Stereoselective synthesis of the lichen metabolite, (+) montagnetol and its congeners as antimicrobial agents

Article abstract of DOI:10.1080/00397911.2018.1519076

In view of structural diversity, (+) montagnetol, the major metabolite of the fruticose lichen, Roccella montagnei was synthesized along with three of its congeners by employing highly efficient protocols. (+) Montagnetol (2 R, 3S; 11) and (-) montagnetol (2S, 3R; 5) were synthesized in 7 and 9 steps, respectively, from L-ascorbic acid. The two new congeners 3 (2 R, 3R) and 6 (2S, 3S), which differ in configuration at C-2 and C-3 positions of the (+) montagnetol, were synthesized from (?) diethyl D-tartrate and (+) diethyl L-tartrate, respectively. The synthesized compounds were evaluated in vitro for antimicrobial activity against two Gram-positive (S. aureus and E. coli) and two Gram-negative (S. typhi and P. aeruginosa) bacteria and one fungal strain Candida albicans. Interestingly, the congener 3 showed promising anti-bacterial activity (MIC: 0.062 μg/ml) against P. aeruginosa, whereas the congener 6 displayed potent anti-fungal activity (MIC: 0.062 μg/ml) against C. Albicans.

Full text of DOI:10.1080/00397911.2018.1519076

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
Stereoselective synthesis of the lichen metabolite,
(+) montagnetol and its congeners as antimicrobial
agents
Uppuluri Venkata Mallavadhani, Ramakrishna Boddu, Balaji B. Rathod &
Prakasam Reddy Setty
To cite this article: Uppuluri Venkata Mallavadhani, Ramakrishna Boddu, Balaji B. Rathod
& Prakasam Reddy Setty (2018): Stereoselective synthesis of the lichen metabolite, (+)
montagnetol and its congeners as antimicrobial agents, Synthetic Communications, DOI:
10.1080/00397911.2018.1519076
To link to this article: https://doi.org/10.1080/00397911.2018.1519076
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https://doi.org/10.1080/00397911.2018.1519076
Stereoselective synthesis of the lichen metabolite,
(+) montagnetol and its congeners as antimicrobial agents
Uppuluri Venkata Mallavadhania,c, Ramakrishna Boddua,c, Balaji B. Rathodb,c, and
Prakasam Reddy Settyb,c
aCentre for Natural Products & Traditional Knowledge, CSIR-Indian Institute of Chemical Technology,
b
Hyderabad, India; Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology
c
Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of
Chemical Technology, Hyderabad, India
ABSTRACT
ARTICLE HISTORY
Received 3 August 2018
In view of structural diversity, (þ) montagnetol, the major metabolite of
the fruticose lichen, Roccella montagnei was synthesized along with
three of its congeners by employing highly efficient protocols. (þ)
Montagnetol (2R, 3S; 11) and (-) montagnetol (2S, 3R; 5) were synthe-
sized in 7 and 9 steps, respectively, from L-ascorbic acid. The two new
congeners 3 (2R, 3R) and 6 (2S, 3S), which differ in configuration at C-2
and C-3 positions of the (þ) montagnetol, were synthesized from (ꢀ)
diethyl D-tartrate and (þ) diethyl L-tartrate, respectively. The synthesized
compounds were evaluated in vitro for antimicrobial activity against two
Gram-positive (S. aureus and E. coli) and two Gram-negative (S. typhi
and P. aeruginosa) bacteria and one fungal strain Candida albicans.
Interestingly, the congener 3 showed promising anti-bacterial activity
(MIC: 0.062 mg/ml) against P. aeruginosa, whereas the congener 6 dis-
played potent anti-fungal activity (MIC: 0.062 mg/ml) against C. Albicans.
KEYWORDS
Antimicrobial activity;
diethyl tartrate; L-ascorbic
acid; montagnetol;
Roccella montagnei;
GRAPHICAL ABSTRACT
Introduction
Lichens are one of the most important and rich natural sources for food, perfume, dyes,
traditional and folk medicine for the past several centuries.[1–5] The lichenized fungi
CONTACT Uppuluri V. Mallavadhani
uvmavadani@yahoo.com
Centre for Natural Products & Traditional
Knowledge, CSIR-Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500 007, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

2
U. V. MALLAVADHANI ET AL.
O
OH
O
OH
1
11
21
OH
4
1
1
11
21
OH
OH
O
3
4
2
O
3
2
2
OH
OH
41
HO
OH
41
HO
HO
OH
(2S, 3S)
(2R, 3R)
(3)
(6)
O
OH
O
OH
1
11
11
OH
4
4
3
O
3
O
2
OH
OH
41
21
(2R, 3S)
41
21
(2S, 3R)
HO
OH
OH
(15)
(11)
(+) Montagnetol
(-) Montagnetol
Figure 1. Montagnetol and its isomers.
produce a variety of secondary metabolites, which are unique and mostly phenolic in
nature.[6–9] The lichen secondary metabolites exhibit promising and diverse biological
activities, including anti-bacterial, anti-fungal, anti-inflammatory, anti-oxidant, anti-viral
and anti-cancer.[10–16] The lichen genus Roccella of Roccellaceae family comprises of 40
species, which are distributed throughout the world.[17] Roccella species were used
widely as sources for dyes and also in traditional medicine for diarrhea, cough, fever
and inflammatory diseases.[18–20] Among the Roccella sp., Roccella montagnei, a fruti-
cose lichen, produces biologically active secondary metabolites such as erythrin, roccellic
acid, montagnetol, usnic acid, methyl orsellinate, and ergosterol.[21–22] Literature survey
reveals that the thallus extracts of R. montagnei and some of its chemical constituents
found with significant biological activities such as anti-viral, anti-microbial, anti-oxidant,
anti-inflammatory, and anti-cancer.[23–25] However, systematic studies on the biological
activities of montagnetol, the major metabolite of R. montagnei have not yet been done.
(þ) Montagnetol, an erythrityl ester of orsellinic acid is found abundantly in the lichen
R. montagnei.[26] Rao and Seshadri were the first to isolate montagnetol from R. montagnei
and its structure was established on the basis of degradative studies without confirming their
configuration.[27] In an attempt to confirm its structure, the same group synthesized racemic
montagnetol from cis-2-butene-1,4-diol.[28] Barrett and coworkers reported an efficient bio-
mimetic synthesis of (þ) and (ꢀ) montagnetol from 1,3-dioxin-4-one.[29] Kumbaraci et al.,
synthesized (ꢀ)-montagnetol from commercially available orsellinic acid and erythritol.[30]
Recently, we have reported the isolation of (þ) montagnetol from Roccella montagnei in
4.66% yield and its structure was established by physical, chemical, and spectral data.[31] In
fact, montagnetol can exist in any of the four possible isomeric forms (Figure 1). In order
to compare the isolated montagnetol with the four possible structures and also for detailed
biological studies to evaluate their anti-microbial potential, we have now taken up the syn-
thesis of montagnetol along with three of its congeners. In this study, a new and short syn-
thetic protocol has been employed to obtain (þ) and (ꢀ) montagnetols from L-ascorbic
acid. The various steps of the synthesis are summarized as follows: synthesis of a-hydroxyl
ester from L-ascorbic acid followed by Mitsunobu reaction, reduction, esterification and
deprotection. The congeners 3 and 6 were synthesized from D and L diethyl tartrate,
respectively, in good yields. The synthesized compounds were evaluated in vitro for their
anti-microbial potential against two Gram-positive (S. aureus, E. coli) and two Gram-
negative (S. typhi, P. aeruginosa) bacteria and anti-fungal activity against C. albicans.

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3
O
OH
O
O
O
O
OH
O
OH
OH
(c)
O
(d)
(a), (b)
O
O
OH
O
HO
OH
O
O
O
OH
D-DET
HO
OH
(2R, 3R)
3-
HO
HO
OH
O
(2R, 3R)
2-
(2R, 3R)
1-
O
OH
O
O
OH
O
OH
OH
(d)
O
(c)
OH
(a), (b)
O
O
O
HO
OH
O
OH
O
(2S, 3S)
4-
HO
OH
(2S, 3S)
OH
(2S, 3S)
L-DET
6-
5-
Scheme 1. Synthesis of compounds 3 and 6. Reaction Condition: (a) 2,2-DMP, p-TsOH, dry acetone,
rt, 12 h; (b) LAH, dry THF, 70 ꢁC, 1 h; (c) DCC, DMAP, THF, rt, 3 h; (b) p-TsOH, MeOH, rt, 1 h.
O
O
O
O
H
O
O
HO
HO
O
O
O
O
Ref [30]
3 Steps
O
(a)
(b)
O
(c)
O
O
O
O
OH
OH
HO
OH
O
O
HO
OH
OH
(2R, 3S)
OH
9-(2R, 3S)
(2R, 3S)
10-
L-Ascorbic acid
8-(2S, 3R)
7-
(d)
O
OH
OH
O
OH
HO
OH
(2R, 3S)
11-
Scheme 2. Synthesis of (þ) Montagnetol 11. Reaction Condition: (a) Ph3P, DEAD, PhCOOH, dry THF,
rt, 12 h; (b) LAH, dry THF, 12 h; (c) Orsellinic acid, DCC, DMAP, THF, rt 3 h; (d) p-TsOH, MeOH, rt, 1 h.
O
HO
O
O
O
HO
O
O
O
(a)
O
(b)
O
(c)
O
OH
OH
O
O
OH
(2R, 3S)
HO
OH
(2S, 3R)
9-
14-
(d)
(2R, 3S)
12-
(2S, 3R)
13-
O
OH
OH
O
OH
OH
(2S, 3R)
HO
15-
Scheme 3. Synthesis of (ꢀ) Montagnetol 15. Reaction Condition: (a) NaH, BnBr, DMF, rt, 12 h;
(b) PTSA, MeOH, rt, 1 h; (c) orsellinic acid, DCC, DMAP, THF, rt 3 h, (d) Pd/C, H2, EtOAc, 3 h.
Results and discussion
Chemistry
The (þ) montagnetol (11) and three of its congeners (3, 6, and 15) were synthesized
from commercially available starting material presented in Schemes 1, 2, and 3. As
shown in Scheme 1, compound 3 (2R, 3R) and 6 (2S, 3S) were synthesized from (ꢀ)
diethyl D-tartrate and (þ) diethyl L-tartrate, respectively. Diols 1 (2R, 3R) and 4 (2S,
3S) were prepared from diethyl tartrate in two steps,[32,33] which were subjected to

4
U. V. MALLAVADHANI ET AL.
Table 1. Physical properties of synthesized compounds.
Compound number
Optical rotation [a]D20
Ret. time
3
6
11
15
ꢀ24.93 (c ¼ 0.4, MeOH)
þ21.02 (c ¼ 0.43, MeOH)
þ17.12 (c ¼ 0.38, MeOH)
ꢀ10.36 (c ¼ 0.6, MeOH)
þ16.8 (c¼ 0.4, EtOH)
1.621
1.708
1.687
1.679
1.689
Montagnetol (Isolated)
further mono esterification with orsellinic acid in presence of DCC and DMAP in THF
at room temperature for 3 h to afford compounds 2 (2 R, 3R) and 5 (2S, 3S) in 76 and
73% yields, respectively. Subsequent deprotection of the compounds 2 and 5 with
TsOH in MeOH at room temperature for 1 h afforded compounds 3 (2R, 3R) and 6
(2S, 3S) in 90 and 95% yields, respectively. The structures of compounds 3 and 6 were
1
established by physical and spectral data (IR, H, 13C NMR, and HRMS). Compounds 3
and 6 showed the characteristic peaks in 1H NMR spectra at d 2.50–2.52 and
d 6.22–6.27, respectively, indicating the aromatic methyl and two aromatic protons.
The 13C NMR spectra of compounds 3 and 6 showed signals at d 172.25 and d 172.03
corresponding to carbonyl carbon in ester functionalities.
The (þ) montagnetol (2R, 3S; 11) was synthesized from L-ascorbic acid, which was
converted into the a-hydroxy ester (2R, 3S; 7) in 76% yield.[34] Inversion of configur-
ation at C-2 of a-hydroxy ester 7 under the Mitsunobu conditions by using benzoic
acid, triphenylphosphine, diisopropylazodicarboxylate (DIAD) in dry tetrahydrofuran at
room temperature afforded the desired compound (2S, 3R; 8) in 82% yield.
Configuration at C-2 position of compound 8 was confirmed by its optical rotation and
1
spectral data. The H NMR spectra of compound 8 showed doublet at d 5.35 and the
coupling constant of the C-2 and C-3 hydrogen atoms showed J ¼ 4.27 Hz, which indi-
cates the two hydrogens are in anti-relation. The two ester groups of compound 8
(2S, 3R) were reduced by the LiAlH4 in dry THF to afford diol 9 (2R, 3S) in 82% yield.
The selective esterification of diol 9 (2R, 3S) with orsellinic acid was achieved in THF
under the DCC and DMAP conditions to furnish compound 10 (2R, 3S). This on
further deprotection with TsOH in MeOH afforded (þ) montagnetol 11 (2R, 3S) in
98% yield (Scheme2).
Similarly, synthesis of (ꢀ) montagnetol 15 (2S, 3R) was synthesized from diol 9
(2R, 3S). The free hydroxy groups in diol 9 were protected with 2 equivalence of benzyl
bromide in presence of sodium hydride in dry DMF solvent provided compound 12
(2R, 3S) in 92% yield, this was further deprotected with TsOH in MeOH solvent
afforded compound 13 (2S, 3R). The esterification of primary hydroxy group in diol 13
with orsellinic acid under DCC, DMAP in THF at room temperature provided com-
pound 14 (2S, 3R) in 60% yield. Finally, hydrogenolysis removed benzyl protecting
group from 14 to give (ꢀ) montagnetol 15 (2S, 3R) (Scheme 3). The structures of the
synthesized (þ) and (ꢀ) montagnetols were confirmed by physical (Table 1) and
spectral data and by comparison with literature data.[29,30]
Biology
Anti bacterial and anti fungal activity for (þ) montagnetol, along with congeners (3, 6,
and 11) were evaluated using four bacterial (P. aeruginosa, S. typhi, S. aureus, and E.

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5
Table 2. Zone of inhibition of synthetic compounds (mm).
Microorganisms
Bacterial strains
Fungal strains
Compound number
P. aeruginosa
S. typhi
S. aureus
E. coli
C. albicans
3
6
11
15
15
10
10
10
25
13
10
9
11
24
10
11
10
10
25
9
11
8
10
22
10
15
10
10
20
Streptomycin
Table 3. In vitro antibacterial and antifungal activity of montagnetol and its isomers (mg/mL).
Microorganism
Bacterial strains
Fungal strains
Compound number
P. aeruginosa
S. typhi
S. aureus
E. coli
C. albicans
3
6
11
15
0.062
0.25
0.25
0.5
0.125
0.25
0.25
0.25
0.015
0.125
0.5
0.5
0.5
0.007
0.5
0.25
0.5
0.25
0.125
0.125
0.062
0.125
0.125
0.031
Streptomycin
0.015
coli) and one yeast strain (C. albicans). Well plate method is followed for both antibac-
terial and antifungal activities evaluation by measuring the zone of inhibitions. For anti-
bacterial activity, test strains used include Escherichia coli, Salmonella typhi,
Staphylococcus aureus, and Pseudomonas aeruginosa, which were grown in nutrient
agar. For antifungal studies test strains used are Candida albicans and the medium used
is yeast extract peptone dextrose. The compounds (3, 6, 11, and 15), along with stand-
ard (Streptomycin) were used for activity studies were dissolved DMSO to get a final
concentration of 1.0 mg/ml. DMSO as such used as control. The media, petri dishes
were autoclaved at 121 ꢁC for 15 min. After sterilization the plates were poured with
appropriate medium, kept for 30 min at room temperature for solidification.[35] Later
the plates were inoculated with 60 ml of test inoculums using sterile cotton swabs. An
8 mm width size wells were made with sterile cork borer and in each well exactly 100 ml
of sample were loaded. Control and standard also placed in separate wells. The plates
were initially incubated for 20–30 min at 4 ꢁC to allow the compounds to diffuse into
the agar, and then subsequently incubated for 24 h at 37 ꢁC for bacteria and 48 h at
28 ꢁC for fungi. Zone diameters were expressed in mm using calibrated scale.
Experiment was triplicate to minimize the deviations. The bio activity profile of synthe-
sized compounds is presented in Tables 2 and 3.
It is evident from the data that limited inhibition of growth of all selected microbial
strains was observed with starting compound i.e., (þ) montagnetol. The derivatives of
montagnetol however, slightly differed with anti microbial properties. This can be evi-
denced from the fact that compound 3 revealed antibacterial activity against P. aerugi-
nosa where the zone of inhibition was noticed to be 15 mm while this compound
against S. typhi showed lesser antibacterial activity (13 mm) compared to P.aeruginosa.
There was no variation was noticed in terms of bioactivity profile with other tested
bacterial strains (S. aureus and E. coli). However, the compound 6 did not show any
inhibitory activity against all tested bacterial and revealed its effectiveness against C.

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U. V. MALLAVADHANI ET AL.
albicans. This data further suggested that configuration change of hydroxyl group at C-
2 and C-3 positions observed to be critical for certain microbial growth inhibition as
noticed that compound 6 inhibited growth of fungal strain (C. albicans) while
compound 3 did not show any effect on C. albicans. To evaluate the MIC (minimum
inhibitory concentration), the compounds were serially diluted from 500 to 1.9 mg/ml
and one tube without drug serves as control. All the tubes were inoculated with 1 ml of
respective cultures (P. aeruginosa, S. typhi, S. aureus, E. coli and C. albicans) having an
OD of 0.2 (ꢂMcFarland standard) and the tubes were incubated at 37 ꢁC for 12–16 h.
The turbidity of each tube was measured with respect to control tube. MIC values are
defined as the lowest concentration of compound at which growth is completely inhib-
ited.[36] After incubation the culture from each tube was plated in nutrient agar to
evaluate the MBC concentration. The concentration at which the cells are completely
dead was defined as minimum bactericidal concentration. The MIC and MBC, results
showed that compound 3 had very lower MIC (0.062 mg/ml) and MBC (0.125 mg/ml)
values against P. aeruginosa and C. albicans, indicating the potential nature these com-
pounds (Table 3).
Conclusions
In conclusion, we have synthesized (þ) montagnetol 11 (2R, 3S) along three of its
congeners 3 (2R, 3R), 6 (2S, 3S) and 15 (2S, 3R) from commercially available starting
materials. The synthesized compounds were evaluated for their antimicrobial
potential. Interestingly, compound 3 was found to exhibit promising anti-bacterial
against P. aeruginosa, and compound 6 displayed potent anti-fungal activity against
C. albicans. The MIC values of compounds 3 and 6 found many folds more than mon-
tagnetol. The configuration of compound 3 and 6 at C-2 and C-3 position seems to be
responsible for the enhanced anti-bacterial and anti-fungal activities.
Experimental
This includes general procedure for the synthesis of compounds. Experimental proce-
dures for the intermediate and spectral data of all compounds are presented in support-
ing information.
(2S,3R)-2,3,4-trihydroxybutyl2,4-dihydroxy-6-methylbenzoate (15)
A suspension of compound 14 (200 mg, 0.44 mmol) and 10% palladium/carbon (50 mg)
in dry ethyl acetate (5 mL) was stirred in H2 for 2 h (TLC control). The suspension was
then filtered through celite, and the filtrate was evaporated. The residue was purified by
column chromatography using chloroform and methanol get the desired compound
solid 15 (98 mg, 82%) as white colored solid; mp: 138–139 ꢁC; IR (KBr, cmꢀ1): 3372,
1
2926, 1642, 1581, 1458, 1322, 1271, 1168, 1038; H NMR (300 MHz, acetone-d6): d
11.56 (s, 1H), 9.43 (s, 1H), 6.27 (d, J ¼ 2.44 Hz, 1H), 6.22 (d, J ¼ 2.44 Hz, 1H), 4.59
(dd, J ¼ 11.49, 2.8 Hz, 1H), 4.41 (dd, J ¼ 11.49, 6.49 Hz, 2H), 4.20 (s, 1H), 3.95–3.97
(m, 2H), 3.82–3.77 (m, 1H), 3.70–3.66 (m, 2H), 2.51 (s, 3H); 13C NMR

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SYNTHETIC COMMUNICATIONSV
7
(125 MHz, acetone-d6þCDCl3): d 173.22, 166.82, 163.97, 145.31, 113.03, 106.22, 102.36,
73.67, 71.93, 68.65, 65.26, 25.39; HRMS (ESI): m/z calcd for C12H16NaO7 [M þ Na]þ
295.0788, found 295.0778.
Acknowledgements
We are thankful to Director, CSIR-IICT for support and encouragement.
Funding
We are thankful to CSIR, Government of India, New Delhi for the award of Senior Research
Fellowship to BRK.
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