New palladium-catalysed access to 3-(1′-indanylidene) phthalide, precursor of the core of fredericamycin A

Article abstract of DOI:10.1055/s-2001-15147

An efficient synthesis of 3-(1′-indanilydene) phthalide is described via a palladium-catalysed biscyclisation step.

Full text of DOI:10.1055/s-2001-15147

LETTER
1191
New Palladium-Catalysed Access to 3-(1’-Indanylidene) Phthalide, Precursor
of the Core of Fredericamycin A
Didier Bouyssi, Geneviève Balme*
Laboratoire de chimie organique 1, associé au CNRS, Université Claude Bernard Lyon 1, CPE, 43 Bd du 11 Novembre 1918, 69622 Vil-
leurbanne, France
Fax 33.4.72.43.12.14; E-mail: balme@univ-lyon1.fr
Received 5 April 2001
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O
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Abstract: An efficient synthesis of 3-(1’-indanilydene) phthalide is
described via a palladium-catalysed biscyclisation step.
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Key words: palladium, cyclisation, tandem reaction, heterocycle,
or
lactone
DIBAL
Fredericamycin A, isolated from Streptomyces griseus in
1981,1 possesses important biological activities against a
large variety of tumours, such as P 388 leukemia, B 16
melanoma, and CD 8F mammary. Furthermore, the Fre-
dericamycin A does not show mutagenicity in the Ames
test (Figure).2
O
O
OH
O
PCC
Scheme 1
O
OMe
HO
O
O
O
OH
O
I
Base
O
O
HO
HO
77 %
Pd (0) 5 %
HN
O
2
1
Fredericamycin A
Scheme 2
Figure
To further extend the scope of this study, we now wish to
describe a novel synthesis for the preparation of 3-(1’-in-
danylidene) phthalide 5 from linear acid 4. Moreover, the
newly discovered method potentially provides an alterna-
tive route to the dibenzo-1,4-diketospiro[4,4]nonane sys-
tem as shown in Scheme 1. Nevertheless, it was
anticipated that application of the same concept to this
new system could lead to the formation of four types of
products (Scheme 3). Indeed, due to the strain generated
by the introduction of an aryl group on the linear system,
the palladium-catalysed biscyclisation reaction could ei-
ther proceed via a five-exo or a six-endo mode leading to
the expected lactone 5 or the isocoumarin 6, respective-
ly.14 Two types of direct regioisomeric cyclisation leading
to 7 and 8 could also be envisaged, since it is well known
that 2-alkynyl benzoic acids are easily transformed into a
mixture of phthalides and isocoumarins in the presence of
transition metal catalyst including palladium(II) species.6
With this in mind, when Pd(II) precatalysts are used as
source of Pd(0), it becomes important to add a preformed
Pd(0)Ln catalyst solution to the reaction mixture.7
The biological activity mentioned above as well as the
unique structure of this hexacycle has prompted several
approaches to the construction of this challenging skele-
ton.3 However, despite the numerous efforts towards this
goal, biological studies have been limited by the rarity of
the product.
The crucial step seems to be introduction of the spirocy-
clic system. One of the ways by which the spirocycle is
generated, is the transformation of ylidene phthalides4a,b
into spirocyclic diketones by a DIBAL reduction of an
enol lactone followed by an in situ aldol condensation
(Scheme 1).4c
As part of our ongoing interest in the construction of poly-
cyclic systems, we have recently reported a new route to
-arylidenelactones via a tandem carbopalladation-het-
erocyclisation sequence.5 In particular, cyclisation of the
linear pentynoic acid 1 has led to the indanylidene lactone
2 (Scheme 2).
Synlett 2001, No. 7, 1191–1193 ISSN 0936-5214 © Thieme Stuttgart · New York

1192
D. Bouyssi, G. Balme
LETTER
In order to find the optimum conditions for biscyclisation,
the effect of the palladium source was first evaluated, (en-
tries 1-5) while other reaction parameters were main-
tained. The results are shown in Table 1.
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5
7
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Table 1 Influence of the nature of the catalyst
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HO
O
O
I
O
4
O
8
6
Scheme 3
The required acid 4 was prepared in three steps from com-
mercially available 2-iodobenzyl bromide (Scheme 4).
The major difficulty encountered in the preparation of 4
was the Sonogashira coupling reaction of the known
alkyne moiety8 9 with methyl o-iodobenzoate. Using liter-
ature reported methods,9 very low yields of the expected
product resulted (20-30%) along with a complex mixture
of uncharacterised byproducts. Nevertheless, a noticeable
improvement was made by modifying the coupling proce-
dure,10 (Pd/C, PPh3, CuI, DME/H2O, ) where 10 was iso-
lated in 52% yield. Finally, smooth alkaline hydrolysis of
the ester with lithium hydroxide in aqueous THF provided
4 in high yield.
a) TFP = tris(2-furyl) phosphine; b) All reactions were run at room
temperature with tBuOK as base.
Of the palladium sources examined, only Pd(OAc)2 re-
11
duced by NaBH4 in the presence of 2 equivalents of
tris(2-furyl) phosphine, afforded the desired product 5
(entry 4). However, although the starting material was
consumed, a low yield of tetracyclic phthalide was isolat-
ed (23%). Zerovalent palladium formed from
PdCl2(PPh3)2 by the reduction with BuLi12 failed to pro-
mote the reaction (entry 5). Commercially available cata-
lysts such as Pd(PPh3)4 (entry 2) and Pd2dba3 CHCl3 with
TFP as ligand (entry 3) were ineffective. The first one led
to a mixture of three inseparable compounds 5, 6 and 8 in
the ratio 1/0.1/0.3. The second catalyst used afforded ex-
clusively compound 8 arising from direct 6-endo cycliza-
I
I
I
CO2Me
MgBr
Br
Pd/C 2%, CuI 4%, PPh3 8%
K2CO3 1.5 eq.DME/H2O 1/1
80°C, 8 h
THF /Et2O
0°C to RT, 5 h
9
90 %
1
tion. All products were easily identified by H NMR,
where product 8 gave a singlet at 6.25 ppm for the ethyl-
enic proton and a doublet centered at 8.27 ppm for one ar-
omatic proton. Product 5, which is a known compound4b
gives a doublet at 8.32 ppm and product 6 a doublet at
8.39 ppm. The solvent effects were also examined: in the
optimized conditions described below, changing the sol-
vent to acetonitrile led to the phthalide 5 as the sole isol-
able product but the yield was still low (38%).
Presumably, the use of a strong base such as tBuOK
LiOH
O
I
90 %
4
OMe
10
THF / H2O
40°C, 15 h
52 %
Scheme 4
In the first attempt, we used a reaction protocol based on caused degradation of the starting material.
reported methods.5 Thus, when 4 was treated with a cata-
lytic amount of Pd(0) complex (5% Pd(OAc)2, 10% TFP,
10% heptene) in DMSO at room temperature in the pres-
Consequently, we have also studied the biscyclisation re-
action of compound 4 with different bases. Results are
summarised in Table 2.
ence of tBuOK as base, only compound 8 resulting from
We have found that inorganic bases such as potassium or
the direct cyclisation of the acid on the triple bond via the
cesium carbonate worked well in DMSO giving 64% of
6-endo mode was isolated in low yield (14%). A control
reaction indicated that in absence of palladium species, af-
ter 20 hours at room temperature, traces of product 8 were
obtained.
the expected product along with 10% of 6 which was eas-
ily removed by recrystallisation.13 Surprisingly, the use of
KHCO3, led to a mixture of products 5 and 6 in excellent
yield, where the regioselectivity of the biscyclisation is re-
versed in favour of 6 (entry 7). It should be noted that the
Synlett 2001, No. 7, 1191–1193 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
New Palladium-Catalysed Access to 3-(1’-Indanylidene) Phthalide
1193
(4) For previous synthesis of ylidene phthalides see: (a) Kelly, T.
R.; Bell, S. H.; Ohashi, N.; Armstrong-Chong, R. J. J. Am.
Chem. Soc. 1988, 110, 6471-6480. (b) Watanabe, M.;
Morimoto, H.; Furukawa, S. Heterocycles 1993, 36, 2681-
2686. (c) For pioneering work see: Holland, H. L.; MacLean,
D. B.; Rodrigo, R. G. A.; Manske, R. F. H. Tetrahedron Lett.
1975, 4323-4326.
Table 2 Influence of the nature of the base
(5) Cavicchioli, M.; Decortiat, S.; Bouyssi, D.; Goré, J.; Balme,
G. Tetrahedron 1996, 52, 11463-11478.
(6) (a) Lambert, C.; Utimoto, K.; Nozaki, H.; Tetrahedron Lett.
1984, 25, 5323-5326. (b) Kundu, N. G.; Pal, M.; Nandi, B. J.
Chem. Soc. Perkin Trans. 1 1998, 561-568 and references
cited therein.
(7) Where necessary the Pd(0) catalyst was preformed by reaction
of palladium acetate with 2 equivalents of monodentate ligand
per Pd in the solvent followed by addition of a reducing agent
(1-heptene or NaBH4).
(8) Wang, R-T.; Chou, F-L.; Luo, F-T. J. Org. Chem. 1990, 55,
4846-4849.
a) except for entry 5, where the product has been purified by recry-
stallisation, all yields were determined by 1H NMR. In all cases, mi-
nor product 6 is also present in small quantities (5-10%).
(9) Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proc. Int. 1995,
129-160.
(10) Bleicher, L. S.; Cosford, N. D. P.; Herbaut, A.; McCallum, J.
S.; McDonald, I. A. J. Org. Chem. 1998, 63, 1109-1118.
(11) Tsuji, J. Palladium Reagents and Catalysts, Wiley, Chichester
1996.
use of PPh3 as ligand in place of TFP significantly im-
proved the reaction efficiency (entry 3).
In conclusion, the palladium-catalysed bis-cyclisation re-
action presented herein constitutes a novel and rapid syn-
thetic route to the phthalide nucleus. We are currently
investigating an extension of this work to study the role of
substituents on aromatic rings, which will be reported in
due course.
(12) Negishi, E-I.; Takahashi, T.; Akiyoshi, K. J. Chem. Soc.,
Chem. Commun. 1986, 1338.
(13) Typical experimental procedure : Carboxylic acid 4 (100 mg,
0.266 mmol) in 3 mL of DMSO was treated with cesium
carbonate (104 mg, 0.319 mmol), the resulting solution was
stirred during 15 min. At this time, Pd (0) solution was added
(5% Pd(OAc)2, 10% PPh3, NaBH4 in 2 mL of DMSO). The
mixture was further stirred at 25 °C and followed by GC until
completion. The mixture is diluted with diethyl ether and
washed with brine. The organic layer was dried on Na2SO4,
condensed in vacuo and the residue chromatographed on silica
gel.
References and Notes
(1) Isolation and structure elucidation : see a) Pandey, R. C.;
Toussaint, M. W.; Stroshane, R. M.; Kalita, C. C.; Garretson,
A. A.; Wei, T. T.; Byrne, K. M.; Geoghegan, Jr., R. F.; White,
R. J. J. Antibiot. 1981, 34, 1389-1401; b) Misra, R.; Pandey,
R. C.; Silverton, J. V. J. Am. Chem. Soc. 1982, 104, 4478-
4479.; c) Misra, R.; Pandey, R. C.; Hilton, B. D.; Roller, P. P.;
Silverton, J. V. J. Antibiot. 1987, 40, 786-802.
(2) (a) Byrne, K. M.; C.; Hilton, B. D.; White, R. J.; Misra, R.;
Pandey, R. C. Biochemistry 1985, 24, 478. (b) Warnick-
Pickle, D. J.; Byrne, K. M.; Pandey, R. C.; White, R. J. J.
Antibiot. 1981, 34, 1402. (c) Von Hoff, D. D.; Cooper, J.;
Bradley, E.; Sandbach, J.; Jones, D.; Makuch, R. Am. J. Med.
1981, 70, 1027. (d) Hilton, B.D.; Misra, R.; Zweier, J.L.
Biochemistry 1986, 25, 5533. (e) Latham, M. D.; King, C. K.;
Gorycki, P.; Macdonald, T. L.; Ross, W.E. Cancer
Chemother. Pharmacol. 1989, 24, 167. (f) Dalal, N.S.; Shi, X.
Biochemistry 1989, 28, 748. (g) Yokoi, K.; Hasegawa, H.;
Narita, M.; Asaoka, T.; Kukita, K.; Ishizeki, S.; Nakajima, T.
Jpn Patent 152468, 1985; Chem. Abstr. 1986, 104, 33948j.
(3) Kita, Y.; Higuchi, K.; Yoshida, Y.; Iio, K.; Kitagi, S.; Akai S.;
Fujioka, H. Angew. Chem. Int. Ed. 1999, 38, 683-686 and
references cited therein.
(14) Analytical data : 1H and 13C NMR spectra of 5 were identical
with those reported in the literature.4b
Product 5: 1H NMR (CDCl3, 300 MHz) 3.05-3.11 (2H, m);
3.21-3.28 (2H, m); 7.28-7.42 (3H, m); 7.50-7.55 (1H, m); 7.71
(1H, ddd, J = 1.1; 7.7; 8.1 Hz); 7.95-8.02 (2H, m); 8.32 (1H,
d, J = 8.1 Hz). 13C NMR (CDCl3, 75 MHz) 31.28; 33.06;
122.19; 124.57; 125.9; 126.13; 126.19; 126.87; 129.43;
129.65; 130.89; 134.59; 137.75; 138.26; 140.5; 150.38;
167.38. The stereochemistry of 5 was determined using
Nuclear Overhauser Effect (NOE) experiments: irradiation of
C4 proton ( 8.32, d, J = 8.1 Hz) of 5 produced NOE
enhancement at the signals of C5 (15.4%) and C14 (10.5%).
NMR data for product 6 have been deducted from mixture of
5/6 (entry 7, Table 2). Product 6 1H NMR (CDCl3, 300 MHz)
2.7-2.82 (2H, m); 2.90-3 (2H, m); 7.1-7.8 (6H, m); 8.12
(1H, d, J = 8.4 Hz); 8.4 (1H, d, J = 8.1 Hz)
Product 8 1H NMR (CDCl3, 300 MHz) 2.82 (2H, t, J = 8.45
Hz); 3.14 (2H, m); 6.23 (1H, s); 6.90 (1H, m), 7.18-7.25 (3H,
m); 7.32 (1H, d, J = 7.7 Hz); 7.46 (1H, m); 7.66 (1H, ddd,
J = 1.1; 7.7; 7.7); 7.82 (1H, d, J = 8.1 Hz); 8.26 (1H, d, J = 8.1
Hz).
Article Identifier:
1437-2096,E;2001,0,07,1191,1193,ftx,en;G06701ST.pdf
Synlett 2001, No. 7, 1191–1193 ISSN 0936-5214 © Thieme Stuttgart · New York