?-Glycosyl Trifluoroborates as Precursors for Direct ?±-C-Glycosylation: Synthesis of 2-Deoxy-?±-C-glycosides

Article abstract of DOI:10.1021/acs.orglett.1c00402

C-Glycosides are metabolically stable mimics of natural O-glycosides and are expected to be useful tools for investigation of the biological functions of glycans. Here, we describe the synthesis of a series of aryl and vinyl C-glycosides by stereoinvertive sp3-sp2 cross-coupling reactions of 2-deoxyglycosyl boronic acid derivatives with aryl or vinyl halide, mediated by a photoredox/nickel dual catalytic system. Hydrogenation of the vinyl C-glycosides afforded C-linked 2′-deoxydisaccharide analogues.

Full text of DOI:10.1021/acs.orglett.1c00402

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Letter
β‑Glycosyl Trifluoroborates as Precursors for Direct α‑C-
Glycosylation: Synthesis of 2‑Deoxy-α‑C‑glycosides
Daiki Takeda, Makoto Yoritate, Hiroki Yasutomi, Suzuka Chiba, Takahiro Moriyama, Atsushi Yokoo,
Kazuteru Usui, and Go Hirai*
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ABSTRACT: C-Glycosides are metabolically stable mimics of
natural O-glycosides and are expected to be useful tools for
investigation of the biological functions of glycans. Here, we
describe the synthesis of a series of aryl and vinyl C-glycosides by
stereoinvertive sp3−sp2 cross-coupling reactions of 2-deoxyglycosyl
boronic acid derivatives with aryl or vinyl halide, mediated by a
photoredox/nickel dual catalytic system. Hydrogenation of the
vinyl C-glycosides afforded C-linked 2′-deoxydisaccharide ana-
logues.
etabolically stable analogues of carbohydrates or
glycoconjugates are important molecular tools for
Despite the advantages of the Stille-type coupling reaction in
terms of reliability and stability of the starting materials,
organostannanes are toxic, and an environmentally friendly
coupling reaction is preferable. Therefore, the Suzuki−Miyaura
coupling reaction was employed to construct C-arylated (or
vinylated) glucal derivatives 2 from C1-sp2 pinacol boronate 6
(Figure 1B).9−12 This provides access to 2-deoxy-β-C-gluco-
sides.13 As for C1-sp3 glycosyl boronates, surprisingly, simple
C-1 borylated monosaccharides have not been reported, except
for C-1 alkylated and B-substituted monosaccharides prepared
by the B−C bond insertion reaction of a glycosyl diazirine.14,15
We envisioned that potassium β-glycosyltrifluoroborates such
as 7, which are obtainable by hydrogenation of sp2-boronate
such as 6 (Figure 1C), would undergo a Ni-catalyzed
metallaphotoredox coupling reaction with aryl or vinyl
halides.16−18 Single-electron oxidation of 7 would generate
glycosyl radical 8,2 which is expected to adopt a standard chair
conformation with α-radical orientation stabilized by the inner
cyclic oxygen atom.19−21 Then, stereoinvertive coupling should
proceed to give 5α selectively (Figure S1).22,23 This approach
would be complementary to the method via compound 2 and
might be useful to synthesize analogues of native 2-deoxy
glycosides (usually β-O-glycosides). Here we report the
synthesis and direct α-C-glycosylation of 7.
M
functional analysis in chemical biology. In particular, C-
glycosides exhibit high structural similarity to native glycans.1,2
For example, we recently demonstrated that C-glycoside
analogues of ganglioside GM3, especially molecules with a
CHF-glycoside linkage, exhibit greater biological activity at the
cell level than analogues with a CH2- or a CF2-linkage.
Furthermore, their conformation is similar to that of native
GM3.3 However, despite many reports of synthetic method-
ology for C-glycosides, there are few efficient strategies for
directly forming a C-glycosidic linkage (direct C-glycosylation)
via intermolecular coupling reaction, like a standard O-
glycosylation reaction.
Among carbohydrate-containing natural products or native
glycans, metabolites containing 2-deoxy sugars are also of
interest to both chemists and biologists, as they can have
unique biological activities.4 The corresponding 2-deoxy-C-
glycosides should therefore be useful chemical tools, but there
are few reports of their synthesis via intermolecular coupling
reaction.4 A representative reaction is Pd-catalyzed sp2−sp2
cross-coupling from C1-sp2 stannanes 1,5,6 which was shown to
be applicable to the synthesis of disaccharide analogues (Figure
1A). The stereochemistry at the anomeric position is
determined at the stage of hydrogenation of 2, usually
affording β-2-deoxyglucosides 3 as the major products. As a
complementary but powerful strategy, direct C-glycosylation
was reported with via Pd-catalyzed sp3−sp2 cross-coupling
from chemically stable C1-sp3 glycosyl stannanes 4 (Figure
1A).7 This methodology is characterized as a stereoretentive
cross-coupling reaction. Namely, α- and β-isomers (5α and
5β) could be selectively obtained from α- and β-glycosyl
stannanes (4α and 4β), respectively. This strategy has also
been applied to the synthesis of C-acyl disaccharides.8
C1-sp3 2-Deoxyglucosyltrifluoroborate 12 was prepared as
follows (Scheme 1). A slight modification of the Ir-catalyzed
Received: February 3, 2021
Published: February 24, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00402
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1940−1944
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Figure S2). Hydrogenation of 10 proceeded after hydrolysis of
MIDA ester to give C1-sp3 boronic acid 11 as a single isomer
in good yield. It should be noted that hydrogenation of the
Bpin adduct was successful under Rh/Al2O3 catalysis, affording
the corresponding C1-sp3 Bpin compound, though purification
by silica gel chromatography caused some loss of the product.
Treatment of 11 with KHF2 solution afforded potassium
glucosyltrifluoroborate 12. 2-Deoxy-D-galactosyltrifluorobo-
rate 13 and 2,6-dideoxy-D-arabinosyltrifluoroborate (D-
olivose-type) 14 were similarly synthesized (Scheme S1),
except that temporary protection with MIDA during the
synthesis of 13 was not conducted because transformation to
MIDA ester from the corresponding Bpin adduct was less
efficient (Table S2).
With the glycosyltrifluoroborates in hand, we examined the
metallophotoredox coupling reaction with aromatic halides
(Figure 2). Employing the literature conditions16 with slight
modifications especially in regards to the solvent (see Tables
S3−S6 for details of the optimization of reaction conditions),
reaction with aryl bromides proceeded to give 16 in a highly α-
selective manner. The use of aryl bromides with an electron-
withdrawing substituent (CF3, CO2Me, CN, and COMe) at
the para-position provided the products 16a−16d in good
yields. We confirmed that the coupling reaction of 12 and 15a
at the 1 mmol scale was also successful. The aryl bromide
showed better reactivity than the corresponding aryl chloride
or aryl iodide (Table S7). Fluorine, methyl, and methoxy
groups were tolerated (16e−16g). The use of ortho- or meta-
substituted aryl bromides afforded o-16b, o-16g, and m-16g in
reasonable yields, though m-16b was obtained in only 24%
yield. Although a free amino group disturbed the formation of
the coupling product, acetamide derivative 16h was obtained
in an acceptable yield. Coupling with heteroaromatic halides,
such as 2-bromofuran or 3-bromothiophene, also proceeded to
afford 16i and 16j in 33% and 64% yields. Unprotected 5-
indole derivative 16k was formed, though in only 18% yield,
but the reaction with Boc-protected 5-bromoindole resulted in
formation of 16l in better yield (53%). Reaction with Ms-
protected 2-bromoindole also occurred to give 16m in 37%
yield. This result prompted us to investigate the coupling with
tryptophan derivative 15n, which afforded α-2-deoxy-C-
mannosyltryptophan26−30 16n in a highly stereoselective
manner.
Figure 1. (A) Representative methods for synthesis of 2-deoxy-C-
glycosides from organostannanes 1 and 4; (B) synthesis from
boronate 6; and (C) our strategy for synthesis of 2-deoxy-α-C-
glycosides 5α from β-glycosyltrifluoroborate 7.
Scheme 1. Synthesis of Potassium 2-Deoxy-β-
glycosyltrifluoroborate 12−14
For other donors 13 and 14, the coupling reaction with
representative aryl bromides (p-trifluoromethyl bromobenzene,
methyl p-bromobenzoate, and p-bromoanisole) gave α-C-aryl
α-glycosides 17 and 18 in good yield. D-Olivose-type C-
glycosides 18a, p-18b, and p-18g exhibited flipped conforma-
tion from standard 4C1 conformation to 1C4 conformation with
an α-aryl group. Considering the glycosyl radical reactivity,
ring-flipping presumably occurs after the coupling reaction,
probably due to steric repulsion between the C1-aryl group
and C3 and C5 hydrogen atoms.
Next, we examined the coupling with vinyl halides 19
(Scheme 2A). The reaction with the simple (E)-vinyl bromide
bearing an alkyl chain gave the aliphatic C-glycosides 20a in a
moderate yield with high α-selectivity, indicating that the 2-
deoxyglycosyltrifluoroborate 12 could be applicable for the
synthesis of disaccharide derivatives. In fact, coupling with (E)-
vinyl bromide 19b prepared from D-glucose derivative
proceeded similarly to give the disaccharide derivative 20b
(41% yield). Hydrogenation of 20a and 20b successfully
provided the aliphatic 2-deoxyglucoside analogue 21 and CH2-
C1-selective C−H borylation of glucal derivative 9 reported by
Miyaura and co-workers gave the corresponding pinacolato-
borate (Bpin adduct) in good yield,24 and this was converted
to N-methyliminodiacetic acid (MIDA) ester25 10 for
purification by silica gel chromatography. Addition of
methanol was effective for this transformation (Table S1 and
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Figure 2. Metallophotoredox coupling of potassium β-glycosyltrifluoroborate 12−14 with aryl bromides 15. (a) Isolated yields of the alpha isomer.
(b) Ratios of α and β isomers of the crude materials are shown in parentheses. (c) Reaction time is 12 h.
linked 2-deoxyGlc-α(1,6)-Glc analogue 22 in good yield
(Scheme 2B). Furthermore, application of 2-deoxyglycosyltri-
fluoroborate 12 to the synthesis of CHF-linked disaccharide
analogue was also successful. Namely, coupling of 12 with
glucose derivatives having (E)-bromofluoro olefin also
occurred α-selectively to afford the corresponding coupling
product 20c in better yield. Both isomers of the CHF-linked 2-
deoxyGlc-α(1,6)-Glc analogue 23 were obtained by hydro-
genation of 20c. To our knowledge, this is the first example of
the synthesis of a CHF-linked disaccharide derivative31−34 by
direct C-glycosylation reaction.
In summary, we first synthesized 2-deoxy-β-glycosyl boronic
acids and their trifluoroborate derivatives 12−14 and then
conducted stereoinvertive cross-coupling reactions with
various aryl bromides and vinyl halides to obtain the α-C-
glycosides selectively. This strategy provides efficient access to
α-C-linked glycans and glycoconjugates, which are expected to
be useful for functional analysis. Application of this strategy to
glycosyl boronic acid derivatives possessing a 2-hydroxyl group
is underway.
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Atsushi Yokoo − Graduate School of Pharmaceutical Sciences,
Kyushu University, Fukuoka 812-8582, Japan
Kazuteru Usui − Graduate School of Pharmaceutical Sciences,
Kyushu University, Fukuoka 812-8582, Japan; Faculty of
Pharmaceutical Sciences, Showa Pharmaceutical University,
Tokyo 194-8543, Japan; orcid.org/0000-0002-2175-
5221
Scheme 2. Metallophotoredox Coupling of Potassium 2-
Deoxy-β-glycosyltrifluoroborate 12 with Vinyl Bromides 19
and Synthesis of CH2- and CHF-Linked 2-Deoxyglucosides
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00402
Author Contributions
D.T., M.Y., H.Y., S.C., T.M., A.Y., and K.U. performed the
synthetic studies. G.H. supervised the research.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was partially supported by PRIME and the Platform
Project for Supporting Drug Discovery and Life Science
Research (BINDS) from the Japan Agency for Medical
Research and Development, AMED, the JSPS KAKENHI
(Grant Numbers 18H04417 for Middle Molecular Strategy,
18H02097, and 20K15957), the Naito Foundation, and the
Sumitomo Foundation.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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1
dures, H- and 13C NMR and HRMS data for new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Go Hirai − Graduate School of Pharmaceutical Sciences,
Kyushu University, Fukuoka 812-8582, Japan; orcid.org/
0000-0003-3420-555X; Email: gohirai@phar.kyushu-
u.ac.jp
Authors
Daiki Takeda − Graduate School of Pharmaceutical Sciences,
Kyushu University, Fukuoka 812-8582, Japan
Makoto Yoritate − Graduate School of Pharmaceutical
Sciences, Kyushu University, Fukuoka 812-8582, Japan;
orcid.org/0000-0003-2182-3914
Hiroki Yasutomi − Graduate School of Pharmaceutical
Sciences, Kyushu University, Fukuoka 812-8582, Japan
Suzuka Chiba − Graduate School of Pharmaceutical Sciences,
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