Revised structure of alboctalol

Article abstract of DOI:10.1021/np9701788

A revised structure was deduced for alboctalol from NMR studies. Racemic alboctalol octamethyl ether was synthesized by treatment of oxyresveratrol tetramethyl ether with acid.

Full text of DOI:10.1021/np9701788

J . Nat. Prod. 1997, 60, 1041-1042
1041
Revised Str u ctu r e of Albocta lol
Robert B. Bates,*,† Sriyani Caldera,† V. H. Deshpande,‡ B. L. Malik,§ and S. K. Paknikar§
Chemistry Department, University of Arizona, Tucson, Arizona 85721, National Chemical Laboratory,
Pune 411008, India, and Chemistry Department, Goa University, Goa 403203, India
Received March 19, 1997X
A revised structure was deduced for alboctalol from NMR studies. Racemic alboctalol
octamethyl ether was synthesized by treatment of oxyresveratrol tetramethyl ether with acid.
Sch em e 1. Possible Biosynthesis of 3
In 1976, alboctalol, a new polyphenol from Morus alba
(family Moraceae), was assigned structure 1a .1 Com-
pound 1a is apparently a dimer of oxyresveratrol (2a ),
a main constituent of the heartwood of this plant.
Alboctalol was not obtained pure, but its octamethyl
ether (proposed to be 1b) was purified through recrys-
tallization. We report spectral data on alboctalol oc-
tamethyl ether, which led to revised structures 3a for
alboctalol and 3b for its octamethyl ether, and that in
support of this new structure, racemic alboctalol octa-
methyl ether 3b was formed in 6% yield when oxyres-
veratrol tetramethyl ether (2b) was treated with acid.
The major mass spectral fragments of 3b (1) are
consistent with this structure. Loss of dimethoxyphenyl
and H from the molecular ion at m/ z 600 (32%) gives a
peak at m/ z 462 (11%), and loss of dimethoxybenzyl give
a peak at 449 (25%). The peaks for about half the dimer
at m/ z 299 (44%) and 300 (37%) come at least partly
through reverse Diels-Alder fragmentation. The base
peak at m/ z 269 (100%) comes from loss of formalde-
hyde from a 299 fragment and/or loss of a methoxyl
radical from a 300 fragment. The peak at m/ z 151
(60%) is due to dimethoxybenzyl and/or dimethoxytro-
pylium cations.
A likely biosynthesis of alboctalol (3a ) from oxyres-
veratrol (2b) is shown in Scheme 1. Since 3a is optically
active,1 the acid-catalyzed reactions are probably enzyme-
mediated. The final cyclization of intermediate 4 to give
a cyclohexane rather than a cyclopentane as reported
by Battersby and Binks2 in the acid-catalyzed dimer-
ization of 3,4,3′,4′-tetramethoxystilbene (5) to 6 is
readily rationalized on the basis of the relative activa-
tion toward electrophilic substitution of the aromatic
rings by methoxyl groups.
The 13C NMR spectrum of alboctalol octamethyl
ether1 did not show two methylenes, one methinyl, and
one quaternary sp3 carbons as required for structure 1b,
but instead one methylene and three methinyls as in
3b. The 500 MHz 1H NMR spectrum showed the
coupling constants and chemical shifts expected for the
stereoisomer of 3b depicted, with the large J 6ax,7 ) 14.4
Hz showing the 7-aryl group to be equatorial, and the
small J 7,8 ) 2.9 Hz showing the 8-aryl group to be axial
and requiring the 9-aryl group to be equatorial for the
benzocyclohexene half-chair observed to be stable. This
conformation has an H8-C8-C9-H9 angle close to 90°,
which is consistent with J 8,9 being too small to observe.
It is also supported by the strong upfield shifts (to δ5.74)
observed for H18 and H22, which indicate that, as
initially deduced from biosynthetic considerations, the
3,5-dimethoxyphenyl group rather than one of the 2,4-
dimethoxyphenyl groups is at position 8.
* Address for correspondence.
† University of Arizona.
‡ National Chemical Laboratory.
§ Goa University.
X Abstract published in Advance ACS Abstracts, September 1, 1997.
S0163-3864(97)00178-X CCC: $14.00
© 1997 American Chemical Society and American Society of Pharmacognosy

1042 J ournal of Natural Products, 1997, Vol. 60, No. 10
Notes
We decided to see if racemic alboctalol octamethyl
ether (3b) could be formed by treatment of oxyresvera-
trol tetramethyl ether (2b) with acid. Compound 2b
was synthesized by a Wittig reaction, but failed to give
3b under several acidic conditions [P2O5/toluene (2),
p-toluenesulfonic acid/benzene, trifluoroacetic acid/
chloroform] used to dimerize stilbenes. Finally, HCl gas
in dry ether gave a 6% yield of 3b, optically inactive,
104.2, 107.1, 128.1, and 129.2; and C at 119.3, 125.0,
128.8, 140.6, 145.0, 157.7, 157.9, 158.5, 158.6, and 4 ×
159.2.
Oxyr esver a tr ol Tetr a m eth yl Eth er (2b). A mix-
ture of triphenylphosphine (352 mg, 1.34 mmol), 3,5-
dimethoxybenzyl chloride (250 mg, 1.33 mmol), and dry
C6H6 (10 mL) was boiled for 3 h. On cooling, the C6H6
was decanted and the solid was washed with benzene
(2 × 10 mL) and dried to give (3,5-dimethoxybenzyl)-
triphenylphosphonium chloride (566 mg, 1.3 mmol,
83%). To this salt in dry ether (10 mL) under N2 was
added dropwise over 15 min with stirring KO-t-Bu
prepared by reacting K (53 mg, 1.34 mmol) with t-BuOH
(10 mL). After 15 min, a solution of 2,4-dimethoxyben-
zaldehyde (225 mg, 1.36 mmol) in dry Et2O (15 mL) was
added over 20 min. After 1 h, the reaction mixture was
poured onto crushed ice. The Et2O layer was separated,
and the aqueous layer was extracted with Et2O (3 × 15
mL). The combined Et2O extracts were washed with
water (2 × 10 mL) and dried, and the solvent was
evaporated. Chromatography of the residual oil on
silica gel, with elution with petroleum ether-C6H6 (4:
1), gave after evaporation 2b (42 mg, 10%): mp 83-84
°C (lit.4 84 °C).
1
but with IR and H and 13C NMR spectra identical to
those of 3b from methylation of natural 3a . This
synthesis of 3b supports the view that the 3,5-dimethoxy-
phenyl group is at position 8 and increases the prob-
ability that alboctalol 3a is indeed a dimer of oxyres-
veratrol (2a ). It is likely that other stereoisomers of 3b
are formed in this reaction, but no other product was
characterized.
While it is expected from the location of their meth-
oxyl groups that acid-catalyzed dimerization of 4,4′-
dimethoxystilbene should give a cyclopentane dimer of
type 63 and that 2b should give a cyclohexane dimer
3b, the cation of type 4 from 3,3′,4,4′-tetramethoxystil-
bene 5 has a choice of similarly activated aromatic rings
to give each type of dimer. Though structure 6 has been
proposed to be the dimer from 5 by analogy with 4,4′-
dimethoxystilbene and this cyclopentane product can be
justified as more likely on entropy grounds,2 a cyclo-
hexane structure of the 3b type should still be consid-
ered as possible for the dimer of 5.
Ra cem ic Albocta lol Octa m eth yl Eth er (3b). Dry
HCl gas was bubbled through dry Et2O (25 mL) cooled
in an ice-salt bath until saturation was complete. 2b
(200 mg, 680 mmol) was added, and the mixture was
stirred at 0 °C for 2 h and then at 25 °C for 2 h. The
mixture was poured onto ice, and the aqueous layer was
neutralized with solid Na2CO3 and extracted with Et2O
(3 × 20 mL). The Et2O extracts were washed with
water (15 mL) and dried, and the solvent was evapo-
rated. The residue was chromatographed on silica gel,
with elution with petroleum ether-EtOAc (3:1), to give
after evaporation 3b (12 mg, 6%): mp 166-168 °C; IR,
1H NMR, and 13C NMR data identical with those of the
natural product.
Exp er im en ta l Section
Albocta lol Octa m eth yl Eth er (3b) fr om Na tu r a l
Albocta lol (3a ). Alboctalol octamethyl ether (3b) was
prepared from crude natural alboctalol (3a ) as previ-
ously described:1 mp 168-169 °C; IR (KBr) 2943, 1608,
1550, 1455, 1390, 1292, 1208, 1158, 1045 and 838 cm-1
;
1H NMR (500 MHz, CDCl3, TMS, δ) 6.56 (d, 8.4 Hz,
H-28), 6.54 (d, 2.4 Hz, H-25), 6.46 (d, 8.4 Hz, H-16), 6.36
and 6.35 (d, 2.5 Hz, H-2 and H-4), 6.34 (d, 2.4 Hz, H-13),
6.33 (dd, 8.4, 2.4 Hz, H-15), 6.27 (dd, 8.4, 2.4 Hz, H-27),
6.20 (t, 2.3 Hz, H-20), 5.74 (d, 2.3 Hz, H-18 and H-22),
4.84 (s, H-9), 3.83 (s, OMe), 3.80 (s, OMe), 3.79 (s, OMe),
3.73 (s, OMe), 3.72 (dt, 14.4, 3.5 Hz, H-7), 3.60 (s, OMe),
3.46 (s, 19-OMe and 21-OMe), 3.39 (s, 1-OMe), 3.27 (d,
2.9 Hz, H-8), 2.85 (dd, 16.8, 14.4 Hz, H-6ax), 2.64 (dd,
16.8, 4.1 Hz, H-6eq); 13C NMR (APT) CH3 at 2 × 54.8,
55.0, 55.2, 2 × 55.3, 55.6, and 55.7; CH2 at 29.9; CH at
31.0, 37.9, 48.0, 97.0, 98.1, 98.3, 2 × 98.4, 102.8, 103.1,
Refer en ces a n d Notes
(1) Deshpande, V. H.; Wakharkar, P. V.; Rama Rao, A. V. Indian
J . Chem. 1976, 14B, 647-650.
(2) Battersby, A. R.; Binks, R. J . Chem. Soc. 1958, 4333-4339.
(3) Baker, W.; Enderby, J . J . Chem. Soc. 1940, 1094-1098.
(4) Mongolsuk, S.; Robertson, A.; Towers, R. J . Chem. Soc. 1957,
2231-2233.
NP9701788