Total synthesis of (-)-2-methoxy-2-butenolide-3-cinnamate and its antimicrobial potentials

Article abstract of DOI:10.1080/14786419.2020.1789979

The first total synthesis of (-)-2-methoxy-2-butenolide-3-cinnamate (butenolide cinnamate) was achieved using commercially available starting material. The synthesized compound was found to have promising antibacterial activity against Gram-negative strai

Full text of DOI:10.1080/14786419.2020.1789979

Natural Product Research
Formerly Natural Product Letters
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Total synthesis of (-)-2-methoxy-2-butenolide-3-
cinnamate and its antimicrobial potentials
Madhukar S. Said , Rohini Udavant , Amit Kumar Sahu , AbuJunaid Khan ,
Rashmi Nayak , Syed G. Dastager , Pradeep Kumar & Jayant Gajbhiye
To cite this article: Madhukar S. Said , Rohini Udavant , Amit Kumar Sahu , AbuJunaid Khan ,
Rashmi Nayak , Syed G. Dastager , Pradeep Kumar & Jayant Gajbhiye (2020): Total synthesis of
(-)-2-methoxy-2-butenolide-3-cinnamate and its antimicrobial potentials, Natural Product Research,
DOI: 10.1080/14786419.2020.1789979
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1789979
Total synthesis of (-)-2-methoxy-2-butenolide-3-cinnamate
and its antimicrobial potentials
Madhukar S. Saida,b, Rohini Udavanta, Amit Kumar Sahub,c, AbuJunaid Khanb,c
,
Rashmi Nayaka,b, Syed G. Dastagerb,c, Pradeep Kumara,b and Jayant Gajbhiyea,b
b
aDivision of Organic Chemistry, National Chemical Laboratory, Pune, India; Academy of Scientific
c
and Innovative Research (AcSIR), Ghaziabad, India; NCIM-Resource Center, CSIR-National Chemical
Laboratory, Pune, India
ABSTRACT
ARTICLE HISTORY
Received 31 March 2020
Accepted 23 June 2020
The first total synthesis of (-)-2-methoxy-2-butenolide-3-cinnamate
(butenolide cinnamate) was achieved using commercially available
starting material. The synthesized compound was found to have
promising antibacterial activity against Gram-negative strains
Escherichia coli (ATCC 8739), Salmonella typhimurium (ATCC
23564) and Pseudomonas aeruginosa (ATCC 19154) with a min-
imum inhibitory concentration of 2.0 mg/mL, 1.0 mg/mL and
2.0 mg/mL, respectively. Notably, the compound was more potent
against Gram-negative test strains than the Gram-positive
test strains.
KEYWORDS
Total synthesis; butenolide
cinnamate; antibacter-
ial activity
1. Introduction
Butenolide is a class of lactone, it was distinguished by a 4-hydroxy-2(5 H)-furanone
ring (Zografos and Georgiadis 2006; Schobert and Schlenk 2008). This five-membered
lactone exhibits multidisciplinary bioactivities like HIV-1 protease inhibitors (Roggo
CONTACT Jayant Gajbhiye
ms.said@ncl.res.in
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1789979.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

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M. S. SAID ET AL.
Figure 1. Butenolide containing some natural product.
et al. 1994), anticancer (Wang et al. 2011), antiepileptic (Zhang et al. 1992), antibacter-
ial (Murray et al. 2014), antifungal (Gamard et al. 1997) and insecticidal activities
(Husain et al. 2010). A large number of butenolide containing natural products are iso-
lated from numerous fungi, molds and lichens (Clark et al. 2005; Parvatkar et al. 2009;
Elkhayat et al. 2016). Butenolide ring is found as a core substructure in various classes
of the natural product including alkaloids, terpenes, macrolides, and tannins (Mori
et al. 2016; El-Kashef et al. 2019). The structure-activity relationship of these butenolide
containing compounds shows that the lactone ring is crucial for bio-activity and
selectivity of the molecule (Patt et al. 1997; Sanchez et al. 2018). Therefore, the synthe-
sis of these compounds has attracted a great deal of interest among the medicinal
and synthetic chemists for more than a century (Boukouvalas and Loach 2008; Mao
et al. 2017). Butenolide is a versatile synthetic intermediate for the assembly of
complex natural products shown in Figure 1, for example, (-)-2-methoxy-2-butenolide-
3-cinnamate (Butenolide cinnamate) (1) penicillicacid (2). pulvinicacid (3) and lantheli-
done (4).
Various synthesis of butenolide containing natural products is reported in the litera-
ture. However, their synthesis is quite challenging because of the unstable nature of
the five-member lactone in acidic and basic conditions (Janecki 2014; Chen et al.
2015). The butenolide cinnamate ((-)-2-methoxy-2-butenolide-3-cinnamate) 1 was first
isolated from Polygonum gaburum (Said et al. 2015). The compound showed in-vitro
anti-HIV-1 activity against HIV-1UG070 (X4, subtype D) and HIV-1VB59 (R5, subtype C)
with IC50 in the range of 15.68–22.43 mg/mL. Also, compound 1 showed in-vitro

NATURAL PRODUCT RESEARCH
3
Scheme 1. Retro-synthesis and total synthesis of (-)-2-methoxy-2-butenolide-3-cinnamate
activity against Mycobacterium tuberculosis H37Ra with IC50 values of 1.43 and 2.27 mg/
mL, respectively in the dormant phase and active phase. Considering its biological pro-
file and a good synthetic target, we hereby report the first total synthesis of buteno-
lide cinnamate 1 in five steps using commercially available tetronic acid and tested its
bioactivity against Gram-positive and Gram-negative bacteria.
2. Results and discussion
The retrosynthesis of butenolide cinnamate is shown in Scheme 1. The target molecule
1 can be synthesized using the acyl coupling of cinnamyl chloride 5 and lactone 6.
The compound 6, in turn, can be synthesized using bromination of compound 8 fol-
lowed by methanolysis of compound 7. Benzoyl protection of the commercially avail-
able tetronic acid 9 could lead to compound 8.
The total synthesis of butenolidecinnamate 1 started from benzoyl protection of
the tetronic acid 9 in the presence of K2CO3 and benzyl bromide in dimethylforma-
mide to produce compound 8 with 72% yield (Bourdreux et al. 2008). Anionic

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M. S. SAID ET AL.
bromination of compound 8 using lithium bis(trimethylsilyl)amide in dry THF at 78 ꢀC
resulted in compound 7 with a 91% yield (Willis et al. 2007). Base promoted methanol-
ysis of compound 7 at 0 ꢀC resulted in compound 6 with an 81% yield. Benzoyl
de-protection of compound 6 in presence of H2PdC to furnished hydroxyl lactone 10,
followed by esterification using cinnamyl chloride to eventually give rise to compound
1 with an overall 80% yield in two steps (Zhao et al. 2012).
After synthesis of butenolide cinnamate 1, the antibacterial activity was performed
against a panel of Gram-negative and Gram-positive bacteria at different drug concen-
trations. The minimum inhibitory concentration (MIC) for respective strains are tabu-
lated in Table S1 (Supplementary material) and the growth curve of representative
test strains in the presence and absence of test compounds was shown in Figure S1
(Supplementary material). The compound 1 showed promising antibacterial activity
against the Gram-negative bacteria like Escherichia coli (ATCC 8739), Salmonella typhi-
murium (ATCC 23564) and Pseudomonas aeruginosa (ATCC 19154) with a minimum
inhibitory concentration of 2.0 mg/mL, 1.0 mg/mL and 2.0 mg/mL, respectively and the
bactericidal concentrations were 2.0 mg/mL, 8.0 mg/mL and 4.0 mg/mL, respectively.
However, the minimum inhibitory concentration for Gram-positive bacteria like Bacillus
subtilis (ATCC 6051), Bacillus cereus (ATCC 10876) and Staphylococcus epidermidis (ATCC
12228) was 4.0 mg/mL, 4.0 mg/mL and 16.0 mg/mL, respectively and the bactericidal
concentrations were 16.0 mg/mL, 4.0 mg/mL and 32.0 mg/mL, respectively. The above
data showed a significant difference in the potency towards Gram-negative and Gram-
positive strains as compound 1 inhibited the Gram-negative strains more efficiently
than the Gram-positive.
3. Conclusion
In this study, we have successfully synthesized (-)-2-methoxy-2-butenolide-3-cinnamate
using commercially available starting material in five steps and antibacterial activity
was tested against Gram-positive and Gram-negative test strains. We observed that
compound 1 showed higher potency towards Gram-negative strain and showed a
good activity against Salmonellatyphimurium (ATCC23564) with a MIC of 1.0 mg/mL.
Further study of compound 1 is underway.
Acknowledgements
M. S. Said thanks to CSIR New Delhi, India for a Senior Research Fellowship. We are grateful to
Director, CSIR-NCL, Pune India for his constant support and encouragement.
Disclosure statement
No potential conflict of interest was reported by the authors.

NATURAL PRODUCT RESEARCH
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