Background and Originality Content

L-Hexoses are essential components of glycans and glycoconjugates of biological relevance.^[1] They are also valuable building blocks of certain therapeutic applications. For instance, L-glucose tracers that emit fluorescence show potential in identifying and characterizing cancerous cells among such cell aggregates;^[2] Additionally, a recent study has proposed 3,6-anhydro-L-galactose (AHG) as a novel anticariogenic agent due to its higher inhibitory activity against Streptococcus mutans than commonly used xylitol.^[3]Furthermore, agarobiose and agarooligosaccharides-containing AHG have also demonstrated anticariogenic activity.^[4] It is worth noting that L-hexoses are considered rare sugars, which are not able to be obtained from natural sources on a scale. As a result, to meet the demand for L-sugars, numerous strategies have been designed and developed to substantially access to such architectures.^[5] They include C-5 configuration inversion of readily available D-sugars,^[6]site-selective epimerization of L-sugars,^[7]one-carbon homologation of pentoses,^[8]head-to-tail inversion,^[9] de novosynthesis,^[10] and C-H functionalization of 6-deoxy-L-hexoses.^[12] According to ”sugar mapping”,^[13] L-glucose, L-galactose, and L-mannose are good precursors to the other L-sugars. We thereby envisaged that ready preparation of L-glucose, L-galactose, and L-mannose would be an ideal route to access L-sugars by use of biomass-derived and inexpensive D-sugars (D-glucose, D-mannose, and D-galactose) and L-sugars (L-rhamnose and L-fucose). In this context, Li and co-workers have described a methodology for the conversion of D-glucosyl acetate into orthogonally protected L-glucosyl acetate following a head-to-tail inversion.^[9] The transformation features one-carbon extension of sugar chain at the anomeric position through Co₂(CO)₈-catalyzed silyloxymethylation and head-to-tail inversion by use of Pb(OAc)₄-mediated decarboxylative acetoxylation. The prepared L-glucosyl acetate was converted into L-galactosyl or L-mannosyl acetate by epimerizing the C4- or the C2-OH. Additionally, the same strategy was applied by Li and colleagues (Scheme 1a) to synthesize L-glucose and L-mannose derivatives starting from 1-methyl-(β-D-C -glucosyl)ethanone and 1-methyl-2-(β-D-C -galactosyl)ethanone constructs.^[9] Due to the limited reactivity exhibited by glycosyl acetates, it is inevitable to covert L-glycosyl acetates into more reactive glycosyl donors, such as glycosyl imidates, thioglycosides, and glycosyl fluorides. A significant breakthrough was achieved by the Pedersen group (Scheme 1b) utilizing the methodology developed by Hartwig and co-workers to prepare 1,3-diol through iridium-catalyzed C-H activation directed by a hydroxy group.^[11] They successfully accomplished the transformation of L-rhamnose and L-fucose into L-mannose and L-galactose, respectively.^[12] Furthermore, the same group extended this strategy to achieve synthesis of all eight L-hexopyranosyl thioglycoside donors from their corresponding 6-deoxy-L-hexopyranosyl thioglycosides.^[7]Recently, we have successfully recorded a head-to-tail switch strategy that enables the convenient synthesis of uncommon 6-deoxy-D-/L-heptopyranosyl fluorides. In this method, allyl α-D-C -glycosides are employed as the starting materials. This approach is noteworthy as it represents one of the limited options available for generating L-sugar settings, which can be directly utilized as glycosyl donors (Scheme 1c).^[14-17]The remarkable characteristics of the transformation encompass two-carbon elongation of a sugar chain at the anomeric position, along with shortening of a one-carbon segment through either radical decarboxylative fluorination^[14] of uronic acids or radical dehydroxymethylative fluorination^[15]of sugar primary alcohols. We employed these methodologies for the assembly of Camplybater jejuni strain CG8486^[16] and BH0142^[17]capsular hexasaccharides composed of →3)-β-D-6dido Hepp -(1→4)-β-D-Glcp NAc-(1→ and →3)-α-D-6dido Hepp -(1→4)-α-D-Galp -(1→ disaccharide repeating units. These oligosaccharides have the potential to serve as antigens against C. jejuni infections.

Drawing inspiration from the aforementioned advancements and acknowledging the biological relevance of glycans containing L-sugar units, this study presents the synthesis of L-glucosyl, L-galactosyl, and L-mannosyl fluorides utilizing a head-to-tail switch strategy (Scheme 1d). Our hypothesis is that the desired L-glycosyl fluorides can be obtained by means of radical decarboxylative fluorination of hydroxymethyl β-D-C -uronic acid derivatives.^[14] The introduction of anomeric hydroxymethyl group can be achieved by reduction of the corresponding aldehydes. These aldehydes can be prepared from 1-phenyl-2-(β-D-C -glycosyl)ethanones, which can be easily derived from the condensation of diphenyl 1,3-pentandione with cost-effective and readily available D-glucose, D-galactose, and D-mannose.^[18]

Scheme 1 Strategies for the synthesis of L-sugars

Results and Discussion

Synthesis of L-glucopyranosyl fluoride and L-galactosyl fluorides

In order to implement the concept, our study commenced with preparing L-glucopyranosyl fluoride from the acetyl-protected 1-phenyl-2-(β-D-C -glucosyl)ethanone1a ^[18] (Scheme 2). Initially, we attempted to convert 1a to olefin 2a by means of the procedure which was reported by the Prasad group.^[19] However, 1a was subjected to reduction with NaBH₄ followed by P₂O₅-mediated dehydration of the alcohol in CH₂Cl₂ at room temperature, resulting in a 36% yield of olefin 2a . The unsatisfactory yield and the difficulty in separating 2a from a viscous and dark reaction mixture prompted us to seek a more convenient approach to 2a . Fortunately, treatment of 1a with NaBH₄followed by triflic anhydride in the presence of 2,6-lutidine at -40^oC in CH₂Cl₂^[20] yielded the desired vinyl C -glycoside 2a in 75% yield. The dehydration reaction occurred through triflation of the hydroxy group and simultaneous elimination of the reactive triflate. It should be noted that the Liang group recently disclosed a novel approach toC -vinyl glycosides through a Heck-type coupling reaction of glycosyl bromide with styrenes under visible light and palladium dual catalysis, providing a new way to the constructs like2a .^[21] With olefin 2a in hand, we successfully made benzyl (Bn)-protected β-D-glucopyranosyl methanol3a in 52% overall yield through a four-step reaction sequence composed of deacetylation, the benzylation of resultant alcohol, the oxidative cleavage of C═C double bond, and the reduction of liberated aldehyde. Conversion of 3a into uronic acid 5a was achieved in 79% yield through a four-step reaction sequence consisting of the benzoyl protection of primary hydroxy group in 3a(leading to 4a ), the chemoselective acetolysis of the benzyl ether of primary hydroxy group, selective

Scheme 2 Synthesis of L-glucopyranosyl fluoride and L-galactopyranosyl fluoride

Reagents and conditions: (a) NaBH₄, MeOH, ice bath; (b) 2,6-lutidine, Tf₂O, CH₂Cl₂, 75% for 2a over two steps, 82% for 2b over two steps; (c) 60% NaH, MeOH; (d) BnBr, 60% NaH, DMF; (e) OsO₄, 2,6-lutidine, NaIO₄, 1,4-dioxane/H₂O; (f) NaBH₄, MeOH, 52% for 3a over four steps, 59% for 3b over four steps; (g) BzCl, DMAP, pyridine; (h) TFA, Ac₂O; (i) AcCl, MeOH (j) TEMPO, BAIB, CH₂Cl₂/H₂O, 79% for5a over four steps, 64% for 5b over four steps; (k) Selectfluor, KF·2H₂O, Ag₂CO₃, acetone/H₂O, 62% for 6a , 65% for 6b . BnBr = Benzyl bromide; DMF =N ,N -dimethyl formamide; BzCl = Benzoyl chloride; DMAP = 4-N ,N -dimethylaminopyridine; TFA = Trifluoroacetic acid; AcCl = Acetyl chloride; TEMPO = 2,2,6,6-Tetramethylpiperidinooxy; BAIB = Iodobenzene diacetate.

deacetylation with methanolic hydrogen chloride, and the oxidation of the obtained alcohol with TEMPO/BAIB. Uronic acid 5a was subjected to Ag₂CO₃-mediated radical oxidatively decarboxylative fluorination^[14] to afford 62% of the expected L-glucosyl fluoride 6a as an α/β 1:1 mixture. Following the same procedure as above, the olefin2b , derived from 1-phenyl-2-(β-D-C -mannosyl)ethanone1b , was smoothly transformed into L-galactosyl fluoride6b with α/β 2.4:1 stereoseletivity in 23% overall yield over nine steps.