Diastereoselective Carbamate Annulation for the Synthesis of 2,5‐Dideoxy‐2,5‐iminoglycitols

Hunt-Painter, Alex A.; Moggré, Gert‐Jan; Tyler, Peter C.; Stocker, Bridget L.; Timmer, Mattie S. M.

doi:10.1002/slct.201701818

Cited by 3 publications

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“…17 Several years later, it was shown that 6-deoxy-6-benzyloxycarbonylamido-ketose 6b 26 or 6deoxy-6-azido-ketose 6c, prepared either enzymatically 27 or chemically, 28 provided convenient access to DNJ (2) using the same hydrogenation strategy, again with exclusive formation of the gluco-isomer, and others have subsequently developed routes for the synthesis of polyhydroxypiperidines utilizing iminium ions as key reactive intermediates. 29 Building on the aforementioned studies and our experience with iminosugar synthesis from ω-deoxy-ω-iodo-glycosides, 30,31 we envisioned that iodo-glycosides would be ideal starting materials for a cascade reaction leading to the efficient syntheses of a variety of iminosugars with minimal use of protecting groups (Scheme 2). Key in our approach is the avoidance of elaborate protecting-group strategies and functional group interconversions to reach the imine intermediate.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Building on the aforementioned studies and our experience with iminosugar synthesis from ω-deoxy-ω-iodo-glycosides, , we envisioned that iodo-glycosides would be ideal starting materials for a cascade reaction leading to the efficient syntheses of a variety of iminosugars with minimal use of protecting groups (Scheme ). Key in our approach is the avoidance of elaborate protecting-group strategies and functional group interconversions to reach the imine intermediate.…”

Section: Introductionmentioning

confidence: 99%

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An Amination–Cyclization Cascade Reaction for Iminosugar Synthesis Using Minimal Protecting Groups

et al. 2022

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The development of a one-step amination–cyclization cascade reaction for the synthesis of N-substituted iminosugars from iodo-pentoses and hexoses is reported. This novel methodology allows for the stereoselective conversion of easily accessible iodo-aldoses and iodo-ketoses into iminosugars in a single step, in highly efficient yields (63–95%), and in aqueous media. Furthermore, the use of functionalized amines allows for the synthesis of N-functionalized iminosugars without additional steps. To illustrate this methodology, a number of biologically important iminosugars were prepared, including 1-deoxynojirimycin, (3 S ,4 R ,5 S ,6 R )-azepane-3,4,5,6-tetraol, and N-functionalized 1-deoxymannojirimycins.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Amination–Cyclization Cascade Reaction for Iminosugar Synthesis Using Minimal Protecting Groups

et al. 2022

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“…As better access to DIA would allow for more in depth investigations into the potential of this molecule as a treatment for Fabry disease, it was desired to establish a highly efficient route for its preparation by utilising the previously developed carbamate proposed that 82 could be prepared without the need for protecting groups (R 1 = H, R 2 = Me), as the annulation strategy is amenable to such an approach, 105 however, the synthesis of iminosugars in the absence of PGs is not without its challenges 63,64 and thus, the use of PGs was also considered in the retrosynthetic plan (R 1 = R 2 = PG). Finally, methyl iodo-glycoside 82 could be prepared from commercially available D-tagatose (25).…”

Section: Retrosynthesismentioning

confidence: 99%

Methodology development for the synthesis of iminosugars

Hunt-Painter¹

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<p>This thesis investigated the development and application of methodology for the synthesis of iminosugars. The first portion of this thesis (Chapters 2 and 3) explored the scope of previously established protecting-group-free Vasella-reductive-amination and I2-mediated carbamate annulation methodology initially developed within the Stocker-Timmer group for the synthesis of pyrrolidines and piperidines from aldose sugars. In this thesis, the Vasella-reductive-amination methodology was extended to include the use of ketose sugars as starting materials, thereby allowing for the synthesis of primary amines directly from in situ formed ketones under protecting-group-free conditions. The scope of the carbamate annulation was then explored, whereby it was determined that both steric and electronic effects appear to affect transition state energies during the annulation reaction. Here, formation of pyrrolidines with the 2,5-trans and 3,4-cis relationships are favoured, however, in circumstances were conflicting electronic- and steric-effects are present, steric-effects dominate thereby favouring the formation of the 2,5-trans product. Using a combination of this Vasella-reductive-amination and carbamate annulation methodology, 2,5-dideoxy-2,5-imino-L-iditol was thus synthesised in 6 steps and 18% overall yield from D-fructose. Next, the same methodology was applied to the synthesis of the promising molecular chaperone 2,5-dideoxy-2,5-imino-D-altritol. Thus, 2,5-dideoxy-2,5-imino-D-altritol was synthesised over 7 steps and in 22% yield from D-tagatose, which is the most efficient synthesis of this iminosugar to date. The second part of this thesis (Chapters 4 and 5) focused on the optimisation and development of synthetic methodology that would allow for the highly efficient synthesis of a variety of iminosugars including piperidines and azepanes. To this end, modifications to existing synthetic methodology allowed for the rapid synthesis of a variety of iodoglycosides, which are important synthons. Next, reductive amination/cyclisation methodology that allowed for the direct transformation of methyl iodoglycosides or isopropylidene-protected iodoglycosides into iminosugars was developed. As such, the piperidines 1-Deoxynojirimycin, 1-Deoxymannojirimycin (DMJ), L-1-Deoxygalactojirimycin (L-DGJ), and (3R,4r,5S)-piperidine-3,4,5-triol were prepared in 4 steps and good overall yields (44%, 62%, 67%, and 53%, respectively). In the case of DMJ and (3R,4r,5S)-piperidine-3,4,5-triol, these are the most efficient syntheses of these materials to date. Factors influencing the stereochemical outcome of the reductive amination reaction were also explored, and evidence suggests that the reduction occurs from the least sterically hindered face of an intermediate cyclic imine, whereby the preferred conformation of the imine is the one which places the largest number of substituents in the pseudo-equatorial position. Using analogous methodology, the azepane (3S,4R,5S,6R)-azepane-3,4,5,6-tetraol was also prepared in 4 steps and good yield (53%).</p>

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Recent synthetic strategies to access diverse iminosugars

Matassini,

Cardona

2024

Synthetic Strategies in Carbohydrate Chemistry

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Diastereoselective Carbamate Annulation for the Synthesis of 2,5‐Dideoxy‐2,5‐iminoglycitols

Cited by 3 publications

References 46 publications

An Amination–Cyclization Cascade Reaction for Iminosugar Synthesis Using Minimal Protecting Groups

An Amination–Cyclization Cascade Reaction for Iminosugar Synthesis Using Minimal Protecting Groups

Methodology development for the synthesis of iminosugars

Recent synthetic strategies to access diverse iminosugars

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