Total synthesis of sinenside a

Article abstract of DOI:10.1021/acs.orglett.5b00505

The first total synthesis of norlignan glucoside sinenside A has been accomplished. An intramolecular acetalization reaction has been employed as the key skeletal construct to forge the central cyclic disaccharide core. The trans-1,2-diol configuration present in the cyclic disaccharide of this natural product is unique and has been addressed by setting this configuration at the beginning. A 1,2-orthoester group has been selected as a handle for both sp glycosidation and for differentiation of the C2′-OH (that participates in the key acetalization reaction) of the sugar unit.

Full text of DOI:10.1021/acs.orglett.5b00505

Letter
pubs.acs.org/OrgLett
Total Synthesis of Sinenside A
Paresh M. Vadhadiya and Chepuri V. Ramana*
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. HomiBhabha Road, Pune 411008, India
S
* Supporting Information
ABSTRACT: The first total synthesis of norlignan glucoside
sinenside A has been accomplished. An intramolecular
acetalization reaction has been employed as the key skeletal
construct to forge the central cyclic disaccharide core. The
trans-1,2-diol configuration present in the cyclic disaccharide of
this natural product is unique and has been addressed by
setting this configuration at the beginning. A 1,2-orthoester
group has been selected as a handle for both sp glycosidation
and for differentiation of the C2′-OH (that participates in the key acetalization reaction) of the sugar unit.
In 2012, Ning Li and co-workers isolated two novel norlignan
glucosides, namely sinensides A (1) and B (2) (Figure 1), along
with six known norlignan glucosides from the ethanolic extract
of the Curculigo sinensis plant.1 Species belonging to the genus
Curculigo (Hypoxidaceae) are widely encountered in the
tropical and subtropical areas of Australia, Asia, South America,
and Africa. In ancient China, various species of these plants
were used in folk medicine to treat child pneumonia,
rheumatism, and dysmenorrhea. In other instances, they have
served as antiaging tonics. In a preliminary screening, the
norlignan glucosides 1 and 2 showed strong 1,1-diphenyl-2-
picrylhydrazyl (DPPH) free radical scavenging activity with
IC50 values comparable to that of the positive control ascorbic
acid (IC50 = 45.84 μM). The structural interpretations were
performed by a variety of spectroscopic tools including 1D/2D
NMR, HRESI-MS, and hydrolysis experiments. A close
examination of the structures of these isolated norlignans
indicates the involvement of novel rearrangements in their
formation. Among them, sinenside A attracts considerable
interest because of its novel structural architecture.2
The central skeleton of sinenside A (1) is characterized by a
unique cyclic disaccharide (or saccharide dianhydride) in which
two pyranose residues are fused with a challenging 1,2-trans-
configuration.3 The presence of a gem-diaryl (with free phenolic
OH groups) unit on one of the tetrahydropyran moieties adds
further complexity. Symmetric saccharide dianhydrides have
been isolated as part of a complex mixture when the
corresponding monomers were treated with acids4 or
anhydrous HF5 or during the hydrolysis of polysaccharide,6
or they have been synthesized selectively by employing
cycloglycosidation.7 There are three reports on cycloglycosida-
tion leading to dianhydrides employing either trichloracetimidyl
or thiomethyl glycosides.8 Nonetheless, in all three cases, the
products resulted in a cis-1,2-diol configuration in both of the
pyranosyl residues (Figure 2). In contrast, in sinenside A (1), a
trans-vicinal diol configuration is present on the sugar pyranose
unit, which adds another challenge in its synthesis.
Figure 1. Structures of norlignan glycosides isolated from Curculigo
sinensis.
In this context, an early installation of the β-glucoside link
present in 1 was planned and the desired tricyclic core of
sinenside A (1) would be constructed from the aldehyde via
intramolecular acetalization, with an olefin unit serving as a
surrogate for this aldehyde group (Figure 3). The orthoester 3
and tertiary alcohols 4 were selected as partners for the key
glycosidation reaction, which was expected to give rise to
exclusive β-anomeric selectivity.9
Our work in this direction commenced with an examination
of the glycosidation of the known orthoester 3 with two
different glycosyl acceptors 4a (see the Supporting Information
for the preparation) and 4b (Scheme 1).10 The acceptor 4a
brings with it the complete carbon framework, and a successful
glycosidation with 4a was expected to provide a product that
could be directly converted into a analogue of 1 in two steps.
However, the glycosidation of 4a with orthoester 3 using BF3·
Et2O (0.15 equiv) in dichloromethane in the presence of 4 Å
molecular sieves gave the β-glucoside 5 along with the cyclized
ether 6.11 This undesired elimination and/or cyclization prior
Received: February 17, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00505
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The deprotection of the TBS group in compound 7 was
carried out with TBAF to obtain the alcohol 8 in 91% yield
(Scheme 2). Next, the alcohol 8 was subjected to a two-stage
Scheme 2. Construction of the Central Tricyclic Core of
Sinenside A
Figure 2. Intramolecular glycosylation strategies reported for the
construction of the aldohexopyranose dianhydrides.
oxidation with Dess−Martin periodinane followed by further
oxidation of the resulting intermediate aldehyde under Pinnick
conditions to obtain the acid 9 in 87% yield over two steps.12
Subsequent methylation of acid 9 with MeI in the presence of
K2CO3 in dry THF gave the ester 10.13
To quickly examine the proposed intramolecular acetaliza-
tion, the key ester 10 was subjected to Grignard reaction with
excess phenylmagnesium bromide. The reaction proceeded
smoothly, providing the diol 11. Oxidative cleavage of the olefin
unit in diol 11 was carried out with OsO4/NaIO4 in the
presence of 2,6-lutidine.14 The intermediate aldehyde was
immediately subjected to acetalization employing a catalytic
amount of CSA in benzene to afford the tricyclic compound 12
in 81% yield over two steps.15 Part of the 1H NMR spectrum of
12 in CDCl3 was comparable with that of the natural product.
For example, the C(1)−H appeared as a singlet at 4.69 ppm
[4.72 (s)] and the C(2)−H appeared at 4.23 ppm (J = 8.9 Hz)
[3.77−3.79 (m)] as a triplet, which are comparable with the
data reported for the natural product.1
Figure 3. Our key retrosynthetic disconnections for sinenside A.
Scheme 1. Optimization of Glycosidation Reaction
After this success in building the complete core of sinenside
A, we next proceeded toward the total synthesis of sinenside A
(Scheme 3). The direct preparation of the Mg-based Grignard
reagent using 3,4-bis(benzyloxy)bromobenzene 13 was found
to be a problem.16 Alternatively, by employing BuLi for
t
halogen−metal exchange, the diaryl addition to ester could be
successfully conducted to obtain the diol 14 in 76% yield.17
Subsequently, the resulting diol 14 was subjected to the
oxidative olefin cleavage using OsO4/NaIO4/2,6-lutidine to
afford an anomeric mixture of lactols 15. An examination of the
spectra of 15 revealed that the tertiary hydroxyl group had
taken part in lactol formation. Next, the treatment of lactols 15
with a catalytic amount of CSA in benzene at rt directly gave
the desired tricyclic compound 16 in 89% yield. Hydrogenolysis
of the benzyl ethers in 16 required substantial experimentation.
Under standard conditions (employing 10% Pd−C in methanol
at 1 bar), the reaction was sluggish. Increasing either the H2
to the glycosidation reaction prompted us to employ the simple
allylic alcohol 4b as an acceptor. The glycosidation of 4b with 3
proceeded smoothly and provided exclusively the β-glucoside 7
in 76% yield.
B
DOI: 10.1021/acs.orglett.5b00505
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Organic Letters
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Scheme 3. Total Synthesis of Sinenside A (1)
ACKNOWLEDGMENTS
■
C.V.R. and P.M.V. thank CSIR (India) for funding this project
(12 FYP ORIGIN program, CSC0108) and for a fellowship to
P.M.V.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and characterization data for
all the new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
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*E-mail: vr.chepuri@ncl.res.in.
Notes
The authors declare no competing financial interest.
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