β-Selective C-Glycosylation and its Application in the Synthesis of Scleropentaside A

Article abstract of DOI:10.1002/anie.201900995

C-Glycosides are carbohydrates that bear a C?C bond to an aglycon at the anomeric center. Due to their high stability towards chemical and enzymatic hydrolysis, these compounds are widely used as carbohydrate mimics in drug development. Herein, we report a general and exclusively β-selective method for the synthesis of a naturally abundant acyl-C-glycosidic structural motif first found in the scleropentaside natural product family. A Corey–Seebach umpolung reaction as the key step in the synthesis of scleropentaside A and analogues enables the β-selective construction of the anomeric C?C bond starting from unprotected carbohydrates in only four steps. The one-pot approach is highly atom-efficient and avoids the use of toxic heavy metals.

Full text of DOI:10.1002/anie.201900995

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Accepted Article
Title: β-Selective C-Glycosylation and its Application in the Synthesis of
Scleropentaside A
Authors: Gordon Jacob Boehlich and Nina Schützenmeister
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900995
Angew. Chem. 10.1002/ange.201900995
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10.1002/anie.201900995
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β-Selective C-Glycosylation and its Application in the Synthesis
of Scleropentaside A
G. Jacob Boehlich,[a] and Nina Schützenmeister*[a]
Dedicated to Prof. Dr. Dietmar Stalke on the occasion of his 65th birthday
Abstract: C-Glycosides are carbohydrates bearing a C−C bond to an
aglycon at the anomeric center. Due to their high stability towards
chemical and enzymatic hydrolysis, these compounds are widely
used as carbohydrate mimics in drug development. Herein, we report
a general and exclusively β-selective method for the synthesis of a
naturally abundant acyl-C-glycosidic structural motif found firstly in the
Scleropentaside natural product family. A Corey-Seebach Umpolung
reaction as the key step in the synthesis of Scleropentaside A and
analogues enables the β-selective construction of the anomeric C−C
bond starting from unprotected carbohydrates in only four steps. The
methodology is highly atom- and pot-efficient avoiding the use of toxic
heavy metals.
the carbohydrate 2.[9] Furthermore, a Corey-Seebach reaction[10]
of a carbohydrate yielding lactol 4, which had to be reduced
subsequently, has also been reported[11]. Recently Walczak et al.
reported a cross-coupling approach using glycosylstannanes 7
and super-stoichiometric amounts of copper salts. [12]
Scleropentasides are a class of natural products, which have
been isolated from the twigs and leaves of scleropyrum
pentadrum[1] and the stems of dendrotrophe frutescens[2]. Both
plants are used in traditional asian medicine for several
indications (e.g. contraceptive, skin treatment, rheumatic pain,
inflammation).[3] This novel natural product class bears an
interesting and so far unprecedented anomeric acyl-β-C-
glycosidic structural motif in herbal natural products. The simplest
member of the natural product class family, Scleropentaside A 1,
displays radical scavenging activity.[1]
Figure 1: Synthetic methods for the construction of acyl-C-glycosides
Our approach employs a heavy metal free Umpolung reaction for
the C−C bond formation at the anomeric centre. The
retrosynthetic analysis of Scleropentaside A 1 requires a
disconnection of the C−C bond and leads back to D-glucose 9 and
fufural 10 as starting materials. Both substrates can be obtained
from natural sources.
Scheme 1. Structure of Scleropentaside A 1
Widely employed methodologies for the synthesis of C-glycosides
are reactions of glycosyl donors with nucleophiles in presence of
Lewis acids. Most of these methods yield predominantly the α-
anomeric C-glycosides[4] or required the use of heavy metal
organometallics or catalysts in the C-C-bond forming step.[5]
Furthermore, a multitude of these synthesized C-glycosides are
arylated at the anomeric position, which can be achieved by
various cross coupling reactions of glycals with arylhalogens[6] or
Grignard reagents[7]
Scheme 2. Retrosynthetic analysis of Scleropentaside A 1
Discussion
Addressing the challenge of the β-selective construction of the
anomeric acyl-C-glycosidic linkage in Scleropentaside A 1 a
Corey-Seebach reaction between glycosyl donor 12 and the
masked carbonyl compound 13 was chosen. The desired β-
anomer 14 could be constructed by nucleophilic attack onto the
α-anomer of donor 12, which is selectively formed in the donor
synthesis due to the anomeric effect.[13] Nucleophilic attack at the
anomeric centre under SN2-control should therefore only deliver
the β-anomer. Subsequent deprotection of the protecting groups
So far, anomeric acyl-β-C-glycosides 5 have been synthesized
via nitrile 3[8], which can be obtained in three steps starting from
[a]
G. J. Boehlich, M.Sc., Prof. Dr. N. Schützenmeister
Fachbereich Chemie, Institut für Pharmazie, Universität Hamburg
Bundesstrasse 45, 20146 Hamburg (Germany)
E-mail: nina.schuetzenmeister@chemie.uni-hamburg.de
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201900995
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and the dithiane will yield Scleropentaside A 1 in four to seven
steps from D-glucose 9 depending on the protecting group pattern.
The benzylated glycosyl donors 12a/b were synthesized using a
literature known procedure starting from D-glucose or D-
galactose.[14]
and the lithiated species of 13a/b delivered the C-
glycosides. By use of THF instead of 2-MeTHF as solvent a
significant decrease in the formation of the desired C-
glycoside 15 was observed. Then, TMS-deprotection with
NaOMe/MeOH and oxidative hydrolysis of the dithiane
yielded ketone 15a-h in excellent yields ranging from 52%
to quantitative in a four-step-one-pot reaction sequence.
Again, in all cases the acyl-β-C-glycosides 15a-h were
exclusively formed. To our delight, the acyl-C-glycosides
15g/h were also obtained with the same β-selectivity from
persilylated 2-deoxy-D-glucose 17d in comparable yields
indicating an SN2-controlled mechanism of nucleophilic
attack at the anomeric centre.
Figure 2: General program for the synthesis of acyl-β-C-glycosides 15
The crude donor, which was obtained by anomeric bromination of
11a/b was allowed to react after solvent exchange to 2-MeTHF
with the lithiated species of the aromatic dithianes 13a/b, which
were synthesized from benzaldehyde or 4-methoxy
benzaldehyde in one step,[15] to yield C-glycosides 14a-d. After
solvent exchange to MeCN/H2O, the perbenzylated crude
dithianes 14a-d were converted under oxidative conditions using
PIFA ((Bis(trifluoroacetoxy)iodo)benzene)[16] to the acyl-β-C-
glycosides 16a-d in 57-68% over three steps. Starting from
carbohydrates 11a/b all steps were performed in a three-step-
one-pot fashion yielding in all cases exclusively the acyl-β-C-
glycosides 16a-d, which has been confirmed by NMR-
spectroscopy.
Table 2. β-selective one-pot synthesis of acyl-C-glycosides 15a-h
Entry
1
Monosaccharide
Ar
Yield
Ph (13a)
4-OMePh (13b)
85% (15a)
62% (15b)
2
Ph (13a)
73% (15c)
48% (15d)
4-OMePh (13b)
3
Ph (13a)
84% (15e)
Table 1. β-selective one-pot synthesis of acyl-C-glycosides 16a-d
4-OMePh (13b)
quant. (15f)
Entry
1
Monosaccharide
Ar
Yield (3 steps)
57% (16a)
4*
Ph (13a)
77% (15g)
52% (15h)
Ph (13a)
4-OMePh (13b)
4-OMePh (13b)
68% (16b)
Reagents and conditions: a) Carbohydrate 17 (1.00 equiv.), TMSI
(1.14 equiv.), CH2Cl2, 0 °C, 15 min; b) dithiane 13 (2.00 equiv.), t-BuLi
(2.02 equiv.), 2-MeTHF, –95 °C, 10 min, then donor 18 (1.0 equiv.), 2-
MeTHF, –95 °C to 0 °C; c) NaOMe (1.00 equiv.), r.t., MeOH, 10 min; d)
PIFA (3.00 equiv.), r.t., MeOH/H2O (9:1).
2
Ph (13a)
60% (16c)
62% (16d)
4-OMePh (13b)
*2-MeTHF used instead of DCM in step a)
For the synthesis of Scleropentaside A 1 dithiane 13c is needed,
which could be synthesized from fufural 10 in one step.[18] Owing
to the higher instability of the furan moiety compared to arenes a
purification step is required before hydrolysis of the dithiane.
While the Corey-Seebach reaction with D-glucose 9 derived donor
12a afforded dithiane 19a in an excellent yield of 73%, a
significant decrease in the yield with D-galactose derivative 19b
to 49% was observed. As in the studies above, in both cases we
observed exclusive formation of the β-C-glycosidic anomer. Using
THF instead of 2-MeTHF as solvent decreased the yield due to
elimination of HBr from the donor 12a.[19] The hydrolysis of
dithiane 19a/b was achieved using I2 and H2O2 in H2O/DCM[20]
yielding the benzylated acyl-β-C-glycosides 16e/f in good to
excellent yields. Furthermore, single crystals X-ray analysis of
Reagents and conditions: a) Carbohydrate 11 (1.00 equiv.), oxalyl
bromide (1.24 equiv.), CH2Cl2, °C to r.t., 1 h; b) dithiane 13
(2.00 equiv.), t-BuLi (2.02 equiv.), 2-MeTHF, –95 °C, 10 min, then donor
12 (1.0 equiv.), 2-MeTHF, –95 °C to 0 °C; c) PIFA (3.00 equiv.), r.t.,
MeCN/H2O (9:1).
0
Next, the methodology was used for TMS-protected
carbohydrates to enable a mild deprotection of the TMS-
groups and to optimize the atom-efficiency. The TMS-
protecting groups enabled the realization of a four-step-one-
pot strategy to the fully deprotected C-glycosides. The
persilylated carbohydrates 17a-d were transformed into the
donors 18a-d using a literature known procedure.[17] Solvent
exchange to 2-MeTHF after donor synthesis and
a
subsequent Corey-Seebach reaction between donor 18a-d
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10.1002/anie.201900995
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COMMUNICATION
16e unambiguously confirms the formation of the β-C-glycosidic
linkage.[21] The perbenzylated Scleropentaside A 16e was finally
hydroxyl group is closer to the reaction centre in case of α-D-
mannose.
[22]
deprotected using FeCl3 in 41% yield to afford the desired
natural product Scleropentaside A 1 (supporting information).
Table 4. β-selective one-pot reactions with dithiane 13c and X-ray
structure of 20d
Table 3. β-selective one-pot reactions with dithiane 13c and X-ray structure
of 16e
Entry
Monosaccharide
Yield
Yield
Corey-Seebach Reaction
Deprotection
Entry
1
Monosaccharide
Yield
Yield
Deprotection
Corey-Seebach Reaction
1
60% (20a)
78% (1)
73% (19a)
49% (19b)
82% (16e)
62% (16f)
2
40% (20b)
77% (1b
2
3
74% (20c)
67% (20d)
70% (1c)
92% (1d)
Reagents and conditions: a) Carbohydrate 11 (1.00 equiv.), oxalyl bromide
(1.24 equiv.), CH2Cl2, 0 °C to r.t., 1 h; b) dithiane 13c (2.00 equiv.), t-BuLi
(2.02 equiv.), 2-MeTHF, –95 °C, 10 min, then donor 12 (1.00 equiv.), 2-
MeTHF, –95 °C to 0 °C; c) I2 (5.00 mol%), H2O2 (4.44 equiv.), SDS
(20.0 mol%), DCM /H2O, r.t., 1 h.
4*
The low yielding final benzyl-deprotection to the natural product 1
was bypassed by the use of the persilylated carbohydrates 17a-
d. Solvent exchange to THF after donor synthesis and a Corey-
Seebach reaction between donor 18a-d and the lithiated species
of 13c delivered the C-glycosides 20a-d. The use of 2-MeTHF as
solvent gave lower yields. The silyl-groups were directly
deprotected after the Corey-Seebach reaction using NaOMe in
MeOH to form 20a-d in good yields over the three steps, which
were carried out in a one-pot fashion. As previously, single crystal
X-ray analysis of 20d unambiguously confirmed the formation of
the β-C-glycosidic linkage.[23] Finally, the oxidative hydrolysis of
dithiane 20a-d was performed using iodine and H2O2 in H2O/DCM
affording Scleropentaside A 1, its D-galactose analogue 1b, its D-
xylose analogue 1c and 2-deoxy-Scleropentaside A 1c in good
yields as pure β-anomers.
In most cases a significant decrease in the yield of the Corey-
Seebach reaction was observed using D-galactose donors. This
effect might be caused by steric shielding of the β-side by the axial
substituents to constrict the attack of the nucleophile. Using α-D-
mannose and α-D-allose donors in the reaction did not yield acyl-
C-glycosides irrespective of the protecting groups. While α-D-
allose donors decomposed under the reaction conditions due to
the inherent instability caused by 1,3-diaxial interactions, α-D-
mannose donors were reisolated. This correlates to the observed
decrease in yield for the D-galactose derivatives since the axial
Reagents and conditions: a) Carbohydrate 17 (1.00 equiv.), TMSI
(1.14 equiv.), CH2Cl2, 0 °C, 15 min; b) dithiane 13c (2.00 equiv.), t-BuLi
(2.02 equiv.), THF, –95 °C, 10 min, then donor 18 (1.00 equiv.), THF,
–95 °C to 0 °C; c) NaOMe (1.00 equiv.), r.t., MeOH, 10 min; d) I2
(5.00 mol%), H2O2 (4.44 equiv.), H2O, r.t., 30 min.
* 2-MeTHF used instead of CH2Cl2 or THF in a) and b)
Conclusion
We herein report a general and exclusively β-selective method for
the synthesis of acyl-C-glycosides. The methodology has been
used for the dramatic short synthesis of Scleropentaside A 1,
which was synthesized in only four synthetic steps in an excellent
overall yield of 47% starting from D-glucose 9 and furfural 10.
Furthermore, the general efficiency of the protocol was
demonstrated in the synthesis of differently substituted anomeric
acyl-β-C-glycosides.
Acknowledgements
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[21] These data are deposited at The Cambridge Crystallographic Data
Centre and can be obtained via www.ccdc.cam.ac.uk/data_request/cif
(CCDC 1880770).
Generous financial support of this research by the Fonds der
Chemischen Industrie (FCI) is gratefully acknowledged. GJB
thanks the Universität Hamburg for a PhD fellowship (Hamburg
Stipendium). Furthermore, we thank I. Nevoigt for technical
assistance.
[22] R. Rodebaugh, J. S. Debenham, B. Fraser-Reid, Tetrahedron Lett. 1996,
37, 5477–5478.
[23] These data are deposited at The Cambridge Crystallographic Data
Centre and can be obtained via www.ccdc.cam.ac.uk/data_request/cif
(CCDC 1880776).
Keywords: Carbohydrates • Umpolung • C-Glycosides •
Scleropentasides • Natural Products
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G. J. Boehlich, N. Schützenmeister*
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β-Selective C-Glycosylation and its
Application in the Synthesis of
Scleropentaside A
Text for Table of Contents
Teaching an old dog new tricks: An exclusively β-selective C-glycosylation employing a Corey-
Seebach Umpolung reaction as key step was developed for the synthesis of Scleropentaside A and
analogues. The method allows the β-selective construction of the anomeric C−C bond starting from
unprotected carbohydrates in only four steps.
This article is protected by copyright. All rights reserved.