Br?nsted acid promoted intramolecular cyclization of O-alkynyl benzoic acids: Concise total synthesis of exserolide F

Article abstract of DOI:10.1080/00397911.2018.1491994

Herein we report the stereoselective total synthesis of Exserolide F. The key step involves triflic acid catalyzed highly regioselective intramolecular cyclization of an O-alkynyl benzoic acid derivative to accomplish the core isocoumarin skeleton of the natural product via 6-endo-dig mode of cyclization. The other important steps are: Sharpless asymmetric epoxidation, Barbier propargylation, Sonogashira coupling en route to access the O-alkynyl benzoic acid derivative.

Full text of DOI:10.1080/00397911.2018.1491994

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Brønsted acid promoted intramolecular cyclization
of O-alkynyl benzoic acids: Concise total synthesis
of exserolide F
Mohan Dumpala, Lingaswamy Kadari & Palakodety Radha Krishna
To cite this article: Mohan Dumpala, Lingaswamy Kadari & Palakodety Radha Krishna (2018):
Brønsted acid promoted intramolecular cyclization of O-alkynyl benzoic acids: Concise total
synthesis of exserolide F, Synthetic Communications, DOI: 10.1080/00397911.2018.1491994
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https://doi.org/10.1080/00397911.2018.1491994
Brønsted acid promoted intramolecular cyclization of
O-alkynyl benzoic acids: Concise total synthesis of
exserolide F
Mohan Dumpala, Lingaswamy Kadari, and Palakodety Radha Krishna
Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad India.
ABSTRACT
ARTICLE HISTORY
Received 25 April 2018
Revised 15 June 2018
Accepted 17 June 2018
Herein we report the stereoselective total synthesis of Exserolide F. The
key step involves triflic acid catalyzed highly regioselective intramo-
lecular cyclization of an O-alkynyl benzoic acid derivative to accom-
plish the core isocoumarin skeleton of the natural product via 6-endo-
dig mode of cyclization. The other important steps are: Sharpless asym-
metric epoxidation, Barbier propargylation, Sonogashira coupling en
route to access the O-alkynyl benzoic acid derivative.
KEYWORDS
6-Endo-dig cyclization;
exserolide F; isocoumarins;
O-alkynyl benzoic acid
derivatives
GRAPHICAL ABSTRACT
Introduction
Most lactonic natural products in the form of isocoumarins and 3,4-dihydroisocoumar-
ins, mainly originate from fungi, bacteria, lichens, liverworts, moulds and to a less
extent from higher plants. These ubiquitous scaffolds are blessed with diverse pharma-
cological activities, such as antimicrobial,[1a] antifungal,[1b] anti-inflammatory,[1c] antiox-
idant,[1d] and anticancer[1e] activities. Recently, Yin and co-workers isolated a series of
new Exserolides A-F along with four known compounds from the solid cultures of plant
endophytic fungus of Exserohilum species.[2] Amongst all, 8-hydroxy 3-substituted iso-
coumarin derivative, i.e. Exserolide F (Figure 1) showed significant antibacterial activity
against both the Gram-positive and Gram-negative bacteria. In view of their biological
significance, new strategies and synthetic methods have been developed for construction
of isocumarins derivatives via intramolecular Cyclization of O-alkynyl benzoic acid
derivatives by using metal catalyst such as Pd[3] and various Au[4] catalysts along with
acids.[5] Recently, Mohapatra et al. reported the total synthesis of Exserolide F using
CONTACT Palakodety Radha Krishna
prkgenius.iict@gov.in
CSIR-Indian Institute of Chemical Technology, Organic
and Biomolecular Chemistry Division, D-211, Discovery Laboratory, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500007 India
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

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M. DUMPALA ET AL.
Scheme 1. Retrosynthetic analysis of target compound.
gold(I)-catalyzed cyclization[4b] to access the isocoumarin skeleton in nine steps. Herein
we report a simple and practical synthesis of Exserolide F using acid catalysed 6-endo-
dig mode of cyclization of alkyne intermediate 2 (Scheme 1). This strategy advances the
scope of acid catalyzed regioselective cyclization protocol and provides an alternative
methodology for the isocoumarin ring construction.
Retrosynthetic analysis
The retrosynthetic analysis of Exserolide F 1 (Scheme 1) strategically hinged on the acid
catalyzed regioselective intramolecular cyclization of O-alkynyl benzoic acid derivative
2, which in turn could be realized by the Sonogashira coupling between aryl triflate 3
and alkyne intermediate 4a. Aromatic precursor 3 was envisioned to be the protected
2,4,6 trihydroxy benzoic acid, while the required alkyne derivative 4a could be derived
from epoxy alcohol, which could be obtained from readily available trans-2-hexenol.
Regioselective ring-opening of epoxy alcohol would yield the corresponding 1,3-diol,
which could be protected with benzaldehyde dimethyl acetal, followed by its selective
opening with DIBAL-H would furnish the primary alcohol 5. Lastly, compound 5 would
be oxidized to aldehyde which on subsequently Barbier reaction would result in the
alkyne 6 as a diastereomeric mixture. The separation of isomers would furnish the
requisite 4a in optically pure form.
Results and discussion
Initially we focused on the construction of alkynyl precursor 4a (Scheme 2), which
commenced with commercially available trans-2-hexen-1-ol according to a reported
procedure.[6] Sharpless asymmetric epoxidation of hexenol in the presence of (þ)-DIPT,
Ti(OiPr)4 and TBHP at -20 ꢀC gave the corresponding 2,3-epoxy alcohol, which on
regioselective ring-opening reaction with Red-Al in anhydrous THF gave the 1,3-diol. It
was then converted into a benzylidene derivative with benzaldehyde dimethyl acetal in
CH2Cl2 using p-TSA (cat) to give an acetal, which on selective opening with DIBAL-H

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Scheme 2. Synthesis of fragment 4.
furnished benzyl protected primary alcohol 5. Alcohol 5 was oxidized with Dess-Martin
periodinane followed by Barbier propargylation using propargyl bromide/Zn/NH4Cl/
0 ꢀC, affording a mixture of inseparable diastereomers 6 (85% yield over two steps) in
3:2 ratio.[7] The ratio was also established from the 1 H NMR spectrum by measuring
the integration of the separable protons (Vide Infra Supporting Information) However,
the mixture could be separated into optically pure diastereomers after the protection of
the hydroxy group as its benzyl ether (NaH/BnBr/TBAI/THF). Thus, 6 gave two separ-
able dibenzyl ethers 4a (54%) and 4 b (36%). Their diastereomeric ratio was confirmed
from the isolated yields. And the purity of compound 4a was determined by LCMS ana-
lysis and de was found to be 95.5% (Vide Infra Supporting Information).
Further, the relative stereochemistry of the major isomer was confirmed as anti-1,3-
diol invoking Rychnovsky’s analogy on the acetonide 7a (Scheme 3) obtained from the
corresponding diol. Thus, 4a on debenzylation using TiCl4 conditions gave the corre-
sponding diol which upon acetonation produced the corresponding diol produced
respective acetonide 7a.[8] The 13 C NMR of 7a revealed the presence of characteristic
methyl groups peaks at 24.9 and 25.6 ppm and the acetal carbon at 100.4 ppm offering
ample evidence of the anti-stereochemistry as well as the absolute stereochemistry of
the newly created stereogenic center as S. Similarly, syn-acetonide 7 b was confirmed by
the appearance of the methyl carbons resonance at 30.1 and 19.8 ppm and the acetal
carbon at 98.7 ppm (Scheme 3).
Next, synthesis of aromatic triflate derivative 3 was contemplated from the 2,4,6-tri-
hydroxy benzoic acid as per the literature procedure (Scheme 4).[9] The unification of
fragments 4a and 3 under Sonogashira cross coupling reaction using palladium(II)
chloride, copper(I) iodide and triethyl amine as base in CH3CN afforded the aryl alkyne
derivative 2 (70%). Compound 2 was characterized by the 1 H NMR spectrum which
revealed the disappearance of acetylenic proton. The presence of protons pertaining to
both fragments is consistent with the assigned structure. For instance, the methylene
protons adjacent to acetylenic functionality appeared at d 2.77 ppm (dd, J ¼ 20.1, 9.3 Hz,
2H), the acetonide methyl protons appeared at d 1.68 ppm (s, 6H) ppm. Additionally,
the IR spectrum revealed the C–C stretching frequency at 2235 cmꢁ1 as a confirmation
of the presence of acetylenic moiety in compound 2, C ¼ O at 1740 cmꢁ1. Finally, regio-
selective intramolecular cyclization of O-alkynyl benzoic acid derivative was accom-
plished upon exposure to one equivalent of Brꢂnsted acid[10] (TfOH/THF/reflux) to

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M. DUMPALA ET AL.
Scheme 3. Synthesis of fragments 7a and 7b.
Scheme 4. Synthesis of Exserolide F (1).
Figure 1. Structure of target Exserolide F.
afford an isocoumarin derivative 8 (90%) as an exclusive product via 6-endo-dig cycliza-
tion as per the Baldwin rules.[11] The 1 H NMR spectrum of isocoumarin 8 displayed
the diagnostic vinyl-H at d 6.20 ppm (s, 1H), the methylene adjacent to isocoumarin
ring appeared at d 2.73 ppm (dd, J ¼ 14.7, 6.3 Hz, 1H) and at d 2.67 ppm (dd, J ¼ 14.5,
6.0 Hz, 1H), the absence of methyl protons due to the acetonide group was also in con-
formity with the assigned structure. The IR spectrum revealed the absence of acetylenic
C–C bond stretching at 2245 cmꢁ1, there was a strong absorption at 1685 cmꢁ1 due the
enol C ¼ O which was otherwise observed at 1740 cmꢁ1 in compound 2. Next, debenzy-
lation was accomplished under the TiCl4 conditions to give the target compound 1

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(95%) which was thoroughly characterized by comparing with the reported data
(Supporting Information).[2]
Conclusion
In summary, we report the concise stereoselective total synthesis of Exserolide F (overall
yield 11.2%) wherein triflic acid was used as a Brꢂnsted acid for the highly regioselec-
tive intramolecular annulation of O-alkynyl benzoic acid derivative to give the core iso-
coumarin skeleton of the natural product via 6-endo-dig mode of cyclization. Other
important reactions being the Sharpless asymmetric epoxidation, Barbier propargylation,
Sonogashira coupling en route to furnish the O-alkynyl benzoic acid derivative. The syn-
thetic strategy described herein is amenable to similar natural products.
Experimental section
General
Dried organic solvents were used (anh. Na2SO4). Air sensitive reagents were transferred by
double-ended needle. TLC: Merck 60 F254 silica-gel plates. All column chromatographic
separations were performed using silica gel (Acme’s, 60–120, 100–200 mesh). Yields refer
to chromatographically and spectroscopically (1H- and 13C NMR) homogenous material.
1H NMR spectra were measured on 300 MHz, 400 , and 500 MHz, instruments, and 13C
NMR spectra on 50 , 75 , and 125 MHz) spectrometer in CDCl3/Acetone D6 (7-10 mM
1
soln), TMS as internal standard. J values are given in Hz. All H and 13 C chemical shifts
are reported in ppm (d). Infrared (IR) spectra were recorded on a Thermo Nicolet Nexus
670 spectrometer. Optical rotations were measured with a JASCO P-1020 instrument and
[a]D values were in units of 10ꢁ1 deg cmꢁ2 gꢁ1 at 25 ꢀC. Mass spectra were recorded on
Finnigan Mat 1210 double focusing mass spectrometer operating at a direct inlet system
and ESI-MS was measured using ion-trap mass spectrometer.
Experimental procedure for synthesis exserolide F (1)
To a stirred solution of 8 (0.05 g, 0.08 mmol) in CH2Cl2 (5 mL), TiCl4 (1.0 mL,
0.24 mmol, 1 M in CH2Cl2) was added at 0 ꢀC and the reaction mixture stirred at room
temperature for 4 h. After completion of the reaction (monitored by TLC), it was
quenched with a saturated solution of NaHCO3 (10 mL). The organic phase was sepa-
rated and the aqueous phase extracted with ethyl acetate (5 ꢃ 15 mL). The combined
organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pres-
sure, and then the residue was purified by silica gel column chromatography (60:40,
hexane/EtOAc) to afford compound 1 (0.02 g, 95%) as a white amorphous solid.
Data
25
25
[a]D ¼ ꢁ15.0 (c ¼ 0.05, MeOH), lit.[3] [a]D ¼ ꢁ15.6 (c ¼ 0.09, MeOH). 1 H NMR
(500 MHz, Acetone-d6): d 11.15 (s, 1 H), 6.43 (s, 1H), 6.40 (d, J ¼ 2.2 Hz, 1 H), 6.37 (d,
J ¼ 2.2 Hz, 1H), 4.31 (m, 1H), 4.20 (br. s, 1H), 3.89 (m, 1H), 3.74 (br. s, 1H), 2.66 (dd,

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M. DUMPALA ET AL.
J ¼ 14.4, 4.4 Hz, 1H), 2.60 (dd, J ¼ 14.3, 8.0 Hz, 1H), 1.62-1.58 (m, 2H), 1.46–1.36 (m,
4H), 0.89 (t, J ¼ 7.0 Hz, 3H). 13 C NMR (100 MHz, Acetone-d6): d 167.2, 166.5, 164.5,
156.5, 141.0, 106.5, 103.4, 102.2, 99.8, 68.3, 66.7, 44.9, 42.8, 41.2, 19.6, 14.5. IR (neat)
ꢀmax 3421, 2926, 2860, 1681, 1625, 1462, 1384, 1168, 845 cmꢁ1. HRMS m/z: calcd for
C16H20O6Na [M þ Na]þ 331.11521 found: 331.11609.
Funding
M.D. and L.K are thankful to the UGC, New Delhi for the financial support in the form
of fellowship.
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