Aziridination of Cyclic Nitrones Targeting Constrained Iminosugars

Letter pubs.acs.org/OrgLett

Aziridination of Cyclic Nitrones Targeting Constrained Iminosugars Salia Tangara, Clara Aupic,† Alice Kanazawa,* Jean-François Poisson, and Sandrine Py* Univ. Grenoble Alpes, DCM, F-38000 Grenoble, France CNRS, DCM, F-38000 Grenoble, France S Supporting Information *

ABSTRACT: Rare C-7-substituted aziridinyl iminosugars can be synthesized through a short reaction sequence involving 1,3cycloaddition of cyclic nitrones with alkynes and a Baldwin rearrangement of isoxazolines into bicyclic 2-acylaziridines. The method is efficient and completely diastereoselective, producing stable aziridinyl iminosugars in high yields.

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system (polyhydroxylated 1-azabicyclo[X.1.0]alcanes) have been little studied with regard to other bicyclic iminosugars such as polyhydroxylated pyrrolizidines and indolizidines.7,8 Besides retaining important features such as basicity of the nitrogen atom and a polyhydroxylated cyclic structure, aziridinyl iminosugars exhibit important conformational restriction due to their small-sized ring and could represent excellent mimics of the oxonium-like transition state of glycosidases. Indeed, Ganem and Tong showed that the aziridinyl iminosugar 1a (Figure 1B) is a highly potent and specific α-galactosidase inactivator, binding irreversibly to the catalytic site of these enzymes.7a Compounds 1b−d7b−d have also been designed as glycosidase inhibitors, but were found unstable and their biological evaluation was thus not reported. Recently, the group of Overkleeft nicely illustrated the design of aziridine-containing activity-based probes (ABPs, Figure 1C) to assess specific glycosidase activities in tissues of healthy and disease-affected patients.9 These ABPs are based on polyhydroxylated 7-azabicyclo[4.1.0]heptanes in which the nitrogen atom is grafted with a fluorophore or a biotin tag. The group of Llebaria has also recently designed N-amino-aziridines with a 7azabicyclo[4.1.0]heptane skeleton as potent irreversible inhibitors of β-galactosidases.10 In continuation of our interest in synthetic applications of polyalkoxylated cyclic nitrones,11 we wished to evaluate their utility as precursors of aziridinyl iminosugars through a sequence involving 1,3-dipolar cycloaddition with alkynes, and a rearrangement of 4-isoxazolines into 2-acylaziridines, known as the Baldwin rearrangement (Scheme 1).12 Only marginal application of this stereoselective sigmatropic process13 is found in organic synthesis,14,15 maybe because isoxazolines and aziridines are known to often undergo rearrangements.16 However, we envisaged such a process to target a novel class of aziridinyl

minosugars are currently the most promising class of glycomimetic for therapeutic application.1 First recognized as glycosidase inhibitors,2 they have more recently appeared as excellent candidates to potentiate the activity of defective mutant enzymes in inherited lysosomal disorders.3 Miglitol,4 miglustat,5 and migalastat6 (Figure 1A) are already marketed, respectively for the treatment of type-II diabetes (inhibition of intestinal αglucosidases), Gaucher disease, and Fabry disease (chaperone effect on mutant β-glucocerebrosidase or α-galactosidase). The development of new drugs in this class relies on the identification of compounds exhibiting improved conformational fit to the catalytic site of specific subclasses of glycosidase, conferring on them not only higher inhibition potency but also enhanced selectivity. Aziridinyl iminosugars in which a nitrogen atom is shared between a three-membered ring and another ring

Figure 1. Iminosugar drugs (A) and the two types of known bicyclic aziridinyl iminosugars (B and C). © 2017 American Chemical Society

Received: July 25, 2017 Published: September 1, 2017 4842

DOI: 10.1021/acs.orglett.7b02283 Org. Lett. 2017, 19, 4842−4845

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Organic Letters iminosugars, bearing a variety of substituents at the C-7 position (1-azabicyclo[4.1.0]alcane numbering).

Table 1. Cycloaddition of Cyclic Nitrones with Alkynes

Scheme 1. Synthetic Approach toward Aziridinyl Iminosugars

Inspired by Dai’s work,14c we first attempted a one-pot aziridination of nitrone 2a17 with phenylacetylene (3a) (Scheme 2). Disappointingly, the expected acylaziridine 5aa was isolated in only 24% yield, together with decomposition products containing no trace of isoxazoline 4aa. Scheme 2. Preliminary Result: Conversion of Nitrone 2a to Acylaziridine 5aa under Dai’s Conditions

Therefore, each step of this transformation was studied separately. Surprisingly, while cycloaddition of cyclic carbohydrate-derived nitrones with alkenes has been widely applied,18 their cycloaddition with alkynes has never been described.19 Our study thus began by investigating the regio- and stereoselectivity of alkyne cycloaddition with nitrones 2a−e (Scheme 3, Table 1). Nitrone 2a and phenylacetylene (used as solvent) were first allowed to react at room temperature until complete conversion of the starting nitrone (2 days). Cycloadduct 4aa was isolated in 81% yield, as a single regio- and stereoisomer resulting from an anti approach of phenylacetylene relative to the C-3 benzyloxy substituent of the nitrone (Table 1, entry 1).20 Nitrone 2a was also found to react efficiently at room temperature with ethyl phenylpropiolate (3b), yielding a single cycloadduct 4ab in 85% yield (Table 1, entry 2). The five-membered ring ketonitrones 2b and 2c21 failed to react with phenylacetylene (Table 1, entries 3 and 4). Conversely, the six-membered ring ketonitrones 2d11b and 2e11d reacted smoothly with phenylacetylene, furnishing isoxazolines 4da and 4ea in 89% and 96% yield, respectively (Table 1, entries 5 and 6). Again, both the regio- and diastereoselectivity of the cycloaddition were excellent. However, in the case of these six-membered ring ketonitrones, the favored approach of the alkyne was syn relative to the C-3 benzyloxy substituent.20 The cycloaddition of D-gluco-configured ketonitrone 2e with a variety of alkynes was next investigated. The latter reacted smoothly with ethyl phenylpropiolate (Table 1, entry 7) as well as with pentyne, hexyne, cyclohexylacetylene, and trimethylsilylacetylene (Table 1, entries 8−11), affording in all cases a single syn cycloadduct in good-to-excellent yield. Propargyl acetate (3g) also reacted with nitrone 2e (Table 1, entry 12) affording cycloadduct 4eg in 71% yield.22

After this brief survey of cycloaddition between cyclic nitrones and alkynes, the subsequent Baldwin rearrangement of the resulting isoxazolines was studied. The thermal rearrangement of 4aa into 2 acyl-aziridine 5aa was chosen as a model reaction to define optimal conditions (see Supporting Information). As raised by Campagne and Vrancken,14b microwave irradiation was beneficial to enable high temperatures to be reached in a short time, thus limiting the occurrence of side reactions. The best yield of isolated 5aa was obtained upon heating a 0.1 M solution 4843

DOI: 10.1021/acs.orglett.7b02283 Org. Lett. 2017, 19, 4842−4845

Letter

Organic Letters of the 4-isoxazoline in ethanol at 110 °C for 20 min under microwave irradiation. Such a procedure transformed isoxazoline 4aa into a 80:20 mixture of diastereomeric products, from which 5aa was isolated in 41% yield. The latter was identified by NMR as a cis aziridine, characterized by two doublets at δ 2.95 and 3.28 ppm with a coupling constant of 6.2 Hz.13,14b A similar group of signals of lower intensity appeared at δ 3.66 and 3.08 ppm, exhibiting a smaller coupling constant (2.4 Hz). These were assigned to the minor trans aziridine. Previously prepared 4-isoxazolines 422 were subjected to similar conditions to induce the Baldwin rearrangement. Except for the isoxazolines 4ab and 4eb, which were converted to complex mixtures of products, all isoxazolines underwent transposition to the corresponding 2-acylaziridines in good yields (Figure 2). Moreover, a single cis diastereomer was obtained from the six-membered ring-fused isoxazolines. The configuration of the acylaziridines 5ea−5ee was determined by NOE analysis (see Supporting Information).

thus demonstrating the utility of the route to access C-7 substituted aziridinyl iminosugars. Scheme 3. Reduction and Debenzylation of 2-Acylaziridines

In summary, this work demonstrates that carbohydrate derived nitrones are useful intermediates to prepare aziridinyl iminosugars in a few steps, and in an atom-economic process involving no other reagent than nitrones and alkynes in the key steps. This overall efficient route to original bicyclic iminosugars should prove useful to access novel molecules with potential as conformationally defined glycosidase inhibitors and activitybased probes (ABPs) designed for specific labeling of glycosidases. It is noteworthy that the method gives access to unprecedented 1-azabicyclo[3.1.0]hexanes and 1-azabicyclo[4.1.0]heptanes bearing a substituent on the aziridine ring. Inhibitory activities of these compounds, as well as application of the described method in the synthesis of ABPs, will be reported in due course.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02283. Characterization data, full experimental procedures, copies of NMR spectra of all new compounds, and temperature−time profiles for microwave experiments (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] ORCID

Alice Kanazawa: 0000-0001-7170-6551 Sandrine Py: 0000-0002-5143-7689 Present Address

Figure 2. Baldwin rearrangement of bicyclic 4-isoxazolines.

†

Aix Marseille Université, Centrale Marseille, CNRS iSm2 UMR 7313, 13397 Marseille cedex 20, France. Notes

Cleavage of the benzylic ethers in compounds containing an aziridine moiety has previously been carried out by Birch reduction.7c,10,23 However, such conditions could not be applied directly to these 2-acylaziridines,24 and reduction of the ketone was necessary prior to debenzylation. Satisfyingly, the treatment of 2-acylaziridines 5ea, 5ec, and 5ee with sodium borohydride smoothly afforded the corresponding aziridinyl alcohols 6ea (81%), 6ec (91%), and 6ee (94%) with complete diastereoselectivity (Scheme 3). The R configuration at the newly formed stereocenter was assigned via Mosher ester analysis (see Supporting Information).25 Finally, while Birch reduction of the benzylic aziridine 6ea failed,26 the stable aziridinyl iminosugars 7ec and 7ee were obtained in good overall yields,

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS S.T. is grateful to Campus France for an “Excellence Doctoral Fellowship”. The authors thank Dr. D. Gueyrard (Université de Lyon) and Dr. P.-Y. Chavant (DCM) for helpful discussions, and M. Fayolle (DCM) for the preparation of nitrones 2d and 2e. We acknowledge support from ICMG FR 2607, Grenoble (through which NMR and MS analyses have been performed) and by the French National Research Agency in the framework of the “Investissements d’avenir” program Glyco@Alps (ANR-15IDEX-02). 4844

DOI: 10.1021/acs.orglett.7b02283 Org. Lett. 2017, 19, 4842−4845

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Organic Letters

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DOI: 10.1021/acs.orglett.7b02283 Org. Lett. 2017, 19, 4842−4845