An efficient synthesis of 2,5-dihydrofuran-fused bicyclic skeletons via the pd(II)-catalyzed tandem-cyclization reaction of 1,ω-bisallenols

Article abstract of DOI:10.1021/ol802794t

A palladium(II)-catalyzed tandem double-cyclization reaction of 1,u-bisallenols was developed to form 2,5-dihydrofuran-fused bicyclic skeletons. With "unsymmetric" substrates, the reaction may also be realized with one hydroxyl group being protected as th

Full text of DOI:10.1021/ol802794t

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1205-1208
An Efficient Synthesis of
2,5-Dihydrofuran-Fused Bicyclic
Skeletons via the Pd(II)-Catalyzed
Tandem-Cyclization Reaction of
1,ω-Bisallenols
Youqian Deng, Yunlong Shi, and Shengming Ma*
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang UniVersity, Hangzhou 310027, Zhejiang, People’s Republic of China
masm@mail.sioc.ac.cn
Received December 4, 2008
ABSTRACT
A palladium(II)-catalyzed tandem double-cyclization reaction of 1,ω-bisallenols was developed to form 2,5-dihydrofuran-fused bicyclic skeletons.
With “unsymmetric” substrates, the reaction may also be realized with one hydroxyl group being protected as the acetate. Optically active
bicyclic products were prepared by applying the Novozym-435 catalyzed kinetic resolution and the tandem double cyclization of these optically
active allenol-allenyl acetates. The reaction may proceed via an oxypalladation, insertion, and elimination process.
Fused bicyclic skeletons are a class of most commonly
observed structural units in natural products1 and unnatural
products with biological potential.2 As we know, 2,5-
dihydrofurans also widely exist in biologically active com-
pounds;3 thus, many new methods have been developed for
the efficient synthesis of 2,5-dihydrofurans.4 Alcaide et al.
reported the cyclization of 2,3-allenols in the presence of
2,3-allenyl acetates.5 In the same year, Hashmi et al. reported
that the AuCl3-catalyzed cyclization of tertiary 2,3-allenols
yielded a mixture of cycloisomerization products, double
cyclization products, and other products.6 Recently, on the
(3) (a) Heaney, H.; Ahn, J. S. In ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 2, pp 297-436. (b) Eicher, T.; Hauptmann, S. The
Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applica-
tions; Wiley-VCH: Weinheim, 2003. (c) Lipshutz, B. H. Chem. ReV. 1986,
86, 795. (d) Deli, J.; Mólnar, P.; Tóth, G.; Baumeler, A.; Eugster, C. H.
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1989, 89, 1617.
(1) (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. In The Total Synthesis of Natural Products; ApSimon, J., Ed.;
John Wiley & Sons: New York, 1983; Vol. 5. (b) Rigby, J. H. In Studies
in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science
Publishers B.V.: Amsterdam, 1988; Vol. 12. (c) Chang, C. W. J.; Scheuer,
P. J. Top. Curr. Chem. 1993, 167, 33. (d) Fraga, B. M. Nat. Prod. Rep.
1995, 12, 303. (e) Fraga, B. M. Nat. Prod. Rep. 1998, 15, 73. (f) Toyota,
M.; Bardon, A.; Kamiya, N.; Takaoka, S.; Asakawa, Y. Chem. Pharm. Bull.
1997, 45, 2119.
(4) (a) Review on the synthesis of dihydrofuran: Kilroy, T. G.;
O’Sullivan, T. P.; Guiry, P. J. Eur. J. Org. Chem. 2005, 4929. (b) Buzas,
A.; Istrate, F.; Gagosz, F. Org. Lett. 2006, 8, 1957. (c) Liu, Y.; Song, F.;
Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409. (d) Ma, S.; Gao, W.
J. Org. Chem. 2002, 67, 6104.
(2) (a) Cornille, F.; Slomczynska, U.; Smythe, M. L.; Beusen, D. D.;
Moeller, K. D.; Marshall, G. R. J. Am. Chem. Soc. 1995, 117, 909. (b) Li,
W.; Moeller, K. D. J. Am. Chem. Soc. 1996, 118, 10106. (c) Wender, P. A.;
Husfeld, C. O.; Langkopf, E.; Love, J. A. J. Am. Chem. Soc. 1998, 120,
1940. (d) Chatani, N.; Morimoto, T.; Fukumoto, Y.; Murai, S. J. Am. Chem.
Soc. 1998, 120, 5335.
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Chem., Int. Ed. 2006, 45, 4501. (b) Alcaide, B.; Almendros, P.; Mart´ınez
del Campo, T.; Carrascosa, R. Chem. Asian. J. 2008, 3, 1140.
10.1021/ol802794t CCC: $40.75
Published on Web 02/13/2009
2009 American Chemical Society

basis of our previous studies on the cyclization of 2,3-allenoic
acids in the presence of 2,3-allenols,7 we have developed
the cyclization of one 2,3-allenol in the presence of another8
or the same9 2,3-allenol, affording 4-(1′,3′-dien-2′-yl)-2,5-
dihydrofuran via an oxypalladation-carbopalladation-ꢀ-
hydroxide elimination mechanism. In this paper, we report
an efficient and controlled double cyclization approach to
the synthesis of 2,5-dihydrofuran-fused bicyclic skeletons
from the readily available bis(2,3-allenol)s or 2,3-allenol-
allenyl acetates, in which even the eight-membered rings
were formed easily (Scheme 1).
Table 1. Effects of Solvent and Catalyst on the Pd(II)-Catalyzed
Tandem-Cyclization Reaction of Bis(2,3-allenol) (1a)
Pd(II)
(5 mol %)
yield of recovery
time (h) 2aa (%) of 1a (%)
entry solvent
1
2
3
4
5
6
7
8
CH2Cl2
CH3NO2 PdI2
PdI2
1.5
2
1.5
1.5
1.5
2
1
1
1
1
23
0
18
32
36
0
45
45
66
57
70
68
61
0
59
81
0
0
0
29
0
0
0
0
Scheme 1
CH3CN
AcOEt
THF
DMPU
DMSO
DMA
DMF
DMF
DMF
DMF
DMF
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdBr2
PdCl2
9
10
11
12b
13
14
15
1
4
1
1
0
0
0
89
Our efforts in this area started with the reaction of
N-tethered bisallenol 1a under the catalysis of 5 mol % PdI2
in CH2Cl2, affording the fused bicyclo[5.3.0]product 2a in
23% yield with 59% of 1a being recovered (Table 1, entry
1). The reaction in other solvents, such as CH3NO2, CH3CN,
CH3CO2C2H5, THF, DMPU, DMSO, or DMA, also yielded
2a (Table 1, entries 2-8), different from what was observed
in the intermolecular reaction.9 There is a solvent effect here:
the reaction in DMA is low-yielding (Table 1, entry 8), and
the best result was obtained when the reaction was conducted
in DMF (Table 1, entry 9). Among different Pd(II) catalysts,
PdCl2 is the best (Table 1, entries 9-15). The reaction of
1a may also proceed at rt to give 2a in the same yield with
a longer reaction time (Table 1, entry 12).
PdCl2
PdCl2(PhCN)2
Pd(OAc)2
PdCl2(PPh3)2
DMF
DMF
1
0
97
a Determined by 1H NMR analysis using 1,3,5-trimethylbenzene as the
internal standard. b The reaction was conducted at 25 °C.
2e, 2f, and 2g smoothly in 57%, 67%, and 65% yields,
respectively, under conditions B (Table 2, entries 6-8).
The reaction may also be catalyzed by applying 5 mol %
PdI2 at 25 °C (Table 2, entry 9). The sulfone tether may
also be used (Table 2, entry 10). In addition, by applying
this protocol, even the bicyclo[6.3.0]products 2i and 2j
can be formed in 68% and 75% yields, respectively,
although the formation of the eight-membered ring is
always not easy (Table 2, entries 11 and 12).10-12 It is
important to note that the CdC bond in the products is in
the E-form, which was established by the NOESY analysis
With the optimized reaction conditions in hand, further
investigation for the scope of the reaction of symmetric
substrates was conducted with the different R substitutents
and tether “X” (Table 2). The bisallenols 1a and 1b with
NTs as the tether provided the bicyclo[5.3.0]products 2a
and 2b in 62% and 78% yields, respectively (Table 2,
entries 1 and 2) under the catalysis of 5 mol % PdCl2 at
25 °C (conditions A). However, no expected product was
formed under conditions A from bisallenol 1c with a
carbon tether (Table 2, entry 3). Fortunately, when 0.5
equiv of NaI was applied as the additive, the reaction
afforded 2c in 58% yield; however, again the reaction
should be carried out in DMF instead of DMA9 to ensure
a good yield (entry 4 in Table 2, defined as conditions
B). The R-aryl-substituted bisallenol 1d can afford the
product 2d in 51% yield under conditions B (Table 2, entry
5). The bisallenols 1e, lf, and 1g with the ether functional
groupasthetethermayalsoprovidethefusedbicyclo[5.3.0]products
1
of 2e. H NMR spectra of the crude product indicated the
formation of only one stereoisomer, which is very different
from what was observed in the intermolecular reaction.9
Unfortunately, when an “unsymmetric” 1,6-bisallenol 1k
was used, as expected the reaction afforded a mixture of
(10) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95
.
(11) For reviews on the synthesis of cyclooctanoids, see: (a) Sieburth,
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Sato, Y.; Sun, R. J. Am. Chem. Soc. 2000, 122, 7815. (e) Wender, P. A.;
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Soc. 1995, 117, 2108. (g) Snapper, M. L.; Tallarico, J. A.; Randall, M. L.
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2006, 128, 4942
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(14) (a) Xu, D.; Li, Z.; Ma, S. Chem. Eur. J. 2002, 8, 5012. (b) Xu, D.;
Li, Z.; Ma, S. Tetrahedron: Asymmetry 2003, 14, 3657
.
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.
.
1206
Org. Lett., Vol. 11, No. 6, 2009

2,3-allenol-allenyl acetates (S)-1n (99% ee) and (S)-1o (99%
ee). Their reactions under standard reaction conditions B
afforded the optically active fused bicyclic products (S)-2n
in 80% yield and 99% ee and (S)-2o in 76% yield and 99%
ee, respectively (Scheme 3) without obvious racemization.
Table 2. Pd(II)-Catalyzed Coupling-Cyclization Reaction of
1,5-Bisallenols 1a
Scheme 3
.
Synthesis and Cyclization of Optically Active
Substrates (S)-1n and (S)-1o
entry
X
R
conditions/time (h) yield of 2 (%)
1
2
3
4
5
6
7
8
9
NTs
NTs
CH2
CH2
CH2
O
O
O
O
C2H5 (1a)
n-C5H11 (1b)
C2H5 (1c)
C2H5 (1c)
p-ClC6H4 (1d)
C2H5 (1e)
i-C3H7 (1f)
n-C4H9 (1g)
n-C4H9 (1g)
C2H5 (1h)
A/4
A/4
A/4
B/1
B/1
B/2
B/2
B/1
4b
62 (2a)
78 (2b)
0 (2c)
58 (2c)
51 (2d)
57 (2e)
67 (2f)
65 (2g)
69 (2g)
81 (2h)
68 (2i)
75 (2j)
10 SO2
11 (CH2)2 n-C4H9 (1i)
12 (CH2)2 p-ClC6H4 (1j)
B/1
B/1
B/1
a Conditions A: 5 mol % PdCl2 was used as the catalyst at 25 °C;
Conditions B: 5 mol % PdCl2 and 0.5 equiv of NaI were used as the catalyst
at 80 °C. b 5 mol % PdI2 was used as the catalyst at 25 °C.
inseparable eight-membered products 2l and 2m in 32% and
50% yields, respectively. However, if one of the hydroxyl
groups was protected, i.e., allenol-allenyl actetates 1l and
1m,5 the reaction afforded the products 2l and 2m in 77%
and 94% yields, respectively (Scheme 2).
a Referred to the resolved allenol part.
The formation of 2,5-dihydrofuran-fused bicyclic skeletons
can be rationalized by the mechanism shown in Scheme 4.
First, the cyclic oxypalladation of the 2,3-allenol moiety in
1 with Pd(II) would form intermediate M1. Then regiose-
lective intramolecular carbopalladation of the remaining
allene unit in M1 would form the π-allylic palladium
intermediate M2. Subsequent trans-ꢀ-hydroxide7-9,15 or
acetate5,16 elimination would afford product 2 highly ste-
reoselectively (Scheme 4).
Scheme 2
Scheme 4
.
Possible Mechanism of the Coupling-Cyclization
Reaction of 1,5-Bisallenols 1
In addition, to prepare highly optically active substrates,
the bis-propargyl bromides 3n or 3o were reacted with
13
aldehydes in the presence of NaI and SnCl2 to afford
propargyl halide-allenols 4n or 4o together with the corre-
sponding bisallenols 1i or 1p. During this reaction the
bromides were converted to a mixture of chlorides, bromides,
and iodides, which were transformed into the related iodides
5n or 5o by the reaction with NaI in acetone. Subsequently,
the free hydroxyl group was protected as acetate to afford
propargyl halide-allenyl acetates 6n or 6o. The propargyl
halide moiety in 6n or 6o was converted to allenol to yield
the racemic allenol-allenyl acetates 1n or 1o, which were
kinetically resolved using Novozym-435, a protocol devel-
oped in this group,14 to afford the optically active starting
Org. Lett., Vol. 11, No. 6, 2009
1207

In conclusion, we have developed a palladium(II)-
catalyzed tandem double-cyclization reaction of 1,ω-bisal-
lenols to form 2,5-dihydrofuran-fused bicyclic skeletons from
the readily available bis(2,3-allenols). With “unsymmetric”
substrates, the reaction may be realized by converting one
hydroxyl group to acetate. Optically active bicyclic products
may be easily prepared by applying the Novozym-435
catalyzed kinetic resolution and the tandem double cycliza-
tion of these optically active substrates. Because of the
importance of fused bicyclic skeletons and 2,5-dihydrofurans,
this method would be potentially useful in organic chemistry
and medicinal chemistry. Further studies in this area are being
pursued in our laboratory.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20732005) and
Major State Basic Research and Development Program
(2006CB806105) is greatly appreciated. S.M. is a Qiu Shi
Adjunct Professor at Zhejiang University. We thank Miss
Zhao Fang in this group for reproducing the results
presented in entries 2, 4, and 10 in Table 2.
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Supporting Information Available: Experimental pro-
1
cedures and copies of H and 13C NMR spectra of all
(16) For the stereoselectivity of ꢀ-heteroatom elimination, see: (a) Frost,
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compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL802794T
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Org. Lett., Vol. 11, No. 6, 2009