Stereoselective total synthesis of (?)-pyrenophorin

Article abstract of DOI:10.1007/s11696-020-01132-2

Abstract: Stereoselective total synthesis of (?)-pyrenophorin was accomplished from commercially available starting material 2-bromo epoxide using regioselective ring opening and the intermolecular Mitsunobu cyclization as key steps. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11696-020-01132-2

Chemical Papers
https://doi.org/10.1007/s11696-020-01132-2
ORIGINAL PAPER
Stereoselective total synthesis of (−)‑pyrenophorin
Perugu Edukondalu1 · Reddymasu Sreenivasulu2 · Rudraraju Ramesh Raju1
Received: 10 September 2019 / Accepted: 11 March 2020
© Institute of Chemistry, Slovak Academy of Sciences 2020
Abstract
Stereoselective total synthesis of (−)-pyrenophorin was accomplished from commercially available starting material 2-bromo
epoxide using regioselective ring opening and the intermolecular Mitsunobu cyclization as key steps.
Graphic abstract
O
OTBS
O
O
O
OMe
O
O
S
S
Br
O
O
Keywords 2-Bromo epoxide · Regioselective ring opening · Mitsunobu cyclization · (−)-Pyrenophorin
Introduction
macrodiolide frameworks are also known to exhibit a wide
range of biological properties including antibiotic, antifun-
gal (Kis et al. 1969; Krohn et al. 2007; Nozoe et al. 1965),
anthelmintic (Kind et al. 1996; Ghisalberti et al. 2002;
Christner et al. 1998), phytotoxic (Kastanias and Chrysayi-
Tokousbalides 2000, 2005; Sugawara and Strobel 1986),
and antileukemic activities. The macrolide dilactone, pyr-
enophorin, is a good antifungal and herbicidal agent and has
been isolated from Pyrenophora avenae (Ishibashi 1961),
Stemphylium radicinum (Grove 1964; Hase et al. 1981), and
Drechslera avenae (Kastanias and Chrysayi-Tokousbalides
2005). This C2-symmetric dilactone is derived by head-to-
tail dimerization of two identical C8 units. The potent bio-
logical activities and interesting structural structural features
made an attractive target for the total synthesis of (−)-pyr-
enophorin (1) (Fig. 1), appeared to be an attractive target
for total synthesis. A number of synthetic methodologies
are reported toward the synthesis of racemic pyrenophorin
(Hase et al. 1981; Asaoka and Takei 1981; Fujisawa et al.
1982; Wakamatsu et al. 1985) and optically active pyreno-
phorin (Steliou and Poupart 1983; Hatakeyama et al. 1987;
Baldwin et al. 1992; Kobayashi et al. 1998; Furstner et al.
2001).
Macrodiolides (macrocyclic dilactones) are well represented
in nature as both homo- and heterodimers and ofer a wide
variety of skeletons, ring sizes, and functional groups (Kang
and Lee 2005).
Diferent macrodiolide lactones (Alluraiah et al. 2014;
Madala et al. 2016; Pratapareddy et al. 2017; Ashok et al.
2018; Edukondalu et al. 2015; Ramakrishna et al. 2016;
Ramanujan et al. 2017; Alluraiah et al. 2018; Pratapareddy
et al. 2019) and macrocyclic monolactones (Alluraiah et al.
2016; Pratapareddy et al. 2015; Murthy et al. 2014) were
synthesized and reported till date. Natural products with
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-020-01132-2) contains
supplementary material, which is available to authorized users.
* Reddymasu Sreenivasulu
reddymasu.msc@gmail.com
1
Department of Chemistry, Acharya Nagarjuna University,
Nagarjuna Nagar, Guntur, Andhra Pradesh 522 510, India
2
Department of Chemistry, University College of Engineering
(Autonomous), Jawaharlal Nehru Technological University,
Kakinada, Andhra Pradesh 533 003, India
Vol.:(0123456789)
1 3

Chemical Papers
Fig. 1 Structure of (−)-pyreno-
phorin (1)
2-bromoethyloxirane 4 (Larson et al. 2011) on alkylation
with 2-vinyl-1,3-dithiane 5 in dry THF gave compound 6
in 75% yield. Later, epoxide in 6 was opened regioselec-
tively with LAH in dry THF at 0 °C to room temperature
for 4 h that leads to a regioselective opening of epoxide to
provide 7 in 83% yield. Alcohol obtained in the above step
was silylated using TBSCl in the presence of imidazole in
CH2Cl2 at room temperature for 4 h to aford compound
3 in 82% yield. Olefn 3 was subjected to ozonolysis in
CH2Cl2 at − 78 °C for 15 min to give the corresponding
aldehyde 3a, which on immediate treatment with (meth-
oxycarbonylmethylene)triphenylphosphorane in benzene
at refux for 2 h furnished exclusively trans-Wittig product
8 in 86% yield. Next, hydrolysis of ester 8 using LiOH
in THF/MeOH/water (3:1:1, 20 mL) at room temperature
for 4 h aforded acid 9 in 79% yield. Further, desilylation
in 9 with TBAF in dry THF at 0 °C to room temperature
for 4 h aforded the hydroxy acid 2 in 86% yield. Having
completed hydroxy acid 2, it was aimed to cyclodimeriza-
tion under the Mitsunobu conditions according to Ger-
lach’s procedure (Gerlach et al. 1977). Thus, a reasonably
dilute solution of hydroxy acid 2 in toluene–THF (10:1)
was treated with Ph3P and DEAD at − 25 °C for 10 h. The
cyclodimerization took place with complete inversion of
chirality at C-7 to furnish 10 in 61% yield. Finally, depro-
tection of 1,3-dithiane group in compound 10 with CaCO3
and I2, in THF/H2O for 20 min, aforded the pyrenophorin
1 in 73% yield as a white solid. m.p. 171–173 °C (lit.
(Nozoe et al. 1965) m.p. 175 °C); [α]D − 57.3 (c 0.65,
acetone) [lit. (Seebach et al. 1977) [α]D − 54.5 (c 0.48,
acetone)]. The 1H and 13C NMR data and optical rotation
value of synthetic 1 were in good accordance with data
reported in the literature (Zhang et al. 2008).
Seuring and Seebach reported this synthesis through
Mitsunobu reaction followed by hydrolysis of thioketal
diolides with mercuric oxide or boron trifuoride (Seur-
ing and Seebach 1978). The reported above methods are
associated with hard reaction conditions, lower yields, and
chiral pool resources. To overcome the problems associated
with the above methods, herein, we reported another alter-
native synthetic route in an entirely diferent strategy. This
methodology involves the synthesis of 1 from inexpensive
starting material, i.e., 2-bromoethyloxirane and subsequent
regioselective ring opening and the intermolecular Mitsu-
nobu cyclization.
Results and discussion
The retrosynthetic analysis of 1 is shown in Scheme 1. The
macrolide 1 could be obtained from the hydroxy acid 2 via
cyclodimerization under the Mitsunobu reaction conditions
followed by a deprotection of 1,3-dithiane. Hydroxy acid
could be achieved from olefn 3, while the olefn 3 could
be prepared by the coupling of 2-vinyl-1,3-dithiane 5 with
bromo epoxide 4.
The stereoselective total synthesis of (−)-pyrenophorin
is shown in Scheme 2. From the retrosynthesis, the known
Scheme 1 Retrosynthetic analysis of (−)-pyrenophorin
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Chemical Papers
OH
O
O
n
5, -BuLi
LAH
Br
S
S
S
S
dry THF, -78 oC to -20 oC
3 h
dry THF, 0 oC - rt, 4 h
4
6
7
OTBS
OTBS
TBSCl, Imidazole
CH2Cl2, rt, 4 h
O3, CH2Cl2
-78 oC, 15 min
CHO
S
Ph3P=CHCOOMe
Benzene, reflux, 2 h
S
S
S
3a
3
OTBS
O
OTBS
O
LiOH
TBAF
THF, 0 oC to rt, 3 h
OMe
OH
OH
S
S
THF:MeOH:H2O (3:1:1)
rt, 4 h
S
S
8
9
S
S
S
S
OH
O
O
Ph3P, DEAD
toluene:THF (10:1) -25 oC
10 h
CaCO3, I2
O
O
S
S
THF:H2O (4:1), 0 oC.
O
2
10
O
O
O
O
O
O
1
Scheme 2 Stereoselective total synthesis of (−)-pyrenophorin
(R)‑2‑(2‑(2‑Vinyl‑1,3‑dithian‑2‑yl)ethyl)oxirane (6)
Experimental section
To a stirred solution of 2-vinyl dithiane (4.7 g, 32.22 mmol)
in dry THF (30 mL) cooled at −78 °C was added a 1.6 M
solution of n-BuLi in hexane (21.8 mL, 34.86 mmol) drop-
wise. The reaction mixture was stirred at −20 °C for 1.5 h.
After cooling to − 78 °C, a solution of bromide 4 (4.0 g,
26.84 mmol) in THF (10 mL) was added dropwise, and
the mixture was kept at −30 °C for 2 h. The reaction was
quenched with water (30 mL), and the mixture was extracted
with Et2O (2×50 mL). The combined extracts were washed
with brine (30 mL), dried (Na2SO4), and concentrated. The
residual oil was purifed by column chromatography on sil-
ica gel chromatography (60–120 silica gel, 10% EtOAc in
pet. ether) to give 6 (4.27 g, 75%) as a colorless oil. 1HNMR
(200 MHz, CDCl3): δ 5.84 (m, 1H), 5.01–4.93 (m, 2H),
3.01–2.90 (m, 1H), 2.83–2.70 (m, 4H), 2.66 (dd, 1H, J=2.7,
General
All the chemical reagents and solvents were supplied by
Sigma-Aldrich and AVRA, India. The solvents were fur-
ther purifed by using basic purifcation techniques. The
progress of the chemical reactions was monitored by TLC
plates supplied by Merck Company. H and 13C NMR
1
spectra were recorded on Bruker spectrometer at 300 and
150/75 MHz, respectively. Chemical shifts and coupling
constants are reported in δ units and Hertz, respectively.
Diferent multiplicities such as singlet, doublet, double
doublet, triplet, quadruplet, and multiplet were indicated
by s, d, dd, t, q, and m. Mass values are noted as ESIMS.
A digital polarimeter was used to measure the optical rota-
tion values at 25 °C.
1 3

Chemical Papers
5.1 Hz), 2.44 (dd, 1H, J=2.7, 4.9 Hz), 2.04–1.88 (m, 2H),
1.73–1.61 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 137.2,
121.3, 65.1, 55.9, 46.3, 37.3, 30.1, 27.3, 24.6; ESIMS: 239
(M+Na)+.
Solution of the above aldehyde 3a in benzene (50 mL)
was treated with (methoxycarbonylmethylene)triphenylphos-
phorane (4.52 g, 13.03 mmol) at refux temperature. After
2 h, solvent was evaporated and the residue was purifed by
column chromatography (60–120 silica gel, 10% EtOAc in
pet. ether) to furnish 8 (3.62 g, 86%) as a yellow liquid.[α]D
−48.6 (c 1.0, CHCl3); 1HNMR (200 MHz, CDCl3): δ 6.96
(d, 1H, J= 15.2 Hz), 6.19 (d, 1H, J= 15.2 Hz), 3.86–3.74
(m, 1H), 3.73 (s, 3H), 2.97–2.72 (m, 4H), 2.12–1.57 (m,
6H), 1.12 (d, 3H, J = 6.3 Hz), 0.89 (s, 9H), 0.26 (s, 3H),
0.12 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.9, 150.3,
122.8, 69.3, 53.9, 40.1, 37.3, 33.4, 27.2, 25.9, 24.8, 23.8,
18.2, −4.3, −4.6; ESIMS: 413 (M+Na)+.
(S)‑4‑(2‑Vinyl‑1,3‑dithian‑2‑yl)butan‑2‑ol (7)
To a stirred suspension of LAH (0.68 g, 28.47 mmol) in
dry THF (5 mL), a solution of 6 (4.1 g, 18.98 mmol) in dry
THF (10 mL) was added dropwise at 0 °C under a nitrogen
atmosphere and the mixture was stirred for 4 h at room tem-
perature. The reaction mixture was cooled to 0 °C, treated
with saturated aq. Na2SO4 solution, and fltered, and the fl-
trate was dried (Na2SO4) and concentrated. The residue was
purifed by column chromatography (60–120 silica gel, 18%
EtOAc in pet. ether) to give 7 (3.42 g, 83%) as a colorless
(S, E)‑3‑(2‑(3‑(tert‑Butyldimethylsilyloxy)
butyl)‑1,3‑dithian‑2‑yl)acrylic acid (9)
1
syrup. [α]D + 28.1 (c 0.49, CHCl3); HNMR (200 MHz,
CDCl3): δ 5.79 (m, 1H), 4.99–4.87 (m, 2H), 3.72–3.60
(m, 1H), 2.91–2.80 (m, 4H), 2.26 (brs, 1H), 1.94–1.77 (m,
2H), 1.73–1.57 (m, 4H), 1.11 (d, 3H, J=6.0 Hz); 13C NMR
(75 MHz, CDCl3) δ 136.9, 120.8, 71.3, 55.8, 36.9, 34.3,
27.2, 24.2, 23.3; ESIMS: 219 (M+H)+.
To a solution of 8 (1.5 g, 3.84 mmol) in THF/MeOH/water
(3:1:1, 20 mL), LiOH (0.27 g, 11.53 mmol) was added
and stirred at room temperature for 4 h. The pH of reac-
tion mixture was adjusted to acidic with 1 N HCl solution
and extracted with ethyl acetate (30 mL). Organic layers
were washed with water (15 mL) and brine (15 mL), dried
(Na2SO4), and evaporated under reduced pressure, and the
residue was purifed by column chromatography (60–120
silica gel, 30% EtOAc in pet. ether) to give 9 (1.14 g, 79%)
(S)‑tert‑Butyldimethyl(4‑(2‑vinyl‑1,3‑dithian‑2‑yl)
butan‑2‑yloxy)silane (3)
1
A mixture of the above alcohol 7 (3.2 g, 14.67 mmol) and
imidazole (2.99 g, 44.03 mmol) in dry CH2Cl2 (50 mL) was
treated with TBSCl (2.40 g, 16.06 mmol) at 0 °C under a
nitrogen atmosphere and stirred at room temperature for 4 h.
The reaction mixture was quenched with aq. NH4Cl solution
(30 mL) and extracted with CH2Cl2 (2×50 mL). The com-
bined extracts were washed with water (30 mL) and brine
(30 mL), dried (Na2SO4), and concentrated. The residue was
purifed by column chromatography (60–120 silica gel, 5%
EtOAc in pet. ether) to furnish 3 (3.99 g, 82%) as a colorless
as a colorless oil. [α]D + 14.6 (c 0.6, CHCl3); H NMR
(CDCl3, 300 MHz): δ 7.03 (d, 1H, J = 15.6 Hz), 6.22
(d, 1H, J = 15.6 Hz), 3.80–3.72 (m, 1H), 2.92–2.80 (m,
4H), 2.06–1.88 (m, 3H), 1.81–1.64 (m, 3H), 1.11 (d, 3H,
J = 6.0 Hz), 0.88 (s, 9H), 0.22 (s, 3H), 0.11 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 171.3, 152.6, 122.7, 68.7, 53.0,
37.3, 33.7, 27.1, 25.9, 23.8, 18.2, −4.4, −4.6; ESIMS: 399
(M+Na)+.
(S, E)‑3‑(2‑(3‑Hydroxybutyl)‑1,3‑dithian‑2‑yl)acrylic
acid (2)
1
liquid. [α]D + 82.6 (c 0.55, CHCl3); H NMR (300 MHz,
CDCl3): δ 5.87 (m, 1H), 5.11–4.92 (m, 2H), 3.77–3.62 (m,
1H), 2.87–2.73 (m, 4H), 1.95–1.80 (m, 3H), 1.72–1.61 (m,
3H), 1.12 (d, 3H, J=6.2 Hz), 0.87 (s, 9H), 0.19 (s, 3H), 0.06
(s, 3H);13C NMR (75 MHz, CDCl3): δ 136.4, 120.7, 72.1,
55.8, 38.3, 35.9, 27.3, 26.0, 24.1, 23.8, 18.3, −4.2, −4.7;
ESIMS: 355 (M+Na)+, 333 (M+H)+.
To a cooled (0 °C) solution of 9 (1.0 g, 2.65 mmol) in dry
THF (10 mL) under nitrogen atmosphere, TBAF (3.9 mL,
3.98 mmol) was added and stirred for 3 h. After completion
of reaction, reaction mixture was diluted with water (5 mL)
and extracted with ethyl acetate (2×50 mL). Organic lay-
ers were washed with water (2×10 mL) and brine (10 mL),
dried (Na2SO4), and evaporated, and the residue was purifed
by column chromatography (60–120 silica gel, 55% EtOAc
in pet. ether) to give 2 (0.59 g, 86%) as a liquid. [α]D −62.6
(S, E)‑Methyl 3‑(2‑(3‑(tert‑butyldimethylsilyloxy)
butyl)‑1,3‑dithian‑2‑yl)acrylate (8)
1
Ozone was bubbled through a cooled (−78 °C) solution of
3 (3.6 g, 10.84 mmol) in CH2Cl2 (40 mL) until the pale
blue color persisted. Excess ozone was removed with Me2S
(4 mL) and stirred for 15 min at 0 °C. The reaction mixture
was concentrated under reduced pressure to give aldehyde
3a, which was used for further reaction.
(c 1.0, CHCl3); H NMR (CDCl3, 300 MHz): δ 7.01 (d,
1H, J=15.8 Hz), 6.19 (d, 1H, J=15.8 Hz), 3.91–3.79 (m,
1H), 2.91–2.76 (m, 4H), 1.99–1.83 (m, 2H), 1.71–1.53 (m,
4H), 1.21 (d, 3H, J=6.1 Hz); 13C NMR (CDCl3, 75 MHz):
δ171.0, 152.1, 123.1, 68.3, 53.2, 37.3, 33.4, 27.2, 25.3, 23.4;
ESIMS: 285 (M+Na)+.
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Chemical Papers
(−)-Cephalosporolide D. Monatsh Chem 147(2):451–455. https
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Macrodilactone (10)
Alluraiah G, Sreenivasulu R, Chandrasekhar C, Raju RR (2018) An
alternative stereoselective total synthesis of (−)-pyrenophorol.
Nat Prod Res. https://doi.org/10.1080/14786419.2018.1499636
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A solution of 2 (0.5 g, 1.90 mmol) and Ph3P (2.49 g,
9.54 mmol) in toluene/THF (10:1, 750 mL) DEAD (3.6 mL,
34.21 mmol) was added at − 25 °C and stirred under N2
atmosphere for 10 h. Solvent was evaporated under reduced
pressure, and the residue was purifed by column chromatog-
raphy (60–120 silica gel, 10% EtOAc in pet. ether) to aford
10 (0.28 g, 61%) as a colorless oil. [α]D-15.7 (c1.03, CHCl3);
1H NMR (CDCl3, 300 MHz): δ 6.81 (d, 2H, J=15.1 Hz),
6.20 (d, 2H, J=15.1 Hz), 5.20–5.09 (m, 2H), 3.03–2.82 (m,
8H), 2.02–1.61 (m, 12H), 1.21 (d, 6H, J=6.1 Hz); 13C NMR
(75 MHz, CDCl3) δ 165.1, 149.2, 124.7, 69.0, 53.2, 34.7,
28.1, 26.9, 25.2, 18.1; ESIMS: 489 (M+H)+.
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(2018) Stereoselective total synthesis of (−)-Pyrenophorol. Chem
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Pyrenophorin (1)
To a solution of compound 10 (0.2 g, 0.40 mmol) and
CaCO3 (0.40 g, 4.09 mmol) in THF/H2O (v/v, 4:1, 10 mL)
was added I2 (0.30 mg, 1.22 mmol) at 0 °C. The result-
ing mixture was stirred at 0 °C for 20 min. The reaction
was quenched by adding saturated aqueous Na2S2O3, fl-
tered through a pad of Celite, then extracted with EtOAc
(3 × 20 mL), water, and brine, dried over Na2SO4, and
concentrated in vacuo. Purifcation by fash chromatog-
raphy on silica gel (60–120 silica gel, 15% EtOAc in pet.
ether) gave compound 1 (92 mg, 73% yield: [α]D −57.3 (c
0.65, acetone); 1H NMR (400 MHz, CDCl3): δ 6.94 (d, 2H,
J=16.1 Hz), 6.48 (d, 2H, J=16.1 Hz), 5.03 (m, 2 H), 2.67
(ddd, 2H, J = 14.1, 8.7, 3.8 Hz), 2.54 (ddd, 2H, J= 14.1,
8.2, 3.8 Hz), 2.14 (m, 2 H), 2.08 (m, 2 H), 1.27 (d, 6H,
J = 6.4 Hz); 13C NMR (75 MHz, CDCl3): δ 199.4, 164.7,
139.7, 131.3, 72.1, 37.4, 32.1, 19.7; ESIMS: 309 (M+H)+.
Fujisawa T, Takeuchi M, Sato T (1982) A short-step synthesis of
( )-pyrenophorin utilizing 3-alkenoate as a masked synthon
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Conclusion
The stereoselective synthesis of pyrenophorin 1 was
achieved from known 2-bromoethyloxirane using regi-
oselective ring opening and the intermolecular Mitsunobu
cyclization as key steps by overcoming the less yield and
hard reaction conditions of earlier reported methods.
Kang EJ, Lee E (2005) Total synthesis of oxacyclic macrodiolide natu-
ral products. Chem Rev 105:4348–4378. https://doi.org/10.1021/
cr040629a
Kastanias MA, Chrysayi-Tokousbalides M (2000) Herbicidal potential
of pyrenophorol isolated from a Drechslera avenae pathotype.
Pest Manag Sci 56:227–232
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