Hydantoins and their hybrids with other molecules represent a very important group of heterocycles because they exhibit diverse biological and pharmacological activities in medicinal and agrochemical applications. They also serve as key precursors in the chemical or enzymatic synthesis of significant nonnatural α-amino acids and their conjugates with medical potential. This review provides a comprehensive treatment of the synthesis of hydantoins via the Bucherer–Bergs reaction including the Hoyer modification but limited to free carbonyl compounds or carbonyl compounds protected as acetals (ketals) and cyanohydrins used as starting reaction components. In this respect, the Bucherer–Bergs reaction provides an efficient and simple method in the synthesis of important natural products as well as for the preparation of new organic compounds applicable as potential therapeutics. The scope and limitations, as well as a comparison with some other methods for preparing hydantoins, are also discussed.

Analogues of mannostatin A were synthesised and evaluated as inhibitors of GH38 α-mannosidases. Different regioselectivity of aziridine opening with sodium methanethiolate was observed and investigated by quantum mechanics calculations.

A synthetic approach to 4a‐carba‐d‐lyxofuranose derivatives starting from d‐lyxose is described. The protected 4a‐carba‐β‐d‐lyxofuranose was employed as the key intermediate for the synthesis of 4a‐carba‐d‐lyxofuranose derivatives including novel 1‐amino‐1‐deoxy‐4a‐carba‐d‐lyxofuranoses. Synthesized 4a‐carba‐d‐lyxofuranoses were evaluated as inhibitors of GH38 α‐mannosidases, namely, the Golgi (GMIIb) and lysosomal (LManII) α‐mannosidases from Drosophila melanogaster and commercial Jack bean α‐mannosidase (JBMan) from Canavalia ensiformis. The biochemical evaluation revealed that only 1‐amino‐1‐deoxy‐4a‐carba‐β‐d‐lyxofuranose exhibited reasonable inhibitory activity against GMIIb (IC50 = 200 µm). In addition, the results of biological evaluation were discussed by means of molecular modelling.

A synthetic approach to 1,4-imino-L-lyxitols with various modifications at the C-5 position is reported. These imino-L-lyxitol cores were used for the preparation of a series of N-(4-halobenzyl)polyhydroxypyrrolidines. An impact of the C-5 modification on the inhibition and selectivity against GH38 α-mannosidases from Drosophila melanogaster, the Golgi (GMIIb) and lysosomal (LManII) mannosidases and commercial jack bean α-mannosidase from Canavalia ensiformis was evaluated. The modification at C-5 affected their inhibitory activity against the target GMIIb enzyme. In contrast, no inhibition effect of the pyrrolidines against LManII was observed. The modification of the imino-L-lyxitol core is therefore a suitable motif for the design of inhibitors with desired selectivity against the target GMIIb enzyme.

Alkyl or aryl 3‐acetamido‐3‐deoxy‐2‐thio‐β‐d‐psicofuranosides bearing a phosphate group at C‐1, which were originally designed as potential GnT‐I inhibitors (GnT = N‐acetylglucosaminyltransferase) by computational methods, were found to be unstable. Therefore their structure was slightly modified to stable 3‐acetamido‐3‐deoxy‐β‐d‐psicofuranosyl sulfones. A model inhibitor of GnT‐I, namely ethyl 3‐acetamido‐3‐deoxy‐1‐O‐phosphono‐β‐d‐psicofuranosyl sulfone, was synthesized based on the transformation of d‐mannose into 3‐azido‐3‐deoxy‐d‐psicofuranose as the key intermediate. Thioglycosylation of 1,2‐O‐diisopropylidene‐protected 3‐azido‐ or 3‐amino‐3‐deoxy‐d‐psicofuranose derivatives with thiols in the presence of BF3·OEt2 was found to be a crucial step in the synthesis of the predicted inhibitor. Biochemical evaluation of the proposed inhibitor revealed only a very weak inhibition of GnT‐I. Additional molecular modeling showed that further modifications of the UDP‐mimicking part of the synthesized inhibitor are necessary to improve its inhibitory activity against GnT‐I.

A novel synthetic strategy leading to 3-acetamido-3-deoxy-D-psicofuranose 9 is presented. The latter compound, after some manipulations, was transformed into fully protected 3-acetamido-3-deoxy-D-psicofuranose 11 as a potential substrate for the synthesis of N-acetylglucosaminyltransferase inhibitors designed by computational methods. After the attempted thioglycosylation of 11 with EtSH in the presence of BF3·OEt2, 2-methyloxazoline derivatives 13 and 14 were isolated.

Based on rational design of the transition state analog inhibitors of glycosyltransferases, four model glycomimetics of this type, viz. benzyl 2-thio-α-dfructofuranoside 1-diethylphosphate (XIa), its β-anomer (XIb), and their ethyl 2-thio analogs — α-anomer (XIIa) and β-anomer (XIIb), were synthesized. In addition, fourteen precursors arising during the synthesis of the desired final model compounds (XI and XII), partially or fully acetylated benzyl and/or ethyl 2-thiofructofuranoside 1-diethyl phosphates, were isolated and characterized with the aim to prepare complete series of glycomimetics, representing donor UDP-GlcNAc designated for biological assays on human GnT’s, viz. GnT-I, Core2GnT, and GnT-V.

The Grignard reaction of 2,3-O-isopropylidene-α-D-lyxo-pentodialdo-1,4-furanoside and benzylmagnesium chloride (or bromide) afforded a non-separable mixture of diastereomeric benzyl carbinols and diastereomeric o-tolyl carbinols. The latter resulted from an unexpected benzyl to o-tolyl rearrangement. The proportion of benzyl versus o-tolyl derivatives depended on the reaction conditions. Benzylmagnesium chloride afforded predominantly o-tolyl carbinols while the application of benzylmagnesium bromide led preferably to the o-tolyl carbinols only when used in excess or at higher temperatures. The structures of the benzyl and o-tolyl derivatives were confirmed unambiguously by NMR spectral data and X-ray crystallographic analysis of their 5-ketone analogues obtained by oxidation of the corresponding mixture of diastereomeric carbinols. A possible mechanism for the Grignard reaction leading to the benzyl→o-tolyl rearrangement is also proposed.

The formation of methyl 4-cyano-6-deoxy-2,3-O-isopropylidene-α-l-talopyranoside (3), methyl 4-cyano-6-deoxy-2,3-O-isopropylidene-α-l-mannopyranoside (4), methyl 4-cyano-6-deoxy-2,3-O-isopropylidene-β-d-allopyranoside (5), and methyl 4-cyano-6-deoxy-2,3-O-isopropylidene-β-d-gulopyranoside (7) from methyl 6-deoxy-2,3-O-isopropylidene-α-l-lyxo-hexopyranosid-4-ulose (1) under Strecker amino nitrile synthesis and Bucherer-Bergs hydantoin synthesis reaction conditions, respectively, is reported. Their structures were determined on the basis of NMR and mass spectral data. The configurations of free cyanohydrins 3 and 4 and 4-O-acetylated cyanohydrins 6 and 8 (obtained by acetylation of 5 and 7, respectively) were established by single-crystal X-ray analysis. The conformations of the six-membered pyranose ring and five-membered 1,3-dioxolane ring in compounds 3, 4, 6, and 8 are also reported.

The crystal structure of benzyl 2,3-anhydro-β-d-ribopyranoside is orthorhombic, P212121, Z = 4. The pyranose ring adopts the E O conformation distorted considerably to the 5 H O direction. The molecules of the title compound are linked into infinite chains running along the a-axis by bifurcated O–H···O hydrogen bonds. Interaction energies of these hydrogen bonds are significantly different, ~−5.4 for the bond with the smaller and ~−1.1 kcal/mol for the bond with the larger O···O separation. The hydrogen-bond pattern is completed by the two weaker C–H···O intermolecular hydrogen bonds, aiming at the epoxy oxygen atom. IR vibrational spectrum was interpreted by means of comparison with the full list of vibrational modes predicted using DFT method in the solid state. While till 1495 cm−1 the individual bands can be reconciled with single calculated modes, the region below this limit is populated by heavily overlapped HCH, HCO, HOC, COC and HCC bending modes merged with few ν(CC) and ν(CO) modes. The respective “red” shifts of the positions of the ν(OH) bands correlate well with the size of the O···O separation.

Two strategies are reported for the diastereoselective synthesis of isoxazolidinyl nucleosides, as potential antiviral agents - a one-step approach based on 1,3-dipolar cycloaddition of sugar-derived nitrones with vinyl nucleobases derived from uracil and adenine, as well as a two-step methodology based on the Vorbruggen nucleosidation of the 5-acetoxyisoxazolidines. The 1,3-dipolar cycloadditions of sugar-derived nitrones with vinyl acetate proceed with very good diastereoselectivity to give the diastereoisomeric isoxazolidines. Condensation of the major diastereomerically pure acetoxyisoxazolidines with silylated uracil, thymine, cytosine, N-acetylguanine and purines occurs with moderate to excellent stereoselectivity with the formation of the expected isoxazolidinyl nucleosides. The stereoselectivity of the addition of the silylated nucleobase is dependent on the structure of the substituent at C-3 originating from the starting chiral nitrone and on the attacking nucleobase.

Ethyl 6-O-tert-butyldimethylsilyl-3,4-di-O-acetyl-2-thio-α-D-fructofuranoside (Va), its β-analog (Vb); as well as benzyl 6-O-tert-butyldimethylsilyl-3,4-di-O-acetyl-2-thio-α-D-fructofuranoside (Xa) and its β-analog (Xb), having an unprotected OH group at C-1, were prepared by sequential synthesis starting from commercially available D-fructose. These compounds represent suitable nucleophiles for the preparation of model carbohydrate mimetics of a glycosyltransferase inhibitor type in transition state. The structures of all compounds were confirmed by NMR spectral data and elemental analyses.

In the title compounds, C(12)H(20)O(6), (I), and C(9)H(16)O(6), (II), the five-membered furanose ring adopts a (4)T(3) conformation and the five-membered 1,3-dioxolane ring adopts an E(3) conformation. The six-membered 1,3-dioxane ring in (I) adopts an almost ideal (O)C(3) conformation. The hydrogen-bonding patterns for these compounds differ substantially: (I) features just one intramolecular O-H...O hydrogen bond [O...O = 2.933 (3) A], whereas (II) exhibits, apart from the corresponding intramolecular O-H...O hydrogen bond [O...O = 2.7638 (13) A], two intermolecular bonds of this type [O...O = 2.7708 (13) and 2.7730 (12) A]. This study illustrates both the similarity between the conformations of furanose, 1,3-dioxolane and 1,3-dioxane rings in analogous isopropylidene-substituted carbohydrate structures and the only negligible influence of the presence of a 1,3-dioxane ring on the conformations of furanose and 1,3-dioxolane rings. In addition, in comparison with reported analogs, replacement of the -CH(2)OH group at the C1-furanose position by another group can considerably affect the conformation of the 1,3-dioxolane ring.

In the title compounds, C 12 H 20 O 6 , (I), and C 9 H 16 O 6 , (II), the five-membered furanose ring adopts a 4 T 3 conformation and the five-membered 1,3-dioxolane ring adopts an E 3 conformation. The six-membered 1,3-dioxane ring in (I) adopts an almost ideal O C 3 conformation. The hydrogen-bonding patterns for these compounds differ substantially: (I) features just one intramolecular O—H...O hydrogen bond [O...O = 2.933 (3) Å], whereas (II) exhibits, apart from the corresponding intramolecular O—H...O hydrogen bond [O...O = 2.7638 (13) Å], two intermolecular bonds of this type [O...O = 2.7708 (13) and 2.7730 (12) Å]. This study illustrates both the similarity between the conformations of furanose, 1,3-dioxolane and 1,3-dioxane rings in analogous isopropylidene-substituted carbohydrate structures and the only negligible influence of the presence of a 1,3-dioxane ring on the conformations of furanose and 1,3-dioxolane rings. In addition, in comparison with reported analogs, replacement of the –CH 2 OH group at the C1-furanose position by another group can considerably affect the conformation of the 1,3-dioxolane ring.

The formation of (4R)-4-carbamoyl-4-[(4R)-3-O-benzyl-1,2-O-isopropylidene-beta-l-threofuranos-4-C-yl]-oxazolidin-2-one instead of expected imidazolidin-2,4-dione (hydantoin) derivative from 5-amino-5-cyano-5-deoxy-3-O-benzyl-1,2-O-isopropylidene-alpha-d-glucofuranose or 3-O-benzyl-1,2-O-isopropylidene-alpha-d-xylo-hexofuranos-5-ulose under Bucherer-Bergs reaction conditions is reported. Single crystal X-ray diffraction data revealed that (3)T(4) is the prefered conformation for the furanose ring, while E(2) and (2)T(1) conformations are adopted by the 1,3-dioxolane and 2-oxazolidinone five-membered rings, respectively.

D-Lyxose derived nitrone 7 was found to effectively undergo an SmI2-mediated radical addition to methyl acrylate affording gamma-N-hydroxylamino ester 8 with high diastereomeric control. The pyrrolidinone 9 was prepared in a single step from 8 involving N-O bond cleavage with Zn/AcOH and subsequent spontaneous cyclization. D-Xylose derived nitrone 10 afforded in the SmI2-induced coupling with methyl acrylate the gamma-N-hydroxylamino ester 11 as minor product. The major product the nitrone 12 is formed by unusual reductive deoxygenation of the starting nitrone.

In the crystal structure of the title compound, C 23 H 22 BrN 3 , a strong conjugation of the pyrazoline chromophore with the aromatic rings at positions 1 and 3 is observed, as well as a significant shift in the synclinal→synperiplanar direction. The absolute structure was unequivocally determined. In the absence of clasical hydrogen-bond donors, the structure is stabilized by weak C—H...π interactions. This paper also reports the electronic structure of the title compound using NBO (natural bond order) analysis. The contributions of lone pairs to the relevant bonds were revealed.

In the crystal structure of the title compound, C(23)H(22)BrN(3), a strong conjugation of the pyrazoline chromophore with the aromatic rings at positions 1 and 3 is observed, as well as a significant shift in the synclinal-->synperiplanar direction. The absolute structure was unequivocally determined. In the absence of clasical hydrogen-bond donors, the structure is stabilized by weak C-H...pi interactions. This paper also reports the electronic structure of the title compound using NBO (natural bond order) analysis. The contributions of lone pairs to the relevant bonds were revealed.

Two strategies for the synthesis of isoxazolidinyl nucleosides as potential antiviral agents are reported: a one-step approach based on 1,3-dipolar cycloaddition of D-lyxosyl nitrone with N,N-dibenzyl-9-vinyl adenine, and a two-step methodology based on the Vorbrüggen nucleosidation of the 5-acetoxyisoxazolidine. The chiral D-lyxosyl nitrone undergoes regioselective 1,3-dipolar cycloadditions with N,N-dibenzyl-9-vinyl adenine and vinyl acetate giving 5-substituted isoxazolidines as a mixture of four diastereoisomers in good yields. The condensation of 5-acetoxyisoxazolidine with silylated uracil, thymine, and N-acetylcytosine proceeded with moderate to good stereoselectivity with the formation of the expected isoxazolidinyl β-and α-nucleosides.