Studies on flavans. 1. Facile synthesis of (±)-7-hydxoxy-3′,4′-methylenedioxyflavan and (±)-4′-hydroxy-7-methoxyflavan by a BF3·Et2O-mediated pyran cyclization

Article abstract of DOI:10.1021/np0001171

A facile approach for the synthesis of flavans was developed by employing a BF₃·Et₂O-catalyzed pyran cyclization in an aprotic polar solvent as a key step, by which concise total syntheses of (±)-7-hydroxy-3′,4′-methylenedioxyflavan (1) and (±)-4′-hydroxy-7-methoxyflavan (2), two naturally occurring flavans, were achieved.

Full text of DOI:10.1021/np0001171

214
J . Nat. Prod. 2001, 64, 214-216
Notes
Stu d ies on F la va n s. 1. F a cile Syn th esis of
(()-7-Hyd r oxy-3′,4′-m eth ylen ed ioxyfla va n a n d (()-4′-Hyd r oxy-7-m eth oxyfla va n
by a BF 3‚Et2O-Med ia ted P yr a n Cycliza tion
Ying Li,* J inhui Yang, Weidong Z. Li, Liming Hou, J ijun Xue, and Yulin Li
National Laboratory of Applied Organic Chemistry & Insitute of Organic Chemistry, Lanzhou University, Lanzhou,
Gansu 730000, People’s Republic of China
Received March 8, 2000
A facile approach for the synthesis of flavans was developed by employing a BF3‚Et2O-catalyzed pyran
cyclization in an aprotic polar solvent as a key step, by which concise total syntheses of (()-7-hydroxy-
3′,4′-methylenedioxyflavan (1) and (()-4′-hydroxy-7-methoxyflavan (2), two naturally occurring flavans,
were achieved.
Naturally occurring flavans, characterized by the pres-
ence of a benzopyran core, exist widely in the plant
kingdom and exhibit many important biological and phar-
macological activities.1-9 Considerable studies on the syn-
thesis of flavan have been carried out, and a number of
synthetic methods have been developed9-24 over the past
decades for the purposes of structural determination and/
or analogue preparation for further biological studies.
Among them, reductive deoxygenation of the flavanone and
protic acid-catalyzed cyclization to form the benzopyran
ring are common approaches, yet these approaches typi-
cally suffer from poor yields and harsh reaction conditions.
For example, a large excess of a hydride reducing agent,
Its structure was confirmed27 by hydrogenation of the
i.e., NaBH4,10 Na(CN)BH4,11 or LiAlH412 is always required
corresponding flavylium salt formed by condensation of the
for the completion of reductive deoxygenation of the fully
appropriately substituted benzaldehyde and acetophenone
assembled flavanones. In some cases, the strong reducing
under acidic conditions.Hydrogenation of chalcone 328 using
conditions (i.e., LiAlH4-AlCl3) result in the cleavage of the
Raney Ni (W-2 type) in ethanol as the catalyst afforded
benzopyran ring.12 The reaction conditions for the cycliza-
benzylic alcohol 5 (93%), the key precursor for benzopyran
tion of corresponding carbinol or styrene derivatives of
cyclization. Treatment of 5 with boron trifluoride etherate
chalcones by exposure to protic acids, i.e., HCl,12 HOAc,13
(0.5 equiv)29 dropwise in anhydrous 1,4-dioxane at room
17
or H3PO4 to form the benzopyran ring are quite harsh
temperature for ca. 20 min30 was followed by extractive
for some acid-labile protecting groups (such as methoxym-
workup with ether to produce the desired cyclization
ethyl, MOM) that may be necessary for further derivati-
product 7 in 57% yield. Ferreira and co-workers re-
zation. Thus, an efficient, general, and direct synthetic
method from readily accessible chalcones is desirable.
In continuation of our ongoing program on the studies
of flavanoids, we report herein a facile synthetic approach
(Scheme 1) based on the Lewis acid (BF3‚Et2O)-mediated
benzopyran formation in an aprotic polar solvent, as
illustrated in the total synthesis of the two naturally
ported31,32 that reduced retro-chalcones can undergo a
similar simultaneous deprotection-cyclization in metha-
nolic aqueous hydrochloric acid (3 M) to afford the corre-
sponding catechin derivatives presumably via an incipient
C-1 carbocation species. It is noteworthy that the meth-
oxymethoxy (MOM) group, usually labile to acid, was left
intact under this condition. Dioxane is the most favorable
solvent tested so far for the cyclization, while other solvents
such as THF, ether, or methylene chloride resulted in poor
occurring flavans, (()-7-hydroxy-3′,4′-methylenedioxyfla-
van (1) and (()-4′-hydroxy-7-methoxyflavan (2).
(()-7-Hydroxy-3′,4′-methylenedioxyflavan (1) and its
yield of the desired product. The title compound 1 was
obtained as its racemate by mild acidic hydrolysis (3 N HCl
7-glucoside were first isolated25 from the native American
medicinal herb Zephyranthes flava, which has been used
in methanol) in 93% yield. The synthetic product has
traditionally for the treatment of diabetes, ear and chest
identical melting point (115-117 °C) and spectroscopic
ailments, and some viral infections. (()-4′-Hydroxy-7-
properties as those reported for the natural product.25
methoxyflavan (2) was first identified26 as a chemical
Following an analogous sequence as described above,
starting from the chalcone 4, compound 2 was synthesized
as a racemic mixture in an overall yield of 74%. The
synthetic (()-2 has the same melting point (143-145 °C)
and spectral properties as the natural product.26,27
component of Stypandra grandis and later characterized
as one of the antifeedant compounds in Lycoris raliata.26
* Corresponding author. Tel: +86-931-8912595. Fax: +86-931-8912283.
E-mail: liyl@lzu.edu.cn.
10.1021/np0001171 CCC: $20.00
© 2001 American Chemical Society and American Society of Pharmacognosy
Published on Web 01/11/2001

Notes
J ournal of Natural Products, 2001, Vol. 64, No. 2 215
Sch em e 1
Sch em e 2a
a
Reagents and conditions: (a) H2/Raney Ni(W-2), EtOH, 22 °C; (b) BF3‚Et2O, 1,4-dioxane, 23 °C, 0.5 h; (c) 3 N HCl, MeOH, reflux.
solution of 5 (50 mg, 0.13 mmol) in 1,4-dioxane (5 mL) was
added dropwise a solution of BF3‚Et2O (0.05 mL, 0.06 mmol)
in 10 mL of 1,4-dioxane at ambient tempature. The resulting
mixture was stirred for 20 min at room temperature, quenched
by the addition of saturated aqueous NaHCO3, and extracted
with ether. The organic extracts were dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The residue
was purified by flash column chromatography on silica gel
(petroleum ether-EtOAc, 16:1) to yield 7 (24 mg, 57%), as a
pale yellow solid (mp 47-48 °C): 1H NMR (CDCl3, 400 MHz)
δ 2.10(2H, m, 3-H), 2.71-2.94(2H, m, 4-H), 3.47(3H, s, OCH3),
4.94(1H, dd, J ) 10.2, 2.2 Hz, 2-H), 5.13(2H, s, 7-OCH2O), 5.97-
(2H, s, 3′,4′-OCH2O), 6.58(1H, d, J ) 2.5 Hz, ArH), 6.61(1H,
dd, J ) 8.4, 2.5 Hz, ArH), 6.81(1H, d, J ) 8 Hz, ArH), 6.88-
(1H, dd, J ) 8.0, 1.2 Hz, ArH), 6.93(1H, d, J ) 1.2 Hz, ArH),
The approach described herein is facile, short, and
applicable to various flavan derivatives. BF3‚Et2O was used
as a unique Lewis acid to catalyze the pyran cyclization in
an aprotic media, without affecting the acid-labile func-
tional group such as MOM.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. IR spectra were
obtained on a FT-170 SX spectrometer. 1H NMR spectra were
obtained on a Bruker AM-400 or AC-80 instrument in CDCl3
solution, and chemical shifts were recorded in ppm (δ) units
using TMS as an internal standard. MS were measured on a
ZAB-HS spectrometer by direct inlet at 70 eV.
1-(3′,4′-Me t h yle n e d ioxyp h e n yl)-3-(2′,4′-d im e t h oxy-
m eth oxyp h en yl)p r op a n ol (5) a n d 1-(4′-Meth oxym eth oxy-
p h en yl)-3-[(2′-m eth oxym eth oxy-4′-m eth oxy)p h en yl]p r o-
p a n ol (6). A solution of 3 (400 mg, 1.1 mmol) and W-2 type
Raney-Ni (100 mg) in EtOH (6 mL) was kept for 24 h under 2
atm pressure of hydrogen. The reaction mixture was filtered
and evaporated under reduced pressure to give an oily residue
that was purified by flash column chromatography on silica
gel (petroleum ether-EtOAc, 8:1) to yield 5 (377 mg, 93%) as
a colorless liquid: 1H NMR (CDCl3, 400 MHz) δ 1.98(2H, m,
2-H), 2.65(2H, t, J ) 7.2 Hz, 3-H), 3.46 and 3.47(6H, s, OCH3),
4.55(1H, dd, J ) 8.0, 5.6 Hz, 1-CH), 5.14 and 5.17(4H, s,
OCH2O), 5.93(2H, s, OCH2O), 6.64(1H, dd, J ) 8.4, 2.4 Hz,
ArH), 6.77(4H, m, ArH), 7.03(1H, d, J ) 8.4 Hz, ArH); IR (KBr)
1015, 1247 cm-1; EIMS m/z [M]+ 376(38), 314(50), 269(54), 148-
(31), 135(14), 84(44), 45(100).
6.98(1H, d, J ) 8 Hz, ArH); IR (KBr) 2896, 1619, 1583 cm-1
;
EIMS m/z [M]+ 314(53), 283(59), 269(23), 253(3), 239(4), 148-
(100), 135(32), 45(86).
F la va n 8 was prepared in an analogous manner from 6 and
was obtained as an amorphous solid in 80% yield (mp 24-25
°C): 1H NMR (CDCl3, 400 MHz): δ 2.11(2H, m, 3-H), 2.82-
(2H, m, 4-H), 3.48, 3.75(6H, s, OCH3), 4.98(1H, dd, J ) 10.1,
2.3 Hz, 2-H), 5.18(2H, s, 4′-OCH2O), 6.46(1H, d, J ) 2.3 Hz,
ArH), 6.48(1H, d, J ) 2.3 Hz, ArH), 6.98(1H, d, J ) 8.1 Hz,
ArH), 7.05(2H, m, ArH), 7.34(2H, dd, J ) 8.5, 2.4 Hz, ArH);
IR (KBr) 2929, 1618, 1583, 1507 cm-1; EIMS m/z [M]+ 300-
(41), 285(31), 134(63), 45(100).
Ack n ow led gm en t. This work was financially supported
by the National Natural Science Foundation of China.
Alcoh ol 6 was prepared in an analogous manner by
hydrogenation of the corresponding chalcone 4 and was
obtained as a colorless liquid in 98% yield: 1H NMR (400 MHz,
CDCl3) δ 2.01(2H, m, 2-H), 2.67(2H, m, 3-H), 3.47, 3.48 and
3.78 (9H, s, OCH3), 4.60(1H, dd, J ) 8.1, 5.2 Hz, 1-CH), 5.17,
5.18(4H, s, OCH2O), 6.51(1H, dd, J ) 8.0, 2.4 Hz, ArH), 6.70-
(1H, d, J ) 2.4 Hz, ArH), 7.01(2H, d, J ) 8.4 Hz, ArH), 7.06-
(2H, d, J ) 8.4 Hz, ArH), 7.29(1H, d, J ) 8.4 Hz, ArH); IR
(KBr) 3425, 1076 cm-1; EIMS m/z [M]+ 362(16), 317(5), 300-
(34), 267(7), 255(13), 239(8), 181(9), 167(9), 164(8), 151(9), 137-
(31), 121(6), 91(4), 45(100).
Su p p or tin g In for m a tion Ava ila ble: This material is available
free of charge via the Internet at http://pubs.acs.org.
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216 J ournal of Natural Products, 2001, Vol. 64, No. 2
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NP0001171