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. 2021 Mar 2;11(16):9410-9420.
doi: 10.1039/d1ra00804h. eCollection 2021 Mar 1.

Synthesis of novel seven-membered carbasugars and evaluation of their glycosidase inhibition potentials

Vignesh Athiyarath  1 , Naveen J Roy  1 , A T V Vijil  1 , Kana M Sureshan  1
Affiliations

Synthesis of novel seven-membered carbasugars and evaluation of their glycosidase inhibition potentials

Vignesh Athiyarath et al. RSC Adv. .

Abstract

Here, we report the synthesis of five novel seven-membered carbasugar analogs. We adopted a chiral-pool strategy starting from the cheap and readily available d-mannitol to synthesize these ring-expanded carbasugars. Apart from several regioselective protecting group manipulations, these syntheses involved Wittig olefination and ring-closing metathesis as the key steps. We observed an unprecedented deoxygenation reaction of an allylic benzyl ether upon treatment with H2/Pd during the synthesis. Preliminary biological evaluation of the carbasugars revealed that these ring expanded carbasugars act as inhibitors of various glycosidases. This study highlights the importance of the synthesis of novel ring expanded carbasugars and their biological exploration.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. (a) Chemical structures of gabosine J (1), gabosinol J-α (2), gabosinol J-β (3) and corresponding seven-membered analogs 4, 5 and 6. (b) Retrosynthetic analysis of seven-membered analogs 4, 5 and 6.
Scheme 1
Scheme 1. Synthesis of seven-membered carbasugars 5 and 6. Reagents and conditions: (a) Zn, allylbromide, THF, 0 °C, 30 min, 70%; (b) Grubb's 2nd generation catalyst, DCM, reflux, 12 h, 81%; (c) Ac2O, DMAP, pyridine, 3 h; (d) NaOMe, methanol, rt, 12 h; (e) BCl3, DCM, −78 °C, 3 h; (f) Dess–Martin periodinane, DCM, rt, 4 h, 96%; (g) BCl3 or BBr3 or FeCl3 (reagent conditions as per the literature).
Scheme 2
Scheme 2. Hydrogenation of 12β resulting in unusual reduction products 15 and 16.
Fig. 2
Fig. 2. ORTEP diagram of compounds (a) 15 and (b) 23 with 50% probability level.
Scheme 3
Scheme 3. Synthesis of compound 4. Reagents and conditions: (a) Bu2SnO, p-methoxybenzyl chloride, toluene, reflux, 24 h, 76%; (b) oxalyl chloride, DMSO, triethylamine, DCM, −78 °C, 2 h, 75%; (c) PPh3PCH3Br, nBuLi, THF, −78 °C, 3 h, 76%; (d) 0.1 M HCl, methanol, rt, 30 min, 76%; (e) trityl chloride, diisopropylethylamine, DCM, rt, 4 h, 88%; (f) p-methoxybenzyl chloride, NaH, DMF, 0 °C to rt, 3 h, 76%; (g) 0.05 M HCl, methanol/chloroform (3 : 1, v/v), rt, 30 min, 79%; (h) Zn, allylbromide, THF, 0 °C, 30 min, 70%; (i) Grubb's 2nd generation catalyst, DCM, 50 °C, 12 h, 83%; (j) Dess–Martin periodinane, DCM, rt, 4 h, 84%; (k) 5% TFA, DCM, 0 °C, 3 h, 74%.
Fig. 3
Fig. 3. Structural comparison of enzyme-inhibitors of various glycosidases with their natural substrates.
See this image and copyright information in PMC

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