Synthesis of (±) wine lactone and its analogues by a diels-alder approach

Article abstract of DOI:10.1002/ejoc.200900486

A novel route to (±)-wine lactone (1) by a cis-selective kinetically controlled intramolecular Diels-Alder (IMDA) cycloaddition of the linear triene 2 is reported. The triene precursor was synthesised by TBAF-catalysed coupling of an acyl fluoride with an silyl enol ether. Four butadienyl but-3-enoates were prepared and cyclised under mild conditions to give a series of wine lactone analogues. The diastereoselectivity of the IMDA cycloadditions was determined by NMR spectroscopy and GC-MS, whereby the formation of the natural cis-configured wine lactone (1) was established. The diastereomeric IMDA transition states were optimised by using density functional theory at the B3LYP/6-31+G(d) level, and the Boltzmann populations of the electronic energies were found to correlate well with the experimentally observed diastereoselectivity.

Full text of DOI:10.1002/ejoc.200900486

FULL PAPER
DOI: 10.1002/ejoc.200900486
Synthesis of (؎) Wine Lactone and Its Analogues by a Diels–Alder Approach
Patrick D. O’Connor,[a] U Bin Kim,[a] and Margaret A. Brimble*[a]
Keywords: Diels–Alder reactions / Cycloaddition / Density functional calculations / Flavour / Lactones
A novel route to (Ϯ)-wine lactone (1) by a cis-selective kinet-
ically controlled intramolecular Diels–Alder (IMDA) cycload-
dition of the linear triene 2 is reported. The triene precursor
was synthesised by TBAF-catalysed coupling of an acyl fluo-
ride with an silyl enol ether. Four butadienyl but-3-enoates
were prepared and cyclised under mild conditions to give a
series of wine lactone analogues. The diastereoselectivity of
the IMDA cycloadditions was determined by NMR spec-
troscopy and GC-MS, whereby the formation of the natural
cis-configured wine lactone (1) was established. The dia-
stereomeric IMDA transition states were optimised by using
density functional theory at the B3LYP/6-31+G(d) level, and
the Boltzmann populations of the electronic energies were
found to correlate well with the experimentally observed dia-
stereoselectivity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Wine lactone (1) is a sweetly scented organic compound
with a coumarinic coconut-like odor, which was first iso-
lated by Southwell in 1975.[1] Since its isolation it has been
identified as a significant odorant in a variety of natural
sources ranging from black pepper to orange juice to vari-
ous essential oils.[2] The natural product derives its name
from the recognition of 1 as an important flavour constitu-
ent of several white wines, specifically those made from the
Gewürztraminer, Scheurebe and Riesling grape varieties.[3]
Of the eight possible stereoisomers, (3S,3aS,7aR)-1 has the
lowest odour detection threshold, a remarkable value of
0.02 pg/L in air, while its enantiomer, ent-1, has the highest
(1.0 µg/L); the difference in potency spans eight orders of
magnitude. The monoterpenoid wine lactones originate
from a biosynthetic pathway involving a cation-initiated
cascade cyclisation.[4] Whereas the natural product has been
the subject of numerous synthetic reports,[5] we present here
a novel approach wherein the cyclohexene ring is assembled
by an intramolecular Diels–Alder (IMDA) cycloaddition of
an appropriately functionalised linear triene precursor 2.
There are several reports concerning the synthesis of bi-
cyclo[4.3.0] lactones by using an IMDA cycloaddition of
1,3,8-nonatrienes,[6] notably the work of Sherburn and Pad-
don-Row, who recently carried out extensive experimental
and computational studies on the pentadienyl acrylate sys-
tem (Scheme 1).[7] The complementary allyl sorbate IMDA
cycloaddition has also been reported.[8]
Scheme 1. IMDA route to wine lactone (1).
However, to the best of our knowledge the regioisomeric
IMDA cycloaddition manifold involving butadienyl but-
enoates (Scheme 2) has not yet been investigated. In order to
test the feasibility and elucidate the π-diastereofacial selectiv-
ity of this novel system, we sought to synthesise the linear
trienes depicted in Scheme 2 where R1 and R2 = Me or H.
Scheme 2. Selected 1,3,8-nonatriene ester IMDA scaffolds.
Results and Discussion
Two synthetic approaches to the desired racemic butadi-
enyl butenoates were found to proceed in useful yields. In
the first case direct acylation of unsaturated potassium al-
dehyde enolates with acyl chlorides afforded the desired tri-
enes in moderate yields.[9] However, a somewhat higher
yielding procedure was later employed whereby TBAF-cata-
lysed O-acylation of conjugated silyloxydienes with acyl
[a] Department of Chemistry, University of Auckland,
23 Symonds Street, Auckland, New Zealand
Fax: +64-9-373-7422
E-mail: m.brimble@auckland.ac.nz
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900486.
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P. D. O ’Connor, U. B. Kim, M. A. Brimble
FULL PAPER
fluorides reproducibly delivered the desired trienes.[10] The
With four linear trienes in hand, the IMDA cycload-
requisite silyloxydienes 3a–b were prepared from the corre- dition was next attempted. Gratifyingly, microwave irradia-
sponding unsaturated aldehydes,[11] whereas acyl fluorides tion of trienes 7 and 2 in a sealed tube in toluene at 218–
4a–b were synthesised from their parent acids 5a–b by using 250 °C resulted in complete consumption of the starting
cyanuric fluoride (6) (Scheme 3).[12] Despite the fact that material after 16 h, while the two analogues 8 and 9 pos-
the reaction appeared relatively clean by TLC analysis, the sessing two C7 methyl groups required slightly shorter reac-
isolated yields of trienes 2 and 7–9 after chromatography tion times, presumably because of the gem-dimethyl ef-
were somewhat disappointing. The low yields were attrib- fect.[13a–13c] In all cases the reaction was accompanied by a
uted to hydrolytic sensitivity and high volatility, which also sweet woody coconut-like odor, which could be detected in
hampered characterisation efforts. The trienes were there- the laboratory even before the “sealed” vessel was opened.
fore directly employed in the subsequent cycloaddition step. Although isolation proved to be difficult owing to the high
volatility of the lactone products, purification was eventu-
ally facilitated by careful removal of toluene by distillation
followed by silica gel chromatography. According to Guth’s
1H NMR spectroscopic analysis of the wine lactones,[5a] the
configuration of each purified diastereomer was determined
by measurement of the multiplicity and coupling constants
of the methine resonances (Table 1). The reaction diastereo-
selectivity was then determined by GC-MS analysis of the
crude mixture. The purified cycloaddition products were
found to be stable to heating, indicating that the reaction
was under kinetic control.
Scheme 3. Synthesis of butadienyl but-1-enoates.
Table 1. Experimental and theoretical IMDA product distribution.
[a] Combined yield of racemic diastereomers after silica gel chromatography. [b] Unscaled ZPVE-corrected B3LYP/6-31+G(d)//B3LYP/
6-31+G(d). [c] Unscaled ZPVE-corrected B3LYP/6-311+G(2d,p)//B3LYP/6-311+G(2d,p).
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(Ϯ) Wine Lactone and Its Analogues by a Diels–Alder Approach
Gas-phase DFT computation of the reaction transition = C1–C4–C8–C9 is defined by Houk et al.[18] as twist-mode
states was performed with the Gaussian 03 suite of pro- asynchronicity and is recognised as an important parameter
grams.[14] Transition-state optimisation and vibrational in defining asynchronous IMDA cycloadditions.[7] A gene-
analyses were performed by using the B3LYP[15] hybrid ral trend observed within the scope of this investigation is
functional with the 6-31+G(d) basis set, a model, which has that the exo transition states leading to trans-lactones have
been shown to give good results for a variety of pericyclic consistently greater asynchronicity parameters ∆Ras, θdh5
,
reactions.[7,16] Given the relative nonpolarity of both sol- θdh6 and θas relative to endo transition states, which lead
vent and starting material, it was thought that the gas- to the corresponding cis-lactones (Table 2). There is also a
phase calculation would provide acceptable results. The sta- greater degree of deviation from the ideal s-cis ester config-
tionary points were verified as transition-state structures by uration for the exo transition states.
observing that the vibrational mode of the single imaginary
frequency corresponded to concerted bond formation along
the reaction coordinate. Unscaled ZPVE-corrected elec-
tronic energies were used in place of free energies, as these
parameters had been shown to give acceptable results for
regioisomeric IMDA cycloadditions.[7c] Although the calcu-
lated Boltzmann populations at 180 °C accurately predicted
the major and minor diastereomers, there appeared to be
some deviation with respect to the ratios of 15/17 and 18/20
(Table 1). The close experimental isomer ratio 18/20 (18:12)
observed experimentally is incorrectly predicted in Table 1.
Reoptimisation of the transition-state structures by using a
larger basis set generated an almost identical Boltzmann
distribution ratio, thereby ruling out basis set effects as the
cause of the discrepancy.
Notwithstanding possible systematic inaccuracies in the
DFT functional,[17] a better agreement with experimental
results may be obtained by comparing free energies com-
puted by using a solvent model. Nevertheless, given the
approximations, the computed transition states were in ex-
cellent agreement with the experimental results.
Figure 1. B3LYP/6-31+G(d)-optimised transition-state structures
for linear triene 2, relative ZPVE-corrected electronic energies [kJ/
mol] shown in parentheses.
Table 2. Geometric parameters for endo and exo transition states
Discussion of IMDA cis/trans Selectivity
TS1 and TS10–TS20 calculated by using B3LYP/6-31+G(d).
The transition-state geometry and weak preference for
Asynchronicity parameter endo-cis range
exo-trans range
cis over trans diastereoselectivity for products illustrated in
Figure 1 is consistent with the trends observed for similarly
substituted pentadienyl acrylate IMDA cycloadditions.[7a]
Overall, the transition states display varying degrees of
asynchronicity with advanced internal bond formation. For
both the endo and exo transition states, a significant ener-
getic penalty is likely incurred due to the inherent inability
of the three-atom tether to accommodate an ideal bonding
arrangement between the diene and dienophile. For ener-
getic reasons, the tether must maintain an approximate syn-
∆Ras
θdh5
θdh6
θas
0.138–0.194 Å
30.5–34.3°
36.4–37.6°
10.5–11.1°
0.309–0.358 Å
36.6–39.2°
68.5–69.4°
14.6–15.6°
Ester dihedral angles
θE1 ≈ s-cis
θE2
3.9–6.4°
89.7–93.2°
7.0–9.1°
139.8–141.1°
It is important to note that other steric and stereoelec-
coplanar or s-cis relationship with respect to the ester func- tronic factors may outweigh the inherent preference for cis
tion (vide infra). The exo transition states are geometrically stereochemistry, which, despite a significant degree of
less able to meet these requirements, and consequently one asynchronicity, may be as little as 4 kJ/mol.[18]
observes a higher degree of asynchronicity, whereby the exo
In all transition states, the ester dihedral angle θE1 = C4–
transition states are geometrically distorted to achieve the O5–C6–C7 adopts a near s-cis conformation in order to
lowest-energy configuration. Asynchronicity can be defined maximise the overlap of the O5 p-type lone pair with the
by four parameters: bond-forming asynchronicity (∆Ras
=
C6 carbonyl group. It is well known that deviations from
|Rpr – Rin|, where Rpr and Rin are the lengths of newly form- planar geometry about the ester R–O–CO–R torsional an-
ing peripheral and internal sp3 bonds),[7a] and the magni- gle are highly unfavourable, and it has been estimated that
tude of the two endocyclic dihedral angles about the two rotation to a perpendicular arrangement would require ap-
newly forming carbon bridgeheads, θdh5 = O5–C4–C8–C7 proximately 42–54 kJ/mol.[19] The adjacent ester dihedral
and θdh6 = C3–C4–C8–C9 (Table 2). The torsional angle θas angle θE2 = C3–C4–O5–C6 may also be important in de-
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P. D. O ’Connor, U. B. Kim, M. A. Brimble
system equipped with DB-5MS column
FULL PAPER
formed by
a
a
termining the degree of O5 lone-pair conjugation to the bu-
tadiene system. However, given the lone-pair conjugation
with the carbonyl group and the seemingly unfavourable
(for overlap) torsional angle θE2 (Table 2), it seems unlikely
that the O5 lone pair is conjugated to any significant degree
into the butadienyl system. Further calculations are re-
quired to confirm this.
(30 mϫ0.25 mm). Helium was used as the carrier gas with a flow
rate of 1 mL/min. A programmed temperature ramp from 40 to
250 °C over 70 min was employed. NMR spectra were recorded
1
with either a 300 MHz spectrometer operating at 300 MHz for H
nuclei and 75 MHz for 13C nuclei or a 400 MHz spectrometer op-
1
erating at 400 MHz for H nuclei and 100 MHz for 13C nuclei. All
chemical shifts are reported in parts per million (ppm) relative to
1
1
For trienes 7 and 2, (Table 1) the two respective endo and
exo transition states each have a high- and a low-energy
CHCl3 at H NMR (δ = 7.26 ppm). H NMR spectroscopic data
are reported as chemical shift, relative integral, multiplicity (s, sing-
conformer corresponding to the configuration of the C7 let; d, doublet; dd, doublet of doublets; dq, doublet of quartets; t,
triplet; m, multiplet), coupling constant (J in Hz) and assignment.
Standard gradient-mode phase-sensitive 2DNOE and gradient-se-
lected magnitude-mode 2DCOSY pulse sequences were em-
ployed.[21]
methyl group. Whereas high-energy conformations appear
to have a weak A1,3 allylic interaction,[20] this is not suf-
ficient to account for the energy differences between the
isomers (ETS18 – ETS19) = 7.8 kJ/mol (Figure 1). It is likely
that a significant contribution arises from a steric clash of
(؎)-2-Methylbut-3-enoic Acid (5a): A single iodine crystal was
the C7 methyl group with the C4 methine group (cf. struc- added to a stirred suspension of activated magnesium (20 g, 0.82
mol) in dry tetrahydrofuran (200 mL). The mixture was heated to
reflux, and a mixture of 3-chlorobut-1-ene (30 g, 0.33 mol) in tetra-
hydrofuran (30 mL) was slowly added at a rate sufficient to main-
tain a gentle reflux. The mixture was cooled to –78 °C, and dry
CO2 was bubbled through it for 1 h. The reaction mixture was then
cooled to room temperature and filtered though Celite®. Water
(200 mL) was added, and the pH was adjusted to 12 by the addition
of 1  NaOH. The organic layer was discarded, and the pH was
re-adjusted to 2 by the addition of 1  HCl. After extraction of
the aqueous layer with Et2O (3ϫ100 mL), the combined organic
tures TS19 and TS20), or from a steric interaction of the
C7 methyl group with the diene moiety (cf. structures TS1
and TS18).
It is important to note that other factors such as
van der Waals forces, electrostatic, and in some cases sec-
ondary orbital interactions may also influence the transi-
tion-state energy. For example, the IMDA reactions of re-
gioisomeric pentadienyl acrylates[7] generally favour the for-
mation of the cis isomer; however, substitution of the C9
carbonyl group can lead to complete reversal of selectivity extracts were washed with brine and dried with MgSO4. The sol-
vent was removed in vacuo, and the yellow, oily residue was dis-
in favour of the trans isomer. Whereas a priori knowledge
of reaction diastereoselectivity may prove to be elusive, the
subtle factors governing relative transition-state energies are
reasonably well accounted for by gas-phase electronic ener-
gies computed at the B3LYP/6-31+G(d) level.
tilled (b.p. 75–80 °C/14 Torr; ref.[22] 80 °C/14 Torr) to afford the title
compound (23.4 g, 70%) as
a
colourless liquid. 1H NMR
(300 MHz, CDCl3): δ = 1.31 (d, J = 6.9 Hz, 3 H, CH3), 3.16 (m, 1
H, 2-H), 5.22–5.13 (m, 2 H, 4-H), 5.88–6.00 (m, 1 H, 3-H), 11.8 (s,
1 H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.4, 43.5, 116.5,
136.4, 181.2 ppm. 1H and 13C NMR spectroscopic data agreed with
published values.[23]
2,2-Dimethylbut-3-enoic Acid (5b):[24] Prenyl chloride (13.8 mL,
122 mmol) was dissolved in anhydrous tetrahydrofuran (55 mL)
and added to a suspension of activated magnesium (12.0 g,
494 mmol) in anhydrous tetrahydrofuran (38 mL) at a rate suf-
ficient to maintain a gentle reflux. An excess of dry carbon dioxide
was bubbled through the reaction mixture for 2 h followed by direct
addition of solid dry ice (ca. 15 g). Upon evaporation of excess
dry ice, the reaction mixture was hydrolysed by the addition of
concentrated hydrochloric acid (14 mL) in water (23.8 mL). After
addition of sufficient NaCl to separate the remaining aqueous
layer, the organic layer was separated, and the aqueous layer was
extracted with diethyl ether (3ϫ50 mL). The combined organic
solutions were dried with sodium sulfate, and the solvent was evap-
orated in vacuo. The crude product was distilled at reduced pres-
sure (b.p. 85–90 °C/37–39 Torr) to give the title compound as a
colourless liquid (5.1 g, 47%). 1H NMR (300 MHz, CDCl3): δ =
1.32 (s, 6 H, CH3), 5.11 (m, 2 H, 4-H), 6.05 (dd, J = 17.5, 10.6 Hz,
1 H, 3-H), 11.60 (s, 1 H, OH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 24.2, 24.3, 44.6, 113.3, 141.9, 183.0 ppm. 1H and 13C NMR
spectroscopic data agreed with literature values.[24]
Conclusions
We have demonstrated the use of butadienyl butenoates
as novel substrates for the 1,3,8-nonatriene IMDA cycload-
dition. The diastereoselectivity of this reaction can be accu-
rately predicted by DFT computational methods. Future
work will involve the enantioselective synthesis and olfac-
tory analysis of the scented Diels–Alder products.
Experimental Section
General: All reactions were carried out in flame- or oven-dried
glassware under dry nitrogen or argon. Tetrahydrofuran and diethyl
ether were dried with sodium wire, toluene was dried with molten
sodium, pyridine and triethylamine were dried with calcium hy-
dride. Glacial acetic acid was used without further purification.
Flash column chromatography was carried out by using 0.063–
0.1 mm silica gel with the desired solvent. Thin-layer chromatog-
raphy (TLC) was performed by using UV fluorescence and/or
staining with vanillin in ethanolic sulfuric acid or iodine. Merck
silica gel 60 F254 plates were used. High-resolution mass spectra
were recorded at a nominal resolution of 5000–10000. Infrared
spectra were recorded with a Fourier transform infrared spectrome-
1-Trimethylsilyloxy-3-methylbuta-1,3-diene (3b): To a stirred solu-
tion of 3-methylbut-2-enal (13.7 mL, 143 mmol), diethyl ether
(25 mL), triethylamine (22 mL, 160 mmol) and zinc chloride
(200 mg, 1.47 mmol) under argon was added trimethylsilyl chloride
(20 mL, 157 mmol) dropwise at room temperature. The red-brown
solution was then heated to reflux for 24 h. After cooling to room
ter and were reported as wavenumbers (ν). GC analyses were per-
˜
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(Ϯ) Wine Lactone and Its Analogues by a Diels–Alder Approach
temperature, n-pentane (150 mL) was added and the precipitate re-
moved by filtration through silica. The solvent was removed in
vacuo to give an oil that was distilled (b.p. 54 °C/15 Torr; ref.[25]
50 °C/15 Torr) to afford the title compound (13.8 g, 62%) as a
colourless oil.
7-H), 6.09 (dq, J = 10.24, 3.3 Hz, 1 H, 6-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.3, 22.9, 25.7, 41.4, 48.9, 79.4, 125.6,
129.5, 179.4 ppm. HRMS (EI+): m/z = 152.0836 [M+]; C9H12O2
1
requires 152.0837. H NMR data for compound 14 were in agree-
ment with published values.[26]
Cyanuric Fluoride (6):[12] A dry 500 mL round-bottomed flask
equipped with a mechanical stirrer, Vigreux column and distillation
head was charged with cyanuric chloride (50.4 g, 273 mmol), so-
dium fluoride (68.3 g, 1.53 mol) and warm sulfolane (217 mL). The
stirred mixture was gradually heated to a pot temperature of 250 °C
while collecting the condensed vapor. The reaction was stopped
when the head temperature reached 100 °C. The crude distillate
was redistilled (71 °C; ref.[12] 72–73 °C) to yield the title compound
(21.3 g, 58%) as a colourless liquid.
(؎)-3,6-Dimethyl-3,3a,4,5-tetrahydrobenzofuran-2(7aH)-ones 1, 18
and 20: By the same procedure as described above for compound
14, carboxylic acid 5a (0.700 g, 7.00 mmol) and silyloxydiene 3b
(1.20 g, 7.68 mmol) afforded, after silica chromatography (pentane/
diethyl ether, 150:1), the crude triene 2 as a colourless liquid. Triene
2 (512 mg, 2.83 mmol) was taken up in toluene (3 mL) and was
stirred in a microwave reactor at 250 °C for 16 h. The toluene was
carefully removed by distillation using a Kugelrohr apparatus leav-
ing a dark yellow residue, which was purified by flash chromatog-
raphy with pentane/diethyl ether (6:1) as eluent to afford three frac-
tions. Evaporation of the solvent to the atmosphere overnight af-
forded three highly scented diastereomers as colourless oils. 1
(96 mg, 19%), 18 (26 mg, 5%), 20 (4 mg, 1%).
(؎)-3-Methyl-3,3a,4,5-tetrahydrobenzofuran-2(7aH)-ones 14, 15 and
17: A solution of cyanuric fluoride (0.12 mL, 1.40 mmol) was
added dropwise to a stirred solution of 2-methylbut-3-enoic acid
(5a) (0.3 g, 3.0 mmol) and pyridine (0.113 mL, 1.4 mmol) in dry
dichloromethane (10 mL) at 0 °C. The resulting white milky mix-
ture was stirred for 2 h. A solution of 1-trimethylsilyloxybuta-1,3-
diene (3a) (0.4 g, 2.8 mmol) in anhydrous tetrahydrofuran (20 mL)
was added dropwise to the reaction mixture at 0 °C. To the result-
ant yellow solution was added solid tetra-n-butylammonium fluo-
ride (ca. 30 mg, 95 µmol), and the mixture was stirred for 2 h. The
reaction mixture was warmed to room temperature, and pentane
(120 mL) was added. The solution was dried with MgSO4, filtered
through Celite®, and the solvent was removed in vacuo. The yellow
oily residue was purified by flash chromatography by using pen-
tane/diethyl ether (100:1) as eluent. Slow evaporation of the solvent
to the atmosphere overnight afforded the crude linear triene 7 as a
colourless oil. Crude triene 7 (470 mg, ca. 3.09 mmol) was taken
up in toluene (4 mL) and stirred in a microwave reactor at 218 °C
for 15 h. The toluene was carefully removed by distillation with a
Kugelrohr apparatus, which left a resultant dark yellow residue.
Purification by silica-gel flash chromatography (pentane/diethyl
ether, 5:1) gave three separable fractions. Evaporation of the solvent
to the atmosphere overnight afforded three sweetly scented (earthy
coumarinic) diastereomers as colourless oils. 14 (47 mg, 10%),[26]
15 (17 mg, 4%), and 17 (17 mg, 4%).
(3SR,3aSR,7aRS)-3,6-Dimethyl-3,3a,4,5-tetrahydrobenzofuran-
2(7aH)-one (1): IR (CDCl ): ν
= 2923, 1764, 1174, 948, 908,
˜
3
max
732 cm–1. H NMR (400 MHz, CDCl3): δ = 1.21 (d, J = 5.5 Hz, 3
H, CH3), 1.74 (s, 3 H, CH3), 1.94–2.03 (m, 4 H, 4,5-H), 2.22–2.31
(m, 1 H, 3a-H), 2.35–2.47 (m, 1 H, 3-H), 4.88–4.91 (m, 1 H, 7a-
H), 5.47–5.51 (m, 1 H, 7-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 14.0, 22.3, 23.6, 26.0, 37.6, 40.4, 75.4, 118.9, 141.4, 179.4 ppm.
HRMS (EI+): m/z = 166.0999 [M+]; C10H14O2 requires 166.0994.
1
(3RS,3aRS,7aRS)-3,6-Dimethyl-3,3a,4,5-tetrahydrobenzofuran-
2(7aH)-one (20): IR (CDCl ): ν
= 2916, 1981, 1769, 1016,
˜
3
max
802 cm–1. H NMR (300 MHz, CDCl3): δ = 1.22 (d, J = 7.3 Hz, 3
H, CH3), 1.53 (s, 3 H, CH3), 1.96–2.23 (m, 4 H), 2.26–2.38 (m, 2
H, 3a,3-H), 4.33–4.41 (m, 1 H, 7a-H), 5.81–5.83 (m, 1 H, 7-H)
ppm. HRMS (EI+): m/z = 166.09880 [M+]; C10H14O2 requires
166.0994.
1
(3RS,3aSR,7aRS)-3,6-Dimethyl-3,3a,4,5-tetrahydrobenzofuran-
2(7aH)-one (18): IR (CDCl ): ν
= 2922, 1980, 1764, 1174, 948,
˜
3
max
909 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.17–1.36 (m, 3 H,
CH3), 1.79 (s, 3 H, CH3), 1.94–2.41 (m, 5 H, 4,5,3a-H), 2.95–2.86
(m, 1 H, 3-H), 4.62–4.65 (m, 1 H, 7a-H), 5.66–5.69 (m, 1 H, 7-
H) ppm. HRMS (EI+): m/z = 166.0991 [M+]; C10H14O2 requires
166.0994. 1H NMR spectroscopic data were in agreement with
published values.[5a]
(3SR,3aSR,7aSR)-3-Methyl-3,3a,4,5-tetrahydrobenzofuran-2(7aH)-
one (14):[26] IR (CDCl ): ν
= 2933, 1765, 1172, 1161, 994 cm–1.
˜
3
max
1H NMR (300 MHz, CDCl3): δ = 1.20 (d, J = 7.3 Hz, 3 H, CH3),
1.68–1.89 (m, 2 H, 4-H), 2.05–2.10 (m, 2 H, 5-H), 2.28–2.37 (m, 1
H, 3a-H), 2.45 (dq, J = 9.1, 7.3 Hz, 1 H, 3-H), 4.87–4.91 (m, 1 H,
7a-H), 5.77 (dq, J = 2.6, 10.2 Hz, 1 H, 7-H), 5.99 (dt, J = 10.3,
3.6 Hz, 1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0,
20.7, 21.8, 37.2, 41.1, 74.3, 124.3, 132.4, 179.7 ppm. HRMS (EI+):
m/z = 152.0833 [M+]; C9H12O2 requires 152.0837.
(؎)-3,3,6-Trimethyl-3,3a,4,5-tetrahydrobenzofuran-2(7aH)-ones 12
and 13: By the same procedure as described above for compound
14, carboxylic acid 5b (1.5 g, 13.1 mmol) and silyloxydiene 3b
(2.04 g, 13.1 mmol) afforded, after silica chromatography (pentane/
diethyl ether, 150:1), the title compound (260 mg, 11%) as a volatile
unstable liquid. A quantity of triene 9 (180 mg, 1.00 mmol) was
taken up in toluene (6 mL), and the reaction mixture was stirred in
the microwave reactor at 200 °C for 6 h. The toluene was carefully
removed by distillation using a Kugelrohr apparatus, and the dark
yellow residue left behind was purified by flash chromatography
(hexanes/diethyl ether, 5:1) to give two fractions. Evaporation of the
solvent to the atmosphere overnight afforded two diastereomers. 12
(20 mg, 11%), and 13 (11 mg, 6%) as colourless oils.
(3RS,3aSR,7aSR)-3-Methyl-3,3a,4,5-tetrahydrobenzofuran-2(7aH)-
1
one (15): IR (CDCl ): ν
= 1672, 1171, 949, 883 cm–1. H NMR
˜
3
max
(300 MHz, CDCl3): δ = 1.20 (d, J = 6.7 Hz, 3 H, CH3), 1.52–1.74
(m, 2 H, 4-H), 1.91–2.26 (m, 2 H, 5-H), 2.37–2.50 (m, 1 H, 3a-H),
2.91 (dq, J = 6.7, 7.3 Hz, 1 H, 3-H), 4.61–4.64 (m, 1 H, 7a-H),
5.92–5.98 (m, 1 H, 7-H), 6.16–6.21 (m, 1 H, 6-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 9.16, 19.2, 23.8, 38.4, 40.1, 73.3, 122.6,
135.2, 178.7 ppm. HRMS (EI+): m/z = 152.0843 [M+]; C9H12O2
requires 152.0837.
(3aSR,7aSR)-3,3,6-Trimethyl-3,3a,4,5-tetrahydrobenzofuran-
2(7aH)-one (12): IR (CDCl ): ν
= 1773, 1107 cm–1. 1H NMR
˜
3
max
(300 MHz, CDCl3): δ = 1.18 (s, 6 H, CH3), 1.19–1.73 (m, 4 H, 4,5-
H), 1.79 (s, 3 H, CH3), 1.92–1.99 (m, 1 H, 3a-H), 4.78 (d, J =
4.9 Hz, 1 H, 7a-H), 5.66 (m, 1 H, 7-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 19.3, 21.5, 23.8, 24.8, 29.4, 73.5, 117.3, 143.7,
(3RS,3aRS,7aSR)-3-Methyl-3,3a,4,5-tetrahydrobenzofuran-2(7aH)-
one (17): IR (CDCl ): ν
= 2934, 1774, 1648, 1134, 1016 cm–1.
max
˜
3
1H NMR (300 MHz, CDCl3): δ = 1.25 (d, J = 6.9 Hz, 3 H, CH3),
1.53–1.88 (m, 2 H, 4-H), 1.99–2.07 (m, 1 H, 3a-H), 2.24–2.38 (m, 181.4 ppm. HRMS (EI+): m/z = 180.114855 [M+]; C11H16O2 re-
3 H), 4.37–4.44 (m, 1 H, 7a-H), 5.70 (dq, J = 10.24, 3.3 Hz, 1 H,
quires 180.1150.
Eur. J. Org. Chem. 2009, 4405–4411
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4409

P. D. O ’Connor, U. B. Kim, M. A. Brimble
FULL PAPER
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2(7aH)-one (13): IR (CDCl ): ν
= 2932, 1774, 1107 cm–1. 1H
˜
3
max
NMR (300 MHz, CDCl3): δ = 1.24 (s, 6 H, CH3), 1.47–1.60 (m, 2
H, 4-H), 1.69 (s, 3 H, CH3), 1.76–1.93 (m, 2 H, 5-H), 2.14–2.27
(m, 1 H, 3a-H), 4.53 (d, J = 9.8 Hz, 1 H, 7a-H), 5.81–5.85 (m, 1
H, 7-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.9, 19.5, 22.9,
23.5, 30.9, 51.4, 77.7, 120.8, 137.6, 182.5 ppm. HRMS (EI+): m/z
= 180.1152 [M+]; C11H16O2 requires 180.1150.
(3aSR,7aSR)-3,3-Dimethyl-3,3a,4,5-tetrahydrobenzofuran-2(7aH)-
one (10): By the same procedure as described above for compound
14, carboxylic acid 5b (1.2 g, 10.5 mmol) and silyloxydiene 3a
(1.5 g, 10.1 mmol) afforded, after silica chromatography (pentane/
diethyl ether, 250:1), the unstable volatile triene 8 (800 mg, 32%).
A quantity of triene 8 (101 mg, 0.60 mmol) was taken up in toluene
(2.5 mL) and stirred in a microwave reactor at 180 °C for 10 h.
The toluene was carefully removed by distillation using a Kugelrohr
apparatus, and the dark yellow residue left behind was purified by
flash chromatography (pentane/diethyl ether, 10:1) to give a single
isolable fraction. Evaporation of the solvent to the atmosphere
overnight afforded the title compound (18.1 mg, 18%) as a sweet
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[10]
[11]
[12]
[13]
(earthy coumarinic) smelling colourless liquid. IR (CDCl ): ν
=
˜
3
max
2924, 1768, 1219, 1135, 772 cm–1. H NMR (300 MHz, CDCl3): δ
= 1.20 (s, 3 H, CH3), 1.34 (s, 3 H, CH3), 1.47–2.10 (m, 4 H, 4,5-
H), 2.15–2.24 (m, 1 H, 3a-H), 4.80 (dd, J = 9.35, 4.6 Hz, 1 H, 7a-
H), 5.93–5.99 (m, 1 H, 7-H), 6.15–6.20 (m, 1 H, 6-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 19.3, 24.1, 24.8, 29.7, 44.9, 72.0,
122.9, 134.8, 179.93 ppm. HRMS (EI+): m/z = 167.10793 [M+];
C10H15O2 requires 167.10720.
1
[14]
Supporting Information (see footnote on the first page of this arti-
cle): Cartesian coordinates for computed transition states with elec-
tronic and zero-point energy (hartrees); 1H NMR coupling con-
stants and chemical shifts required for identification of IMDA
product structure, and reaction diastereoselectivity as determined
by GC-MS analysis.
Acknowledgments
[15]
[16]
The authors thank Dr. Tilo Söhnel and Assoc. Prof. Peter Boyd
for helpful discussions regarding the computational analysis.
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4410
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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(Ϯ) Wine Lactone and Its Analogues by a Diels–Alder Approach
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Eur. J. Org. Chem. 2009, 4405–4411
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4411