Stereoselective synthesis of functionalized perhydropyrrolo[1,2-b]isoxazoles based on (3 + 2)-annulation of donor–acceptor cyclopropanes and isoxazolines

Abstract

A stereoselective route to access substituted pyrrolidine cores via Lewis acid catalyzed (3 + 2)-annulation of donor–acceptor cyclopropanes (DACs) and isoxazolines has been developed. Exclusive cis-2,5-stereoselectivity was governed by kinetically controlled conditions using Sn(OTf)₂ as the catalyst, while excellent trans-2,5-stereoselectivity was achieved by thermodynamically controlled conditions using Sc(OTf)₃ as the catalyst. For DACs bearing electron-poor substituents, Yb(NTf₂)₃ proved to be the most efficient catalyst due to its higher Lewis acidity compared to triflates. The isoxazoline (3 + 2)-annulation reaction was also extended to bicyclo[1.1.0]butanes (BCBs), providing easy access to the 2-azabicyclo[2.1.1]hexane core, which may be considered as a promising 3D-bioisosteric replacement for pyrrole and pyrrolidine motifs.

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The stereoselective synthesis of complex functionalized structures from readily available compounds in a minimal number of steps remains one of the pressing challenges in the development of modern synthetic methodologies.¹ Over the past decades, cycloaddition and annulation reactions of donor–acceptor cyclopropanes (DACs) with various substrates have demonstrated broad potential for controlling the chemo-, regio-, and stereoselectivity of these processes through subtle variation of reaction conditions.²

DAC cycloaddition reactions are widely used to construct various substituted five- and six-membered heterocycles.³ Among the various heterocycles synthesized through DAC cycloaddition reactions, pyrrolidine derivatives are of particular interest since the substituted pyrrolidine moiety is a key structural unit in a number of biologically active and naturally occurring compounds that exhibit diverse types of activities (Scheme 1A).⁴

Scheme 1

Under the action of various Lewis acids, DACs undergo cycloaddition with acyclic imines with rather high efficiency to afford, in most cases, substituted pyrrolidines with high diastereoselectivity.⁵ The only, yet significant, limitation is the requirement to use imines derived exclusively from aromatic aldehydes, which substantially reduces the synthetic significance of this methodology. This limitation does not apply to reactions with cyclic imines.⁶ Accordingly, an alternative synthetic approach to access substituted pyrrolidines may involve DAC cycloaddition with pyrazolines, oxazolines, and related C=N–X-containing heterocycles to yield pyrrolidine-fused structures in which the N–X bond can be readily cleaved under reductive conditions to give functionalized pyrrolidine moieties (Scheme 1B).⁷ However, the available data on such DAC cycloaddition reactions are highly limited.

In the previous work, we showed that the reaction of 2-arylcyclopropane-1,1-dicarboxylates 1 with pyrazolines is efficiently catalyzed by Sc(OTf)₃ to give 1,2-diazabicyclo[3.3.0]octanes 2 as single diastereomers with trans-selectivity of the 2,5-substituents at the pyrrolidine moiety that is formed (Scheme 1C).⁸

A similar [3 + 2]-cycloaddition of DAC 1 to the C=N bond of unsaturated six-membered nitrogen-containing heterocycles was reported by Banerjee et al.⁹ Its distinguishing feature is the opposite cis-selectivity of the 2,5-substituents at the pyrrolidine moiety formed (Scheme 1C).

An elegant stereodivergent method for the intramolecular construction of a hexahydropyrroloisoxazole derivative via opening of a three-membered ring was demonstrated by Kerr et al.¹⁰ The bicyclic product 4 was obtained through intramolecular [3 + 2]-cycloaddition of a zwitterionic intermediate, which is formed by the reaction of cyclopropylalkoxylamine 5 with aldehydes, to the C=N bond of the oxime. In this case, the cis/trans isomerism of cyclization products 4 was determined by the order of mixing of the aldehyde and the catalyst with cyclopropyl derivative 5; however, in all cases, hexahydropyrroloisoxazoles 4 were obtained with high diastereoselectivity. The heterocycle 4 formed in this process contained both ester groups at the β-position to the nitrogen atom (Scheme 1C).

In this work, we propose a stereoselective method for constructing the pyrrolidine moiety via [3 + 2]-cycloaddition of DACs with isoxazolines catalyzed by Lewis acids. In this case, stereoselectivity is regulated by kinetic or thermodynamic control, depending on the choice of the metal catalyst (Sn or Sc). Directed regulation of the Lewis acidity of the catalyst through the selection of a weakly coordinating counter-ion (WCA) NTf₂ instead of OTf allowed us to successfully use less-reactive DACs bearing strongly electron-acceptor aromatic substituents in this process (Scheme 1D).

In the first step, 2-(4-methoxyphenyl)cyclopropane-1,1-dicarboxylate 1a and isoxazoline 6a were chosen as the model substrates, while 10 mol% of scandium, gallium, indium, ytterbium, copper, and tin triflates were chosen as the Lewis acids. All the reactions were carried out in dichloromethane at 25 °C (Table 1).

Table 1 Optimization of the model reaction between DAC 1a and isoxazoline 6a^a

Entry	Lewis acid (10 mol%)	t, h	Yields^b (%)
			endo-7a	exo-7a
a Reactions were carried out at rt in CH2Cl2 with 1 equiv. of 1a and 6a, Lewis acid (10 mol%), and Ar atmosphere. b NMR yields (1,4-dinitrobenzene as the internal standard). c Isolated yields.
1	Sc(OTf)3	2	7^c	91^c
2	Sc(OTf)3	12	Trace	93
3	Yb(OTf)3	2	Trace	63^c
4	In(OTf)3	12	21	26
5	Ga(OTf)3	12	18	12
6	Cu(OTf)2	12	33	34
7	Cu(OTf)2	72	32	39
8	Sn(OTf)2	12	89	–

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It was found that the same expected products of formal (3 + 2)-annulation – four diastereomers of substituted 1-aza-2-oxabicyclo[3.3.0]octane 7a – were obtained in all cases. The yields and isomer ratios varied significantly, depending on the nature of the catalysts used. The stereochemical outcome differed primarily in the endo- or exo-orientation of the para-methoxyphenyl substituent in the bicyclo[3.3.0]octane moiety (Table 1), whereas the ratio of the diastereomers (referred to here as anti- and syn-isomers for clarity) at the C(3) atom remained ca. 1.8 : 1 for endo-7a and 1.2 : 1 for exo-7a.

Nearly complete conversion of the initial cyclopropane 1a was observed in all cases; however, scandium and tin triflates exhibited the highest efficiency in this process, while the other catalysts predominantly led to side reactions of cyclopropane 1a.

The stereochemistry of all the diastereomers obtained in the reaction was determined by X-ray crystallography and NMR spectroscopy. Crystallographic data obtained for one of the crystals of the exo,anti-7a isomer, along with the assignment of its signals in the ¹H and ¹³C NMR spectra, served as the basis for the assignment of the remaining isomers using 2D {¹H,¹H}-NOESY NMR experiments (Fig. 1).

Fig. 1 Key NOE interactions for diastereomers 7a and X-ray crystal structure of exo,anti-7a.

Next, after information on the stereochemistry of the products was obtained, the mechanism of the formation of exo- and endo-diastereomers 7a was clarified by NMR monitoring of this reaction in the presence of Sc(OTf)₃. It was found that significant conversion of the initial cyclopropane 1a occurred already within 1 h, with the initial cycloaddition products being the pair of endo-diastereomers 7a, which subsequently underwent slow conversion to the corresponding pair of exo-diastereomers (Fig. 2). The isomerization rate of the syn-diastereomer was higher than that of the anti-isomer. Apparently, endo-7a forms more rapidly under the (3 + 2)-annulation conditions; however, due to the presence of a strongly polarized C–C bond in 7a, the annulation is reversible, which results in the gradual isomerization of endo-7a into the more thermodynamically stable exo-isomers.

Fig. 2 ¹H NMR monitoring of the reaction mixture.

To confirm the possibility of the cleavage of the C(5)–C(6) bond in the resulting bicyclic endo-7a adducts and their irreversible isomerization to more thermodynamically stable exo-7a isomers, a series of control experiments were carried out. For this purpose, both pairs of isomeric products, endo- and exo-7a, were preliminarily isolated in relatively pure form. It was found that both syn- and anti-isomers of endo-7a underwent substantial isomerization to exo-7a within 12 h in the presence of Sc(OTf)₃. In contrast, the reverse isomerization of exo-7a to endo-7a was not observed in the presence of Sc(OTf)₃ or Sn(OTf)₂ (Scheme 2), which supports our hypothesis.

Scheme 2 Isomerization of kinetic (endo-7a) and thermodynamic (exo-7a) products.

It is interesting to note that a change in the configuration of the aryl substituent leads to a change in the orientation of the Me and CO₂Me substituents relative to the bicyclic moiety. As a result, the seemingly more favorable position of the anti-CO₂Me group is converted into the syn-position. Consequently, the isomerization rate of the endo,anti-7a isomer appears to be lower than that of the endo,syn-isomer.

It was also found that the C(5)–C(6) bond could be cleaved even under thermal conditions in the absence of any added Lewis acid, but only at significantly higher temperatures. In fact, endo-7a undergoes isomerization by 11% within 2 h at 150 °C, while the content of exo-7a isomers reaches 60% after 4 h at 170° C. As in the catalytic variant, the isomerization rate of the syn-isomer was higher than that of the anti-isomer. The reverse transformation of exo-7a into endo-7a was practically not observed.

The regularities described above clearly indicate that the endo-7a diastereomer is formed as the kinetically controlled product, while exo-7a is the thermodynamically controlled product. The proposed mechanism involves activation of the three-membered ring 1a by the Lewis acid through the carboxylate groups, followed by a nucleophilic attack by the nitrogen atom of isoxazoline 6 to form intermediate I. The subsequent attack of the malonyl moiety at the C=N bond creates the target bicyclo[3.3.0]octane skeleton. The stereoselectivity of the formation of the endo-7a kinetic product is presumably controlled by the more favorable conformation of intermediate II for the nucleophilic attack at the C=N bond compared to that of conformation III (Scheme 3). In turn, the presence of two geminal ester groups, additionally coordinated by the Lewis acid on the one hand and by the donor O–N moiety on the other hand, leads to strong polarization of the C(5)–C(6) bond in endo-7a and, consequently, to its cleavage and regeneration of intermediate I. This, in turn, makes it possible to shift the equilibrium toward the thermodynamically more favorable exo-7a isomers with increasing reaction time.

Scheme 3 Plausible stereochemical model of the reaction (the Lewis acid on the malonate fragment of ACDC and the substituent of the isoxazoline moiety are omitted for clarity).

Next, we carried out a series of [3 + 2]-cycloaddition reactions of isoxazoline 6a with donor–acceptor cyclopropanes 1a–i bearing various aromatic substituents in the DAC moiety. One of the drawbacks of the [3 + 2] cycloaddition reactions was the high sensitivity of the process to the electronic effects of substituents in the donor part of the DAC. In fact, when Sc(OTf)₃ or Sn(OTf)₂ was used, only cyclopropanes containing strong electron-donor substituents efficiently underwent the target reaction, giving the desired products in high yields as either exo- or endo-isomers, with the configuration of the main center depending on the Lewis acid used (Scheme 4A).

Scheme 4 Substrate scope for the reactions of DACs with isoxazolines. ^a Reactions were carried out at rt in CH₂Cl₂ with 1 equiv. of 1 and 6, Lewis acid (10 mol%), and Ar atmosphere; ^b Isolated yields and anti/syn-ratios are given (for the anti/syn-ratios before chromatography, see the SI).

It was also shown that the rather highly reactive PMP-DAC 1a successfully reacted with other isoxazolines, in particular, 5-methoxycarbonyl- and 5,5-diphenylisoxazolines 6b and 6c, exhibiting the same regularities as in the case of isoxazoline 6a (Scheme 4B).

Incorporation of a second phenyl substituent into the donor part of the DAC (1l) does not significantly affect the efficiency of the process in the presence of either Sc(OTf)₃ or Sn(OTf). However, it eliminates the formation of a mixture of exo- and endo-isomers, and isomer 7l with the syn-position of the methoxycarbonyl group at the C(3) atom relative to the bicyclic system becomes predominant in this case (Scheme 4C).

At the same time, even DACs lacking electron-acceptor groups in the aryl moiety, such as Ph, undergo annulation only with great difficulty. For example, the conversion of 1e in the presence of Sc(OTf)₃ at room temperature was as low as 19% after 20 h (Table 2, entry 1). A somewhat better result was obtained at 40 °C; however, the conversion of cyclopropane was also below 40% in this case (Table 2, entry 2).

Table 2 Yields of adducts 7e in the presence of triflimides (10 mol%)

Entry	Lewis acid	T, °C (t, h)	Conv. 1e, %	Yields, % (dr)
				exo-7e (anti/syn)	endo-7e (anti/syn)
1	Sc(OTf)3	20 (20)	19	17	2
2	Sc(OTf)3	40 (8)	38	36 (1.2 : 1)	2
3	Yb(NTf2)3	20 (20)	100	62 (1.2 : 1)	19 (1 : 1.2)
4	Sc(NTf2)3	20 (20)	100	59 (1.3 : 1)	20 (1 : 2)
5	Sn(NTf2)2	20 (20)	<10	4	4
6	Yb(NTf2)3	40 (6)	100	65 (1 : 1)	15 (syn)
7	Yb(NTf2)3	80 (6)	100	63 (1 : 1)	8 (syn)

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This drawback was overcome by the use of triflimides, which are more reactive Lewis superacids.¹¹ Scandium, ytterbium, and tin(II) triflimides were synthesized using the reported procedures.¹²

As expected, replacement of the catalyst with the more electrophilic Lewis acids Yb(NTf₂)₃ and Sc(NTf₂)₃ resulted in the acceleration of the (3 + 2)-annulation of non-activated DACs with isoxazolines. For example, cyclopropane 1e reacted with isoxazoline 6a even at room temperature with complete conversion, affording the target product 7e in yields up to 80% (Table 2, entries 3 and 4). Sn(NTf₂)₂ exhibited low activity, which did not allow endo-7e to become the predominant reaction product (Table 2, entry 5).

However, unlike the DACs with electron-donor aryl substituents, this reaction could not be completely shifted toward the thermodynamically stable exo-7e isomers by increasing the reaction temperature (Table 2, entries 6 and 7), which may be caused by catalyst deactivation.

Next, using the developed triflimide methodology, a series of [3 + 2] cycloaddition reactions were carried out with low-activity DACs bearing various electron-acceptor groups in the aromatic moiety, which reduce the reactivity of cyclopropane. It was found that even in the case of DACs such as the 4-cyano- and 4-nitrophenyl derivatives, ytterbium triflimide demonstrated high efficiency in reactions with isoxazoline 6a, affording the formal [3 + 2] cycloaddition products 7m–p in 57–84% yields with a high degree of exo-orientation of the aryl substituent (Scheme 5).

Scheme 5 Scope of electron-poor aryl groups successfully introduced using the triflimide approach.

The reaction of isoxazoline 6a catalyzed by Yb(NTf₂)₃ occurs with 2-vinylcyclopropane-1,1-dicarboxylate 1r as well. Although the yield was not high, the corresponding bicyclic adduct 7r was also isolated as two anti- and syn-isomers with exo-orientation of the vinyl substituent (Scheme 6).

Scheme 6 Reaction of DAC 1r with isoxazoline 6a.

The possibility of selective reduction of the N–O bond in the exo-7a adduct was also demonstrated. Direct reduction with Zn in AcOH yielded the pyrrolidine derivative 8 with the substituents at positions 2 and 5 exclusively in the trans-configuration (Scheme 7). At the same time, conversion of 7a into N-oxide 9 prior to the reduction made it possible to obtain the dihydropyrrole derivative 10 that also finds use as a key structural fragment in a number of biologically active compounds.

Scheme 7 Reduction of exo-7a.

Bicyclo[1.1.0]butanes (BCBs) have found extremely broad application in various cycloaddition reactions in recent years, providing easy access to a range of bicyclo[n.1.1]alkanes, which are currently being actively studied as promising 3D bioisosteres of diverse arenes and heteroarenes.¹³

BCBs bearing aryl donors and carbonyl acceptors can be regarded as extremely strained variants of well-known donor–acceptor cyclopropanes (DACs). Therefore, we demonstrated that isoxazolines can also be successfully involved in formal [3 + 3]-cycloaddition with 1-aryl-3-EWG-substituted BCBs in the presence of catalytic amounts of Sc(OTf)₃ or Yb(NTf₂)₃ (Scheme 8). It should be noted that the optimized yields of ca. 40% of compound 12 (see the SI for details) are due to the high propensity of BCBs to undergo oligomerization, a behavior typical of many reactions involving BCBs.

Scheme 8 [3 + 3]-Cycloaddition with BCB 11.

The 2-azabicyclo[2.1.1]hexane moiety obtained in this reaction can be considered as a 3D bioisosteric replacement both for the planar aromatic pyrrole moiety and for the conformationally non-rigid saturated pyrrolidine moiety. To demonstrate this possibility, simplified model structures 13–15 were used as examples and their geometric and electronic parameters were compared (Table 3, Fig. 3). As can be seen from Table 3, substitution of either the pyrrole moiety in 13 or the pyrrolidine moiety in 14 with a 2-azabicyclo[2.1.1]hexane moiety (structure 15) results in only minor changes in the molecular geometry, the molecular surface area (ASA), and the topological polar surface area (TPSA). At the same time, parameters such as lipophilicity, solubility in aqueous media, and skin permeability increase, indicating the strong potential of such 3D bioisosteric replacement for drug design.

Fig. 3 2-Azabicyclo[2.1.1]hexane vs. pyrrole and pyrrolidine moieties.

Table 3 Comparison of the calculated characteristics of potential biological activity of compounds 13–15

	13	14	15
Lipophilicity, log Po/w (ref. 14)	1.47	1.60	1.81
Water solubility, log S (ref. 15)	−2.66	0.60	0.84
Skin permeation, log Kp, cm s^−1 (ref. 16)	−6.64	−8.84	−9.07
TPSA, Å^2	73.32	69.56	69.56
ASA, Å^2	252.104	268.592	276.355
Lipinsky rule of five	5	5	5
Bioavailability score (ref. 17)	0.82	0.55	0.55

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Conclusions

In this work, we propose a stereoselective intermolecular approach for the construction of the pyrrolidine moiety via [3 + 2] cycloaddition of DACs with isoxazolines catalyzed by Lewis acids. Stereoselectivity is controlled either kinetically or thermodynamically, which is achieved by employing Sn or Sc triflates. In addition, directed regulation of the Lewis acidity of the catalyst by selecting a weakly coordinating anion (WCA) NTf₂ instead of OTf enables successful involvement of low-reactivity DACs bearing electron-acceptor substituents at the aromatic ring. The reaction of isoxazoline [3 + 2] cycloaddition was further extended to bicyclo[1.1.0]butanes (BCBs), providing easy access to the 2-azabicyclo[2.1.1]hexane core, which can be considered as a promising 3D-bioisosteric replacement of pyrrole and pyrrolidine motifs.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: experimental procedures, characterization data, NMR spectra of compounds and X-ray crystallographic data Supplementary information is available. See DOI: https://doi.org/10.1039/d5ob01604e.

CCDC 2491505–2491507: Experimental Crystal Structure Determination, 2025, https://dx.doi.org/10.5517/ccdc.csd.cc2pmm43, https://dx.doi.org/10.5517/ccdc.csd.cc2pmm54, https://dx.doi.org/10.5517/ccdc.csd.cc2pmm65, contain the supplementary crystallographic data for this paper.^18a–c

Acknowledgements

This work was funded by the Russian Science Foundation (RSF) under the research project no. 25-13-00574. This work was performed using the equipment in the Shared Research Center (Department of Structural Studies) of the N. D. Zelinsky Institute of Organic Chemistry, RAS, Moscow. A. A. Korlyukov and A. D. Volodin are grateful to the Ministry of Science and Higher Education of the Russian Federation (Contract No. 075-00276-25-00) for providing access to the equipment of the Center for Collective Use of INEOS RAS in X-ray crystallographic studies.

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