Stereoselective synthesis of peracetylated (?)-gloeosporiol via acid catalysed intramolecular etherification

Article abstract of DOI:10.1016/j.tetlet.2016.12.083

A simple and an efficient strategy have been developed for the stereoselective synthesis of peracetylated (?)-gloeosporiol by acid catalysed cyclisation from the commercially available starting materials.

Full text of DOI:10.1016/j.tetlet.2016.12.083

Accepted Manuscript
Stereoselective synthesis of peracetylated (-)-gloeosporiol via acid catalysed
intramolecular etherification
Aravind Reddy Dorigundla, Raju Gurrapu, Venkateswara Rao Batchu
PII:
S0040-4039(16)31750-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.083
TETL 48495
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 November 2016
27 December 2016
29 December 2016
Please cite this article as: Reddy Dorigundla, A., Gurrapu, R., Rao Batchu, V., Stereoselective synthesis of
peracetylated (-)-gloeosporiol via acid catalysed intramolecular etherification, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.12.083
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Stereoselective synthesis of peracetylated
(-)-gloeosporiol via acid catalysed intramolecular etherification
Aravind Reddy Dorigundlaa, Raju Gurrapua and Venkateswara Rao Batchu a,

1
Tetrahedron Letters
journal h omepage: www.els evier. com
Stereoselective synthesis of peracetylated (-)-gloeosporiol via acid catalysed
intramolecular etherification
Aravind Reddy Dorigundlaa, Raju Gurrapua and Venkateswara Rao Batchu a,
a
Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and an efficient strategy have been developed for the stereoselective synthesis of
peracetylated (-)-gloeosporiol by acid catalysed cyclisation from the commercially available
starting materials.
Available online
Keywords:
C-aryl-nucleosides
Antioxidant
Cyclisation
Stereoselective synthesis
1-deoxy-1-phenyl-b-D-ribo furanose 3, 1-deoxy-1’-(3,4-
Introduction:
Natural C-nucleosides and their synthetic analogs
dihydroxyphenyl)-b-D-ribofuranose 4, magnones 5, virgatusin 6,
goniothalesdiol 7 and gloeosporiol 8 belongs to this unique class.
In specific, the 3,4-dihydroxy tetrahydrofuran with C-2 aryl
group may be an important factor for the interesting activity of
above compounds.12
In 2006 Collado et al.13b isolated tetrahydrofuran ring
contain natural product (-)-gloeosporiol 8 as a peracetylated
derivative 9 from a culture of the fungus Colletotrichum
gloeosporioides which shows great radical scavenging activity.
To the best of our knowledge so far a couple of synthesis for this
molecule is reported in the literature13, where they carried
resolution to get the optically active isomer.
constitute an important class of organic compounds and shows
significant therapeutic properties such as antiviral, antitumor and
anticancer activities1. Several naturally occurring ribofuranosyl
C-nucleosides, such as showdomycin, pseudouridine,
pyrazomycin and formycin are showing interesting antibiotic and
antitumor activities.2-5 Among the C-nucleosides, the aryl-
nucleosides have attracted more attention in studying DNA-DNA
and DNA-protein interactions.6 The C-aryl-nucleosides which
have been designed are incorporated as base surrogates into DNA
to study base stacking interactions,7 to enable new base pairing
modes,8,9 and also to find out the reaction mechanisms of DNA-
polymerases10 and DNA-repair enzymes.11 The interesting
biological activity of these C-nucleosides has prompted organic
chemists to design and synthesize non-natural C-nucleosides to
study the structure-activity relationships.
Especially 2-aryl tetrahydrofuran system is present in
some important biologically active compounds of both natural &
synthetic origin. For example altholactone 1, isoaltholactone 2,
———
 Corresponding author. Tel./ fax: +91 40 27193003;
E-mail addresses: venky@iict.res.in , drb.venky@gmail.com.

2
Tetrahedron Letters
aldehyde. The crude aldehyde was then directly used for Wittig
reaction to give compound 15. The olefin compound 15 was
subjected to catalytic dihydroxylation with OsO4 and gave
exclusively anti diol compound 16.
Table 1: Cyclisation studies on compound 16 with different
Lewis acids.
S.No.
Lewis acid (LA)
(10 mol%)
Ratioa
17/18
Ratioa
19/20
Yield %
1
Sc(OTf)3
Yb(OTf)3
BF3.Et2O
TMSOTf
TFA
4:1
4:1
4:1
4:1
--
--
90
90
78
80
85
90
0
2
3
4
5
6
7
8
--
--
--
Figure.1 Some aryl C-nucleosides
4:1
4:1
--
With these considerations, as well as in continuation of
SnCl4.5H2O
CuCl2.2H2O
p-TSA
--
our interest in the synthesis of natural and natural product like
molecules, herein we disclose a flexible synthetic route to
peracetylated (-)-gloeosporiol 9 which involves the construction
of tetrahydrofuran ring using acid mediated cyclisation.
--
--
--
0
a Ratios was calculated based on the isolated yields
Next, our plan was to construct the 2-
aryltetrahydrofuran ring from diol 16. For this purpose
compound 16 was subjected to different acids. This reaction
afforded two sets of cyclised products 17 & 18 and 19 & 20 as
summarized in table 1. The major product during cyclisation is
the trans isomer, where the phenyl group is trans to acetonide as
in 17 and in diol 19. In most of the cases the acetonide is intact,
but in the case of TFA and SnCl4.5H2O catalyzed reaction the
deprotection of acetonide occurred and gave the diol compounds
19 and 20. In all the above cases the yields of the products are in
the range of 78-90%.
Scheme 1: Retro synthetic analysis
Our retro synthetic analysis of the target molecule is
outlined in Scheme 1. As indicated we envisaged that peracetyl
derivative of (-)-gloeosporiol 9 could be synthesized by acid
mediated cyclisation of compound 16. The requisite poly
hydroxy aryl derivative inturn, can be accessed from
commercially available caffeic acid 10 by simple
transformations.
Our synthetic endeavor commenced with simple
esterification of the acid group in caffeic acid 10 and protection
of the two phenoxy groups as benzyl ethers using benzyl bromide
& K2CO3 to get compound 11 in 95% yield. The compound 11
was subjected to asymmetric dihydroxylation14 with AD-mix-β &
methane sulfonamide to get selectively the β-dihydroxy
compound 12. Subsequently, the resulting two hydroxy groups
were protected as acetonide by treatment with acetone & 2,2-
dimethoxypropane in presence of catalytic amount of acid to give
compound 13 in 90% yield. The ester functionality in compound
13 was easily reduced with lithium aluminium hydride (LAH) to
afford the compound 14 in good yield. The primary alcohol in
compound 14 was oxidized under Swern conditions to give

3
Scheme 2. Conditions: a) (i) H2SO4, dry MeOH, rt, 12 h; (ii)
different acids. This pathway was shown to be applicable for
°
K2CO3, BnBr, acetone, 56 C, 15 h, 95% (over 2 steps) ; b) AD-
the synthesis of many compounds containing tetrahydrofuran
moiety.
mix-β, methane sulfonamide in t-BuOH-H2O, rt, 12 h, 90%; c)
2,2-dimethoxy propane, acetone, BF3.OEt2, 2 h, 90%; d) LAH,
°
THF, 0 C, 1 h, 85%; e) (i) (COCl)2, DMSO, Et3N, CH2Cl2, -78
Acknowledgments:
°
°C, 3h; (ii) Ph3P=CH2, THF, 0 C, 4h, 80% (over 2 steps) ; f)
A.R.D thanks UGC, G.R thanks CSIR, New Delhi for
Research fellowship and we would like to thank CSIR for
financial support in the form of ORIGIN (CSC-0108), DENOVA
(CSC-0205). The authors also thank Director, CSIR-IICT for the
constant support and encouragement.
OsO4, NMO, acetone:H2O (4:1), 0 °C, 3 h 80%; g) Acid, CH2Cl2,
0 °C, 30min.
The mechanism for the formation of products 17 and 18
involves shifting of acetonide followed by cyclisation in presence
of acid (Scheme 3). The benzylic C-O bond was cleaved in
presence of acid giving rise to stable benzylic carbocation which
undergoes cyclisation with the free primary hydroxy group
leading to tetrahydrofuran system having trans configuration as
major.
References:
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The deprotection of the compound 17 with 1N HCl in
MeOH afforded the compound 19. Stirring of the compound 19
with PtO2 in MeOH under hydrogen for 2 h and treatment of the
crude with Ac2O and pyridine gave the compound 9. The spectral
data of compound 9 was in good agreement with reported values
(Scheme 4).13b
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Scheme 4. Conditions: a) 1N HCl, MeOH, 0 °C, 30 min. b) (i)
PtO2, MeOH, H2 (30 psi), 2 h; (ii) Ac2O, Pyridine, 0 °C (98%
over 2 steps).
Conclusions:
In summary, an efficient and novel synthetic pathway
has been developed to synthesize peracetylated derivative of (-)-
gloeosporiol 9 from commercially available caffeic acid using
acid catalysed cyclisation which involves the migration of the
acetonide group and this reaction was studied in presence of

4
Tetrahedron Letters
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5
Highlights
 An efficient stereoselective synthesis of
peracetylated (-)-gloeosporiol.
 Cyclisation and acetonide migration occurs in a
single step under acid condition.
 This strategy can be used in the synthesis of
many compounds contains tetrahydrofuran ring.