Stereodivergent synthesis of diastereoisomeric carba analogs of glycal‐derived vinyl epoxides: A new access to carbasugars

Frau, Ileana; Bussolo, Valeria Di; Favero, Lucilla; Pineschi, Mauro; Crotti, Paolo

doi:10.1002/chir.21003

Cited by 17 publications

(9 citation statements)

References 19 publications

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“…This prompted us to pursue an alternative synthetic route. Several other carbocyclic sugar analogues have been previously synthesized using a Claisen rearrangement approach, which centers on a key thermal [3,3]-sigmatropic rearrangement of a homologated glycal, as shown in Figure . − …”

Section: Resultsmentioning

confidence: 99%

Carbocyclic Substrate Analogues Reveal Kanosamine Biosynthesis Begins with the α-Anomer of Glucose 6-Phosphate

et al. 2020

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NtdC is an NAD-dependent dehydrogenase that catalyzes the conversion of glucose 6-phosphate (G6P) to 3-oxoglucose 6-phosphate (3oG6P), the first step in kanosamine biosynthesis in Bacillus subtilis and other closely-related bacteria. The NtdC-catalyzed reaction is unusual because 3oG6P undergoes rapid ring opening, resulting in a 1,3-dicarbonyl compound that is inherently unstable due to enolate formation. We have reported the steady-state kinetic behavior of NtdC, but many questions remain about the nature of this reaction, including whether it is the α-anomer, β-anomer, or open-chain form that is the substrate for the enzyme. Here, we report the synthesis of carbocyclic G6P analogues by two routes, one based upon the Ferrier II rearrangement to generate the carbocycle and one based upon a Claisen rearrangement. We were able to synthesize both pseudo-anomers of carbaglucose 6-phosphate (C6P) using the Ferrier approach, and activity assays revealed that the pseudo-αanomer is a good substrate for NtdC, while the pseudo-β-anomer and the open-chain analogue, sorbitol 6-phosphate (S6P), are not substrates. A more efficient synthesis of α-C6P was achieved using the Claisen rearrangement approach, which allowed for a thorough evaluation of the NtdC-catalyzed oxidation of α-C6P. The requirement for the α-anomer indicates that NtdC and NtdA, the subsequent enzyme in the pathway, have co-evolved to recognize the α-anomer in order to avoid mutarotation between enzymatic steps.

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Section: Resultsmentioning

confidence: 99%

Carbocyclic Substrate Analogues Reveal Kanosamine Biosynthesis Begins with the α-Anomer of Glucose 6-Phosphate

et al. 2020

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“…The synthesis of the panel of target compounds as depicted in Figure 2 started with the preparation of 4‐methoxybenzyl protected 1‐ epi ‐validamine 20 , which we envisioned would be a suitably protected construct to investigate the aza‐MIRC reaction. To this end, epoxide 16 , which could be obtained according to literature procedures, [40] was treated with NaN 3 in DMF at elevated temperatures to yield a separable mixture of regioisomers 17 and 18 in a 1 : 1 ratio and an overall yield of 81 % (Scheme 1A). Subsequent protection of the 2‐ and 6‐OH in 18 under standard Williamson etherification conditions (NaH, PMBCl) yielded fully protected compound 19 in 77 % yield.…”

Section: Resultsmentioning

confidence: 99%

“…With effective conditions in hand to generate the exocyclic aziridines we next set out to assemble the diasteroisomeric set of target compounds from validamine 7 (Scheme 3). The primary hydroxyl in compound 25 , obtained according to literature procedures, [40] was protected as a PMB ether under standard Williamson etherification conditions (NaH, PMBCl) to yield fully protected compound 26 in 85 % yield. A stereoselective Sharpless aminohydroxylation on alkene 26 (K 2 [OsO 2 (OH) 4 ], chloramine‐T (CAT), TEBACl) resulted in a separable, regioisomeric mixture of α‐ cis ‐amino alcohols 27 and 28 in 31 % and 54 % respectively [45] .…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Exocyclic Cyclitol Aziridines as Potential Mechanism‐Based Glycosidase Inactivators

et al. 2023

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Cyclophellitol aziridines have found wide application as mechanism-based, covalent, and irreversible inhibitors of retaining glycosidases. These compounds, like their parent compound, cyclophellitol (a natural product retaining β-glucosidase inactivator), make use of the mechanism of action of retaining glycosidases, which process their substrate through the formation of a transient covalent intermediate. In contrast, inverting glycosidases, the other main family of glycosyl hydrolases, do not employ such a covalent intermediate, and, as a consequence, useful scaffolds for mechanism-based inhibitor design have yet to be discovered. In this work, we explore chemistries that allow for the construction of cyclitol aziridines with the aziridine electrophile attached in an exocyclic fashion, more distal from the anomeric carbon -thus putatively closer to an inverting glycosidase active site nucleophile. The developed chemistries have allowed for the synthesis of a focused library of differently N-substituted, α-and β-glucopyranose configured cyclitol aziridines for future evaluation as inhibitors or inactivators of α-and β-glucosidases alike.

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“…Our study started with the synthesis of the model substrate 4α (Scheme 3) with the aim of investigating the possible effects of the Lewis acid partner on the regioselectivity of the ring opening reaction. Carbocyclic system 1 was built by the known Claisen rearrangement developed by Sudha and Nagarajan, starting from tri- O -acetyl glucal [47,48]. The primary hydroxyl group was then removed by means of a tosylation and a subsequent reduction with LiAlH 4 in Et 2 O, to afford the desired methyl compound 3 .…”

Section: Resultsmentioning

confidence: 99%

Remarkable Effect of [Li(G4)]TFSI Solvate Ionic Liquid (SIL) on the Regio- and Stereoselective Ring Opening of α-Gluco Carbasugar 1,2-Epoxides

et al. 2019

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Carba analogues of biologically relevant natural carbohydrates are promising structures for the development of future drugs endowed with enhanced hydrolytic stability. An open synthetic challenge in this field is the optimization of new methodologies for the stereo- and regioselective opening of α-gluco carbasugar 1,2-epoxides that allow for the preparation of pseudo mono- and disaccharides of great interest. Therefore, we investigated the effect of Lewis acids and solvate ionic liquids (SILs) on the epoxide ring opening of a model substrate. Of particular interest was the complete stereo- and regioselectivity, albeit limited to simple nucleophiles, toward the desired C(1) isomer that was observed using LiClO4. The results obtained with SILs were also remarkable. In particular, Li[NTf2]/tetraglyme ([Li(G4)]TFSI) was able to function as a Lewis acid and to direct the attack of the nucleophile preferentially at the pseudo anomeric position, even with a more complex and synthetically interesting nucleophile. The regioselectivity observed for LiClO4 and [Li(G4)]TFSI was tentatively ascribed to the formation of a bidentate chelating system, which changed the conformational equilibrium and ultimately permitted a trans-diaxial attack on C(1). To the best of our knowledge, we report here the first case in which SILs were successfully employed in a ring-opening process of epoxides.

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Stereodivergent synthesis of diastereoisomeric carba analogs of glycal‐derived vinyl epoxides: A new access to carbasugars

Cited by 17 publications

References 19 publications

Carbocyclic Substrate Analogues Reveal Kanosamine Biosynthesis Begins with the α-Anomer of Glucose 6-Phosphate

Carbocyclic Substrate Analogues Reveal Kanosamine Biosynthesis Begins with the α-Anomer of Glucose 6-Phosphate

Design and Synthesis of Exocyclic Cyclitol Aziridines as Potential Mechanism‐Based Glycosidase Inactivators

Remarkable Effect of [Li(G4)]TFSI Solvate Ionic Liquid (SIL) on the Regio- and Stereoselective Ring Opening of α-Gluco Carbasugar 1,2-Epoxides

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