Studies on the reactivity of a tertiary allylic alcohol in an acetophenonic series, a model for natural products synthesis

Article abstract of DOI:10.1211/0022357011776379

The synthesis of benzopyranic simplified analogues of dibenzopyranic natural compound is described, together with the access to a precursor of a new furobenzopyranic natural product. These natural products have anti-cancer activity. The 1,3-diacetoxy-2-acetyl-4-(3-hydroxy-3-methylbut-1-enyl) benzene synthone is used as a common precursor to these structures.

Full text of DOI:10.1211/0022357011776379

Journal of
Pharmacy and Pharmacology
JPP 2001, 53: 955–958
# 2001 The Authors
Received December 19, 2000
Accepted April 4, 2001
ISSN 0022-3573
Studies on the reactivity of a tertiary allylic alcohol in
an acetophenonic series, a model for natural products
synthesis
J. J. Helesbeux, D. Seraphin, O. Duval, P. Richomme and J. Bruneton
Abstract
The synthesis of benzopyranic simplified analogues of dibenzopyranic natural compounds is
described, together with the access to a precursor of a new furobenzopyranic natural product.
These natural products have anti-cancer activity. The 1,3-diacetoxy-2-acetyl-4-(3-hydroxy-3-
methylbut-1-enyl)benzene synthone is used as a common precursor to these structures.
Introduction
As part of our work on natural product isolation, diverse coumarinic coumpounds
were isolated from Calophyllum dispar. Among these structures, a known
dipyranobenzenic (1) and a new furobenzopyranic (2) molecule were characterized
(Figure 1) and demonstrated weak activity against N6 non small-cell lung cancer
strain (Guilet 2000). Coumarins are widely spread in nature and are known to be
responsible for a variety of biological and clinical actions (O’Kennedy & Thornes
1997).
We recently described photo-oxygenation as a straighforward access to ortho-(2-
hydroxy-3-methylbut-3-enyl)phenols without the need of any phenolic protecting
group by using the diphenolic compound 3 (Helesbeux et al 2000). The reduction
of the Schenk-ene reaction products, 4 and 5, conducted at low temperature, yields
secondary (6) and tertiary (7) alcohols (Figure 2). Attempt to separate this
ultimate mixture, over silica gel, leads to the isolation of 6 and a very small amount
of 7, along with the benzopyranic compound 8.
A 2-(3-hydroxy-3-methylbut-1-enyl)phenol pattern could represent a key inter-
mediate for the synthesis of both pyrano (1) and furano (2) derivatives. Therefore,
we first decided to focus our work on improving the pathway leading to this type of
compound.
SONAS, UFR des Sciences
Pharmaceutiques et Ingenierie
de la Sante, 16 Bd Daviers,
49100 Angers, France
J. J. Helesbeux, D. Seraphin,
O. Duval, P. Richomme,
J. Bruneton
Materials and Methods
NMR spectra were recorded on Jeol GSX WB 270 MHz and Bruker Avance
DRX 500 MHz instruments using tetramethylsilane as the internal standard.
Correspondence: O. Duval,
SONAS, UFR des Sciences
Pharmaceutiques et Ingenierie
de la Sante, 16, boulevard
Daviers, 49100 Angers,
France. E-mail:
1,3-Diacetoxy-2-acetyl-4-(3-hydroxy-3-methylbut-1-enyl)benzene (13)
Dried air was bubbled through a solution of diacetate 9 (764 mg, 2.51 mmol) in
acetone (150 mL) containing haematoporphyrin (10 mg, 0.017 mmol). The reaction
olivier.duval!univ-angers.fr
955

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J. J. Helesbeux et al
methane (30 mL) and 292 mg of triphenylphosphine
(1.1 mmol). The solution was stirred overnight. The
residue after evaporation was chromatographed over
silica gel (dichloromethane–acetone, 90:10) to yield
260 mg of the amorphous mass 13. The overall yield was
32%. 1H NMR (CDCl3) δ 1.41 (6H, 2s, 2 CCH3), 2.29,
2.30 (6H, 2s, 2 OCOCH3), 2.46 (3H, s, COCH3), 6.33
(1H, d, CHꢀCH, J l 16.2 Hz), 6.56 (1H, d, CHꢀCH,
J l 16.2 Hz), 7.07 (1H, d, CHꢀCH, J l 8.6 Hz), 7.57
(1H, d, CHꢀCH, J l 8.6 Hz).
Figure 1 Dipyranobenzenic (1) and furobenzopyranic (2) cou-
marins isolated from Calophyllum dispar.
8-Acetyl-7-hydroxy-2,2-dimethyl-
2H[1]benzopyran (14)
mixture was water-cooled at 15mC and irradiated with a
halogen lamp (500 W) for 3 h. After evaporation, the To a solution of 20 mg of 13 in 1.5 mL methanol and
residue was chromatographed over silica gel, eluted 0.75 mL water was added 0.75 mL of saturated sodium
with a cyclohexane–ethyl acetate mixture (70:30), to hydrogen carbonate solution. After one hour stirring,
give 10 and 11 (Figure 3). The mixture was introduced the solution was neutralized with 1 hydrochloride
into a 100-mL flask containing a solution of dichloro- solution, extracted with ethyl acetate, dried and evapo-
Figure 2 Synthesis of secondary (6) and tertiary (7) alcohols and benzopyranic compound (8). Reagents: i, TPP, CH2Cl2, O2, k30mC, hν;
ii, PPh3, CH2Cl2, RT; iii, PPh3, CH2Cl2, k30mC, liquid chromatography.
Figure 3 Synthesis of diphenolic secondary (12) and tertiary (13) allylic alcohol diacetate derivatives. Reagents: i, TPP, CH2Cl2, O2, 15mC,
hν; ii, PPh3, CH2Cl2, liquid chromatography.

957
Reactivity of tertiary allylic alcohol in acetophenonic series
rated. The residue was subjected to TLC (cyclohexane–
ethyl acetate, 80:20) to yield 8 mg of the amorphous
mass 14. 1H NMR (CDCl3) δ 1.52 (6H, s, 2 CCH3), 2.73
(3H, s, COCH3), 5.48 (1H, d, CHꢀCH, J l 9.9 Hz),
6.25 (1H, d, CHꢀCH, J l 9.9 Hz), 6.46 (1H, d,
CHꢀCH, J l 8.0 Hz), 7.06 (1H, d, CHꢀCH, J l
8.0 Hz), 13.05 (1H, OH).
Figure 4 Synthesis of the 8-acetyl-7-hydroxy-2,2-dimethyl-2H[1]-
benzopyran 14.
1,3-Diacetoxy-2-acetyl-4-(1,2-epoxy-3-hydroxy-
3-methylbutyl)-benzene (15)
Compound 13 (29 mg; 0.09 mmol) and meta-chloro-
perbenzoic acid (5 mol equiv) were stirred at room
temperature for 2 h, in dry dichloromethane (8 mL).
The solution was then washed successively with 10%
aqueous sodium sulphite (2i10 mL) and 5% aqueous
sodium hydrogen carbonate solution (2i10 mL). After
evaporation, the residue was chromatographed on a
silica column (chloroform–ethyl acetate, 70:30) to yield
1
23 mg of the amorphous mass 15 (76% yield). H
NMR (CDCl3) δ 1.36, 1.49 (6H, 2s, 2 CCH3), 2.30, 2.31
(6H, 2s, 2 OCOCH3), 2.47 (3H, s, COCH3), 2.87 (1H, d,
CH-CH, J l 2.2 Hz), 3.97 (1H, d, CH-CH, J l 2.2 Hz),
7.09 (1H, d, CHꢀCH, J l 8.6 Hz), 7.37 (1H, d,
CHꢀCH, J l 8.6 Hz).
Figure 5 Oxidation of compound 13 followed by deacylation, to
produce the diphenol 17 instead of the expected epoxyphenol 16.
Reagents: i, mCPBA, CH2Cl2, RT; ii, Zn, MeOH–CH2Cl2.
1,3-Dihydroxy-2-acetyl-4-(2-acetoxy-3-hydroxy-
1-methoxy-3-methyl-but-1-enyl)-benzene (17)
Murray & Forbes 1978; Ito & Furukawa 1989; Murray
& Zeghdi 1989; Ito et al 1991). The diphenolic secondary
(12) and tertiary (13) allylic alcohol diacetate derivatives
are obtained from 9 (Jain et al 1970) in an overall good
yield and in a ratio of 1:2 (Figure 3).
Activated zinc (5 mg) was added to 30 mg of 15 in 4 mL
dry methanol and 4 mL dichloromethane. The suspen-
sion was stirred for 72 h. The zinc was filtered through
celite and washed with methanol. The solvents were
then evaporated under reduced pressure. The residue
was subjected to TLC (dichloromethane–ethyl acetate,
65:35) to yield 9 mg of 17 (32% yield), mp 160–162mC.
1H NMR (CDCl3) δ 1.20, 1.41 (6H, 2s, 2 CCH3), 1.98
(3H, s, OCOCH3), 2.70 (3H, s, COCH3), 3.38 (3H, s,
OCH3), 5.00 (1H, broad s, H3COCH), 4.98 (1H, d, CH-
OCOCH3, J l 2.9 Hz), 6.47 (1H, d, CHꢀCH, J l
8.5 Hz), 7.13 (1H, d, CHꢀCH, J l 8.5 Hz), 11.2 (1H,
OH) ; 13C NMR δ 20.5 (OCOCH3), 26.8 (CH3), 27.7
(CH3), 33.5 (COCH3), 57.1 (OCH3), 72.7 (CHOH), 78.3
(CHOCOCH3), 80.7 (CHOCH3), 108.0 (CHꢀC), 110.9
(CHꢀC), 111.2 (CꢀC), 134.9 (CHꢀC), 160.2 (HO-
CꢀC), 162.3 (HO-CꢀC), 170.1 (CꢀO), 205.5 (CꢀO).
Before embarking on the functionalization of the
exocyclic double bond, the hydrolysis of the diacetate 13
was attempted under alkaline conditions. A single prod-
uct was identified as the benzopyranic phenol 14. This
compound was presumably obtained through a [4j2]
cycloaddition of a methylenequinone formed after re-
arrangement of the phenate along with loss of the
tertiary hydroxy group (Figure 4).
Taking into account these results and with the aim of
synthesizing furobenzenic structures, we considered the
funtionalization of the aliphatic side chain prior to the
phenolic deprotection. Hence, oxidation of 13 using
meta-chloroperbenzoic acid led to the corresponding
epoxide 15 in a good yield (Figure 5). Then we used
deacetylating conditions, via a catalytic-type reaction,
by treatment with activated zinc in methanol (Gonzales
Results and Discussion
Different works on coumarins have shown that the et al 1981). This method, which was carried out in
protection of the phenolic groups could greatly improve neutral medium, was expected to give the epoxyphenol
the yield of tertiary allylic alcohol (Fourrey et al 1970; 16, but instead we isolated the unexpected diphenol 17.

958
J. J. Helesbeux et al
with the deprotection of the phenols and transacetyl-
ationreactioninvolvingthegeneratedsecondaryalcohol
and the nearest acetylated phenol, is observed.
In summary, we have shown that benzopyranic cycli-
zation is easily obtained when basic conditions are used
on allylic tertiary alcohol. These results could explain
the presence of this sort of derivative in plant extracts.
Our preliminary syntheses have led to a polyfunc-
tionalized acetophenonic precursor (17), which could
yield, by further cyclization, to a model of the new
coumarin 2. Further studies toward synthesis of the
benzodihydrofuranic structure using direct nucleophilic
substitution of the acetate, or involving Mitsunobu
reaction, are currently under investigation in our lab-
oratory. Anti-cancer pharmacological studies on these
simplified structures are in progress.
Figure 6 A. Selected HMBC correlations. B. Selected significant
nuclear Overhauser enhancement results.
The structure of this compound was elucidated using
1
extensive NMR spectroscopy. Analyses of the H and
13C NMR spectra, including correlation spectroscopy
and heteronuclear multiple-quantum correlation, sug-
gested the presence of an aliphatic chain consisting of an
acetoxyl group (δC 20.5; δH 1.98), a methine group linked
to another one (δC 80.6, δC 78.2; δH 5.00, δH 4.98) and
two methyl groups adjacent to a quaternary carbon
bearing a hydroxyl group (δC 27.7, δC 26.7; δH 1.20, δH
1.41). The linked arrangement of these partial structural
units was elucidated by heteronuclear multiple-bond
coherence spectroscopy. Significant C-H long-range
correlations useful in the structure determination are
shown as lines in Figure 6A. Long-range correlations
of a methyl carbon signal at δC 27.0 (C-4h) with proton
signals at δH 4.98 (H-2h), correlations of the carbonyl
(δC 170.1) with H-2h (δH 4.98) and correlations of
the benzylic H-1h proton (δH 5.00) with C-3 and C-4
(δC 160.2, δC 134.9) allowed linkage of structural units
as shown in structure 17. The salient proton enhance-
ments from nuclear Overhauser and exchange spectro-
scopy experiments are summarized in Figure 6B.
Among the most prominent were those recorded follow-
ing pre-saturation of the methoxy, acetoxy, H-1h and
H-2h protons. Pre-saturation of the methoxy protons
caused enhancements of H-5, H-1h and acetoxy protons.
Moreover, irradiation of the acetoxy group led to H-2h
and 4-methyl proton enhancements (a weak enhance-
ment was recorded on H-5 proton).
References
Fourrey, J. L., Rondest, J., Polonsky, J. (1970) Sur quelques oxy-
dations de type biogenetique. Bull. Soc. Chim. Fr. 26: 3839–3847
Gonzales, A. G., Jorge, Z. D., Lopez Dorta, H. (1981) Deacylation of
aromatic acetates. A new method of selective protection of the
hydroxyl fuction. Tetrahedron Lett. 22: 335–336
Guilet, D. (2000) Etude phytochimique d’une clusiaceae malaise, le
calophyllum dispar. These de l’universite d’Angers
Helesbeux, J. J., Guilet, D., Seraphin, D., Duval, O., Richomme, P.,
Bruneton, J. (2000) ortho-Prenylphenol photooxygenation as a
straighforward access to ortho-(2-hydroxy-3-methylbut-3-enyl)-
phenols. Tetrahedron Lett. 41: 4559–4562
Ito, C., Furukawa, H., (1989) Two new coumarins from murraya
plants. Chem. Pharm. Bull. 37: 819–820
Ito, C., Fujiwara, K., Karta, M., Ju-Ichi, M., Takemura, Y., Suzuki,
Y., Tanaka, K., Omura, M., Furukawa, H. (1991) New coumarins
from citrus plants. Chem. Pharm. Bull. 39: 2509–2513
Jain, A. C., Lal, P., Seshadri, T. R. (1970) A study of nuclear
prenylation of β-resacetophenane-II. Synthesis of bavachalcone 4h-
O-methylbavachalcone and bavachin. Tetrahedron 26: 2631–2635
Murray, R. D. H., Forbes, I. T. (1978) Synthesis of the coumarins,
avicennol, dipetaline and dipetalolactone. Tetrahedron 34: 1411–
1414
Murray, R. D. H., Zeghdi, S. (1989) Synthesis of the natural cou-
marins, murraol (CM-c2), trans-dehydroosthol and swieteno-
coumarin G. Phytochemistry 28: 227–230
During this synthesis, the oxirane ring opening, in-
volving a nucleophilic methanolic attack concomitantly
O’Kennedy, R., Thornes, R. D. (1997) Coumarins Biology, Appli-
cations and Mode of Action. John Wiley, Chichester