An effective one-pot synthesis of 3-benzylfurans and their potential utility as versatile precursors of 3,4-dibenzyltetrahydrofuran lignans. Formal synthesis of (±)-burseran

Full text of DOI:10.1021/jo0017990

J . Org. Chem. 2001, 66, 4069-4073
4069
Sch em e 1
An Effective On e-P ot Syn th esis of
3-Ben zylfu r a n s a n d Th eir P oten tia l Utility
a s Ver sa tile P r ecu r sor s of
3,4-Diben zyltetr a h yd r ofu r a n Lign a n s.
F or m a l Syn th esis of (()-Bu r ser a n
Ste´phanie Garc¸on,† Stamatia Vassiliou,†
Marcello Cavicchioli,† Benoˆıt Hartmann,‡
Nuno Monteiro,† and Genevie`ve Balme*,†
Laboratoire de Chimie Organique 1, CNRS UMR 5622,
Universite´ Claude Bernard, Lyon I, CPE 43, Bd du 11
Novembre 1918, 69622 Villeurbanne, France, and Aventis
Cropscience, 14 / 20 rue Baizet, 69623 Lyon, France
quently underwent a palladium-mediated cyclization
involving an unsaturated halide (or triflate) 1 as a
coupling partner.6,7 The effectiveness of the methodology
encouraged us to investigate a possible extension of this
chemistry to the synthesis of 3-benzyl-(or allyl-)furans
5. It was indeed hoped that substitution of the benzyli-
dene (or alkylidene) malonates for their ethoxymethylene
analogues (3, R3 ) OEt) as activated olefins would result
in the formation of the corresponding 2-ethoxy-4-arylidene-
tetrahydrofurans which we anticipated to be particularly
prone to decarboxylative elimination. If so, the resulting
3-arylidene 2,3-dihydrofurans would then be expected to
undergo isomerization to afford the desired aromatized
compounds (Scheme 1).
balme@univ-lyon1.fr
Received December 28, 2000
In tr od u ction
Furans are widely diffused among natural substances
which exhibit interesting biological activities.1 Addition-
ally, they can serve as building blocks in natural product
synthesis as well as in heterocyclic chemistry.2 For these
reasons, new synthetic methods leading to this class of
compounds are of considerable interest. With a view to
efficiency, new procedures should be simple to carry out,
use readily available starting marterials, and offer a
flexible entry to polysubstituted molecules accommodat-
ing considerable functionalities.3 For such purposes,
multicomponent sequential reactions are at a premium
because they create diversity and allow for the construc-
tion of complex molecules by combining several trans-
formations without isolation of intermediates.4
In this paper, we report the successful execution of this
strategy and its use in the formal synthesis of the lignan
antitumor agent, burseran.
Resu lts a n d Discu ssion
As part of a program devoted to the development of
new strategies for the synthesis of heterocyclic struc-
tures,5 we recently reported a novel three-component
reaction that permitted the preparation of highly func-
tionalized 3-arylidene-(or alkenylidene-)tetrahydrofurans
4. The proposed one-pot procedure proved very practical
and versatile, involving commercially available or easily
accessible starting materials. From a mechanistic point
of view, the strategy was based on a domino reaction in
which the enolate resulting from initial 1,4-addition of a
propargylic alkoxide 2 to a conjugate acceptor 3 subse-
Tw o-St ep Syn t h esis: P r elim in a r y R esu lt s a n d
Scop e. One of the problems that we expected to face
when we started this study was a possible premature
departure of the nucleofuge ethoxy group during the
reversible initial 1,4-addition step which would have
resulted in the formation of transetherification products,
thereby consuming part of the propargyl alcohol. For
initial evaluation of the approach, the commercially
available diethyl ethoxymethylene malonate (3a ) was
subjected to our previously reported6 reaction conditions.
3a was thus reacted in THF:DMSO (2:1) with equimolar
quantities of lithium propargyl alkoxide and phenyl
iodide in the presence of a catalytic system issued from
the reduction of PdCl2(PPh3)2 with n-BuLi. Pleasingly,
stirring the reaction mixture for 1 h at room temperature
led to the exclusive formation of the expected 2-ethoxy-
4-benzylidene tetrahydrofuran 4a in 70% isolated yield.
In line with previous synthetic studies reported by our
laboratory,8 it was then found that potassium tert-
butoxide was highly effective for the decarboethoxylation
of diester 4a . Thus, treatment of the later with a slight
excess of this reagent in THF at room temperature
* To whom correspondence should be addressed: Fax: Int + (0)4-
72-43-12-14.
† Universite´ Claude Bernard, Lyon I.
‡ Aventis Cropscience.
(1) Donnelly, D. M. X.; Meegan, M. J . in Comprehensive Heterocyclic
Chemistry; Katritzky, A.; Reese, C. W., Eds.; Pergamon Press: Oxford,
1994; Vol. 4, Part 3. Lipshuts, B. H. Chem. Rev. 1986, 86, 795.
(2) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179.
(3) The synthesis of furans has been recently reviewed: Hou, X. L.;
Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong,
H. N. C. Tetrahedron 1998, 54, 1955.
(4) (a) Hall, N. Chemists Clean Up Synthesis With One-Pot Reac-
tions. Science 1994, 266, 32. (b) Ugi, I.; Do¨mling, A.; Ho¨rl, W.
Multicomponent Reactions in Organic Synthesis. Endeaviour 1994, 18,
115. (c) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.;
Keating, T. A. Acc. Chem. Res. 1996, 29, 123. (d) Tietze, L. F. Chem.
Rev. 1996, 96, 115.
(5) See: Marat, X.; Monteiro, N.; Balme, G. Synlett 1997, 845. Clique,
B.; Monteiro, N.; Balme, G. Tetrahedron Lett. 1999, 40, 1301. Woods,
M.; Monteiro, N.; Balme, G. Eur. J . Org. Chem. 2000, 1711. Monteiro,
N.; Balme, G. J . Org. Chem. 2000, 65, 3223.
(6) Bottex, M.; Cavicchioli, M.; Hartmann, B.; Monteiro, N.; Balme,
G. J . Org. Chem. 2001, 66, 175.
(7) The reaction of allylic alcohols had previously been investi-
gated: Cavicchioli, M.; Sixdenier, E.; Derrey, A.; Bouyssi, D.; Balme,
G. Tetrahedron Lett. 1997, 38, 1763.
(8) Monteiro, N.; Gore, J .; Balme, G. Tetrahedron 1992, 48, 10103.
Monteiro, N.; Balme, G.; Gore, J . Synlett 1992, 227.
10.1021/jo0017990 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/05/2001

4070 J . Org. Chem., Vol. 66, No. 11, 2001
Ta ble 1. Syn th esis of 3-Ben zylfu r a n s: Step w ise ver su s On e-P ot P r oced u r e
Notes
a
b
All reactions were performed at room temperature on a 1 mmol scale. Equimolar amounts of the three partners were used. c The
d
reactions were carried out in THF. Yields in brackets refer to overall yields of the two reactions performed independently (stepwise
procedure). e Not isolated as a pure compound. Contains small amounts of an unidentified product, presumably a 1,4-addition adduct of
type (RO)2CHCH(CO2Et)2.
afforded within 1 h the desired benzylfuran 5a in 85%
isolated yield.
7 (entry 9). Interestingly, the use of potassium tert-
butoxide was not always needed to induce the decarboxyl-
ative elimination. Indeed, in two of the cases that were
examined, those involving m-methoxyphenyl iodide and
p-methoxycarbonylphenyl iodide as the unsaturated ha-
lide partners, the three-component reaction spontane-
ously produced the decarboethoxylated aromatized het-
erocycles (entries 5, 6). In any of those cases could the
tetrahydrofuran intermediate be isolated. Such a differ-
ence in reactivity is somewhat surprising. From a mecha-
nistic point of view, the present decarboethoxylation
presumably occurs via attack of one of the ester groups
by the alkoxide8,9 resulting in the generation of an γ-aryl-
dienolate which then evolves through elimination of the
nucleofuge ethoxy group (Scheme 2). Substituents on the
aryl ring should therefore exert significant effect on the
Once the validity of our approach had been established,
we sought to gauge the scope and limitations of this
chemistry. In this regard, we have submitted 3a , several
propargylic alkoxides, and organic halides (or triflates)
to the two-step protocol. The results are summarized in
Table 1. As can be seen, the procedure proved very
effective for the preparation of various 3-benzylfurans 5.
For this purpose, aryl halides were partners of choice in
the three-component reaction (entries 1-8), whereas the
corresponding triflates have been found essentially un-
reactive under identical conditions. On the other hand,
vinyl triflates should prove useful as versatile starting
materials for the preparation of 3-allylfurans as illus-
trated with the synthesis of the cyclohexenyl derivative

Notes
J . Org. Chem., Vol. 66, No. 11, 2001 4071
Sch em e 2
Sch em e 3. P la n for th e Syn th esis of
3,4-Diben zyltetr a h yd r ofu r a n s
tetrahydrofuran intermediates probably just made up for
the lower performance of the decarboxylative elimination
that was anticipated in the new solvent system. Even
so, the one-pot methodology may be preferred for eco-
nomical and environmental reasons.
polarization of the carbon-carbon bond to be broken and,
thereby, affect the reactivity of the tetrahydrofurans
toward decarboethoxylation. It is expected that their
stability will increase with the electron density of the aryl
ring. According to this, the elimination reaction leading
to 5e should be greatly facilitated by the presence of the
electron-withdrawing group at the para position. We may
therefore suggest that propargyl alkoxide itself is nucleo-
philic enough to initiate the decarboethoxylative process
which may then proceed by action of the continuously
generated ethoxide anion. However, the case of 5f
remains unclear especially in view of the fact that 4b
involving more electron-donating substituents could be
successfully isolated. Fairly subtle electronic effects seem
to govern the outcome of these reactions.
Attempts were also made to involve another electron-
deficient olefin that differed from 3a in the nature of one
of the electron-withdrawing groups, i.e., the commercially
available ethyl (ethoxymethylene) cyanoacetate (3b).
Unfortunately, when 3b was reacted with lithium pro-
pargyl alkoxide and phenyl iodide under our standard
conditions, complex mixtures were obtained from which
we were unable to isolate the desired tetrahydrofuran.
On e-P ot P r oced u r e. The similarities between the
optimized reaction conditions for both steps led us to next
consider the possibility of integrating the stepwise chemi-
cal process into a general one-pot reaction for an expedi-
ent synthesis of the targeted compounds. The two steps
would be conducted sequentially in the same reaction
vessel without isolation of the intermediates. Since the
use of DMSO as cosolvent could not be avoided in the
first step,7 we conducted a test experiment on tetra-
hydrofuran 4h that showed that the decarboxylative
elimination reaction was compatible with the presence
of such a solvent, although a slightly lower yield (76%
compared to 79%) was obtained.10 The one-pot protocol
was as follows: the reaction mixtures obtained by com-
bining the three partners were treated with a solution
of potassium tert-butoxide in THF once these had reacted
(GC; 1-3 h), and stirring was continued until complete
decarboxylation was observed (<1 h). As indicated in
Table 1, we did not observe significant differences
between yields obtained through the stepwise procedure
and those obtained by using the one-pot protocol. Avoid-
ing material loss during isolation and purification of the
F or m a l Syn th esis of Bu r ser a n . In an effort to find
a possible application of this methodology to natural
product synthesis, we found that furans 5 were potential
precursors of 3,4-dibenzyltetrahydrofuran lignans. These
compounds have been recognized as important synthetic
targets because of their widespread occurrence in nature
and the interesting biological properties exhibited by
some of them. In addition, 3,4-dibenzyltetrahydrofurans
may also be transformed into bicyclic lignans of the
phenyltetralin and dibenzocyclooctane series, thus em-
phasizing the importance of discovering new synthetic
routes to this class of lignans.11 In our plan (Scheme 3),
we relied on previous work reported by Hanessian and
co-workers which concerned the facile transformation of
racemic 4-benzyltetrahydrofuran-3-carboxaldehydes 8
into various 3,4-dibenzyl tetrahydrofurans 9 by a three-
step sequence that allowed the production of both the (-)-
and (+)-enantiomers.12 As a formal synthesis of 3,4-
dibenzyltetrahydrofurans we envisioned the conversion
of the 4-benzylfuran-3-carboxylates 5, which we are now
able to synthesize in a single-step procedure, into the
corresponding 4-benzyltetrahydrofuran-3-carboxalde-
hydes by the following series of steps: reduction of the
ester into the corresponding alcohol, hydrogenation, and
oxidation.
To illustrate the viability of this concept, we have
achieved the formal synthesis of the lignan antitumor
burseran. Thus, reaction of furan 5b with LiAlH4 fur-
nished the corresponding alcohol 10 in essentially quan-
titative yield. Hydrogenation of the furan ring13 was then
achieved over Raney Ni under 10 bar of H2 at room
temperature to give a mixture of two isomeric tetrahy-
drofurans 11 (trans:cis, 1:1). Finally, oxidation of the later
under Swern conditions afforded the targeted aldehyde
8b in 90% isolated yield as a mixture of diastereomers
(trans:cis, 2.5:1). In accordance with Hanessian’s findings,
equilibration with DBU (CH2Cl2, rt) afforded 8b as a
highly enriched trans isomer (20:1) (Scheme 4). The
desired precursor of burseran has thus been obtained in
only four synthetic steps and in 47% overall yield from a
combination of three simple building blocks.
(11) Reviews: Ayres, D. C.; Loike, J . D. in Lignans: Chemical,
Biological and Clinical Properties; Cambridge University Press: Cam-
bridge, 1990. Ward, R. S. Nat. Prod. Rep. 1999, 16, 75-96, and previous
reports referred to therein.
(12) Hanessian, S.; Le´ger, R. Synlett 1992, 402.
(9) Similar alkoxide-induced decarboxylations had been previously
reported; see Eglinton, G.; Whiting, M. C. J . Chem. Soc. 1953, 3052.
Bottini, A. T.; Maroski, J . G.; Dev, V. J . Org. Chem. 1973, 38, 1767.
See also ref 8.
(10) A new concept aimed at designing one-pot processes by the
integration of several synthetic steps was recently introduced by Otera
and termed “Integrated Chemical Process”: See Orita, A.; Yoshioka,
N.; Struwe, P.; Braiser, A.; Beckmann, A.; Otera, J . Chem. Eur. J . 1999,
5, 1355 and references therein.
(13) It should be noted that carboxylate 5b proved essentially
unreactive toward saturation of the furan ring despite extensive
modification of the reaction parameters (hydrogen pressure, temper-
ature, solvent) and the nature of the catalyst (Pd/C.; PtO2; Raney-Ni).
In contrast, the same transformation had been successfully achieved
on analogue 5a (Raney-Ni, MeOH, 1 atm H2, 50 °C). Prior reduction
of the carboxylic ester proved essential in the case of 5b. Hydrogenation
of furan 3,4-dicarboxylates has been reported to work under Pd/C
catalysis: Pei, W.; Pei, J .; Li, S.; Ye, X. Synthesis 2000, 2069.

4072 J . Org. Chem., Vol. 66, No. 11, 2001
Notes
afford the tetrahydrofuran 4a (243 mg, 70%). Oil. IR (neat) 2980,
Sch em e 4. F or m a l Tota l Syn th esis of Bu r ser a n
1
1770 1740, 1260-1220, 1100-1020 cm-1. H NMR (CDCl3, 300
MHz) δ 7.35-7.21 (2m, 5H), 6.93 (t, J ) 2.6, 1H), 5.67 (s, 1H),
4.87 (dd, J ) 13.6 and 2.6, 1H), 4.76 (dd, J ) 13.6 and 2.6, 1H),
4.23 (m, 4H), 3.79 (m, 1H), 3.59 (m, 1H), 1.29 (m, 6H), 1.16 (t, J
) 7, 3H). 13C NMR (CDCl3, 50 MHz) δ 167.3, 166.2, 136.6, 133.8,
128.7, 128.6, 128.5, 127.6, 127.5, 104.4, 69.0, 68.8, 63.8, 62.0,
61.6, 14.9, 14.1, 14.0. HRMS calcd for C19H24O6 (M+) 348.1573;
found 348.1573.
Data for compounds 4b-d , 4g-h , and 6 are provided in the
Supporting Information.
R ep r esen t a t ive P r oced u r e for t h e Deca r b oxyla t ive
E lim in a t ion . Syn t h esis of E t h yl 4-b en zyl-fu r a n -3-ca r -
boxyla te (5a ). A solution of potassium tert-butoxide (100 mg,
0.9 mmol) in THF (1 mL) was added dropwise to a solution of
4a (278 mg, 0.8 mmol) in THF (4 mL). The reaction mixture
was stirred at room temperature for 1 h and concentrated in
vacuo. The residue was purified by flash chromatography (eluent
ethyl acetate/petroleum ether) to afford furan 5a (156 mg, 85%).
Oil. IR (neat) 3180, 3020, 2980, 1740, 1230, 1080. 1H NMR
(CDCl3, 300 MHz) δ 8.01 (d, J ) 1.8, 1H), 7.27 (m, 5H), 7.04 (d,
J ) 1.8, 1H), 4.29 (q, J ) 7.0, 2H), 4.03 (s, 2H), 1.31 (t, J ) 7.0,
3H). 13C NMR (CDCl3, 50 MHz) δ 163.5, 149.1, 142.0, 139.8,
128.8, 128.4, 126.2, 125.0, 118.5, 60.2, 30.4, 14.3. Anal. Calcd
for C14H14O3; C, 73.03; H, 6.13. Found C, 73.31; H, 5.93.
Gen er al P r ocedu r e for th e On e-P ot Syn th esis of Fu r an s.
The propargylic alcohol, the unsaturated halide, and diethyl
ethoxymethylene carboxylate (1 mmol each) were reacted as
described above. After total consumption of the later (GC; 1-3
h) the reaction mixture was treated with a solution of potassium
tert-butoxide (1.1 mmol) in THF (1.5 mL), and stirring was
continued until complete conversion was observed (TLC; 1 h).
After usual workup with aqueous NH4Cl solution and diethyl
ether, the organic layer was dried over Na2SO4 and concentrated
in vacuo. The residue was subjected to column chromatography
(silica gel; ethyl acetate/petroleum ether) to afford the desired
furan 5.
Con clu sion
A novel two-step synthetic entry into functionalized
furan derivatives has been devised. It successively in-
volves a conjugate addition, a palladium-catalyzed cou-
pling-cyclization, an alkoxide-induced decarboxylative
elimination, and finally, a double bond isomerization. The
stepwise chemical process may be integrated into a one-
pot reaction that allows for the preparation of various
analogues by simply combining three starting materials,
most of which are commercially available. As exemplified
by a short formal synthesis of burseran, the title com-
pounds should prove useful as versatile precursors of
naturally occurring lignans, as well as their unnatural
analogues.
Eth yl 4-(3,4,5-Tr im eth oxyben zyl)-fu r a n -3-ca r boxyla te
(5b). Oil. IR (neat) 3120, 2980, 1730, 1240, 1080 cm-1. 1H NMR
(CDCl3, 300 MHz) δ 7.97 (d, J ) 1.8, 1H.), 7.04 (d, J ) 1.8, 1H),
6.46 (s, 2H), 4.24 (q, J ) 7.0, 2H), 3.93 (s, 2H), 3.80 (s, 9H), 1.31
(t, J ) 7.0, 3H). 13C NMR (CDCl3, 50 MHz) δ 163.5, 158.1, 149.0,
141.9, 135.4, 125.1, 117.9, 105.7, 60.1, 60.8, 56.0, 30.7, 14.32.
HRMS calcd for C17H20O6 (M+) 320.1260; found 320.1260.
Eth yl 4-Ben zo[1,3]d ioxol-5-yl Meth yl-fu r a n -3-ca r boxyl-
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, all reactions were
carried out under a nitrogen atmosphere using standard syringe,
cannula, and septa techniques. Commercially available reagents
were used as purchased. 5-Iodo-1,2,3-trimethoxybenzene,14 4-iodo-
1,2-(methylenedioxy)benzene,15 and cyclohex-1-enyl triflate16
were prepared according to known procedures. Tetrahydrofuran
and dimethyl sulfoxide were distilled over calcium hydride. Thin-
layer chromatography was carried out on Merck silica 60/F-254
aluminum-backed plates. Flash chromatography was performed
using Merck silica gel 60 (40-63 µm). NMR spectra were
recorded in CDCl3. Chemical shifts (δ) are quoted in parts per
million. J values are given in Hz.
R ep r esen t a t ive P r oced u r e for t h e Th r ee-Com p on en t
Rea ction . Syn th esis of Eth yl 4-Ben zylid en e-2-eth oxy-tet-
r a h yd r ofu r a n -3,3-d ica r boxyla te (4a ). n-BuLi (2.0 M in hex-
anes, 500 µL, 1.0 mmol) was added dropwise to an ice-cooled
solution of propargyl alcohol (60 µL, 1.0 mmol) in THF (3 mL),
and the solution was allowed to reach room temperature (15
min). In a separate flask, n-BuLi (2.0 M in hexanes, 50 µL, 0.1
mmol) was added dropwise to a well-stirred suspension of PdCl2-
(PPh3)2 (35 mg, 0.05 mmol) in DMSO (2 mL) to give a dark red
homogeneous solution. To this palladium complex solution were
successively added via cannula a mixture of diethyl ethoxy-
methylene malonate (216 mg, 1.0 mmol) and phenyl iodide (205
mg, 1.0 mmol) in THF (1 mL), and the propargyl alkoxide
solution. The reaction mixture was stirred at room temperature
for 1 h and after usual workup with aqueous NH4Cl solution
and diethyl ether, the organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue was subjected to column
chromatography (silica gel; ethyl acetate/petroleum ether) to
1
a te (5c). IR (neat) 3120, 2980, 1730, 1250, 1080 cm-1. H NMR
(CDCl3, 300 MHz) δ 7.97 (d, J ) 1.8., 1H), 7.04 (d, J ) 1.8, 1H),
6.72 (m, 3H), 5.92 (s, 2H), 4,28 (q, J ) 7.0, 2H), 3.91 (s, 2H),
1.31 (t, J ) 7.0, 3H). 13C NMR (CDCl3, 50 MHz) δ 163.5, 149.1,
147.6, 145.9, 141.9, 133.6, 125.2, 121.6, 118.3, 109.3, 108.2, 100.9,
60.2, 30.0, 14.3. HRMS calcd for C15H14O5 (M+) 274.0841; found
274.0839.
E t h yl 4-(4-Met h oxy-b en zyl)-fu r a n -3-ca r b oxyla t e (5d ).
Oil. IR (neat) 3120, 2980, 1730, 1250, 1080 cm-1 1H NMR
.
(CDCl3, 300 MHz) δ 7.99 (d, J ) 1.8, 1H), 7.15 (d, J ) 8.8, 2H),
7.0 (d, J ) 1.8, 1H), 6.85 (d, J ) 8.8, 2H), 4.28 (q, J ) 7.0, 2H),
3.94 (s, 2H), 3.79 (s, 3H), 1.33 (t, J ) 7.0, 3H). 13C NMR (CDCl3,
50 MHz) δ 163.6, 158.1, 149.1, 141.9, 131.9, 129.8, 125.6, 118.4,
113.8, 60.1, 55.3, 29.5, 14.3. HRMS calcd for C15H16O4 (M+)
260.1049; found 260.1050.
E t h yl 4-(3-Met h oxy-b en zyl)-fu r a n -3-ca r b oxyla t e (5e).
Treatment with t-BuOK was not needed. Oil. IR (neat) 3120,
2980, 1730, 1250, 1080 cm-1. 1H NMR (CDCl3, 300 MHz) δ 7.97
(d, J ) 1.8, 1H), 7.18 (m, 2H), 6.98 (d, J ) 1.8, 1H), 6.88 (m,
2H), 4.26 (q, J ) 7.0, 2H), 3.99 (s, 2H), 3.82 (s, 3H), 1.31 (t, J )
7.0, 3H). 13C NMR (CDCl3, 50 MHz) δ 163.7, 157.4, 148.8, 142.1,
130.0, 128,4, 127.5, 124.3, 120.4, 118.6, 110.3, 60.1, 55.3, 24.4,
14,2. HRMS calcd for C15H16O4 (M+) 260.1049; found 260.1050.
Eth yl 4-(4-Meth oxyca r bon yl-ben zyl)-fu r a n -3-ca r boxyl-
a te (5f). Treatment with t-BuOK was not needed. Oil. 1H NMR
(CDCl3, 300 MHz) δ 7.96 (s, 1H), 7.93 (d, J ) 8.0, 2H), 7.28 (d,
J ) 8.0, 2H), 7.07 (s, 1H), 4.23 (q, J ) 7.0, 2H), 4.04 (s, 2H),
3.73 (s, 3H), 1.28 (t, J ) 7.0, 3H). 13C NMR (CDCl3, 50 MHz) δ
167.1, 166.2, 163.3, 149.2, 145.3, 142.0, 129.7, 128.7, 128.3, 123.9,
118.3, 101.1, 63.3, 61.5, 60.2, 52.0, 30.2, 15.2, 14.3, 14.1. HRMS
calcd for C16H16O5 (M+) 288.0998; found 288.0998.
(14) Bowden, B. F.; Read, R. W.; Taylor, W. C. Aust. J . Chem. 1981,
34, 799.
(15) Pearson, W. H.; Postich, M. J . J . Org. Chem. 1994, 59, 5662.
(16) Martinez, A.; Garcia, R.; Martinez, E.; Teso, J . J . Heterocycl.
Chem. 1988, 25, 1237.

Notes
Eth yl 4-Ben zyl-5-p h en yl-fu r a n -3-ca r boxyla te (5g). Oil. IR
J . Org. Chem., Vol. 66, No. 11, 2001 4073
2H), 3.56-3.48 (m, 2H), 2.85 (dd, J ) 13.6 and 5.46 Hz,1H), 2.75
(dd, J ) 13.6 and 7.2 Hz, 1H), 2.71-2.62 (m, 2H), 2.55-2.49
(m, 2H), 2.18 (m, 1H), 1.70 (brs, 2H).13C NMR (CDCl3, 50 MHz)
δ 153.2, 136.4, 136.0, 105.6, 105.5, 73.2, 72.4, 70.9, 70.8, 64.4,
61.3, 60.8, 56.1, 47.4, 44.0, 43.3, 42.5, 39.8, 33.8. Anal. Calcd
for C15H22O5 C, 63.81; H, 7.85. Found C, 63.74; H, 7.95.
(neat) 3020, 2980, 1730, 1240, 1080 cm-1.1H NMR (CDCl3, 300
MHz) δ 8.13 (s, 1H), 7.57-7.22 (m, 10H), 4.33 (s, 2H), 4.20 (q, J
) 7.0, 2H), 1.22 (t, J ) 7.0, 3H).13C NMR (CDCl3, 50 MHz) δ
163.3, 152.4, 147.7, 140.1, 128.8, 128.5, 128.1, 126.2, 126.0, 120.5,
118.3, 60.2, 29.8, 14.2. HRMS calcd for C20H18O3 (M+) 306.1256;
found 306.1256.
P r ep a r a tion of Ald eh yd e 8. A solution of oxalyl chloride
(70µL, 0.78 mmol) in CH2Cl2 (2.5 mL) was cooled to -78 °C.
Dimethyl sulfoxide (100 µL, 1.57 mmol) in 0.5 mL of CH2Cl2 was
added dropwise over 3 min. Alcohol 11 (100 mg, 0.35 mmol) in
6 mL of CH2Cl2 was added, and the reaction mixture was stirred
for 30 min at -78 °C. Triethylamine (580 µL, 4.14 mmol) was
then added dropwise, and the solution was warmed to room
temperature and stirred 30 min. The reaction was quenched by
addition of water, and the product was extracted with CH2Cl2.
Organics were washed with 10% HCl, sodium bicarbonate, and
brine and then dried over magnesium sulfate. Flash chroma-
tography on silica gel with 6:4 hexanes:ethyl acetate afforded
90 mg (90% yield) of the corresponding aldehyde as a 2.5:1
mixture of the trans and cis isomers, respectively. Equilibration
with DBU (CH2Cl2, rt, overnight) afforded 8 as the highly
enriched trans isomer (20:1). Oil. IR (neat) 2930, 1725, 1240,
Eth yl 4-Ben zyl-5-p r op yl-fu r a n -3-ca r boxyla te (5h ). Oil. IR
1
(neat) 3020, 2980, 1730, 1240, 1080 cm-1. H NMR (CDCl3, 300
MHz) δ 7.92 (s, 1H), 7.17 (m, 5H), 4.19 (q, J ) 7.0, 2H), 4.01 (s,
2H), 2.58 (t, J ) 7.0, 2H), 1.62 (m, 2H), 1.22 (t, J ) 7.0, 3H), 0.9
(t, J ) 7.0, 3H). 13C NMR (CDCl3, 50 MHz) δ 163.8, 154.8, 146.8,
140.9, 128.2, 128.1, 125.8, 118.9, 117.2, 59.9, 29.2, 28.2, 21.6,
14.2, 13.7. HRMS calcd for C17H20O3 (M+) 272.1412; found
272.1412.
Eth yl 4-Cycloh ex-1-en ylm eth yl-fu r a n -3-ca r boxyla te (7).
1
Oil. H NMR (CDCl3, 300 MHz) δ 7.95 (d, J ) 1.5, 1H), 7.17 (s,
1H), 5.40 (s, 1H), 4.26 (q, J ) 7.0, 2H), 3.27 (s, 2H), 2.05-1.85
(m, 4H), 1.62-1.52 (m, 4H), 1.32 (t, J ) 7.0, 3H). 13C NMR
(CDCl3, 50 MHz) δ 163.6, 148.8, 141.7, 135.9, 123.6, 122.5, 118.8,
60.0, 31.9, 28.4, 25.7, 23.0, 22.5, 14.3. HRMS calcd for C14H19O3
(MH+) 235.1334; found 235.1334.
F or m a l Syn th esis of Bu r ser a n . P r ep a r a tion of Alcoh ol
10 fr om 5b. To an ice-cooled solution of 5b (250 mg, 0.78 mmol)
in dry THF (5.5 mL) was added LiAlH4 (30 mg, 0.78 mmol), and
the suspension was stirred at room temperature for 1 h. After
the usual workup, the alcohol 10 (210 mg, quant.) was isolated
following percolation on silica gel with 3:1 hexanes:ethyl acetate.
1
1120 cm-1. H NMR (CDCl3, 300 MHz) δ 9.53 (d, J ) 2.0, 1H),
6.37 (s, 2H), 4.12 (dd, J ) 9.5 and 5.1, 1H), 3.95 (m, 2H), 3.85
(s, 6H), 3.84 (s, 3H), 3.55 (dd, J ) 8.6 and 5.9, 1H), 2.82 (m,
2H), 2.74 (m, 2H). 13C NMR (CDCl3, 50 MHz) δ 200.5, 153.4,
136.8, 134.9, 105.7, 73.2, 67.4, 60.9, 57.2, 56.2, 42.6, 38.9. HRMS
calcd for C15H20O5 (M+) 280.1311; found 280.1311.
Solid. mp 92-95 °C. IR (KBr) 3060-3200, 2930, 1250, 1050 cm-1
.
1H NMR (CDCl3, 300 MHz) δ 7.35 (s,1H), 7.16 (s,1H), 6.43 (s,
2H), 4.38 (s, 2H), 3.80 (s, 9H), 3.72 (s, 2H), 1.90 (brs, 1H, OH).
13C NMR (CDCl3, 50 MHz) δ 153.3, 141.3, 141.0, 135.7, 124.8,
123.5, 105.5, 60.9, 56.1, 55.5, 30.1. Anal. Calcd for C15H18O5 C,
64.74; H 6.52. Found C, 64.66; H, 6.57.
Ackn owledgm en t. The authors wish to thank Aven-
tis Cropscience and the Centre National de la Recherche
Scientifique for their generous support of this work
(M.C.), the European Union TMR program for a Fel-
lowship (S.V.) (No ERB FMRX-CT98-0235), and Prof.
S. Hanessian, University of Montreal, for kindly provid-
ing copies of NMR spectra for key compound 8.
P r ep a r a tion of Alcoh ol 11. A pressure tube equipped with
a magnetic stirbar was charged with the preceding alcohol (10)
in 3 mL of THF. A catalytic amount of Raney-Ni was then added
to the solution. The vessel was flushed with H2 under stirring
and then pressurized to 10 bar and maintained at that pressure
for 15 h at room temperature. The pressure was released, and
the reaction mixture was filtered through a short pad of Celite.
Removal of the solvent in vacuo afforded 200 mg (93% yield) of
alcohol 11 as a mixture of diastereomers (trans:cis)1:1). Solid.
Su p p or tin g In for m a tion Ava ila ble: IR and NMR data
for 2-ethoxytetrahydrofurans 4b-d , 4f-h , and 6 including
copies of 1H (or 13C) NMR spectra for 4a -d , 4g,h , 5a -e, 5g,h ,
6, and 7. This material is available free of charge via the
Internet at http://pubs.acs.org
IR (KBr) 3060-3200, 2930, 1250, 1050 cm-1 1H NMR (CDCl3,
.
500 MHz) δ (mixture of isomers) 6.43 (s, 2H), 6.41 (s, 2H), 3.99
(m, 2H), 3.92-3.79 (m, 22H), 3.76-3.68 (m, 2H), 3.63-3.58 (m,
J O0017990