Stereoselective synthesis of trans-2,3-disubstituted pyrrolidines via addition to N-acyliminium ions

Article abstract of DOI:10.1016/j.tetlet.2006.02.059

An efficient and stereoselective synthesis of trans-2,3-disubstituted pyrrolidines is described. The intermolecular alkylation of racemic N-acyliminium ions generated in situ from the corresponding 3-substituted lactams proceeds stereoselectively and in h

Full text of DOI:10.1016/j.tetlet.2006.02.059

Tetrahedron Letters 47 (2006) 2489–2492
Stereoselective synthesis of trans-2,3-disubstituted pyrrolidines
via addition to N-acyliminium ions
*
´
´
Nuria Diaz Buezo, Alma Jimenez, Concepcion Pedregal and Paloma Vidal
Departamento de Investigacio´n Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain
Received 12 January 2006; revised 6 February 2006; accepted 13 February 2006
Abstract—An efficient and stereoselective synthesis of trans-2,3-disubstituted pyrrolidines is described. The intermolecular alkyl-
ation of racemic N-acyliminium ions generated in situ from the corresponding 3-substituted lactams proceeds stereoselectively
and in high yield.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of syntheses of 2,3-disubstituted pyrrolidines in the litera-
ture in which the pyrrolidine ring is constructed by
the formation of various different bonds from acyclic
precursors.3
Pyrrolidine derivatives are an important class of organic
compounds due to their frequent occurrence in nature
and their use as intermediates in the synthesis of natural
products and pharmaceuticals.1 Several polysubstituted
pyrrolidines have shown very potent activities as enzyme
inhibitors, or as agonists or antagonists of receptors.
In addition to pharmaceutical applications, the pyrrol-
idine moiety has also seen wide use as a chiral auxiliary
for asymmetric synthesis.2 Accordingly, development of
efficient general methods for the preparation of pyrrol-
idines is of significant value. There are numerous reports
One of the most useful ways to obtain functionalization
at the a position of amines is nucleophilic addition to N-
acyliminium ion intermediates 4 (Scheme 1), which have
been shown to have great synthetic potential.4 N-Acyl-
iminium ions can be generated from a-alkoxycarbonyl
amines 2, obtained either from the corresponding
amines 1 by electrochemical oxidation5 or from lactams
3 by partial reduction to the hemiaminal.6
O
OR2
[O]
[H]
R1
R1
R1
R3
N
R3
R3
N
N
CO2R4
CO2R4
CO2R4
1
3
2
-R2OH
Nu
+
R1
HNu
R1
R3
N
R3
N
CO2R4
CO2R4
4
Scheme 1.
*
Corresponding author. Tel.: +34 91 6633426; fax: +34 91 6633411; e-mail: Pedregal_Concepcion@lilly.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.059

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N. D. Buezo et al. / Tetrahedron Letters 47 (2006) 2489–2492
R1
R1
R1
NuH
1. [H]
RO
O
Nu
N
N
N
2. R2OH/H+
CO2R
CO2R
CO2R
Scheme 2.
R1
R1
R1
LiBEt3H/THF
-78 oC
MeOH/TsOH
rt
O
MeO
HO
N
N
N
CO2tBu
CO2tBu
CO2tBu
5a R1= Me
5b R1= Ph
7a R1= Me
7b R1= Ph
6a R1= Me
6b R1= Ph
Scheme 3.
R1
Intermediates 4 have been reacted with various nucleo-
philes or trapped intramolecularly by alkenes, alkynes,
arenes, or heteronucleophiles, in the presence of Lewis
acids.4 In particular, additions of carbon nucleophiles
to non-substituted cyclic five-membered iminium ions
have been described, and this has been applied to the
synthesis of a natural product.7 Furthermore, additions
to the corresponding substituted N-acyliminium ions to
give 2,5 disubstituted pyrrolidines or prolines have been
described with various stereochemical outcomes.8 How-
ever, the intermolecular addition9 of a nucleophile to the
3-substituted10 N-acyl pyrrolidinium ion has not been
reported to date.
R1
1. R2Cu.MgX2
2. TFA, SCX
MeO
R2
N
N
H
CO2tBu
7a R1= Me
7b R1= Ph
8a-8g
Table 1. Study of the addition of organocopper reagents to the N-
acyliminium ions generated from aminals 7a and 7ba
Entry
R1
R2
Trans/cisb
Yield (%)c
1
2
3
4
5
6
7
Me
Me
Me
Me
Ph
iso-Bu
Ph
3-F–Ph
3-Me–Ph
iso-Bu
Ph
60:40
50
82
96
97
87
97
92
In our quest for 2,3-trans-pyrrolidines we envisioned
a straightforward synthesis from suitable 3-substituted
lactams by addition of the corresponding nucleophiles
to the N-acyl pyrrolidinium generated in situ (Scheme 2).
88:123a,b,p
87:13
88:12
74:26
Ph
Ph
91:93o
88:12
3-F–Ph
a All the reactions were carried out according to the general procedure.
b Diastereomeric ratio and configurational assignment were deter-
mined by NMR analysis. Diastereomeric ratio by integration of
respective protons at position 2 and configurational assignment by
the observation of NOE effects between the methyl signal in position
3 and proton in position 2 for major isomer trans 8b and between
phenyl proton signals and proton in position 2 for major isomer trans
8g. The remaining compounds follow the same pattern.
2. Discussion
The required aminals 7a,b, precursors of the reactive
N-acyliminium intermediates, were prepared from the
corresponding substituted lactams 5a11 and 5b (Scheme
3).12 Selective partial reduction of the lactam group was
accomplished using superhydride in THF at À78 ꢁC.13
Subsequent reaction of the hemiaminals 6a,b in metha-
nol in the presence of a catalytic amount of p-toluene-
sulfonic acid gave the corresponding aminals in
quantitative yields. These compounds were used without
further purification. The reaction of 7a,b with 4 equiv of
R2CuÆMgX2 gave, after deprotection of the nitrogen, a
mixture of 2,3-disubstituted pyrrolidines (Table 1) in
good yields. The organocopper reagent was generated
in situ from stoichiometric amounts of a Grignard
reagent and copper(I) bromide–dimethyl sulfide com-
plex at À40 ꢁC with stirring for 45 min. The reaction
mixture was cooled to À78 ꢁC, and BF3ÆOEt2 was
added. After 30 min, the aminal 7a or 7b was added
c Yields refer to isolated pure compounds after SCX chromatography.
and the mixture allowed to react as it warmed from
À78 ꢁC to room temperature. Finally, hydrolysis of
the carbamate group with TFA gave rise to the free
pyrrolidines (Scheme 3). The diastereomeric ratio of
the crude reaction mixture was determined by NMR,
the major isomer being trans.
Table 1 shows that a variety of Grignard reagents can be
successfully used, demonstrating the general applicabil-
ity of this organometallic species in this reaction. Use

N. D. Buezo et al. / Tetrahedron Letters 47 (2006) 2489–2492
2491
of the readily available Grignard reagents to generate
References and notes
the alkylcopper makes these the reagents of choice com-
pared with their alkyllithium counterparts. The stereo-
selectivity of the reaction is dictated by purely steric
factors, trans attack by the organometallic species
taking place preferentially. The trans diastereoisomer
is obtained with higher stereoselectivity when the
organocopper reagent is bulkier (compare entry 1 with
2–4 and entry 5 with 6 and 7). However, the nature of
substituent R1 is not so important in the stereochemical
outcome of the reaction when the organocopper reagent
is of the aryl type (compare entries 2–4 with 6 and
7). Nonetheless, it is notably more important when an
alkyl organocopper reagent is used (compare entry 1
with 5).
1. A search on the pyrrolidine moiety in the MDDR
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´
C4 bond: (n) Pedrosa, R.; Andres, C.; Duque-Soladana, J.
To a stirred suspension of CuBrÆMe2S (4 mmol) in dry
ether (8 mL), at À40 ꢁC under N2, was added dropwise
a solution of the corresponding Grignard reagent
(4 mmol). After stirring for 45 min, the mixture was
cooled to À78 ꢁC, and BF3ÆOEt2 (4 mmol) was added
dropwise. After 30 min, a solution of 7a or 7b (1 mmol)
in dry ether (1.5 mL) was added dropwise. The mixture
was stirred for 15 min and allowed to reach room tem-
perature over a period of 3 h. After 1 h at room tempera-
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aqueous saturated NH4Cl solution and concentrated
NH3 (1:1) (5 mL) and the mixture stirred for 1 h. The
organic layer was separated, and the aqueous layer
was extracted with ether (3 · 10 mL). The combined
organic extracts were washed with saturated aqueous
NaHCO3 solution (5 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure.
The crude product was dissolved in CH2Cl2 (20 mL)
and TFA (10 mmol) was added. The resulting solution
was stirred overnight. The reaction mixture was concen-
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1
was determined by H NMR from this mixture.14
Chromatographic separation of the major diastereoiso-
mer (except in the isobutyl cases, entries 2 and 5) yielded
final products that were fully characterized.15
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Acknowledgments
We are grateful to O. de Frutos for providing 5b com-
pound and J. F. Espinosa and H. Broughton for their
useful comments.

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N. D. Buezo et al. / Tetrahedron Letters 47 (2006) 2489–2492
9. There are two intramolecular examples reported: (a)
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14. N-Boc deprotection was required due to doubling of
the 1H NMR signals because of rotamers, which makes
the proton assignment very complex.
15. 1H NMR for 8c, 8d, and 8g in CDCl3 are respectively:
7.28–7.20 (m, 2H), 7.15–7.10 (m, 1H), 6.95–6.90 (m, 1H),
3.55 (d, J: 8.5 Hz, 1H), 3.30–3.00 (m, 2H), 2.20–1.85
(m, 3H), 1.60–1.40 (m, 1H), 1.10 (d, J: 6.5 Hz, 3H);
7.25–7.05 (m, 4 H), 3.45 (d, J: 8.5 Hz, 1H), 3.30–3.15
(m, 1H), 3.05–2.95 (m, 1H), 2.38 (s, 3H), 2.20–2.00
(m, 3H), 1.65–1.50 (m, 1H), 1.10 (d, J: 6.5 Hz, 3H);
7.30–7.10 (m, 6H), 7.05–6.85 (m, 3H), 4.14 (d, J: 8.8 Hz,
1H), 3.40–3.20 (m, 2H), 3.10 (dd, J: 17.7 and 8.8 Hz, 1H),
2.30–2.15 (m, 3H).
11. Non-protected nitrogen 5a is commercially available.