
interaction between the methyl group and the allyl moiety in
transition state 24 makes it less favorable than 23 which gives
the observed products.
Diastereoselectivity in the Domino Reaction. We have
recently demonstrated that our domino reaction follows a radical/
polar crossover mechanism.19 The cyclization step occurs
through a radical pathway (Scheme 8), and the diastereoselec-
tivity has been explained by the cyclization of the radical
intermediate 25 obtained after radical Michael addition. Pyr-
rolidinylmethyl radical 26 is then obtained, giving the observed
trans organometallic species 27 after reduction.
intermediate 28 (similar to organometallic intermediate 23 in
Figure 2) should be favored over intermediate 29 (similar to
organometallic intermediate 24). The bases of the chirality
transfer are thus the same in both polar and radical/polar
mechanisms, although the enantioselectivity and the diastereo-
selectivity of both reactions are decided through the reaction
of a different intermediate (organometallic or radical species).
We have shown recently that when dialkylzincs are used
instead of copper-zinc mixed reagents in the domino reaction,
it still follows a radical/polar mechanism.19 But in this case,
presumably due to the lower Lewis acidity of dialkylzincs, no
chelation to the carbomethoxy moiety is observed, and the latter
adopts a pseudoequatorial position in the radical intermediate
leading to the cis product. It was thus interesting to test the
possible chirality transfer by using the R-methylbenzyl group
as chiral auxiliary in such a reaction. Unfortunately, when
performed with n-Bu2Zn at room temperature on chiral Michael
acceptor 15, the domino reaction showed no chirality transfer
(Scheme 9), as a mixture of the four possible diastereomers was
obtained. A similar result was observed at a lower temperature.
Although this result precludes the enantioselective synthesis of
cis 3,4-disubstituted â-prolines by using the starting material
15, it is in agreement with our hypothesis of a direct interaction
between the R-methybenzyl group, a metal salt, and the
carbomethoxy moiety.
In such a mechanism, the high diastereoselectivity observed
in the case of copper-zinc mixed reagents when using an
R-methylbenzyl group instead of a benzyl group can be again
explained by an Ar-metal interaction (Figure 3). The radical
Conclusion
3,4-Disubstituted â-prolines can be easily prepared in a
stereoselective and enantioselective fashion through a carbo-
metalation reaction or a domino radical/polar crossover reaction.
The R-methylbenzylamino auxiliary has proven to be highly
efficient in such reactions, allowing the possibility to control
the enantioselective formation of two contiguous quaternary
carbon centers. A domino version of this carbometalation
reaction has been also reported. The mechanism of this reaction
(a radical/polar crossover mechanism) is entirely different from
(18) (a) Ellison, J. J.; Power, P. P. Inorg. Chem. 1994, 33, 4231-4234.
(b) Marek, I.; Beruben, D.; Normant, J. F. Tetrahedron Lett. 1995, 36,
3695-3698. (c) Beruben, D.; Marek, I.; Normant, J. F.; Platzer, N. J. Org.
Chem. 1995, 60, 2488-2501. (d) Lorthiois, E.; Marek, I.; Normant, J. F.
J. Org. Chem. 1998, 63, 566-574. (e) Brasseur, D.; Rezaei, H.; Fuxa, A.;
Alexakis, A.; Mangeney, P.; Marek, I.; Normant, J. F. Tetrahedron Lett.
1998, 39, 4821-4825. (f) Ferreira, F.; Bejjani, J.; Denichoux, A.; Chemla,
F. Synlett 2004, 2051-2065.
(19) (a) Denes, F.; Chemla, F.; Normant, J. F. Angew. Chem., Int. Ed.
2003, 42, 4043-4046. (b) Denes, F.; Perez-Luna, A.; Cutri, S.; Chemla, F.
Chem.-Eur. J. 2006, 12, 6506-6513.
402 J. Org. Chem., Vol. 72, No. 2, 2007

Synthesis of 3,4-Disubstituted â-Prolines
6.0 Hz), 3.64 (3H-minor, s), 3.70 (3H-major, s), 3.89 (1H-major,
q, J ) 6.9 Hz), 3.96 (1H-minor, q, J ) 6.8 Hz), 5.08-5.18 (2H,
m), 5.74-5.86 (1H, m), 7.21-7.36 (5H, m); 13C NMR (CDCl3,
100 MHz): δ 14.0, 14.4, 16.6, 22.5, 27.1, 27.2, 30.3, 30.4, 31.7,
45.4, 45.7, 51.3, 52.3, 52.7, 53.1, 53.5, 57.9, 59.0, 116.5, 126.6,
126.7, 127.8, 127.9, 128.0, 137.0, 137.1, 142.8, 143.8, 176.1, 176.3;
Anal. Calcd for C20H31NO2: C, 75.67; H, 9.84; N, 4.41. Found:
C, 75.31; H, 9.76; N, 4.48.
the one of the carbometalation reaction. However, the stereo-
and enantiocontrol is still excellent and allows the enantiose-
lective preparation of diversely substituted â-prolines in high
yield.
Experimental Section
(1R)-Methyl 3-(N-Allyl-N-(1-phenylethyl)amino)-propanoate
5a. To a stirred solution of amine 4 (8.05 g, 50 mmol) in MeOH
(120 mL) was added methyl acrylate (8.60 g, 100 mmol, 2 equiv)
at room temperature. The solution was stirred at room temperature
until completion (72 h). The solvent and the excess of the methyl
acrylate were removed under reduced pressure to give the title
compound (12.1 g, 98%), which was used for further transformation
without purification. [R]20D +17.1 (c 1.17, CHCl3); IR (neat): 3062,
2973, 2814, 1736, 1435, 1194, 915, 699 cm-1; 1H NMR (400 MHz,
CDCl3): δ 1.35 (3H, d, J ) 7.1 Hz), 2.44 (2H, t, J ) 7.4 Hz), 2.76
(1H, dt, J ) 13.2, 7.4 Hz), 2.88 (1H, dt, J ) 13.2, 7.4 Hz), 3.02
(1H, dd, J ) 14.2, 6.1 Hz), 3.12 (1H, dd, J ) 14.2, 6.6 Hz), 3.64
(3H, s), 3.86 (1H, q, J ) 6.8 Hz), 5.08-5.18 (2H, m), 5.81 (1H,
ddt, J ) 17.3, 10.2, 6.6 Hz), 7.20-7.35 (5H, m); 13C NMR (100
MHz, CDCl3): δ 16.8, 33.3, 45.5, 51.5, 53.3, 59.0, 116.7, 126.8,
127.6 (2C), 128.1 (2C), 136.7, 143.9, 173.2; Anal. Calcd for C15H21-
NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.79; H, 8.68; N,
5.64.
General Procedure for Alkylation. To a solution of LDA (12
mmol) in THF (16 mL) was added dropwise a solution of ester
(10 mmol) in THF (10 mL) at -78 °C. The solution was stirred at
-78 °C for 1 h. A solution of alkyl halide (12 mmol) in THF (10
mL) was added slowly at -78 °C. The solution was stirred at -78
°C for 2 h. The cold bath was removed, and the reaction mixture
was stirred at room temperature overnight. The reaction was
quenched with NH4Cl/NH3 (2:1). Et2O (30 mL) was added, and
the layers were separated, the aqueous one being extracted three
times with Et2O. The combined organic layers were washed with
brine and dried over K2CO3, and the solvents were evaporated under
reduced pressure.
(1′R)-Methyl 2-[N-Allyl-N-(1′-phenylethyl)-aminomethyl]-
pent-4-enoate 5d. 5d was prepared according to the general
procedure from 5a (2.47 g, 10 mmol) and allylbromide (885 µL,
12 mmol). Purification by flash chromatography (cyclohexane/ethyl
acetate ) 90:10) afforded the title compound (2.24 g, 78%, dr )
55:45) as a colorless oil. IR (CHCl3): 3077, 2973, 2815, 1736,
1641, 1193, 914, 699 cm-1; 1H NMR (CDCl3, 400 MHz): δ 1.34
(3H-minor, d, J ) 6.8 Hz), 1.36 (3H-major, d, J ) 6.8 Hz), 2.22
(2H-major, m), 2.28 (2H-minor, m), 2.42 (1H-major, dd, J ) 12.6,
5.8 Hz), 2.58 (1H-minor, m), 2.68-2.78 (1H and 1H-minor, m),
2.83 (1H-major, dd, J ) 12.6, 9.0 Hz), 2.99 (1H-major, ddm, J )
14.4, 6.6 Hz), 3.04 (2H-minor, dbr, J ) 6.1 Hz), 3.14 (1H-major,
ddm, J ) 14.4, 6.3 Hz), 3.64 (3H-minor, s), 3.69 (3H-major, s),
3.91 (1H-major, q, J ) 6.8 Hz), 3.96 (1H-minor, q, J ) 6.8 Hz),
4.96-5.20 (4H, m), 5.62-5.86 (2H, m), 7.21-7.35 (5H, m); 13C
NMR (CDCl3, 100 MHz): δ 14.7, 16.2, 34.4, 34.5, 45.1, 45.4, 51.3,
51.8, 52.1, 53.2, 53.4, 58.1, 58.9, 116.5, 116.6, 116.7, 126.6, 126.7,
127.8, 127.94, 127.96, 135.4, 135.5, 136.8, 137.0, 142.9, 143.6,
175.2, 175.4; Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N,
4.87. Found: C, 75.07; H, 8.91; N, 4.81.
(1′R)-Methyl 3-(N-Allyl-N-(1′-phenylethyl)amino)-2-benzyl-
propanoate 5e. 5e was prepared according to the general procedure
from 5a (2.47 g, 10 mmol) and benzylbromide (2.05 g, 12 mmol).
Purification by flash chromatography (cyclohexane/ethyl acetate
) 90:10) afforded 5e (1.99 g, 59%, dr ) 61:39) as a colorless oil.
1
IR (CHCl3): 3026, 2971, 1735, 1202, 1159, 739, 698 cm-1; H
NMR (CDCl3, 400 MHz): δ 1.35 (3H-major, d, J ) 6.8 Hz), 1.35
(3H-minor, d, J ) 6.8 Hz), 2.45 (1H-minor, dd, J ) 12.1, 4.9 Hz),
2.62 (1H-major, dd, J ) 12.9, 5.8 Hz), 2.76-3.00 (4H and 1H-
minor, m), 3.05 (2H-major, dbr, J ) 6.3 Hz), 3.15 (1H-minor, dd,
J ) 14.4, 6.3 Hz), 3.56 (3H-major, s), 3.62 (3H-minor, s), 3.91
(1H-minor, q, J ) 6.8 Hz), 3.95 (1H-major, q, J ) 6.8 Hz), 5.09-
5.16 (2H, m), 5.80 (1H, m), 7.12-7.35 (10H, m); 13C NMR (CDCl3,
100 MHz): δ 14.8, 16.4, 36.5, 47.5, 47.8, 51.4, 52.2, 52.5, 53.3,
53.5, 58.2, 59.0, 116.8, 126.3, 126.7, 126.8, 127.8, 127.9, 128.0,
128.4, 128.7, 136.8, 136.9, 139.5, 142.8, 143.5, 175.3, 175.4; Anal.
Calcd for C22H27NO2: C, 78.30; H, 8.06; N, 4.15. Found: C, 78.26;
H, 8.21; N, 4.06.
(1′R)-Methyl 3-(N-Allyl-N-(1′-phenylethyl)amino)-2-methyl-
propanoate 5b. 5b was prepared according to the general procedure
from 5a (2.47 g, 10 mmol) and methyl iodide (747 µL, 12 mmol).
Purification by flash chromatography (cyclohexane/ethyl acetate
) 90:10) afforded the title compound (1.88 g, 72%, dr ) 63:37)
as a colorless oil. IR (CHCl3): 2973, 2814, 1735, 1493, 1195, 1155,
1
915, 699 cm-1; H NMR (CDCl3, 400 MHz): δ 1.08 (3H-major,
d, J ) 6.8 Hz), 1.14 (3H-minor, d, J ) 6.8 Hz), 1.35 (3H-minor,
d, J ) 6.8 Hz), 1.36 (3H-major, d, J ) 7.1 Hz), 2.34 (1H-major,
dd, J ) 12.6, 6.6 Hz), 2.52 (1H-minor, dd, J ) 11.9, 5.4 Hz), 2.64-
2.78 (1H and 1H-minor, m), 2.85 (1H-major, dd, J ) 12.9, 8.6
Hz), 2.97-3.15 (2H, m), 3.63 (3H-minor, s), 3.69 (3H-major, s),
3.92 (1H-major, q, J ) 6.8 Hz), 3.94 (1H-minor, q, J ) 6.8 Hz),
5.15-5.20 (2H, m), 5.65-5.85 (1H, m), 7.21-7.30 (1H, m), 7.30-
7.36 (4H, m); 13C NMR (CDCl3, 100 MHz): δ 15.2, 15.8, 39.2,
39.4, 51.4, 53.3, 53.5, 53.7, 58.4, 58.7, 116.5, 126.6, 126.7, 127.8,
127.9, 128.0, 137.0, 137.1, 143.1, 143.6, 176.5, 176.6; Anal. Calcd
for C16H23NO2: C, 73.53; H, 8.87; N, 5.36. Found: C, 73.46; H,
8.89; N, 5.39.
(1′R,3S,4S)-Methyl 4-Methyl-1-(1′-phenylethyl)-pyrrolidine-
3-carboxylate 6a. To a stirred solution of diisopropylamine (0.8
mL, 5.7 mmol) in Et2O (20 mL) was added n-BuLi (2.2 mL, 2.2 N
in hexanes, 4.8 mmol) at -70 °C. After being stirred at -70 °C
for 30 min and then at 0 °C for an additional 30 min, the solution
was cooled at -78 °C. A solution of ester 5a (989 mg, 4 mmol) in
Et2O (5 mL) was then added, and the reaction mixture was stirred
at -78 °C for 1 h. An ethereal solution of zinc iodide (20 mL, 1
N in Et2O, 20 mmol) was added dropwise at -70 °C, and the
reaction mixture was allowed to warm to room temperature. The
biphasic mixture was stirred at room temperature for 20 h. The
reaction was hydrolyzed with an aqueous solution of NH4Cl/NH4-
OH (2:1). The layers were separated, and the aqueous one was
extracted three times with ethyl acetate. The combined organic
layers were washed with brine and dried over MgSO4, and the
solvent was evaporated under reduced pressure. Purification by flash
chromatography (cyclohexane/AcOEt ) 80:20) afforded the title
(1′R)-Methyl 2-[N-Allyl-N-(1′-phenylethyl)-aminomethyl]-
heptanoate 5c. 5c was prepared according to the general procedure
from 5a (2.47 g, 10 mmol) and bromopentane (1.81 g, 12 mmol)
in THF (10 mL). Purification by flash chromatography (cyclohex-
ane/ethyl acetate ) 90:10) afforded the title compound (793 mg,
25%, dr ) 59:41) as a colorless oil. IR (CHCl3): 2928, 2857, 1736,
1493, 1372, 1201, 1165, 914, 826, 735, 699 cm-1; 1H NMR (CDCl3,
400 MHz): δ 0.87 (3H, m), 1.20-1.50 (11H, m), 2.33 (1H-major,
dd, J ) 12.3, 5.3 Hz), 2.53 (1H-minor, dd, J ) 12.3, 5.3 Hz), 2.63
(1H, m), 2.74 (1H-minor, dd, J ) 12.2, 9.3 Hz), 2.82 (1H-major,
dd, J ) 12.8, 9.5 Hz), 2.96 (1H-major, ddbr, J ) 14.6, 6.6 Hz),
3.03 (2H-minor, d, J ) 6.3 Hz), 3.14 (1H-major, ddbr, J ) 14.6,
compound (394 mg, 40%) as a pale yellow oil. [R]20 +17.1 (c
D
1.07, CHCl3); IR (neat): 2967, 2780, 1734, 1452, 1434, 1162, 763,
1
700 cm-1; H NMR (400 MHz, CDCl3): δ 1.11 (3H, d, J ) 6.6
Hz), 1.34 (3H, d, J ) 6.6 Hz), 2.22 (1H, dd, J ) 9.2, 7.1 Hz),
2.37-2.49 (1H, m), 2.48-2.55 (1H, m), 2.65-2.69 (2H, m), 2.88
(1H, dd, J ) 9.2, 6.1 Hz), 3.20 (1H, q, J ) 6.6 Hz), 3.67 (3H, s),
J. Org. Chem, Vol. 72, No. 2, 2007 403

Denes et al.
7.21-7.34 (5H, m); 13C NMR (100 MHz, CDCl3): δ 19.7, 23.1,
36.6, 50.4, 51.8, 55.7, 60.5, 65.4, 127.0, 127.3 (2C), 128.3 (2C),
145.5, 175.2; Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N,
5.66. Found: C, 72.78; H, 8.58; N, 5.54.
1.15, CHCl3); IR (neat): 3061, 2971, 2933, 2874, 2780, 1727, 1603,
1
1452, 1208, 1099, 765, 701 cm-1; H NMR (400 MHz, CDCl3):
δ 1.20 (3H, d, J ) 7.0 Hz), 1.39 (3H, d, J ) 6.4 Hz), 2.37-2.43
(1H, m), 2.45 (1H, d, J ) 10.1 Hz), 2.47-2.57 (1H, m), 2.81-
2.84 (2H, m), 3.08 (1H, d, J ) 10.1 Hz), 3.18 (1H, d, J ) 13.1
Hz), 3.30 (1H, q, J ) 6.4 Hz), 3.62 (3H, s), 7.07-7.09 (2H, m),
7.18-7.27 (4H, m), 7.31-7.36 (2H, m), 7.38-7.40 (2H, m); 13C
NMR (100 MHz, CDCl3): δ 14.0, 22.8, 37.8, 40.5, 51.5, 55.2, 58.4,
59.3, 65.3, 126.4, 126.9, 127.3 (2C), 128.1 (2C), 128.2 (2C), 129.6
(2C), 138.2, 145.4, 176.2; Anal. Calcd for C22H27NO2: C, 78.30;
H, 8.06; N, 4.15. Found: C, 78.32; H, 8.04; N, 4.07.
General Procedure for the Carbocyclization Reaction. To a
stirred solution of diisopropylamine (1 mL, 7.1 mmol) in Et2O (10
mL) was added n-BuLi (2.4 mL, 2.5 in hexanes, 6 mmol) at -70
°C. After being stirred at -70 °C for 30 min and then at 0 °C for
an additional 30 min, the solution was cooled at -78 °C. A solution
of ester (2 mmol) in Et2O (5 mL) was then added, and the reaction
mixture was stirred at -60 °C for 2 h. The cold bath was removed,
and the ethereal solution of zinc bromide (6 mL, 1 N in Et2O, 6
mmol) was added at -40 °C. The trouble mixture was stirred at
room temperature for 4 h and hydrolyzed with an aqueous solution
of NH4Cl/NH4OH (2:1). The layers were separated, and the aqueous
one was extracted three times with ethyl acetate. The combined
organic layers were washed with brine and dried over MgSO4, and
the solvents were evaporated under reduced pressure.
(3S,4S)-Methyl 4-(Iodomethyl)-3-methyl-1-((R)-1-phenylethyl)-
pyrrolidine-3-carboxylate 7. Diisopropylamine (0.22 mL, 1.6
mmol) was added to nBuLi (2.3 M in hexanes, 0.63 mL, 1.45
mmol). Once the gummy mixture formed, Et2O (2 mL) was added
and the solution was cooled to -78 °C. An Et2O (2 mL) solution
of ester 5b (130 mg, 0.50 mmol) was added dropwise, and the
mixture was allowed to warm to -30 °C over 3 h before being
cooled back to -60 °C. ZnBr2 (1 M in Et2O, 2.0 mL, 2.0 mmol)
was added, and once a white suspension formed the cooling bath
was removed. The biphasic mixture was stirred at room temperature
(RT) for 16 h and then cooled to -20 °C. A THF (3 mL) solution
of I2 (509 mg, 2.0 mmol) was added dropwise, and the cooling
bath was removed. The mixture was stirred at RT for 3 h and then
hydrolyzed with a saturated aqueous solution of Na2S2O3 (3 mL)
followed by an aqueous solution of NH4Cl/NH4OH (2:1) (10 mL).
The aqueous layer was extracted with Et2O (3 × 20 mL). The
combined organics were washed with brine (30 mL), dried over
MgSO4, filtered, and concentrated. Purification by flash chroma-
tography (pentane/ether ) 90:10) afforded the title compound (96
(1′R,3S,4S)-Methyl 3,4-Dimethyl-1-(1′-phenylethyl)-pyrroli-
dine-3-carboxylate 6b. 6b was prepared according to the general
procedure from 5b (522 mg, 2 mmol). Purification by flash
chromatography (cyclohexane/AcOEt ) 80:20) afforded the title
compound (402 g, 77%) as a pale yellow oil. [R]20D +28.9 (c 1.16,
CHCl3); IR (neat): 3025, 2971, 2932, 2874, 2780, 1732, 1452,
1209, 1124, 765, 702 cm-1; 1H NMR (400 MHz, CDCl3): δ 0.96
(3H, d, J ) 7.1 Hz), 1.20 (3H, s), 1.34 (3H, d, J ) 6.6 Hz), 2.15
(1H, t, J ) 8.5 Hz), 2.27 (1H, d, J ) 9.6 Hz), 2.55-2.64 (1H, m),
2.75 (1H, t, J ) 8.5 Hz), 3.23 (1H, q, J ) 6.6 Hz), 3.35 (1H, d, J
) 9.6 Hz), 3.68 (3H, s), 7.21-7.34 (5H, m); 13C NMR (100 MHz,
CDCl3): δ 13.8, 19.5, 23.2, 38.7, 50.2, 52.0, 59.6, 63.6, 65.4, 126.9,
127.3 (2C), 128.4 (2C), 145.7, 178.0; Anal. Calcd for C16H23NO2:
C, 73.53; H, 8.87; N, 5.36. Found: C, 73.52; H, 8.99; N, 5.35.
(1′R,3S,4S)-Methyl 4-Methyl-3-pentyl-1-(1′-phenylethyl)-pyr-
rolidine-3-carboxylate 6c. 6c was prepared according to the general
procedure from 5c (634 mg, 2 mmol). Purification by flash
chromatography (cyclohexane/AcOEt ) 80:20) afforded the title
mg, 52%) as a colorless oil. [R]20 -13.5 (c 0.99, CHCl3); IR
D
(neat): 2970, 2780, 1729, 1491, 1452, 1371, 1259, 1109, 763, 700
1
cm-1; H NMR (400 MHz, CDCl3): δ 1.21 (3H, s), 1.30 (3H, d,
J ) 6.6 Hz), 2.40 (1H, d, J ) 9.4 Hz), 2.50 (1H, dd, J ) 9.4, 7.2
Hz), 2.91 (1H, m), 2.99 (1H, m), 3.04-3.11 (2H, m), 3.25 (1H, q,
J ) 6.6 Hz), 3.33 (1H, dd, J ) 9.1, 4.4 Hz), 3.66 (3H, s), 7.20-
7.30 (5H, m); 13C NMR (100 MHz, CDCl3): δ 5.6, 18.4, 23.0,
46.8, 50.7, 52.3, 58.6, 63.9, 64.7, 127.0, 127.1 (2C), 128.3 (2C),
145.1, 176.5. HRMS calcd for C16H23INO2 [M - H]+: 388.0768.
Found: 388.0766.
compound (469 mg, 74%) as a pale yellow oil. [R]20 +33.8 (c
D
1.03, CHCl3); IR (neat): 2951, 2932, 2864, 2777, 1734, 1452, 1196,
1131, 764, 701 cm-1; 1H NMR (400 MHz, CDCl3): δ 0.90 (3H, t,
J ) 7.0 Hz), 1.00 (3H, d, J ) 7.6 Hz), 1.03-1.22 (2H, m), 1.23-
1.33 (4H, m), 1.36 (3H, d, J ) 6.6 Hz), 1.45 (1H, dt, J ) 12.4, 4.6
Hz), 1.72 (1H, dt, J ) 12.4, 4.6 Hz), 2.02 (1H, t, J ) 8.8 Hz), 2.23
(1H, d, J ) 9.6 Hz), 2.39-2.49 (1H, m), 2.75 (1H, dd, J ) 8.8,
7.3 Hz), 3.22 (1H, q, J ) 6.6 Hz), 3.53 (1H, d, J ) 9.6 Hz), 3.68
(3H, s), 7.18-7.23 (1H, m), 7.24-7.27 (4H, m); 13C NMR (100
MHz, CDCl3): δ 13.8, 14.0, 22.5, 23.1, 25.1, 32.4, 32.9, 39.5, 51.7,
54.2, 59.9, 60.1, 65.4, 126.8, 127.1 (2C), 128.2 (2C), 145.8, 177.2;
Anal. Calcd for C20H31NO2: C, 75.67; H, 9.84; N, 4.41. Found:
C, 75.53; H, 9.91; N, 4.45.
(1′R, 3S)-Methyl 1-(1′-Phenylethyl)-3,4,4-trimethylpyrroli-
dine-3-carboxylate 12. To a solution of LDA (1.6 mmol) in Et2O
(2 mL) was added dropwise an Et2O (2 mL) solution of ester 11
(120 mg, 0.44 mmol) at -78 °C. Once the addition was completed,
the mixture was allowed to warm to -30 °C over 3 h before being
cooled to -60 °C. ZnI2 (1 M in Et2O, 1.8 mL, 1.8 mmol) was
added, and once a white suspension formed the cooling bath was
removed. The biphasic mixture was stirred at room temperature
for 16 h and then hydrolyzed with an aqueous solution of NH4Cl/
NH4OH (2:1) (4 mL). The aqueous layer was extracted with Et2O
(20 mL). The combined organics were washed with brine (10 mL),
dried over MgSO4, filtered, and concentrated. Purification by flash
chromatography (cyclohexane/ethyl acetate ) 85:15) afforded the
title compound (colorless oil, 76 mg, 63%) as an unseparated
diastereomeric mixture (dr ) 86:14). IR (CHCl3): 2968, 2873,
(1′R,3S,4S)-Methyl 3-Allyl-4-methyl-1-(1′-phenylethyl)-pyr-
rolidine-3-carboxylate 6d. 6d was prepared according to the
general procedure from 5d (574 mg, 2 mmol). Purification by flash
chromatography (cyclohexane/AcOEt ) 80:20) afforded the title
compound (448 mg, 78%) as a pale yellow oil. [R]20 +35.9 (c
D
1.00, CHCl3); IR (neat): 2970, 2776, 1729, 1452, 1207, 1130, 763,
1
1728, 1491, 1139, 1096, 762, 700 cm-1; H NMR (CDCl3, 400
1
700 cm-1; H NMR (400 MHz, CDCl3): δ 1.02 (3H, d, J ) Hz),
MHz, major diastereoisomer): δ 1.00 (3H, s), 1.12 (3H, s), 1.30
(3H, s), 1.33 (3H, d, J ) 6.6), 2.44 (1H, d, J ) 9.9 Hz), 2.48 (1H,
d, J ) 8.8 Hz), 2.69 (1H, d, J ) 8.8 Hz), 3.31 (1H, d, J ) 9.9 Hz),
3.43 (1H, q, J ) 6.8 Hz), 3.68 (3H, s), 7.20-7.30 (1H, m), 7.30-
7.39 (4H, m); 13C NMR (CDCl3, 100 MHz, major diastereoiso-
mer): 21.3, 23.3, 23.5, 25.6, 42.8, 51.3, 53.7, 61.7, 65.0, 65.3, 126.6,
127.2 (2C), 128.2 (2C), 146.3, 176.6; Anal. calcd for C17H25NO2:
C, 74.14; H, 9.15; N, 5.09. Found: C, 74.06; H, 9.15; N, 4.91.
(1′R,3S,4R)-Methyl 3,4-Dimethyl-4-iodomethyl-1-(1′-phenyl-
ethyl)-pyrrolidine-3-carboxylate 13. To a solution of LDA (1.6
mmol) in Et2O (2 mL) was added dropwise an Et2O (2 mL) solution
of ester 11 (120 mg, 0.44 mmol) at -78 °C. Once the addition
was completed, the mixture was allowed to warm to -30 °C over
1.33 (3H, d, J ) 6.6 Hz), 2.11 (1H, t, J ) 8.5 Hz), 2.22 (1H, dd,
J ) 13.7, 8.1 Hz), 2.32 (1H, d, J ) 9.7 Hz), 2.47-2.52 (2H, m),
2.73 (1H, t, J ) 8.5 Hz), 3.21 (1H, q, J ) 6.4 Hz), 3.33 (1H, d, J
) 9.7 Hz), 3.67 (3H, s), 4.99-5.06 (2H, m), 5.55-5.65 (1H, m),
7.20-7.32 (5H, m); 13C NMR (100 MHz, CDCl3): δ 13.8, 23.0,
37.1, 39.4, 51.6, 53.9, 59.4, 59.5, 65.2, 117.6, 126.7, 127.0 (2C),
128.1 (2C), 134.3, 145.4, 176.2; Anal. Calcd for C18H25NO2: C,
75.22; H, 8.77; N, 4.87. Found: C, 75.21; H, 8.91; N, 4.73.
(1′R,3S,4S)-Methyl 3-Benzyl-4-methyl-1-(1′-phenylethyl)-pyr-
rolidine-3-carboxylate 6e. 6e was prepared according to the general
procedure from 5e (674 mg, 2 mmol). Purification by flash
chromatography (cyclohexane/AcOEt ) 80:20) afforded the title
compound (398 mg, 59%) as a pale yellow oil. [R]20 +36.6 (c
D
404 J. Org. Chem., Vol. 72, No. 2, 2007

Synthesis of 3,4-Disubstituted â-Prolines
3 h before being cooled to -60 °C. ZnI2 (1 M in Et2O, 1.8 mL, 1.8
mmol) was added, and once a white suspension formed the cooling
bath was removed. The biphasic mixture was stirred at room
temperature for 16 h and then cooled to -50 °C. I2 (509 mg, 2.0
mmol) in THF (3 mL) was added dropwise, and the cooling bath
was removed. The mixture was stirred at RT for 4 h and then
hydrolyzed with a saturated aqueous solution of Na2S2O3 (3 mL)
followed by an aqueous solution of NH4Cl/NH4OH (2:1) (10 mL).
The aqueous layer was extracted with Et2O (3 × 20 mL). The
combined organics were washed with brine (30 mL), dried over
MgSO4, filtered, and concentrated. Purification of the crude (dr )
70:11:10:9) by flash chromatography (cyclohexane/ethyl acetate )
85:15) afforded the title compound (pale yellow oil, 74 mg, 43%)
as an unseparated mixture of two diastereoisomers (dr ) 90:10).
IR (CHCl3): 2969, 2815, 1727, 1491, 1452, 1373, 1286, 1211, 762,
700 cm-1; 1H NMR (CDCl3, 400 MHz, major diastereoisomer): δ
1.15 (3H, s), 1.32 (3H, s), 1.35 (3H, d, J ) 6.6 Hz), 2.51 (1H, d,
J ) 9.5 Hz), 2.60 (1H, d, J ) 9.9 Hz), 3.06 (1H, d, J ) 9.5 Hz),
3.24 (1H, d, J ) 9.9 Hz), 3.40-3.47 (2H, m), 3.65-3.69 (4H, m),
7.20-7.30 (1H, m), 7.30-7.39 (4H, m); 13C NMR (CDCl3, 100
MHz, major diastereoisomer): δ 18.1, 21.0, 23.2, 24.9, 45.3, 51.7,
52.8, 61.9, 63.9, 64.5, 126.8, 127.1 (2C), 128.3 (2C), 145.5, 175.4;
HRMS calcd for C17H25INO2 [M - H]+: 402.0930. Found:
402.0922.
General Procedure for the Domino Conjugate Addition/
Cyclization with Zinc-Copper Mixed Reagents. To a suspension
of copper cyanide (197 mg, 2.2 mmol) in Et2O (10 mL) was added
dropwise an ethereal solution of zinc bromide (2.2 or 8 mL, 1 M
in Et2O, 2.2 or 8 mmol, see text), followed by RLi (2.2 mmol) at
-10 °C. The reaction mixture was stirred at 0 °C for 1 h, and a
solution of 15 (2 mmol) in Et2O was added dropwise at 0 °C. The
cold bath was removed, and the biphasic mixture was stirred at
room temperature for 1-12 h. The reaction was hydrolyzed with
an aqueous solution of NH4Cl/NH4OH (2:1). The layers were
separated, and the aqueous one was extracted three times with ethyl
acetate. The combined organic layers were washed with brine and
dried over MgSO4, and the solvents were evaporated under reduced
pressure.
7.3 Hz), 3.21 (1H, q, J ) 6.5 Hz), 3.52 (1H, d, J ) 9.6 Hz), 3.69
(3H, s), 7.20-7.23 (1H, m), 726-7.35 (4H, m); 13C NMR (100
MHz, CDCl3): δ 13.9, 14.2, 22.7, 23.2, 25.5, 29.2, 30.2, 31.9, 33.1,
39.5, 51.8, 54.2, 60.0, 60.2, 65.4, 126.8, 127.2 (2C), 128.2 (2C),
145.8, 177.3; Anal. Calcd for C22H35NO2: C, 76.47; H, 10.21; N,
4.05. Found: C, 76.46; H, 10.36; N, 4.06.
(1′R,3S,4S)-Methyl 3-(Cyclohex-1-enyl)methyl-4-methyl-1-(1′-
phenylethyl)-pyrrolidine-3-carboxylate 6h. 6h was prepared
according to the general procedure from 15 (519 mg, 2 mmol) using
an ethereal solution of zinc bromide (4 mL, 1 M in Et2O, 4 mmol)
and cyclohexenyllithium (2.26 mL, 1.77 M in Et2O, 4 mmol).
Purification by flash chromatography (cyclohexane/AcOEt ) 80:
20) afforded the title compound (348 mg, 51%) as a pale yellow
oil. [R]20 +38.1 (c 1.01, CHCl3); IR (neat): 2932, 2835, 1730,
D
1
1452, 1203, 1100, 764, 701 cm-1; H NMR (400 MHz, CDCl3):
δ 1.04 (3H, d, J ) 6.9 Hz), 1.36 (3H, d, J ) 6.6 Hz), 1.43-1.57
(4H, m), 1.69-1.86 (2H, m), 1.93-2.00 (2H, broad s), 2.11-2.16
(2H, m), 2.36 (1H, d, J ) 9.8 Hz), 2.36-2.43 (1H, m), 2.48 (1H,
d, J ) 13.9 Hz), 2.73 (1H, dd, J ) 8.8, 7.9 Hz), 3.23 (1H, q, J )
6.6 Hz), 3.38 (1H, d, J ) 9.8 Hz), 3.66 (3H, s), 5.40 (1H, broad s),
7.20-7.23 (1H, m), 7.27-7.31 (2H, m), 7.32-7.36 (2H, m); 13C
NMR (100 MHz, CDCl3): δ 13.7, 22.2, 23.0, 23.1, 25.4, 28.9, 40.8,
41.0, 51.6, 53.3, 59.2, 59.5, 65.5, 124.5, 126.7, 127.2 (2C), 128.1
(2C), 134.4, 145.7, 177.2; Anal. Calcd for C22H31NO: C, 77.38;
H, 9.15; N, 4.10. Found: C, 77.33; H, 9.18; N, 4.03.
(1′R,3S,4S)-Methyl 4-Methyl-3-(2-methylallyl)-1-(1′-phenyl-
ethyl)-pyrrolidine-3-carboxylate 6i. 6i was prepared according to
the general procedure from 15 (519 mg, 2 mmol) using an ethereal
solution of zinc bromide (4 mL, 1 M in Et2O, 4 mmol) and
isopropenyllithium (3.51 mL, 1.14 M in Et2O, 4 mmol). Purification
by flash chromatography (cyclohexane/AcOEt ) 80:20) afforded
the title compound (350 mg, 58%) as a pale yellow oil. [R]20D +38.7
(c 1.10, CHCl3); IR (neat): 3074, 2970, 2932, 2779, 1731, 1452,
1
1199, 764, 702 cm-1; H NMR (400 MHz, CDCl3): δ 1.04 (3H,
d, J ) 7.1 Hz), 1.36 (3H, d, J ) 6.6 Hz), 1.64 (3H, s), 2.09 (1H,
m), 2.21 (1H, d, J ) 14.2 Hz), 2.36 (1H, d, J ) 9.9 Hz), 2.43 (1H,
m), 2.56 (1H, d, J ) 14.2 Hz), 2.75 (1H, dd, J ) 9.1, 7.3 Hz), 3.24
(1H, q, J ) 6.6 Hz), 3.50 (1H, d, J ) 9.9 Hz), 3.69 (3H, s), 4.66
(1H, s), 4.78 (1H, s), 7.20-7.36 (5H, m); 13C NMR (100 MHz,
CDCl3): δ 13.7, 23.1, 23.4, 40.6, 40.8, 51.8, 53.1, 59.5, 59.6, 65.4,
113.4, 126.8, 127.3 (2C), 128.2 (2C), 142.4, 145.7, 177.1; Anal.
Calcd for C19H27NO2: C, 75.71; H, 9.03; N, 4.65. Found: C, 75.61;
H, 9.09; N, 4.54.
(1′R,3S,4S)-Methyl 4-Methyl-1-(1′-phenylethyl)-3-propylpyr-
rolidine-3-carboxylate 6f. 6f was prepared according to the general
procedure from 15 (579 mg, 2 mmol) using an ethereal solution of
zinc bromide (8.2 mL, 1 M in Et2O, 8.2 mmol) and EtLi (1.60
mL, 1.26 M in Et2O, 2.2 mmol). Purification by flash chromatog-
raphy (cyclohexane/AcOEt ) 80:20) afforded the title compound
(359 mg, 62%) as a pale yellow oil. [R]20D +33.9 (c 1.03, CHCl3);
IR (neat): 3025, 2959, 2932, 2872, 2777, 1732, 1452, 1130, 764,
(3S*,4S*)-Methyl 1-Cyclohexylmethyl-3,4-dimethylpyrroli-
dine-3-carboxylate 20. To a stirred solution of diisopropylamine
(1 mL, 7.1 mmol) in Et2O (10 mL) was added n-BuLi (2.4 mL,
2.5 in hexanes, 6 mmol) at -70 °C. After being stirred at -70 °C
for 30 min and then at 0 °C for an additional 30 min, the solution
was cooled at -78 °C. A solution of aminoester 19 (507 mg, 2
mmol) in Et2O (5 mL) was then added, and the reaction mixture
was stirred at -60 °C for 2 h. The cold bath was removed, and the
ethereal solution of zinc bromide (6 mL, 1 N in Et2O, 6 mmol)
was added at -40 °C. The trouble mixture was stirred at room
temperature for 4 h and hydrolyzed with an aqueous solution of
NH4Cl/NH4OH (2:1). The layers were separated, and the aqueous
one was extracted three times with ethyl acetate. The combined
organic layers were washed with brine and dried over MgSO4, and
the solvents were evaporated under reduced pressure. Purification
by flash chromatography (cyclohexane/ethyl acetate ) 80:20)
afforded the title compound as a pale yellow oil (243 mg, 48%);
IR (neat): 2932, 2854, 1732, 1667, 1450, 1275, 1128, 917, 731
1
701 cm-1; H NMR (400 MHz, CDCl3): δ 0.92 (3H, t, J ) 7.2
Hz), 1.00 (3H, d, J ) 7.1 Hz), 1.04-1.31 (2H, m), 1.36 (3H, d, J
) 6.6 Hz), 1.38-1.47 (1H, m), 1.65-1.74 (1H, m), 1.96-2.02
(1H, m), 2.22 (1H, d, J ) 9.6 Hz), 2.39-2.48 (1H, m), 2.75 (1H,
dd, J ) 8.9, 7.3 Hz), 3.21 (1H, q, J ) 6.6 Hz), 3.54 (1H, d, J )
9.6 Hz), 3.69 (3H, s), 7.20-7.34 (5H, m); 13C NMR (100 MHz,
CDCl3): δ 13.8, 14.7, 18.8, 23.1, 35.4, 39.5, 51.7, 54.2, 60.0, 60.2,
65.4, 126.8, 127.2 (2C), 128.2 (2C), 145.8, 177.3; Anal. Calcd for
C18H27NO2: C, 74.70; H, 9.40; N, 4.84. Found: C, 74.65; H, 9.55;
N, 4.80.
(1′R,3S,4S)-Methyl 3-Heptyl-4-methyl-1-(1′-phenylethyl)-pyr-
rolidine-3-carboxylate 6g. 6g was prepared according to the
general procedure from 15 (519 mg, 2 mmol) using an ethereal
solution of zinc bromide (8.2 mL, 1 M in Et2O, 8.2 mmol) and
HexLi (0.88 mL, 2.5 M in hexane, 2.2 mmol). Purification by flash
chromatography (cyclohexane/AcOEt ) 80:20) afforded the title
1
cm-1; H NMR (400 MHz, CDCl3): δ 0.79-0.88 (2H, m), 0.97
compound (373 mg, 54%) as a pale yellow oil. [R]20 +30.3 (c
(3H, d, J ) 7.1 Hz), 1.17 (3H, s), 1.14-1.24 (2H, m), 1.33-1.42
(1H, m), 1.64-1.82 (6H, m), 2.07-2.19 (3H, m), 2.27 (1H, dd, J
) 11.7, 8.1 Hz), 2.56-2.65 (1H, m), 2.88 (1H, t, J ) 8.4 Hz),
3.27 (1H, d, J ) 9.7 Hz), 3.67 (3H, s); 13C NMR (100 MHz,
CDCl3): δ 13.8, 19.2, 26.3, 27.0, 31.8, 32.0, 38.7, 50.3, 52.0, 61.9,
63.7, 65.1, 178.0; Anal. Calcd for C15H27NO2: C, 71.10; H, 10.74;
N, 5.53. Found: C, 71.04; H, 10.76; N, 5.41.
D
1.07, CHCl3); IR (neat): 3025, 2931, 2856, 2777, 1734, 1452, 1208,
1131, 764, 701 cm-1; 1H NMR (400 MHz, CDCl3): δ 0.91 (3H, t,
J ) 6.9 Hz), 1.00 (3H, d, J ) 7.1 Hz), 1.05-1.20 (2H, m), 1.25-
1.32 (8H, m), 1.35 (3H, d, J ) 6.5 Hz), 1.44 (1H, dt, J ) 12.6, 4.5
Hz), 1.71 (1H, dt J ) 12.6, 5.4 Hz), 2.00 (1H, t, J ) 8.8 Hz), 2.22
(1H, d, J ) 9.6 Hz), 2.38-2.48 (1H, m), 2.74 (1H, dd, J ) 8.8,
J. Org. Chem, Vol. 72, No. 2, 2007 405

Denes et al.
Methyl 1-(1′-Cyclohexylethyl)-3,4-dimethylpyrrolidine-3-car-
boxylate 22. To a stirred solution of diisopropylamine (1 mL, 7.1
mmol) in Et2O (10 mL) was added n-BuLi (2.4 mL, 2.5 in hexanes,
6 mmol) at -70 °C. After being stirred at -70 °C for 30 min and
then at 0 °C for an additional 30 min, the solution was cooled at
-78 °C. A solution of ester 21 (535 mg, 2 mmol) in Et2O (5 mL)
was then added, and the reaction mixture was stirred at -60 °C
for 2 h. The cold bath was removed, and the ethereal solution of
zinc bromide (6 mL, 1 N in Et2O, 6 mmol) was added at -40 °C.
The trouble mixture was stirred at room temperature for 4 h and
hydrolyzed with an aqueous solution of NH4Cl/NH4OH (2:1). The
layers were separated, and the aqueous one was extracted three
times with ethyl acetate. The combined organic layers were washed
with brine and dried over MgSO4, and the solvents were evaporated
under reduced pressure. Purification by flash chromatography
(cyclohexane/ethyl acetate ) 80:20) afforded the title compound
as a mixture of inseparable diastereomers (439 mg, 82%, dr ) 57:
43). IR (neat): 2932, 2854, 1732, 1667, 1450, 1275, 1128, 917,
1.54-1.80 (5H, m), 2.06-2.17 (1H and 1H-major, m), 2.23 (1H-
minor, m), 2.30 (1H-major, d, J ) 9.1 Hz), 2.36 (1H-minor, d,
J ) 9.1 Hz), 2.59 (1H, m), 2.91 (1H-minor, m), 2.98 (1H-major,
m), 3.25 (1H-minor, d, J ) 9.1 Hz), 3.31 (1H-major, d, J ) 9.1
Hz), 3.69 (3H, s); 13C NMR (100 MHz, CDCl3): δ 11.8, 12.5,
13.6, 18.7, 26.6, 26.78, 26.84, 27.0, 27.4, 30.8, 38.2, 41.4, 41.6,
48.8, 51.7, 57.0, 58.0, 61.3, 61.5, 62.3, 62.9, 177.6, 177.7; HRMS
calcd for C16H30NO2 [M - H]+: 268.2277. Found: 268.2272.
Acknowledgment. We thank the Ministe`re de la Recherche
for a grant (to F.D.) and Monique Baudry for preparing the
starting materials.
Supporting Information Available: Multistep preparation of
compounds 11, 15, 19, and 21, chemical correlation (compounds
1
8-10) as well as H and 13C spectra for compounds 5a-e, 6a-i,
7, 9-13, 15, and 19-22. This material is available free of charge
1
731 cm-1; H NMR (400 MHz, CDCl3): δ 0.85-1.43 (6H, m),
via the Internet at http://pubs.acs.org.
0.90 (3H-minor, d, J ) 6.6 Hz), 0.92 (3H-major, d, J ) 6.6 Hz),
0.98 (3H, d, J ) 7.1 Hz), 1.18 (3H-major, s), 1.19 (3H-minor, s),
JO061603H
406 J. Org. Chem., Vol. 72, No. 2, 2007