The first stereoselective total synthesis of a new antitumour and anti-inflammatory neolignan, surinamensinol A

Article abstract of DOI:10.1039/c3ra45419c

The stereoselective total synthesis of an antitumour and anti-inflammatory 8-O-4′-neolignan, surinamensinol A has been accomplished starting from two aldehydes, 3,4,5-trimethoxy benzaldehyde and vanillin. The key steps involve an asymmetric reduction using a chiral oxazaborolidine complex, a Sharpless asymmetric dihydroxyllation and a Mitsunobu reaction. This is the first report of the total synthesis of surinamensinol A.

Full text of DOI:10.1039/c3ra45419c

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DOI: 10.1039/C3RA45419C
GRAPHICAL ABSTRACT
The first stereoselective total synthesis of a new antitumour and anti-
inflammatory neolignan, surinamensinol A
Parigi Raghavendar Reddy and Biswanath Das*
OMe
OMe
MeO
OH
MeO
MeO
( R)
( S)
O
MeO
OMe
OBn
MeO
MeO
OH
( R)
O
(R)
O
OH
OMe
OTBS
HO
HO
OMe
OMe

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DOI: 10.1039/C3RA45419C
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Communication
The first stereoselective total synthesis of a new antitumour and anti-
inflammatory neolignan, surinamensinol A†
Parigi Raghavendar Reddy and Biswanath Das*
5
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
The retrosynthetic analysis (Scheme 1) indicates that
surinamensinol (1) can be synthesized from the chiral diol 3 and
55 the TBS ether 4. Compounds 3 and 4 can, in turn, be obtained
from 3,4,5ꢀtrimethoxy benzaldehyde (5) and vanillin (6)
respectively.
Abstract: The stereoselective total synthesis of an antitumour
and antiꢀinflammatory 8ꢀOꢀ4׳ꢀneolignan, surinamensinol A has
been accomplished starting from two aldehydes, 3,4,5ꢀtrimethoxy
10 benzaldehyde and vanillin. The key steps involve the asymmetric
reduction using a chiral oxazaborolidine complex, Sharpless
asymmetric dihydroxyllation and Mitsunobu reaction. This is the
first report of the total synthesis of surinamensinol A.
OMe
MeO
60
OH
15 Introduction
(R)
(R)
MeO
O
Surinamensinol A (1) and B (2), two new diastereomeric 8ꢀOꢀ4׳ꢀ
neolignans along with several other phenolics have recently been
isolated from the rhizomes of the aquatic plant, Acorus gramineus
20 (Araceae).1 The first compound bears (7R, 8R) configuration
while the latter (7S, 8R). The compound 1 and 2 were found to
possess potent cytotoxicity against the A549 cell line and
moderate activity against SKꢀOVꢀ3, SKꢀMELꢀ2 and HCTꢀ15 cell
lines.1 Both the compounds 1 and 2 also exhibited impressive
25 antiꢀinflammatory activity. They significantly inhibited NO levels
in LPSꢀstimulated BVꢀ2 cells.1 In continuation to our work2 on
the construction of natural products herein we disclose the total
synthesis of 1. This is the first report of the synthesis of this
molecule. Synthesis of some 8ꢀOꢀ4׳ꢀoxyneolignan derivatives
30 have been reported,3 but earlier synthetic approaches were
different compared to our present work. Our current approach
involves two nonꢀchiral easily available aldehydes as the starting
materials. The reagents are also commercially available and the
synthetic steps are limited.
OH
OMe
65
1
OMe
OTBS
MeO
MeO
OH
HO
(R)
(S)
70
OMe
3
OBn
4
O
OMe
75
MeO
HO
O
MeO
OMe
5
80
6
35
OMe
OH
MeO
MeO
Scheme 1. Retrosynthetic route for surinamensinol A
For the synthesis of chiral diol 3, 3,4,5ꢀ trimethoxy benzaldehyde
O
(R)
7
OMe
(R)
8
85 (5) was treated with vinyl magnesium bromide to produce the
alcohol 7 (Scheme 2).4 The alcohol 7 was oxidized with IBX and
the corresponding ketone was subjected to chiral reduction using
(R)ꢀ(+) 2ꢀmethyl–CBSꢀoxazaborolodine and BH3SMe2 to furnish
the chiral alcohol 8 (ee 91%).5 The free hydroxyl group of 8 was
90 protected as Bnꢀether (9) by treatment with BnBr and NaH.
Compound 9 underwent Sharpless asymmetric dihydroxylation6
with ADꢀmix β in tꢀBuOH:H2O (1:1) to furnish the diol 10 along
with its minor diastereomer (diastereomeric ratio 82:18) which
was separated out. The primary hydroxyl group of 10 was
95 tosylated with TsCl to form the monoꢀhydroxy compound 11.
Subsequent reduction of 11 with LiAlH4 afforded the desired
fragment 3 in high yield.7
OH
40
1
OMe
OH
MeO
O
(S)
7
8
OH
OMe
MeO
(R)
2
45 ________________________________________
Division of Natural Products Chemistry, CSIR-Indian Institute of
Chemical Technology, Hyderabad 500 607, India.
Corresponding author: Fax: +91ꢀ40ꢀ27193198; Eꢀmail:
biswanathdas@yahoo.com (B.Das)
50
†Electronic supplementary information (ESI) available: Experimental
procedures, Copies of 1H and 13C NMR spectrum of products. see
DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 1

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DOI: 10.1039/C3RA45419C
OMe
OMe
60
OMe
MeO
MeO
MeO
MeO
a
b
5
MeO
OTBS
OH
O
(R)
HO
MeO
(S)
7
OH
5
65
70
75
OMe
OBn
OMe
3
OMe
OMe
4
a
MeO
MeO
MeO
d
OH
f
OH
3
(S)
(R)
MeO
(S)
OBn OR
MeO
10
O
OR
(R)
7
OMe
MeO
8(R)
OH
8
10
R=H
R=H
c
e
1
9
11
R=Ts
R=Bn
15
Scheme 4.Reagents and conditions:(a) (i) Ph3P, DEAD, dry THF,
reflux; (ii) pꢀTsOH, MeOH, rt; (iii) 10% Pd–C, H2, rt, 40%.
Scheme 2.Reagents and conditions: (a) H2C=CHMgBr, THF, 0
°C to rt, 85%; (b) (i) IBX, DMSO, CH2Cl2, 0 °C to rt; (ii) (R)ꢀ(+)ꢀ
2ꢀmethylꢀCBSꢀoxazaborolidine, BH3.SMe2, THF, ꢀ40 °C, 65%
(ee 91%); (c) NaH, BnBr, THF, 0 °C to rt, 83%; (d) ADꢀmix β, tꢀ
20 BuOH:H2O (1:1), 0 °C, 80% (82:18); (e) TsCl, Et3N, DCM,
DMAP, 0 °C to rt, 76%; (f) LiAlH4, THF, 0 °C to reflux, 89%.
80 In conclusion, we have demonstrated the first stereoselective total
synthesis of the bioactive neolignan, surinamensinol A starting
from two easily available aldehydes, 3,4,5ꢀ trimethoxy
benzaldehyde and vanillin. Chiral reduction, asymmetric
dihydroxylation and Mitsunobu reaction are the key steps in the
85 present synthesis. The overall yield of 1 starting from 5 is 10%
involving sixteen steps.
For synthesis of another fragment 4 vanillin (6) was subjected to
Wittig reaction with Ph3PCHCOOEt to form the unsaturated ester
25 128 (Scheme 3) with E/Z ratio of 92:8. The reduction of 12 with
NaBH4 in the presence of NiCl2.6H2O followed by protection of
the phenolic hydroxyl group by treatment with BnBr and NaH
and subsequent reduction with LiAlH4 afforded the saturated
alcohol 13. The hydroxyl group of 13 was protected as TBS ether
Acknowledgments
The authors thank CSIR and UGC, New Delhi for financial
30 (14) by using TBSCl and imidazole and the compound 14 was 90 assistance. They are also thankful to NMR, Mass and IR divisions
then hydrogenated in the presence of 10% PdꢀC to produce the
of CSIRꢀIICT for spectral recording.
fragment 4.9
References
O
†Part 68 in the series, “Synthetic studies on natural products
COOEt
b,c,d
35
a
OR
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HO
HO
R'O
OMe
OMe
OMe
6
12
13
14
R=H, R'=Bn
e
f
40
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4
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reflux, 81%, (E/Z ratio 92:8); (b)NaBH4, NiCl2.6H2O, MeOH, 0
°C to rt; (c) NaH, BnBr, THF 0 °C to rt; (d) LAH, dry THF,
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50 10% Pd–C, H2, EtOAc, rt, 91%.
110
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by Mitsunobu reaction10 using Ph3P and DEAD and the resulting
product on treatment with pꢀTsOH in MeOH followed by
55 hydrogenation in the presence of 10% PdꢀC yielded the target
molecule, surinamensinol A (1) (Scheme 4) with 90% ee. The
physical and spectral properties of the compound were compared
to those reported for the natural product.1
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115
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