Selective Lewis acid catalyzed transformation (γ-butyrolactone versus cyclopropane) of 2-methoxy-4-benzyltetrahydrofuran derivatives. Efficient synthesis of lignan lactones

Article abstract of DOI:10.1021/ol050690h

(Chemical Equation Presented) A short synthesis of lactone lignans exploiting a three-component coupling strategy is presented using a new Lewis acid catalyzed ring-opening/cyclization reaction of 2-methoxytetrahydrofuran derivatives 4 leading to γ-butyro

Full text of DOI:10.1021/ol050690h

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3143-3146
Selective Lewis Acid Catalyzed
Transformation ( -Butyrolactone
versus Cyclopropane) of
γ
2-Methoxy-4-benzyltetrahydrofuran
Derivatives. Efficient Synthesis of
Lignan Lactones
Laurent Ferrie´, Didier Bouyssi,* and Genevie`ve Balme*
Laboratoire de Chimie Organique 1, associe´ au CNRS, UniVersite´ Claude Bernard
Lyon 1, CPE, 43 Bd du 11 NoVembre 1918, 69622 Villeurbanne, France
balme@uniV-lyon1.fr; bouyssi@uniV-lyon1.fr
Received April 1, 2005
ABSTRACT
A short synthesis of lactone lignans exploiting a three-component coupling strategy is presented using a new Lewis acid catalyzed ring-
opening/cyclization reaction of 2-methoxytetrahydrofuran derivatives 4 leading to -butyrolactones as a key step. By simply changing the
reaction conditions, it was possible, from the same substrates 4, to obtain selectively cyclopropane derivatives.
γ
Lactone lignans are a class of natural products that have
received considerable interest because of their biological and
medicinal properties.1 Several strategies for the synthesis of
dibenzyl butyrolactone lignans 1 have been reported (Figure
1).2 Among them, the alkylation of â-substituted γ-butyro-
lactones 2 with an appropriate benzylic halide is the most
widely used.3 The major drawbacks of this synthetic route
are the necessity to add an undesirable complexing agent
such as the carcinogenic hexamethylphosphoric triamide
(HMPA) to assist the alkylation step and to carry out this
reaction under low-temperature conditions.3d,4
For some time now, we have been interested in developing
new processes to form several carbon-carbon and carbon-
(1) (a) Cho, M. K.; Jang, Y. P.; Kim, Y. C., Kim, S. G. Int.
Immunopharm. 2004, 4, 1419-1429. (b) Midori, T.; Takao, K.; Katsuko,
K.; Harukuni, T.; Hoyoru, N. Cancer Lett. 2000, 158, 53-59. (c) Sibi, M.
P.; Liu, P.; Johnson, M. D. Can. J. Chem. 2000, 78, 133-138. (d) Li, N.;
Wu, J. L.; Sakai, J. I.; Ando, M. J. Nat. Prod. 2003, 66, 1421-1426. (e)
Ayreas, D. C.; Loike, J. D. Chemistry & Pharmacology of Natural Products.
Lignans, Chemical, Biological and Clinical Properties; Cambridge Uni-
versity Press: New York, 1990. (f) Usia, T.; Watabe, T.; Kadota, S.; Tesuka,
Y. J. Nat. Prod. 2005, 68, 64-68.
Figure 1. Natural lignans and strategic synthons.
(2) For review, see: Raffaelli, B.; Hoikkala, A.; Leppa¨la¨, E.; Wa¨ha¨la¨,
K. J. Chromatogr. B 2002, 777, 29-43.
10.1021/ol050690h CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/28/2005

heteroatom bonds in one reaction.5 In line with this, we
recently reported an efficient palladium-catalyzed three-
component synthesis of 2-methoxy-4-arylidenetetrahydro-
furan derivatives 3 by a one-pot coupling reaction of
commercially available or easily accessible propargyl alco-
hols, diethyl methoxymethylenemalonate, and aryl halides.
This strategy was successfully applied to the synthesis of
the lignan antibiotic burseran.6
However, upon treatment of compound 4a in CH2Cl2, with
m-CPBA in the presence of catalytic amounts of boron
trifluoride (10 mol %) only unreactive starting material was
recovered. Surprisingly, when the reaction was performed
in the presence of a large excess of BF3‚Et2O (5 equiv), an
inseparable mixture of the expected lactone 5a and of the
targeted lactone 6a (75%) was obtained in a 1:4 ratio
(Scheme 3).
It was then envisaged to extend this methodology to the
synthesis of dibenzyl butyrolactone lignans 1. Our approach
to this class of compounds synthesis is outlined in Scheme
1. It was anticipated that hydrogenation of 3 would furnish
Scheme 3. Obtention of Lactone 6a from Furan 4a
Scheme 1. Retrosynthetic Analysis
Modifications of the experimental conditions by introduc-
ing a catalytic amount (20 mol %) of Sc(OTf)3 in place of
the conventional Lewis acid BF3‚Et2O did not afford the
expected product 5a.9 Under these conditions, the lactone
6a was isolated in 45% yield along with the cyclopropanic
compound 7a (12% yield). When the same reaction was
carried out in methanol, under reflux for 4 days, lactol ether
4a was directly converted to lactone 6a in a single step and
in 70% yield. We further found that a simple treatment of
4a with 10 mol % of Sc(OTf)3 in methanol at reflux for 10
h provided the lactone 6a in 87% yield.
4, which after conversion of the protected lactol into lactone
5 and subsequent decarbalkoxylation would provide the
desired key intermediate 6. A significant advantage to this
methodology is that alkylation of 6 would be highly
facilitated by the presence of the ester group which could
be removed in a subsequent step.
Our investigations began with the preparation of acetals
3a and 3b which were readily available on a multigram scale
using a slight modification of our previously reported
procedure.6,7 Hydrogenation of 3a and 3b by using palladium
on carbon (Pd/C) provided the corresponding reduced
products 4a and 4b isolated in the form of a single isomer
in nearly quantitative yield (Scheme 2). Subsequent trans-
formation of the lactol ether in 4a into the corresponding
lactone was envisaged through the oxidative Grieco method.8
(3) (a) Itoh, T.; Chika, J.; Takagi, Y.; Nishiyama, S. J. Org. Chem. 1993,
58, 5717-5723. (b) Yang, L.-M.; Lin, S.-J.; Yang, T.-H.; Lee, K.-H. Bioorg.
Med. Chem. Lett. 1996, 6, 941-944. (c) Bode, J. W.; Doyle, M. P.;
Protopopova, M. N.; Zhou, Q.-L. J. Org. Chem. 1996, 61, 9146-9155. (d)
Kamlage, S.; Sefkow, M.; Pool-Zobel, B. L.; Peter, M. G. Chem. Commun.
2001, 331-332. (e) Koul, S.; Singh, B.; Taneja, S. C.; Qazi, G. N.
Tetrahedron 2003, 59, 3487-3491. (f) Isemori, Y.; Kobayashi, Y. Synlett
2004, 1941-1944.
(4) Ma¨kela¨, T. H.; Wa¨ha¨la¨, K. T.; Hase, T. A. Steroids 2000, 65, 437-
441.
Scheme 2. Synthesis of Furans 4
(5) (a) Balme, G.; Bouyssi, D.; Monteiro, N. Metal-Catalyzed Multi-
component Reactions. In Multicomponent Reactions; Zhu, J., Bienayme´,
H., Eds.; Wiley VCH: Weinheim, 2005; pp 224-276. (b) Balme, G.;
Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101-4111. (c)
Balme, G.; Bouyssi, D.; Lomberget, T.; Monteiro, N. Synthesis 2003, 2115-
2134.
(6) Garc¸on, S.; Vassiliou, S.; Cavicchioli, M.; Hartmann, B.; Monteiro,
N.; Balme, G. J. Org. Chem. 2001, 66, 4069-4073. See also: Doe,
M.; Shibue, T.; Haraguchi, H.; Morimoto, Y. Org. Lett. 2005, 7, 1765-
1768.
(7) More practically, PdCl2(AsPPh3)2 was used for this large-scale
synthesis instead of in situ n-BuLi reduction of PdCl2(PPh3)2 which was
employed in the initial paper.
(8) Grieco, P.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett. 1978, 19,
419-420.
(9) Sc(OTf)3 is known to be an effective catalyst to generate a reactive
oxocarbenium ion from an acetal; see: Heaney, H.; Simcox, M. T.; Slawin,
A. M. Z.; Giles, R. G. Synlett, 1998, 640-642. Kobayashi, S.; Sugiura,
M.; Kitagawa, H.; Lam, W. W.-L. Chem. ReV. 2002, 102, 2227-2302.
3144
Org. Lett., Vol. 7, No. 15, 2005

A series of Lewis acids was then surveyed to determine
which were the most effective for this reaction, and the
results are summarized in Table 1.
Scheme 4. Proposal for the Formation of Lactone 6a
Table 1. Screening of Lewis Acids
entry
Lewis acid
equiv
time (h)
yield (%)
1
2
3
4
5
6
7
8
BF3‚Et2O
CF3CO2H
Zn(OTf)2
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3 MS 3 Å
2.0
2.0
0.1
0.2
0.1
0.1
0.02
0.1
10
24
24
12
10
4
a
a
9b
70b
87
94
92
a
40
48
a No reaction. b Starting material was partially recovered.
Conventional Lewis acid (BF3‚Et2O) as well as strong
protic acids (CF3CO3H) were not effective for this reaction
(Table 1, entries 1 and 2). Addition of metal triflate salts
such as Zn(OTf)2 provided a small amount of the lactone
with most of the starting material recovered (Table 1, entry
3). An improvement in the yield was observed with Cu(OTf)2
(Table 1, entry 4). Of these metals, Yb(III) complexes gave
the best results in this reaction. Indeed, 6a was isolated in
94% yield when using 10 mol % of Yb(OTf)3 in methanol
at reflux for 4 h (Table 1, entry 6). Decreasing the amount
of catalyst to 2 mol % allowed us to obtain lactone 6a in
92% yield but required a prolonged reaction time to complete
the reaction (Table 1, entry 7). It should be emphasized that
the starting material 4a was entirely recovered when the
reaction was performed in the presence of 10 mol % of Yb-
(OTf)3 and of molecular sieves as drying agent (Table 1,
entry 8). Using the optimized conditions, 4b was readily
transformed in lactone 6b in a very good yield (93%).
8a under Krapcho’s condition12 (NaCl, DMF, 130 °C)
afforded methyl ether of chamalignolide 1a which was
obtained predominantly as the trans alkylated product (85:
15) in 92% yield.13 Equilibration with DBU (CH2Cl2, rt)
afforded 1a as a highly enriched isomer (19:1).
At this point, a more direct alkylation/decarbalkoxylation
method was envisaged. The two steps were conducted
sequentially in the same reaction vessel without isolation of
the intermediate by adding LiCl (5 equiv) and water (2 equiv)
to the resulting product of the alkylation reaction. Heating
the mixture at 130 °C for 4 h resulted in the formation of
dibenzyl butyrolactone 1a as a 85:15 mixture of diastereo-
isomers in 87% yield (Scheme 5). Application of the same
Scheme 5. One-Step Alkylation-Decarboxylation Sequence
A plausible mechanism for this direct conversion of 4a to
6a is proposed in Scheme 4. Lewis activation of the acetal
presumably promotes ring cleavage of the 2-methoxytetra-
hydrofuran and generates a stabilized malonic enolate and
an oxonium species. Two routes (path A and path B) could
be then proposed for the lactone ring formation. In path A,
the oxonium species could be captured by methanol or by
water, present as contaminant in the reaction mixture. The
resulting alcohol could then attack one of the ester groups
to give 6a. Lactone 6a could also arise from the intramo-
lecular cyclization of one of the esters onto the reactive
carbon bearing the leaving group as depicted in path B.10
one-pot procedure to lactone 6b resulted in the formation of
isoyateine 1b in 94% yield. This natural lignan 1b has been
obtained in only four synthetic steps and in an excellent 69%
overall yield. The spectra of 1b (1H NMR, 13C NMR) were
in accordance with those reported in the literature.14
Next, we examined the alkylation of lactone 6a with a
benzyl halide such as 3,4-methylenedioxybenzyl bromide.
This was accomplished in 90% yield when the reaction was
performed in DMF at room temperature in the presence of
K2CO3 as base.11 Decarbalkoxylation of the resulting lactone
(12) Krapcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 14, 957-
960.
(13) Chamalignolide is a new lignan recently isolated from the heartwood
of Chamaecyparis obtusa var. formosana; see: Kuo, Y.-H.; Chen, C.-H.,
Lin, Y.-L. Chem. Pharm. Bull. 2002, 50, 978-980. Removal of the
O-methyl group was recently carried out on related dibenzylbutyrolactone
lignans; see ref 3f.
(10) Christie, S. D. R.; Davoile, R. J.; Elsegood, M. R. J.; Fryatt, R.;
Jones, R. C. F.; Pritchard, G. J. Chem. Commun. 2004, 2474-2475.
(11) 8a was isolated as a single isomer, but the stereochemistry was not
determined.
Org. Lett., Vol. 7, No. 15, 2005
3145

On the basis of the preceding results (Scheme 3), it was
envisioned that this strategy could also be applied to the
synthesis of cyclopropanic compounds 7. These cyclized
products would arise from an intramolecular enolate ester
attack on the carbon bearing the leaving group. We suspected
that water, present as a contaminant in the reaction mixture,
may be an important factor that influences the outcome of
the reaction (lactone formation versus cyclopropanation).
Consequently, various reactions were performed under
anhydrous conditions by adding molecular sieves 3 Å (MS
3 Å) as drying reagent. The conditions and results are shown
in Table 2. Under the strictly dried conditions, mainly
unreacted starting material was recovered when the reaction
was performed in CH2Cl2 at reflux (Table 2, entries 1 and
2). In marked contrast, the reaction conducted in toluene at
reflux in the presence of 30 mol % of Yb(OTf)3 resulted in
the exclusive formation of the expected cyclopropanic
substrate 7a in 65% yield (Table 2, entry 3). The yield was
improved when Sc(OTf)3 was used instead of Yb(OTf)3 as
a catalyst (Table 2, entry 4). Under these conditions, the
starting material was completely consumed and the cyclo-
propanic substrate 7a was formed in high yield (86%). With
lactol ether 4b, the corresponding cyclopropanic substrate
7b was also formed and best results were obtained when
the reaction was performed in toluene at 70 °C for 4 h (Table
2, entry 5).15
In summary, we have developed a convergent, high
yielding and practical synthesis of dibenzylbutyrolactone
lignans based on the one-pot Lewis acid Yb(OTf)3-catalyzed
ring opening/cyclization reaction of the readily available
functionalized 2-methoxy-4-benzyltetrahydrofuran deriva-
tives 4. Additionally, by simply changing the reaction
conditions, we have demonstrated that it is possible from
the same substrates 4 to obtain selectively functionalized
cyclopropanic compounds.
Table 2. Selective Formation of Cyclopropane 7a
Supporting Information Available: Detailed synthetic
procedures and spectroscopic characterization of new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
entry furan
conditionsa
time (h) yield (%)
1
2
3
4
5
4a Sc(OTf)3 (20%), CH2Cl2, reflux
4a Yb(OTf)3 (20%), CH2Cl2, reflux
4a Yb(OTf)3 (30%), toluene, reflux
4a Sc(OTf)3 (30%), toluene, reflux
4b Sc(OTf)3 (30%), toluene, 70 °C
24
24
96
24
4
12b
0b
65
86
65
OL050690H
(14) Badheka, L. P.; Prabhu, B. R.; Mulchandani, N. B. Phytochemistry
1986, 25, 487-489.
(15) When reaction was conducted at toluene reflux, degradation of the
starting material was observed.
a All reactions were conducted in the presence of MS 3 Å. b Starting
material was recovered.
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Org. Lett., Vol. 7, No. 15, 2005