Synthesis of 5-(1-Alkoxyalkylidene)tetronates by Direct Condensation Reactions of Tetronates with Thionolactones and Thionoesters

Article abstract of DOI:10.1021/acs.joc.0c02502

We report a two-step approach to bicyclic and monocyclic 5-(1-alkoxyalkylidene)tetronates starting from lactones/esters. The method features the use of thionolactones and thionoesters as activated forms of lactones/esters that allows the direct condensati

Full text of DOI:10.1021/acs.joc.0c02502

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Synthesis of 5‑(1-Alkoxyalkylidene)tetronates by Direct
Condensation Reactions of Tetronates with Thionolactones and
Thionoesters
Ya-Qing Huang,# Xiong-Zhi Huang,# and Pei-Qiang Huang*
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ABSTRACT: We report a two-step approach to bicyclic and
monocyclic 5-(1-alkoxyalkylidene)tetronates starting from lac-
tones/esters. The method features the use of thionolactones and
thionoesters as activated forms of lactones/esters that allows the
direct condensation with tetronates via one-pot enolate formation,
nucleophilic addition, S-methylation, and DBU-promoted elimi-
nation. The value of the method was demonstrated by the
stereoselective syntheses of two natural products: 5,6-Z-fadyeno-
lide (Z/E ratio = 6:1) and 9,10-methylenedioxy-5,6-Z-fadyenolide (Z/E ratio = 9:1).
belong to the stemofoline groups 2−5 and protostemonamide
(6), isolated from Stemona plants. The latter have been used in
China and in East Asia for thousands of years as insecticides
and anti-cough agents. Stemofoline (2) has been found to
reverse multidrug resistance of certain types of cancer.1a
Monocyclic 5-(1-alkoxyalkylidene)tetronates are found in
some secondary metabolites isolated from Piper species.2 For
example, both 5,6-E- and 5,6-Z-fadyenolides 7 and 8 were
isolated from Piper fadyenii collected from Jamaica in 19813a,b
and from Piper malacophyllum collected from Brazilian Atlantic
Forest and Cerrado.3c Both geometric isomers fadyenolides 7
and 8 displayed antifungal activities.3c More recently, three
such natural products including 9,10-methylenedioxy-5,6-Z-
fadyenolide (9) and 5,6-E-fadyenolide (7) were isolated from
the leaves of Piper hispidum Swingle (Piperaceae).4 8 and 9
were identified as the serotonin receptor 5-HT7 and estrogen
receptor agonists, respectively.4 These activities are consistent
with the Q’eqchi traditional use of the plant for the treatment
of disorders associated with the female reproductive cycle
including amenorrhea, dysmenorrhea, and pain.4b
INTRODUCTION
■
5-(1-Alkoxyalkylidene)tetronates, namely, a tetronate con-
nected to a lactone or an ester in the form of either an E- or
a Z-ene diether (1 in Figure 1), constitute a key structural
feature of many bioactive natural products isolated from
traditional medicinal plants. Salient examples are the
structurally complex Stemona alkaloids1 such as those that
Although synthetic efforts toward 5-(1-alkoxyalkylidene)-
tetronate motifs 1 can be traced back to the early 1980s,3a
efficient construction of such motifs remains rare and
challenging, yet in high demand.
For the synthesis of 5,6-Z/E-fadyenolides 7 and 8, Pelter
and co-workers developed a two-step (Scheme 1, a1) and a
Received: October 21, 2020
Published: January 25, 2021
Figure 1. Representative bioactive natural products containing 5-
(alkoxyalkylidene)tetronate motifs.
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report herein a two-step method for the versatile synthesis of
both bicyclic and monocyclic 5-(alkoxyalkylidene)tetronate
motifs 1 from lactones/esters.
Scheme 1. Known Concise Methods for the Construction of
5-(Alkoxyalkylidene)tetronate Motifs
RESULTS AND DISCUSSION
■
Retrosynthetically, the most straightforward method for the
synthesis of 5-(alkoxyalkylidene)tetronates 1 would be the
direct condensation of tetronate enolates 10a/12a with esters/
lactones 15 (Scheme 2). However, esters3a,5 and lactones6
Scheme 2. Our Strategy for the Efficient Construction of
(Alkoxyalkylidene)tetronates
turned out to be unreactive toward the lithium enolates (10a/
12a) of tetronates (10/12). The previous reported methods
used either the highly electrophilic alkoxyoxonium ions
generated in situ from orthoesters/acetals or lactones3a,5,6 or
aldehydes8,9 as alternates. Given that lactone/esters 15 are not
reactive enough to serve as the electrophilic partners, we
reasoned that thionolactones and thionoesters 16, readily
available from the formers using thionation11 reagents such as
Lawesson’s reagent,11,12 would serve as valuable reactive
partners for the direct condensation reaction with lithium
enolates 10a/12a (Scheme 2).
four-step (Scheme 1, a2) approach to Z- and E-diastereomer
from methyl tetronate 10 and trimethyl orthobenzoate,
respectively.5 Although highly stereoselective, the methods
suffer either from low efficiency (lengthy and low overall yield)
or from the use of strong base t-BuLi, which renders the
method of low functional group tolerance. Indeed, this method
is limited to the synthesis of monocyclic 5-(1-
alkoxyalkylidene)tetronate motifs with an aryl group.6 For
the motifs such as piperolide (13a) that bears a styryl group, it
was formed as a minor product in only 30% yield (Scheme 1,
At the outset, the known γ-thionolactone (16a)13a was
selected as a model compound for our investigation. Dropwise
addition of γ-thionolactone (16a) to a solution of lithium
enolate 12a in THF at −78 °C, followed by trapping the
resulting lithium thiolate intermediated with MeI, afforded
unexpectedly vinylic methyl sulfide 18 in 56% yield (Scheme 3,
protocol A). On the basis of the consideration that 18 might
be a retro-oxy-conjugate addition product generated from 17
under basic conditions, a base-promoted re-oxy-conjugate
addition was attempted. Pleasantly, exposure of 18 to DBU in
MeCN at reflux produced directly 1a in 88% yield as a mixture
of Z/E-geometric isomers in a 4:1 ratio (Scheme 3, protocol
A). The stereochemistry of the major geometric isomer was
determined to be Z- by NOESY experiments (see the
Supporting Information). Furthermore, a modification of the
protocol consisting of the addition of a mixture of 16a and MeI
in THF to enolate 12a (0 °C, 10 min; rt, 30 min) led to the
formation of a mixture of labile 17 and 1a. Without separation,
this mixture was treated with DBU in MeCN at reflux, and the
desired product 1a was obtained in 70% yield (Scheme 3,
́
a2). In 2002, Velazquez and Olivo reported a two-step method
for the synthesis of bicyclic 5-(1-alkoxyalkylidene)tetronate
motifs that feature the addition of methyl 5-lithiotetronate to
highly electrophilic alkoxy oxonium ions, generated in situ from
lactones and 6.0 equiv of trialkyloxonium tetrafluoroborate
(Scheme 1, b).6
For the construction of the 5-(1-alkoxyalkylidene)tetronate
motifs 1 in the context of total synthesis of stemofoline (2)
and/or isostemofoline (3), the early efforts of Thomas
featuring the addition of a α-lithio α-benzenesulfonyl
tetrahydropyran to a methyl 5-hydroxy-3-methyltetronate
followed by elimination of benzenesulfinic acid resulted in a
mixture of hydroxyspiroketals instead of the desired 5-(1-
alkoxyalkylidene)tetronates.7 In Kende’s seminal total syn-
thesis of ( )-isostemofoline (4),8 in the last step of a four-step
approach to generate the 5-(1-alkoxyalkylidene)tetronate
motif, the dehydration reaction proceeded in only 12% yield.
In 2003, Overman and co-workers accomplished the total
synthesis of ( )-didehydrostemofoline (3) and ( )-isodidehy-
drostemofoline (5), in which a five-step protocol was
established for building the 5-(1-alkoxyalkylidene)tetronate
moiety.9 This protocol was adopted by Huang and co-workers
for the enantioselective total synthesis of methoxystemofoline
and isomethoxystemofoline.10a,c In connection with our
interest in the total synthesis of stemofoline alkaloids,10 we
protocol B). Next, in the light of the work of Nicolaou,14
a
cascade addition−elimination reaction was envisioned. Thus,
after the enolate addition, 1,4-diiodobutane was used to
replace MeI to trap the presumed thiolate intermediate to
generate 19, which was followed by warming up in the
presence of N-methyl-2,2,6,6-pentamethylpiperidine, a non-
nucleophilic base14 (Scheme 3, protocol C). In this manner,
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(LiHMDS + DBU; n-BuLi + DBU; NaHMDS + DBU)
afforded satisfactory results in terms of both chemical yield and
Z-selectivity (Table 1, entries 5−7). Finally, we found that the
amount of DBU could be decreased to 1.0 equiv. Thus, the
optimal conditions were determined as follows: by using 1.1
equiv of NaHMDS for the deprotonation of 12 (1.3 equiv), 1.5
equiv of MeI for S-methylation, and 1.0 equiv of DBU for the
elimination reaction, the desired 1a15 was obtained in 68%
yield with a Z/E stereoselectivity of 7:1 (Table 1, entry 8).
With the optimized conditions for the one-pot reaction in
hand, we proceeded to examine the scope of the one-pot
reaction (Scheme 4), and the results are displayed in Table 2.
Scheme 3. Two-Step Protocols for the Synthesis of 1a from
Thionolactone 16a
Scheme 4. One-Pot Synthesis of 1 from 10/12 and
Thionolactones/Thionoesters 16
Extension of the reaction to oxepane-2-thione (16b) led to the
formation of the corresponding 1b15 in a high yield of 81%
(Table 2, entry 2), but the Z/E geometric isomeric ratio was
low (2:1). Interestingly, the reaction of macrocyclic
thionolactone 16c not only gave the expected product 1c in
high yield (82%), but also the Z/E ratio was higher (4:1, entry
3). The enolate (10c) of the parent methyl tetronate (10)
served also as a useful nucleophile in the coupling with 16c,
which produced Z-1d15 in 60% yield [80% based on the
recovered starting material (BRSM)] as a single geometric
isomer (entry 4). Chromane-2-thione (16e) exhibited a low
reactivity toward enolate 12c, providing 1e15 in low yield.
However, the yield was improved to 61% by replacing DBU
with NaHMDS as the base for the elimination, and an excellent
geometric isomeric selectivity was observed with only the Z-
isomer obtained (entry 5). Next, the condensation reaction
using esters as the electrophilic partner was examined. The
condensation reaction of O-methyl benzothionoester (16f)
with enolate 10c proceeded smoothly to give stereoselectively
(Z/E ratio = 6:1) the natural product 5,6-Z-fadyenolide (7)
and 5,6-E-fadyenolide (8) in a combined yield of 62% (92%
the desired product 1a was directly obtained in 58% yield.
However, the Z/E ratio dropped to 1.7:1, and this route was
not pursued.
Next, our efforts were devoted to converting the two-step
procedure (Scheme 3, B) into a one-pot reaction. Addition of
2 times the same base such as NaHMDS and KHMDS (2.0;
3.0 equiv) afforded the desired product 1a in low yield and low
geometric selectivity (Table 1, entries 1 and 2). The use of
LiHMDS afforded a higher yield of 65%; however, the
selectivity was still low (Table 1, entry 3). Employing LDA
as the base provided a disappointing yield (Table 1, entry 4).
Encouragingly, the strong base−weak base combination
a
Table 1. Optimization of Reaction Conditions
1
BRSM) (entry 6). The H and 13C{1H} NMR data of our
synthetic 7 and 8 fully matched those reported for the natural
products.3 O-Methyl benzothionoester with a methyl group at
the para-position of the phenyl group (16g) led to a higher
yield of 83% with a Z/E ratio = 2:1 (entry 7).15 However, the
reaction of the substrate with a tert-butyl group at the para-
position (16h) resulted in a moderate yield of 55% (90%
BRSM) and Z-selectivity (Z/E ratio = 1.6:1, entry 8). By
modifying the reaction conditions consisting of trebling the
equivalents of the main reagents as compared with those of the
general procedure, the yield was increased to 80%, and a higher
Z-selectivity was observed (Z/E ratio = 4.7:1, entry 8). The
substrate bearing a methoxy group at the para-position (16i)
reacted smoothly to afford 1i in 88% yield in favor of the Z-
isomer (Z/E ratio = 2:1, entry 9). The reaction of electron-rich
substrate O-methyl benzo[d][1,3]dioxole-5-carbothionoester
(16j) provided the natural product 9,10-methylenedioxy-5,6-Z-
fadyenolide (Z-9) at a modest conversion (48% yield, 95%
BRSM) but in high geometric selectivity (Z/E ratio = 9:1,
base 1
12
base 2
product 1a
entry
1
(n equiv)
(n equiv)
(n equiv)
(% yield)
NaHMDS
(2.0)
2.5
NaHMDS
(3.0)
KHMDS (3.0)
LiHMDS (3.0) 65%, Z/E = 1.5:1
LDA (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
30%, Z/E = 1.3:1
2
3
4
5
6
7
KHMDS (2.0)
LiHMDS (2.0)
LDA (2.0)
n-BuLi (2.0)
LiHMDS (2.0)
NaHMDS
(2.0)
NaHMDS
(1.1)
2.5
2.5
2.5
2.5
2.5
2.5
25%, Z/E = 1.1:1
19%, Z/E = 3:1
59%, Z/E = 7:1
54%, Z/E = 3:1
62%, Z/E = 7:1
b
8
1.3
DBU (1.0)
68%, Z/E = 7:1
a
b
1.1 equiv of MeI used. 1.5 equiv of MeI used.
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a
Table 2. Scope of the Direct Condensation Reactions of Tetronates with Thionolactones/Thionoesters
a
The reaction was carried out under the optimized reaction conditions featuring the following ratios: 10c or 12c (1.0 equiv)/MeI (1.5 equiv),
b
c
NaHMDS (1.1 equiv); NaHMDS (1.0 equiv) (Scheme 4). Z/E ratio determined by 1H NMR of crude. Stereochemistry determined by NOESY
d
e
experiments. Z/E geoisomers partially separable. Stereochemistry determined by comparison of the 13C{1H} NMR data (cf. Supporting
f
g
Information Table S4 and ref 3a). MeI (1.5 equiv), NaHMDS (1.3 equiv), and NaHMDS (1.0 equiv) used. MeI (4.5 equiv), NaHMDS (3.3
equiv), and DBU (3.0 equiv) used. Two regioisomers could not be separated in a pure form.
h
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1
entry 10). The H and 13C{1H} NMR data of our synthetic 9
observed (Z/E ratios = 2:1 to 100:0). The method has been
applied to the stereoselective syntheses of natural products 5,6-
Z-fadyenolide and 9,10-methylenedioxy-5,6-Z-fadyenolide. It is
expectable that this method will find application in the total
synthesis of Stemona alkaloids containing a 5-(1-
alkoxyalkylidene)tetronate moiety.
fully matched those reported for the natural product.4a
Considering the high Z-selectivity of the reaction (Z/E =
9:1), the yield of the Z-isomer obtained from 16j is higher than
that from 16i. It is worth noting that O-methyl furan-2-
carbothionoester (16k), an electron-rich substrate, reacted
with 12c to yield E-1k as the major geometric isomer in a Z/E
ratio of 1:4 (combined yield: 63%, entry 11). Interestingly, as
can been seen from entries 12−14, the reaction also tolerates
electron-withdrawing groups such as F, CF3, and Cl. In these
cases, by modifying the reaction conditions consisting of
trebling the equivalents of the main reagents, the reaction of O-
methyl 4-fluorobenzothionoester (16l) furnished 1l in
excellent yield (88%) and in good Z-selectivity (Z/E ratio =
6:1) (entry 12). The reactions of O-methyl p-trifluoro and p-
chloro-benzothionoesters produced Z-1m and Z-1n in 80 and
83% yields and with Z/E ratio = 1:1 and 1:1.3, respectively.
Besides methyl ester, other esters such as i-propyl ester 16o
reacted similarly in terms of both yield (87%) and Z-selectivity
(Z/E ratio = 3.7:1) (entry 15). As can be seen from entries
16−18, the reaction could be further extended to aliphatic
thionoesters (16p−16r), and the desired products were
obtained in moderate yields (50−58%) and Z-selectivity (Z/
E ratio = 2:1 to 3.7:1). It is worth noting that due to the acidity
of the benzylic protons, the reaction of O-methyl 2-
phenylethanethionoester (16p, Table 2, entry 16) led to ca.
54% of the normal product 1p, along with ca. 25% of the
olefinic bond-migrated product 1p′. We were unable to obtain
pure samples of the two isomers; however, inspection of the
1H NMR spectrum of the mixture 1p/1p′ allowed concluding
that both isomers 1p and 1p′ contain only one geometric
isomer.
EXPERIMENTAL SECTION
■
General. NMR spectra were recorded on a Bruker AV 400, AV
500, AV 600, or AV 850 spectrometer at 25 °C in the solvents
indicated. NMR spectra were recorded in CDCl3 with tetramethylsi-
lane as an internal standard. Chemical shifts (δ) are reported in ppm
and referenced to the internal standard Me4Si and solvent signals
1
(Me4Si, 0 ppm for H NMR, and CDCl3, 77.0 ppm for 13C{1H}
NMR). Melting points were determined on a Buchi M560 automatic
̈
melting point apparatus and are uncorrected. HRMS spectra were
recorded on a 7.0 T FT-MS apparatus using an ICR analyzer. Infrared
spectra were measured with a Nicolet Avatar 330 FT-IR spectrometer
using film KBr pellet technique. Silica gel (200−300 mesh) was used
for flash column chromatography (FC), eluting (unless otherwise
stated) with the ethyl EtOAc/n-hexane mixture. Structural assign-
ments were made with additional information from NOESY
experiments. All other commercially available compounds were used
as received. THF and toluene were distilled over sodium
benzophenone ketyl under N2.
General Procedure for Synthesis of Thionolactone/Thio-
noester 16. A solution of lactone/ester 15 (10 mmol, 1.0 equiv) and
Lawesson’s reagent (8 mmol, 0.8 equiv) in refluxing xylene (30 mL)
was stirred overnight (oil bath). The reaction mixture was filtered
with diatomite and concentrated by reduced pressure to give the
crude product. The residue was purified by FC on silica gel to afford
the desired product 16.
O-Methyl benzo[d][1,3]dioxole-5-carbothionoester (16j). Ester
15j (1.80 g, 10 mmol, 1.0 equiv) and Lawesson’s reagent (3.23 g, 8
mmol, 0.8 equiv) were used. The residue was purified by flash
chromatography (eluent: n-hexane) to afford 16j (1.47 g, yield: 75%)
as a yellow solid. mp: 74−75 °C; IR (film) νm1ax: 2940, 1501, 1486,
1435, 1261, 1236, 1103, 1033, 810, 671 cm−1; H NMR (400 MHz,
CDCl3): δ 7.86 (dd, J = 8.3, 1.8 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H),
6.78 (d, J = 8.3 Hz, 1H), 6.03 (s, 2H), 4.26 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 210.6, 151.8, 147.5, 133.0, 124.9, 109.0,
107.5, 101.9, 59.1 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C9H8O3SNa, 219.0086; found, 219.0077.
The preferential formation of the Z-isomer [(Z)-1] may be
understood in terms of the destabilizing electronic effect due to
repulsion by electron pair−electron pair interaction of the E-
isomer18 as indicated in Scheme 5. It is worth noting that such
Scheme 5. Plausible Reasons for the Preferential Formation
of the Z-Isomer
O-Methyl 4-Fluorobenzothionoester (16l). Ester 15l (1.54 g, 10
mmol, 1.0 equiv) and Lawesson’s reagent (3.23 g, 8 mmol, 0.8 equiv)
were used. The residue was purified by flash chromatography (eluent:
n-hexane) to afford 16l (1.45 g, yield: 85%) as an orange oil. 1H NMR
and 13C{1H} NMR data of 16l matched those reported.13h
O-Methyl Hexadecanethionoester (16q). Ester 15q (2.75 g, 10
mmol, 1.0 equiv) and Lawesson’s reagent (3.23 g, 8 mmol, 0.8 equiv)
were used. The residue was purified by flash chromatography (eluent:
n-hexane) to afford 16q (1.86 g, yield: 65%) as a pale yellow oil. IR
(film) νmax: 2924, 2853, 1441, 1266, 1189, 1151, 1086, 429 cm−1; 1H
NMR (400 MHz, CDCl3): δ 4.06 (s, 3H), 2.72 (t, J = 7.6 Hz, 2H),
1.77−1.69 (m, 2H), 1.31−1.24 (m, 24H), 0.88 (t, J = 6.9 Hz, 3H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 225.4, 58.8, 46.7, 31.9,
29.7 (3C), 29.6 (3C), 29.4, 29.3 (2C), 28.8, 28.7, 22.7, 14.1 ppm;
HRMS (ESI) m/z: [M + H]+ calcd for C17H35OS, 287.2403; found,
287.2407.
O-Hexadecyl Hexadecanethionoester (16r). Ester 15r (2.87 g, 10
mmol, 1.0 equiv) and Lawesson’s reagent (3.23 g, 8 mmol, 0.8 equiv)
were used. The residue was purified by flash chromatography (eluent:
n-hexane) to afford 16r (2.21 g, yield: 58%) as a pale yellow oil. IR
(film) νmax: 2924, 2853, 1466, 1378, 1276, 1181, 1088, 721, 411 cm−1;
1H NMR (400 MHz, CDCl3): δ 4.42 (t, J = 6.6 Hz, 2H), 2.72 (t, J =
7.6 Hz, 2H), 1.80−1.68 (m, 4H), 1.42−1.24 (m, 50H), 0.88 (t, J =
6.8 Hz, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 224.9, 72.5,
47.2, 31.9 (2C), 29.7 (12C), 29.6 (2C), 29.5 (2C), 29.4 (2C), 29.3,
a Z-selectivity is also found in both the natural products
containing such motifs1−3 and in synthetic methods featuring
an elimination reaction as the last step for the formation of the
motif.5,6
CONCLUSIONS
■
In summary, we have developed a practical protocol for the
one-pot condensation of tetronates 10/12 with thionolac-
tones/thionoesters 16, which constitutes an efficient two-step
approach to 5-(1-alkoxyalkylidene)tetronates 1 from feedstock
lactones and esters. The method is broad in scope, allowing the
synthesis of both monocyclic and bicyclic 5-(1-
alkoxyalkylidene)tetronates from lactones as well as from
aromatic and aliphatic esters. In most cases, Z-selectivity was
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29.2, 28.8, 28.6, 28.1, 22.7 (2C), 14.1 (2C) ppm; HRMS (ESI) m/z:
[M + Na]+ calcd for C32H64OSNa, 519.4570; found, 519.4569.
Detailed Procedure for the Synthesis of Thionolactone/
Thionoester 16. Dihydrofuran-2(3H)-thione (16a),13a oxepane-2-
thione (16b),13b oxacyclohexadecane-2-thione (16c),13b chromane-2-
thione (16e),13c O-methyl benzothionoester (16f),13d O-methyl 4-
methylbenzothionoester (16g),13g O-methyl 4-(tert-butyl)-
benzothionoester (16h),13f O-methyl 4-methoxybenzothionoester
(16i),13e O-methyl furan-2-carbothionoester (16k),13f O-isopropyl
benzothionoester, O-methyl 4-(trifluoromethyl)benzothioate
(16m),13g O-methyl 4-chlorobenzothioate (16n),13e O-isopropyl
benzothionoester (16o),13b and O-methyl 2-phenylethanethionoester
(16p)13g were prepared according to the reported procedures.
General Procedure for the Synthesis of 5-(1-
Alkoxyalkylidene)tetronates. 4-methoxy-3-methylfuran-2(5H)-
one (12)16 and 4-methoxyfuran-2(5H)-one (10)17 were prepared
according to the reported procedures.
Method A. To a cooled solution (−78 °C) of compound 12 or 10
(1.3 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere
was added NaHMDS (1.1 mmol, 2.0 M in THF) dropwise. After
stirring for 30 min, a solution of 16 (1.0 mmol) and MeI (1.5 mmol)
in the THF (5 mL) was added dropwise. The reaction mixture was
stirred at the same temperature for 10 min; then, DBU (1.0 mmol)
was added. The mixture was warmed to reflux and then stirred for 2 h
(oil bath). Then, the reaction was quenched with a saturated aqueous
solution of NH4Cl (5 mL). The organic layer was separated and the
aqueous layer was extracted with EtOAc (3 × 20 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by FC on silica gel to afford the desired product.
56%) as a pale yellow solid. mp: 59−60 °C; IR (film) νmax: 3436,
1
2928, 2869, 1743, 1615, 1353, 1218, 1063, 974, 753 cm−1; H NMR
(400 MHz, CDCl3): δ 4.18 (s, 3H), 3.65 (t, J = 6.2 Hz, 2H), 2.74−
2.68 (m, 2H), 2.40 (s, 3H), 2.04 (s, 3H), 1.96 (br s, 1H), 1.82−1.74
(m, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 169.7, 162.1,
138.0, 126.3, 100.0, 61.7, 59.2, 32.6, 25.3, 15.1, 9.0 ppm; HRMS
(ESI) m/z: [M + Na]+ calcd for C11H16O4SNa, 267.0662; found,
267.0670.
(Z)-5-(Dihydrofuran-2(3H)-ylidene)-4-methoxy-3-methylfuran-
2(5H)-one (Z-1a) and (E)-5-(Dihydrofuran-2(3H)-ylidene)-4-me-
thoxy-3-methylfuran-2(5H)-one (E-1a). Following the general
method B, the reaction of the thionolactone 16a (102 mg, 1 mmol)
with 12c (1.1 mmol) gave, after FC (eluent: EtOAc/n-hexane = 2:3),
Z-1a and E-1a (133 mg, yield: 68%, Z/E = 7:1) as a colorless oil. Z-
1a: IR (film) νmax: 2925, 1736, 1694, 1613, 1461, 1332, 1147, 1064,
1024, 966 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.29 (t, J = 6.9 Hz,
2H), 4.12 (s, 3H), 2.89 (t, J = 7.7 Hz, 2H), 2.17−2.09 (m, 2H), 2.05
(s, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3): δ 170.4, 163.9,
144.2, 122.8, 95.7, 72.3, 58.9, 27.9, 24.6, 9.0 ppm; HRMS (ESI) m/z:
[M + Na]+ calcd for C10H12O4Na, 219.0628; found, 219.0634. E-1a:
IR (film) νmax: 2921, 1752, 1686, 1668, 1612, 1394, 1330, 1160, 1047,
1
989 cm−1; H NMR (600 MHz, CDCl3) data of the minor isomer
read from the spectrum of the mixture of E-1a and starting material
12c: δ 4.37 (t, J = 6.8 Hz, 2H), 4.14 (s, 3H), 2.94 (t, J = 7.7 Hz, 2H),
2.09 (t, J = 7.3 Hz, 2H), 2.04 (s, 3H) ppm; 13C{1H} NMR (150
MHz, CDCl3) data of the minor isomer read from the spectrum of the
mixture of E-1a and starting material 12c: δ 170.9, 163.0, 148.2,
124.8, 97.9, 74.1, 59.4, 29.0, 23.5, 8.8 ppm; HRMS (ESI) m/z: [M +
Na]+ calcd for C10H12O4Na, 219.0628; found, 219.0633.
(Z)-4-Methoxy-3-methyl-5-(oxepan-2-ylidene)furan-2(5H)-one
(Z-1b) and (E)-4-Methoxy-3-methyl-5-(oxepan-2-ylidene)furan-
2(5H)-one (E-1b). Following the general method A, the reaction of
the thionolactone 16b (130 mg, 1 mmol) with 12c (1.1 mmol) gave,
after FC (eluent: EtOAc/n-hexane = 1:3), Z-1b and E-1b (182 mg,
yield: 81%, Z/E = 2:1) as a white solid. Z-1b: mp: 125−127 °C; IR
(film) νmax: 2926, 2857, 1731, 1682, 1463, 1393, 1329, 1260, 1186,
970 cm−1; 1H NMR (400 MHz, CDCl3): δ 4.24−4.20 (m, 2H), 4.10
(s, 3H), 2.84−2.80 (m, 2H), 2.05 (s, 3H), 1.82−1.75 (m, 2H), 1.70−
1.65 (m, 4H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 169.6,
163.8, 146.8, 126.9, 98.0, 69.9, 59.2, 30.1, 29.1, 27.3, 26.0, 9.2 ppm;
HRMS (ESI) m/z: [M + Na]+ calcd for C12H16O4Na, 247.0941;
found, 247.0950. E-1b: mp: 87−89 °C; IR (film) νmax: 2928, 2867,
1732, 1679, 1463, 1393, 1332, 1187, 968 cm−1; 1H NMR (500 MHz,
CDCl3): δ 4.19−4.16 (m, 2H), 4.09 (s, 3H), 2.77−2.73 (m, 2H), 2.02
(s, 3H), 1.82−1.78 (m, 2H), 1.73−1.66 (m, 4H) ppm; 13C{1H}
NMR (125 MHz, CDCl3): δ 170.4, 163.8, 150.0, 128.9, 99.9, 70.6,
59.6, 30.2, 29.1, 27.7, 26.6, 8.7 ppm; HRMS (ESI) m/z: [M + Na]+
calcd for C12H16O4Na, 247.0941; found, 247.0940.
(Z)-5-(Oxacyclohexadecan-2-ylidene)-4-methoxy-3-methylfur-
an-2(5H)-one (Z-1c) and (E)-5-(Oxacyclohexadecan-2-ylidene)-4-
methoxy-3-methylfuran-2(5H)-one (E-1c). Following the general
method A, the reaction of the thionolactone 16c (256 mg, 1.0 mmol)
with 12c (1.1 mmol) gave, after FC (eluent: EtOAc/n-hexane = 1:3),
Z-1c and E-1c (287 mg, yield: 82%, Z/E = 4:1) as a white solid. Z-1c:
mp: 88−89 °C; IR (film) νmax: 2929, 2857, 1749, 1649, 1621, 1458,
1361, 1153, 1064, 753 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.29 (t,
J = 5.8 Hz, 2H), 4.10 (s, 3H), 2.46 (t, J = 7.6 Hz, 2H), 2.05 (s, 3H),
1.65−1.59 (m, 2H), 1.57−1.49 (m, 2H), 1.47−1.41 (m, 2H), 1.37−
1.28 (m, 18H) ppm; 13C{1H} NMR (125 MHz, CDCl3): δ 170.1,
164.7, 146.5, 126.9, 97.0, 73.0, 59.2, 30.3, 29.5, 27.5, 27.4, 27.1, 26.9,
26.7, 26.6, 26.05, 26.01, 25.9, 25.5, 24.6, 9.1 ppm; HRMS (ESI) m/z:
[M + Na]+ calcd for C21H34O4Na, 373.2349; found, 373.2360. E-1c:
mp: 86−87 °C; IR (film) νmax: 2929, 2857, 1754, 1622, 1457, 1397,
1362, 1205, 1062, 754 cm−1; 1H NMR (500 MHz, CDCl3): δ 4.09 (s,
3H), 3.81 (t, J = 6.3 Hz, 2H), 2.47 (t, J = 7.7 Hz, 2H), 2.02 (s, 3H),
1.71−1.67 (m, 2H), 1.57−1.51 (m, 2H), 1.50−1.44 (m, 2H), 1.39−
1.28 (m, 18H) ppm; 13C{1H} NMR (125 MHz, CDCl3): δ 170.3,
163.3, 147.9, 133.8, 100.6, 71.0, 59.5, 28.9, 28.1, 27.34, 27.29, 27.1,
26.6, 26.4, 26.3, 26.2, 25.9, 25.8, 25.7, 24.5, 8.7 ppm; HRMS (ESI)
m/z: [M + Na]+ calcd for C21H34O4Na, 373.2349; found, 373.2357.
Method B. To a cooled solution (−78 °C) of compound 12 or 10
(1.3 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere
was added NaHMDS (1.1 mmol, 2.0 M in THF) dropwise. After
stirring for 30 min, a solution of 16 (1.0 mmol) and MeI (1.5 mmol)
in THF (5 mL) was added dropwise. The reaction mixture was stirred
at the same temperature for 10 min; then, NaHMDS (1.0 mmol) was
added. The mixture was warmed to reflux and then stirred for 2 h (oil
bath). Then, the reaction was quenched with a saturated aqueous
solution of NH4Cl (5 mL). The organic layer was separated and the
aqueous layer was extracted with EtOAc (3 × 20 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by FC on silica gel to afford the desired product.
Method C. To a cooled solution (−78 °C) of compound 12 or 10
(3.9 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere
was added NaHMDS (3.3 mmol, 2.0 M in THF) dropwise. After
stirring for 30 min, a solution of 16 (1.0 mmol) and MeI (4.5 mmol)
in THF (5 mL) was added dropwise. The reaction mixture was stirred
at the same temperature for 10 min; then, DBU (3.0 mmol) was
added. The mixture was warmed to reflux and then stirred for 2 h (oil
bath). Then, the reaction was quenched with a saturated aqueous
solution of NH4Cl (5 mL). The organic layer was separated and the
aqueous layer was extracted with EtOAc (3 × 20 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by FC on silica gel to afford the desired product.
5-(4-Hydroxy-1-(methylthio)butylidene)-4-methoxy-3-methylfur-
an-2(5H)-one (18). To a cooled solution (−78 °C) of compound 12a
(320 mg, 2.5 mmol) in anhydrous THF (5 mL) under a nitrogen
atmosphere was added n-BuLi (2 mmol, 2.5 M in hexane) dropwise.
After stirring for 30 min, 16a (102 mg, 1 mmol) in THF (5 mL) was
added dropwise. The reaction mixture was stirred at the same
temperature for 10 min. The mixture was warmed to room
temperature and MeI (3 mmol) was added. Then, the reaction was
quenched with a saturated aqueous solution of NH4Cl (5 mL). The
organic layer was separated and the aqueous layer was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by FC (eluent: EtOAc/n-
hexane = 1:1) on silica gel to afford compound 18 (136.6 mg, yield:
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Article
(Z)-5-(Oxacyclohexadecan-2-ylidene)-4-methoxyfuran-2(5H)-
one (Z-1d). Following the general method A, the reaction of the
thionolactone 16c (256 mg, 1 mmol) with 10c (1.1 mmol) gave, after
FC (eluent: EtOAc/n-hexane = 1:3), Z-1d (202 mg, yield: 60%,
BRSM 80%, single Z-isomer) as a colorless oil. IR (film) νmax: 2930,
(208 mg, 1 mmol) with 12c (1.1 mmol) gave, after FC (eluent:
EtOAc/n-hexane = 1:3), Z-1h and E-1h: (166 mg, yield: 55%, BRSM
90%, Z/E = 1.6:1) as a colorless oil. Following the general method C,
the reaction of the thionoester 16h (208 mg, 1 mmol) with 12c (3.3
mmol) gave, after FC (eluent: EtOAc/n-hexane = 1:3), Z-1h and E-
1
2856, 1747, 1652, 1588, 1443, 1384, 1203, 1088, 903, 784 cm−1; H
1h: (242 mg, yield: 80%, Z/E = 4.7:1). Z-1h and E-1h: IR (film) νmax
:
NMR (400 MHz, CDCl3): δ 5.06 (s, 1H), 4.37 (t, J = 5.7 Hz, 2H),
3.89 (s, 3H), 2.48 (t, J = 7.5 Hz, 2H), 1.67−1.60 (m, 2H), 1.58−1.51
(m, 2H), 1.48−1.40 (m, 2H), 1.40−1.28 (m, 18H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 172.0, 168.1, 147.0, 126.0, 85.9, 73.1,
59.1, 30.3, 29.5, 27.4, 27.2, 27.0, 26.9, 26.7, 26.4, 25.9 (3C), 25.5, 24.5
ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C20H32O4Na, 359.2193;
found, 359.2210.
(Z)-5-(Chroman-2-ylidene)-4-methoxy-3-methylfuran-2(5H)-one
(Z-1e). Following the general method B, the reaction of the
thionolactone 16e (164 mg, 1 mmol) with 12c (1.1 mmol) gave,
after FC (eluent: EtOAc/n-hexane = 1:3), Z-1e (157 mg, yield: 61%,
2961, 2869, 1748, 1621, 1456, 1394, 1361, 1268, 1162, 1060, 994
1
cm−1; H NMR (500 MHz, CDCl3, data of two geometric isomers,
ratio Z/E = 1.5:1): δ 7.64−7.61 (m, 0.8H), 7.44−7.37 (m, 2H),
7.32−7.27 (m, 1.2H), 4.19 (s, 1.2H), 3.68 (s, 1.8H), 3.64 (s, 1.8H),
3.62 (s, 1.2H), 2.10 (s, 1.2H), 2.00 (s, 1.8H), 1.33 (s, 5.4H), 1.32 (s,
3.6H) ppm; 13C{1H} NMR (500 MHz, CDCl3, data of two geometric
isomers, ratio = Z/E = 1.5:1): δ 170.4, 169.9, 164.3, 163.7, 153.2,
152.9, 143.6, 143.0, 135.0, 129.9 (2C), 129.7, 128.72, 128.65 (2C),
128.1, 125.5 (2C), 124.7 (2C), 100.7, 100.6, 60.6, 59.8, 58.9, 58.8,
34.83, 34.81, 31.22 (3C), 31.16 (3C), 9.0, 8.8 ppm; HRMS (ESI) m/
z: [M + Na]+ calcd for C18H22O4Na, 325.1410; found, 325.1415.
(Z)-4-Methoxy-5-(methoxy(4-methoxyphenyl)methylene)-3-
methylfuran-2(5H)-one (Z-1i) and (E)-4-Methoxy-5-(methoxy(4-
methoxyphenyl)methylene)-3-methylfuran-2(5H)-one (E-1i). Fol-
lowing the general method A, the reaction of the thionoester 16i
(182 mg, 1 mmol) with 12c (1.1 mmol) gave, after FC (eluent:
EtOAc/n-hexane = 1:3), Z-1i and E-1i (243 mg, yield: 88%, Z/E =
2:1) a white solid. Z-1i: mp: 78−79 °C; IR (film) νmax: 2942, 1747,
1606, 1511, 1456, 1362, 1252, 1175, 1063, 1036 cm−1; 1H NMR (400
MHz, CDCl3): δ 7.36−7.29 (m, 2H), 6.95−6.89 (m, 2H), 3.86 (s,
3H), 3.72 (s, 3H), 3.68 (s, 3H), 2.02 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3): δ 169.7, 163.6, 160.7, 142.7, 131.5 (2C), 129.4,
123.0, 113.1 (2C), 99.6, 58.9, 58.5, 55.2, 8.7 ppm; HRMS (ESI) m/z:
[M + Na]+ calcd for C15H16O5Na, 299.0890; found, 299.0895. E-1i:
mp: 96−97 °C; IR (film) νmax: 2935, 1746, 1605, 1510, 1456, 1359,
1255, 1178, 1062, 1029 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.69−
7.64 (m, 2H), 6.95−6.90 (m, 2H), 4.19 (s, 3H), 3.84 (s, 3H), 3.63 (s,
3H), 2.10 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 170.3,
164.3, 160.6, 143.4, 134.4, 130.4 (2C), 124.0, 113.9 (2C), 100.5, 60.6,
59.7, 55.8, 8.9 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C15H16O5Na, 299.0890; found, 299.0897.
9,10-Methylenedioxy-5,6-Z-fadyenolide (Z-9) and 9,10-Methyl-
enedioxy-5,6-E-fadyenolide (E-9). Following the general method A,
the reaction of the thionoester 16j (196 mg, 1 mmol) with 10c (1.1
mmol) gave, after FC (eluent: EtOAc/n-hexane = 1:2), Z-9 and E-9
(132 mg, yield: 48%, BRSM 95%, Z/E = 9:1) as a white solid. Z-9:
mp: 164−165 °C; IR (film) νma1x: 2918, 1746, 1590, 1505, 1490, 1236,
1213, 1099, 1038, 906 cm−1; H NMR (500 MHz, CDCl3): δ 6.91
(dd, J = 8.0, 1.4 Hz, 1H), 6.85 (d, J = 1.4 Hz, 1H), 6.82 (d, J = 8.0 Hz,
1H), 6.03 (s, 2H), 5.13 (s, 1H), 3.75 (s, 3H), 3.66 (s, 3H) ppm;
13C{1H} NMR (125 MHz, CDCl3): δ 170.8, 167.8, 149.2, 147.4,
146.8, 129.0, 124.9, 124.2, 110.2, 107.9, 101.5, 87.6, 58.92, 58.90
ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C14H12O6Na, 299.0526;
found, 299.0532. E-9: mp: 140−141 °C; IR (film) νmax: 2919, 1748,
1591, 1489, 1380, 1252, 1236, 1104, 1037, 988 cm−1; 1H NMR (500
MHz, CDCl3): δ 7.30 (dd, J = 8.1, 1.2 Hz, 1H), 7.25 (d, J = 1.2 Hz,
1H), 6.88 (d, J = 8.1 Hz, 1H), 6.02 (s, 2H), 5.26 (s, 1H), 3.99 (s,
3H), 3.66 (s, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3): δ 171.6,
168.1, 149.1, 148.0, 144.3, 134.4, 125.1, 123.9, 108.9, 108.5, 101.5,
88.6, 60.8, 59.5 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C14H12O6Na, 299.0526; found, 299.0531.
single Z-isomer) as a white solid. mp: 176−177 °C; IR (film) νmax
:
2922, 1743, 1689, 1622, 1455, 1282, 1260, 1223, 1009, 757 cm−1; 1H
NMR (500 MHz, CDCl3): δ 7.21−7.19 (m, 1H), 7.09−7.04 (m, 2H),
6.99−6.95 (m, 1H), 4.17 (s, 3H), 3.05−3.01 (m, 2H), 2.84−2.80 (m,
2H), 2.11 (s, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3): δ 169.6,
163.6, 151.7, 137.8, 128.5, 125.1, 126.9, 122.7, 122.6, 116.8, 98.8,
59.2, 23.4, 21.4, 9.2 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C15H14O4Na, 281.0784; found, 281.0794.
5,6-Z-Fadyenolide (7) and 5,6-E-Fadyenolide (8). Following the
general method A, the reaction of the thionoester 16f (152 mg, 1
mmol) with 10c (1.1 mmol) gave, after FC (eluent: EtOAc/n-hexane
= 1:3), 5,6-Z-fadyenolide (7) and 5,6-E-fadyenolide (8) (144 mg,
yield: 62%, BRSM 92%, Z/E = 6:1) as a white solid. 5,6-Z-
Fadyenolide (7): mp: 131−132 °C; IR (film) νmax: 2944, 1742, 1658,
1589, 1439, 1388, 1215, 1131 cm−1; 1H NMR (400 MHz, CDCl3): δ
7.45−7.37 (m, 5H), 5.12 (s, 3H), 3.75 (s, 3H), 3.60 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3): δ 170.8, 167.9, 144.0, 130.6,
130.1, 130.1, 129.0, 127.9, 87.5, 60.5, 58.9, 58.8 ppm; HRMS (ESI)
m/z: [M + Na]+ calcd for C13H12O4Na, 255.0628; found, 255.0637.
5,6-E-Fadyenolide (8): mp: 130−131 °C; IR (film) νmax: 2926, 1770,
1747, 1590, 1438, 1376, 1213, 1133 cm−1; 1H NMR (400 MHz,
CDCl3) data of the minor isomer read from the spectrum of the
mixture of geometric isomers 7 and 8: δ 7.74−7.70 (m, 3H), 7.48−
7.40 (m, 2H), 5.28 (s, 1H), 3.99 (s, 3H), 3.65 (s, 3H) ppm; 13C{1H}
NMR (400 MHz, CDCl3) data of the minor isomer read from the
spectrum of the mixture of geometric isomers 7 and 8: δ 171.6, 168.1,
144.6, 134.9, 131.1, 129.9, 129.0 (2C), 128.5 (2C), 88.8, 60.5, 59.5
ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C13H12O4Na, 255.0628;
found, 255.0636.
(Z)-4-Methoxy-5-(methoxy(p-tolyl)methylene)-3-methylfuran-
2(5H)-one (Z-1g) and (E)-4-Methoxy-5-(methoxy(p-tolyl)-
methylene)-3-methylfuran-2(5H)-one (E-1g). Following the general
method C, the reaction of the thionoester 16g (166 mg, 1 mmol) with
12c (1.1 mmol) gave, after FC (eluent: EtOAc/n-hexane = 1:5), Z-1g
and E-1g (216 mg, yield: 83%, Z/E = 2:1) as a white solid. Z-1g: mp:
136−137 °C; IR (film) νmax: 2922, 1748, 1674, 1621, 1456, 1390,
1
1273, 1211, 1149, 983 cm−1; H NMR (400 MHz, CDCl3): δ 7.29−
7.25 (m, 2H), 7.23−7.18 (m, 2H), 3.70 (s, 3H), 3.67 (s, 3H), 2.40 (s,
3H), 2.02 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 169.8,
163.6, 142.9, 139.9, 130.0 (2C), 129.6, 128.5 (2C),128.0, 99.9, 58.9,
58.6, 21.4, 8.8 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C15H16O4Na, 283.0941; found, 283.0950. E-1g: mp: 93−94 °C; IR
(film) νmax: 2928, 1748, 1615, 1455, 1392, 1357, 1216, 1162, 1060,
969 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.62−7.57 (m, 2H),
7.24−7.19 (m, 2H), 4.18 (s, 3H), 3.61 (s, 3H), 2.37 (s, 3H), 2.10 (s,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 170.3, 164.2, 143.5,
139.8, 134.9, 129.2 (2C), 128.73 (2C), 128.68, 100.6, 60.4, 59.7, 21.4,
8.9 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C15H16O4Na,
283.0941; found, 283.0949.
(Z)-5-(Furan-2-yl(methoxy)methylene)-4-methoxy-3-methylfur-
an-2(5H)-one (Z-1k) and (E)-5-(Furan-2-yl(methoxy)methylene)-4-
methoxy-3-methylfuran-2(5H)-one (E-1k). Following the general
method A, the reaction of the thionoester 16k (142 mg, 1 mmol) with
12c (1.1 mmol) gave, after FC (eluent: EtOAc/n-hexane = 1:3), Z-1k
and E-1k: (149 mg, yield: 63%, Z/E = 1:4) as a brown red oil. Z-1k:
IR (film) νmax: 2924, 1749, 1673, 1622, 1456, 1394, 1360, 1219, 1157,
1
1038, 1021, 994 cm−1; H NMR (400 MHz, CDCl3) data of the
major read from the spectrum of the mixture of geometric isomers Z-
1k and E-1k: δ 7.53 (dd, J = 1.8, 0.8 Hz, 1H), 6.64 (dd, J = 3.4, 0.8
Hz, 1H), 6.52 (dd, J = 3.4, 1.8 Hz, 1H), 3.87 (s, 3H), 3.72 (s, 3H),
2.04 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) data of the
major read from the spectrum of the mixture of geometric isomers Z-
(Z)-5-((4-(tert-Butyl)phenyl)(methoxy)methylene)-4-methoxy-3-
methylfuran-2(5H)-one (Z-1h) and (E)-5-((4-(tert-Butyl)phenyl)-
(methoxy)methylene)-4-methoxy-3-methylfuran-2(5H)-one (E-1h).
Following the general method A, the reaction of the thionoester 16h
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Article
1k and E-1k: δ 169.3, 163.0, 144.6, 144.2, 132.5, 132.0, 114.8, 111.1,
100.7, 59.2 (2C), 8.9 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C12H12O5Na, 259.0577; found, 259.0587. E-1k: IR (film) νmax: 2921,
1748, 1680, 1614, 1397, 1360, 1202, 1162, 1065, 1017, 977 cm−1; 1H
NMR (400 MHz, CDCl3): δ 7.55 (dd, J = 1.7, 0.7 Hz, 1H), 6.98 (dd,
J = 3.4, 0.7 Hz, 1H), 6.52 (dd, J = 3.4, 1.7 Hz, 1H), 4.17 (s, 3H), 3.80
(s, 3H), 2.10 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ
169.8, 164.0, 146.8, 144.0, 134.8, 134.5, 114.9, 112.3, 101.3, 62.5,
59.8, 9.0 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C12H12O5Na,
259.0577; found, 259.0587.
(Z)-5-((4-Fluorophenyl)(methoxy)methylene)-4-methoxy-3-
methylfuran-2(5H)-one (Z-1l) and (E)-5-((4-Fluorophenyl)-
(methoxy)methylene)-4-methoxy-3-methylfuran-2(5H)-one (E-1l).
Following the general method C, the reaction of the thionoester
16l (170 mg, 1 mmol) with 12c (3.3 mmol) gave, after FC (eluent:
EtOAc/n-hexane = 1:3), Z-1l and E-1l: (232 mg, yield: 88%, Z/E =
59.8, 9.0 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for
C14H13ClO4Na, 303.0395; found, 303.0397.
(Z)-5-(Isopropoxy(phenyl)methylene)-4-methoxy-3-methylfur-
an-2(5H)-one (Z-1o) and (E)-5-(Isopropoxy(phenyl)methylene)-4-
methoxy-3-methylfuran-2(5H)-one (E-1o). Following the general
method C, the reaction of the thionoester 16o (180 mg, 1 mmol)
with 12c (3.3 mmol) gave, after FC (eluent: EtOAc/n-hexane = 1:3),
Z-1o and E-1o (238 mg, yield: 87%, Z/E = 3.7:1) as a white solid. Z-
1o: mp: 120−121 °C; IR (film) νmax: 2964, 1747, 1620, 1391, 1361,
1
1217, 1171, 1060, 1023, 995 cm−1; H NMR (400 MHz, CDCl3): δ
7.43−7.34 (m, 5H), 4.19 (dq, J = 18.4, 6.2 Hz, 1H), 3.67 (s, 3H),
2.01 (s, 3H), 1.23 (d, J = 6.2 Hz, 6H) ppm; 13C{1H} NMR (100
MHz, CDCl3): δ 170.2, 163.4, 141.0, 131.9, 131.5, 130.0 (2C), 129.6,
127.7 (2C), 100.4, 72.8, 58.8, 22.3 (2C), 8.8 ppm; HRMS (ESI) m/z:
[M + Na]+ calcd for C16H18O4Na, 297.1097; found, 291.1102. E-1o:
pale yellow oil; IR (film) νmax: 2926, 1748, 1621, 1614, 1394, 1362,
1
1167, 1106, 1065, 984 cm−1; H NMR (400 MHz, CDCl3): δ 7.63−
6:1) as a white solid. Z-1l and E-1l: mp: 119−120 °C; IR (film) νmax
:
2925, 2854, 1755, 1622, 1456, 1366, 1273, 1211, 1149, 846 cm−1; 1H
NMR (400 MHz, CDCl3, data of two geometric isomers, ratio Z/E =
1.2:1): δ 7.73−7.68 (m, 0.9H), 7.38−7.34 (m, 1.1H), 7.12−7.05 (m,
2.0H), 4.20 (s, 1.3H), 3.72 (s, 1.7H), 3.70 (s, 1.7H), 3.61 (s, 1.3H),
2.11 (s, 1.3H), 2.02 (s, 1.7H) ppm; 13C{1H} NMR (100 MHz,
CDCl3, data of two geometric isomers, ratio Z/E = 1.2:1): δ 170.1,
7.60 (m, 2H), 7.43−7.33 (m, 3H), 4.17 (s, 3H), 4.08 (dq, J = 18.4,
6.1 Hz, 1H), 2.10 (s, 3H), 1.23 (d, J = 6.1 Hz, 6H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 170.4, 164.3, 141.6, 135.3, 132.3, 129.5,
129.0 (2C), 128.3 (2C), 100.9, 73.7, 59.4, 21.9 (2C), 8.9 ppm;
HRMS (ESI) m/z: [M + Na]+ calcd for C16H18O4Na, 297.1097;
found, 297.1100.
4-Methoxy-5-(1-methoxy-2-phenylethylidene)-3-methylfuran-
2(5H)-one (1p) and 4-Methoxy-5-(1-methoxy-2-phenylvinyl)-3-
methylfuran-2(5H)-one (1p′). Following the general method A, the
reaction of the thionoester 16p (166 mg, 1 mmol) with 12c (1.1
mmol) gave, after FC (eluent: EtOAc/n-hexane = 1:3), 1p and 1p′
(206 mg, yield: 79%, 1p/1p′ = 2.2:1) as a colorless oil. 1p and 1p′: IR
(film) νmax: 2923, 2851, 1747, 1621, 1454, 1392, 1351, 1271, 1155,
1067, 1031, 993, 721 cm−1; 1H NMR (400 MHz, CDCl3, data of two
geometric isomers, ratio 1p/1p′ = 1.2:1): δ 7.36−7.28 (m, 3H),
7.25−7.21 (m, 2H), 6.07 (s, 0.4H), 5.46 (s, 0.4H), 4.13 (s, 1.6H),
3.95 (s, 1.4H), 3.88 (s, 1.0H), 3.86 (s, 1.6H), 3.67 (s, 1.4H), 2.09 (s,
1.6H), 1.92 (s, 1.4H) ppm; 13C{1H} NMR (100 MHz, CDCl3, data of
two geometric isomers, ratio 1p/1p′ = 1.2:1): δ 174.8, 171.0, 169.6,
163.8, 150.8, 143.4, 137.4, 134.9, 129.0 (2C), 128.5 (2C), 128.4
(2C), 128.3 (2C), 126.7, 126.6, 107.2, 99.3, 97.7, 77.2, 74.1, 59.4,
59.3, 58.4, 55.4, 35.0, 9.1, 7.8 ppm; HRMS (ESI) m/z: [M + Na]+
calcd for C15H16O4Na, 283.0941; found, 283.0948.
169.6, 164.1, 163.5 (d, JC−F = 250.0 Hz, 1C), 163.3, 163.2 (d, JC−F
=
251.1 Hz, 1C), 142.2, 141.4, 135.3, 132.1 (d, JC−F = 8.1 Hz, 2C),
130.9 (d, JC−F = 8.5 Hz, 2C), 129.8, 127.9 (d, JC−F = 3.7 Hz, 1C),
127.4 (d, JC−F = 3.3 Hz, 1C), 115.6 (d, JC−F = 21.3 Hz, 2C), 114.9 (d,
J
C−F = 22.0 Hz, 2C), 100.9, 99.8, 60.6, 59.7, 59.0, 58.8, 9.0, 8.8 ppm;
HRMS (ESI) m/z: [M + Na]+ calcd for C14H13FO4Na, 287.0690;
found, 287.0693.
(Z)-4-Methoxy-5-(methoxy(4-(trifluoromethyl)phenyl)-
methylene)-3-methylfuran-2(5H)-one (Z-1m) and (E)-4-Methoxy-5-
(methoxy(4-(trifluoromethyl)phenyl)methylene)-3-methylfuran-
2(5H)-one (E-1m). Following the general method B, the reaction of
the thionoester 16m (220 mg, 1 mmol) with 12c (1.1 mmol) gave,
after FC (eluent: EtOAc/n-hexane = 1:3), Z-1m and E-1m (251 mg,
yield: 80%, Z/E = 1:1) as a white solid. Z-1m: mp: 119−120 °C; IR
(film) νmax: 2949, 1756, 1623, 1456, 1325, 1273, 1163, 1068, 996, 856
1
cm−1; H NMR (850 MHz, CDCl3): δ 7.63 (m, 2H), 7.51 (m, 2H),
3.73 (s, 6H), 2.03 (s, 3H) ppm; 13C{1H} NMR (212.5 MHz, CDCl3):
δ 169.5, 162.9, 140.7, 135.3, 131.4 (q, JC−F = 33.0 Hz, 1C), 130.5
(3C), 124.6 (2C), 123.8 (q, JC−F = 272.2 Hz, 1C), 99.7, 59.3, 58.8,
8.9 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C15H13F3O4Na,
(Z)-4-Methoxy-5-(1-methoxyhexadecylidene)-3-methylfuran-
2(5H)-one (Z-1q) and (E)-4-Methoxy-5-(1-methoxyhexadecyli-
dene)-3-methylfuran-2(5H)-one (E-1q). Following the general
method A, the reaction of the thionoester 16q (286 mg, 1 mmol)
with 12c (1.1 mmol) gave, after FC (eluent: EtOAc/n-hexane = 1:6),
Z-1q and E-1q (190 mg, yield: 50%, Z/E = 3.7:1) as a colorless oil. Z-
1q: IR (film) νmax: 2923, 2854, 1748, 1627, 1457, 1376, 453 cm−1; 1H
NMR (500 MHz, CDCl3): δ 4.10 (s, 3H), 3.91 (s, 3H), 2.46 (t, J =
7.7 Hz, 2H), 2.04 (s, 3H), 1.51−1.44 (m, 2H), 1.28−1.22 (m, 24H),
0.85 (t, J = 6.9 Hz, 3H) ppm; 13C{1H} NMR (125 Hz, CDCl3): δ
169.8, 164.2, 146.3, 127.7, 97.2, 59.3, 59.1, 31.8, 29.62 (3C), 29.60
(3C), 29.5, 29.3 (2C), 29.1, 29.0, 27.9, 22.6, 14.0, 9.0 ppm; HRMS
(ESI) m/z: [M + Na]+ calcd for C23H40O4Na, 403.2819; found,
403.2834. E-1q: IR (film) νmax: 2924, 2853, 1748, 1621, 1456, 1366,
337.0658; found, 337.0658. E-1m: mp: 101−102 °C; IR (film) νmax
:
1
2946, 1758, 1617, 1410, 1355, 1217, 1162, 1111, 993, 854 cm−1; H
NMR (500 MHz, CDCl3): δ 7.83 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3
Hz, 2H), 4.20 (s, 3H), 3.61 (s, 3H), 2.11 (s, 3H) ppm; 13C{1H}
NMR (125 MHz, CDCl3): δ 169.7, 163.9, 141.1, 136.7, 135.4, 131.1
(q, JC−F = 32.8 Hz, 1C), 128.9 (2C), 125.4 (q, JC−F = 3.7 Hz, 2C),
123.8 (q, JC−F = 272.5 Hz, 1C), 101.26, 60.8, 59.7, 8.9 ppm; HRMS
(ESI) m/z: [M + Na]+ calcd for C15H13F3O4Na, 337.0658; found,
337.0661.
(Z)-5-((4-Chlorophenyl)(methoxy)methylene)-4-methoxy-3-
methylfuran-2(5H)-one (Z-1n) and (E)-5-((4-Chlorophenyl)-
(methoxy)methylene)-4-methoxy-3-methylfuran-2(5H)-one (E-1n).
Following the general method A, the reaction of the thionoester 16n
(187 mg, 1 mmol) with 12c (1.1 mmol) gave, after FC (eluent:
EtOAc/n-hexane = 1:3), Z-1n and E-1n (233 mg, yield: 83%, Z/E =
1:1.3) as a white solid. Z-1n: mp: 145−146 °C; IR (film) νmax: 2943,
1
1017, 801, 435 cm−1; H NMR (500 MHz, CDCl3): δ 4.11 (s, 3H),
3.67 (s, 3H), 2.48 (t, J = 7.7 Hz, 2H), 2.04 (s, 3H), 1.55−1.48 (m,
2H), 1.32−1.23 (m, 24H), 0.87 (t, J = 6.8 Hz, 3H) ppm; 13C{1H}
NMR (125 MHz, CDCl3): δ 170.4, 163.3, 148.2, 132.8, 100.3, 59.5,
57.6, 31.9, 29.68 (2C), 29.65, 29.64 (2C), 29.60, 29.5, 29.4, 29.34,
29.27, 27.3, 27.1, 22.7, 14.1, 8.8 ppm; HRMS (ESI) m/z: [M + Na]+
calcd for C23H40O4Na, 403.2819; found, 403.2829.
1
1754, 1625, 1456, 1273, 1211, 1149, 1076, 981, 842 cm−1; H NMR
(500 MHz, CDCl3): δ 7.36 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz,
2H), 3.74 (s, 3H), 3.71 (s, 3H), 2.03 (s, 3H) ppm; 13C{1H} NMR
(125 MHz, CDCl3): δ 169.6, 163.1, 141.3, 135.8, 131.4 (2C), 130.1,
129.9, 128.1 (2C), 99.7, 59.1, 58.9, 8.9 ppm; HRMS (ESI) m/z: [M +
Na]+ calcd for C14H13ClO4Na, 303.0395; found, 303.0397. E-1n: mp:
124−125 °C; IR (film) νmax: 2946, 1759, 1619, 1449, 1356, 1211,
1162, 1012, 992, 841 cm−1; 1H NMR (850 MHz, CDCl3): δ 7.67 (d, J
= 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.21 (s, 3H), 3.62 (s, 3H),
2.12 (s, 3H) ppm; 13C{1H} NMR (212.5 MHz, CDCl3): δ 170.0,
164.0, 141.9, 135.8, 135.5, 130.3, 130.0 (2C), 128.8 (2C), 101.1, 60.8,
(Z)-5-(1-(Hexadecyloxy)hexadecylidene)-4-methoxy-3-methyl-
furan-2(5H)-one (Z-1r) and (E)-5-(1-(Hexadecyloxy)-
hexadecylidene)-4-methoxy-3-methylfuran-2(5H)-one (E-1r). Fol-
lowing the general method A, the reaction of the thionoester 16r (497
mg, 1 mmol) with 12c (1.1 mmol) gave, after FC (eluent: EtOAc/n-
hexane = 1:10), Z-1r and E-1r (307 mg, yield: 52%, Z/E = 2:1) as a
white solid. Z-1r: mp: 58−59 °C; IR (film) νmax: 2954, 2849, 1725,
1607, 1467, 1398, 1361, 1158, 435 cm−1; 1H NMR (400 MHz,
CDCl3): δ 4.17 (t, J = 6.6 Hz, 2H), 4.10 (s, 3H), 2.48 (t, J = 7.5 Hz,
2H), 2.05 (s, 3H), 1.68−1.58 (m, 2H), 1.53−1.46 (m, 2H), 1.38−
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Article
1.23 (m, 50H), 0.86 (m, 6H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ 169.9, 164.4, 146.0, 127.6, 97.2, 72.0, 59.1, 31.9 (2C),
30.0, 29.7 (11C), 29.6 (3C), 29.5 (2C), 29.32 (3C), 29.30, 29.1, 27.9,
25.8, 22.6 (2C), 14.0 (2C), 9.0 ppm; HRMS (ESI) m/z: [M + Na]+
calcd for C38H70O4Na, 613.5166; found, 613.5181. E-1r: mp: 55−56
°C; IR (film) νmax: 2915, 2849, 1731, 1621, 1470, 1399, 1201, 1165,
431 cm−1; 1H NMR (400 MHz, CDCl3): δ 4.09 (s, 3H), 3.82 (t, J =
6.4 Hz, 2H), 2.47 (t, J = 7.6 Hz, 2H), 2.04 (s, 3H), 1.69−1.63 (m,
2H), 1.55−1.47 (m, 2H), 1.42−1.24 (m, 50H), 0.87 (m, 6H) ppm;
13C{1H} NMR (100 MHz, CDCl3): δ 170.4, 163.4, 147.6, 133.2,
100.1, 70.3, 59.3, 31.9 (2C), 29.8, 29.7 (6C), 29.65 (5C), 29.61 (3C),
29.5, 29.4, 29.39, 29.34 (3C), 27.6, 27.1, 25.8, 22.7 (2C), 14.1 (2C),
8.8 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C38H70O4Na,
613.5166; found, 613.5185.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02502.
(5) Pelter, A.; Al-Bayati, R. I. H.; Ayoub, M. T.; Lewis, W.;
Pardasani, P.; Hansel, R. Synthetic Routes to the Piperolides,
Fadyenolides, Epoxypiperolides, and Related Compounds. J. Chem.
Soc., Perkin Trans. 1 1987, 717−742.
Comparison of NMR data and copies of NMR spectra;
comparison of 13C{1H} NMR data for deducing
stereochemistry; and NOESY spectra of Z-1a, Z-1b, Z-
1d, Z-1e, Z-1g, and Z-1r (PDF)
́
(6) Velazquez, F.; Olivo, H. F. Synthesis of Bicyclic γ-
Ylidenetetronates. Org. Lett. 2002, 4, 3175−3178.
AUTHOR INFORMATION
Corresponding Author
Pei-Qiang Huang − Department of Chemistry and Fujian
Provincial Key Laboratory of Chemical Biology, College of
Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, P. R. China; orcid.org/0000-
0003-3230-0457; Email: pqhuang@xmu.edu.cn
(7) Baylis, A. M.; Helliwell, M.; Regan, A. C.; Thomas, E. J.
Synthesis of 5-Hydroxy-1,7-dioxaspiro[5.5]undec-3-en-2-ones from 2-
Benzenesulfonyltetra-hydropyrans and 5-Hydroxybutenolides: X-Ray
Crystal Structure Determination for (5RS,6SR)-5-Acetoxy-4-methoxy-
3-methyl-1,7-dioxaspiro[5.5]undec-3-en-2-one. J. Chem. Soc., Perkin
Trans. 1 1993, 411−416.
■
(8) Kende, A. S.; Smalley, T. L.; Huang, H. Total Synthesis of
( )-Isostemofoline. J. Am. Chem. Soc. 1999, 121, 7431−7432.
̈
(9) Bruggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M.
D.; Schwink, L.; Scott, J. P. Total Synthesis of ( )-Didehydrostemo-
foline (Asparagamine A) and ( )-Isodidehydrostemofoline. J. Am.
Chem. Soc. 2003, 125, 15284−15285.
(10) (a) Huang, P.-Q.; Huang, S.-Y.; Gao, L.-H.; Mao, Z.-Y.; Chang,
Z.; Wang, A.-E Enantioselective Total Synthesis of (+)-Methox-
ystemofoline and (+)-Isomethoxystemofoline. Chem. Commun. 2015,
51, 4576−4578. (b) During the resubmission of this manuscript, our
work on the enantioselective total syntheses of (+)-stemofoline and
congeners appeared: Huang, X.-Z.; Gao, L.-H.; Huang, P.-Q.
Enantioselective Total Syntheses of (+)-Stemofoline and Three
Congeners Based on a New Biogenetic Hypothesis. Nat. Commun.
2020, 11, 5314. (c) Huang, S.-Y.; Gao, L.-H.; Huang, X.-Z.; Huang,
P.-Q. Enatioselective Total Syntheses of the Proposed and Revised
Structures of Methoxystemofoline: A Stereochemical Revision. J. Org.
Chem. 2021, DOI: 10.1021/acs.joc.0c02667.
Authors
Ya-Qing Huang − Department of Chemistry and Fujian
Provincial Key Laboratory of Chemical Biology, College of
Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, P. R. China
Xiong-Zhi Huang − Department of Chemistry and Fujian
Provincial Key Laboratory of Chemical Biology, College of
Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02502
Author Contributions
#Y.-Q. Huang and X.-Z. Huang contributed equally.
(11) For reviews on the preparation of thionolactones and
thionoesters, see: (a) Jones, B. A.; Bradshaw, J. S. Synthesis and
Reduction of Thiocarboxylic O-Esters. Chem. Rev. 1984, 84, 17−30.
(b) Cava, M. P.; Levinson, M. I. Thionation Reactions of Lawesson’s
Reagents. Tetrahedron 1985, 41, 5061−5087. For a recent example,
see: (c) Matsumoto, Y.; Nakatake, D.; Yazaki, R.; Ohshima, T. An
Expeditious Route to trans-Configured Tetrahydrothiophenes En-
abled by Fe(OTf)3-Catalyzed [3+2] Cycloaddition of Donor−
Acceptor Cyclopropanes with Thionoesters. Chem.Eur. J. 2018,
24, 6062−6066.
(12) Scheibye, S.; Pedersen, B. S.; Lawesson, S.-O. Studies on
Organophosphorus Compounds XXI. The Dimer of p-Methoxyphe-
nylthionophosphine Sulfide as Thiation Reagent. A New Route to
Thiocarboxamides. Bull. Soc. Chim. Belg. 1978, 87, 229−238.
(13) (a) Scheibye, S.; Kristensen, J.; Lawesson, S.-O. Studies on
Organophosphorus CompoundsXXVII Synthesis of Thiono-,
Thiolo- and Dithiolactones. Tetrahedron 1979, 35, 1339−1343.
(b) Curphey, T. J. Thionation with the Reagent Combination of
Phosphorus Pentasulfide and Hexamethyldisiloxane. J. Org. Chem.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the
National Natural Science Foundation of China (22071204)
and the National Key R&D Program of China (grant no.
2017YFA0207302). We thank Dr. Jian-Liang Ye for assistance
in recording and interpreting the NOESY spectra.
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