Total syntheses of surinone B, alatanones A–B, and trineurone A

Article abstract of DOI:10.1080/10286020.2018.1460362

The total syntheses of four polyketides, surinone B (1), alatanones A–B (2–3), and trineurone A (4) were accomplished through an efficient and unified strategy via one-pot C-acylation reaction coupling 1,3-cyclohexadiones with EDC-activated acids under mild conditions. Alatanone A (2) was found to be a potent anti-microbial agent against Gram-positive and Gram-negative bacteria with MIC 31.25?μg/ml while alatanone B (3) was found to be a potent anti-fungal agent against Cladosporium cladosporioides with MIC 62.5?μg/ml compared to cycloheximide MIC 125?μg/ml. Our methodology allows performing kilogram scale of these scarce polyketides for the development of new antimicrobials.

Full text of DOI:10.1080/10286020.2018.1460362

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: http://www.tandfonline.com/loi/ganp20
Total syntheses of surinone B, alatanones A–B, and
trineurone A
Narayana Rao Gundoju, Ramesh Bokam, Nageswara Rao Yalavarthi,
Sudheer Kumar Buddana, R. S. Prakasham & Mangala Gowri Ponnapalli
To cite this article: Narayana Rao Gundoju, Ramesh Bokam, Nageswara Rao Yalavarthi, Sudheer
Kumar Buddana, R. S. Prakasham & Mangala Gowri Ponnapalli (2018): Total syntheses of
surinone B, alatanones A–B, and trineurone A, Journal of Asian Natural Products Research, DOI:
10.1080/10286020.2018.1460362
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Journal of asian natural Products research, 2018
https://doi.org/10.1080/10286020.2018.1460362
Total syntheses of surinone B, alatanones A–B, and
trineurone A
Narayana Rao Gundojua, Ramesh Bokama, Nageswara Rao Yalavarthia, Sudheer
Kumar Buddanab, R. S. Prakashamb and Mangala Gowri Ponnapallia
adepartment of natural Products chemistry, indian institute of chemical technology, hyderabad, india;
bdepartment of Medicinal chemistry & Biotechnology, indian institute of chemical technology, hyderabad,
india
ABSTRACT
ARTICLE HISTORY
received 5 June 2017
accepted 30 March 2018
The total syntheses of four polyketides, surinone B (1), alatanones A–B
(2–3), and trineurone A (4) were accomplished through an efficient
and unified strategy via one-pot C-acylation reaction coupling
1,3-cyclohexadiones with EDC-activated acids under mild conditions.
Alatanone A (2) was found to be a potent anti-microbial agent against
Gram-positive and Gram-negative bacteria with MIC 31.25 μg/ml
while alatanone B (3) was found to be a potent anti-fungal agent
against Cladosporium cladosporioides with MIC 62.5 μg/ml compared
to cycloheximide MIC 125 μg/ml. Our methodology allows performing
kilogram scale of these scarce polyketides for the development of
new antimicrobials.
KEYWORDS
Polyketides; surinone B;
alatanones a–B; trineurone
a; c-acylation; antimicrobial
screening
1. Introduction
Polyketides represent a unique group of natural products with vast structural diversity
and promising biological profiles as a vital source of therapeutics including antibiotics,
CONTACT Mangala Gowri Ponnapalli
mangala@iict.res.in, pmgowri@yahoo.com
supplemental data for this article can be accessed https://doi.org/10.1080/10286020.2018.1460362.
© 2018 informa uK limited, trading as taylor & francis Group

2
N. R. GUNDOJU ET AL.
Figure 1. structures of surinone B, alatanones (a–B), and trineurone a.
immunosuppresants, antiparasitics, antitumorals, cholesterol-lowering agents [1–3], and
chemical messengers [4–6]. ese metabolites are also known as 2-acyl-1, 3-cyclo hexadi-
ones, which are found in bacteria, fungi, plants belonging to Piperaceae, and protists [7].
Piperaceae is a basal angiosperm family consisting of more than 4000 species distributed in
five genera, Piper, Peperomia, Zippelia, Manekia, and Verhuellia [8]. Peperomia genus was
found to be the second most abundant source of bioactive metabolites although few studies
were carried out due to its predominant ornamental use within Piperaceae [9]. ese aro-
matic polyketides are scarce in nature and continue to attract attention within the chemical
community since they have also provided the basis for many important pharmaceuticals of
enormous commercial value [10].
Surinone B (1), alatanones A–B (2–3), and trineurone A (4) are naturally occurring aro-
matic polyketides from Peperomia sui. [11]. P. alata and P. trineura [12], respectively (Figure
1). Of these aromatic polyketides, alatanone A, the most potent and prevalent congener,
demonstrated remarkable anti-fungal activity [13–15]. Notable biological activities of these
compounds attracted us to synthesize target compounds. As part of our ongoing program
on the synthesis of bioactive constituents, we herein report the total syntheses of surinone
B (1), alatanones A–B (2–3), and trineurone A (4) based on a unified strategy utilizing
C-acylation reaction coupling 1,3-cyclohexadiones with N-(3-Dimethylaminopropyl)-N′-
ethylcarbodiimide hydrochloride (EDC) activated acid as key step. In addition, antimicro-
bial activities of these metabolites were also reported. Retrosynthetic analysis of the target
compounds is depicted in Scheme 1.
2. Results and discussion
Our synthetic studies on polyketides (1–4) were based on a strategy of C-acylation reaction
coupling 1, 3-cyclohexadione with EDC-activated acids under mild conditions. As shown
in Scheme 2, we thought that the target compounds (1–4) might be synthesized from com-
mercially available starting materials. First, we strongly preferred coupling 5 with 6–9 in a
one-pot procedure with minimal handling of a reagent, which includes the ease of reaction
workup and product purification. Only few patents related to the acylation of 1,3-diones
with carboxylic acids activated by N,N′-Dicyclohexylcarbodiimide (DCC) as coupling agent
have been reported in the literature so far [16]. It was also employed for the C-acylation
of Meldrum’s acids, tetronic acids, and β-keto-δ-valerolactones [17]. e combination of
DCC, triethylamine, and 4-N, N-dimethylaminopyridine (DMAP) in dichloromethane
(DCM) was reported by Conclaves et al. We attempted to synthesize polyketides (1–4) by
this method, which resulted in 30% yield. Moreover, this reagent (and its dicyclohexylurea

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Scheme 1. retrosynthetic analysis of surinone B (1), alatanones a–B (2–3), and trineurone a (4).
Scheme 2. synthetic route of acid 7 and 8. reagents and conditions: (a) tBscl, imidazole, ch2cl2, rt 88/
90%; (b) (i) (cocl)2, dMso, et3 n, ch2cl2, −78 °c (ii) diethylbenzylphosphonate, nah, thf, 60 °c, 2 h. (80%
over 2 steps); (c) csa, Meoh, 2 h, rt, 88%; (d) BaiB, teMPo, acetonitrile:water (3:1), 14 h. rt, 90/95%.
byproduct) can be difficult to purge without chromatography and poses significant handling
concerns. We then explored the scope of coupling with EDC, another carbodiimide, which
has an amino side chain that allows for its easy extraction from reaction mixtures during
workup under mild conditions. Recently Alexander et al. reported syntheses of polyket-
ides (2–4) of same origin using EDC, DMAP in toluene at 80 °C following Claisen–Hasse
rearrangement [18]. Our methodology allows simple C-acylation under mild conditions
using EDC, DMAP, triethylamine, DCM at room temperature without Claisen–Hasse rear-
rangement, which is much easier to perform kilogram scale of these scarce polyketides for
development of new antimicrobials.
As shown in Scheme 2, polyketides (1/2/4) were prepared from commercially available
diol (10/11), which was mono protected as a TBS ether (14/15) under solvent dilution in
order to avoid diprotection and then oxidized to the corresponding aldehyde with oxalyl
chloride by Swern oxidation. e resulting aldehyde was transformed into olefin (16/17)
by Wittig olefination with NaH and diethyl benzyl phosphonate [19]. Further TBS group
was deprotected with (+)-camphor 10-sulfonic acid (CSA), to the corresponding alco-
hol (18/19), in 60% yield and subsequent oxidation of the alcohol to the acid (7/8) using

4
N. R. GUNDOJU ET AL.
Scheme 3. synthetic route of acid 6. reagents and conditions: (i) Pd/c, etoac, 4 h, 90% (j) (a) (cocl)2,
dMso, et3 n, ch2cl2, −78 °c; (b) c2h5ocochPPh3, toluene, 60 °c 88% (k) nicl2.6h2o, naBh4, Meoh, rt,
5 min 89%; (l) lioh.h2o, thf: h2o (3:1), overnight 92%.
Scheme 4. synthetic route of acid 9. reagents and conditions: (e) ch2i2, K2co3, dMf, 80 °c, 2 h, 97%; (f)
c2h5ocochPPh3, toluene, 60 °c, 86%; (g) nicl2.6h2o, naBh4, Meoh, rt 5 min 95%; (h) lioh.h2o, thf: h2o
(3:1), overnight 93%.
Diacetoxyiodobenzene (BAIB) (2, 2, 6, 6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) in water
and acetonitrile (1:3) [20].
Surinone B (1) was synthesized from styrenyl alcohol (18). e complete synthetic route
was outlined in Scheme 3. Upon catalytic hydrogenation of compound 18 afforded long
chain aryl alcohol (20) in 89% yield. is was oxidized to the corresponding aldehyde with
oxalyl chloride by Swern oxidation. e resulting aldehyde was transformed into aromatic
long chain unsaturated ester (21) in 70% yield, which was accomplished by heating alde-
hyde with C2 Wittig salt at 60 °C for 2 h. Further, subsequent reduction of unsaturated ester
(21) with NaBH4 in the presence of NiCl2 .6H2O at room temperature for 5 min afforded
saturated ester [21] (22) in 85% yield followed by hydrolysis with LiOH. H2O furnished
the required acid (6) in 90% yield.
Alatanone B (3) was prepared from the commercially available 3, 4-di hydroxy benza-
ldehyde (13). e complete synthetic route was outlined in Scheme 4. e methlenedioxy
group was introduced by the treatment of 13 with diiodomethane and K2CO3 at 80 °C for
5 h and this resulted in 3, 4-methylene dioxy benzaldehyde [22] (23) in 80% yield. Required
acid (9) in 90% yield was obtained following the same procedure as mentioned in Scheme 3.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
Scheme 5. synthetic route of compounds 1–4. reagents and conditions: (m) edc. hcl, dMaP, et3 n, dcM,
rt.,16 h, 89–95%.
Table 1. antimicrobial activity of compounds (1–4).
Gram-positive bacteria
Gram-negative bacteria
Fungus
Lysinobacillus
sp.
Bacillus circu-
lans
Pseudomonos
putida
Xanthomonas
campestris
Salmonella
paratyphi
Cladosporium
cladosporoides
Com-
pounds
ZI
MIC
ZI
MIC
ZI
MIC
ZI
MIC
ZI
MIC
ZI
MIC
surinone
B (1)
alatanone
a (2)
alatanone
B (3)
trineurone
a (4)
13
250.00
12
250.00
14
125.00
11
250.00
12
24
18
11
250.00
14
250.00
28
19
11
31.25
62.50
24
18
11
31.25
62.50
24
17
14
31.25
21
11
13
31.25
125.00
250.00
31.25
62.50
20
23
12
125.00
62.50
125.00
125.00
250.00
250.00
250.00
500.00
ampicillin
cyclohex-
imide
25
NA
31.25
NA
25
NA
31.25
NA
25
NA
31.25
NA
24
NA
31.25
NA
27
NA
31.25 NA
NA 19
NA
125.00
Zi – zone of inhibition in millimeter; Mic – minimum inhibition concentration in μg/ml.
Finally surinone B (1), alatanones A–B (2–3), and trineurone A (4) were obtained through
C-acylation reaction coupling EDC-activated acid (6–9) with 1,3-cyclohexadione (5) using
EDC. HCl at room temperature (Scheme 5). e physical and spectroscopic data of 1–4
were identical with those reported for polyketides isolated from Peperomia species [11,12].
Antimicrobial activity profile of synthesized polyketides (1–4) was evaluated against
two Gram-positive (Lysinobacillus sp. and Bacillus circulans), three Gram-negitive bacteria
(Pseudomonos putida, Xanthomonos campestris, and Samonella paratyphi), and a fungal
strain (Cladosporium cladosporioides) by agar well plate method (zone of inhibition) and
tube dilution method for determining the minimum inhibitory concentration. e data
are summarized in Table 1. Antimicrobial activity results based on zone of inhibition data
indicated that compound 2 was effective for bacterial strains while compound 3 was potent
for fungal growth inhibition (see Table 1). Preliminary observation based on MIC indicated

6
N. R. GUNDOJU ET AL.
that alatanone A (2) and alatanone B (3) exhibited significant antimicrobial activity com-
pared to surinone B (1) and trineurone A (4).
In conclusion, we have synthesized four related polyketides by coupling different aromatic
long chain organic acids with cyclohexa-1, 3-dione using activated EDC in one pot. Our
results suggested that the length of the spacer exerted a major impact on antimicrobials.
3. Experimental
3.1. General experimental procedures
All reagents and solvents were purchased from Sigma-Aldrich or commercial grade suppli-
ers (Merck & Co., Hyderabad, India) and used as received. e IR spectra were recorded on
a Nicolet-740 FT-IR spectrophotometer (ermo Scientific, Hyderabad, India). e NMR
spectra were recorded with Bruker Avance (300 MHz), and Bruker Avance (500 MHz),
1
(Bruker, Hyderabad, India), for H, and 75/125 MHz for 13C NMR spectra in CDCl3
with TMS as internal standard. Coupling constants are given in Hz. e ESIMS (Agilent
Technologies, Hyderabad, India) data were recorded on an Agilent 1100 MSD with ESI SL
Trap. e HR-ESIMS (Agilent Technologies, Hyderabad, India) data were acquired on an
Agilent 6510 Q-TOF and ESI probe.
3.2. 3-Hydroxy-2-(13-phenyltridecanoyl)-2-cyclohexen-1-one (1)
To the acid compound (6) (100 mg, 0.57 mmol), EDC.HCl (216 mg, 1.1 mmol), Et3 N
(0.2 ml, 1.5 mmol), and catalytic amount of DMAP were added successively to a solution
of the 1, 3 cyclohexadione (1.2 mmol) in DCM and the reaction mixture was stirred for
16 h. e reaction mixture was diluted with DCM, washed with water and brine, dried over
anhydrous Na2SO4, and filtered. e filtrate was concentrated under vacuum. e residue
was purified through silica gel column chromatography (60–120 mesh) to afford the desired
pure product (1) in 74% yield. IR (KBr): νmax 2923, 2852, 1669, 1585, 1462, 760 cm−1. 1H
NMR (400 MHz, CDCl3, TMS): δ 18.27 (brs, 1H), 7.28–7.25 (m, 2H), 7.18–7.15 (m, 3H),
3.0 (t, 2H, J = 7.6 Hz), 2.67–2.64 (t, 2H, J = 6.4 Hz), 2.61–2.58 (t, 2H, J = 7.6 Hz), 2.49–2.46
(t, 2H, J = 6.4 Hz), 1.99–1.94 (quint, 2H, J = 6.4 Hz), 1.63–1.58 (quint, 4H, J = 7.6 Hz), 1.25
(brs,16H). 13CNMR (100 MHz, CDCl3, TMS): δ 206.3, 198.6, 195.2, 142.9, 128.3, 128.3,
128.1, 128.1, 125.4, 113.0, 40.6, 38.8, 35.9, 33.3, 31.5, 29.7, 29.6, 29.6, 29.5, 29.4, 29.4, 29.3,
24.7, 19.0. HR-ESI-MS: m/z 407.2547 [M + Na]+ (calcd for C25H36O3Na, 407.2557).
3.3. 3-Hydroxy-2-(5′-phenylpent-4′E-enoyl)-2-cyclohexen-1-one (2)
e title compound was prepared by the reaction of compound (7) as described above to
furnish 2 [18] as yellow oil in 82% yield. IR (KBr): 3447, 2923, 2853, 1735, 1610, 763 cm−1.
1H NMR (300 MHz, CDCl3, TMS): δ 18.14 (brs, 1H), 7.35–7.17 (m, 5H), 6.47–6.41 (d, 1H,
J = 16.1 Hz), 6.31–6.21 (dt, 1H, J = 15.7, 6.9 Hz), 3.21–3.25 (t, 2H, J = 7.3 Hz), 2.69–2.65 (t,
2H, J = 6.2 Hz), 2.58–2.54 (t, 2H, J = 6.9 Hz), 2.51–2.47 (t, 2H, J = 6.6 Hz), 1.93–2.02 (quint,
2H, J = 6.6 Hz). 13C NMR (125 MHz, CDCl3, TMS): δ 205.2, 198.1, 195.3, 137.4, 130.6, 129.0,
128.4, 126.9, 125.9, 113.1, 40.4, 38.7, 33.0, 27.7, 19.0; HR-ESI-MS: m/z 293.1156 [M + Na]+
(calcd for C17H18O3Na, 293.1148).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
3.4. 3-Hydroxy-2-(3′-phenyl-6′-methylenedioxypropanoyl)-2-cyclohexen-1-one (3)
e title compound was prepared by the reaction of compound (9) as described above to
furnish 3 [18] as yellow amorphous solid in 80% yield. IR (KBr): 3449, 2923, 1661, 1599,
1568, 1494, 1442, 1245, 1038, 770 cm−1. 1H NMR (300 MHz, CDCl3, TMS): δ 18.10 (s, 1H),
6.77–6.68 (m, 3H), 5.91 (s, 2H), 3.33–3.28 (t, 2H, J = 7.7 Hz), 2.88–2.83 (t, 2H, J = 7.7 Hz),
2.69–2.65 (t, 2H, J = 6.2 Hz), 2.51–2.49 (t, 2H, J = 6.9 Hz), 2.02–1.93 (quint, 2H, J = 6.6 Hz).
13C NMR (100 MHz, CDCl3, TMS): δ 204.8, 198.2, 195.3, 147.3, 145.6, 134.6, 121.1, 112.9,
108.9, 108.0, 100.6, 42.7, 38.5, 32.9, 30.0, 18.9. HR-ESI-MS: m/z 311.0900 [M + Na]+ (calcd
for C16H16O5Na, 311.0890).
3.5. 3-Hydroxy -2-(11′-phenylundec-10′E-enoyl)-2-cyclohexen-1-one (4)
e title compound was prepared by the reaction of compound (8) as described above to
furnish 4 [18] as yellow oil in 78% yield. IR (KBr): 3448, 2925, 2854, 1661, 1606, 767 cm−1.
1H NMR (300 MHz, CDCl3, TMS): δ 18.28 (s, 1H), 7.35–7.15 (m, 5H), 6.40–6.34 (d, 1H,
J = 15.7), 6.27–6.15 (dt, 1H, J = 6.6, 15.7 Hz) 3.04–2.99 (t, 2H, J = 7.3 Hz) 2.63–2.68 (t, 2H,
J = 6.2 Hz), 2.46–2.50 (t, 2H, J = 6.2 Hz), 2.23–2.16 (q, 2H, J = 6.9 Hz) 1.97 (q, 2H, J = 6.2 Hz),
1.61 (q, 2H, J = 6.6 Hz), 1.46 (m, 2H), 1.33 (s, 8H). 13C NMR (125 MHz, CDCl3, TMS):
δ 206.3, 198.6, 195.3, 137.9, 131.2, 129.6, 128.4, 126.6, 125.8, 113.0, 40.6, 38.8, 33.3, 33.0,
31.9, 31.4, 30.1, 29.7, 29.4, 29.1, 24.6, 22.7, 19.1, 14.1. HR-ESI-MS: m/z 377.2077 [M + Na]+
(calcd for C23H30O3Na, 377.2087).
Acknowledgement
We are thankful to director, Dr. S. Chandrasekhar, IICT for constant support and UGC for awarding
SRF to NRG.
Funding
is work was supported by Dr. S. Chandrasekhar, IICT.
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