Total synthesis of (+)-varitriol via a symmetrical furanose diol as the key intermediate

Article abstract of DOI:10.1016/j.tetlet.2011.10.076

Alternative, simple and efficient route for (+)-varitriol (1), a marine-derived natural product with potent biological activity, has been synthesized from d-ribose. In this synthetic strategy symmetrical diol (6) with mono alcohol protection, the key inte

Full text of DOI:10.1016/j.tetlet.2011.10.076

Tetrahedron Letters 52 (2011) 7075–7078
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Total synthesis of (+)-varitriol via a symmetrical furanose diol as the
key intermediate
⇑
Lingaiah Nagarapu , Venkateswarlu Paparaju, Apuri Satyender, Rajashaker Bantu
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Alternative, simple and efficient route for (+)-varitriol (1), a marine-derived natural product with potent
Received 19 September 2011
Revised 11 October 2011
Accepted 13 October 2011
Available online 25 October 2011
biological activity, has been synthesized from D-ribose. In this synthetic strategy symmetrical diol (6)
with mono alcohol protection, the key intermediate, was produced in eight steps with 35% overall yield
and the significance of 6 as the key furanoside building block for the synthesis of novel analogues of 1 for
SAR studies was explained.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
(+)-Varitriol
Anti-cancer activity
Symmetrical diol
Total synthesis
Analogues
Cancer is commonly viewed as, at best, minimally controlled by
modern medicine1 especially when compared to other diseases.
The new era in cancer research calls for stronger working relation-
ships between chemistry and biology for the discovery of more
selective drugs. This situation emphasized the discovery of natural
products with potential anticancer activity, establishing synthetic
methodologies for their synthesis and the synthesis of their ana-
logues for SAR studies.
total synthesis of 1 starting from methyl
Later, a few more synthetic strategies8 from methyl
ranoside, -mannitol, -ribose, vinyl oxirane, -glucose, dimethyl
tartarate, ribonolactone and ethyl (S)-lactate, have been demon-
strated. The key furanoside building blocks in these methods are
depicted in Figure 2. We have reported9 novel analogues of 1 for
D
-mannopyranoside.
D-mannopy-
D
D
D
(+)Varitriol (1) is a marine derived2 natural product, which
shows significant activity against a variety of tumor cell lines. In
particular it shows more than 100-fold increased potency (over
the mean toxicity) toward the RXF 393, T-47D, and SNB-75 cell
lines and lower potency against DU-145, HL-60, CCRF-CEM,
SNB-19, and COLO 205 cell lines, through an unknown mode of ac-
tion. Hence, in our on-going research program to discover new
anticancer agents3 we aimed to develop a furanoside building
block from which we can synthesize 1 and simultaneously its ana-
logues. After a comprehensive literature search, we came to the
conclusion that symmetrical diol4 with selective protection could
be the best furanoside building block (6) (Fig. 1) for the synthesis
of 1 and also its novel analogues of 1 for SAR studies.
O
O
HO
OR
O
HO
OH
O
O
O
O
6
OH
HO
HO
OH
where R = Bn
2
1
Figure 1. (+)-Varitriol (1), (À)-varitriol (2) and symmetric diol (6).
The combination of potent biological activity and a relatively
straight forward molecular structure of 1 has fascinated many
researchers to articulate its synthesis. Initial research efforts by
Jenning5 and Taylor6 groups, have foreseen the total synthesis of
(À)varitriol (2). In 2008, Shaw and co-worker7 described the first
I
SO2PT
O
O
O
O
O
O
O
O
O
O
O
O
19
17
18
9
⇑
Corresponding author.
E-mail address: lnagarapuiict@yahoo.com (L. Nagarapu).
Figure 2. Furanoside building blocks used in the synthesis of (+)-varitriol (1).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.076

7076
L. Nagarapu et al. / Tetrahedron Letters 52 (2011) 7075–7078
O
O
O
OH
O
OAc
OAc
+
O
O
O
O
11
10
9
HO
OH
1
Ph
OBn
OH
OH
N
O
O
N
D-ribose
Ph
O
O
O
O
4
6
Scheme 1. Retrosynthetic analysis of (+)-varitriol (1).
Methylation
at C-1 carbon
OH
5
1 O
4
HO
(-)-Varitriol (2)
(+)-Varitriol (1)
3
O
2
O
Methylation
at C-5 carbon
D(-) Ribose
Figure 3. The concept of methylation at C-1 and C-5 carbon for the synthesis of (+)-varitriol (1) and (À)-varitriol (2) from
D-ribose.
Ph
O
O
OH
OBz
N
Ref.5
a
O
O
AcO
AcO
AcO
BzO
N
Ph
5 steps
O
O
OBz
O
10
11
4
3
Scheme 3. Synthesis of aromatic olefin. Reagents and conditions: (a) Ph3PCH3Br, t-
BuOK, 0 °C to rt, 4 h, 72%.
Scheme 2. Synthesis of alcohol (4) from benzyl derivative (3) of D-ribose.
the first time and evaluated their cytotoxicity. Recently, Annamalai
and Indiana10 have also reported some analogues.
In continuation of our earlier work, we have been successful in
our attempt to synthesize the symmetrical furanoside diol (6) from
The synthesis was initiated with benzyl derivative (3) of D-ri-
bose, followed by Jenning synthetic strategy9 to furnish alcohol 4
in five steps (Scheme 2). Compound 4 was the key intermediate
for synthesizing both 1 and 2.
D
-ribose and furnished the total synthesis of 1 from it.
Our retro synthetic approach of 1 is shown in Scheme 1. We
Alcohol 4 was protected as its Bn-ether by treatment with BnBr
to afford compound 5 in a 91% yield. Hydrolysis of 5 with PTSA
gave slightly unstable aldehyde11 which was immediately reduced
with sodium borohydride to furnish key intermediate 6. Tosylation
and deoxygenation of hydroxyl moiety of 6 in tandem produced 7
in high yield. Having obtained the required 7, the next step called
for debenzylation using liq.NH3 and sodium to give alcohol 8 in a
70% yield. The formation of 8 was characterized by the appearance
of methyl protons at d 1.27 as doublet and specific rotation.5
Oxidation of 8 (to aldehyde) and subsequent Wittig olefination
using Ph3P@CH2 allowed the introduction of an additional one car-
bon fragment, thus affording olefin 9, furanoside part of 1, with a
27% yield7 (Scheme 4).
envisaged that the target molecule 1 can be accomplished through
cross-metathesis reaction of furanoside unit 9 and aromatic unit 11
was crucial. Aromatic unit in turn could be clearly derived from
suitably substituted benzaldehyde 10. Furanoside moiety 9 can
apparently be realized from the key subunit 6, which in turn could
easily be obtained from 4 by the process of reduction and finally 4
was derived from D
-ribose.5
In the process of synthesizing 6, we identified that Jenning has
obtained the methyl group present in the furanoside unit of 2,
simply by deoxygenating at C-5 carbon of
an expectation that the synthesis of 1 might be possible from
bose whereas in our synthesis, the methylation was carried out at
C-1 carbon of -ribose thus leading to the formation of furanoside
D-ribose (Fig. 2) and laid
L-ri-
The synthesis of aromatic part of 1 was initiated from substi-
tuted benzaldehyde 10.12 Single carbon Wittig olefination of 10
with Ph3P@CH2 in THF gave olefin 11, aromatic part of 1, in a
72% yield (Scheme 3).
D
fragment of 1. The concept of methylation at C-1 and C-5 carbon is
shown in Figure 3.

L. Nagarapu et al. / Tetrahedron Letters 52 (2011) 7075–7078
7077
Ph
Ph
OBn
OBn
OBn
HO
OH
N
N
O
O
O
b
O
c
a
N
N
Ph
Ph
O
O
O
O
O
e
O
O
O
7
6
4
d
5
OH
O
O
f
(+)-Varitriol (1)
O
O
O
O
9
8
Scheme 4. Synthesis of (+)-varitriol (1) from alcohol 4. Reagents and conditions: (a) BnBr, NaH, DMF, 0 °C to rt, 4 h, 91%; (b) (i) p-CH3C6H6S03HÁH2O, CH3COCH3, rt, 15 min; (ii)
NaBH4, MeOH, rt, 2 h, 75%; (c) (i) TsCl, Py, rt, overnight then LAH, dry THF, 75 °C, 5 h, 90.8%; (d) Liq. NH3, Na, À78 °C, 30 min, 72%; (e) Ref.6c (COCl)2, Et3N, CH2Cl2, À78 °C then
Ph3PCH3Br, t-BuOK, 0 °C to rt, 4 h, 18%; (f) (i) 11, Grubbs second generation catalyst, CH2Cl2, reflux, 18 h, 45%; (ii) 1 M HCl, THF, rt, 3 h, 81%; (iii) K2CO3, MeOH, rt, 1 h, 81%.
OBn
HO
I
SO2PT
TPO2S
O
I
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
6
18
17
OH
OH
O
O
O
O
O
O
O
O
O
O
19
8
O
O
(-)-varitriol
(2)
(+)-varitriol
(1)
O
O
O
O
9
Scheme 5. The possible way of synthetic sequence of conversions for the synthesis of (+)-varitriol (1), (À)-varitriol (2) and their analogues from alcohol 6.
Finally, with the two olefins 9 and 11 in hand, cross metathesis
has been performed using Grubbs IInd generation catalyst. Imme-
diately after coupling, acetonide and acetate groups were depro-
tected and resulted in desired 1 in a 30% overall yield.
made to develop novel analogues of 1 for SAR studies and will be
reported in due course.
Acknowledgments
Coming to the significance of alcohol 6, the alcohols present on
either side can be converted into a number of other functional
groups, thus making it a very useful building block for the synthe-
sis of novel analogues of 1. More importantly, the synthesis of 6
was established in eight steps, with 35% overall yield, without
any chiral protocols, inversions, racemisations, diastereomers
formation, and the usage of any metal-ligand catalysts. These
advantages have encouraged us to synthesize 6 as a key furanoside
building block for the synthesis of 1. The possible way of synthetic
sequence of conversions13 for the analogues of 1 from 6 was
depicted in Scheme 5.
The authors thank the Head, Organic Chemistry Division-II, and
Director, IICT for their support. P.V. and A.S. thank CSIR, New Delhi,
for financial assistance.
Supplementary data
Supplementary data (experimental data) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.10.076.
In conclusion, a new and alternative protocol for (+)-varitriol (1)
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