Studies towards the synthesis of trocheliophorolides

Article abstract of DOI:10.1016/j.tetlet.2018.04.045

Total synthesis of trocheliophorolide C epimer is reported. The synthetic strategy involves generation of lactone skeleton and preparation of unsaturated side chain followed by cross-metathesis. The Eglinton oxidative coupling, Cadiot-Chodkiewicz cross-coupling and cross-metathesis are the key reactions used in the synthesis. We also attempted the synthesis of trocheliophorolide D epimer, which includes Cu catalyzed various cross-coupling reactions.

Full text of DOI:10.1016/j.tetlet.2018.04.045

Accepted Manuscript
Synthetic Study of Trocheliophorolides
Navnath B. Khomane, Harshadas M. Meshram, Haridas B. Rode
PII:
S0040-4039(18)30515-X
https://doi.org/10.1016/j.tetlet.2018.04.045
TETL 49908
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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12 April 2018
18 April 2018
Please cite this article as: Khomane, N.B., Meshram, H.M., Rode, H.B., Synthetic Study of Trocheliophorolides,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.04.045
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Synthetic Study of Trocheliophorolides
Navnath B. Khomanea,b , Harshadas M. Meshramc,d and Haridas B. Rodea,b

1
Tetrahedron Letters
Synthetic Study of Trocheliophorolides
Navnath B. Khomanea,b , Harshadas M. Meshramc,d and Haridas B. Rodea,b
aDepartment of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India
bAcademy of Scientific and Innovative Research, New Delhi, 110 025,India
cPast address: Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.
dcurrent address: Meshram Life Sciences Pvt. Ltd., Hyderabad, 500007, India.
ABSTRACT
Total synthesis of trocheliophorolide C epimer is reported. The synthetic strategy
involves generation of lactone skeleton and preparation of unsaturated side chain
followed by cross-metathesis. The Eglinton oxidative coupling, Cadiot-Chodkiewicz
cross-coupling and cross-metathesis are the key reactions used in the synthesis. We
also attempted the synthesis of trocheliophorolide D epimer, which includes Cu
catalyzed various cross-coupling reactions.
ARTICLE INFO
Article history:
Received
2009 Elsevier Ltd. All rights reserved.
Received in revised form
Accepted
Available online
Keywords:
Trocheliophorolides
Butenolides
Eglinton oxidative dimerization
Cadiot-Chodkiewicz cross coupling
Cross Metathesis
Introduction
bacteria (Escherichia coli). Further, these trocheliophorolide
were lethal to brine shrimp, Artemia salina.2 Structural
Butenolides are important class of compounds which have shown
varied biological and pharmacological activities.1 In 2001, four
butenolides were isolated by Rezanka and Dembitsky from the
two soft corals namely Sarcophyton trocheliophorum and
Lithophyton arboretum2 from the Red Sea (figure 1). Later these
butenolides were named as trocheliophorolide A to D.3
elucidation of these trocheliophorolides was done using 2D NMR
spectroscopic methods along with circular dichroism spectra.2
Trocheliophorolide C (3) possesses conjugated diyne associated
with terminal olefin and two stereogenic (S, S) hydroxy groups
with methine system at C6-C7. The configuration at C6-C7 was
confirmed as cis based on coupling of the respective protons (J=
10.9 Hz).2 The reported optical rotation for 3 is [α]D = +47.1 (c
0.11, EtOH). 2 Another family member trocheliophorolide D (4),
holds triacetylene framework coupled with a lactone in cis
fashion. The reported optical rotation for 4 is [α]D = +39.5 (c
0.14, EtOH).2 Both the compounds possess same lactone moiety
with (S)-methyl group and an unsaturated side chain attached at
the 2-position of the butenolide. 2
Total synthesis of proposed structure of trocheliophorolide B
was successfully accomplished by Troste et al. using Ru-
catalyzed alkene-alkyne coupling and ynone catalytic cross-aldol
condensation as key steps.4 While Kim et al. synthesized
proposed structure of trocheliophorolide D in an efficient manner
using aldol condensation, lactonization and dehydration as key
steps.5 Rezanka et al. discussed the stereochemistry at C-4 as "S"
in 3 and 4 but unfortunately the "R" stereochemistry was shown
in the chemical drawing.2 The detail spectroscopic study by
Troste et al.4 and Kim et al.5 confirmed that the structures of 2
Figure 1. Structure of butenolides
These trocheliophorolides showed antibacterial activity
against Gram-positive bacteria (Staphylococcus aureus and
Bacillus subtilis) but were inactive against Gram-negative
———
 Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: haridas.rode@iict.res.in

2
Tetrahedron
and 4 reported by Rezanka et al. needs revision. Based on the
above observations, we used the proposed structures of
trocheliophorolide term in this work.
The selective inhibition of Gram-positive bacteria by these
trocheliophorolides is an important biological property2 and can
be explored for the development of new antibacterials. Therefore,
we embarked on the synthesis of epimer of proposed structure of
trocheliophorolide C and D (5 and 6, figure 2) aiming to
understand the antibacterial potential of these new isomers. This
was in line with our continued efforts towards synthesis of
bioactive natural products.6
Figure 2. Epimer of trocheliophorolide C and D
Scheme 2. Synthesis of butenolide 7
The retrosynthetic analysis is depicted in scheme 1.
Compounds 5 and 6 share the common lactone moiety, hence we
envisaged to synthesize the lactone 7 and the respective
unsaturated side chains and finally couple them. The construction
of butenolide 7 was planned from chiral synthon 9 whereas the
diyne fragment 8 could be obtained from enantiopure alcohol 10
using Eglinton coupling. For compound 6, fragment 11 could be
prepared from 12 and 13. The cross metathesis between 7 and 8
was planned for compound 5 whereas formation of 6 was
envisaged using the cross coupling of 11 and 7.
Initially, the aldehyde 15 was obtained from reduction of silyl
protected ethyl lactate 14 using DIBAL-H in DCM at -78 °C.
7,6b
The key intermediate 16 was obtained by treating aldehyde 15
with the in situ generated ethyl acetate anion using LDA in THF
at -78 °C in 76% yield8 with dr 50:50. The lactonisation process
was carried out in mild basic medium which initially results in
deprotection of silyl group followed by in situ cyclization.9
Hence, the adduct 16 with TBAF in THF led to the formation of
lactone 17 as diastereomeric mixture (dr 54:46) with the requisite
stereochemistry of methyl group without any side product. The
alkylation of sodium enolate of γ-lactone 17 with allyl bromide
then furnished 18 as diastereomeric mixture (dr 47:42:11) in 75%
yield.10 The desired butenolide 7 was obtained from 18 by
dehydrating the hydroxy group of 18 using trifluoroacetic
anhydride with excess of triethylamine in 73% yield.11 At this
stage, we completed the synthesis of butenolide 7 from
commercially available R-ethyl lactate (9) in five steps.
Scheme 3. Synthesis of diacetylene 8
Scheme 1. Retrosynthetic analysis of compound 5 and 6
Next, the diacetylene 8 was successively prepared from 19
(scheme 3). Fragment 20 was achieved from the nucleophilic
addition of TMS acetylene on acrolein in 70% yield.12 To achieve
the required stereochemistry and enantiomerically pure alcohol
10, we either needed to use resolution method or the oxidation-
reduction protocol. Herein, we applied enzymatic resolution to
obtain enantiomerically pure alcohol 10 from 20 and reduced a
step by avoiding oxidation-reduction method. Alcohol 20 treated
with amino lipase from Pseudomonas fluorescens and vinyl
acetate in hexane for 24 h and further purification resulted in
alcohol 10 in 40% yield with ˃ 99 % ee.13 Both hydroxy groups
of diyne fragment 8 have same stereochemistry (S), hence we
Results and discussion
Our synthesis began with the preparation of butenolide ring and
is shown in scheme 2.

3
decided to go for dimerization of 10. This dimerization of alkyne
10 was achieved using Eglinton oxidative coupling protocol with
Cu(OAc)2.H2O, K2CO3, and pyridine in methanol to produce
dimerized product 8 in 61% yield.14
The synthesis of ene-triyne 11, a fragment needed for
synthesis of compound 6, is shown in scheme 4. The CuBr
catalyzed reaction of TMS acetylene with allyl bromide 21 and n-
BuLi at ambient temperature afforded 22 in 70% yield.15 After
deprotection of silyl group of 22, bromination of terminal alkyne
23 was carried out with N-bromo succinimide using silver nitrate
and acetone in dark condition to furnish bromo compound 13 in
good yield.16 This lachrymatory brominated alkyne fragment 13
was further used for Cadiot-Chodkiewicz cross coupling reaction.
The diyne 25 formation was successfully furnished by utilizing
CuI and tetramethylethylenediamine (TMEDA) mediated cross-
coupling reaction of TMS acetylene and propargylic alcohol 24.
17
The reported protocol states 58% yield for 25,17 whereas we
observed that when the air is replaced by oxygen (this protocol),
the yield for 25 was improved to 68%. The diyne 25 was
desilylated with K2CO3 in methanol,18 produced fragment 12 for
further use. The ene-triyne framework 11 was achieved by
coupling of bromo compound 13 with a diacetylenic partner 12
using CuCl, NH2OH.HCl and aq. ethyl amine (70%) in diethyl
ether 19 in 65% yield.
Scheme 5. Synthesis of 5 and 6
A reaction of diene and terminal conjugated enynes was first
reported by Lee and group with Grubbs' second generation
catalyst.20 An efficient method for Z- selective cross-metathesis
(CM) of conjugated enynes has been reported.20 In our synthesis,
we were pleased to find that when the same protocol of CM was
used to couple 7 and 8, the compound 5 was successfully
obtained in 20% yield along with unknown impurities. The low
yield of 5 may be due to the generation of polar byproducts along
with 20% unreacted 7. Attempts to isolate these byproducts were
unsuccessful. In the 1HNMR spectrum of 5, a resonance signal at
δ 5.28 with J = 10.1 Hz can be assigned to H6 while that of δ
5.06 with J = 10.1, 1.0 Hz can be assigned to H7. This confirms
the cis geometry of C6-C7 double bond of compound 5. This
compound showed optical rotation of [α]D22.6 = + 39.66 (c 0.002,
CHCl3) and [α]D27.8 = + 62.50 (c 0.002, EtOH). The overall yield
for 5 from R-ethyl lactate (9) is 5.4%. The physical and
spectroscopic data of epimer of trocheliophorolide C (5) is
provided in the supplementary information. Compound 5 was
found to be semi-stable which jeopardized our objective to screen
it for antibacterial activity.
A complex mixture was observed when the same
protocol was used for the coupling of ene-triyne 11 with 7.20 The
CM reaction for 6 was carried out in different solvents (CH2Cl2,
CHCl3, toluene)21 and at different temperatures (rt to reflux). All
the attempts were unsuccessful to obtain 6.
Scheme 4. Synthesis of ene-triyne 11
In conclusion, we have developed a synthesis of epimer
of proposed structure of trocheliophorolide C (5). The synthesis
involves the Eglinton oxidative coupling, Cadiot-Chodkiewicz
cross coupling and cross-metathesis as key reactions. We also
attempted the synthesis of epimer of proposed trocheliophorolide
D (6), which included Cu catalyzed various cross-coupling
reactions.
Having chiral butenolide 7, diyne 8 and ene-triyne fragment
11 in hand, we proceeded to synthesize 5 and 6 using cross
metathesis. The Grubbs 2nd generation catalyst 26 was used for
the cross-metathesis reaction (scheme 5).
Acknowledgments
N.B.K thanks University Grant Commission of Government
of India for the fellowships. The author thanks CSIR, New Delhi,
for financial support as part of XII five year plan program under
the title ORIGIN (CSC-0108).

4
Tetrahedron
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5
1. The synthesis is accomplished using
commercially available (R)-ethyl lactate
2. Enzymatic resolution of alcohol using
amino lipase
3. The Eglinton oxidative coupling and
Cadiot-Chodkiewicz cross coupling as key
reactions
4. The cross metathesis using Grubbs II
generation catalyst