Synthesis of chiral pyrrolidine and pyrrole derivatives through the chemoselective Dieckmann reaction of α,β-aminodiesters

Article abstract of DOI:10.1016/S0957-4166(00)00377-3

α,β-Aminodiesters were allowed to react with t-BuOK in THF at -78°C. The chemoselectivity of the Dieckmann cyclization was controlled by the nature of the substituents R₃ and R₄, allowing the preparation of pyrrolidine or pyrrole derivatives. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00377-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4239–4243
Synthesis of chiral pyrrolidine and pyrrole derivatives
through the chemoselective Dieckmann reaction of
a,b-aminodiesters
Ame´rico C. Pinto, Rodrigo V. Abdala and Paulo R. R. Costa*
Laborato´rio de Qu´ımica Bioorgaˆnica (LQB), Nu´cleo de Pesquisas de Produtos Naturais,
Centro de Cieˆncias da Sau´de, bloco H, Ilha da Cidade Universita´ria, Universidade Federal do Rio de Janeiro,
21941-590 Rio de Janeiro, Brazil
Received 1 September 2000; accepted 7 September 2000
Abstract
a,b-Aminodiesters were allowed to react with t-BuOK in THF at −78°C. The chemoselectivity of the
Dieckmann cyclization was controlled by the nature of the substituents R3 and R4, allowing the
preparation of pyrrolidine or pyrrole derivatives. © 2000 Elsevier Science Ltd. All rights reserved.
Pyrrolidine derivatives present a diversity of pharmacological properties and potential phar-
maceutical applications.1 Different strategies have been developed to construct the pyrrolidine
nucleus,2 among them the Dieckmann reaction involving a,b-aminodiesters and related com-
pounds as substrates.3 Herein, we report the Dieckmann reaction of a,b-aminodiesters of type
1. The chemoselectivity of the cyclization (formation of 2 or 3) was shown to be dependent on
the nature of the substituents R3 and R4.
The synthesis of a,b-aminodiesters 1a–g from enoates 4a–c is shown in Scheme 1. Conjugate
addition of benzylamine to 4a led to adduct 5a in good yield. This compound was then alkylated
with BrCH2CO2Et and BrCH2CO2t-Bu, furnishing, respectively, 1a and 1b. The N-debenzylated
derivative 1c was prepared from 1a by hydrogenolysis.
* Corresponding author. E-mail: lqb@nppn.ufrj.br
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00377-3

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Scheme 1. Preparation of a,b-aminoesters 1a–g. (a) Neat BnNH2, −30°C, 48 h, 5a (90%), 5b, (78%), 5c (67%); (b)
BrCH2CO2R (t-Bu or Et), THF/H2O, Na2CO3, reflux, 14 h, 1a (86%), 1b (83%), 1d (84%), 1e (81%), 1f (67%), c-Pd–C
(10%), AcOEt, H2 60 Psi, 4 h, rt, 1c (95%), 1g (96%)
The key step for the synthesis of chiral a,b-aminodiesters 1d–g was the syn-selective conjugate
addition of benzylamine to enantiomerically pure enoates 4b,c, easily prepared from -(+)-man-
D
nitol (Scheme 1). Compound 5b was obtained in 80% de (>95% de after chromatographic
purification) by reacting 4b with neat BnNH2, as previously described by Yamada et al.4
Compound 5c was also prepared with a high syn-selectivity when 4c was used as acceptor. These
adducts were then alkylated with the required a-bromoacetates leading to 1d–f. Hydrogenolysis
of 1e furnished 1g.
The Dieckmann reaction of 1a–g was investigated in the presence of t-BuOK in THF at
−78°C (Scheme 2). Under these conditions compound types 2, 3 or 6 were obtained with
different chemoselectivities, depending on the nature of groups R3 and R4.5
When 1a,b (R3=H; R4=Bn) were used as substrates, the chemoselectivity favored 2a (Scheme
2, entries 1 and 2), despite the nature of the ester group R2, while from N-debenzylated
derivative 1c (entry 3), a complex mixture of products was formed.
In the chiral series, aminoesters 1d–f (R3=1,2-dihydroxyethyldimethylacetal group, R4=Bn)
led exclusively to type 2 pyrrolidines (2b and 2c, respectively), despite the nature of R1 and R2
(entries 4–6), although the chemical yield was lower from 1f (entry 6), even when a more
prolonged reaction time was used. The chemoselectivity could be reversed when N-debenzylated
derivative 1g was used as substrate, but in this case the expected b-ketoester was not isolated,
being transformed into 6 in the reaction medium, probably through enolization followed by
aromatization.6,7
The configuration at C3 in 2b,c was determined by NOE experiments (Fig. 1) once irradiation
at H3 led to an increase in the absorption of one of the hydrogen atoms of the dimethylacetal
moiety (Hc or Hc%) and Hb, while no effect was observed on H2. The NOE experiments also
suggest that in the main conformers of 2b,c the benzyl group at the nitrogen is a-oriented, once
irradiation of H2 led to an increase in the absorption of Ha, Ha% and H5a.
In Scheme 3 we propose a mechanistic rationale to explain the observed results. Due to the
electronic effect of the nitrogen atom, the kinetic deprotonation of 1 led preferentially to

A. C. Pinto et al. / Tetrahedron: Asymmetry 11 (2000) 4239–4243
4241
enolates type E-2, but once potassium enolates equilibrate, even at −78°C,8 the enolate
distribution is thermodynamically controlled, allowing the formation of enolates type E-1,
required to explain the formation of products type 2. On the other hand, the cyclization step is
kinetically controlled once the product distribution did not change when the experiments were
interrupted at different reaction times. Since the cyclization of 1a led preferentially to 2a, one
can conclude that TS1a was favored over TS2a (R3=H, R4=Bn). A possible explanation is that
in the first case CO2R1 and Bn (R4) groups are assuming a 1,3-relationship, while in the second
a stronger 1,2-steric interaction between these groups would be observed (Scheme 3). On the
other hand, when R3 is the dimethylacetal group and R4=Bn, the three substituents in both
transition states TS1b and TS2b are expected to be assuming a trans-trans orientation. However,
while in TS1b CO2R1 and Bn groups are 1,3-cis oriented, the same relationship occurs in TS2b
Scheme 2. Dieckmann reaction of aminodiesters 1a–g
Fig. 1. Experiments of NOE in 2c

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between CO2R2 and dimethylacetal group. This latter interaction should be stronger since both
groups are bulky and polar (stereoelectronic interactions), disfavoring TS2b and, consequently,
providing only compounds type 2. Finally, when R3 is the dimethylacetal group and R4=H, a
1,2-steric interaction occurs between CO2R1 and the dimethylacetal moiety (R3) in the TS1c,
while in TS2c the steric interaction is released once these groups are in a 1,3-relationship.
Therefore, the chemoselectivity was reversed, with the preferential formation of a b-ketoester
type 3, precursor of aromatic derivative 6.
Scheme 3. Proposed transition states leading to 2 and 3
The use of this strategy to prepare enantiomerically pure bioactive pyrrolidine derivatives is
underway in our laboratory.
Acknowledgements
To PRONEX, CNPq and CAPES for financial support. To Francisco A. Santos for 1H NMR
and 13C NMR. To CNPq for fellowships for the authors.
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7. Data for b-ketoester 2b: [h]2D5=+57.6 (c=1.32, CH2Cl2); H NMR (200 MHz, CDCl3/TMS) l (ppm) 1.33 (s, 3H),
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(ppm) 24.29, 25.58, 52.52, 56.19, 58.98, 61.86, 64.77, 65.78, 75.53, 109.65, 128.30, 128.40, 137.36, 167.86, 205.24.
Data for b-ketoester 2c: [h]2D5=+55.85 (c=3.76, CH2Cl2); 1H NMR (200 MHz, CDCl3/TMS) l (ppm) 1.34 (s, 3H),
1.45 (s, 3H), 1.48 (s, 9H), 2.90 (d, 1H, J=17.7 Hz), 3.20 (d, 1H, J=9.0 Hz), 3.39 (d, 1H, J=17.7 Hz), 3.51 (d,
1H, J=13.3 Hz), 3.76 (dd, 1H, J=9.0; 5.6 Hz), 3.89 (dd, 1H, J=8.7; 6.9 Hz), 4.01 (dd, 1H, J=8.7; 6.8 Hz), 4.27
(d, 1H, J=13.3 Hz), 4.49 (ddd, 1H, J=6.9; 6.8; 5.6 Hz), 7.20–7.40 (m, 5ArH); 13C NMR (50 MHz, CDCl3/TMS)
l (ppm) 24.51, 26.04, 27.80, 57.44, 59.10, 61.90, 65.10, 65.82, 76.14, 82.23, 109.70, 127.37, 128.38, 137.55, 166.65,
205.80. Data for pyrrole derivative 6: [h]2D5=+1.7 (c=1.79, CH2Cl2); mp=114–115°C; UV umax=268 80 nm,
1
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1H, J=8.1; 6.7 Hz), 4.27 (dd, 1H, J=8.1; 6.4 Hz), 5.04 (dd, 1H, J=6.7; 6.4 Hz), 5.73 (d, 1H, J=2.8 Hz).
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.
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