Total synthesis of (-)-pyrenophorol

Article abstract of DOI:10.1055/s-0031-1289703

An efficient synthetic route has been developed for the synthesis of (-)-pyrenophorol employing Sharpless asymmetric epoxidation, olefin cross-metathesis, and intermolecular Mitsunobu cyclization. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289703

PAPER
783
Total Synthesis of (–)-Pyrenophorol
Total
Synh
i
l
phorol lu S. Yadav,*a Ganapuram Madhusudhan Reddy,a,b Tenneti Srinivasa Rao,a Basi V. Subba Reddy,a
Ahmad Al Khazim Al Ghamdic
a
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
University of Hyderabad, Hyderabad 500046, India
Engineer Abdullah Baqshan for Bee Research, King Saudi University, Saudi Arabia
b
c
Received 8 October 2011; revised 14 December 2011
address this problem, and also as part of our ongoing pro-
gram on natural products synthesis,14 we herein report a
new and efficient synthetic route for the synthesis of
(–)-pyrenophorol via Sharpless asymmetric epoxidation
and olefin metathesis followed by an intermolecular
Mitsunobu cyclization.
Abstract: An efficient synthetic route has been developed for the
synthesis of (–)-pyrenophorol employing Sharpless asymmetric ep-
oxidation, olefin cross-metathesis, and intermolecular Mitsunobu
cyclization.
Key words: macrodiolide, stereoselectivity, natural products,
Sharpless asymmetric epoxidation, cross-metathesis
The retrosynthetic route adopted is outlined in Scheme 1.
(–)-Pyrenophorol (1) was proposed to be synthesized by
intermolecular Mitsunobu cyclization of seco acid 14,
which could be obtained by Sharpless asymmetric epoxi-
dation followed by olefin metathesis of allylic alcohol 11.
The allylic alcohol 11 could be derived from a commer-
cially available lactate ester.
Lactone-containing natural products have attracted con-
siderable attention due to their interesting biological prop-
erties.1 Naturally occurring macrodiolide antibiotics
(Figure 1) are divided into two groups: compounds having
a C2 symmetry and a 16-membered ring derived from a
head-to-tail dimerization of two identical C8 hydroxy acid
subunits such as pyrenophorol (1),2 pyrenophorin (2),3 tet-
rahydropyrenophorol (3),4 and vermiculin (4),5 and those
having an unsymmetrical 14-membered ring such as col-
letallol (5).6
The synthesis of pyrenophorol (1) began from lactate ester
(Scheme 2), which was protected as its silyl ether using
tert-butyldiphenylsilyl chloride (TBDPSCl) and imida-
zole in anhydrous dichloromethane (CH2Cl2). Reduction
of the TBS ether of the lactate ester with diisobutylalumi-
num hydride (DIBAL-H) in anhydrous CH2Cl2 at –78 °C
gave the corresponding aldehyde, which was then subject-
ed to Wittig olefination with Ph3PCHCOOEt in benzene
under reflux conditions to give the unsaturated ester 6 in
92% yield. Reduction of the double bond using NaBH4 in
the presence of NiCl2 gave the saturated ester 7 in 90%
yield. Further reduction of ester 7 with DIBAL-H fol-
Structurally related macrolide dilactones such as pyreno-
phorol (1) and pyrenophorin (2) are produced by the plant
pathogenic fungi Byssachlamys nivea2a and Pyrenophora
avenae,7 respectively. These two macrolides have also
been isolated from the culture filtrates of Stemphylium
radicinum.2b They exhibit prominent antifungal antibiotic
activity. Subsequently, pyrenophorol was also isolated
from the imperfect fungus Alternaria alternata and was
named as helmidiol,8 which exhibits pronounced anthel-
mintic properties.8,9 Pyrenophorol was moderately active
against the fungus Microbotryum violaceum.4
OH
O
O
O
O
O
O
O
O
The first total synthesis of the natural isomer of pyreno-
phorol was reported by Zwanenburg et al.10 Later,
Kibayashi et al.11 reported its total synthesis by employing
two successive esterifications. The synthesis of the
(5R,8S,13R,16S)-isomer of pyrenophorol has been ac-
complished by Le Floc’h et al.12 Recently, we have report-
ed the synthesis of (–)-pyrenophorol by employing
Jacobsen’s hydrolytic kinetic resolution and MacMillan’s
a-hydroxylation to establish two stereogenic centers.13
The use of Jacobsen’s hydrolytic kinetic resolution leads
to the formation of the required isomer in less than 50%
yield, which limits its usage in large-scale synthesis. To
O
O
O
OH
1
O
2
OH
O
O
OH
3
O
O
O
O
O
O
O
O
O
OH
SYNTHESIS 2012, 44, 783–787
Advanced online publication: 13.02.2012
x
x
.x
x
.2
0
1
1
O
4
5
DOI: 10.1055/s-0031-1289703; Art ID: Z96211SS
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Naturally occurring macrodiolide antibiotics

784
J. S. Yadav et al.
PAPER
lowed by Wittig olefination gave ester 8 in 94% yield. Re- then subjected to an intermolecular Mitsunobu cycliza-
duction of ester 8 using DIBAL-H in anhydrous CH2Cl2 tion.
gave the allylic alcohol 9 in 92% yield, which was then
Mitsunobu cyclization of 14 was carried out by using
subjected to Sharpless asymmetric epoxidation to give the
Gerlach’s procedure16 to achieve the macrolactonization
epoxy alcohol 10 in 78% yield. Iodination of 10 followed
with complete inversion of configuration at C4 to give
compound 15 (Scheme 3). Finally, cleavage of the THP
by epoxide opening with metallic zinc powder in reflux-
ing MeOH15 afforded the allylic alcohol 11 in 82% yield.
ether furnished the target macrolide (1) in 96% yield as a
Olefin cross metathesis of 11 with methyl acrylate gave
white solid. The analytical and spectral data of the mac-
the enoate 12 in 78% yield. Protection of the hydroxy
rolide (1) were in good agreement with those of an authen-
group of enoate 12 as its tetrahydropyranyl ether (THP),
followed by hydrolysis of the ester moiety under basic
conditions gave the carboxylic acid 13 in 85% yield. De-
silylation of 13 gave the key intermediate 14, which was
tic sample.13
In summary, we have developed an efficient approach
for the total synthesis of (–)-pyrenophorol involving
OH
O
OH
OTBDPS
OH
COOH
O
O
COOMe
OTHP
OH
O
14
11
OH
1
Scheme 1 Retrosynthetic analysis of 1
OH
OTBDPS
OTBDPS
a, b, c
d
e, f
COOMe
COOEt
COOEt
6
7
OTBDPS
OTBDPS
g
h
OTBDPS
OH
OH
COOEt
O
8
9
10
OTBDPS
OTBDPS
OTBDPS
l, m
i, j
k
COOMe
COOH
OH
OH
OTHP
11
OH
12
13
n
COOH
MesN
Cl
NMes
Ph
OTHP
14
Ru
Cl
PCy3
16
Scheme 2 Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2, 0 °C→r.t., 30 min, 98%; (b) DIBAL-H, CH2Cl2, –78 °C, 20 min, 80%;
(c) Ph3PCHCOOEt, benzene, reflux, 1 h, 92%; (d) NiCl2·6H2O, NaBH4, MeOH, 0 °C, 1 h, 90%; (e) DIBAL-H, CH2Cl2, –78 °C, 15 min, 82%;
(f) Ph3PCHCOOEt, benzene, reflux, 1 h, 94%; (g) DIBAL-H, CH2Cl2, –78→0 °C, 1 h, 92%; (h) L-(+)-DIPT, Ti(Oi-Pr)4, TBHP, CH2Cl2,
–20 °C, 7 h, 78%; (i) I2, imidazole, Ph3P, THF–MeCN (4:1), 0 °C→r.t., 30 min, 92%; (j) Zn, MeOH, reflux, 12 h, 82%; (k) methyl acrylate,
16, CH2Cl2, reflux, 24 h, 78%; (l) 3,4-dihydropyran, CSA, CH2Cl2, r.t., 1 h, 88%; (m) 20% aq NaOH, MeOH, r.t., 30 min, 85%; (n) TBAF,
THF, 60 °C, 2 h, 90%.
OTHP
OH
O
O
OH
a
b
COOH
O
O
O
O
OTHP
14
O
O
OTHP
OH
1
15
Scheme 3 Reagents and conditions: (a) Ph3P, DEAD, toluene–THF (10:1), –25 °C, 24 h, 60%; (b) PTSA, MeOH, r.t., 30 min, 96%.
Synthesis 2012, 44, 783–787 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (–)-Pyrenophorol
785
for 1 h. The aqueous phase was extracted with CH2Cl2 (3 × 30 mL)
and the combined organic layers were washed with brine (10 mL),
dried over MgSO4, and the solvent was removed in vacuo. The
crude aldehyde was dissolved in benzene (30 mL) and then
Ph3PCHCOOEt (3.43 g, 9.87 mmol) was added. The resulting mix-
ture was heated to reflux for 1 h. Upon completion, the reaction was
quenched with H2O (15 mL) and the aqueous phase was extracted
with EtOAc (3 × 20 mL). The combined organic layers were dried
over MgSO4 and the solvent was removed in vacuo. The residue
was purified by silica gel flash chromatography (EtOAc–n-hexane,
1%) to give 8.
Sharpless asymmetric epoxidation, olefin cross metathe-
sis and intermolecular Mitsunobu cyclization starting
from a readily available lactate ester. This approach may
find application in generating new derivatives of (–)-
pyrenophorol.
Melting points were recorded with a Büchi R-535 apparatus and are
uncorrected. IR spectra were recorded with a Perkin–Elmer FTIR
240-c spectrophotometer using KBr optics. 1H and 13C NMR spec-
tra were recorded with a Gemini-200 spectrometer (200 MHz) or a
Bruker-300 spectrometer (300 MHz) in CDCl3 using TMS as inter-
nal standard. Mass spectra were recorded with a Finnigan MAT
1020 mass spectrometer operating at 70 eV. Column chromatogra-
phy was performed using E. Merck 60–120, mesh silica gel. Optical
rotations were measured with a JASCO DIP-370 polarimeter oper-
ating at 25 °C.
Yield: 2.53 g (94%); colorless oil; [a]D25 –19.4 (c 2.75, CHCl3).
IR (neat): 2953, 2859, 1721, 1269, 1172, 1109, 1045, 738, 703, 618
cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.64–7.69 (m, 4 H), 7.33–7.46 (m,
6 H), 6.81–6.92 (m, 1 H), 5.73 (d, J = 15.6 Hz, 1 H), 4.17 (q, J =
7.1 Hz, 2 H), 3.82–3.91 (m, 1 H), 2.16–2.26 (m, 2 H), 1.50–1.66
(m, 2 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.03–1.08 (m, 12 H).
Compound 6
13C NMR (CDCl3, 75 MHz): d = 149.1, 149.0, 135.8, 129.6, 129.4,
127.5, 127.4, 121.1, 68.7, 60.3, 37.4, 27.8, 27.0, 23.1, 14.2.
To a stirred solution of (2S)-2-tert-butyldimethylsilyloxypropanal
(3.25 g, 10.41 mmol) in benzene (50 mL), was added
Ph3PCHCOOEt (4.35 g, 12.5 mmol) and the resulting mixture was
heated to reflux for 1 h. The reaction was then quenched with H2O
(20 mL) and extracted with EtOAc (3 × 30 mL). The combined or-
ganic layers were dried over MgSO4, the solvent was removed in
vacuo and the residue was purified by silica gel flash chromatogra-
phy (EtOAc–n-hexane, 1%) to give 6.
MS (ESI): m/z = 411 [M + H].
Compound 9
A solution of 8 (2.30 g, 5.61 mmol) in CH2Cl2 (25 mL) was cooled
to 0 °C and then DIBAL-H (1 M in toluene, 14.0 mL, 14.0 mmol)
was slowly added over 10 min under a N2 atmosphere. After addi-
tion was complete, stirring was continued for 1 h at 0 °C. Upon
completion, the mixture was carefully quenched with sat. aq potas-
sium sodium tartrate (25 mL) and then allowed to stir vigorously for
1 h. The aqueous phase was extracted with CH2Cl2 (3 × 30 mL) and
the combined organic layers were washed with brine (10 mL) and
dried over MgSO4. The solvent was removed in vacuo and the crude
product was subjected to silica gel flash chromatography (EtOAc–
n-hexane, 10%) to give 9.
Yield: 3.66 g (92%); colorless oil; [a]D25 –39.6 (c 2.0, CHCl3).
IR (neat): 3071, 2965, 2931, 2860, 1736, 1473, 1427, 1376, 1267,
1177, 1135, 1110, 1029, 997, 822, 742, 701 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.66–7.73 (m, 4 H), 7.33–7.44 (m,
6 H), 6.92 (dd, J = 15.1, 4.7 Hz, 1 H), 6.08 (d, J = 15.1 Hz, 1 H),
4.40–4.44 (m, 1 H), 4.09 (q, J = 7.1 Hz, 2 H), 1.25 (t, J = 7.1 Hz,
3 H), 1.04–1.08 (m, 12 H).
13C NMR (CDCl3, 75 MHz): d = 166.4, 151.0, 135.6, 134.1, 129.8,
129.4, 127.5, 127.4, 119.1, 68.6, 60.2, 26.9, 23.2, 19.2, 14.2.
Yield: 1.89 g (92%); colorless liquid; [a]D25 –11.4 (c 2.5, CHCl3).
IR (neat): 3380, 3069, 2930, 2857, 1665, 1464, 1427, 1375, 1188,
1107, 1050, 1003, 972, 821, 739, 703, 611, 507 cm–1.
MS (ESI): m/z = 383 [M + H].
1H NMR (CDCl3, 300 MHz): d = 7.63–7.70 (m, 4 H), 7.34–7.45 (m,
6 H), 5.50–5.56 (m, 2 H), 3.98–4.03 (m, 2 H), 3.79–3.89 (m, 1 H),
1.99–2.09 (m, 2 H), 1.40–1.63 (m, 2 H), 1.00–1.11 (m, 12 H).
13C NMR (CDCl3, 75 MHz): d = 135.9, 133.1, 129.4, 128.8, 127.5,
127.4, 68.9, 63.7, 38.7, 27.9, 27.0, 23.1, 19.2.
Compound 7
To a solution of 6 (3.542 g, 9.27 mmol) in anhydrous MeOH (30
mL) at 0 °C, was added NiCl2·6 H2O (0.66 g, 2.78 mmol) and
NaBH4 (0.70 g, 18.54 mmol) portion-wise. The resulting mixture
was stirred at the same temperature for 1 h. Upon completion, the
reaction mixture was filtered through Celite, the filtrate was con-
centrated under reduced pressure and the residue was purified by
silica gel flash chromatography (EtOAc–hexane, 1%) to give 7.
MS (ESI): m/z = 369 [M + H].
Compound 10
Yield: 3.20 g (90%); colorless oil; [a]D25 –6.2 (c 2.0, CHCl3).
To a stirred suspension of 4 Å molecular sieves (10 g) in anhydrous
CH2Cl2 (250 mL) under N2 was added L-(+)-diisopropyl tartrate
(0.127 mL, 0.606 mmol, 0.12 equiv) in one portion. The mixture
was then cooled to –20 °C and Ti(OiPr)4 (0.148 mL, 0.50 mmol, 0.1
equiv) was added. After 10 min, t-BuOOH (8.69 M in CH2Cl2, 1.16
mL, 10.04 mmol, 2 equiv) was added dropwise over 5 min. The
mixture was stirred at –20 °C for 30 min and then a solution of al-
lylic alcohol 9 (1.85 g, 5.05 mmol) in anhydrous CH2Cl2 (50 mL)
was added dropwise over 30 min. The mixture was stirred at –20 °C
for 7 h and then quenched with H2O (10 mL), diluted with EtOAc
(100 mL) and the resulting mixture was allowed to warm to r.t. The
organic layer was separated, washed with H2O (50 mL) and dried
over anhydrous MgSO4. Evaporation of the solvent in vacuo, fol-
lowed by purification by silica gel chromatography (EtOAc–n-hex-
ane, 15%) gave 10.
IR (neat): 3071, 2959, 2931, 2856, 1722, 1656, 1472, 1428, 1367,
1272, 1152, 1110, 1051, 980, 822, 740, 702 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.66–7.73 (m, 4 H), 7.33–7.44 (m,
6 H), 4.10 (q, J = 7.1 Hz, 2 H), 3.92–3.94 (m, 1 H), 2.38 (t, J =
7.5 Hz, 1 H), 2.37 (t, J = 7.5 Hz, 1 H), 1.78 (m, 2 H), 1.23 (t, J =
7.1 Hz, 3 H), 1.03–1.08 (m, 12 H).
13C NMR (CDCl3, 75 MHz): d = 173.6, 136.2, 134.0, 129.6, 129.4,
127.5, 127.4, 68.4, 60.0, 34.5, 30.0, 27.2, 23.0, 19.2, 14.1.
MS (ESI): m/z = 385 [M + H].
Compound 8
A solution of DIBAL-H (1.0 M in toluene, 9.5 mL, 9.5 mmol) was
added dropwise to a solution of ester 7 (3.08 g, 8.03 mmol) in
CH2Cl2 (35 mL) at –78 °C and stirred for 15 min at the same tem-
perature. The reaction mixture was then quenched with sat. aq po-
tassium sodium tartrate (20 mL) and then allowed to stir vigorously
Yield: 1.51 g (78%); colorless oil; [a]D25 –6.0 (c 1.0, CHCl3).
IR (neat): 3424, 3069, 2927, 2856, 1740, 1463, 1427, 1376, 1262,
1107, 1047, 1002, 877, 821, 739, 703, 611, 507 cm–1.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 783–787

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J. S. Yadav et al.
PAPER
1H NMR (CDCl3, 300 MHz): d = 7.64–7.71 (m, 4 H), 7.32–7.47 (m,
6 H), 3.80–3.95 (m, 2 H), 3.51–3.59 (m, 1 H), 2.79–2.87 (m, 2 H),
1.49–1.66 (m, 2 H), 1.30–1.33 (m, 2 H), 1.01–1.10 (m, 12 H).
13C NMR (CDCl3, 75 MHz): d = 135.8, 129.6, 129.5, 127.5, 127.4,
69.0, 68.7, 61.6, 58.4, 35.2, 29.7, 27.0, 23.1, 19.2.
layer was extracted with EtOAc (3 × 10 mL) and the combined or-
ganic layers were washed with brine (10 mL), dried over MgSO4,
and the solvent was removed in vacuo. The crude product was then
subjected to silica gel flash chromatography (EtOAc–hexane, 40%)
to give 13.
Yield: 0.36 g (85%); colorless liquid; [a]D25 –10 (c 0.65, CHCl3).
MS (ESI): m/z = 407 [M + Na].
IR (neat): 3424, 2923, 2854, 1703, 1655, 1460, 1376, 1265, 1122,
1108, 1072, 1044, 1026, 980, 811, 771, 738, 705, 609, 509 cm–1.
Compound 11
To a vigorously stirred solution of epoxy alcohol 10 (1.5 g, 3.90
mmol) in anhydrous THF–MeCN (4:1, 30 mL) was successively
added imidazole (1.59 g, 23.4 mmol), Ph3P (2.93 g, 11.2 mmol) and
I2 (2.84 g, 11.2 mmol). Stirring was continued at r.t. for 30 min, then
Et2O (20 mL) was added to precipitate out the Ph3P=O. The solids
were filtered through a short pad of silica gel and the filtrate was
concentrated in vacuo to obtain the crude iodo epoxide. To a vigor-
ously stirred solution of iodo epoxide in MeOH (25 mL) was added
Zn dust (2.61 g, 40 mmol) and the mixture was heated under reflux
for 12 h. After cooling to r.t., the mixture was filtered through a
short pad of Celite, washed thoroughly with MeOH, and the filtrate
was concentrated in vacuo. Purification of the residue by silica gel
flash chromatography (EtOAc–hexane, 10%) gave allylic alcohol
11.
1H NMR (CDCl3, 300 MHz): d = 7.60–7.67 (m, 4 H), 7.29–7.41 (m,
6 H), 6.75–6.83 (m, 1 H), 5.85 (d, J = 15.8 Hz, 1 H), 4.49–4.61 (m,
1 H), 4.14–4.2 (m, 1 H), 3.69–3.89 (m, 2 H), 3.36–3.47 (m, 1 H),
1.38–1.86 (m, 10 H), 1.07 (d, J = 6.1 Hz, 3 H), 1.04 (s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 170.5, 150.4, 135.8, 129.5, 129.4,
129.3, 127.3, 127.2, 121.6, 95.9, 74.6, 74.3, 74.1, 69.1, 62.2, 62.1,
34.6, 30.9, 30.7, 30.5, 30.4, 29.6, 29.0, 27.0, 25.4, 25.3, 23.0, 19.2.
MS (ESI): m/z = 495 [M – H].
Compound 14
To a solution of 13 (0.35 g, 0.70 mmol) in anhydrous THF (40 mL)
was added TBAF (1.0 M in THF, 0.85 mL, 0.85 mmol) at 0 °C, and
the resulting mixture was stirred for 2 h at r.t. Upon completion, the
reaction was quenched with sat. aq NH4Cl. The organic layer was
separated and the aqueous layer was extracted with EtOAc (3 × 30
mL). The combined organic layers were dried over anhydrous
MgSO4 and concentrated in vacuo. The crude product was purified
by silica gel flash chromatography (EtOAc–hexane, 70%) to afford
14.
Yield: 1.08 g (82%); colorless oil; [a]D25 –5.8 (c 1.0, CHCl3).
IR (neat): 3420, 3067, 2926, 2859, 1108, 871, 844, 819, 737, 704,
665, 610 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.63–7.72 (m, 4 H), 7.34–7.45 (m,
6 H), 5.72–5.87 (m, 1 H), 5.04–5.21 (m, 2 H), 4.16–4.23 (m, 1 H),
3.46–3.56 (m, 1 H), 1.46–1.81 (m, 7 H), 1.05 (s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 139.1, 135.6, 129.4, 127.5, 127.3,
115.7, 73.5, 71.2, 33.1, 31.4, 28.6, 26.9, 21.2.
Yield: 0.164 g (90%); yellow liquid; [a]D25 +4.0 (c 0.5, CHCl3).
IR (neat): 3421, 2923, 2852, 1702, 1656, 1459, 1378, 1266, 1122,
1072, 1026, 982, 810, 771 cm–1.
MS (ESI): m/z = 369 [M + H].
1H NMR (CDCl3, 300 MHz): d = 6.79–7.07 (m, 1 H), 5.94–6.13 (m,
1 H), 4.73–4.77 (m, 1 H), 4.55–4.59 (m, 1 H), 4.33–4.44 (m, 1 H),
3.39 (t, J = 7.3 Hz, 2 H), 1.97–2.11 (m, 2 H), 1.46–1.88 (m, 8 H),
1.20 (d, J = 6.2 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 170.5, 150.8, 120.1, 97.3, 74.8,
67.9, 60.3, 33.9, 30.6, 29.9, 25.2, 23.4, 19.2.
Compound 12
To a solution of 11 (0.50 g, 1.37 mmol) in CH2Cl2 (50 mL), Grubbs
II catalyst (0.058 g, 0.067 mmol) was added and the mixture was
heated to reflux for 24 h in a N2 atmosphere. The solvent was par-
tially distilled off and the resulting solution was stirred at r.t. for 2
h under open air in order to decompose the catalyst. The mixture
was evaporated to dryness to give a brown residue, which was puri-
fied by silica gel flash chromatography (EtOAc–hexane, 15%) to
give 12.
MS (ESI): m/z = 281 [M + Na].
Compound 15
To a solution of 14 (0.13 g, 0.50 mmol) in anhydrous toluene–THF
(20:1, 80 mL), was added Ph3P (0.66 g, 2.51 mmol) at –40 °C under
an argon atmosphere. DEAD (0.437 g, 2.51 mmol) was added at the
same temperature and the mixture was stirred at –25 °C for 24 h.
The solvent was removed in vacuo and the residue was subjected to
silica gel flash chromatography (EtOAc–hexane, 25%) to afford 15.
Yield: 0.45 g (78%); colorless syrup; [a]D25 –15.5 (c 0.35, CHCl3).
IR (neat): 3447, 2925, 2855, 1724, 1657, 1461, 1432, 1376, 1272,
1168, 1108, 1045, 820, 738, 703, 611, 506 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.65–7.70 (m, 4 H), 7.34–7.44 (m,
6 H), 6.90 (dd, J = 1.5, 15.8 Hz, 1 H), 6.02 (dt, J = 1.5, 15.8 Hz,
1 H), 4.18–4.26 (m, 1 H), 3.91 (q, J = 12.0, 6.0 Hz, 1 H), 3.75 (s,
3 H), 1.52–1.64 (m, 4 H), 1.20 (d, J = 6.2 Hz, 3 H), 1.05 (s, 9 H).
Yield: 0.072 g (60%); yellow liquid; [a]D25 +7.5 (c 0.75, CHCl3).
IR (neat): 3446, 2924, 2854, 1749, 1718, 1647, 1459, 1373, 1271,
1073, 1271, 1073, 1026, 987, 868, 764 cm–1.
1H NMR (CDCl3, 300 MHz): d = 6.54–6.81 (m, 2 H), 5.78–5.88 (m,
2 H), 4.99–5.09 (m, 2 H), 4.65–4.70 (m, 1 H), 4.45–4.49 (m, 1 H),
3.99–4.18 (m, 4 H), 3.69–3.85 (m, 1 H), 3.36–3.47 (m, 1 H), 1.72–
1.84 (m, 4 H), 1.41–1.56 (m, 4 H), 1.12–1.32 (m, 18 H).
13C NMR (CDCl3, 75 MHz): d = 150.4, 150.3, 135.8, 129.6, 127.6,
127.4, 119.7, 71.1, 69.1, 51.6, 34.2, 31.6, 29.7, 27.0, 22.3.
MS (ESI): m/z = 427 [M + H].
Compound 13
13C NMR (CDCl3, 75 MHz): d = 165.0, 146.3, 122.8, 96.5, 73.9,
69.5, 64.0, 30.7, 29.7, 28.8, 25.3, 19.2, 18.4, 14.3, 14.1.
3,4-Dihydropyran (0.41 g, 4.93 mmol) was added to a solution of 12
(0.42 g, 0.98 mmol) in CH2Cl2 (10 mL) and then a catalytic amount
of 10-camphorsulfonic acid (CSA; 0.023 g, 0.1 mmol) was added.
The resulting mixture was stirred at r.t. for 1 h. The solvent and ex-
cess dihydropyran were removed in vacuo and the crude product
was purified by silica gel flash chromatography (EtOAc–hexane,
5%) to give the protected alcohol as a colorless syrup. The syrup
was then dissolved in MeOH (10 mL) and treated with 20% aq
NaOH (2 mL) for 30 min. The reaction mixture was neutralized
with aq HCl and the solvent was evaporated in vacuo. The aqueous
MS (ESI): m/z = 503 [M + Na].
HRMS (ESI): m/z calcd for C26H40O8Na: 503.2620; found:
503.2601.
Compound 1
To a stirred suspension of 15 (0.026 g, 0.054 mmol) in MeOH (1.5
mL) was added a catalytic amount of PTSA (0.001 g, 0.005 mmol)
Synthesis 2012, 44, 783–787
© Thieme Stuttgart · New York

PAPER
Total Synthesis of (–)-Pyrenophorol
787
and the resulting mixture was stirred at r.t. for 30 min. The solvent
was evaporated in vacuo and the crude product was purified by sil-
ica gel flash chromatography (EtOAc–hexane, 40%) to afford 1.
(3) Wakamatsu, T.; Yamada, S.; Ozaki, Y.; Ban, Y.
Tetrahedron Lett. 1985, 26, 1989; and references therein.
(4) Karsten, K.; Umar, F.; Ulrich, F.; Barbara, S.; Siegfried, D.;
Gennaro, P.; Piero, S.; Sándor, A.; Tibor, K. Eur. J. Org.
Chem. 2007, 3206.
25
Yield: 0.015 g (96%); white solid; mp 136–138 °C; [a]D –3.2 (c
0.25, acetone).
(5) Findlay, J. A.; Li, G.; Miller, J. D.; Womiloju, T. O. Can. J.
IR (KBr): 3382, 2924, 2854, 1713, 1647, 1274, 1173, 1119 cm–1.
Chem. 2003, 81, 284.
1H NMR (CDCl3, 300 MHz): d = 6.83 (dd, J = 15.6 Hz, 2 H), 5.89
(m, 2 H), 5.10–5.01 (m, 2 H), 4.24–4.16 (m, 2 H), 2.69–2.48 (m,
2 H), 2.01–1.53 (m, 8 H), 1.20 (m, 6 H).
13C NMR (CDCl3, 75 MHz): d = 165.0, 149.3, 122.0, 70.3, 69.7,
30.4, 28.8, 18.2.
(6) MacMillan, J.; Simpson, T. J. Chem. Soc., Perkin Trans. 1
1973, 1487.
(7) Nozoe, S.; Hirai, K.; Tsuda, K.; Ishibashi, K.; Shirasak, M.
Tetrahedron Lett. 1965, 4675.
(8) Kind, R.; Zeeck, A.; Grabley, S.; Thiericke, R.; Zerlin, M.
J. Nat. Prod. 1996, 59, 539.
(9) Christner, C.; Kullertz, G.; Fischer, G.; Zerlin, M.; Grabley,
S.; Thiericke, R.; Taddei, A.; Zeeck, A. J. Antibiot. 1998, 51,
368.
MS (ESI): m/z = 335 [M + Na].
HRMS (ESI): m/z calcd for C16H24O6: 313.1651; found: 313.1656.
(10) Dommerholdt, E. J.; Thijs, L.; Zwanenburg, B. Tetrahedron
Lett. 1991, 32, 1499.
(11) Machinaga, N.; Kibayashi, C. Tetrahedron Lett. 1993, 34,
841.
(12) Amigoni, S.; Le Floc’h, Y. Tetrahedron: Asymmetry 1997,
8, 2827.
(13) Yadav, J. S.; Reddy, U. V. S.; Reddy, B. V. S. Tetrahedron
Lett. 2009, 50, 5984.
Acknowledgment
G.M.R. and T.S.R. thank the CSIR, New Delhi for financial support
in the form of fellowships. J.S.Y. acknowledges partial support by
the King Saud University for Global Research Network for Organic
Synthesis (GRNOS).
(14) (a) Yadav, J. S.; Pandurangam, T.; Reddy, V. V. B.; Reddy,
B. V. S. Synthesis 2010, 4300. (b) Sabitha, G.; Prasad, M.
N.; Shankaraiah, K.; Reddy, N. M.; Yadav, J. S. Synthesis
2010, 3891. (c) Sabitha, G.; Reddy, S. S. S.; Bhaskar, V.;
Yadav, J. S. Synthesis 2010, 1217. (d) Srihari, P.;
Kumaraswamy, B.; Somaiah, R.; Yadav, J. S. Synthesis
2010, 1039.
References
(1) (a) Clemer, C. F. W. D. Pure Appl. Chem. 1971, 28, 413.
(b) Boeckman, R. K. Jr.; Fayos, J.; Clardy, J. J. Am. Chem.
Soc. 1974, 96, 5954. (c) Omura, O.; Nakagawa, A.
J. Antibiot. 1975, 28, 401. (d) Omura, S. Macrolide
Antibiotics: Chemistry, Biology and Practice; Academic
Press: New York, 1984.
(15) Nicolaou, K.; Duggan, M. E.; Ladduwahetty, T.
Tetrahedron Lett. 1984, 25, 2069.
(16) Gerlach, H.; Gertle, K.; Thahnann, A. Helv. Chim. Acta
1977, 60, 2860.
(2) (a) Kis, Z.; Furger, P.; Sigg, H. P. Experientia 1969, 25,
123. (b) Grove, J. F. J. Chem. Soc. C 1971, 2261.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 783–787