An access to the β-anomer of 4'-thio-C-ribonucleosides: hydroboration of 1-C-aryl- or 1-C-heteroaryl-4-thiofuranoid glycals and its regiochemical outcome

We have developed a novel method for the synthesis of the β-anomer of 4'-thio-C-ribonucleosides from 3,5-O-(di-tert-butylsilylene)-4-thiofuranoid glycal. Palladium-catalyzed coupling of 1-tributylstannyl-4-thiofuranoid glycal with iodobenzene or a heteroaryl halide gave 1-C-phenyl- or 1-C-heteroaryl-glycals. Hydroboration of these glycals proceeded at the α-face, and subsequent alkaline hydrogen peroxide treatment of the resulting 2'-α-borane furnished the respective β-anomer of 4'-thio-C-ribonucleosides. These results demonstrate that this synthetic method has a wider scope in terms of heterocyclic base structure. During this study, unexpected Markovnikov-oriented hydroboration has been observed to lead to the respective 1'-α-boranes. These 1'-boranes were converted into either the ring-opened structure or the 2'-deoxy derivatives depending upon their stability.     

High-pressure (2+2)cycloaddition of toluene-4-sulphonyl isocyanate to glycals

High-pressure (2+2)cycloaddition of toluene-4-sulphonyl isocyanate to glycals is examined. Reactions proceed regiospecifically to afford single products in case of all 3-substituted glycals. Upon heating or even after standing at room temperature adducts undergo retro-addition to give starting glycals. Various aspects of the cycloaddition are discussed, especially ret-ro-reaction and rearrangement of β-lactams to α,β-unsaturated amides.     

Stereoelectronic factors in the stereoselective epoxidation of glycals and 4-deoxypentenosides

Glycals and 4-deoxypentenosides (4-DPs), unsaturated pyranosides with similar structures and reactivity profiles, can exhibit a high degree of stereoselectivity upon epoxidation with dimethyldioxirane (DMDO). In most cases, the glycals and their corresponding 4-DP isosteres share the same facioselectivity, implying that the pyran substituents are largely responsible for the stereodirecting effect. Fully substituted dihydropyrans are subject to a "majority rule", in which the epoxidation is directed toward the face opposite to two of the three groups. Removing one of the substituents has a variable effect on the epoxidation outcome, depending on its position and also on the relative stereochemistry of the remaining two groups. Overall, we observe that the greatest loss in facioselectivity for glycals and 4-DPs is caused by removal of the C3 oxygen, followed by the C5/anomeric substituent, and least of all by the C4/C2 oxygen. DFT calculations based on polarized-π frontier molecular orbital (PPFMO) theory support a stereoelectronic role for the oxygen substituents in 4-DP facioselectivity, but less clearly so in the case of glycals. We conclude that the anomeric oxygen in 4-DPs contributes toward a stereoelectronic bias in facioselectivity whereas the C5 alkoxymethyl in glycals imparts a steric bias, which at times can compete with the stereodirecting effects from the other oxygen substituents.     

Stereoselective synthesis of the beta-anomer of 4'-thionucleosides based on electrophilic glycosidation to 4-thiofuranoid glycals

Three types of 4-thiofuranoid glycal with different 3,5-O-silyl protecting groups were prepared and their electrophilic glycosidation was investigated. The 3,5-bis-O-(tert-butyldimethylsilyl)-4-thiofuranoid glycal (5) was obtained through mesylation of 2-deoxy-4-thio-D-erythro-pentofuranose (4) and subsequent base-promoted elimination, while thermal elimination of sulfoxide derivatives was suitable for the preparation of 3,5-O-(tetraisopropyldisiloxane-1,3-diyl) (9) and 3,5-O-(di-tert-butylsilylene) (11) 4-thioglycals. The glycosidation reactions of these 4-thioglycals were carried out, in the presence of either PhSeCl or NIS, by using silylated derivatives of uracil, thymine, cytosine, and N(6)-benzoyladenine. Among the three 4-thioglycals, 11 was found to be an excellent glycosyl donor, forming the desired beta-anomer exclusively irrespective of the nucleobase employed.     

Efficient Synthesis of 2-OH Thioglycosides from Glycals Based on the Reduction of Aryl Disulfides by NaBH4

An improved method to efficiently synthesize 2-OH thioaryl glycosides starting from corresponding per-protected glycals was developed, where 1,2-anhydro sugars were prepared by the oxidation of glycals with oxone, followed by reaction of crude crystalline 1,2-anhydro sugars with NaBH₄ and aryl disulfides. This method has been further used in a one-pot reaction to synthesize glycosyl donors having both “armed” and “NGP (neighboring group participation)” effects.     

The synthesis of optically pure β-lactams derived from sugars. High-pressure [2+2] cycloaddition of toluene-4-sulphonyl isocyanate to glycals.

[2+2] Cycloaddition of toluene-4-sulphonyl isocyanate to glycals 1 - 4 at room temperature under 10 kbar pressure gave respective β-lactams 5 - 8 in good yields. The reaction proceeds regio- and stereospecifically to afford the four-membered ring in position trans to the acetoxy group at C-3 of the glycal moiety.     

Synthesis of L-sugars from 4-deoxypentenosides

[reaction: see text] 4-Deoxypentenosides, which are readily derived from D-sugars, resemble glycals in structure and reactivity and can undergo stereoselective epoxidation and S(N)2 nucleophilic addition to produce L-sugars in pyranosidic form.     

C-Glycosides of 2-amino-2-deoxy sugars. beta-C-Glycosides and 1,1-disubstituted variants

[reaction: see text] C(1)-Substituted anomeric selenides, derived from azidoselenation of C(1)-methylated glycals, provide access to anomeric radical reactivity that has been used to generate beta-C-glycosides and 1,1-disubstituted C-glycosides based on galacto, gluco, and manno variants of N-acetyl-2-amino sugars.     

Highly facialselective synthesis of pyranose 1,3-oxazines and their ring opening with nucleophiles: a novel entry to 2-C-branched glycosides

A TMSOTf-promoted cycloaddition of N-benzoyl-N,O-acetals with various glycals and 3-deoxy glycals affords pyranose 1,3-oxazines with high facial selectivity. In addition, a highly diastereoselective ring opening of the resulting pyranose 1,3-oxazines is reported. With diverse nucleophiles, these reactions take place upon heating at 80 °C. This novel ring-opening reaction affords structurally diversified 2-C-branched glycosides with three newly formed contiguous stereocenters.     

Dynamics of alkene radical cation/phosphate anion pair formation from nucleotide C4' radicals. The DNA/RNA paradox revisited

The fragmentation of nucleotide C4' radicals generated by thiyl radical addition to C4'C5' exocyclic glycals has been re-examined and found to be a function of the thiol and, probably, the initiating system employed. It has been demonstrated that C4' radicals of DNA and RNA models fragment even in the very nonpolar benzene solution if the correct (aliphatic) thiol is employed. (17)O-Labeling experiments are used to demonstrate that the fragmentation of nucleotide C4' radicals (2-deoxyribo- and ribo-) to contact ion pairs is either irreversible or so rapidly reversible as to preclude prior reorganization of the contact ion pair. Formation of the solvent-separated ion pair is an irreversible step, with all such ion pairs proceeding to product formation.     

Synthesis of 2-iodoglycals, glycals, and 1,1'-disaccharides from 2-Deoxy-2-iodopyranoses under dehydrative glycosylation conditions

Treatment of 2-deoxy-2-iodopyranoses under dehydrative glycosylation conditions afforded pyranose glycals, 2-iodoglycals, and 1,1'-disaccharides instead of the expected glycoside products. While the product distribution revealed that this reaction is very sensitive to the configuration of the 2-deoxy-2-iodopyranose, 2-iodopyranoid glycals can be obtained almost exclusively in good yields by employing 3,4-O-isopropylidene as a cyclic bifunctional protecting group. The behavior of 2-deoxy-2-iodopyranoses during the dehydrative elimination reaction has been analyzed in detail.     

InBr3-catalyzed glycosidation of glycals with arylamines: an alternative approach to access 4-aminocyclopent-2-enones

To turn side products into major products, a novel strategy to access biologically active 4-aminocyclopent-2-enones was developed. These compounds were originally identified as side products but became major products when 3,5-dimethylpyran-3,4-diol 7a was used as the substrate and 30% InBr(3) as the catalyst. Aryl- or heteroarylamines as well as variously substituted glycals can be used in this reaction, and the corresponding 4-aminocyclopent-2-enones were obtained in moderate to good yields. These compounds can be further used to prepare 4-aminocarbocyclic nucleosides.     

Convenient syntheses and transformations of 2-C-malonyl carbohydrates

2-C-malonyl carbohydrates were synthesized in only few steps and high yields by radical additions of malonates to glycals. For the first time, the undesired formation of nitrates was completely suppressed with anhydrous cerium ammonium nitrate (CAN) as oxidizing agent. A coherent explanation for the high stereoselectivities of the additions to gluco-configured glycals was provided by variation of the substituents in the 3-position. We established steric effects for the face selectivity, and electronic effects strongly influence the reactivity of the double bonds. The scope and limitation of transition-metal-mediated radical reactions in the synthesis of 2-C-branched carbohydrates was thoroughly investigated. Thus, unsaturated disaccharides and benzyl-protected glycals were used as substrates for the first time. Finally, the 2-C-malonyl carbohydrates were transformed into various products by decarboxylation, saponification and reduction, which afforded interesting precursors for C-disaccharides. In this paper we describe the syntheses of more than 40 new 2-C-analogues of carbohydrates, which were isolated in high yields in analytically pure form. Therefore, the transition-metal-mediated radical addition of malonates to glycals offers a simple and convenient entry to such important carbohydrate derivatives.     

SnCl4 versus TiCl4-mediated coupling between N-6-benzoyladenine and perbenzoylated 2-deoxypyranose: Application to the synthesis of certain homochiral acyclo and carboacyclonucleosides

1,3,4-tri- -benzoyl 2-deoxyribopyranose and persilylated N-6-benzoyladenine react in two different and regioselective ways according to the nature of the coupling reagent SnCl₄ or TiCl₄. The former Lewis acid gives rise to the anomeric mixture of N-9 nucleosides and the latter affords mainly 3′-deoxy 3′-(N-6-benzoyl-9-adenyl) glycals. These two series of derivatives constitute useful synthons for the preparation of homochiral acyclo and carboacyclonucleosides.     

Mild synthesis of disaccharidic 2,3-enopyranosyl cyanides and 2-C-2-deoxy pyranosyl cyanides with Hg(CN)(2)/HgBr(2)/TMSCN

Lewis acid-catalyzed dimerization of mono- and disaccharidic per-O-acetylated glycals gave di- and tetrasaccharidic O-acetylated C-glycosides, respectively. 2,3-Enopyranosyl cyanides were obtained from per-O-acetylated glycals by a new, mild anomeric S(N)'-acetoxy displacement with Hg(CN)(2)/HgBr(2)/TMSCN. Per-O-acetylated 2-C-2-deoxy-pyranoses were converted into pyranosyl cyanides by the same reagent. An unprecedented acetic acid elimination from dimers with D-galacto- and L-fuco-configurations accompanied the S(N)-displacement under those conditions. A new set of (1)H NMR coupling constants for 2,3-enopyranosyl systems was used for configurational assignment of complicated tetrasaccharide mimics.     

Efficient route to 2-deoxy beta-O-aryl-d-glycosides via direct displacement of glycosyl iodides

[reaction: see text]. The conversion of glycals to 2-deoxy glycosyl acetates followed by reaction with trimethylsilyl iodide affords the corresponding glycosyl iodides, which readily undergo substitution with aryl alkoxy anions to provide 2-deoxy-beta-O-aryl glycosides. Direct displacement of the anomeric iodide alleviates the need to introduce temporary C-2 stereodirecting groups that require subsequent removal. The only observable byproducts from the glycosylations result from elimination of HI giving the starting glycals, which can be recycled through the reaction sequence.     

Facile synthesis of C-aryl glycals from sugar-derived lactones

A general entry to C(1) aryl-substituted glycals from the corresponding sugar lactones is described. This approach features one-pot access to aryl glycals. A variety of aryllithium reagents can be used and the method is compatible with various 2-deoxysugar lactones.     

Lewis acid catalyzed cyclization of glycals/2-deoxy-D-ribose with arylamines: additional findings on product structure and reaction diastereoselectivity

The cyclization reactions of arylamines with 2-deoxy-D-ribose or glycals were reinvestigated in the current report. In the montmorillonite KSF- or InCl(3)-initiated reactions of 2-deoxy-D-ribose with arylamines, a pair of diastereomeric tetrahydro-2H-pyran-fused tetrahydroquinolines was obtained in a nearly 1:1 ratio where the structure of one diastereomer was incorrectly assigned in the literature. Meanwhile, the diastereoselectivity in InBr(3)-catalyzed cyclization of glycals with arylamines was also incorrectly reported previously. It was found that high diastereomeric selectivity was achieved only when a C5-substituted glycal was used; otherwise, a pair of diastereomers was obtained in moderate yield with 1:1 diastereomeric ratio. Furthermore, tetrahydrofuran-fused tetrahydroquinolines 5b and 5b' were also prepared successfully by using TBDPS-protected ribose as the glycal precursor and montmorillonite KSF as the activator.     

C2-amidoglycosylation. Scope and mechanism of nitrogen transfer

A one-pot C2-amidoglycosylation reaction for the synthesis of 2-N-acyl-2-deoxy-beta-pyranosides from glycals is described. Glycal donors activated by the reagent combination of thianthrene-5-oxide (11) and Tf2O, followed by treatment with an amide nucleophile and a glycosyl acceptor, lead to the formation of various C2-amidoglycoconjugates. Both the C2-nitrogen transfer and the glycosidic bond formation proceed stereoselectively, allowing for the introduction of both natural and nonnatural amide functionalities at C2 with concomitant anomeric bond formation in a one-pot procedure. Tracking of the reaction by low-temperature NMR spectroscopy employing 15N- and 18O-isotope labels suggests a mechanism involving the formation of the C2-sulfonium glycosyl imidate 39 as well as oxazoline 37 as key intermediates in this novel oxidative glycosylation process.     

Acetamidoglycosylation with Glycal Donors: A One-Pot Glycosidic Coupling with Direct Installation of the Natural C(2)-N-Acetylamino Functionality

Nitrogen transfer to glycals: A new method for direct C2-aza-glycosylation with glycal donors has been developed (see scheme), employing the new reagent combination of thianthrene-S-oxide and trifluoroacetic anhydride for glycal activation, in an overall one-pot procedure.