Chiral bis(imidazolidine)pyridine-Cu(OTf)2: Catalytic asymmetric endo-selective [3 + 2] cycloaddition of imino esters with nitroalkenes

Article abstract of DOI:10.1021/ja100265j

The novel C₂-symmetric bis(imidazolidine)pyridine (PyBidine) ligand was easily synthesized in a single condensation of 2,6-pyridyl aldehyde and optically active (S,S)-diphenylethylenediamine. In the C₂- symmetric PyBidine?Cu(OTf)₂ complex, imidazolidine rings act as chiral fences to shield the first and third quadrants. Use of the PyBidine?Cu(OTf)₂ complex as a catalyst enabled the highly endo-selective reaction of imino esters and nitroalkenes to give the adducts in up to 99% ee.

Full text of DOI:10.1021/ja100265j

Published on Web 03/26/2010
Chiral Bis(imidazolidine)pyridine-Cu(OTf)2: Catalytic Asymmetric
Endo-Selective [3 + 2] Cycloaddition of Imino Esters with Nitroalkenes
Takayoshi Arai,*,† Asami Mishiro,† Naota Yokoyama,† Kuniko Suzuki,† and Hiroyasu Sato‡
Department of Chemistry, Graduate School of Science, Chiba UniVersity, Inage, Chiba 263-8522, Japan, and
Application Laboratory, Rigaku Corporation, Akishima, Tokyo 196-8666, Japan
Received January 17, 2010; E-mail: tarai@faculty.chiba-u.jp
Pyrrolidines, which are five-membered N-heterocycles, are widely
observed in biologically significant compounds and thus have become
a core skeleton of many drug candidates. Catalytic asymmetric 1,3-
dipolar cyclization1 using chiral metal catalysts (containing metals such
as Co,2 Zn,3 Ag,4 Cu,5 Ca,6 and Ni7) and organocatalysts8 for the
stereoselective construction of the pyrrolidine ring has been successfully
developed. In particular, the reaction of the azomethine ylide generated
from an imino ester and a nitroalkene is a fascinating reaction system
in which an additional nitro functionality can be introduced onto the
pyrrolidine ring.9-12 For this particular reaction, Carretero and co-
workers10a reported one example of exo-selective asymmetric pyrro-
Figure 1. X-ray structure of the PyBidine-Cu(OTf)2-H2O complex.
lidine ring construction in 2005. Although Hou and co-workers11
Counteranions and protons have been omitted for clarity.
succeeded in switching the endo/exo selectivity by tuning the electron
density of the chiral ligand, endo-selective cyclization remains rather
limited.12 Herein, we report the highly efficient catalytic asymmetric endo-
selective [3 + 2] cycloaddition of imino esters with nitroalkenes using a
newly developed bis(imidazolidine)pyridine-Cu(OTf)2 complex.13
The novel C2-symmetric bis(imidazolidine)pyridine (PyBidine)
ligand14 was easily synthesized in a single condensation of 2,6-
pyridyl aldehyde and optically active (S,S)-diphenylethylenediamine
(Scheme 1). The all-trans stereochemical outcome on the imida-
zolidine ring was designed on the basis of the steric repulsion
relayed from the substituents of the chiral diamine.13d
Figure 2. Structural comparison of the PyBidine-metal and pybox-metal
complexes.
Scheme 1. Synthesis of the Bis(imidazolidine)pyridine (PyBidine)
Ligand
themselves act as the chiral fences in the C2-symmetric
PyBidine-Cu(OTf)2 complex to shield the first and third quadrants.
The catalytic activity was demonstrated in the [3 + 2] cycload-
dition of imino esters with nitroalkenes. The PyBidine-Cu(OTf)2
complex smoothly catalyzed the reaction of trans-nitrostyrene
(NA1) and an imino ester (IE1) with the assistance of a basic
additive. Under the optimized reaction conditions using Cs2CO3 in
dioxane (Table 1, entry 8), the 1,3-dipolar cycloaddition was
smoothly catalyzed by PyBidine-Cu(OTf)2 to give the endo
pyrrolidine product in 96% yield (endo/exo ) 99:1). The enanti-
oselectivity of the endo adduct was as high as 99% ee.
The newly developed PyBidine ligand readily provided a metal
complex with Cu(OTf)2. The structure was determined by X-ray
crystallographic analysis of a single crystal as an aqua complex
(Figure 1). The two triflate anions occupy the apical positions, and
the imidazolidines of PyBidine coordinate to the Cu with retention
of the protons on the nitrogen atoms (see the Supporting Informa-
tion). Figure 2 shows a comparison of the tridentate coordination
feature of PyBidine and the structure of the famous C2-symmetric
bis(oxazolinyl)pyridine (pybox) ligand.15 In the pybox-metal
complex, the pyridine and oxazoline rings lie sprawled in the
equatorial plane in coordination with the metal center, and the two
alkyl groups at the stereogenic centers of the oxazolines are arranged
as “chiral fences.” In the current PyBidine-Cu(OTf)2 complex, the
two imidazolidine rings stand perpendicular (∼93°) to the equatorial
tridentate coordination plane. Thus, the imidazolidine rings
Table 1. Optimization of the Reaction Conditions for PyBidine-
Cu(OTf)2-Catalyzed [3 + 2] Cycloaddition
entry
base
solvent
time (h)
yield (%)
endo/exo
ee of endo (%)
1
2
3
4
5
6
7
8
none
dioxane
dioxane
CH3CN
CH2Cl2
toluene
THF
23
21
21
21
21
21
24
22
18
84
83:17
96:4
51
74
35
70
72
n.d.
95
99
Et3N
Et3N
58
78:2
Et3N
>99
90:10
Et3N
65
89:11
a
a
a
Et3N
<66
n.d.
K2CO3
Cs2CO3
dioxane
dioxane
89
96
96:4
99:1
† Chiba University.
‡ Rigaku Corporation.
a Inseparable byproducts were included.
9
5338 J. AM. CHEM. SOC. 2010, 132, 5338–5339
10.1021/ja100265j  2010 American Chemical Society

C O M M U N I C A T I O N S
The generality of the PyBidine-Cu(OTf)2-catalyzed pyrrolidine
synthesis is summarized in Table 2. Electron-deficient and electron-
rich substituents were compatible for both R1 and R3, maintaining
high endo selectivity and excellent enantiomeric excesses. Aliphatic
nitroalkenes were also successfully employed in the reaction (entries
14-16). Furthermore, using trisubstituted nitroalkenes afforded
products having chiral quaternary carbon centers in 99% ee (entries
17 and 18). The reaction using the alanine-derived imino ester (IE9)
constructed the chiral quaternary carbon center at the 2-position of
the pyrrolidine ring. The PyBidine-Cu(OTf)2 catalyst was tolerant
of the hydroxy functionality of NA5.
In conclusion, we have succeeded in the development of a new
bis(imidazolidine)pyridine-Cu complex for the highly endo-
selective [3 + 2] cycloaddition of imino esters to nitroalkenes. The
unique reaction sphere produced by PyBidine has the potential to
furnish highly efficient asymmetric catalyses.
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
Supporting Information Available: Detailed descriptions of ex-
perimental procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
Table 2. PyBidine-Cu(OTf)2-Catalyzed Pyrrolidine Synthesis
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