A facile approach for the total synthesis of neurotrophic diyne tetraol petrosiol A and petrosiol E

Article abstract of DOI:10.1016/j.tet.2016.08.009

The first total synthesis of neurotrophic diacetylenic tetraol, petrosiol A and stereoselective total synthesis of petrosiol E was accomplished. The total synthesis involves Cadiot-Chodkiewicz coupling reaction as the key step for petrosiol A. The diastereorich chiral alcohol (third chiral center) was synthesized from CBS mediated stereoselective ketone reduction reaction for petrosiol E. Of the three chiral centers, the two chiral centers are originated from (+)-diethyl L-tartrate and the third chiral center was generated by an addition reaction of lithium trimethylsilylacetylide leading to two diastereomers which were used for the synthesis of both the natural products and their diastereomer C6-epi-petrosiol A and C6-epi-petrosiol E, respectively.

Full text of DOI:10.1016/j.tet.2016.08.009

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A facile approach for the total synthesis of neurotrophic diyne tetraol petrosiol A and
petrosiol E
Pamarthi Gangadhar, A. Sathish Reddy, Pabbaraja Srihari
PII:
S0040-4020(16)30767-0
10.1016/j.tet.2016.08.009
TET 27990
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 June 2016
Revised Date: 27 July 2016
Accepted Date: 3 August 2016
Please cite this article as: Gangadhar P, Sathish Reddy A, Srihari P, A facile approach for the total
synthesis of neurotrophic diyne tetraol petrosiol A and petrosiol E, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.08.009.
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Graphical Abstract
A facile approach for the total synthesis of
neurotrophic diyne tetraol petrosiol A and
petrosiol E
Leave this area blank for abstract info.
P. Gangadhar, A. Sathish Reddy, P. Srihari*

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Tetrahedron
journal homepage: www.elsevier.com
A facile approach for the total synthesis of neurotrophic diyne tetraol petrosiol A and
petrosiol E
Gangadhar Pamarthi, A. Sathish Reddy, Srihari Pabbaraja
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad – 500007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first total synthesis of neurotrophic diacetylenic tetraol, petrosiol A and stereoselective total
synthesis of petrosiol E was accomplished. The total synthesis involves Cadiot-Chodkiewicz
coupling reaction as the key step for petrosiol A. The diastereorich chiral alcohol (third chiral
center) was synthesized from CBS mediated stereoselective ketone reduction reaction for
petrosiol E. Of the three chiral centers, the two chiral centers are originated from (+)-diethyl L-
tartrate and the third chiral center was generated by an addition reaction of lithium
trimethylsilylacetylide leading to two diastereomers which were used for the synthesis of both
the natural products and their diastereomer C6-epi-petrosiol A and C6-epi-petrosiol E
respectively.
Available online
Keywords:
polyacetylene
neurotrophic
Cadiot Chodkiewicz
Swern oxidation
CBS reduction
2009 Elsevier Ltd. All rights reserved.
1. Introduction
The first contribution was from our own group6 wherein we
have accomplished the total synthesis of petrosiol D in a linear
Polyacetylene containing molecules continue to attract
significant attention due to their impressive biological properties
such as anti-inflammatory, antimicrobial, antitumor, antiviral,
cytotoxic, neurotrophic and phytotoxic properties.1 For example
panaxydol2 1 displayed antiproliferative effects against malignant
cells and panaxytriol3 2 displayed inhibitory activity against MK-
1 cells with IC50 8.5 ng/mL. Very often the scarce availability of
natural products becomes the bottleneck for investigating their
further biological properties, and this challenge can be easily
overcome by their total synthesis. For example, our recent
attempt for the total synthesis of diacetylene natural products
oploxyne A (3) and B (4) not only lead to the accessibility of the
materials but also ended up with structural revision of the natural
product oploxyne B.4 Also, on further investigation these
molecules were found to display cytotoxicity against
neuroblastoma and prostate cancer cell lines. In continuation to
our studies on the total synthesis of natural products and their
analogues for CNS activities,5 we have recently accomplished the
first total synthesis of petrosiol D 5,6 which was isolated from an
extract of the Okinawan sponge Petrosia strongylata along with
four other acetylene metabolites petrosiol A-C (6-8) (Figure 1)
and petrosiol E 9 by Ojika et al.7 In biological aspects, these
compounds induced nerve growth factor (NGF)-like neuronal
differentiation of PC12 cells and in terms of cytotoxicity, the IC50
value of petrosiol A was found to be 5.4 µM in the MTT assay
and 0.22 µM for A431(human epidermoid) cell line.7 So far there
have been only two synthetic contributions for petrosiols.
fashion and the second contribution was from Yoguo Du et al.
wherein they have accomplished the total synthesis of (-)-
petrosiol E following a chiron approach starting from D-xylose.8
Herein, we describe the total synthesis of petrosiol A, petrosiol E
and their diastereomers starting from the readily available
material (+)-Diethyl L-tartrate.
Figure 1: Diacetylene polyol compounds
———
Corresponding author. Tel.: +914027191815; fax: +914027160512; e-mail: srihari@iict.res.in

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Tetrahedron
2. Results and discussion
sequence i.e., oxidation, Ohira Bestmann reaction, coupling of
acetylene with n-iodo octane, Lindlars reduction of triple bond to
cis double bond and finally TBDPS deprotection or in 3-step
sequence i.e., oxidation, 9-carbon Wittig reaction and TBDPS
deprotection. Compound 13 can be synthesized from 14 through
one pot benzyl deprotection and olefin reduction. Compound 14
in turn can be obtained from known intermediate 15 by an
oxidation reaction followed by a 7-carbon Wittig reaction.
Compound 15 can be easily accessible from commercially
available inexpensive (+)-diethyl L-tartrate.
Our retrosynthetic analysis for petrosiol A is depicted in
scheme 1. Accordingly, we envisaged the target compound 6 to
be synthesized by Cadiot-Chodkiewicz coupling reaction of 3-
bromo-2-propyne-1-ol 10 with substituted alkyne 11 followed by
acetonide deprotection. The intermediate 11 can be synthesized
from alcohol 12 in three steps i.e., oxidation of primary alcohol
to
aldehyde,
an
addition
reaction
with
lithium
trimethylsilylacetylide followed by trimethylsilyl deprotection.
The alcohol 12 in turn can be synthesized from 13 through 5-step
Scheme 1: Retrosynthesis for petrosiol A
2.1 Synthesis of petrosiol A 6
alcohol was further oxidized with IBX to yield aldehyde and was
subjected to Ohira-Bestmann reaction to get the terminal
acetylene 16. Coupling of 16 with n-iodo octane afforded
disubstituted acetylene 17. Lindlar’s reduction of alkyne 17
afforded cis olefin 18 exclusively. Alternatively, 18 was also
synthesized in 2-step sequence from 13 through an oxidation
reaction (IBX oxidation) followed by the Wittig reaction with (1-
nonyl)triphenylphosphonium bromide in presence of n-BuLi to
give cis-Wittig product 18 exclusively.11 The compound 18 upon
exposure to TBAF furnished desilylated alcohol 12.
The synthesis began with the oxidation of the readily available
alcohol 15 (synthesized from (+)-diethyl L-tartrate in three steps
with an overall yield of 81%)6,9 employing iodoxybenzoic acid
(IBX)10 to yield the aldehyde which was subjected to a Wittig
reaction with 7-(benzyl)oxy-1-heptyl-(triphenyl)phosphonium
iodide and n-BuLi to provide the corresponding olefin 14. One
pot debenzylation and double bond saturation was easily
achieved with Pd(OH)2 under hydrogen atmosphere to yield the
alcohol 13 in 92% yield (Scheme 2). The resulting primary
O
1. IBX, THF:DMSO, rt, 2 h
OH
3 steps
(+)-Diethyl L-tartrate
TBDPSO
81% overall yield
2.
I(Ph)3P
OBn
O
5
15
n-BuLi, THF, -78 oC - rt
8 h, 82% (for 2 steps)
O
O
OBn
Pd(OH)2, H2, EtOAc
8 h, 92%
TBDPSO
TBDPSO
OH
7
5
O
O
14
13
O
n-BuLi, THF, -78 o
C
IBX, THF:DMSO (1:1), rt, 2 h
TBDPSO
I
7
OHIRA BESTMANN REAGENT,
K2CO3, MeOH, 0 oC - rt, 3 h, 87%
O
8 h, 73%
16
O
O
7
5 mol% Pd- BaSO4, H2
THF, 1 h, rt, 94%
TBDPSO
TBDPSO
7
7
O
O
17
6
18
O
1. IBX, THF, rt, 2 h
TBAF, THF, 0 oC - rt
2 h, 87%
12
13
TBDPSO
7
2. nC9H19P(Ph)3Br, n-BuLi
THF, -78 oC - rt
O
8 h, 84% (for 2 steps)
6
18
Scheme 2: Synthesis of intermediate 12.