One-pot synthesis and theoretical calculation for trifluoromethylated pyrrolizidines by 1,3-dipolar cycloaddition with azomethine ylides and β-trifluoromethyl acrylamides
Graphical abstract
The reaction with β-trifluoromethyl acrylamide 3e and azomethine ylides generated from l-proline and several aldehydes provided the corresponding trifluoromethylated pyrrolizidines with excellent diastereoselectivity (>20/1) in all cases and moderate regioselectivity (up to 1/5.9). A DFT calculation was also examined to reveal the origin of these stereoselectivities.
Introduction
Pyrrolizidine alkaloids are found in many natural products and have a wide variety of bioactivities [1]. Therefore, structurally diverse pyrrolizidines are attractive targets for organic chemists. Many synthetic strategies were developed over the last few decades with high regio- and stereoselectivity [2]. Unfortunately, most synthetic protocols involve environmentally unfriendly compounds, such as transition metals and the resulting chemical waste from these reactions. However, the intermolecular 1,3-dipolar cycloaddition with olefins and azomethine ylides, decarboxylatively generated from l-proline and aldehydes, alleviates these environmental concerns [3]. All three reagents can be incorporated into the final products by a single one-pot reaction with no extra reagents; moreover, water (H2O) and carbon dioxide (CO2) are the only waste products from this reaction (Scheme 1) [4].
Although there are many previous reports on this intriguing synthetic approach toward pyrrolizidines, most studies have encountered problems [5]. First, low chemical yields were often observed. This problem arises from the similar reactivities of carbonyls and olefins as dipolarophiles toward azomethine ylides. As a result of low chemoselectivity, the reaction often results in a large amount of byproducts, such as 1-oxapyrrolizidines [6].
Second, low regio- and/or diastereoselectivity are observed in some reactions because the optimized conditions apply to only a narrow range of substrates [7].
The introduction of fluorinated functional groups into heterocyclic compounds is frequently attempted in drug discovery, and this dramatically alters the pharmacological properties of the parent molecules [8]. The importance of a trifluoromethyl group among several types of fluoroalkyl moieties was observed in many therapeutic medicines [9]. Recently, the stereoselective synthesis of trifluoromethylated pyrrolizidine was reported and expected possible enhancements of biological activity when changing CH3 to CF3 [10]. Despite the elegance of their syntheses, these precedent studies did not investigate expanding the range of substrates.
In this article, we focused on the unique electronic and steric properties of trifluoromethylated olefin and report that β-trifluoromethyl acrylamides are good dipolarophiles toward azomethine ylides generated from l-proline and aldehydes [11]. As a result, various 1-trifluoromethylated pyrrolizidines were obtained in moderate yields and had excellent diastereoselectivities. We also examined a DFT calculation to rationalize these selectivities.
Section snippets
Synthesis
The investigation was started by screening solvents, as shown in Table 1.
In order to suppress the undesired 1-oxapyrrolizidine from the 1,3-dipolar cycloaddition of azomethine ylides and 2a, an excess of dipolarophile should be applied. However, due to cost considerations and fluorinated reagent availability, the screening was initially carried out with 1 equivalent of ethyl 4,4,4-trifluorocrotonate 3a. In fact, most solvents mainly resulted in 1-oxapyrrolizidine as the byproduct and a trace
Conclusions
The azomethine ylides, generated from reacting l-proline and several aldehydes, easily reacted with β-trifluoromethyl acrylates and acrylamides to provide the corresponding trifluoromethylated pyrrolizidines with excellent diastereoselectivity in all cases. The acrylamide 3e gave better regioselectivity in spite of a slower reaction-rate, which was overcome by a separate addition method. To reveal the origin of these selectivities, a theoretical calculation was conducted. The calculation showed
Experimental section
1H NMR spectra were measured on Bruker (400 MHz) spectrometer. Data were reported as follows: chemical shifts in ppm from tetramethylsilane as an internal standard in CDCl3 or CD3OD, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet-doublet, m = multiplet, br = broad), coupling constants (Hz), and assignment. 13C NMR spectra were measured on Bruker (100 MHz) spectrometer with complete proton decoupling. Chemical shifts were reported in ppm from the residual solvent as
Acknowledgments
The authors thank Dr. Michael Chandro Roy and Prof. Fujie Tanaka at Okinawa Institute of Science and Technology Graduate University for help with HRMS. The computations were performed at the Research Center for Computational Science, Okazaki, Japan. This work was supported by MEXT/JSPS KAKENHI (Grant-in-Aid for Scientific Research) Grant Numbers 26810008, 16H00778 and 16KT0165, and a grant from Institute for Quantum Chemical Exploration.
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