Intramolecular Diels-Alder Reactions of Tethered Enoate Substituted Furans Induced by Dialkylaluminum Chloride

Article abstract of DOI:10.1021/acs.joc.7b02117

Gold(I)-catalyzed cycloisomerization of enynols 11 and 17, obtained by Sonogashira coupling, led to the tethered enoate-substituted furans 14 and 19. While attempts at thermal and several Lewis acid induced intramolecular Diels-Alder reactions remained fr

Full text of DOI:10.1021/acs.joc.7b02117

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Intramolecular Diels-Alder Reactions of Tethered Enoate
Substituted Furans Induced by Dialkylaluminium Chloride
Sibylle Riedel, Cäcilia Maichle-Mössmer, and Martin E. Maier
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02117 • Publication Date (Web): 07 Nov 2017
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Intramolecular Diels-Alder Reactions of
Tethered Enoate Substituted Furans
Induced by Dialkylaluminium Chloride
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Sibylle Riedel†, Cäcilia Maichle-Mössmerǂ, and Martin E. Maier*†
†Institut für Organische Chemie, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076
Tübingen, Germany
ǂInstitut für Anorganische Chemie, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076
Tübingen, Germany
martin.e.maier@uni-tuebingen.de
TOC graphic
ABSTRACT: Gold(I) catalyzed cycloisomerization of enynols 11 and 17, obtained by Sonogashira coupling,
led to the tethered enoate substituted furans 14 and 19. While attempts of thermal and several Lewis
acid induced intramolecular Diels-Alder reactions remained fruitless, dialkylaluminium chloride led to the
formation of hexahydroindene and octahydronaphthalene derivatives 20 – 23. Their formation can be
explained by Lewis acid induced opening of the epoxy bridge with transfer of one alkyl group to the
intermediate cycloadduct.
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The importance of furan in chemistry is undisputed. Thus, a furan ring is part of many natural products
(Figure 1), where it can be annulated to another ring, like in auxofuran1,2 (1), a fungal-growth-promoting
substance produced by a Streptomyces species or cafestol3 (2), a diterpene contained in coffee, or be a
substituent as in salvinorin A4 (3). Frequently, a furan ring serves as a functional group or a vehicle that is
transformed into some other polyfunctionalized subunit.5 For example, furan can function as
heterodiene in inter- and intramolecular Diels-Alder reactions. In connection with the synthesis of
polycyclic natural products intramolecular Diels-Alder reactions of furans have found growing interest.6
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Figure 1. Examples of natural products that contain a furan ring.
As is generally the case for intramolecular cycloadditions the synthesis of the substrate can be
challenging. With tethered dienophile substituted furans, substrate synthesis typically involves
functionalization of an existing furan ring.6 However, with the possibility of synthesizing substituted
furans by transition metal catalysis from acyclic precursors,7 the synthesis of substrates for
intramolecular Diels-Alder reactions might become more efficient (Scheme 1). For example,
cycloisomerization of a terminally functionalized enynol 4 via vinylgold intermediate 5 would lead to
furan derivative 6.
Scheme 1. Cycloisomerization of enynol 4 to functionalized furan derivative 6.
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In this paper we describe the synthesis of the two tethered acrylate substituted furans 14 and 19 from
conjugated enynols 11 and 17 by gold (I) catalysis and studies of their intramolecular Diels-Alder
reactions.
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While many examples of intramolecular Diels-Alder reactions of furans are known, frequently there are
heteroatoms in the tether or the aliphatic sector of the tether is substituted. The latter can favor the
cycloaddition due to the Thorpe-Ingold effect.8 With substrates like 6-(furan-2-yl)hex-1-en-3-one, where
an activating group is on the tether, intramolecular Diels-Alder reactions of furans are also known. Such
reactions with internally activated IMDAF substrates are promoted by high pressure,9 Lewis acids10 or by
simple heating.11 In addition, substituents like heteroatoms on the furan12 or as part of the tether13 affect
the IMDAF. As we aimed at substrates 14 and 19 featuring an unsubstituted tether we hoped that we
can isolate the primary cycloadducts, which are actually not known in the literature. For the furan
synthesis we chose the method of Liu et al. which is based on the gold(I) catalyzed cycloisomerization of
enynols (Scheme 1).14,15,16 Thus, intramolecular hydroalkoxylation is followed by isomerization to the
furan ring. The required (Z)-enynols should be easily available by Sonogashira cross-coupling.17
First, ethyl propiolate18 was converted to (Z)-3-bromoacrylate19 (7) which upon reduction with DIBAL-H
gave 3-bromopropenol20 (8). In parallel, 4-pentynol21 (9) was subjected to an one pot Swern
oxidation/Wittig reaction22 using the ylide methyl (triphenylphosphoranylidene) acetate.23 This furnished
enoate 10 in 75% yield (Scheme 2).24 The seemingly straightforward Sonogashira coupling between vinyl
bromide 8 and alkyne 10 was hampered by the formation of the Glaser product, diyne 12. However, if
the reaction was run in Et3N at 10 °C, an almost quantitative yield of enynol 11 could be secured. The
crucial cyclization of enynol 11 to furan 14 was best performed in methanol using 2 mol% of Echavarren
catalyst (acetonitrile) [(2-biphenyl)di-tert-butylphosphine]gold(I) hexafluoroantimonate25 (13a). These
conditions led to a 98% yield of furan derivative 14. With the simple gold catalyst 13b (2 mol%) furan 14
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was formed in 66% yield. Using a similar strategy 5-hexynol26 (15) was transformed to homolog 17. Thus,
the domino Swern oxidation/Wittig olefination sequence on hexynol 15 led to enyne27 16 in reasonable
yield. This was followed by the Sonogashira coupling with vinyl bromide 8 which provided enynol 17 in
high yield. Again, the gold (I) catalyzed cycloisomerization of the enynol went smoothly furnishing the
substituted furan 19 in almost quantitative yield. Surprisingly, in this case the simple catalyst 13b
performed better (95% yield) than catalyst 13a (77% yield). As before, the formation of diyne 18 could be
suppressed by running the coupling reaction at 10 °C.
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Scheme 2. Synthesis of 6-(furan-2-yl)hex-2-enoate (14) and the 7-(furan-2-yl)hept-2-enoate (19) via
cycloisomerization of enynols 11 and 17.
With the tethered enoate substituted furans 14 and 19 in hand, we could examine the intramolecular
Diels-Alder reaction. Initial studies were performed with enoate 14. Attempts at a thermal cycloaddition
(60 – 110 °C, toluene, 140 °C, xylenes) were unsuccessful. Below 110 °C, the substrate 14 remained,
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whereas above this temperature prolonged reaction times caused decomposition. We then looked at
Lewis acid catalysis. Unfortunately, most of them either left the substrate unchanged or produced a
complex mixture (Table 1).
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Table 1. Intramolecular Cycloaddition of Furanylenoates 14 and 19.
entry
substrate, molarity
[mol/L]
solvent
Lewis Acid, equiv
t [°C]
result,
yield [%]
NRa
1
14 or 19, 0.035
14 or 19, 0.035
14, 0.04
toluene
xylene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
60 to 110
140
b
2
–
–
3
BF3·Et2O, 0.05 – 1
BF3·Et2O, 0.05 – 3
AlCl3, 3
–20
NRa
b
4
14, 0.04
–20 to 40
–20 to rt
–20 to 0
–80 to rt
0 to rt
–
b
5
14, 0.02
–
c
6
14 or 19, 0.05
14, 0.05
EtAlCl2, 2
Me3Al, 2
–
b
7
–
d
8
14, 0.05
Sc(OTf)3, 0.5
Me2AlCl, 2
Me2AlCl, 2
Et2AlCl, 2
–
9
14, 0.2
–30 to rt
–30 to rt
–30 to rt
20, 42
20, 67
21, 72
10
11
14, 0.048
14, 0.06
aNo reaction, starting material remained. bDecomposition of starting material. In presence of butylated
hydroxytoluene (BHT, 8 mol%) no reaction was observed and the starting material could be re-isolated.
cPossibly bimolecular cycloadditions. dComplex mixture.
But with the Lewis acid dimethylaluminium chloride (Me2AlCl, 2 equiv, sequential addition of the Lewis
acid) in CH2Cl2 as solvent and a substrate concentration of 0.044
M, a new product could be isolated. This
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compound only showed one olefinic proton in the 1H NMR spectrum. The presence of a methyl doublet
at δ = 0.96 ppm made it clear that the product had incorporated a methyl group from the Lewis acid.
Further spectroscopic analysis suggested hexahydroindene derivative 20 as the structure. The coupling
constants observed for 4-H (J = 10.8 Hz) and 5-H (10.8, 6.2 Hz) were indicative of the trans-trans
arrangement of the protons 3a, 4 and 5. An ultimate prove of the structure 20 came from the X-ray
analysis (Scheme 3).
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Scheme 3. Domino intramolecular Diels-Alder reactions and nucleophilic opening of the ether bridge of
Furanylenoates 14 and 19.
The formation of the hexahydroindene 20 can be explained by an intramolecular Diels-Alder reaction
followed by transfer of a methyl group from the Lewis acid, complexed to the ether bridge. Examples of
allylic substitution of bridged ether furan Diels-Alder adducts have been reported, employing
organolithium nucleophiles.28 Related ring opening reactions of strained oxa/azabicyclic alkenes are well
known in the literature.29,30
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In initial runs we only obtained moderate yields for hydroxyester 20. Analysis of the reaction mixture
indicated that bimolecular Diels-Alder reactions must have taken place. The yield for the
hexahydroindene derivative 20 substantially increased if the reaction was run under higher dilution. In a
similar manner the reaction of furanylhexenoate 14 in presence of diethylaluminium chloride gave the
ethyl derivative 21 in 72% yield.
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With the substrate 19 having four methylene groups in the tether, the domino Diels-Alder
reaction/epoxy bridge opening worked as well. In this case however, two diastereomers namely, the
major octahydronaphthalene derivative 22-endo and the minor isomer 22-exo were observed.
Compound 22-endo results from the intermediate endo-cycloadduct, whereas the minor isomer 22-exo
was formed from the exo-cycloadduct. In contrast to the endo-product 22-endo, where 1-H and 2-H
show large coupling constants (J = 11.0 Hz), among the corresponding protons of the exo-product 22-exo
only 1-H shows a large coupling constant (J = 10.3 Hz) indicating the trans-arrangement of 8a-H and 1-H
and the cis-arrangement of 1-H and 2-H.
The same reaction in presence of Et2AlCl gave comparable results. Thus, we isolated 62% of 23-endo and
17% of exo-product 23-exo. The structure of 23-exo was unambiguously confirmed by an X-ray analysis.
It clearly showed the all cis arrangement of the C1-C3 substituents. Thus, in all cases the alkyl group from
the Lewis acid was introduced syn to the epoxy bridge. ORTEPs for compounds 20, 21, 22-endo, 23-endo,
23-exo, and 24 (vide infra) are included in the SI.
By running the reaction of furanylenoate 19 with only one equivalent of the Lewis acid Et2AlCl we hoped
to isolate the primary cycloadduct B (Scheme 4). Keeping the reaction conditions as before (–30 to 0 °C,
1 h, then rt, 12 h) we observed the formation of several products that are derivatives of the initial
cycloadducts B-endo and B-exo. It can be assumed that the initial cycloadducts B-endo and B-exo are in
equilibrium with the starting furanylenoate 19. Thus, enol 24 was formed as the major product (14% /
26% brsm). The formation of this enol can be explained by opening of the epoxy bridge and subsequent
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semipinacol rearrangement of both B-endo and B-exo31. Its structure was proven by NMR and an X-ray
analysis. In addition, a lot of starting material 19 (48%) was recovered under these conditions. Further
elution of the column gave a fraction containing a small amount of octahydronaphthalene 23-endo
(about 1%) and the chlorohydrin 25-endo (5% / 9% brsm). Attempts to separate 25-endo from 23-endo
yielded only pure 23-endo (about 0.8%) and the diol 26-endo (4% / 8% brsm) resulting from solvolysis of
the unstable chlorohydrin 25-endo. Attack of water takes place at C-4a of 25-endo, so that the two rings
are trans fused. It can be assumed that cycloadduct B-exo is even more unstable than B-endo. Most
likely, the latter completely reacted to enol 24. The formation of the chlorohydrin 25-endo arises from
transfer of a chloride ion of the Lewis acid causing opening of the epoxy bridge of B-endo. A change in
the reaction conditions (Et2AlCl, –30 to 15 °C, 72 h) gave similar results (16% of 24). The largest coupling
constant of 3-H to its neighbors is around 4 Hz, indicating the pseudoaxial orientation of the chlorine
atom.
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We also performed the same experiment on substrate 19 where we added two equivalents of Et2AlCl in
one portion and kept the reaction conditions the same as before. Here 23-endo was the major product
(33% / 35% brsm). Enol 24 was also isolated (10% / 11% brsm). In addition, a small amount of
octahydronaphthalene 23-exo (4.1% / 4.4% brsm) was formed. Finally, we were able to detect the
chlorohydrin 25-exo (3.6% / 3.8%) and some starting 19 (6%). These results can be interpreted as follows:
Clearly, the additional Lewis acid promotes the transfer of the ethyl group from the aluminium center to
the initial cycloadducts more efficiently. Since the ratio 23-endo/23-exo (8:1) is significantly different
from the one observed in the sequential addition of the Lewis acid (3.75:1, Scheme 3) one can conclude
that cycloadduct B-exo is less stable and either reacts to enol 24 or the chlorohydrin 25-exo. Under the
conditions chlorohydrin 25-endo cannot form since cycloadduct B-endo must react faster to give 23-
endo.
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The reason why the sequential addition of the two equivalents of Et2AlCl gives 23-endo and 23-exo in
high combined yield (79%) is difficult to explain and to clarify this issue would require additional
experiments. As has been noted by Snider et al.32 with two equivalents of Me2AlCl a more reactive
substrate·(Me2AlCl)2 complex is formed. Moreover, it was claimed that alkylaluminium halides can also
function as proton scavengers.
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Scheme 4. Domino intramolecular Diels-Alder reaction and semipinacol rearrangement of 19 to give enol
24; reaction of 19 with Et2AlCl under two different conditions; brsm = based on recovered starting
material.
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In conclusion, we demonstrated the usefulness of the Liu strategy for the synthesis of functionalized
furans. Thus, starting with a terminal alkyne, a Sonogashira coupling with (Z)-bromopropenol 8 gave
conjugated (Z)-enynols 11 and 17. Through a gold-catalyzed cycloisomerization the tethered enoate
substituted furans 14 and 19 were obtained. Probably due to the lack of substituents on the tether and
the facile retro Diels-Alder reaction, the subsequent intramolecular cycloaddition only worked in
presence of a Lewis acid, here R2AlCl, R = Me, Et, that not only catalyzes the cycloaddition but also is able
to trap the unstable cycloadducts. With the aluminium based Lewis acids R2AlCl, R = Me, Et, the
intramolecular cycloaddition was followed by a transfer of an alkyl group to the cycloadducts with
concomitant opening of the epoxy bridge. This way hexahydroindene and octahydronaphthalene
derivatives were obtained. As it turned out, the outcome of the experiments depends on the amount
and order of addition of the Lewis acid.
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Experimental Section
General. Reactions were generally run under nitrogen atmosphere in oven dried glassware. Progress of
the reactions was followed using TLC plates "POLYGRAM SIL G/UV254", petroleum ether, ethyl acetate
(EtOAc), dichloromethane, methanol and mixtures of them as an eluent. Dry diethyl ether (Et2O) and
tetrahydrofuran were distilled from sodium and benzophenone, whereas dry CH2Cl2, methanol and
EtOAc were distilled from CaH2. Distilled petroleum ether with a boiling range of 40–60 °C was used. 1H
NMR (400.160 MHz) and 13C NMR (100.620 MHz) spectra were measured on a "Bruker Avance 400"
spectrometer using CDCl3 or C6D6 as solvent at room temperature. Some of the spectra were acquired on
a Bruker Avance 600 spectrometer, (1H NMR at 600.13 MHz, 13C NMR at 150.90 MHz) or Bruker Avance
700 spectrometer, (1H NMR at 700.29 MHz, 13C NMR at 176.09 MHz). Peak assignments were done by
NMR spectroscopy (1H, 13C, DEPT-135, H,H-COSY, HSQC, and HMBC). Infrared spectra were recorded on a
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single-reflection diamond ATR spectrometer as thin films. In the IR spectra only the
strongest/structurally most important peaks (ν, cm−1) are listed. High-resolution mass spectra (HRMS)
were recorded on a "Bruker maXis 4G" instrument with electron spray ionization (ESI) and TOF mass
detector.
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Methyl (E)-hept-2-en-6-ynoate (10). Under nitrogen-atmosphere dry CH2Cl2 (130 mL) was brought to –75
°C, then oxalyl chloride (5.40 mL, 8.05 g, 63.4 mmol, 1.2 equiv) was added. Thereafter, dry DMSO (8.90
mL, 9.79 g, 125 mmol, 2.3 equiv) was added dropwise over 10 min. The solution was stirred for 10 min
and after that a solution of 4-pentyn-1-ol21 (4.52 g, 53.7 mmol, 1 equiv) in dry CH2Cl2 (43 mL) was added
dropwise within 10 min. The mixture was stirred for 15 min and subsequently dry triethylamine (37.0 mL,
27.0 g, 267 mmol, 5 equiv) was added over 25 min. The resulting yellow mixture was brought to 0 °C and
under vigorous stirring methyl (triphenylphosphoranylidene)acetate23 (21.2 g, 63.4 mmol, 1.2 equiv) was
added in one portion. The reaction mixture was stirred at rt for 1 h and then quenched with water (200
mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The
residue was purified first by flash chromatography (petroleum ether/EtOAc 15:1) to remove the
unpreferred cis-isomer and then the obtained yellow liquid was distilled (107 °C, 25 mbar). Ester24 10
(5.57 g, 40.3 mmol, 75%) was obtained as a colorless liquid. Rf = 0.26 (petroleum ether/EtOAc, 15:1); 1H
NMR (400 MHz, CDCl3): δ = 1.98 (t, 4J = 2.6 Hz, 1H, 7-H), 2.31-2.36 (m, 2H, 5-H), 2.39-2.45 (m, 2H, 4-H),
3.72 (s, 3H, OCH3), 5.88 (dt, 3J = 15.7 Hz, 4J = 1.5 Hz, 1H, 2-H), 6.96 (dt, 3J = 15.7 Hz, 3J = 6.6 Hz, 1H, 3-H);
13C NMR (100 MHz, CDCl3): δ = 17.4 (C-5), 31.0 (C-4), 51.5 (OCH3), 69.4 (C-7), 82.6 (C-6), 122.1 (C-2), 146.6
(C-3), 166.8 (C-1).
Methyl (E)-oct-2-en-7-ynoate (16). Under nitrogen-atmosphere dry CH2Cl2 (112 mL) was brought to –80
°C, then oxalyl chloride (4.70 mL, 6.94 g, 54.7 mmol, 1.2 equiv) was added. Thereafter, dry DMSO (7.70
mL, 108 mmol, 2.3 equiv) was added dropwise over 10 min. The solution was stirred for 10 min and after
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that a solution of 5-hexyn-1-ol26 (15) (4.55 g, 46.4 mmol, 1 equiv) in dry CH2Cl2 (37 mL) was added
dropwise within 10 min. The mixture was stirred for 1 h before dry triethylamine (33.0 mL, 23.3 g, 230
mmol, 5 equiv) was added within 20 min. The resulting yellow mixture was brought to 0 °C and under
vigorous stirring methyl (triphenylphosphoranylidene)acetate (31.0 g, 92.7 mmol, 2.0 equiv) was added
in one portion. The reaction mixture was stirred at rt for 1 h and then quenched with water (200 mL).
The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The combined
organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue
was purified first by flash chromatography (petroleum ether/EtOAc, 20:1) to remove the unpreferred cis-
isomer and then the yellow liquid was distilled (105 °C, 12 mbar). Enoate27 16 (5.23 g, 34.2 mmol, 74%)
was obtained as a colorless liquid. Rf = 0.53 (petroleum ether/EtOAc, 5:1); 1H NMR (400 MHz, CDCl3): δ =
1.66 (tt (app. quin), 3J = 7.2 Hz, 2H, 5-H), 1.95 (t, 4J = 2.7 Hz, 1H, 8-H), 2.19 (td, 3J = 7.0 Hz, 4J = 2.7 Hz, 2H,
6-H), 2.30 (dtd (app. qd), 3J = 7.2 Hz, 4J = 1.6 Hz, 2H, 4-H), 3.69 (s, 3H, OCH3), 5.83 (dt, 3J = 15.7 Hz, 4J = 1.6
Hz, 1H, 2-H), 6.86 (dt, 3J = 15.7 Hz, 3J = 7.0 Hz, 1H, 3-H); 13C NMR (100 MHz, CDCl3): δ = 17.8 (C-6), 26.6 (C-
5), 30.9 (C-4), 51.4 (OCH3), 69.0 (C-8), 83.4 (C-7), 121.6 (C-2), 148.1 (C-3), 166.9 (C-1).
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Methyl (2E,8Z)-10-hydroxydeca-2,8-dien-6-ynoate (11). Under argon-atmosphere dry triethylamine (127
mL) was brought in a water bath to 10 °C. Under stirring, alcohol20 8 (2.00 g, 14.6 mmol, 1 equiv), alkyne
10 (2.82 g, 20.4 mmol, 1.4 equiv), Pd(PPh3)4 (844 mg, 0.730 mmol, 0.05 equiv) and CuI (556 mg, 2.92
mmol, 0.22 equiv) were added consecutively. Then the yellow mixture was slowly allowed to come to rt
in the water bath, initially having a temperature of 10 °C. After 48 h the olive-brown mixture was diluted
with hexane (50 mL), filtered (repeatedly rinsed) and evaporated. The olive-brown oil was purified by
flash chromatography (CH2Cl2/EtOAc, 20:1, 0.1% triethylamine) to obtain enynol 11 (2.75 g, 14.2 mmol,
97%) as a yellow oil. Rf: 0.26 (CH2Cl2/EtOAc, 20:1); 1H NMR (600 MHz, CDCl3): δ = 1.70 (bs, 1H, OH), 2.42-
2.45 (m, 2H, 4-H), 2.49-2.52 (m, 2H, 5-H), 3.73 (s, 3H, OCH3), 4.35 (dd, 3J = 6.6 Hz, 4J = 1.5 Hz, 2H, 10-H),
5.53 (dt, 3J = 10.7 Hz, 4J = 1.5 Hz, 1H, 8-H), 5.90 (dt, 3J = 15.8 Hz, 4J = 1.5 Hz, 1H, 2-H), 6.02 (dt, 3J = 11.0 Hz,
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3J = 6.3 Hz, 1H, 9-H), 6.98 (dt, 3J = 15.8 Hz, 3J = 6.6 Hz, 1H, 3-H); 13C NMR (150 MHz, CDCl3): δ = 18.5 (C-5),
31.2 (C-4), 51.6 (OCH3), 60.9 (C-10), 77.5 (C-7), 94.3 (C-6), 110.9 (C-8), 122.2 (C-2), 140.6 (C-9), 146.9 (C-
3), 166.9 (C-1); IR: 3436, 2951, 2919, 2850, 2361, 2341, 1721, 1659, 1539, 1508, 1436, 1320, 1263, 1205,
1158, 1087, 1021, 801, 726; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C11H14O3Na 217.0835; found
217.0835.
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If the reaction was carried out at rt, or the palladium catalyst was not good enough or there was oxygen
present, one observed a significant amount of the dimeric side product 12 as a light amorphous yellow
solid and conversely the yield of the enynol 11 decreased.
Dimethyl (2E,12E)-tetradeca-2,12-dien-6,8-diynedioate (12). Rf = 0.51 (CH2Cl2/EtOAc, 20:1); 1H NMR (700
MHz, CDCl3): δ = 2.41-2.44 (m, 8H, 4-H, 5-H, 10-H, 11-H), 3.73 (s, 6H, OCH3), 5.88 (d, 3J = 15.6 Hz, 2H, 2-H,
13-H), 6.94 (dt, 3J = 15.7 Hz, 3J = 6.3 Hz, 2H, 3-H, 12-H); 13C NMR (175 MHz, CDCl3): δ = 18.2 (C-5, C-10),
30.8 (C-4, C-11), 51.6 (OCH3), 66.1 (C-7, C-8), 76.0 (C-6, C-9), 122.3 (C-2, C-13), 146.3 (C-3, C-12), 166.7 (C-
1, C-14); IR: 3375, 2953, 2361, 1717, 1658, 1434, 1320, 1265, 1204, 1174, 1157, 1085, 1019, 971, 851,
737, 721, 703, 668; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H18O4Na 297.1097; found 297.1102.
Methyl (2E,9Z)-11-hydroxyundeca-2,9-dien-7-ynoate (17). Under argon-atmosphere dry triethylamine
(95 mL) was brought in a water bath to 10 °C. Under stirring, alcohol 8 (1.50 g, 11.0 mmol, 1 equiv),
alkyne 15 (2.50 g, 16.4 mmol, 1.5 equiv), Pd(PPh3)4 (633 mg, 0.55 mmol, 0.05 equiv) and CuI (417 mg,
2.19 mmol, 0.2 equiv) were added consecutively. Then the yellow mixture was slowly allowed to reach
rt, while keeping the flask in the water bath. After 50 h the olive-brown mixture was diluted with hexane
(40 mL), filtered (repeatedly rinsed) and evaporated. The olive-brown oil was purified by flash
chromatography (petroleum ether/EtOAc, 3.5:1, 0.1% triethylamine) to obtain enynol 17 (2.10 g, 10.1
mmol, 92%) as a yellow oil. Rf = 0.26 (petroleum ether/EtOAc, 2:1); 1H NMR (700 MHz, C6D6): δ = 1.20 (tt
(app. quin), 3J = 7.3 Hz, 2H, 5-H), 1.34 (bs, 1H, -OH), 1.82 (dtd (app. qd), 3J = 7.1 Hz, 4J = 1.5 Hz, 2H, 4-H),
1.92 (tt (app. td) 3J = 7.1 Hz, 4J = 2.2 Hz, 2H, 6-H), 3.41 (s, 3H, OCH3), 4.31 (dd, 3J = 6.2 Hz, 4J = 1.1 Hz, 2H,
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11-H), 5.43 (dt, 3J = 11.0 Hz, 4J = 1.5 Hz, 1H, 9-H), 5.80 (dt, 3J = 15.7 Hz, 4J = 1.5 Hz, 1H, 2-H), 5.80 (dt, 3J =
10.8 Hz, 3J = 6.5 Hz, 1H, 10-H), 6.91 (dt, 3J = 15.7 Hz, 3J = 7.1 Hz, 1H, 3-H); 13C NMR (175 MHz, C6D6): δ =
19.4 (C-6), 27.4 (C-5), 31.6 (C-4), 51.4 (OCH3), 61.4 (C-11), 78.1 (C-6), 95.7 (C-7), 110.7 (C-9), 122.3 (C-2),
142.0 (C-10), 148.6 (C-3), 166.9 (C-1); IR: 3423, 2950, 2360, 2343, 1721, 1658, 1436, 1325, 1269, 1203,
1153, 1094, 1024, 798; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H16O3Na 231.0992; found 231.0990.
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If the reaction was carried out at rt, or the palladium catalyst was not good enough or there was oxygen
present, one observed a significant amount of the dimeric side product 18 as a yellow oil and conversely
the yield of enynol 17 decreased.
Dimethyl (2E,14E)-hexadeca-2,14-dien-7,9-diynedioate (18). Rf = 0.57 (petroleum ether/EtOAc, 7:2); 1H
NMR (400 MHz, C6D6): δ = 1.13 (tt (app. sept), 3J = 7.3 Hz, 4H, 5-H, 12-H), 1.73-1.78 (m, 8H, 4-H, 6-H, 11-
H, 13-H), 3.42 (s, 6H, OCH3), 5.72 (dt, 3J = 15.7 Hz, 4J = 1.5 Hz, 2H, 2-H, 15-H), 6.79 (dt, 3J = 15.7 Hz, 3J =
6.97 Hz, 2H, 3-H, 14-H); 13C NMR (100 MHz, C6D6): δ = 19.0 (C-6, C-11), 27.0 (C-5, C-12), 31.3 (C-4, C-13),
51.3 (OCH3), 67.4 (C-8, C-9), 77.3 (C-7, C-10), 122.4 (C-2, C-15), 148.1 (C-3, C-14), 166.7 (C-1, C-16); IR:
2951, 2850, 2359, 2341, 1720, 1658, 1435, 1324, 1262, 1198, 1150, 1094, 1027, 976, 801; HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C18H22O4Na 325.1410; found 325.1410.
Methyl (E)-6-(furan-2-yl)hex-2-enoate (14). Under nitrogen-atmosphere enynol 11 (2.06 g, 10.6 mmol, 1
equiv) was dissolved in dry methanol (195 mL) and (acetonitrile)[(2-biphenyl)di-tert-
butylphosphine]gold(I)hexafluoro-antimonate (13a) (164 mg, 0.212 mmol, 0.02 equiv) was added to the
light yellow solution. The reaction mixture was stirred for 30 h at rt and then quenched with tetra-n-
butylammonium bromide (TBAB)-solution (1M, 200 mL). Then diethyl ether to reach phase separation
was added, followed by extraction of the aqueous phase with diethyl ether (4 × 200 mL). The combined
organic layers were dried over MgSO4, filtered and concentrated in vacuo. The light yellow oil was
purified by flash chromatography (petroleum ether/EtOAc, 30:1) to obtain furan derivative 14 (2.02 g,
10.4 mmol, 98%) as a colorless liquid. Rf = 0.22 (petroleum ether/EtOAc, 30:1); 1H NMR (400 MHz, CDCl3):
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δ = 1.80 (tt (app. quin), 3J = 7.3 Hz, 2H, 5-H), 2.32 (dtd (app qd), 3J = 7.3 Hz, 4J = 1.6 Hz, 2H, 4-H), 2.64 (t, 3J
= 7.5 Hz, 2H, 6-H), 3.72 (s, 3H, OCH3), 5.83 (dt, 3J = 15.7 Hz, 4J = 1.6 Hz, 1H, 2-H), 5.97 (dd, 3J = 3.1 Hz, 4J =
0.8 Hz, 1H, 3'-H), 6.26 (dd, 3J = 3.1 Hz, 3J = 1.8 Hz, 1H, 4'-H), 6.95 (dt, 3J = 15.7 Hz, 3J = 7.0 Hz, 1H, 3-H),
7.29 (dd, 3J = 1.8 Hz, 4J = 0.8 Hz, 1H, 5'-H); 13C NMR (100 MHz, CDCl3): δ = 26.4 (C-5), 27.2 (C-6), 31.4 (C-4),
51.4 (OCH3), 105.2 (C-3'), 110.1 (C-4'), 121.4 (C-2), 141.0 (C-5'), 148.7 (C-3), 155.3 (C-2'), 167.0 (C-1); IR:
3700, 2950, 2359, 2337, 1722, 1658, 1652, 1435, 1271, 1199, 1149, 1008, 864, 732; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C11H14O3Na 217.0835; found 217.0835.
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Methyl (E)-7-(furan-2-yl)hept-2-enoate (19). Under nitrogen-atmosphere enynol 17 (2.00 g, 9.60 mmol, 1
equiv) was dissolved in dry methanol (96 mL) and (acetonitrile)[triphenylphosphine]gold(I)
hexafluoroantimonate (13b) (141 mg, 0.192 mmol, 0.02 equiv) was added to the light yellow solution.
The reaction mixture was stirred for 30 h at rt and then quenched with TBAB-solution (1M, 100 mL). Then
diethyl ether was added to reach phase separation and after separation of the layers, the aqueous phase
was extracted with diethyl ether (4 × 100 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated under reduced pressure. The light yellow oil was purified by flash
chromatography (petroleum ether/EtOAc, 20:1) to obtain furan 19 (1.89 g, 9.08 mmol, 95%) as a
colorless liquid. Rf = 0.56 (petroleum ether/EtOAc, 5:1); 1H NMR (400 MHz, C6D6): δ = 1.06 (tt (app. quin),
3J = 7.5 Hz, 2H, 5-H), 1,34 (tt (app. quin), 3J = 7.5 Hz, 2H, 6-H), 1.69 (dtd (app. qd), 3J = 7.3 Hz, 4J = 1.5 Hz,
2H, 4-H), 2.34 (t, 3J = 7.3 Hz, 2H, 7-H), 3.43 (s, 3H, OCH3), 5.79 (dt, 3J = 15.7 Hz, 4J = 1.6 Hz, 1H, 2-H), 5.81
(dd, 3J = 3.3 Hz, 4J = 0.9 Hz, 1H, 3'-H), 6.12 (dd, 3J = 3.1 Hz, 3J = 1.8 Hz, 1H, 4'-H), 6.93 (dt, 3J = 15.7 Hz, 3J =
7.0 Hz, 1H, 3-H), 7.12 (dd, 3J = 1.8 Hz, 4J = 0.9 Hz, 1H, 5'-H); 13C NMR (100 MHz, C6D6): δ = 27.9 (C-5), 28.1
(C-6), 28.2 (C-7), 32.2 (C-4), 51.3 (OCH3), 105.6 (C-3'), 110.8 (C-4'), 121.9 (C-2), 141.4 (C-5'), 149.3 (C-3),
156.5 (C-2'), 166.9 (C-1); IR: 3733, 2935, 2861, 2359, 2343, 1723, 1657, 1596, 1508, 1436, 1315, 1272,
1199, 1176, 1148, 1095, 1038, 1008, 808, 739, 670, 601; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C12H16O3Na 231.0992; found 231.0995.
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Methyl (rel 3aS,4S,5S,6S)-5-hydroxy-6-methyl-2,3,3a,4,5,6-hexahydro-1H-indene-4-carboxylate (20).
Under argon-atmosphere furan 14 (119 mg, 0.613 mmol, 1 equiv) was dissolved in dry CH2Cl2 (13 mL)
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and brought to –30 °C. Me2AlCl (0.9
The light-yellow solution was allowed to warm to 0 °C within 1 h. Then additional Me2AlCl (0.9
heptane, 0.75 mL, 0.68 mmol, 1.1 equiv) was added dropwise again. The yellow solution was stirred at rt
overnight and then poured on ice-cooled sodium potassium tartrate solution (1 , 13 mL) and stirred at
M
in heptane, 0.75 mL, 0.68 mmol, 1.1 equiv) was added dropwise.
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in
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rt until phase-separation. The aqueous layer was extracted with CH2Cl2 (3 × 15 mL) and the combined
organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue
was purified by flash chromatography (petroleum ether/EtOAc, 10:1) to obtain hexahydroindene 20
(87.0 mg, 0.414 mmol, 67%) as colorless needles. mp 97.8-98.0 °C (petroleum ether/EtOAc, 5:1); Rf =
0.24 (petroleum ether/EtOAc, 5:1); 1H NMR (700 MHz, CDCl3): δ = 0.96 (d, 3J = 6.9 Hz, 3H, CH3), 1.16-1.24
(m, 1H, 3-H), 1.53-1.60 (m, 1H, 2-H), 1.72-1.77 (m, 1H, 2-H), 1.88-1.92 (m, 1H, 3-H), 2.15-2.20 (m, 1H, 1-
H), 2.30 (dd (app. t), 3J = 10.8 Hz, 3H, 1-H, 4-H, OH), 2.41-2.45 (m, 1H, 3a-H), 2.49-2.54 (m, 1H, 6-H), 3.74
(s, 3H, OCH3), 4.15 (dd, 3J = 10.8 Hz, 3J = 6.2 Hz, 1H, 5-H), 5.34-5.35 (m, 1H, 7-H); 13C NMR (175 MHz,
CDCl3): δ = 15.1 (CH3), 23.4 (C-2), 29.1 (C-1), 31.9 (C-3), 35.1 (C-6), 45.1 (C-3a), 48.8 (C-4), 51.8 (OCH3),
71.4 (C-5), 122.0 (C-7), 141.4 (C-7a), 175.7 (CO2CH3); IR: 3448, 2960, 2931, 2865, 2360, 2341, 1730, 1436,
1314, 1283, 1197, 1170, 1077, 1044, 857, 669; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H18O3Na
233.1148; found 233.1150.
Methyl (rel 3aR,4R,5R,6R)-6-ethyl-5-hydroxy-2,3,3a,4,5,6-hexahydro-1H-indene-4-carboxylate (21).
Under argon-atmosphere furan 14 (119 mg, 0.613 mmol, 1 equiv) was dissolved in dry CH2Cl2 (10 mL)
and brought to –30 °C. Then Et2AlCl (0.9M in toluene, 0.75 mL, 0.68 mmol, 1.1 equiv) was added
dropwise. The light-yellow solution was allowed to warm to 0 °C over 1 h. Then additional Et2AlCl (0.9
in toluene, 0.75 mL, 0.68 mmol, 1.1 equiv) was added dropwise. The yellow solution was stirred at rt
M
overnight and then poured on ice-cooled sodium potassium tartrate solution (1M, 10 mL) and the
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mixture stirred at rt until phase-separation. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and
the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography (petroleum ether/EtOAc, 10:1) to obtain
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hexahydroindene 21 (99.0 mg, 0.440mmol, 72%) as colorless needles. Rf = 0.28 (petroleum ether/EtOAc,
5:1); mp 107.1-108.2 °C (petroleum ether/EtOAc, 5:1); 1H NMR (700 MHz, CDCl3): δ = 0.96 (t, 3J = 7.4 Hz,
3H, CH2CH3), 1.04-1.11 (m, 1H, CH2CH3), 1.17-1.24 (m, 1H, 3-H), 1.54-1.62 (m, 1H, 2-H), 1.73-1.78 (m, 1H,
2-H), 1.79-1.84 (m, 1H, CH2CH3), 1.89-1.93 (m, 1H, 3-H), 2.17-2.22 (m, 1H, 1-H), 2.23-2.27 (m, 1H, 6-H),
2.28 (d, 3J = 4.9 Hz, 1H, OH), 2.29-2.31 (m, 1H, 1-H), 2.33 (dd (app t), 3J = 10.5 Hz, 1H, 4-H), 2.39-2.44 (m,
1H, 3a-H), 3.74 (s, 3H, OCH3), 4.17 (ddd (app. quin), 3J = 10.5 Hz, 3J = 6.3 Hz, 3J = 4.9 Hz, 1H, 5-H), 5.50-
5.52 (m, 1H, 7-H); 13C NMR (175 MHz, CDCl3): δ = 12.0 (CH2CH3), 22.8 (CH2CH3), 23.4 (C-2), 29.2 (C-1), 32.0
(C-3), 41.5 (C-6), 44.9 (C-3a), 49.5 (C-4), 51.8 (OCH3), 71.6 (C-5), 119.7 (C-7), 142.2 (C-7a), 175.8 (CO2CH3);
IR: 3447, 2957, 2864, 2361, 2341, 1732, 1660, 1438, 1378, 1316, 1281, 1199, 1171, 1080, 1051, 866, 796,
671; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H20O3Na 247.1305; found 247.1308.
Methyl (rel 1R,2R,3R,8aR)-2-hydroxy-3-methyl-1,2,3,5,6,7,8,8a-octahydronaphthalene-1-carboxylate (22-
endo) and methyl (rel 1S,2R,3R,8aS)-2-hydroxy-3-methyl-1,2,3,5,6,7,8,8a-octahydronaphthalene-1-
carboxylate (22-exo). Under argon-atmosphere a solution of furan 19 (82.0 mg, 0.390 mmol, 1 equiv) in
dry CH2Cl2 (49 mL) was treated dropwise at –30 °C with Me2AlCl (0.9M in heptane, 0.48 mL, 0.43 mmol,
1.1 equiv). The light-yellow solution was allowed to warm to 0 °C over 1 h. Then, further Me2AlCl (0.9
heptane, 0.48 mL, 0.43 mmol, 1.1 equiv) was added dropwise. The yellow solution was stirred at rt
M in
overnight and then poured on ice-cooled sodium potassium tartrate solution (1M, 50 mL) and stirred at
rt until phase-separation. The aqueous layer was extracted with CH2Cl2 (3 × 50 mL) and the combined
organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue
was purified by flash chromatography (petroleum ether/EtOAc, 10:1) to obtain octahydronaphthalenes
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22-endo (57.0 mg, 0.254 mmol, 64%) and 22-exo (13.0 mg, 0.058 mmol, 15%) as colorless needles. dr 22-
endo / 22-exo = 3.75 / 1.0.
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Octahydronaphthalene 22-endo: Rf = 0.19 (petroleum ether/EtOAc, 5:1); mp 106.9-107.8 °C (petroleum
ether/EtOAc, 5:1); 1H NMR (700 MHz, CDCl3): δ = 0.96 (d, 3J = 6.9 Hz, 3H, CH3), 0.99-1.03 (m, 1H, 8-H),
1.16-1.22 (m, 1H, 6-H), 1.26-1.32 (m, 1H, 7-H), 1.66 (bs, 1H, -OH), 1.69-1.73 (m, 2H, 6-H, 7-H), 1.82-1.84
(m, 1H, 8-H), 1.90-1.94 (m, 1H, 5-H), 2.19-2.22 (m, 1H, 5-H), 2.29-2.32 (m, 1H, 8a-H), 2.37-2.39 (m, 1H, 3-
H), 2.40 (dd (app. t), 3J = 11.0 Hz, 1H, 1-H), 3.74 (s, 3H, OCH3), 4.05 (dd, 3J = 11.0 Hz, 3J = 5.6 Hz, 1H, 2-H),
5.30-5.31 (m, 1H, 4-H); 13C NMR (175 MHz, CDCl3): δ = 14.5 (CH3), 25.6 (C-7), 27.1 (C-6), 33.7 (C-8), 34.6
(C-5), 34.7 (C-3), 41.3 (C-8a), 50.5 (C-1), 51.9 (OCH3), 70.8 (C-2), 123.3 (C-4), 137.6 (C-4a), 175.9 (CO2CH3);
IR: 3459, 2923, 2858, 2361, 2343, 1737, 1437, 1332, 1294, 1199, 1169, 1092, 1050, 1042, 845, 689;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H20O3Na 247.1305; found 247.1305.
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Octahydronaphthalene 22-exo: Rf = 0.28 (petroleum ether/EtOAc, 5:1); mp 71.1-72.3 °C (petroleum
ether/EtOAc, 5:1); 1H NMR (700 MHz, C6D6): δ = 0.86-0.92 (m, 1H, 8-H), 1.04 (d, 3J = 7.3 Hz, 3H, CH3),
1.12-1.18 (m, 1H, 6-H), 1.21-1.28 (m, 1H, 7-H), 1.56-1.61 (m, 2H, 6-H, 7-H), 1.85-1.89 (m, 1H, 5-H), 1.98-
2.01 (m, 1H, 8-H), 2.08-2.09 (m, 1H, 3-H), 2.09-2.12 (m, 1H, 5-H), 2.18-2.19 (m, 1H, OH), 2.25 (dd, 3J =
10.3 Hz, 4J = 1.7 Hz, 1H, 1-H), 2.62-2.66 (m, 1H, 8a-H), 3.35 (s, 3H, OCH3), 3.93-3.95 (m, 1H, 2-H), 4.91-
4.93 (m, 1H, 4-H); 13C NMR (175 MHz, C6D6): δ = 17.5 (CH3), 26.7 (C-7), 28.2 (C-6), 34.3 (C-8), 35.6 (C-8a),
35.7 (C-5), 36.1 (C-3), 51.7 (OCH3), 53.4 (C-1), 70.4 (C-2), 122.2 (C-4), 138.7 (C-4a), 175.5 (CO2CH3); IR:
3531, 2926, 2852, 2360, 2341, 1734, 1684, 1436, 1260, 1195, 1161, 1124, 1062, 1014, 671; HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C13H20O3Na 247.1305; found 247.1307.
Methyl (rel 1R,2R,3R,8aR)-3-ethyl-2-hydroxy-1,2,3,5,6,7,8,8a-octahydronaphthalene-1-carboxylate (23-
endo) and methyl (rel 1S,2R,3R,8aS)-3-ethyl-2-hydroxy-1,2,3,5,6,7,8,8a-octahydronaphthalene-1-
carboxylate (23-exo). Under argon atmosphere furan 19 (103 mg, 0.495 mmol, 1 equiv) was dissolved in
dry CH2Cl2 (19 mL) and brought to –30 °C. Et2AlCl (0.9M in toluene, 0.60 mL, 0.54 mmol, 1.1 equiv) was
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added dropwise. The light-yellow solution was allowed to warm to 0 °C over 1 h. Then, further Et2AlCl
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, 20 mL) and stirred
rt overnight and then poured on ice-cooled sodium potassium tartrate-solution (1
M
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at rt until phase-separation. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL) and the combined
organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue
was purified by flash chromatography (petroleum ether/EtOAc, 10:1) to give octahydronaphthalenes 23-
endo (73.0 mg, 0.306 mmol, 62%) and 23-exo (20.0 mg, 0.084 mmol, 17%) as colorless needles. dr 23-
endo / 23-exo = 3.75 / 1.0.
Octahydronaphthalene 23-endo: Rf = 0.21 (petroleum ether/EtOAc, 5:1); mp 115.0-116.8 °C (petroleum
ether/EtOAc, 5:1); 1H NMR (700 MHz, CDCl3): δ = 0.98 (t, 3J = 7.3 Hz, 3H, CH2CH3), 0.99-1.05 (m, 1H, 8-H),
1.06-1.13 (m, 1H, CH2CH3), 1.17-1.25 (m, 1H, 6-H), 1.27-1.34 (m, 1H, 7-H), 1.70-1.75 (m, 3H, 6-H, 7-H,
OH), 1.76-1.82 (m, 1H, CH2CH3), 1.83-1.86 (m, 1H, 8-H), 1.92-1.96 (m, 1H, 5-H), 2.11-2.15 (m, 1H, 3-H),
2.21-2.23 (m, 1H, 5-H), 2.28-2.32 (m, 1H, 8a-H), 2.43 (dd (app. t), 3J = 11.0 Hz, 1H, 1-H), 3.73 (s, 3H,
OCH3), 4.07 (dd, 3J = 11.0 Hz, 3J = 5.4 Hz, 1H, 2-H), 5.42-5.43 (m, 1H, 4-H); 13C NMR (175 MHz, CDCl3): δ =
12.0 (CH2CH3), 22.8 (CH2CH3), 25.7 (C-7), 27.3 (C-6), 33.9 (C-8), 34.9 (C-5), 41.2 (C-8a), 41.5 (C-3), 51.1 (C-
1), 51.9 (OCH3), 71.0 (C-2), 121.2 (C-4), 138.3 (C-4a), 175.9 (CO2CH3); IR: 3451, 2927, 2855, 2359, 2342,
1732, 1660, 1437, 1378, 1286, 1197, 1169, 1101, 1052, 995, 860, 671; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C14H22O3Na 261.1461; found 261.1462.
Octahydronaphthalene 23-exo: Rf = 0.32 (petroleum ether/EtOAc, 5:1); mp 74.2-75.4 °C (petroleum
ether/EtOAc, 5:1); 1H NMR (700 MHz, CDCl3): δ = 0.95-1.01 (m, 1H, 8-H), 0.98 (t, 3J = 7.5 Hz, 3H, CH2CH3),
1.19-1.27 (m, 1H, 6-H), 1.35-1.43 (m, 2H, CH2CH3, 7-H), 1.49-1.56 (m, 1H, CH2CH3), 1.74-1.78 (m, 2H, 6-H,
7-H), 1.89-1.91 (m, 1H, 8-H), 2.01-2.09 (m, 2H, 3-H, 5-H), 2.21-2.24 (m, 1H, 5-H), 2.26 (d, 3J = 5.4 Hz, 1H,
OH), 2.32 (dd, 3J = 10.5 Hz, 4J = 1.7 Hz, 1H, 1-H), 2.47-2.50 (m, 1H, 8a-H), 3.74 (s, 3H, OCH3), 4.10-4.13 (m,
1H, 2-H), 5.06-5.08 (m, 1H, 4-H); 13C NMR (175 MHz, CDCl3): δ = 11.6 (CH2CH3), 24.3 (C-6), 26.0 (C-7), 27.5
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(CH2CH3), 33.6 (C-8), 35.1 (C-5), 35.5 (C-8a), 42.3 (C-3), 51.9 (OCH3), 52.5 (C-1), 67.9 (C-2), 120.0 (C-4),
138.8 (C-4a), 175.7 (CO2CH3); IR: 3504, 2926, 2854, 2361, 2342, 1724, 1659, 1507, 1435, 1261, 1195,
1171, 1093, 1020, 797; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H22O3Na 261.1461; found 261.1464.
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Reaction of furanylenoate 19 with one equivalent of Et2AlCl: Under argon-atmosphere furan 19 (161 mg,
0.773 mmol, 1 equiv) was dissolved in dry CH2Cl2 (30 mL) and cooled to –30 °C before Et2AlCl (0.9M in
toluene, 0.860 mL, 0.773 mmol, 1 equiv) was added dropwise. The light-yellow solution was allowed to
warm up to 0 °C over 1 h. Then the solution was stirred at rt overnight. The reaction mixture was
quenched with ice-cooled sodium-potassium-tartrate-solution (1M, 30 mL) and stirred at room
temperature until phase-separation. The aqueous phase was extracted with CH2Cl2 (3 × 30 mL) and the
combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography (petroleum ether/EtOAc, 30:1) to obtain enol 24 (22.0
mg, 0.106 mmol, 14%, 26% brsm) as a white solid. Some starting material could be recovered (77.1 mg,
0.370 mmol). Rf (enol) = 0.51 (petroleum ether/EtOAc, 5:1); Rf (ketone) 0.84 (petroleum ether/EtOAc,
5:1), they are not separable.
Methyl 2-hydroxy-3,5,6,7,8,8a-hexahydronaphthalene-1-carboxylate (24). mp 59.6-61.0 °C; 1H NMR (400
MHz, C6D6): δ = 1.00-1.10 (m, 1H, 8-H), 1.18-1.29 (m, 1H, 6-H), 1.33-1.45 (m, 1H, 7-H), 1.62-1.69 (m, 2H,
6-H, 7-H), 1.81-1.90 (m, 1H, 5-H), 2.08-2.13 (m, 1H, 5-H), 2.24-2.30 (m, 1H, 8-H), 2.79-2.83 (m, 2H, 3-H),
2.87-2.95 (m, 1H, 8a-H), 3.32 (s, 3H, OCH3), 4.99 (bs, 1H, 4-H), 12.96 (s, 1H, OH); 13C NMR (100 MHz,
C6D6): δ = 27.4 (C-7), 29.7 (C-6), 30.9 (C-3), 36.6 (C-5), 37.0 (C-8), 39.3 (C-8a), 51.3 (OCH3), 100.5 (C-1),
112.8 (C-4), 140.6 (C-4a), 171.2 (C-2), 173.3 (CO2CH3); IR: 2927, 2853, 2361, 1652, 1615, 1441, 1358,
1316, 1286, 1219, 1070, 1057, 1015, 826, 808, 744, 668; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C12H16O3Na 231.0992; found 231.0994.
After washing the column with ethyl acetate a mixture (19.3 mg) was obtained. NMR and mass spectra
indicated that the mixture contains 23-endo, 25-endo and 26-endo. Separation by flash chromatography
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(PE/EtOAc, 10:1 to 1:1) provided a mixture (10.6 mg) of 23-endo and 25-endo (9.01 mg, 0.0368 mmol,
5%, 9% brsm, according to NMR) and pure 26-endo (7.0 mg, 0.0309 mmol, 4%, 8% brsm) as a white solid.
A second flash chromatography (CH2Cl2/EtOAc, 40:1 to 5:1) of the mixture of 23-endo and 25-endo only
provided 23-endo (1.40 mg, 0.00587 mmol, 0.8%, 1% brsm) and 26-endo (8.10 mg, 0.0358 mmol, 5%, 8%
brsm). Chlorohydrin 25-endo underwent solvolysis to the diol 26-endo on the column.
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Methyl (rel 1R,2S,3R,8aR)-3-chloro-2-hydroxy-1,2,3,5,6,7,8,8a-octahydronaphthalene-1-carboxylate (25-
endo). Rf = 0.44 (CH2Cl2/EtOAc, 20:1); 1H NMR (700 MHz, C6D6): δ = 0.92-0.99 (m, 3H, 6-H, 7-H, 8-H), 1.36-
1.37 (m, 2H, 6-H, 7-H), 1.53-1.57 (m, 1H, 5-H), 1.72-1.74 (m, 1H, 8-H), 1.87-1.89 (m, 1H, 5-H), 2.15 (d, 3J =
10.8 Hz, 1H, OH), 2.39-2.45 (m, 1H, 8a-H), 2.79 (dd, 3J = 10.3 Hz, 3J =11.2 Hz, 1H, 1-H), 3.44 (s, 3H, OCH3),
3.97 (ddd (app. td), 3J = 3.8 Hz, 3J = 11.0 Hz, 1H, 2-H), 4.25-4.27 (m, 1H, 3-H), 5.15 (dt, 4J = 2.0 Hz, 3J = 5.8
Hz, 1H, 4-H); 13C NMR (175 MHz, C6D6): δ = 25.7 (C-6 or C-7), 27.1 (C-6 or C-7), 33.6 (C-8), 34.7 (C-5), 42.1
(C-8a), 51.5 (C-1), 51.9 (OCH3), 62.5 (C-3), 70.4 (C-2), 119.1 (C-4), 144.9 (C-4a), 174.4 (CO2CH3); HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C12H17ClO3Na 267.0758; found 267.0761.
Methyl (1R,2S,3S,8aR)-2,3-dihydroxy-1,2,3,5,6,7,8,8a-octahydronaphthalene-1-carboxylate (26-endo). Rf
= 0.34 (petroleum ether/EtOAc, 1:2); mp 149.3–152.9 °C; 1H NMR (400 MHz, DMSO-d6): δ = 0.97-0.99 (m,
1H, 8-H), 1.07-1.28 (m, 2H, 5-H, 6-H), 1.35-1.48 (m, 3H, 7-H, 8-H, 8a-H), 1.56-1.71 (m, 3H, 5-H, 6-H, 7-H),
2.60 (dd, 3J = 9.7 Hz, 3J = 11.0 Hz, 1H, 1-H), 3.59 (s, 1H, OCH3), 4.20-4.24 (m, 1H, 2-H), 4.36 (s, 1H, 4a-OH),
5.03 (d, 3J = 6.2 Hz, 1H, 2-OH), 5.44-5.52 (m, 2H, 3-H, 4-H); 13C NMR (100 MHz, DMSO-d6): δ = 20.6 (C-7),
24.3 (C-8), 25.4 (C-6), 37.3 (C-5), 44.3 (C-8a), 50.1 (C-1), 51.0 (OCH3) 65.7 (C-4a), 69.3 (C-2), 131.3 (C-3),
134.2 (C-4), 174.8 (CO2CH3); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H18O4Na 249.1097; found
249.1101.
Reaction of furanylenoate 19 with two equivalents of Et2AlCl: Under argon-atmosphere furan 19 (170
mg, 0.816 mmol, 1 equiv) was dissolved in dry CH2Cl2 (32 mL) and cooled to –30 °C before Et2AlCl (0.9M in
toluene, 1.81 mL, 1.63 mmol, 2 equiv) was added dropwise. The light-yellow solution was allowed to
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temperature until phase-separation. The aqueous phase was extracted with CH2Cl2 (3 × 40 mL) and the
combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography (petroleum ether/EtOAc, 10:1) to give
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octahydronaphthalene 23-endo (64.2 mg, 0.269 mmol, 33%, 35% brsm), enol 24 (17.2 mg, 0.0826 mmol,
10%, 11% brsm), a mixture (15.1 mg, white solid) of chlorohydrin 25-exo (7.10 mg calculated by 1H NMR,
0.0290 mmol, 3.6%, 3.8% brsm) and naphthalene 23-exo (8.00 mg, calculated by 1H NMR, 0.0336 mmol,
4.1%, 4.4% brsm) and some recovered starting material 19 (10.2 mg, 0.0490 mmol).
Methyl (rel 1S,2R,4aR,8aS)-4a-chloro-2-hydroxy-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate
(25-exo). Rf = 0.32 (petroleum ether/EtOAc, 5:1), same Rf-value as naphthalene 23-exo. 1H NMR (400
MHz, CDCl3): δ =0.78-2.29 (m, 9H, CH2, OH), 2.40 (dd, 3J = 2.1 Hz, 3J = 8.9 Hz, 1H, 1-H), 2.60-2.69 (m, 1H,
8a-H), 3.75 (s, 3H, OCH3), 4.25-4.27 (m, 1H, 2-H), 4.72-4.75 (m, 1H, 3-H), 4.26-4.28 (m, 1H, 4-H); 13C NMR
(100 MHz, CDCl3): δ = 25.2 (CH2), 27.5 (CH2), 33.7 (CH2), 34.9 (CH2), 34.7 (C-8a), 50.6 (C-1), 52.2 (OCH3),
60.7 (C-3), 68.3 (C-2), 117.0 (C-4), 143.6 (C-4a), 172.9 (CO2CH3); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C12H17ClO3Na 267.0758; found 267.0758.
ASSOCIATED CONTENT
Supporting Information
Copies of NMR spectra for all new compounds, cif-files and ORTEP plots for 20, 21, 22-endo, 23-endo, 23-
exo, and 24. The Supporting Information is available free of charge on the ACS Publications website.
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AUTHOR INFORMATION
Corresponding Author
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* E-mail: martin.e.maier@uni-tuebingen.de
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Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the
final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the state of Baden-Württemberg. The authors would like to acknowledge
networking contribution by the COST Action CM1407 "Challenging organic syntheses inspired by nature -
from natural products chemistry to drug discovery". We also thank Claudia Braun and student Julian
Seidel for contributions to this project.
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