Enantioselective synthesis of α-heteroarylpyrrolidines by copper-catalyzed 1,3-dipolar cycloaddition of α-silylimines

Article abstract of DOI:10.1021/ol5007373

α-Heteroarylpyrrolidines have been efficiently prepared via 1,3-dipolar cycloaddition between silylimines and activated olefins. In the presence of Cu(CH₃CN)₄PF₆/Walphos as catalytic system, high levels of enantioselectivity (up to >99% ee) and diastereoselectivity were achieved (major formation of C-2/C-4 trans-substituted pyrrolidines). The reaction is compatible with a broad variety of dipolarophiles including maleimides, maleates, fumarates, nitroalkenes, and vinylsulfones. The resulting cycloadducts can be transformed into bioactive pyrrolidine derivatives.

Full text of DOI:10.1021/ol5007373

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of α‑Heteroarylpyrrolidines by Copper-
Catalyzed 1,3-Dipolar Cycloaddition of α‑Silylimines
Ana Pascual-Escudero, María Gonzalez-Esguevillas, Silvia Padilla, Javier Adrio,* and Juan C. Carretero*
́
́ ́
Departamento de Química Organica, Facultad de Ciencias, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
S
* Supporting Information
ABSTRACT: α-Heteroarylpyrrolidines have been efficiently
prepared via 1,3-dipolar cycloaddition between silylimines and
activated olefins. In the presence of Cu(CH3CN)4PF6/
Walphos as catalytic system, high levels of enantioselectivity
(up to ≥99% ee) and diastereoselectivity were achieved (major
formation of C-2/C-4 trans-substituted pyrrolidines). The
reaction is compatible with a broad variety of dipolarophiles
including maleimides, maleates, fumarates, nitroalkenes, and vinylsulfones. The resulting cycloadducts can be transformed into
bioactive pyrrolidine derivatives.
Scheme 1. Rational Design for the Synthesis of α-
Heteroarylpyrrolidines
yrrolidines are considered to be important pharmaco-
1
Pphores widely used in drug design. In particular, the α-
heteroarylpyrrolidine skeleton is present in a large number of
natural products and biologically active compounds. Examples
include nicotine2 and analogues3 (such as α-nicotine4 and ABT
4185), (R)-harmicine,6 BIRZ-227,7 and 3-hydroxy-11-norcyti-
sine8 (Figure 1). All these α-heteroarylpyrrolidines have in
common the absence of substitution at C-5 at the pyrrolidine
unit.
Figure 1. Selected examples of biologically active heteroarylpyrroli-
dines.
We have recently developed an enantioselective procedure to
furnish 5-unsubstituted proline derivatives14 by using N-
(trimethylsilyl)methylimines of pyruvic esters (Scheme 1, eq
2). With these results in mind, we envisaged that a potentially
coordinating heterocyclic moiety could act as an activating
group in silylimine cycloadditions, generating a presumed N,N-
chelated chiral metalodipole that would lead to the desired 5-
unsubstituted α-heteroarylpyrrolidine (Scheme 1, eq 3). This
type of asymmetric cycloaddition would represent a very direct
way for the asymmetric synthesis of α-heteroarylpyrrolidines.
As model reaction we chose the cycloaddition of the
silylimine 1a, prepared from picolinealdehyde, with N-phenyl-
In addition, α-arylated pyrrolidines have found broad
application as ligands and organocatalysts in asymmetric
synthesis.9 Despite the interest of these compounds, except
for a few examples,10 the approaches reported for its
enantioselective preparation are usually based on the use of
chiral auxiliaries.11
Among the current methods for the asymmetric synthesis of
pyrrolidines, the enantioselective metal-catalyzed 1,3-dipolar
cycloaddition of azomethine ylides has emerged as one of the
most powerful.12 However, although great progress has been
recently achieved in this field, the structural scope of this
enantioselective cycloaddition is usually restricted to the use of
Schiff bases of amino acid esters12 or related imines as dipole
precursors13 to provide 5-substituted pyrrolidine derivatives
(Scheme 1, eq 1).
Received: March 10, 2014
Published: April 3, 2014
© 2014 American Chemical Society
2228
dx.doi.org/10.1021/ol5007373 | Org. Lett. 2014, 16, 2228−2231

Organic Letters
Letter
maleimide. Initially, we examined our previously reported
conditions for 1,3-dipolar cycloaddition of pyruvate-derived α-
silylimines14 (3 equiv of silylimine, Cu(CH3CN)4PF6 as metal
source, DTBM-Segphos (4) as ligand and toluene as solvent, at
room temperature). Even though the desired pyrrolidine 3a
was obtained in 70% yield, the cycloaddition occurred with
extremely poor diastereoselectivity and enantioselectivity
(Table 1, entry 1). The use of a silver catalyst (AgOAc)
Table 2. Influence of Lewis Bases in the Cycloaddition
b
c
d
entry additive X (mol %) trans/ cis
yield (%) ee (trans) (%)
Table 1. Reaction Conditions for the Model Reaction
1
2
3
4
5
6
7
Et3N
DMAP
CsF
10
10
10
10
10
10
5
>98/<2
>98/<2
98/2
75
65
54
77
87
85
74
81
93
83
84
96
97
76
DMF
H2O
H2O
H2O
>98/<2
88/12
88/12
88/12
e
a
b
c
CuPF6 = Cu(CH3CN)4PF6. Determined by 1H NMR. Isolated
trans/
d
e
a
b
c
yield. Determined by HPLC. 5 equiv of H2O was used.
entry
[M]
solvent
L*
cis
yield (%) ee (trans) (%)
d
1
2
3
4
5
CuPF6
toluene
toluene
toluene
CH2Cl2
THF
4
4
5
5
5
5
50/50
61/39
52/48
50/50
50/50
70/30
70
39
72
63
84
62
<2
<2
75
79
85
95
Scheme 2. Enantioselective [3 + 2] Cycloaddition of 1e−n
with N-Phenylmaleimide
AgOAc
d
CuPF6
CuPF6
CuPF6
CuPF6
d
d
d
e
6
THF
a
b
c
1
Determined by H NMR. Isolated yield. Determined by HPLC.
d
e
CuPF6 = Cu(CH3CN)4PF6. Reaction at −10 °C.
produced a significant decrease in the reactivity without
improving the selectivity (entry 2). We next screened a
structurally varied set of commercially available chiral ligands
under Cu-catalyzed conditions in toluene as solvent,15 finding
out that Walphos ligand 5 provided the best enantioselectivity
(entry 3, 75% ee). A further enhancement of the
enantioselectivity and diastereoselectivity was observed using
THF as solvent at −10 °C (trans/cis 70/30, 95% ee, entry 6).
We had previously observed with silylimines derived from
pyruvic esters that the use of Lewis bases played a significant
role in the process.14 Thus, we next investigated the influence
of silyl scavengers in the cycloaddition (Table 2). In the
presence of several Lewis bases the amount of the starting silyl
amine could be reduced from 3 to 1.5 equiv while maintaining
good levels of reactivity (entries 1−4). Among the additives
tested, water afforded the best enantioselectivity and similar
results were obtained using either 1 or 5 equiv of water (entries
5 and 6, 96% ee and 97% ee). The cycloaddition can be also
performed using a lower catalyst loading (CuPF6/Walphos, 5
mol % instead of 10 mol %) albeit with a significant erosion of
the enantioselectivity (entry 7).
To demonstrate the scope of the cycloaddition a variety of
silylimines bearing diverse heterocyclic substituents were
subjected to the optimized reaction conditions16 (Scheme 2).
In all cases, the cycloadditions took place with very high
diastereoselectivity (trans/cis >95:<5), providing the trans
adduct in good isolated yield (47−96% yield) and with high
enantioselectivity regardless of the electronic nature and
position of the substituents (82−98% ee). The absolute and
relative configuration of pyrrolidine 3k, obtained by reaction
a
b
Yield for isolated trans adduct. Yield for the trans/cis mixture.
c
Determined by HPLC.
with 4-bromophenylmaleimide, was unequivocally established
by X-ray diffraction.17
Gratifyingly, we found that silylimines with other hetero-
cyclic substitution such as 2-quinolyl, 2-benzothiazolyl, and 2-
thiazolyl proved also to be suitable partners in the cycloaddition
affording the corresponding adducts with high yields, almost
complete trans diastereoselectivity, and high enantioselectivity.
A screening of alternative dipolarophiles was next tested to
explore the scope of this [3 + 2] cycloaddition. It was found
2229
dx.doi.org/10.1021/ol5007373 | Org. Lett. 2014, 16, 2228−2231

Organic Letters
Letter
that acyclic cis symmetrically substituted diactivated alkenes
(such as malonate and bisphenylsulfonyletylene) gave excellent
results, affording the corresponding pyrrolidines with high
diastereoselectivity and asymmetric induction (Scheme 3,
Na(Hg), proving otherwise the absolute configuration at C-2 of
the sulfonylated adducts 12.
A simplified mechanistic hypothesis for the 1,3-dipolar
cycloaddition is shown in Scheme 5. First, we observed that
Scheme 3. Cycloaddition with Other Dipolarophiles
Scheme 5. Mechanistic Hypothesis
no cycloaddition takes place under the optimal reaction
conditions when phenyl-, 3-pyridyl-, or 4-pyridyl-substituted
silylimines were used instead of 1a (see the Supporting
Information). These results suggest that the bidentate
coordination of copper chiral complex with the silylimine 1a
is crucial for the activation of the substrate presumably to form
the starting N,N-complex I. Next, water would facilitate the
desylilation step leading to the key metalodipole II, which
would undertake the cycloaddition with the dipolarophile to
afford the metalated adduct III. Final protonation would
provide the free pyrrolidine and the recovery of the copper
catalyst.
In summary, a practical and efficient procedure for the direct
enantioselective synthesis of α-heteroarylpyrrolidines, via [3 +
2] cycloaddition of heteroarylsilylimines with activated alkenes,
has been developed. By use of Cu(CH3CN)4PF6/Walphos 5 as
the catalyst system, high enantioselectivity and moderate to
high diastereoselectivity have been obtained with a wide variety
of azomethine precursors and dipolarophiles.
a
b
Yield for isolated trans adduct. Yield for the trans/cis mixture (cis/
c
trans terminology with regard to C-2/C-3 substitution). Determined
by HPLC.
adducts 6 and 7). In the cycloaddition with diethyl fumarate
Walphos ligand 5 provided the pyrrolidine 8 with high
enantioselectivity, albeit lower diastereoselectivity (cis/trans
66/34). The cycloaddition with trans unsymmetrically sub-
stituted alkenes such as 2-sulfonyl acrylate and nitrostyrene
took place with complete regioselectivity18 and high diaster-
eoselectivity and enantioselectivity (Scheme 3, adducts 9 and
10).
The stereochemical assignment of compound 9i was
unequivocally established by X-ray diffraction.19 On the other
hand, the cycloaddition of 1,1-(bis-sulfonyl)ethylene afforded a
73/27 mixture of trans/cis isomers with very high enantiose-
lectivity (compound 11).
Similarly, an excellent reactivity was observed in the
cycloaddition with phenyl vinyl sulfone, providing a mixture
of both regioisomers20 12a and 12b in 88% yield (Scheme 4).
This mixture was directly transformed into the known α-
nicotine precursor 1321 (87% ee) by protection of the nitrogen
as Cbz and reductive sulfonyl elimination by treatment with
ASSOCIATED CONTENT
* Supporting Information
X-ray crystallographic data of 3k and 9i. Experimental
procedures, characterization data for new compounds, and
copies of NMR spectra and HPLC charts. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
Scheme 4. Synthesis of α-Nicotine Precursor
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: javier.adrio@uam.es.
*E-mail: juancarlos.carretero@uam.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Ministerio de Economia y
■
́
Competitividad (MINECO, project CTQ2012-35790) and
́
́
Consejeria de Educacion de la Comunidad de Madrid
2230
dx.doi.org/10.1021/ol5007373 | Org. Lett. 2014, 16, 2228−2231

Organic Letters
Letter
(13) For related dipoles, see: azlactones: (a) Melhado, A. D.; Luparia,
M.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12638. α-
Iminophosphonates: (b) Yamashita, Y.; Guo, X.-X.; Takashita, R.;
Kobayashi, S. J. Am. Chem. Soc. 2010, 132, 3262. α-Iminonitriles:
(c) Robles-Machín, R.; Alonso, I.; Adrio, J.; Carretero, J. C. Chem.
Eur. J. 2010, 16, 5286. (d) N-(2-Pyridylmethyl)imines: Padilla, S.;
Tejero, R.; Adrio, J.; Carretero, J. C. Org. Lett. 2010, 12, 5608. (e) α-
(programme AVANCAT; S2009/PPQ-1634) is greatly appre-
ciated. M.G.-E. and A.P.-E. thank the MINECO for predoctoral
contracts.
REFERENCES
■
(1) For selected reviews, see: (a) Bellina, F.; Rossi, R. Tetrahedron
2006, 62, 7213. (b) Xu, W.-F.; Cheng, X.-C.; Wang, Q.; Fang, H. Curr.
Med. Chem. 2008, 15, 374. (c) Calliford, C. V.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 8748.
Iminoamides: Gonzal
Chem. Commun. 2012, 48, 2149.
(14) Hernandez-Toribio, J.; Padilla, S.; Adrio, J.; Carretero, J. C.
́
ez-Esguevillas, M.; Adrio, J.; Carretero, J. C.
́
Angew. Chem., Int. Ed. 2012, 51, 8854.
(2) (a) Bannon, A. W.; Decker, M. W.; Holladay, M. W.; Curzon, P.;
Donelly-Roberts, D.; Puttfarcken, P. S.; Bitner, R. S.; Diaz, A.;
Dickerson, A. H.; Porsolt, R. D.; Williams, M.; Arneric, S. P. Science
1998, 279, 77. (b) Wagner, F. F.; Comins, D. L. Tetrahedron 2007, 63,
8065.
(3) Nicotine analogues have attracted much attention because of
their potential use in the treatment of Alzheimer’s and Parkinson’s
diseases: (a) Sarkar, T. K.; Basak, S.; Wainer, I.; Moaddel, R.;
Yamaguchi, R.; Jozwiak, K.; Chen, H.-T.; Lin, C.-C. J. Med. Chem.
2004, 47, 6691. (b) Kang, C.-Q.; Cheng, Y.-Q.; Guo, H.-Q.; Qiu, X.-
P.; Gao, L.-X. Tetrahedron: Asymmetry 2005, 16, 2141. (c) Blum, A. P.;
Lester, H. A.; Dougherty, D. A. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
13206.
(4) (a) Waterman, L.; Oosterhuis, A. G. J. Pharmacol. Exp. Ther.
1938, 63, 318. (b) Whidby, J. F.; Edwards, W. B., III; Pitner, T. P. J.
Org. Chem. 1979, 44, 794. (c) Che, D.; Siegl, J.; Seitz, G.
Tetrahedron:Asymmetry 1999, 10, 573.
(5) Arneric, S. P.; Anderson, D. J.; Bannon, A. W.; Briggs, C. A.;
Buddafusco, J. J.; Brioni, J. D.; Cannon, J. B.; Decker, M. W.; Donelly-
Roberts, D.; Gopalakrishnan, M.; Holladay, M. W.; Kyncl, J.; Marsh, K.
C.; Pauly, J.; Radek, A.; Rodrigues, A. D.; Sullivan, J. P. CNS Drug Rev.
1995, 1, 1.
(15) See the Supporting Information for details.
(16) Typical procedure for the Asymmetric [3 + 2] Cycloaddition:
(3aS,4S,6aR)-2-Phenyl-4-(2-pyridinyl)tetrahydropyrrolo[3,4-c]pyr-
role-1,3(2H,3aH)-dione (3a). To a solution of Walphos (15.8 mg,
17.10−3 mmol) and Cu(CH3CN)4PF6 (6.3 mg, 17.10−3 mmol) in
THF (0.5 mL), under nitrogen atmosphere, at −10 °C, were
successively added water (3 μL, 0.17 mmol), a solution of N-
phenylmaleimide (30.0 mg, 0.17 mmol) in THF (0.5 mL), and a
solution of 1a (50.0 mg, 0.26 mmol) in THF (0.5 mL). After 24 h at
−10 °C, the mixture was diluted with dichloromethane and washed
with ammonium hydroxide (3 × 5 mL) and brine (3 × 5 mL). The
organic layer was separated, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel flash
chromatography (hexane−EtOAc 2:1) to afford a mixture (88:12) of
the cycloadduct trans-3a and cis-3a (43.9 mg, 87%, colorless solid).
(17) Crystallographic data of 3k are available in the Supporting
Information.
(18) In other 1,3-dipolar cycloadditions of (Z) sulfonyl acrylates, the
regioselectivity was also controlled by the sulfonyl group. See: Lop
Perez, A.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48,
340.
́
ez-
́
(19) Crystallographic data of 9i are available in the Supporting
Information.
(6) Harmicine possesses antileishmania activity: (a) Raheem, I. T.;
Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007,
129, 13404. (b) Szawkalo, J.; Czarnocki, S. J.; Zawadzka, A.;
Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.; Czarnocki, Z.;
Drabowicz, J. Tetrahedron: Asymmetry 2007, 18, 406. (c) Chiou, W.-
H.; Lin, G.-H.; Hsu, C.-C.; Chaterpaul, S. J.; Ojima, I. Org. Lett. 2009,
11, 2659.
(20) The structure of these regioisomers was established by 1H
NMR. See the Supporting Information for details.
(21) Chelucci, G.; Falorni, M.; Giacomelli, G. Synthesis 1990, 1121.
(7) Yee, N. K.; Nummy, L. J.; Byrne, D. P.; Smith, L. L.; Roth, P. G. J.
Org. Chem. 1998, 63, 326.
(8) Per
2012, 29, 555.
́ ́ ́
ez, E. G.; Mendez-Galvez, C.; Cassels, B. K. Nat. Prod. Rep.
(9) For reviews, see: (a) MacMillan, D. W. C. Nature 2008, 455, 304.
(b) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167.
(c) Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Chem. Soc.
Rev. 2012, 41, 2406.
(10) (a) Ozawa, F.; Hayashi, T. J. Organomet. Chem. 1992, 428, 267.
(b) Willoughby, C. A.; Buchwald, S. L. J. Org. Chem. 1993, 58, 7627.
(c) McGrath, M. J.; O’Brien, P. J. Am. Chem. Soc. 2005, 127, 16378.
(11) For recent examples, see: (a) Leemans, E.; Mangelinckx, S.; De
Kimpe, N. Chem. Commun. 2010, 46, 3122. (b) Reddy, L. R.; Prashad,
M. Chem. Commun. 2010, 46, 222. (c) Reddy, L. R.; Das, S. G.; Liu, Y.;
Prashad, M. J. Org. Chem. 2010, 75, 2236. (d) Reddy, L. R.; Gupta, A.
P.; Villhauer, E.; Liu, Y. J. Org. Chem. 2012, 77, 1095.
́
(12) For recent reviews, see: (a) Najera, C.; Sansano, J. M. Top.
Heterocycl. Chem. 2008, 12, 117. (b) Stanley, L. M.; Sibi, M. P. Chem.
Rev. 2008, 108, 2887. (c) Adrio, J.; Carretero, J. C. Chem. Commun.
2011, 47, 6784. For very recent examples, see: (d) Narayan, R.; Bauer,
J. O.; Strohmann, C.; Antonchick, A. P.; Waldmann, H. Angew. Chem.,
Int. Ed. 2013, 52, 12892. (e) Yan, S.; Zhang, C.; Wang, Y.-H.; Cao, Z.;
Zheng, Z.; Hub, X.-P. Tetrahedron Lett. 2013, 54, 3669. (f) Liu, K.;
Teng, H.-L.; Yao, L.; Tao, H.-Y.; Wang, C.-J. Org. Lett. 2013, 15, 2250.
(g) Hutka, H.; Tsubogo, T.; Kobayashi, S. Adv. Synth. Catal. 2013,
355, 1516. (h) Wang, Z.; Luo, S.; Zhang, S.; Yang, W.-L.; Liu, Y.-Z.; Li,
H.; Luo, X.; Deng, W.- P. Chem.Eur. J. 2013, 19, 6739. (i) Gonzal
́
ez-
Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem. Commun. 2013, 49,
4649. (j) He, Z.-L.; Teng, H.-L.; Wang, C.-J. Angew. Chem., Int. Ed.
2013, 52, 2934.
2231
dx.doi.org/10.1021/ol5007373 | Org. Lett. 2014, 16, 2228−2231