Silver-catalyzed dynamic systemic resolution of α-iminonitriles in a 1,3-dipolar cycloaddition process

Article abstract of DOI:10.1039/c4cc00944d

A dynamic azomethine ylide system was established using Sc(OTf)₃ and Ag/Taniaphos as catalysts. The system was subsequently kinetically resolved in a tandem 1,3-dipolar cycloaddition process where the silver complex acted as both a reaction catalyst and an external selector, resulting in the formation of an exclusive pyrrolidine product in good yield and enantiopurity. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00944d

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Silver-catalyzed dynamic systemic resolution
of a-iminonitriles in a 1,3-dipolar cycloaddition
process†
Cite this: Chem. Commun., 2014,
50, 3792
Received 5th February 2014,
Accepted 18th February 2014
Lei Hu and Olof Ramstrom*
¨
DOI: 10.1039/c4cc00944d
www.rsc.org/chemcomm
A dynamic azomethine ylide system was established using Sc(OTf)3 and for asymmetric heterocycle synthesis using biocatalytic action.30,31
Ag/Taniaphos as catalysts. The system was subsequently kinetically The efficient construction of enantiopure and structurally diverse
resolved in a tandem 1,3-dipolar cycloaddition process where the silver heterocycles is one of the most important tasks in synthetic
complex acted as both a reaction catalyst and an external selector, medicinal chemistry. For instance, access to five-membered
resulting in the formation of an exclusive pyrrolidine product in good heterocycles, especially pyrrolidines, is highly desirable because
yield and enantiopurity.
of their wide presence in synthetic building blocks, natural
products, and active pharmaceutical ingredients.32–34 Repre-
Dynamic chemistry at the constitutional level remains one of sentative structures include, e.g., proline, hygrine, the antibiotic
the most powerful methods for the generation and exploration of (ꢀ)-anisomycin, and the anti-cholinergic agent procyclidine for
complex systems. Based on kinetically labile bonds of covalent or the treatment of parkinsonism and akathisia. Herein, we
non-covalent nature, the spontaneous generation of systems of describe a dynamic systemic resolution protocol to enantio-
interconvertible adducts or complexes can be accomplished enriched pyrrolidine-2-carbonitrile structures carrying four
under thermodynamic control. Due to the adaptive nature of contiguous chiral centers using a combination of transimina-
the systems, the application of internal or external pressures can tion and ylide formation/cycloaddition catalysis (Fig. 1).
lead to responsive states, where the constituents are forced to
The dynamic system was generated from a sequential rever-
adjust to form the optimal overall arrangement. As a result of sible process involving imine formation and Ag+-catalyzed
this rearrangement process, amplification of the optimal azomethine ylide formation in the presence of base. Ag+/Cu+-
constituent(s) can take place at the expense of less favored catalyzed 1,3-dipolar (Huisgen) cycloaddition is in this context
combinations, in a primitive sense, resulting in a thermo- considered to be one of the best strategies for the stereo-
dynamically controlled evolutive process.1–22
selective synthesis of pyrrolidine derivatives due to the high
Although reversibility is a cornerstone to achieve these selectivity with different chiral ligands and its atom-economical
effects, the resulting entities are inherently labile. Kinetically properties.35–40 Initially, generation of dynamic a-iminonitrile
controlled steps can, however, be efficiently coupled to dynamic systems was investigated under Lewis acidic conditions, using
systems, much in the sense of common natural processes, glycine methyl ester and four different aldehydes. The systems
leading to kinetic resolution of the systems, i.e. dynamic were thus established using 0.1 equivalents of ZnBr2 or Sc(OTf)3
systemic resolution (DSR). If the kinetic steps are selective, as transimination catalysts, respectively.25,41 ZnCl2 and Zn(OTf)2
complete amplification of the best fitting species will occur
essentially regardless of the thermodynamic equilibrium.7,17,23–29
In addition to developing methods to explore the features
and properties of complex systems per se, this resolution
concept also enables efficient screening and identification of
components and conditions of synthetic processes. We have,
for example, more recently explored dynamic systemic resolution
Department of Chemistry, KTH – Royal Institute of Technology, Teknikringen 30,
Stockholm, Sweden. E-mail: ramstrom@kth.se
† Electronic supplementary information (ESI) available: Experimental procedures;
Fig. 1 Dynamic systemic resolution of metal-coordinated azomethine
analytical data. See DOI: 10.1039/c4cc00944d
ylide system.
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Table 1 Screening of reaction conditionsa
Entry Solvent T (1C) Base
Yieldb (%) drc (%) eed (%)
1
2
3
4
5
DCM
Diethyl ether rt
THF
THF
THF
rt
TEA
TEA
TEA
NaOAc 76
TEA 74
54
61
72
69 : 31
90 : 10
78 : 22
75 : 25
89 : 11
62
82
89
76
92
rt
rt
0
a
Reaction conditions: compound 2a (0.12 mmol), aldehyde 1b–m
(0.12 mmol), dimethyl fumarate (0.16 mmol), Sc(OTf)3 (0.006 mmol),
b
c
AgOAc (0.012 mmol), Taniaphos (0.012 mmol). Isolated yield. Deter-
Fig. 2 1H NMR spectra of the dynamic system: (bottom) at imine equili-
brium; (top) after resolution.
1
d
mined by H NMR from the crude 4k–4k0 mixture. Determined by
chiral HPLC (Chiralpak OJ column).
were in this case also tested, however, resulting in lower rates. used to generate the dynamic metal coordinated azomethine ylide
According to 1H NMR spectroscopy, imine exchange was expectedly system and catalyze the ensuing kinetic 1,3-dipolar cycloaddition.
observed in both catalysts, where in this case Sc(OTf)3 proved Other ligands were also evaluated, however, resulting in low
more efficient than ZnBr2, promoting equilibrium formation enantioselectivities. Upon addition of dimethyl fumarate as
within two hours. However, imine decomposition was also dipolarophile, pyrrolidines 4k (major) and 4k0 (minor) were
observed with both catalysts, where the imines were completely observed as the only products in 54% yield, 69 : 31 dr and 62% ee
decomposed after an additional two hours reaction time in the after 6 hours of reaction time (Scheme 1).
presence of Sc(OTf)3. The reason for this decomposition is most
Since the stereoselective cycloaddition process results from
likely due to polymerization of the glycine methyl ester in the the coordination between the azomethine ylide and the metal–
presence of Lewis acid. Less reactive ethyl and isopropyl esters chiral ligand complex, additional coordination sites in the
resulted in gradual decomposition overnight, and were also formed complex would potentially produce stronger binding
deemed not suitable for the resolution process. In order to and a more stable transition state. In the a-iminonitrile system,
avoid any potential polymerization, 2-aminoacetonitrile was both monodentate and bidentate species could be formed, of
selected instead for the process. Besides promoting ylide for- which heteroaromatic imines 3b, 3k and 3l in principle provide
mation, it is worth noting that 2-cyanopyrrolidine derivatives two coordination sites towards Ag+, thus potentially enhancing
are compounds that possess important bioactivities.42,43 The their interactions with the catalyst and resulting in resolution
dynamic imine system was thus generated from the 2-(benzyl- preference in comparison to the other species in the system.
ideneamino)acetonitrile (2a), mixed with 1 equivalent each of
However, among the heteroaromatic imines, only imine 2k
12 different aldehydes in the presence of 0.05 equivalents resulted in the corresponding cycloaddition products. This can
of Sc(OTf)3 in CDCl3. The equilibrium under these conditions be rationalized from geometry and electronic effects, favoring
was attained within 10 minutes, and no decomposition was metal-coordinated azomethine ylide 3k. Potential cycloaddition
observed even after overnight reaction. The stabilities of the with compound 2b is thus prevented due to impaired chelation
different imines were also of comparable order, showing rela- geometry with the metal center. Imines 2k and 2l share more
tively isoenergetic behavior (Fig. 2). The dynamic a-iminonitrile similarity in the geometry; however, the less efficient over-
system was subsequently subjected to azomethine ylide for- lapping between the S and Ag+ orbitals makes compound 2l
mation in the presence of triethylamine in dichloromethane in less preferred in the following 1,3-dipolar cycloaddition.
a one-pot process. The Ag(I)–Taniaphos complex,44 which exhi-
In order to improve the dynamic systemic resolution conditions,
bits high enantioselectivity in similar reactions, was in this case several reaction parameters were subsequently studied (Table 1).
Scheme 1 Silver-catalyzed asymmetric resolution of sequential dynamic system.
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ˇˇ ´
13 A. M. Belenguer, T. Friscic, G. M. Day and J. K. M. Sanders, Chem.
Among the three solvents tested: dichloromethane (DCM),
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In summary, a sequential, dynamic metal-coordinated azo-
methine ylide system has been designed and developed, sub-
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3794 | Chem. Commun., 2014, 50, 3792--3794
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