Accessing 2-substituted piperidine iminosugars by organometallic addition/intramolecular reductive amination: aldehyde vs. nitrone route

Mirabella, Stefania; Fibbi, Giulia; Matassini, Camilla; Faggi, Cristina; Goti, Andrea; Cardona, Francesca

doi:10.1039/c7ob01848g

Cited by 11 publications

(18 citation statements)

References 34 publications

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“…Concerning the synthesis of nitrone 10a ( Table 1 , entry 1), this method compares very well with the previously reported condensation procedure of aldehyde 8 with N -benzyl hydroxylamine (85%), 14 especially considering the difference of costs with benzylamine ( 13a ).…”

Section: Resultssupporting

confidence: 80%

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Piperidine Azasugars Bearing Lipophilic Chains: Stereoselective Synthesis and Biological Activity as Inhibitors of Glucocerebrosidase (GCase)

et al. 2021

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We report a straightforward synthetic strategy for the preparation of trihydroxypiperidine azasugars decorated with lipophilic chains at both the nitrogen and the adjacent carbon as potential inhibitors of the lysosomal enzyme glucocerebrosidase (GCase), which is involved in Gaucher disease. The procedure relies on the preparation of C -erythrosyl N -alkylated nitrones 10 through reaction of aldehyde 8 and primary amines 13 followed by oxidation of the imines formed in situ with the methyltrioxorhenium catalyst and urea hydrogen peroxide. The addition of octylMgBr to nitrone 10e provided access to both epimeric hydroxylamines 21 and 22 with opposite configuration at the newly created stereocenter in a stereodivergent and completely stereoselective way, depending on the absence or presence of BF 3 ·Et 2 O. Final reductive amination and acetonide deprotection provided compounds 14 and 15 from low-cost d -mannose in remarkable 43 and 32% overall yields, respectively, over eight steps. The C-2 R -configured bis-alkylated trihydroxypiperidine 15 was the best ligand for GCase (IC 50 = 15 μM), in agreement with MD simulations that allowed us to identify the chair conformation corresponding to the best binding affinity.

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Section: Resultssupporting

confidence: 80%

“…Conversely, when an equimolar amount of BF 3 ·Et 2 O is added, chelation is prevented, thus favoring the nucleophilic attack to the more accessible Re face of nitrone 10e , which leads to the hydroxylamine 22 with the R configuration at the newly formed stereocenter ( Figure 3 B). 14 , 17 …”

Section: Resultsmentioning

confidence: 99%

Piperidine Azasugars Bearing Lipophilic Chains: Stereoselective Synthesis and Biological Activity as Inhibitors of Glucocerebrosidase (GCase)

et al. 2021

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“…The synthesis of “ all-cis ” trihydroxypiperidines alkylated at C-3 by addition of organometallic reagents to the carbonyl group of 8 was then addressed. Ketone 8 was first reacted with Grignard reagents (octylMgBr, ethylMgBr, and methylMgBr, Scheme 4 ) under conditions which had proved successful for Grignard additions to aldehyde 16 and a nitrone derived thereof [ 23 , 30 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors

et al. 2020

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Pharmacological chaperones (PCs) are small compounds able to rescue the activity of mutated lysosomal enzymes when used at subinhibitory concentrations. Nitrogen-containing glycomimetics such as aza- or iminosugars are known to behave as PCs for lysosomal storage disorders (LSDs). As part of our research into lysosomal sphingolipidoses inhibitors and looking in particular for new β-galactosidase inhibitors, we report the synthesis of a series of alkylated azasugars with a relative “all-cis” configuration at the hydroxy/amine-substituted stereocenters. The novel compounds were synthesized from a common carbohydrate-derived piperidinone intermediate 8, through reductive amination or alkylation of the derived alcohol. In addition, the reaction of ketone 8 with several lithium acetylides allowed the stereoselective synthesis of new azasugars alkylated at C-3. The activity of the new compounds towards lysosomal β-galactosidase was negligible, showing that the presence of an alkyl chain in this position is detrimental to inhibitory activity. Interestingly, 9, 10, and 12 behave as good inhibitors of lysosomal β-glucosidase (GCase) (IC50 = 12, 6.4, and 60 µM, respectively). When tested on cell lines bearing the Gaucher mutation, they did not impart any enzyme rescue. However, altogether, the data included in this work give interesting hints for the design of novel inhibitors.

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“…3.1.9. Synthesis of (2R,3R,4S,5R)-3-Hydroxy-4,5-O-(1-methylethylidene)-N-Boc-2pentylpiperidine (25) To a stirred solution of 15 (190 mg, 0.78 mmol) and NaHCO 3 (98 mg, 1.17 mmol) in H 2 O (3 mL), MeOH (3 mL), and Boc 2 O (252 mg, 1.17 mmol) were added. The mixture was stirred at room temperature for 48 h until a TLC control (CH 2 Cl 2 /MeOH/NH 4 OH (6%) 10:1:0.1) attested to the disappearance of the starting material.…”

Section: Synthesis Of (2s3r4s5r)-3-hydroxy-45-o-(1-methylethylidene)-...mentioning

confidence: 99%

“…The piperidine intermediates 14 and 15 could be obtained via intramolecular reductive amination (RA) [24] of hydroxylamines 16 and 17 with an S or R absolute configuration at the newly formed stereocenter, in turn, derived from Grignard reagent additions onto nitrone 18 in the presence or absence of a suitable Lewis Acid (Scheme 1). Nitrone 18 was readily accessed from 19 with an 85% yield by reaction with N-benzyl hydroxylamine in dry CH 2 Cl 2 [25]. Aldehyde 19 was synthesized in four steps from D-mannose on a gram scale [26].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a New β-Galactosidase Inhibitor Displaying Pharmacological Chaperone Properties for GM1 Gangliosidosis

et al. 2022

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GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme β-galactosidase (β-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal β-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different positions of the piperidine ring and different absolute configurations of the alkyl chain at C-2 and the hydroxy group at C-3. The organometallic addition of a Grignard reagent onto a carbohydrate-derived nitrone in the presence or absence of a suitable Lewis Acid was exploited, providing structural diversity at C-2, followed by the ring-closure reductive amination step. An oxidation-reduction process allowed access to a different configuration at C-3. The N-pentyl trihydroxypiperidine iminosugar was also synthesized for the purpose of comparison. The biological evaluation of the newly synthesized compounds was performed on leucocyte extracts from healthy donors and identified two suitable β-Gal inhibitors, namely compounds 10 and 12. Among these, compound 12 showed chaperoning properties since it enhanced β-Gal activity by 40% when tested on GM1 patients bearing the p.Ile51Asn/p.Arg201His mutations.

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Accessing 2-substituted piperidine iminosugars by organometallic addition/intramolecular reductive amination: aldehyde vs. nitrone route

Cited by 11 publications

References 34 publications

Piperidine Azasugars Bearing Lipophilic Chains: Stereoselective Synthesis and Biological Activity as Inhibitors of Glucocerebrosidase (GCase)

Piperidine Azasugars Bearing Lipophilic Chains: Stereoselective Synthesis and Biological Activity as Inhibitors of Glucocerebrosidase (GCase)

Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors

Synthesis of a New β-Galactosidase Inhibitor Displaying Pharmacological Chaperone Properties for GM1 Gangliosidosis

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