The first regiospecific synthesis of helioxanthin by novel palladium-catalyzed benzannulation reaction of α,β-bisbenzylidene-γ-lactone

Article abstract of DOI:10.1016/S0040-4039(00)01982-1

We achieved the first regiospecific and biomimetic transformation of α,β-bisbenzylidene-γ-lactone to an arylnaphthalene lignan lactone, helioxanthin, using a novel palladium-catalyzed benzannulation reaction.

Full text of DOI:10.1016/S0040-4039(00)01982-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 437–439
The first regiospecific synthesis of helioxanthin by novel
palladium-catalyzed benzannulation reaction of
a,b-bisbenzylidene-g-lactone
Hideya Mizufune,* Minoru Nakamura and Hiroyuki Mitsudera
Chemical Development Laboratories, Pharmaceutical Production Division, Takeda Chemical Industries, Ltd.,
Jusohonmachi 2-17-85, Yodogawaku, Osaka 532-8686, Japan
Received 2 October 2000; revised 30 October 2000; accepted 2 November 2000
Abstract—We achieved the first regiospecific and biomimetic transformation of a,b-bisbenzylidene-g-lactone to an arylnaph-
thalene lignan lactone, helioxanthin, using a novel palladium-catalyzed benzannulation reaction. © 2001 Elsevier Science Ltd. All
rights reserved.
3
Arylnaphthalene lignan lactones occur widely in nature,
and by themselves or their analogues show various
biological activities, such as leuckotriene biosynthesis
or the intramolecular Diels–Alder reactions, conjugate
4
5
addition reactions, biaryl coupling reactions, and a
certain benzannulation reaction. These methods are
1
6
inhibition, hypolipidemic activity and phosphodi-
esterases inhibition; therefore, this class of compounds
has received the wide attention of synthetic chemists. A
number of methods have been developed to construct the
arylnaphthalene lignan skeleton, for example, classified
useful for certain types among this class of compounds,
but not individually appropriate for regioselective syn-
thesis of various lignan lactones. Particularly, the total
2b,3b,c
synthesis
of helioxanthin 1 has suffered from forma-
tion of by-products, its regioisomers, such as 2 (justi-
cidine E), 3 (taiwanin C) and 4 (retroherioxanthin).
2
by the key reaction of the strategy, the intermolecular
O
O
R4
O
O
R1
R2
O
O
O
R4
O
O
O
O
R3
R5
O
O
O
O
R5
O
O
O
5
(Taiwanin A)
R -R = R -R =OCH O
1
(Helioxanthin)
2 (Justicidine E)
3 (Taiwanin C)
R -R =OCH O, R =H
:
:
4
4
5
5
2
1
2
2
3
4
(Retrohelioxanthin)
R =H, R -R =OCH O
6 : R =OMe, R =H
4 5
:
1
2
3
2
7
: R =H, R =OMe
4 5
Keywords: lignans; palladium and compounds; naphthalenes; biaryls.
*
Corresponding author. E-mail: Mizufune Hideya@takeda.co.jp
–
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01982-1

4
38
H. Mizufune et al. / Tetrahedron Letters 42 (2001) 437–439
I
O
O
I
O
O
O
O
O
O
OMe
OMe
OH
O
d , e
CHO
c
a , b
O
I
OMe
8
9
O
10
O
O
I
O
O
O
(E)
O
O
O
O
O
O
O
O
1 (Helioxanthin)
f
O
O
IPd
Ar
O
O
PdI
O
O
H
(E)
Ar
13
O
11
12
O
O
O
(E)
O
O
O
O
PdI
O
O
IPd
O
O
PdI
O
O
Ar
Ar
Ar = 3,4 - methyenedioxy
(Z)
H
H
14
Ar
15
16
Scheme 1. Reagent and conditions: (a) (CH COOEt) , NaOMe, MeOH, aq. NaOH, 62%; (b) MeOH, H SO , 84%; (c) piperonal,
2
2
2
4
NaOMe, MeOH, 82%; (d) LiEt BH, THF, 67%; (e) ClCOOEt, Et N, THF, 88%; (f) Pd(OAc) (0.1 equiv.), K CO (2.2 equiv.),
3
3
2
2
3
NMP, 110°C, 50 min, 60%.
Thus, herein, we wish to report the first regiospecific
synthesis of 1 (helioxanthin) by a novel palladium-cata-
lyzed benzannulation reaction of a,b-bisbenzylidene-g-
lactone, which may be applicable to a synthetic study of
arylnaphthalene lignans and also various biaryl com-
pounds. As shown in Scheme 1, the key intermediate,
a,b-bisbenzylidene-g-lactone 11, was derived from 2-
tion on the Pd(OAc) (0.1 equiv.)/K CO /NMP system,
2 2 3
†
by which a,b-bisbenzylidene-g-lactone 11 was regiospe-
‡
cifically transformed to helioxanthin 1 (HPLC yield
†
1
Identification of a,b-bisbenzylidene-g-lactone 11: H NMR (DMSO-
d6, TMS, 300 MHz) l (ppm): 5.06 (2H, d, J=1.5 Hz), 5.85 (2H, s),
.98 (1H, d, J=1.5 Hz), 6.09 (2H, s), 6.19 (2H, s), 6.41 (1H, d-d,
J=8.0 and 1.1 Hz), 6.56 (1H, d, J=8.0 Hz), 6.66 (1H, brs), 7.38
7
iodopiperonal 8 by application of the syntheses for the
5
similar (E,E)-a,b-bisbenzylidene-g-lactones 5, 6 and 7.
−
1
Namely, the two-stage Stobbe condensation reaction of
(1H, d, J=0.9 Hz), IR (KBr, cm ): 1743, 1456, 1340, 1244, 1182,
1047, MS (EI, m/z): 476 (M ). Elemental analysis: calcd for
8
a
+
diethyl succinate with 2-iodopieronal 8 and the fol-
lowing piperonal provided bisbenzylidene-halfester 10,
in which the ester moiety distant from the reacting
carbon was selectively saponified by the typical Stobbe
condensation method. The halfester 10 was converted
into a,b-bisbenzylidene-g-lactone 11 by the Super-Hy-
C H O I; C, 50.44; H, 2.75, found for C, 50.51; H, 2.99.
20 13 6
‡
Synthetic procedure of helioxanthin: to a solution of a,b-bisbenzyli-
dene-g-lactone 11 (250 mg, 0.525 mmol) in NMP (5 ml), were added
Pd(OAc)2 (11.8 mg, 0.0525 mmol) and K CO (160 mg, 1.16 mmol)
2
3
under a nitrogen atmosphere. The reaction mixture was stirred at
room temperature for 1 h and heated at 110°C for 50 minutes. After
cooling, the insoluble matter in the reaction mixture was filtered off
and washed with NMP and AcOEt. To the mixture of the filtrate and
the washings, aq. Na S O was added and the organic and aqueous
8
b
8c
dride reduction and the following lactonizaion. The
geometrical configuration of a,b-bisbenzylidene-g-lac-
tone 11 was assigned as (E,E)-configuration on the
basis of the NOESY spectrum which showed the rela-
tionship between benzylidene and lactone protone.
2
2
3
layers were separated. The aqueous layer was extracted twice with
AcOEt. The combined organic layer was washed (aq. Na S O and
2
2
3
brine), dried (MgSO ), decolorized (activated carbon), and concen-
4
trated in vacuo. To a solution of the residue in toluene–AcOEt, silica
gel was added, stirred for 1 h and filtered off. The filtrate was
evaporated, and the solid residue was washed with methanol to give
Our aim is to achieve the first regiospecific transforma-
tion of a,b-bisbenzylidene-g-lactone 11 to an arylnaph-
7
thalene lignan lactone, helioxanthin 1. It is known that
1
helioxanthin 1 (110 mg, 60%) as pale yellow crystals. H NMR
the similar a,b-bisbenzylidene-g-lactones 5, 6 and 7,
including the natural lignan 5 (taiwanin A), were con-
verted to a regioisomeric mixture of 1-phenyl-2,3-naph-
(CDCl , TMS, 300 MHz), l (ppm): 5.20 (2H, dd, J=25.0 and 15.2
Hz), 5.95 (2H, dd, J=7.0 and 1.4 Hz), 6.05 (2H, dd, J=8.6 and 1.4
Hz), 6.7–6.8 (2H, m), 6.88 (1H, d-d, J=7.5 and 0.7 Hz), 7.31 (1H, d,
3
J=8.7 Hz), 7.70 (1H, d, J=8.7 Hz), 8.42 (1H, s), (DMSO-d , TMS,
thalide type lignans (e.g.
3
and 4) via the
6
3
6
6
00 MHz) l (ppm): 5.30 (2H, s), 6.01 (2H, dd, J=5.8 and 0.8 Hz),
.10 (2H, dd, J=14.9 and 0.7 Hz), 6.90 (1H, dd, J=7.9 and 1.6 Hz),
photo-cyclization process, which is interesting from the
viewpoint of biosynthesis. Our efforts were focused on
the intramolecular palladium-catalyzed reaction of a,b-
bisbenzylidene-g-lactone 11. After some screening of
the palladium-catalytic systems, we fortunately discov-
ered a novel palladium-catalyzed benzannulation reac-
.98 (1H, d, J=7.9 Hz), 7.03 (1H, d, J=1.6 Hz), 7.52 (1H, d, J=8.7
−1
Hz), 7.95 (1H, d, J=8.8 Hz), 8.58 (1H, s), IR (KBr, cm ): 1760,
+
1
234, 1072, MS (EI, m/z): 348 (M ). Elemental analysis: calcd for
C20H12O ·0.2H O; C, 68.26; H, 3.55, found for C, 68.39; H, 3.66, mp:
6
2
2
b
3b
241–243°C (lit. ; 239–242°C, lit ; 243–244°C).

H. Mizufune et al. / Tetrahedron Letters 42 (2001) 437–439
439
8
3%, isolated yield 60%). Therefore, this novel benzan-
In conclusion, we have achieved the first regiospecific
and biomimetic transformation of bisbenzylidene-g-lac-
tone 11 to helioxanthin 1 using a novel palladium-cata-
lyzed benzannulation. Now we are investigating the
expansion and application of this synthetic method.
nulation reaction may be applicable to regiospecific and
biomimetic synthesis of other arylnaphthalene lignans
(
e.g. 2, 3 and 4), by using some a,b-bisbenzylidene-g-
lactones derived from various 2-halobenzaldehydes and
benzaldehydes.
Acknowledgements
On the other hand, to our knowledge, a benzene ring
formation using the intramolecular Heck reaction of an
arylhalide or a vinylhalide to the conjugated 1,3-diene
system has not been investigated. A few examples of
The authors wish to thank Mr. H. Mizutani for the
measurement of the NOESY spectrum.
9
naphthalene synthesis from 3-allyl-4-bromoindole
derivative using the intramolecular Heck reaction are
known. Additionally, the palladium-mediated synthesis
of the dihydronaphthalene lignan lactone was achieved
by Ishibashi et al., in which method, however, sub-
strates are limited to such as a carbonyl-conjugated
olefin and the (Z)-olefin configuration isomer.
References
1
0
1
. (a) (recent review) Ward, R. S. Nat. Prod. Rep. 1997, 14,
3; (b) Therien, M.; Fitzsimmons, B. J.; Scheigetz, J.;
Macdonald, D.; Choo, L. Y.; Guay, J.; Falgueyret, J. P.;
Riendeau, D. Bioorg. Med. Chem. Lett. 1993, 3, 2063; (c)
Ukita, T.; Nakamura, Y.; Kubo, A.; Yamamoto, Y.;
Takahashi, M.; Kotera, J.; Ikeo, T. J. Med. Chem. 1999,
4
Thus, it is important to discuss the mechanism of our
novel benzannulation reaction of (E,E)-a,b-bisbenzyli-
dene-g-lactones 11. The following reaction mechanism
including two conceivable processes is proposed in
Scheme 1. In the first process, the oxidative addition of
palladium into the CꢀI bond of substrate 11 generates
s-arylpalladium complex 12 based on the (E,E)-
configuration isomer. Despite steric hindrance of the
other aryl group, the stable palladium(II) complex with
the 1,3-diene system (square-planar complex) acceler-
ates syn insertion of s-arylpalladium complex 12 to the
intramolecular alkene, to give s-dihydronaphthalene–
palladium complex 13. Then, the palladium(II) species
42, 1293.
2
. (a) Silva, S. O.; Denis, C. S.; Rodrigo, R. J. Chem. Soc.,
Chem. Commun. 1980, 995; (b) Charlton, J. L.; Oleschuk,
C. J.; Chee, G. J. Org. Chem. 1996, 61, 3452; (c) Padwa,
A.; Cochran, J. E.; Kappe, C. O. J. Org. Chem. 1996, 61,
706.
. (a) Block, E.; Stevenson, R. J. Org. Chem. 1971, 36, 3453;
b) Holmes, T. L.; Stevenson, R. J. Chem. Soc. (C) 1971,
3
3
(
2
5
091; (c) Stevenson, R.; Weber, J. V. J. Nat. Prod. 1989,
2, 367.
4
. (a) Ogiku, T.; Yoshida, S.; Ohmizu, H.; Iwasaki, T. J.
Org. Chem. 1995, 60, 4585; (b) Kobyashi, K.; Tokimatsu,
J.; Maeda, K.; Morikawa, O.; Konishi, H. J. Chem. Soc.,
Perkin Trans. 1 1995, 3013.
. (a) Meyers, A. I.; Avila, W. B. J. Org. Chem. 1981, 46,
881; (b) Hattori, T.; Tanaka, H.; Okaishi, Y.; Miyano,
S. J. Chem. Soc., Perkin Trans. 1 1995, 235.
1
3 smoothly undergoes syn b-hydride elimination to
yield the naphthalene product 1.
In the other process, s-arylpalladium complex 12 based
on the (E,E)-configuration isomer is isomerized to
5
3
(
E,Z)-type s-arylpalladium complex 14 because of the
delocalized p-electron system on the 1,3-diene complex
with the palladium(II) species. The following syn inser-
tion of s-arylpalladium complex 14 to the intramolecu-
lar alkene provides s-dihydronaphthalene–palladium
complex 15 which can undergo the formal anti b-hy-
dride elimination via p-allylpalladium complex 16 to
yield the naphthalene product.
6
. (a) Ohta, K.; Marumo, S.; Chen, Y. L.; Munakata, K.
Agric. Biol. Chem. 1971, 35, 431; (b) Tanabe, Y.; Seko,
S.; Nishi, Y.; Yoshida, T.; Utsumi, N.; Suzukamo, G. J.
Chem. Soc., Perkin Trans. 1 1996, 2157.
. (a) Heller, H. G.; Strydom, P. J. J. Chem. Soc., Chem.
Commun. 1976, 50; (b) Horii, Z.; Ohkawa, K.; Iwata, C.
Chem. Pharm. Bull. 1972, 20, 624; (c) Momose, T.;
Kanai, K.; Hayashi, K. Chem. Pharm. Bull. 1978, 26,
7
In both processes, the role of the 1,3-diene system in
the proposed reaction mechanism can be responsible
for our intramolecular-annulation reaction of the aryl-
halide to the different configuration alkene with the
different substituent ((E)-configuration isomer without
the conjugated lactone) from Ishibashi’s case ((Z)-
3
195 and references cited therein.
8
. (a) Young, W. B.; Masters, J. J.; Danishefsky, S. J. Am.
Chem. Soc. 1995, 117, 5228; (b) Momose, T.; Tanabe, G.;
Tsuzimori, H.; Muraoka, O. Chem. Pharm. Bull. 1992,
40, 2525; (c) Sai, H.; Ogiku, T.; Nishitani, T.; Hiramatsu,
H.; Horikawa, H.; Iwasaki, T. Synthesis 1995, 582.
9. Harrington, P. J.; Hegedues, L. S. J. Org. Chem. 1984,
49, 2657.
10. Ishibashi, H.; Ito, K.; Hirano, T.; Tabuchi, M.; Ikeda, M.
Tetrahedron 1993, 49, 4173.
10
configuration isomer with it).
Furthermore, our
methodology might be applied to general 1-(o-
halophenyl)-1,3-butadiene systems bearing various sub-
stituents as a substrate.
.
.