Total synthesis of infectopyrone, aplysiopsenes A-C, ent-aplysiopsene D, phomapyrones A and D, 8,9-dehydroxylarone, and nectriapyrone

Article abstract of DOI:10.1016/j.tet.2012.06.104

The total synthesis of the 2-pyrone natural products nectriapyrone, aplysiopsenes A-C, ent-aplysiopsene D, phomapyrones A and D, and of 8,9-dehydroxylarone were achieved by Wittig olefination starting with vermopyrone. Infectopyrone was synthesized by Horner-Wadsworth-Emmons reaction starting with phomapyrone D. Racemic phomapyrone C methyl ether was obtained by hydrogenation of nectriapyrone. The total syntheses were achieved starting from commercially available 3,5-heptanedione and led to the desired natural products in 18-46% over 5-6 steps, whereupon all five-step syntheses were carried out with a single chromatographic workup. The total synthesis of infectopyrone, aplysiopsenes A-D, of phomapyrones A and D, and of 8,9-dehydroxylarone were achieved for the first time, giving unambiguous proof for the proposed structures of these natural products.

Full text of DOI:10.1016/j.tet.2012.06.104

Tetrahedron 68 (2012) 7280e7287
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Tetrahedron
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Total synthesis of infectopyrone, aplysiopsenes AeC, ent-aplysiopsene
D, phomapyrones A and D, 8,9-dehydroxylarone, and nectriapyrone
*
Oliver Geiseler, Joachim Podlech
€
€
Institut fur Organische Chemie, Karlsruher Institut fur Technologie (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of the 2-pyrone natural products nectriapyrone, aplysiopsenes AeC, ent-aplysiopsene
D, phomapyrones A and D, and of 8,9-dehydroxylarone were achieved by Wittig olefination starting with
vermopyrone. Infectopyrone was synthesized by HornereWadswortheEmmons reaction starting with
phomapyrone D. Racemic phomapyrone C methyl ether was obtained by hydrogenation of nectriapyrone.
The total syntheses were achieved starting from commercially available 3,5-heptanedione and led to the
desired natural products in 18e46% over 5e6 steps, whereupon all five-step syntheses were carried out
with a single chromatographic workup. The total synthesis of infectopyrone, aplysiopsenes AeD, of
phomapyrones A and D, and of 8,9-dehydroxylarone were achieved for the first time, giving un-
ambiguous proof for the proposed structures of these natural products.
Received 6 June 2012
Accepted 28 June 2012
Available online 4 July 2012
Keywords:
Polyketides
Fungal metabolites
Olefination
2-Pyrones
Ó 2012 Elsevier Ltd. All rights reserved.
Total synthesis
1. Introduction
Aplysiopsene D (7) was also isolated from the sea fan-derived fun-
gus Nigrospora sp. PSU-F1210 and aplysiopseneC (6) wasisolatedfrom
2-Pyrones, a class of natural products with a vast variety of
structures, are present in bacteria, microbials, plants, insects, and
animal systems. They show a plethora of different biological activi-
ties.1 Among the 2-pyrones are prominent representatives like the
coumarins, e.g., the anticoagulants warfarin2 and dicoumarol. The
extremely toxic and carcinogenic aflatoxins also have a 2-pyrone
substructure.3 They are produced by Aspergillus ssp. growing on
food and feed and thus are mycotoxins.4 Infectopyrone (1),
a 2-pyrone first isolated from Alternaria infectoria is furthermore
produced by Stemphyllium and Ulocladium sp. (Fig. 1). It shows cy-
Xylaria hypoxylon (here named as xylarone).11 Hardly anything is
known about biological activities of these compounds, but aply-
siopsene C is cytotoxicdit reduces cell proliferation by 50% (IC50
between 40 g/mL (Colo-320 cells) and 50 g/mL (L1210 cells), where
8,9-dehydroxylarone (8) was slightly more active (25e50
g/mL).11
)
m
m
m
Phomapyrone A (9, phomenin A) was isolated (together with pho-
menin B) for the first time from Phoma tracheiphila in 199312 and in
2009 from A. infectoria.13 Phomapyrones AeG (9e15) were isolated
from Leptosphaeria maculans, the anamorphous stage of Phoma lin-
gams,14 phomapyrones B (10) and C (11) were isolated from Paecilo-
myces lilacinus,15 and phomapyrones A (9), D (12) and G (15) were
isolated together with infectopyrone from Alternaria brassicicola in
totoxicity against mouse P388 leukemia cells (ID50 >25
m
g/mL).5
Vermopyrone (2) and nectriapyrone (3) are truncated derivatives
of infectopyrone,6 where nectriapyrone is antibiotic against Staph-
ylococcus aureus at a 30 ppm level.7 The biosynthesis of nectriapyr-
one and vermopyrone was investigated by Avent et al. giving proof
for the polyketide character of the 2-pyrones although they were
supposed to be monoterpens. 13C-labeled sodium acetate, methio-
nine and acetic acid were separately fed to Gliocladium vermoesenii
disproving the terpenoid origin of nectriapyrone and vermopyrone.8
The structurally closely related aplysiopsenes AeD (4e7) were
first isolated from the hermaeidan sacoglossan Aplysiopsis formosa. It
is supposed that they are part of the chemical defense of the mollusks
and are involved in the recovery of detached extremities. They are
polyketides produced via a mixed acetate/propionate pathway.9
2009.16 Phomapyrone A showed activity (LD50: 38.9
mg/mL) in a brine
shrimp bioassay indicating cytotoxicityand insecticidal activity12 and
phomapyrones AeC are phytotoxic.14 Vermopyrone, nectriapyrone
and various not yet named pyrones, e.g., (6-(1,2-dimethyloxiran-1-
yl)-4-methoxy-3-methyl-2H-pyran-2-one) were isolated from
Cephalotaxus hainanensis. This fungus is notorious to Chinese medi-
cine for its anticancer activity, but detailed biological studies have not
yet been reported for these recently isolated pyrones.17 Where total
syntheses of nectriapyrone18 and of gymnoconjugatins A and B19
have been published, no total syntheses of aplysiopsenes, of pho-
mapyrones and most of the related 2-pyrones have been reported. As
a part of our ongoing activities in the synthesis of mycotoxins from
Alternaria ssp.,20 we developed total syntheses of infectopyrone,
aplysiopsenes AeD, of phomapyrones A, C, and D, of 8,9-
dehydroxylarone and of nectriapyrone, which are given in this paper.
* Corresponding author. Tel.: þ49 721 608 43209; fax: þ49 721 608 47652; e-mail
addresses: joachim.podlech@kit.edu, joachim.podlech@ioc.uka.de (J. Podlech).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.104

O. Geiseler, J. Podlech / Tetrahedron 68 (2012) 7280e7287
7281
a drawbackdwe additionallygained access to Z-configured products,
which could be similarly tested on their biological activities. For
a proof of principle, we started with the synthesis of nectriapyrone
(3), a pyrone first synthesized in 1976 by Boll et al. in 6% over four
steps.18 Vermopyrone(2) wasreactedwithanylidepreparedfromthe
respective ethylphosphonium salt to yield nectriapyrone (3) with an
E/Z selectivity of 7:3, where the natural E isomer was obtained by
a simple chromatography (Scheme 2). It was obtained with an im-
proved 44% yield (over five steps) and was unambiguously identified
by comparison of published analytical data.
Scheme 2. Synthesis of nectriapyrone (3).
Aplysiopsenes were obtained by analogous olefination pro-
tocols. Reaction of vermopyrone (2) with the respective phospho-
rous ylides (prepared from the phosphonium bromides with butyl
lithium) gave rise to the corresponding aplysiopsenes with 33e80%
yield as mixtures of diastereoisomers (Table 1). Chromatography
furnished the E-configured natural aplysiopsenes AeC with
18e56% yield and thus with total yields of 10e31% over five steps.
While the precursor vermopyrone was stable at rt at least for
several weeks, the aplysiopsenes turned out to be quite unstable.
NMR samples showed signals of decomposition products when
stored for one week at 4 ꢀC.
Fig. 1.
a-Pyrone-derived natural products.
Table 1
2. Total synthesis of nectriapyrone and aplysiopsenes
Wittig reactions toward 2-pyrone-derived natural products
We considered vermopyrone (2) a suitable starting material for
the aplysiopsenes following a Wittig olefination strategy. Vermo-
pyrone (2) had been synthesized by Coleman et al.19 in four steps
starting with 3,5-heptanedione (16); we used their protocol with
minor modifications (Scheme 1). After formation of the pyrone
scaffold 18,21 we oxidized the allylic position using selenium di-
oxide19 followed by an oxidation with manganese dioxide to fur-
nish vermopyrone (2) with 55% yield over four steps. Utilizing
manganese dioxide, activated according to a method by Attenbur-
row,22 led to the given, somewhat better yield anddmore impor-
tantdto essentially pure vermopyrone (2), making special
purification protocols obsolete and thus significantly facilitating the
next steps of the total syntheses. Oxidation of the intermediate
allylic alcohol could also be achieved with DesseMartin period-
inane or using a mixture of commercially available manganese di-
oxide and potassium permanganate,23 albeit with lower yields.
In contrast to Coleman’s work, where a Takai olefination followed
by a Stille coupling was employed,19 we chose a Wittig olefination to
assemble the olefinic natural products. Using this route, we
could avoid hazardous organostannanes anddnot essentially
Product
R
Yield [%]
E/Z
Yield E [%]
Nectriapyrone (3)
Me
81
76
44
80
33
78
84
70
7:3
7:3
4:6
7:3
1:1
9:11
7:3
7:3
57
53
18
56
17
35
59
49
Aplysiopsene A (4)
Aplysiopsene B (5)
Aplysiopsene C (6)
(ent)-Aplysiopsene D (7)
Phomapyrone A (9)
Phomapyrone Da (12)
8,9-Dehydroxylarone (8)
Et
iPr
Pr
sBu
(E)-But-2-en-2-yl
Ac
(E)-Propen-1-yl
a
Differing reaction conditions. See Experimental section.
Synthesis of enantiomerically pure (S)-2-methylbut-1-
yltriphenylphosphonium bromide (20), the Wittig precursor for
the olefination toward aplysiopsene D (7), turned out to be not
straightforward. The standard protocol24a for the reaction of the
bromide 19 with triphenylphosphine yielded the phosphonium salt
20 together with a rearranged product 21 in a 2:1 ratio (Scheme 3).
This side product was not mentioned in the published synthesis of
the phosphonium salt 20.24
Scheme 3. Side reaction in the formation of phosphonium salt 20.
Scheme 1. Synthesis of vermopyrone (2).

7282
O. Geiseler, J. Podlech / Tetrahedron 68 (2012) 7280e7287
The synthesis of aplysiopsene D (7) could be accomplished with
Z¼w5:1) for the synthesis of the phosphonium salt. The Wittig
reaction was successful but gave rise to a 64% yield of an in-
separable mixture of four diastereoisomeric dehydroxylarones. By
using isomerically pure (E)-methyl crotonate (27) as precursor for
the Wittig salt we were able to synthesize pure (E)-(but-2-en-1-yl)
triphenylphosphonium bromide (30) in 51% yield over three steps
(Scheme 6), which in the further course was transferred via Wittig
olefination into 8,9-dehydroxylarone (8) with 70% yield and with
an E/Z ratio of 7:3. The pure natural product was thus obtained with
49% yield.
this mixture (4 equiv were employed), albeit with a quite low yield.
The olefination yielded 33% of a 1:1 mixture, which upon chro-
matographic purification gave rise to a 17% yield of the natural
product. The total synthesis of aplysiopsene D (7) was thus possible
in five steps with 9% yield. Comparison of the synthetic material’s
optical rotation with that of the natural product gave evidence for
the absolute configuration of aplysiopsene D. The specific rotation
of the natural product was given by Ciavatta et al. with ½a D25
ꢂ42.4
ꢁ
(c 0.04, CHCl3).9 As we obviously synthesized (S)-aplysiopsene D
and measured a specific rotation of ½a D20
þ27.5 (c 0.2, CHCl3), we
ꢁ
conclude that the natural product is R-configured and that the
synthetic product in fact is ent-aplysiopsene D (ent-7).
3. Total synthesis of phomapyrones and of 8,9-
dehydroxylarone
Phomapyrone A (9) could be synthesized according to the pro-
tocol used for the aplysiopsenes. The required phosphorus ylide
was obtained from (E)-1-bromo-2-methylbut-2-ene (24), which
was prepared from tiglic acid (22) with slight variation of a pub-
lished procedure.25 Reaction of vermopyrone (2) with the ylide
derived from the corresponding phosphonium salt 25 yielded an
olefination product as a mixture of diastereoisomers (E/Z¼9:11)
with 78% yield (Scheme 4). Separation of the isomers furnished the
E isomer phomapyrone A (9) with 35% yield and consequently with
a total yield of 19% over five steps.
Scheme 6. Synthesis of 8,9-dehydroxylarone (8).
Hydrogenation of nectriapyrone (3) with 10% palladium on
charcoal as catalyst led to racemic 9-O-methylphomapyrone C (31)
with excellent yield, but demethylation with boron tribromide
failed due to the instability of the starting material (Scheme 7).
Asymmetric hydrogenation of trisubstituted alkenes has been
reported to be successful with Crabtree’s catalyst.26 Unfortunately,
even with 25 mol % of Crabtree’s catalyst, we could not observe any
hydrogenation of nectriapyrone (3).
Scheme 7. Synthesis of (rac)-9-O-methylphomapyrone C (31).
Scheme 4. Synthesis of phomapyrone A (9).
4. Total synthesis of infectopyrone
Synthesis of phomapyrone D (12) turned out to be not possible
by following the established protocol. When the ylide 26 was
prepared by deprotonation of acetonyl(triphenylphosphonium)
bromide with butyl lithium, a poor 12% yield of the Z-isomer was
obtained in the subsequent olefination. However, variation of the
protocol by precipitation of the ylide 26 with aqueous sodium hy-
droxide followed by Wittig reaction in benzene led to the successful
synthesis of phomapyrone D (12) with 84% yield for the E/Z-mix-
ture of diastereoisomers and with 59% yield for the natural product
(Scheme 5).
The total synthesis of infectopyrone (1) was considered possible
starting with phomapyrone D (12). However, Wittig reaction of this
ketone with ethyl (triphenylphosphoranylidene)acetate gave
a non-sufficient 14% yield even after seven days at 120 ꢀC in a sealed
vial. Therefore we tested a HornereWadswortheEmmons (HWE)
reaction using triethyl phosphonoacetate (32) deprotonated with
sodium hydride. Here a satisfactory 69% yield of a mixture of iso-
mers 33 (E/Z¼7:3) was achieved. Unfortunately, basic saponifica-
tion resulted in a complete decomposition of the material. Using
commercially available diethylphosphonoacetic acid for a one-step
synthesis of infectopyrone via HWE reaction with phomapyrone D
(2 equiv of base were used) was not successful. However, olefina-
tion using the corresponding tert-butyl diethyl phosphonoacetate
(34) deprotonated with butyl lithium was achieved with 54% yield
(E/Z¼2:1), where both isomers 35 could be separated and obtained
in pure form. Cleavage of the E-configured ester (E,E)-35 with 25%
trifluoroacetic acid in dichloromethane for 30 min furnished
infectopyrone (1) with quantitative yield (Scheme 8).
Scheme 5. Synthesis of phomapyrone D (12).
Comparison of the spectroscopic data unambiguously proved
the constitution and configuration of infectopyrone (1). A 0.11 ppm
upfield shift of all proton signals published for the natural product
For the synthesis of 8,9-dehydroxylarone (8) we started with
commercially available crotyl bromide (technical quality, E/

O. Geiseler, J. Podlech / Tetrahedron 68 (2012) 7280e7287
7283
overnight at 4 ꢀC to yield pyrone 17 as colorless crystals (5.30 g,
34.4 mmol, 73%). Mp 180 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d¼1.10
(t, J¼7.5 Hz, 3H, CH3), 1.74 (s, 3H, CH3), 2.43 (q, J¼7.5 Hz, 2H, CH2),
5.97 (s, 1H, CH), 11.10 (br s, 1H, OH).
6.2.2. 6-Ethyl-4-methoxy-3-methyl-2H-pyran-2-one (18). Me2SO4
(36.0 g, 27.3 mL, 285 mmol) was added under an Ar atmosphere
slowly to a suspension of 17 (4.40 g, 28.5 mmol) and K2CO3 (39.4 g,
285 mmol) in anhydrous acetone (250 mL) and the mixture was
heated to reflux overnight and cooled to rt. H2O (50 mL) was added,
stirring was continued for 30 min and the aqueous layer was
extracted with EtOAc (3ꢃ100 mL). The combined organic layers
were dried (Na2SO4) and concentrated in vacuo to yield 18 as
a yellowish solid (4.79 g, 28.5 mmol, quant.), which was used
Scheme 8. Synthesis of infectopyrone (1).
without purification. 1H NMR (300 MHz, CDCl3):
d
¼1.22 (t, J¼7.5 Hz,
3H, CH3), 1.88 (s, 3H, CH3), 2.51 (q, J¼7.5 Hz, 2H, CH2), 3.86 (s, 3H,
is obviously due to a differing calibration.5 With this correction, all
deviations are within a 0.02 ppm range. For the 13C NMR spectra,
a consistent upfield shift of 0.2 ppm was similarly observed for all
signals.
OCH3), 5.98 (s, 1H, CH).
6.2.3. 6-Acetyl-4-methoxy-3-methyl-2H-pyran-2-one (2, vermopyr-
one). SeO2 (19.0 g, 172 mmol) was added to a soln of 18 (4.81 g,
28.6 mmol) in dioxane (150 mL) and the mixture was heated to
110 ꢀC overnight, cooled to rt, diluted with Et2O (300 mL), filtered
(Celite) and concentrated in vacuo. The crude product and MnO2
(freshly precipitated,22 24.9 g, 286 mmol) were suspended in
CH2Cl2 (150 mL), stirred at rt for 2 d, and filtered (Celite) to yield
vermopyrone (2, 3.91 g, 21.5 mmol, 75%) as a yellowish solid. Mp
5. Conclusion
In summary, we presented an efficient approach to nectriapyr-
one (3), aplysiopsenes AeC (4e6), phomapyrone A and D (9 and
12), 8,9-dehydroxylarone (8) and to (rac)-9-O-methylphomapyrone
C (31), where only one chromatographic purification over all steps
was necessary in each of the total syntheses. Furthermore we could
prove the absolute configuration of aplysiopsene D (7). The total
synthesis of infectopyrone (1), a major metabolite of A. infectoria,
was also successfully completed for the first time using phoma-
pyrone D as a suitable starting material. Our synthetic strategy did
not only give access to the mentioned natural products but fur-
thermore yielded the non-natural Z-configured pyrones.
111 ꢀC. Rf¼0.22 (hexanes/EtOAc, 2:1). IR (ATR): v 3084 cmꢂ1, 2926,
~
1685, 1628, 1555, 1464, 1396, 1359, 1339, 1253, 1219, 1162, 1024,
1004, 974, 937, 869, 745, 733, 678, 660, 613, 530, 491, 436. 1H NMR
(250 MHz, CDCl3):
d
¼2.01 (s, 3H, CH3), 2.54 (s, 3H, CH3), 3.95 (s, 3H,
OCH3), 7.06 (s, 1H, CH). 13C NMR (75 MHz, CDCl3):
d
¼9.4, 25.9, 56.7,
98.0, 109.7, 153.1, 163.3, 164.1, 191.6. MS (EI): m/z (%)¼182 (35) [Mþ],
139 (100) [(MꢂCH3CO) ], 83 (62). HRMS (12C9 H1016O4þ, EI): calcd
þ
1
182.0579 amu; found 182.0576 amu. The spectroscopic data are in
full agreement with published data.19 A small fraction of the
mentioned crude product of the SeO2 oxidation was purified for
analytical reasons with column chromatography (silica gel, CH2Cl2/
6. Experimental
acetone, 25:1/2:1). 1H NMR (400 MHz, CDCl3):
d
¼1.46 (d,
6.1. General procedure (GP) for Wittig olefinations
J¼6.6 Hz, 3H, CH3), 1.86 (s, 3H, CH3), 3.60 (br s, 1H, OH), 3.88 (s, 3H,
OMe) 4.59 (q, J¼6.6 Hz, 1H, CH), 6.41 (s, 1H, CH). 13C NMR (100 MHz,
nBuLi (1.6 M in hexanes, 1 equiv) is added dropwise to a sus-
pension of the corresponding Wittig salt in anhydrous THF (8 mL
per 1 mmol Wittig salt) under an Ar atmosphere at 0 ꢀC. After
stirring for 30 min at this temperature, a soln of the ketone
(1 equiv) in anhydrous THF (8 mL per mmol ketone) is added
dropwise to the yellowish soln. When addition was completed, the
reaction mixture was allowed to warm to rt and stirred overnight,
quenched by addition of satd aq NH4Cl soln (1 mL per mL nBuLi).
The organic layer is filtered (Celite, rinsing with EtOAc), dried
(Na2SO4), concentrated, and purified by short column chromatog-
raphy (silica gel, hexanes/EtOAc, 15:1) to yield the olefins as
a mixture of isomers. Separation of the isomers is achieved with
MPLC (silica gel, hexanes/EtOAc, 20:1) if not mentioned otherwise.
CDCl3):
d
¼8.4 (CH3), 21.7 (CH3), 56.4 (CH3), 66.7 (CH), 92.1 (CH),
101.3 (C), 165.6 (C), 166.3 (C), 166.4 (C).
6.3. (E)-6-(But-2-en-2-yl)-4-methoxy-3-methyl-2H-pyran-2-
one (3, nectriapyrone)
Vermopyrone (2, 13.0 mg, 71
the GP yielding a mixture of nectriapyrone (3) and Z-3 (11.2 mg,
58
mol, 81%, E/Z¼7:3) as a colorless waxy solid. The E isomer was
mmol) was converted according to
m
separated by short column chromatography (silica gel, hexanes/
EtOAc, 15:1). 1H NMR (300 MHz, CDCl3):
d
¼1.82 (d, 3J¼7.1 Hz, 3H,
CH3), 1.86 (s, 3H, CH3), 1.91 (s, 3H, CH3), 3.89 (s, 3H, OCH3), 6.08 (s,
1H, CH), 6.67 (qq, 3J¼7.1 Hz, 4J¼1.1 Hz, CH). 13C NMR (75 MHz,
CDCl3):
d
¼8.6, 12.1, 14.2, 56.1, 91.5, 102.0, 127.0, 129.7, 160.2, 165.1,
6.2. Vermopyrone (2)
165.9. The spectroscopic data are in full agreement with published
data.7
6.2.1. 6-Ethyl-4-hydroxy-3-methyl-2H-pyran-2-one (17). LDA (2 M
soln in THF, 46.8 mL, 93.6 mmol) was added under an Ar atmo-
sphere dropwise at ꢂ15 ꢀC to a soln of heptan-3,5-dione (16, 6.00 g,
6.34 mL, 46.8 mmol) in anhydrous THF (25 mL). The mixture was
stirred for 30 min and poured on ground dry ice and left for 30 min.
Hydrochloric acid (5 M) was added very carefully until the evolu-
tion of gas stopped. The mixture was extracted with EtOAc
(3ꢃ50 mL), dried (Na2SO4), and concentrated. Ac2O (50 mL) was
added and the soln was left for 2 h. When crystallization started,
the soln was covered with a layer of hexanes (150 mL) and left
6.4. Aplysiopsenes
6.4.1. (E)-4-Methoxy-3-methyl-6-(pent-2-en-2-yl)-2H-pyran-2-one
(4, aplysiopsene A). Vermopyrone (2, 19.0 mg, 104
verted according to the GP. A mixture of aplysiopsene A (4) and Z-4
(16.4 mg, 79
mmol) was con-
m
mol, 76%, E/Z¼7:3) was obtained as a colorless solid.
The isomers were separated by MPLC (silica gel, hexanes/EtOAc,
20:1). E isomer (aplysiopsene A): IR (ATR): v 3339 cmꢂ1, 2926, 1679,
~
1639, 1551, 1460, 1388, 1245, 1170, 1010, 904, 801, 752, 542, 410. 1H

7284
O. Geiseler, J. Podlech / Tetrahedron 68 (2012) 7280e7287
NMR (300 MHz, CDCl3):
d
¼1.07 (t, 3J¼7.5 Hz, 3H, CH3), 1.88 (d,
(400 MHz, CDCl3):
d
¼0.74 (t, J¼7.4 Hz, 3H, CH3), 0.91 (d, J¼6.7 Hz,
4J¼1.0 Hz, 3H, CH3), 1.94 (s, 3H, CH3), 2.24 (quint, 3J¼7.5 Hz, 2H,
CH2), 3.90 (s, 3H, OCH3), 6.10 (s, 1H, CH), 6.61 (tq, 3J¼7.5 Hz,
3H, CH3), 1.35e1.47 (m, 2H, CH2), 1.67e1.80 (m, 1H, CH), 3.49e3.71
(m, 2H, CH2), 7.60e7.85 (m, 15H, 3 Ph). 13C NMR (100 MHz, CDCl3):
4J¼1.0 Hz, 1H, CH). 13C (125 MHz, CDCl3)
d¼8.6 (CH3), 12.3 (CH3),
d
¼20.3 (d, JCeP¼7 Hz, CH3), 23.2 (CH3), 29.1 (d, JCeP¼48 Hz, CH2),
13.5 (CH3), 22.0 (CH2), 56.1 (CH3), 91.6 (CH), 101.9 (C), 125.4 (C),
30.6 (CH2), 118.7 (d, JCeP¼85 Hz, C), 130.4 (d, JCeP¼13 Hz, CH), 133.5
136.8 (CH), 160.1 (C), 165.1 (C), 165.9 (C). MS (EI): m/z (%)¼208 (100)
(d, JCeP¼10 Hz, CH), 134.9 (d, JCeP¼3 Hz, CH). Compound 21: 1H
þ
þ
[M ], 180 (48), 165 (80), 139 (40), 91 (64). HRMS (12C12 H1616O3
,
NMR (400 MHz, CDCl3):
d¼1.00 (t, J¼7.3 Hz, 3H, CH3), 1.53 (d,
1
EI): calcd 208.1099 amu; found 208.1101 amu. The spectroscopic
JHeP¼18.4 Hz, 6H, 2ꢃ CH3), 1.84e1.92 (m, 2H, CH2), 7.60e7.85 (m,
data are in full agreement with published data.9
15H, 3 Ph). 13C NMR (100 MHz, CDCl3):
d¼7.2 (d, JCeP¼12 Hz, CH3),
11.1 (CH3), 30.8 (d, JCeP¼10 Hz, CH2), 38.5 (d, JCeP¼42 Hz, C),117.1 (d,
JCeP¼79 Hz, C), 130.7 (d, JCeP¼12 Hz, CH), 134.4 (d, JCeP¼8 Hz, CH),
135.2 (d, JCeP¼3 Hz, CH).
6.4.2. (E)-4-Methoxy-3-methyl-6-(4-methylpent-2-en-2-yl)-2H-py-
ran-2-one (5, aplysiopsene B) and (Z)-4-methoxy-3-methyl-6-(4-
methylpent-2-en-2-yl)-2H-pyran-2-one (Z-5). Vermopyrone (2,
40.0 mg, 220
3 equiv of BuLi and the corresponding Wittig salt) yielding a mix-
ture of aplysiopsene B (5) and Z-5 (21.3 mg, 96
m
mol) was converted according to the GP (with
6.4.5. (S,E)-4-Methoxy-3-methyl-6-(4-methylhex-2-en-2-yl)-2H-py-
ran-2-one (ent-7, ent-aplysiopsene D). Vermopyrone (2, 39.2 mg,
mmol, 44%, E/Z¼4:6)
215
and the corresponding Wittig salt) to a mixture of ent-aplysiopsene
D (ent-7) and Z-ent-7 (16.8 mg, 71
mmol) was converted according to the GP (with 4 equiv of BuLi
as a colorless solid. The isomers were separated by MPLC (silica gel,
hexanes/EtOAc, 20:1). Compound 5: IR (ATR): v 2955 cmꢂ1, 2922,
m
mol, 33%, E/Z¼1:1). The E iso-
~
2861, 1683, 1636, 1608, 1551, 1469, 1442, 1390, 1356, 1336, 1253,
1231, 1177, 1123, 1101, 1013, 961, 913, 895, 860, 819, 747, 665, 602,
mer was separated using MPLC (silica gel, hexanes/EtOAc, 20:1).
½
a 2D0
ꢁ
þ27.5 (c 0.2, CHCl3). IR (ATR): v 3086 cmꢂ1, 2958, 2923, 2867,
~
543, 518, 417. 1H NMR (300 MHz, CDCl3):
d
¼1.04 (d, J¼6.6 Hz, 6H,
2852, 1683, 1638, 1608, 1549, 1442, 1387, 1357, 1342, 1264, 1245,
1175, 1127, 1091, 1032, 1010, 973, 945, 909, 893, 871, 857, 818, 794,
779, 747, 694, 665, 603, 539, 518, 418. 1H NMR (400 MHz, CDCl3):
2ꢃ CH3), 1.89 (d, J¼1.2 Hz, 3H, CH3), 1.93 (s, 3H, CH3, CH3), 2.69
(dsept, J¼6.6, 9.6 Hz, 1H, CH), 3.90 (s, 3H, OCH3), 6.09 (s, 1H, CH),
6.46 (dq, J¼1.2, 9.6 Hz, 1H, CH). 13C NMR (75 MHz, CDCl3):
d
¼8.6
d
¼0.85 (t, J¼7.4 Hz, 3H, CH3), 1.01 (d, J¼6.6 Hz, 3H, CH3), 1.30e1.49
(CH3), 12.4 (CH3), 22.4 (CH), 28.0 (CH), 56.1 (CH3), 91.7 (CH3), 102.0
(m, 2H, CH2), 1.89 (d, J¼1.1 Hz, 3H, CH3), 1.93 (s, 3H, CH3), 2.39e2.50
(m, 1H, CH), 3.90 (s, 3H, OCH3), 6.10 (s, 1H, CH), 6.41 (dd, J¼1.1,
(C), 123.8 (C), 142.1 (CH3), 160.2 (C), 165.1 (C), 165.9 (C). MS (EI): m/z
(%)¼222 (100)þ [Mþ], 207 (44), 179 (28), 139 (20). HRMS
10.0 Hz, 1H, CH). 13C NMR (100 MHz, CDCl3):
d
¼8.6 (CH3), 12.0
(
C
1H1816O3 , EI): calcd 222.1256 amu; found 222.1258 amu. Z-
(CH3), 12.7 (CH3), 20.1 (CH3), 29.9 (CH2), 35.0 (CH), 56.1 (CH3), 91.7
(CH), 101.9 (C), 124.7 (C), 141.2 (CH), 160.2 (C), 165.1 (C), 166.0 (C).
12
13
5: 1H NMR (300 MHz, CDCl3):
d¼1.02 (d, J¼6.6 Hz, 6H, 2ꢃ CH3), 1.94
(s, 3H, CH3), 1.95 (d, J¼1.4 Hz, 3H, CH3), 2.95 (dsept, J¼6.6, 10.1 Hz,
1H, CH), 3.88 (s, 3H, OCH3), 5.51 (dq, J¼1.4, 10.1 Hz, 1H, CH), 6.08 (s,
MS (EI): m/z (%)¼236 (78) [Mþ], 168 (100), 152 (37), 109 (25), 83
12
(56). HRMS (½
C
1H2016O3þꢁ, EI): calcd 236.1412 amu, found
14
1H, CH). 13C NMR (75 MHz, CDCl3):
d¼8.6, 21.8, 23.1, 28.5, 56.1, 95.0,
236.1412 amu. The spectroscopic data are in full agreement with
102.2, 124.9, 143.8, 160.4, 165.2, 165.4. The spectroscopic data are in
published data.9
full agreement with published data.9
6.5. Phomapyrones
6.4.3. (E)-6-(Hex-2-en-2-yl)-4-methoxy-3-methyl-2H-pyran-2-one
(6, aplysiopsene C). Vermopyrone (2, 19.0 mg, 104
verted according to the GP yielding a mixture of aplysiopsene C (6)
and Z-6 (18.4 mg, 83
m
mol) was con-
6.5.1. (E)-2-Methylbut-2-en-1-ol (23). In slight variation of a pub-
lished protocol25 tiglic acid (22, 5.00 g, 49.9 mmol) was dissolved in
anhydrous Et2O (20 mL) and added dropwise to an ice-cooled
suspension of LiAlH4 (3.79 g, 99.9 mmol) in anhydrous Et2O
(50 mL). When addition was completed, the suspension was stirred
at 0 ꢀC for a further 15 min, and stirred at rt overnight. After hy-
drolysis at 0 ꢀC and filtration over Celite, the organic layer was
washed with satd aq NaHCO3 soln (50 mL), 1 M HCl (50 mL) and
brine (50 mL), dried (Na2SO4) and was carefully evaporated (50 ꢀC,
850 mbar). Alcohol 23 was obtained as a colorless liquid (3.32 g,
m
mol, 80%, E/Z¼7:3) as a colorless solid. The
isomers were separated by MPLC (silica gel, hexanes/EtOAc, 20:1).
Compound 6: IR (ATR): v 2957 cmꢂ1, 2927, 2869, 1681, 1640, 1617,
~
1554, 1451, 1405, 1383, 1356, 1247, 1169, 1008, 900, 799, 747, 638,
605, 546, 494. 1H NMR (300 MHz, CDCl3):
d
¼0.94 (t, J¼7.4 Hz, 3H,
CH3), 1.45e1.53 (m, 2H, CH2), 1.88 (d, J¼1.0 Hz, 3H, CH3), 1.93 (s, 3H,
CH3), 2.16e2.24 (m, 2H, CH2), 3.90 (s, 3H, OCH3), 6.10 (s, 1H, CH),
6.62 (tq, J¼1.0, 7.5 Hz, 1H, CH). 13C NMR (75 MHz, CDCl3):
¼8.6
d
(CH3), 12.5 (CH3), 13.9 (CH3), 22.2 (CH2), 30.7 (CH2), 56.1 (CH3), 91.6
(CH), 101.9 (C), 126.0 (C), 135.3 (CH), 160.1 (C), 165.1 (C), 166.0 (C).
38.5 mmol, 77%). 1H NMR (300 MHz, CDCl3):
d
¼1.62 (dq, J¼1.3,
6.7 Hz, 3H, CH3),1.67 (m, 3H, CH3), 4.00 (m, 2H, CH2), 5.49 (qq, J¼1.1,
MS (EI): m/z (%)þ¼222 (100) [Mþ], 194 (22), 165 (57), 139 (13). HRMS
6.7 Hz, 1H, CH).
(
C
1H1816O3 , EI): calcd 222.1256 amu; found 222.1258 amu.
13
12
The spectroscopic data are in full agreement with published data.9
6.5.2. (E)-1-Bromo-2-methylbut-2-ene (24). In slight variation of
a published protocol25 alcohol 23 (3.32 g, 38.5 mmol) in anhydrous
Et2O (50 mL) was cooled to 0 ꢀC and PBr3 (1.83 mL, 5.22 g,
19.3 mmol) was added dropwise via a syringe. The reaction mixture
was stirred at 0 ꢀC for 30 min and for 3 h at rt before quenching
with satd aq Na2CO3 soln (10 mL). The organic layer was washed
with brine (50 mL), dried (Na2SO4), and distilled (65 ꢀC, 100 mbar)
yielding the bromide 24 as a colorless liquid (2.91 g, 19.5 mmol,
6.4.4. (S)-2-Methylbut-1-yltriphenylphosphonium bromide
(20).24a (S)-1-Bromo-2-methylbutane (19, 1.00 g, 6.62 mmol) and
Ph3P (1.74 g, 6.63 mmol) in MeCN (5 mL) were placed under an Ar
atmosphere in a sealed tube and heated to 130 ꢀC for 72 h. The
mixture was concentrated, the residue was dissolved in CH2Cl2
(5 mL) and the Wittig salt was precipitated by addition of Et2O
(50 mL). The white solid was collected and excessively washed with
51%). 1H NMR (300 MHz, CDCl3):
1.75 (m, 3H, CH3), 3.98 (m, 2H, CH2), 5.69 (q, J¼6.8 Hz, 1H, CH).
d¼1.63 (dq, J¼0.8, 6.8 Hz, 3H, CH3),
Et2O
(10ꢃ50
mL)
yielding
20
and
tert-pentyl-
triphenylphosphonium bromide (21) as an inseparable mixture
(2.33 g, 5.64 mmol, 85%, 2:1 mixture of isomers). Mixture of iso-
6.5.3. (E)-2-Methylbut-2-en-1-yltriphenylphosphonium
bromide
mers: IR (ATR): v 2965 cmꢂ1, 2866, 1584, 1483, 1459, 1435, 1314,
(25). Bromide 24 (1.00 g, 6.71 mmol) and Ph3P (1.76 g, 6.71 mmol)
were dissolved in anhydrous MeCN (5 mL) under an Ar atmosphere
in a sealed tube and heated to 120 ꢀC for 2 h. The white precipitate
was filtered while hot and washed with EtOAc (10 mL). The
~
1189, 1147,1101, 995, 840,þ753, 717, 687, 527, 509, 437. MS (FAB): m/z
12
(%)¼333 (100) [(MꢂBr) ]. HRMS (½
C
1H2631Pþꢁ, FAB): calcd
23
331.1772 amu, found 333.1774 amu. Compound 20: 1H NMR

O. Geiseler, J. Podlech / Tetrahedron 68 (2012) 7280e7287
7285
phosphonium compound 25 (2.23 g, 5.05 mmol, 75%) was obtained
9-O-methylphomapyrone C (31) as a yellowish oil (12.9 mg,
as a colorless solid. IR (ATR): v 3006 cmꢂ1, 2865, 2831, 2764, 1586,
65.8
m
mol, 98%). IR (ATR): v 3407 cmꢂ1, 3098, 2966, 2930, 2876,
~
~
1485, 1435, 1387, 1325, 1261, 1184, 1161, 1106, 1024, 995, 869, 838,
1703, 1645, 1571, 1463, 1404, 1381, 1355, 1323, 1240, 1195, 11,163,
801, 765, 755, 739, 714, 690, 579, 494, 447, 431. 1H NMR (300 MHz,
1132, 1031, 973, 898, 808, 756, 699, 519, 408. 1H NMR (300 MHz,
DMSO-d6):
JHeP¼15.6 Hz, 2H, CH2), 5.31 (t, J¼6.5 Hz,1H, CH), 7.74e7.92 (m,15H,
3 Ph). 13C NMR (75 MHz, DMSO-d6):
d
¼1.34 (br s, 3H, CH3),1.45 (t, J¼6.5 Hz, 3H, CH3), 4.44 (d,
CDCl3):
d
¼0.87 (t, J¼7.4 Hz, 3H, CH3), 1.22 (d, J¼6.9 Hz, 3H, CH3),
1.48e1.59 (m, 1H, CH2), 1.67e1.75 (m, 1H, CH2), 1.90 (s, 3H, CH3),
d¼13.7 (d, JCeP¼3.1 Hz, CH3),
2.43e2.52 (m, 1H, CH), 3.88 (s, 3H, OCH3), 5.97 (s, 1H, CH). 13C NMR
17.6 (d, JCeP¼2.1 Hz, CH3), 31.6 (d, JCeP¼46.1 Hz, CH2), 118.5 (d,
JCeP¼84.6 Hz, 3ꢃ C), 123.2 (d, JCeP¼10.6 Hz, C), 129.9 (d,
JCeP¼11.9 Hz, C) 130.1 (d, JCeP¼12.3 Hz, 6ꢃ CH), 133.9 (d,
JCeP¼9.8 Hz, 6ꢃ CH), 135.0 (d, JCeP¼2.9 Hz, 3ꢃ CH).þMS (FAB): m/z
(75 MHz, CDCl3):
d¼8.4 (CH3), 11.7 (CH3),18.0 (CH3), 27.5 (CH2), 40.4
(CH), 56.1 (CH3), 93.2 (CH), 101.0 (C), 165.8 (C), 166.0 (C), 168.0 (C).
MS (EI): m/z (%)¼196 (45) [Mþ], 139 (100), 83 (21). HRMS
12
(½
C
11
1H1616O3þꢁ, EI): calcd 196.1099 amu, found 196.1098 amu.
þ
(%)¼331.2 (100) [(MꢂBr) ]. HRMS (½
C
23
1H2431P ꢁ, FAB): calcd
The spectroscopic data are in full agreement with published data.14
12
331.1616 amu, found 331.1614 amu.
6.6. 8,9-Dehydroxylarone (8)
6.5.4. (E,E)-4-Methoxy-3-methyl-6-(4-methylhexa-2,4-dien-2-yl-
2H-pyran-2-one) (9, phomapyrone A). Vermopyrone (2, 44.0 mg,
6.6.1. (E)-But-2-en-1-ol (28). Anhydrous AlCl3 (1.65 g, 12.5 mmol)
was added portionwise to an ice-cooled suspension of LiAlH4
(1.52 g, 40.0 mmol) in anhydrous Et2O (150 mL).28 The suspension
was stirred at rt for 30 min. A soln of pure (E)-methyl crotonate (27,
5.00 g, 49.9 mmol) in anhydrous Et2O (15 mL) was added dropwise
at ꢂ15 ꢀC to the suspension via a syringe. The mixture was stirred at
ꢂ15 ꢀC for 30 min and was then carefully quenched with satd aq
NH4Cl soln. The aluminum salts were removed by filtration (Celite)
and the filter cake was excessively rinsed with Et2O. The etheric
filtrate was dried (Na2SO4) and carefully concentrated (30 ꢀC,
500 mbar) to yield (E)-but-2-en-1-ol (3.28 g, 45.5 mmol, 91%) as
a colorless liquid with minor impurities. The crude alcohol 28 was
used without further purification. 1H NMR (300 MHz, CDCl3):
242
were converted according to the GP to a mixture of phomapyrone A
(9) and Z-9 (44.0 mg, 188
mmol) and phosphonium compound 25 (99 mg, 242 mmol)
m
mol, 78%, E/Z¼45:55) as a colorless solid.
The (E,E)-isomer was separated by MPLC (silica gel, hexanes/EtOAc,
20:1). Compound 9: IR (ATR): v 2918 cmꢂ1, 1680, 1627, 1607, 1549,
~
1447, 1402, 1373, 1353, 1252, 1231, 1187, 1163, 1085, 1044, 1010, 912,
891, 826, 800, 745, 583, 560, 544, 516, 402. 1H NMR (300 MHz,
CDCl3):
d
¼1.75 (d, J¼6.9 Hz, 3H, CH3),1.83 (br s, 3H, CH3),1.94 (s, 3H,
CH3), 2.03 (d, J¼0.9 Hz, 3H, CH3), 3.91 (s, 3H, OCH3), 5.63 (dquart,
J¼6.9, 0.9 Hz, 1H, CH), 6.15 (s, 1H, CH), 6.99 (br s, 1H, CH). 13C NMR
(75 MHz, CDCl3):
d¼8.6 (CH3), 14.0 (CH3), 14.1 (CH3), 16.5 (CH3), 56.1
(CH3), 92.3 (CH), 102.0 (C), 123.9 (C), 129.1 (CH), 133.0 (C), 136.7
(CH),160.8 (C),165.0 (C),165.9 (C). MS (EI): m/z (%)¼234 (100) [Mþ],
d
¼1.69 (d, J¼5.1 Hz, 3H, CH3), 1.84 (br s, 1H, OH), 4.04 (d, J¼4.0 Hz,
12
219 (54), 191 (35), 157 (37), 83 (27). HRMS (½
C
1H1816O3þꢁ, EI):
2H, CH2), 5.58e5.75 (m, 2H, 2ꢃ CH). 13C NMR (75 MHz, CDCl3):
14
calcd 234.1256, found 234.1254. The spectroscopic data are in full
d¼17.6 (CH3), 63.6 (CH2), 128.0 (CH), 130.2 (CH).
agreement with published data.14
6.6.2. (E)-1-Bromobut-2-ene (29). PBr3 (2.13 mL, 6.16 g, 22.7 mmol)
was added to an ice-cooled soln of crude 28 (3.28 g, 45.5 mmol) in
anhydrous Et2O (50 mL). The soln was stirred overnight at rt and
neutralized with satd aq NaHCO3 soln. The organic layer was washed
with brine, dried (Na2SO4), and the solvent was carefully evaporated.
The residue was distilled (bp 97e99 ꢀC, lit. 98e102 ꢀC29) to yield the
bromide 29 as a colorless liquid (3.97 g, 29.4 mmol, 65%). 1H NMR
6.5.5. (E)-4-Methoxy-3-methyl-6-(4-oxopent-2-en-2-yl)-2H-pyran-
2-one (12, phomapyrone D). A few drops of 5 M NaOH were added
to a soln of (2-oxopropyl)triphenylphosphonium bromide (500 mg)
in H2O (10 mL) and the evolving white precipitate was filtered and
lyophilized. The resulting ylide 26 (74 mg, 232
mmol) and vermo-
pyrone (2, 26 mg, 145 mol) were dissolved in anhydrous benzene
m
(4 mL) under an Ar atmosphere in a sealed tube and heated to
120 ꢀC for 24 h. After removal of the solvent under reduced pres-
sure, the brown residue was purified by column chromatography
(silica gel, hexanes/EtOAc, 3:1) yielding phomapyrone D (12,
(300 MHz, CDCl3):
d
¼1.74 (d, J¼5.8 Hz, 3H, CH3), 3.94 (d, J¼7.0 Hz,
2H, CH2), 5.66e5.86 (m, 2H, 2ꢃ CH). 13C NMR (75 MHz, CDCl3):
d¼17.6 (CH3), 33.5 (CH2), 127.6 (CH), 131.4 (CH).
14.0 mg, 63.1
58.6
mol, 40%) as yellowish solids. Compound 26: 1H NMR
(300 MHz, CDCl3):
m
mol, 44%) and a mixture of 12 and Z-12 (13.0 mg,
6.6.3. (E)-(But-2-en-1-yl)triphenylphosphonium bromide (30). Ph3P
(1.73 g, 6.60 mmol) was added to a soln of bromide 29 (891 mg,
6.60 mmol) in anhydrous MeCN (5 mL) under an Ar atmosphere
and the mixture was heated to 120 ꢀC in a sealed tube for 30 min.
The white precipitate was filtered hot and washed with EtOAc
(25 mL) yielding the phosphonium compound 30 (2.29 g,
m
d¼2.09 (d, J¼1.6 Hz, 3H, CH3), 3.69 (br s, 1H, CH),
7.43e7.69 (m, 15H, 3ꢃ Ph). Compound 12: Rf¼0.42 (hexanes/EtOAc,
1:1). IR (ATR): v 3517 cmꢂ1, 3100, 3003, 2926, 2560, 1678, 1627,
~
1586, 1545, 1469, 1443, 1405, 1354, 1257, 1230, 1181, 1165, 1109,
1048, 1012, 967, 944, 901, 836, 745, 688, 643, 575, 543, 509, 452. 1H
5.76 mmol, 87%) as a colorless solid. IR (ATR): v 3005 cmꢂ1, 2862,
~
NMR (300 MHz, CDCl3):
3.95 (s, 3H, OCH3), 6.49 (s, 1H, CH), 7.12 (s, 1H, CH). 13C NMR
(75 MHz, CDCl3):
d
¼1.98 (s, 3H, CH3), 2.33 (s, 6H, 2ꢃ CH3),
2827, 2762, 1586, 1486, 1435, 1324, 1238, 1181, 1160, 1108, 1061, 996,
966, 920, 850, 802, 749, 735, 720, 689, 537, 502, 473, 442, 401. 1H
d
¼9.0 (CH3), 13.5 (CH3), 32.6 (CH3), 56.3 (CH3),
NMR (300 MHz, D2O/DMSO-d6, 1:1):
d
¼1.48 (t, J¼5.9 Hz, 3H, CH3),
97.1 (CH), 105.8 (C), 126.1 (CH), 139.4 (C), 157.7 (C), 164.0 (C), 164.8
4.08 (dd, JHeH¼7.0 Hz, JHeP¼15.1 Hz, 2H, CH2), 5.20e5.29 (m, 1H,
(C), 199.2 (C). MS (EI): m/z (%)¼222.1 (35) [Mþ], 151.1þ(62), 141.1
CH), 5.51e5.64 (m, 1H, CH), 7.60e7.82 (m, 15H, 3ꢃ Ph). 13C NMR
12
(40),125.1 (46), 83 (36), 43 (100). HRMS (
C
1H1416O4 , EI): calcd
(100 MHz, D2O/DMSO-d6, 1:1):
d
¼19.0 (CH3), 26.9 (d, JCeP¼50 Hz,
12
222.0892 amu, found 222.0895 amu. The spectroscopic data are in
CH2), 116.1 (d, JCeP¼10 Hz, vinyl-CH), 119.1 (d, JCeP¼86 Hz, Car), 131.4
(d, JCeP¼12 Hz, CHar), 134.7 (d, JCeP¼10 Hz, CHar), 136.4 (CHar), 138.3
full agreement with published data.27
(d, JCeP¼13 Hz, vinyl-CH). MS (FAB): m/z (%)¼317 (100) [(MꢂBr)þ],
1H2231Pþꢁ, FAB): calcd 317.1461 amu, found 317.1459
12
6.5.6. 6-But-2-yl-4-methoxy-3-methyl-2H-pyran-2-one [31, (rac)-9-
O-methylphomapyrone C]. H2 was passed for 2 min through a soln
HRMS (½
C
22
amu.
of nectriapyrone (3, 13 mg, 67.0
mmol) in EtOAc (2 mL). Pd/C
(10 mol %, 14.3 mg, 6.7 mol) was added and the soln was stirred
m
6.6.4. (E,E)-6-(Hexa-2,4-dien-2-yl)-4-methoxy-3-methyl-2H-pyran-
until TLC showed complete conversion (approximately 15 min). The
suspension was filtered (Celite) and the filter cake was rinsed
thoroughly with EtOAc. The filtrate was concentrated to yield (rac)-
2-one (8, 8,9-dehydroxylarone). Vermopyrone (2, 50.0 mg,
274
mmol) and phosphonium compound 30 (109 mg, 274 mmol)
were converted according to the GP yielding a mixture of 8,9-

7286
O. Geiseler, J. Podlech / Tetrahedron 68 (2012) 7280e7287
dehydroxylarone (8) and Z-8 [42.2 mg, 192
mmol, 70%, (2E,4E)/
CH), 6.24 (s, 1H, CH), 7.00 (s, 1H, CH). 13C NMR (100 MHz, CDCl3):
(2E,4Z)¼7:3] as a yellow solid. Separation of the isomers was ach-
ieved by column chromatography (silica gel, hexanes/EtOAc, 10:1)
yielding the pure natural product 8 and a mixture of isomers.
d
¼8.8 (CH3), 14.2 (CH3), 19.0 (CH3), 28.3 [C(CH3)3], 56.2 (OCH3), 80.4
(C), 93.9 (CH), 103.5 (C), 122.3 (CH), 128.1 (C), 134.7 (CH), 150.5 (C),
159.1 (C), 164.6 (C), 165.4 (C), 165.9 (C). MS (EI): m/z (%)¼320 (16)
Compound 8: IR (ATR): v 2923 cmꢂ1, 2854, 1678, 1622, 1585, 1546,
[Mþ], 253 (40), 219 (51), 208 (90),149 (38),125 (69), 57 (100). HRMS
~
1H2416O5þꢁ, EI): calcd 320.1624 amu, found 320.1621 amu.
12
1439, 1383, 1357, 1244, 1176, 1155, 1133, 1038, 1009, 974, 955, 914,
(½
C
18
883, 806, 745, 722, 694, 621, 540, 519, 464, 423. 1H NMR (400 MHz,
(E,Z)-35: IR (ATR): v 2976 cmꢂ1, 2927, 2865, 1689, 1630, 1551, 1458,
1381, 1335, 1294, 1248, 1161, 1135, 1012, 969, 940, 903, 855, 800,
773, 750, 682, 645, 559, 469, 405. 1H NMR (400 MHz, CDCl3):
~
CDCl3):
d
¼1.88 (d, J¼6.8 Hz, 3H, CH3), 1.94 (s, 3H, CH3), 1.96 (s, 3H,
CH3), 3.90 (s, 3H, OCH3), 6.04e6.14 (m, 1H, CH), 6.12 (s, 1H, CH), 6.41
(dq, J¼1.7, 11.3 Hz, 1H, CH), 7.12 (d, J¼11.3 Hz, 1H, CH). 13C NMR
d
¼1.42 (s, 9H, C(CH3)3), 1.89 (d, J¼1.1 Hz, 3H, CH3), 1.95 (s, 3H, CH3),
1.98 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 5.78 (q, J¼1.1 Hz, 1H, CH), 6.23
(s, 1H, CH), 7.26 (s, 1H, CH). 13C NMR (100 MHz, CDCl3):
(100 MHz, CDCl3):
d
¼8.7 (CH3), 12.5 (CH3), 19.0 (CH3), 56.0 (CH3),
92.1 (CH), 102.1 (C), 123.2 (C), 127.4 (CH), 132.1 (CH), 136.6 (CH),
d
¼8.7 (CH3),
160.0 (C), 165.0 (C), 165.9 (C). MS (EI): m/z (%)¼220 (100) [Mþ], 205
13.9 (CH3), 24.4 (CH3), 28.1 (3ꢃ CH3), 56.1 (CH3), 80.0 (C), 93.1 (CH),
12
(24), 177 (22), 149 (19), 133 (33), 93 (29). HRMS (½
C
1H1616O3þꢁ,
103.0 (C), 121.8 (CH), 127.3 (C), 132.1 (CH), 149.5 (C), 159.3 (C), 164.7
13
EI): calcd 220.1099 amu, found 220.1102 amu. The spectroscopic
(C), 164.9 (C), 165.5 (C). MS (EI): m/z (%)¼320 (5) [Mþ], 264 (100),
data are in full agreement with published data.11
219 (43), 182 (10), 139 (23). HRMS (½
C
18
1H2416O5þꢁ, EI): calcd
12
320.1624 amu, found 320.1623 amu.
6.7. Infectoyprone (1)
6.7.3. (E,E)-5-(4-Methoxy-3-methyl-2-oxo-2H-pyran-6-yl)-3-
6.7.1. Ethyl (E,E)-5-(4-methoxy-3-methyl-2-oxo-2H-pyran-6-yl)-3-
methylhexa-2,4-dienoic acid (1, infectopyrone). Infectopyrone tert-
methylhexa-2,4-dienoate (33, infectopyrone ethyl ester). A soln of
butyl ester [(E,E)-35, 12.2 mg, 38
mmol] was treated for 30 min with
triethyl phosphonoacetate (32, 21.0 mg, 94
mmol) in anhydrous
F3CCO2H (500 L) in CH2Cl2 (2 mL). The solvent was removed under
m
dimethoxy ethane (DME, 1 mL) was added dropwise to an ice-
cooled suspension of NaH (60% dispersion in mineral oil, 4.0 mg,
reduced pressure and the residue was co-evaporated with CH2Cl2
(3ꢃ5 mL) yielding infectopyrone (1) as a yellow solid (9.9 mg,
mol, 98%). IR (ATR): v 2921 cmꢂ1, 2852, 1679, 1622, 1600, 1552,
~
100
mmol) in anhydrous DME (2 mL) under Ar atmosphere and
37
m
stirred for 30 min. A soln of phomapyrone D (20.4 mg, 92
m
mol) in
1459, 1406, 1377, 1353, 1301, 1248, 1223, 1190, 1160, 1084, 1012, 913,
anhydrous DME (4 mL) was added dropwise to the ice-cooled re-
action mixture. The ice bath was removed after complete addition
and the mixture was stirred overnight at rt before quenching by
889, 865, 811, 747, 720, 702, 665, 582, 528, 510, 467, 434. 1H NMR
(400 MHz, DMSO-d6):
3H, CH3), 3.97 (s, 3H, OCH3), 5.78 (s, 1H, CH), 6.70 (s, 1H, CH), 6.85 (s,
1H, CH), 12.27 (br, 1H, COOH). 13C NMR (100 MHz, DMSO-d6):
d¼1.82 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.25 (s,
addition of satd aq NH4Cl soln (500
mL). After filtration over Na2SO4
d
¼8.6
and Celite, the solvent was removed and the residue purified by
column chromatography (silica gel, hexanes/EtOAc, 7:3) yielding
(CH3), 13.9 (CH3), 18.6 (CH3), 56.8 (OCH3), 95.3 (CH), 101.2 (C), 121.1
(CH), 129.5 (C), 133.0 (CH), 150.6 (C), 158.2 (C), 163.1 (C), 165.7 (C),
the pure (E,E)-isomer 33 (6.1 mg, 21
mmol, 23%) and a mixture of
167.0 (C). MS (EI): m/z (%)¼264 (69) [Mþ], 219 (100), 191 (19), 97
1H1616O5þꢁ, EI): calcd 264.0998 amu, found
12
isomers [(E,E)-33/(E,Z)-33¼6:4, 12.1 mg, 41
mmol, 45%] as yellow
(18). HRMS (½
C
14
oils. (E,E)-33: IR (KBr): v 3487 cmꢂ1, 3091, 2981, 2926, 2866, 2247,
1694, 1634, 1555, 1464, 1382, 1357, 1327, 1250, 1166, 1095, 1036,
1016, 910, 867, 804, 768, 752, 732, 646, 562, 521, 405. 1H NMR
264.1000 amu.5
~
6.7.4. (2Z,4E)-5-(4-Methoxy-3-methyl-2-oxo-2H-pyran-6-yl)-3-
(300 MHz, CDCl3):
2.07 (s, 3H, CH3), 2.30 (s, 3H, CH3), 3.93 (s, 3H, OCH3), 4.20 (q,
d
¼1.31 (t, J¼7.1 Hz, 3H, CH3), 1.96 (s, 3H, CH3),
methylhexa-2,4-dienoic acid [Z-1, (Z)-infectopyrone]. Infectopyrone
tert-butyl ester [(Z,E)-35, 3.4 mg, 10.6
mmol] was treated for 30 min
J¼7.1 Hz, 2H, CH2), 5.77 (s, 1H, CH), 6.25 (s, 1H, CH), 7.02 (s, 1H, CH).
with F3CCO2H (500 L) in CH2Cl2 (2 mL). The solvent was removed
under reduced pressure and the residue was co-evaporated with
m
13C NMR (100 MHz, CDCl3):
d
¼8.8 (CH3), 14.1 (CH3), 14.3 (CH3), 19.2
(CH3), 56.2 (CH3), 60.0 (CH2), 94.1 (CH), 103.6 (C), 120.4 (CH), 128.4
(C), 134.5 (CH), 152.0 (C), 159.0 (C), 164.5 (C), 165.4 (C), 166.3 (C). MS
CH2Cl2 (3ꢃ5 mL) yielding Z-infectopyrone (Z-1) as a yellow solid
~
(2.8 mg, 10.6
m
mol, quant.). IR (ATR): v 2922 cmꢂ1, 1681, 1624, 1602,
(EI): m/z (%)¼292 (61) [Mþ], 219 (85),195 (33),139 (48), 107 (43), 84
1551, 1440, 1406, 1379, 1353, 1301, 1248, 1224, 1190, 1162, 1084,
1009, 974, 913, 888, 858, 813, 746, 720, 684, 569, 528, 510, 468, 434.
12
(100) 77 (71). HRMS (½
C
1H2016O5þꢁ, EI): calcd 292.1311 amu,
16
found 292.1312 amu.
1H NMR (300 MHz, DMSO-d6):
d
¼1.82 (s, 3H, CH3), 1.91 (s, 3H, CH3),
2.03 (s, 3H, CH3), 3.96 (s, 3H, OCH3), 5.86 (s,1H, CH), 6.61 (s, 1H, CH),
6.7.2. (E,E)- and (E,Z)-tert-butyl 5-(4-methoxy-3-methyl-2-oxo-2H-
7.27 (s,1H, CH),12.18 (br,1H, COOH). 13C NMR (100 MHz, DMSO-d6):
pyran-6-yl)-3-methylhexa-2,4-dienoate [35, (E,E)- and (E,Z)-in-
d
¼8.6 (CH3),13.7 (CH3), 23.9 (CH3), 56.7 (OCH3), 94.3 (CH),100.8 (C),
fectopyrone tert-butyl ester]. nBuLi (95
m
L, 2.2 M in cyclohexane,
mol) was added under Ar atmosphere to an ice-cooled soln of
tert-butyl diethyl phosphonoacetate (34, 55.7 mg, 210 mol) in
anhydrous THF (2 mL) and stirred for 30 min. A soln of phoma-
pyrone D (12, 31.1 mg, 140 mol) in anhydrous THF (5 mL) was
120.7 (CH), 127.8 (C), 131.0 (CH), 150.3 (C), 158.3 (C), 163.2 (C), 165.8
210
m
(C), 166.2 (C). MS (EI): m/z (%)¼264 (71) [Mþ], 219 (100), 139 (26).
m
HRMS (½
C
14
1H1616O5þꢁ, EI): calcd 264.0998 amu, found 264.0995
12
amu.
m
added dropwise to the ice-cooled mixture. The ice bath was re-
moved after complete addition and the mixture was stirred over-
night at rt before quenching by addition of satd aq NH4Cl soln
Acknowledgements
(500
m
L), filtered (Na2SO4/Celite), and concentrated and the residue
We gratefully acknowledge Nils Jasinski for his help with the
laboratory work.
was purified by column chromatography (silica gel, hexanes/EtOAc,
7:3) yielding a mixture of isomers [(E,E)/(E,Z)¼2:1, 24.2 mg,
76 mmol, 54%] as a yellow oil. Separation of the isomers was ach-
~
ieved by MPLC (hexanes/EtOAc, 10:1). (E,E)-35: IR (KBr):
v
Supplementary data
2976 cmꢂ1, 2929, 1696, 1638, 1554, 1458, 1365, 1245, 1164, 1138,
1110, 1014, 897, 848, 769, 751, 598, 520, 409. 1H NMR (400 MHz,
Spectra for compounds 1, Z-1, 2e9, 12, 20, 21, 33, (E,E)-35, and
(E,Z)-35. Supplementary data related to this article can be found
online at http://dx.doi.org/10.1016/j.tet.2012.06.104.
CDCl3):
d
¼1.50 (s, 9H, C(CH3)3), 1.95 (s, 3H, CH3), 2.06 (d, J¼1.3 Hz,
3H, CH3), 2.25 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 5.69 (q, J¼1.3 Hz, 1H,

O. Geiseler, J. Podlech / Tetrahedron 68 (2012) 7280e7287
7287
17. Lu, X.; Xu, N.; Dai, H.-F.; Mei, W.-L.; Yang, Z.-X.; Pei, Y.-H. J. Asian Nat. Prod. Res.
2009, 11, 397e400.
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