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 -40oC 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.