Stereoselective total synthesis of (?)-pyrenophorol

Article abstract of DOI:10.1007/s11696-017-0331-4

Abstract: A simple and efficient stereoselective synthesis of macrodilactone of (?)-pyrenophorol (1) has been accomplished in 12 steps in 8.3% overall yield, from inexpensive and commercially available (S)-ethyl lactate. This convergent synthesis utilizes an oxidation–reduction protocol and cyclodimerisation under the Mitsunobu reaction conditions as key steps.

Full text of DOI:10.1007/s11696-017-0331-4

Chem. Pap.
DOI 10.1007/s11696-017-0331-4
ORIGINAL PAPER
Stereoselective total synthesis of (−)‑pyrenophorol
Dongamanti Ashok1 · Sridhar Pervaram1 · Venkata Ramana Reddy Chittireddy2 ·
Sreenivasulu Reddymasu3 · Naresh Kumar Vuppula4
Received: 28 May 2017 / Accepted: 30 October 2017
© Institute of Chemistry, Slovak Academy of Sciences 2017
Abstract A simple and efcient stereoselective synthesis
of macrodilactone of (−)-pyrenophorol (1) has been accom-
plished in 12 steps in 8.3% overall yield, from inexpensive
and commercially available (S)-ethyl lactate. This conver-
gent synthesis utilizes an oxidation–reduction protocol and
cyclodimerisation under the Mitsunobu reaction conditions
as key steps.
Introduction
Macrolide molecules are large lactone ring compounds and
derived by the internal esterifcation from the corresponding
hydroxy acids (Collins 1999). Macrodiolides and macrocy-
clic monolactones are two types of macrolides. Research-
ers across the universe concentrate on the synthesis of both
these types of macrocyclic dilactones (Alluraiah et al. 2014;
Madala et al. 2016; Ramakrishna et al. 2016; Pratapareddy
et al. 2017; Ramanujan et al. 2017) and macrocyclic monol-
actones (Murthy et al. 2014; Pratapareddy et al. 2015; Allu-
raiah et al. 2016).
Graphical Abstract
OH
OTBS
O
O
OH
CO2Et
OMe
O
O
OMOM
O
Macrodiolides belong to one relatively small but inter-
esting class of natural products which can be isolated from
various fungi and marine sponges, exhibiting many difer-
ent bioactivities. Macrocyclic dilactones (macrodiolides)
are well-represented in nature as both homodimers such
as pyrenophorol (Kis et al. 1969; Grove 1971; Kind et al.
1996; Kastanias and Chrysayi-Tokousbalides 2000; Ghisal-
berti et al. 2002; Krohn et al. 2007), pyrenophorin (Nozoe
et al. 1965; Grove 1971), tetrahydropyrenophorol (Krohn
et al. 2007), vermiculin (Findlay et al. 2003) and heterodi-
mers, it includes colletodiol (Grove et al. 1966; MacMillan
and Pryce 1968; Powell and Whalley 1969; MacMillan and
Simpson 1973) and grahamimycin A1 (Ronald and Gurusid-
daiah 1980). Many of these diolides show strong antifungal
(Kis et al. 1969; Krohn et al. 2007), antihelmintic (Kind
et al. 1996; Ghisalberti et al. 2002), and phytotoxic activity
(Kastanias and Chrysayi-Tokousbalides 2000).
OH
Keywords (S)-ethyl lactate · Wittig olefnation ·
Intermolecular Mitsunobu cyclization · (−)-Pyrenophorol.
Electronic supplementary material The online version of
this article (https://doi.org/10.1007/s11696-017-0331-4) contains
supplementary material, which is available to authorized users.
* Dongamanti Ashok
pervaramsridhar@gmail.com
1
Department of Chemistry, Osmania University, Hyderabad,
Telangana 500 007, India
2
Department of Chemistry, Jawaharlal Nehru Technological
Pyrenophorol (1) (Fig. 1) a sixteen-membered diolide,
was previously isolated from the fungus Byssochlamys
nivea (Kis et al. 1969), and subsequently found in Stemphy‑
lium radicinum (Grove 1971), Alternaria alternata (Kind
et al. 1996), Drechslera avenae (Kastanias and Chrysayi-
Tokousbalides 2000) and Phoma sp (Krohn et al. 2007).
University, Hyderabad, Telangana 500 082, India
3
Department of Chemistry, University College of Engineering
(Autonomous), Jawaharlal Nehru Technological University,
Kakinada, Andhra Pradesh 533 003, India
4
Department of Chemistry, Sri Chaitanya P.G College,
Godavarikhani, Telangana 505 209, India
Vol.:(0123456789)
1 3

Chem. Pap.
Sutherland 2007) in 70% yield. Reduction of ester 5 with
DIBAL-H at − 78 °C in dichloromethane to give the cor-
responding aldehyde, which on treatment with dimethyl(2-
oxopropylphosphonate), tosyl azide, K2CO3 (acetonitrile,
methanol) at 0 °C aforded the known alkyne compound 6
(Brimble and Bryant 2007). The characterization data (1H,
13C NMR) were well matched with the literature value.
Alkyne 6 was treated with n-BuLi in THF at − 78 °C and
the resulting acetylenic anion was quenched with aldehyde
7 [prepared from d-mannitol] (Chatopadyay and Mam-
dapur 1995), furnished 3 (Scheme 2) in 71% (with 20%
de) yield. In order to increase the diastereoselectivity in
favor of the requisite stereocenter (anti to the existing one),
we reported to an oxidation–reduction protocol. Hence,
propargylic alcohol 3 was oxidized with Dess–Martin
periodinane in dry CH2Cl2 at 0 °C to room temperature
for 4 h aforded the corresponding keto compound, which
on selective reduction with Zn(BH4)2 (Takahashi et al.
1985) aforded alcohol 8 and 8a in 82% (74% de), which
were separated by column chromatography. Later, Pro-
tection of compound 8 as MOM ether with MOM-Cl in
the presence of DIPEA as a base and catalytic amount
of DMAP in dry CH2Cl2 at 0 °C to room temperature for
6 h gave compound 9 in 91% yield. Reduction of 9 using
H2/Pd–C in MeOH gave 10 in 92% yield. Then acetonide
deprotection in compound 10 with aq. 60% acetic acid at
room temperature for 12 h aforded the required diol 11 in
74% yield. Oxidative cleavage of diol 11 with NaIO4 and
NaHCO3 in CH2Cl2 followed by Wittig olefnation of the
resulting aldehyde aforded 12 in 88% yield.
OH
13
O
16
O
8
O
2
5
O
OH
Pyrenophorol (1)
(5S, 8R, 13S, 16R)
Fig. 1 Structure of (−)-Pyrenophorol
Pyrenophorol (1) exhibits pronounced anthelmintic prop-
erties (Kind et al. 1996; Christner et al. 1998) and which
was moderately active against the fungus Microbotryum
violaceum. So far pyrenophorol (1) has been synthesized
by several groups (Dommerholdt et al. 1991; Kibayashi and
Machinaga 1993; Yadav et al. 2009; Oh and Kang 2011;
Yadav et al. 2012; Edukondalu et al. 2015) due to its interest-
ing structural features combined with its biological activity.
Results and discussion
Retrosynthetic analysis of (−)-pyrenophorol (Scheme 1)
reveal that it could be obtained from the hydroxy acids 2 via
cyclodimerisation under the Mitsunobu conditions followed
by deprotection of MOM ether. Hydroxy acid 2 could be
prepared from the racemic allylic alcohol 3, which could be
easily prepared from (S)-ethyl lactate 4 by simple chemical
transformations.
Ester 12 on subsequent hydrolysis (LiOH in
THF:MeOH:H2O-3:1:1) provided acid 13 (Scheme 3),
which on desilylation with TBAF in dry THF aforded the
hydroxy-acid 2 in 86% yield. Hydroxy-acid 2 on cyclodi-
merisation under Mitsunobu reaction conditions according
to Gerlach’s procedure (Gerlach et al. 1977) with Ph3P
and DEAD at − 25 °C for 10 h furnished 14 in 53% yield.
Finally, deprotection of MOM group in 14 with 10% HCl
in THF for 5 h aforded the (−)-pyrenophorol (1) in 77%
The synthesis of Pyrenophorol (1) commenced from
commercially available (S)-ethyl lactate (4) as chiral syn-
thon. Thus, protection of the hydroxyl group with TBSCl
and imidazole in CH2Cl2 gave ester 5 (Jamieson and
Scheme 1 Retrosynthesis of
OH
(−)-pyrenophorol
O
OH
O
OTBS
O
O
O
OH
O
OMOM
O
OH
OH
2
3
1
OH
CO2Et
4
1 3

Chem. Pap.
OTBS
OTBS
OH
CO2Et
OTBS
CO2Et
O
b
c
a
O
4
5
6
3
OH
OTBS
OTBS
OTBS
O
O
e
O
f
O
d
O
O
OMOM
10
(major)
OH
O
8
OMOM
+
9
OTBS
O
OH (minor)
8a
O
O
OTBS
O
OTBS
OH
CHO
h
g
OH
7
OMe
OMOM
12
OMOM
11
Scheme 2 Reagents and conditions: a TBSCl, Imidazole, CH2Cl2, rt,
4 h; b i) DIBAL-H, CH2Cl2, − 78 °C, 1 h; ii) dimethyl(2-oxopropyl)
phosphonate, tosyl azide, K2CO3, acetonitrile : methanol (2:1), 0 °C-
rt, 8 h; c n-BuLi, dry THF, − 78 °C, 7, 3 h; d i) Dess–Martin peri-
odinane, CH2Cl2, 0 °C-rt, 4 h; ii) Zn(BH4)2, ether, − 30 °C, 3 h; e
MOMCl, DIPEA, DMAP, CH2Cl2, rt, 6 h; f 10% Pd/C, H2, MeOH,
12 h; g aq. 60% acetic acid, rt, 12 h; h i) NaIO4, sat. NaHCO3 soln.,
CH2Cl2, rt, 5 h; ii) Ph3P=CHCOOMe, benzene, refux, 2 h
OTBS
O
OTBS
O
OH
O
a
b
OMe
OH
OH
OMOM
O
OMOM
OMOM
2
13
12
OMOM
OH
O
O
c
d
O
O
O
O
O
OMOM
OH
14
1
Scheme 3 Stereoselective total synthesis of (–)-pyrenophorol. Reagents and conditions: a LiOH, THF:MeOH:H2O (3:1:1), rt, 4 h; b TBAF,
THF, 0 °C to rt, 3 h; c Ph3P, DEAD, toluene:THP (10:1) − 25 °C, 10 h; d 10% aq. HCl, THF, 0 °C to rt, 5 h
yield, whose spectral and optical rotation data were com-
parable with the data reported in the literature (Table 1).
In conclusion, a stereoselective total synthesis of
(–)-pyrenophorol was accomplished by a versatile strategy.
A combination of oxidation–reduction protocol, Wittig
olefnation and cyclodimerisation under Mitsunobu reac-
tion condition was efectively utilized in accomplishing
the synthesis.
Experimental section
General
Solvents were dried over standard drying agents on freshly
distilled prior to use. Chemicals were purchased and used
without further purifcation. All column chromatographic
separations were performed using silica gel (60–120 mesh).
1 3

Chem. Pap.
Table 1 Comparison of 1H
and 13C NMR (CDCl3) data
for natural and synthetic
Pyrenophorol (1) (signals for
one half of the symmetric
molecule)
No.
Naturally isolated pyrenophorol
1H NMR in δ ppm
Synthesized pyrenophorol
13C NMR in 1H NMR in δ ppm
13C NMR
in δ ppm
δ ppm
1
2
3
4
5
6
7
8
9
–
–
–
–
–
–
164.9
122.1
149.5
70.4
30.4
28.9
69.7
18.1
164.8
122.2
149.6
70.3
30.5
28.9
69.6
18.3
5.97 (dd, 1H, J = 15.7, 1.7 Hz)
6.89 (dd, 1H, J = 15.7, 5.5 Hz);
4.29 (m, 1H)
1.88 (m, 2H)
1.69 (m, 2H)
5.12, m, H
1.27 (d, J = 6.5 Hz)
5.95 (d, 1H, J = 15.4 Hz)
6.88 (dd, 1H, J = 15.4, 5.4 Hz)
4.28–4.19 (m, 1H)
1.98–1.83 (m, 2H)
1.77–1.64 (m, 2H)
5.12–5.02 (m, 1H)
1.26 (d, 3H, J = 6.7 Hz)
Organic solutions were dried over anhydrous Na2SO4 and
concentrated below 40 °C in vacuo. 1H NMR spectra were
acquired at 300 MHz, 500 and 600 MHz, while, 13C NMR
at 75 and 125 MHz with TMS as internal standard for solu-
tions in CDCl3. J values were given in Hz. IR-spectra were
recorded on FT IR spectrophotometer with NaCl optics.
Optical rotations were measured on digital polarimeter at
25 °C. Mass spectra were recorded on direct inlet system or
LC by MSD trap SL.
27.7 mmol) at 0 °C and stirred for 4 h at room temperature.
The reaction mixture was quenched with 1:1 ratio of sat.
NaHCO3 sol. and Hypo sol. (35 mL) and allowed to stirr
for 30 min. extracted with CH2Cl2 (2 × 50 mL). The com-
bined organic layers were washed with water (50 mL), dried
(Na2SO4) and concentrated. The crude residue was purifed
by column chromatography (60–120 Silica gel, 7% EtOAc
in pet. ether) to give corresponding ketone (5.3 g, 92%) as
a pale yellow liquid.
To a stirred solution of above obtained ketone (5.2 g,
16.6 mmol) in dry ether (50 mL), was added Zn(BH4)2
(5.7 mL, 24.9 mmol, 4.4 M solution in n-hexane) at − 30 °C
and stirred for 3 h The reaction mixture was quenched with
aqueous NH4Cl solution (30 mL) and allowed to stirred for
15 min. Organic layer was separated and the aqueous layer
was washed with ethyl acetate (2 × 50 mL). The combined
organic layers were washed with water (2 × 50 mL), brine
(30 mL), dried (Na2SO4) and concentrated under reduced
pressure. The crude product was purifed by column chro-
matography (60–120 Silica gel, 10% EtOAc in pet. ether)
to give 8 (4.2 g, 82% yield) as colorless liquid. [α]D − 59.0
(S)‑4‑(tert‑Butyldimethylsilyloxy)‑1‑((R)‑2,2‑dime‑
thyl‑1,3‑dioxolan‑4‑yl)pent‑2‑yn‑1‑ol (3)
To a stirred solution of compound 6 (5.0 g, 27.17 mmol) in
dry THF (25 mL), was added n-BuLi (16.8 mL, 40.75 mmol,
2.5 M solution in n-hexane) at − 78 °C and stirred for 1 h. A
solution of 7 (3.5 g, 27.17 mmol) in dry THF (10 mL) was
added at − 78 °C and stirred for 2 h at same temperature.
The reaction mixture was quenched with aq. NH4Cl solution
(10 mL) and allowed to stir for 15 min. Organic layer was
separated and the aqueous layer washed with ethyl acetate
(2 × 20 mL). The combined organic layers were washed
with water (2 × 10 mL), brine (10 mL), dried (Na2SO4)
and concentrated under reduced pressure. The crude prod-
uct was purifed by column chromatography (60–120 Silica
gel, 10% EtOAc in pet. ether) to give 3 (6.1 g, 71%) as a
1
(c 0.5, CHCl3); H NMR (200 MHz, CDCl3): δ 4.44 (d,
1H, J = 6.4 Hz, –OCH), 4.29 (q, 1H, J = 6.4 Hz, –OCH),
3.98-3.78 (m, 3H, –OCH2, –OCH), 1.38, 1.35 (2 s, 6H, 2
× –CH3), 1.07 (d, 3H, J = 6.4, –CH3), 0.91 (s, 9H, t-butyl),
0.38 (s, 6H, 2 × –CH3); 13C NMR (CDCl3, 100 MHz):
δ 113.3, 86.3, 83.6, 79.1, 64.2, 63.8, 57.8, 26.1, 24.5,
23.7, 22.1, − 4.1; IR (neat): 750, 890, 1106, 1513, 2932,
3442 cm−1; HRMS (ESI): m/z calculated for C15H24O2S2Na
[M + Na]+ 337.1811, found 337.1813.
1
colorless liquid. H NMR (CDCl3, 200 MHz): δ 4.36 (m,
1H, –OCH), 4.22 (q, 1H, J = 6.6 Hz, –OCH2), 3.92–3.75 (m,
3H, –OCH2, –OCH), 1.37, 1.33 (2 s, 6H, 2 × –CH3), 1.11
(d, 3H, J = 6.4, –CH3), 0.91 (s, 9H, t‑butyl), 0.38 (s, 6H,
2 × –CH3); HRMS (ESI): m/z calculated for C16H30O4SiNa
[M + Na]+ 337.1811, found 337.1817.
Spectral data of Minor isomer (8a): 1H NMR (200 MHz,
CDCl3): δ 4.41 (d, 1H, J = 6.1 Hz, –OCH), 4.31–4.26 (m,
1H, –OCH), 4.03-3.90 (m, 2H, –OCH2), 3.84–3.77 (m,
1H, –OCH), 1.37, 1.31 (2 s, 6H, 2 × –CH3), 1.11 (d, 3H,
J = 6.1, –CH3), 0.94 (s, 9H, t-butyl), 0.33 (s, 6H, 2 × –CH3);
13C NMR (CDCl3, 100 MHz): δ 113.5, 86.4, 83.7, 78.7,
64.4, 64.1, 57.7, 26.3, 24.4, 23.7, 22.3, − 4.4; ESIMS: 337
(M + Na)+.
(1S,4S)‑4‑(tert‑Butyldimethylsilyloxy)‑1‑((R)‑2,2‑dimethyl‑
1,3‑dioxolan‑4‑yl)pent‑2‑yn‑1‑ol (8)
To a stirred solution of 3 (5.8 g, 18.47 mmol) in dry CH2Cl2
(50 mL), was added Dess-Martin periodinane (11.7 g,
1 3

Chem. Pap.
(5S,8S)‑5‑((R)‑2,2‑Dimethyl‑1,3‑diox‑
olan‑4‑yl)‑8,10,10,11,11‑pentamethyl‑2,4,9‑trioxa‑10‑si‑
ladodec‑6‑yne (9)
and dried (Na2SO4). Evaporation of solvent under reduced
pressure and purifcation of the residue by column chro-
matography (60–120 Silica gel, 40% EtOAc in pet. ether)
1
furnished 11 (3.5 g, 74%) as a yellow liquid. H NMR
To a cooled (0 °C) solution of 8 (4.1 g, 13.05 mmol) in
CH2Cl2 (25 mL), were added DIPEA (9.1 mL, 52.2 mmol)
and MOM-Cl (2.1 mL, 26.11 mmol) sequentially and
stirred at room temperature for 6 h. The reaction mixture
was concentrated under reduced pressure and the residue
was purifed by column chromatography (60–120 Silica gel,
8% EtOAc in pet. ether) to aford 9 (4.5 g, 91%) as a yel-
low liquid. [α]D +27.1 (c 0.6, CHCl-3); 1H NMR (CDCl3,
300 MHz): δ 4.51, 4.39 (2d, 2H, J = 9.4 Hz, –OCH2), 4.17
(q, 1H, J = 5.9 Hz, –OCH), 3.99–3.89 (m, 2H, –OCH2),
3.76–3.64 (m, 2H, 2 × –OCH), 3.34 (s, 3H, –OCH3), 1.32,
1.28 (2 s, 6H, 2 × –CH3), 1.12 (d, 3H, J = 6.2 Hz, –CH3),
0.88 (s, 9H, t-butyl), 0.03 (s, 6H, 2 × –CH3); 13C NMR
(CDCl3, 100 MHz): δ 107.8, 97.2, 84.3, 79.1, 76.2, 72.1,
63.9, 58.1, 56.0, 25.8, 24.2, 23.1, 21.3, − 4.8; IR (neat):
2929, 2858, 1720, 1609, 1460, 1101, 837 cm−1; HRMS
(ESI): m/z calculated for C18H34O5SiNa [M + Na]+
381.2073, found 381.2080.
(CDCl3, 300 MHz): 4.52 (m, 2H, –OCH2), 4.08–3.88 (m,
3H, –OCH2, –OCH), 3.57 (m, 1H, –OCH), 3.43 (m, 1H,
–OCH), 3.34 (s, 3H, -OCH3), 1.74–1.48 (m, 4H, 2 × –CH2),
1.11 (d, 3H, J = 6.0 Hz, –CH3), 0.92 (s, 9H, t-butyl), 0.33 (s,
6H, 2 × –CH3); 13C NMR (CDCl3, 75 MHz): δ 97.1, 83.1,
66.6, 63.8, 56.0, 35.4, 29.0, 25.9, 24.2, 18.3, − 4.1, − 4.6;
IR (neat): 3456, 2990, 2942, 2863, 1613, 1513 cm−1; HRMS
(ESI): m/z calculated for C15H35O5Si [M + H]+ 323.2254,
found 323.2259.
(4S,7S,E)‑Methyl 7‑(tert‑butyldimethylsilyloxy)‑4‑(meth
oxymethoxy)oct‑2‑enoate (12)
To a cooled (0 °C) solution of 11 (2.5 g, 7.76 mmol) in
CH2Cl2 (30 mL), were added NaIO4 (2.49 g, 11.64 mmol)
followed by sat. NaHCO3 (2 mL) and stirred at room tem-
perature for 5 h. Reaction mixture was dried (Na2SO4), fl-
tered and evaporated under reduced pressure to gave cor-
responding aldehyde, which was directly used as such for
the next step.
(5S,8S)‑5‑((R)‑2,2‑Dimethyl‑1,3‑diox‑
olan‑4‑yl)‑8,10,10,11,11‑pentamethyl‑2,4,9‑trioxa‑10‑si‑
ladodecane (10)
Aldehyde was dissolved in benzene (30 mL) and treated
with (methoxycarbonylmethylene) triphenyl phosphorane
(3.2 g, 9.31 mmol) at refux. After 2 h, solvent was evapo-
rated from reacton mixture and the residue was purifed by
column chromatography (60–120 Silica gel, 10% EtOAc in
pet. ether) to furnish 12 (2.3 g, 88%) as a yellow liquid. [α]D
− 134.6 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 6.78
(dd, 1H, J = 6.1, 15.6 Hz, olefnic), 5.94 (d, 1H, J = 15.6 Hz,
olefnic), 4.54 (q, 2H, J = 6.7 Hz, –OCH2), 3.82 (q, 1H,
J = 5.4, 10.8 Hz, –OCH), 3.68–3.61 (m, 1H, –OCH), 3.59
(s, 3H, –OCH3), 3.32 (s, 3H, –OCH3), 1.71–1.38 (m, 4H, 2 ×
–CH2), 1.11 (d, 3H, J = 6.0 Hz, –CH3), 0.88 (s, 9H, t-butyl),
0.03 (s, 6H, 2 × –CH3); 13C NMR (CDCl3, 100 MHz): δ
165.9, 149.3, 129.6, 117.2, 96.8, 78.3, 66.9, 56.3, 51.2,
35.9, 31.2, 26.1, 25.9, 24.6, 19.2, − 4.6; IR (neat): 3446,
2932, 1722, 1612, 1512, 1448, 1386, 1164, 1037 cm−1;
HRMS (ESI): m/z calculated for C17H34O5SiNa [M + Na]+
369.2073, found 369.2081.
To a stirred solution of 9 (4.4 g, 12.11 mmol) in EtOAc
(20 mL), a catalytic amount of 10% Palladium on carbon
(Pd/C) (0.12 g) was added into the reaction mixture and
stirred under H2 atmosphere for 12 h. The reaction mixture
was fltered through Celite washed with EtOAc (2 × 20 mL)
and the fltrate was concentrated under reduced pressure.
The crude product was purifed by column chromatography
(60–120 Silica gel, 5% EtOAc in pet. ether) to give 10 (4.1 g,
92%) as colorless syrup. [α]2D8 = − 37.80 (c 1.7, CHCl3);
1H NMR (CDCl3, 200 MHz): δ 4.49 (s, 2H, –OCH2), 3.98-
3.79 (m, 3H, -OCH2, –OCH), 3.54 (m, 1H, –OCH), 3.48
(m, 1H, –OCH), 3.32 (s, 3H, –OCH3), 1.64–1.51 (m, 4H,
2 × –CH2), 1.37, 1.33 (2 s, 6H, 2 × –CH3), 1.09 (d, 3H,
J = 5.9 Hz, –CH3), 0.91 (s, 9H, t-butyl), 0.37 (s, 6H, 2 ×
–CH3); 13C NMR (CDCl3, 75 MHz): δ 103.5, 97.1, 83.6,
78.9, 66.2, 64.3, 55.8, 35.1, 28.9, 25.6, 25.4, 24.2, 18.3,
− 3.9; HRMS (ESI): m/z calculated for C18H38O5SiNa
[M + Na]+ 385.2386, found 385.2394.
(4S,7S,E)‑7‑(tert‑Butyldimethylsilyloxy)‑4‑(methoxymet
hoxy)oct‑2‑enoic acid (13)
(2R,3S,6S)‑6‑(tert‑Butyldimethylsilyloxy)‑3‑(methoxyme
To a solution of 12 (1.1 g, 3.17 mmol) in THF: MeOH:
water (3:1:1, 10 mL), was added LiOH (0.3 g, 12.7 mmol)
and stirred at room temperature for 4 h. The pH of reaction
mixture was adjusted to acidic with 1 N HCl solution and
extracted with ethyl acetate (20 mL). Organic layers were
washed with water (15 mL), brine (15 mL), dried (Na2SO4),
evaporated under reduced pressure and the residue was
thoxy)heptane‑1,2‑diol (11)
A solution of 10 (4 g, 11.04 mmol) in aq. 60% acetic acid
(40 mL) was stirred at room temperatature for 12 h. After
completion of reaction, it was neutralized with anhydrous
NaHCO3 and extracted with ethyl acetate (2 × 100 mL)
1 3

Chem. Pap.
purifed by column chromatography (60–120 Silica gel,
30% EtOAc in pet. ether) to give 13 (0.85 g, 81%) as a col-
ourless oil. [α]D + 14.6 (c 0.6, CHCl3); 1H NMR (CDCl3,
300 MHz): δ 6.74 (dd, 1H, J = 5.9, 15.4 Hz, olefnic), 5.97
(d, 1H, J = 15.4 Hz, olefnic), 4.51 (s, 2H, –OCH2), 3.84
(q, 1H, J = 5.9, 9.9 Hz, –OCH), 3.68–3.57 (m, 1H, –OCH),
3.39 (s, 3H, –OCH3), 2.09–1.89 (m, 2H, –CH2), 1.79–1.68
(m, 2H, –CH2), 1.13 (d, 3H, J = 6.1 Hz, –CH3), 0.81 (s,
9H, t-butyl), 0.01 (s, 6H, 2 × –CH3); 13C NMR (75 MHz,
CDCl3): δ 170.7, 152.1, 124.3, 67.9, 67.2, 66.8, 55.2,
35.6, 29.8, 25.3, 18.2, − 4.3; IR (neat): 3540, 3031, 2930,
2857, 1710, 1097 cm−1; HRMS (ESI): m/z calculated for
C16H32O5SiNa [M + Na]+ 355.1917, found 355.1923.
(m, 8H, 4 × –CH2), 1.11 (d, 6H, J = 6.0 Hz, 2 × –CH3); 13
C
NMR (75 MHz, CDCl3): 166.4, 146.9, 123.2, 102.9, 97.3,
79.9, 67.8, 56.6, 39.7, 29.7, 19.6; IR (neat): 3416, 3068,
2932, 2859, 1722, 1608, 1527, 1462, 1427, 1273, 1105, 918,
702 cm−1; HRMS (ESI): m/z calculated for C20H32O8Na
[M + Na]+ 423.1995, found 423.1992.
Pyrenophorol (1)
To a stirred solution of 14 (75 mg, 0.18 mmol) in THF
(2 mL) cooled to 0 °C, was treated with 10% aq. HCl (1 mL)
and stirred at room temperature for 5 h. The reaction mix-
ture was quenched with sat. NaHCO3 solution (5 mL) and
extracted with EtOAc (2 × 20 mL). The combined organic
layers were washed with water (2 × 10 mL), brine (10 mL),
dried (Na2SO4), concentrated under reduced pressure and
the residue was purifed by column chromatography (60–120
Silica gel, 15% EtOAc in pet. ether) to give 1 (45 mg, 77%)
as a colourless liquid. m.p.: 137–139 °C; lit. [1] m.p. 135 °C;
[α]D − 3.7 (c 0.83, acetone); lit.[1] [α]D − 3.0 (c 1.0, ace-
tone); 1H NMR (CDCl3, 300 MHz): (signals for one half of
the symmetric molecule) δ 6.88 (dd, 1H, J = 15.4, 5.4 Hz,
olefnic), 5.95 (d, 1H, J = 15.4 Hz, olefnic), 5.12-5.02 (m,
1H, -OCH), 4.28–4.19 (m, 1H, -OCH), 1.98-1.83 (m, 2H,
×CH2), 1.77×1.64 (m, 2H, × CH2), 1.26 (d, 3H, J = 6.7 Hz,
×CH3); 13C NMR (75 MHz, CDCl3): δ 164.8, 149.6, 122.1,
70.3, 69.6, 30.5, 28.9, 18.3; IR (neat): 3442, 2922, 2853,
1721, 1630, 1126, 835 cm−1; HRMS (ESI): m/z calculated
for C16H24O6Na [M + Na]+ 335.1471, found 335.1579.
(4S,7S,E)‑7‑Hydroxy‑4‑(methoxymethoxy)oct‑2‑enoic acid
(2)
To a cooled (0 °C) solution of 13 (0.75 g, 2.25 mmol) in
dry THF (10 mL) under nitrogen atmosphere, was added
TBAF (0.7 mL, 2.7 mmol) and stirred for 3 h. After com-
pletion of reaction, reaction mixture was diluted with
water (5 mL) and extracted with ethyl acetate (2 × 50 mL).
Organic layers were washed with water (2 × 10 mL), brine
(10 mL), dried (Na2SO4), evaporated and the residue was
purifed by colomn chromatography (60–120 Silica gel, 55%
EtOAc in pet. ether) to give 2 (0.42 g, 86%) as a liquid.
[α]D − 32.6 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz):
δ 6.89 (dd, 1H, J = 6.3, 15.6 Hz, olefnic), 5.97 (d, 1H,
J = 15.6 Hz, olefnic), 4.71–4.59 (m, 2H, –OCH2), 3.74 (q,
1H, J = 6.1, 10.4 Hz, –OCH), 3.62–3.54 (m, 1H, –OCH),
3.33 (s, 3H, –OCH3), 1.95–1.53 (m, 4H, 2 × –CH2), 1.22
(d, 3H, J = 6.3 Hz, –CH3); 13C NMR (CDCl3, 75 MHz):
δ 172.0, 152.4, 121.3, 95.3, 68.0, 67.1, 54.4, 35.1, 27.3,
23.2; IR (neat): 3451, 2929, 2857, 2102, 1722, 1612, 1514,
1360, 1041, 777 cm−1; HRMS (ESI): m/z calculated for
C10H18O5Na [M + Na]+ 241.1052, found 241.1057.
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