Efficient synthesis of octandrenolone and related dipyranoacetophenones

Article abstract of DOI:10.1021/np9902845

Octandrenolone (1) was prepared in high yield by condensation of 2',4',6'-trihydroxyacetophenone with 3-chloro-3-methylbut-1-yne in the presence of a catalytic amount of copper(I) iodide. Methylation of 1 afforded O-methyloctandrenolone (2). Oxidation of 2 with m-chloroperoxybenzoic acid followed by hydrolysis gave the racemic trans-(+)-1-(9,10-dihydro-9,10- dihydroxy-5-methoxy-2,2,8,8-tetramethyl-2H,8H-benzo[1,2-b:3,4-b']dipyran-6- yl)ethanone (3), which confirmed the structure of the natural product previously isolated from Melicope erromangensis.

Full text of DOI:10.1021/np9902845

J . Nat. Prod. 2000, 63, 245-247
245
Efficien t Syn th esis of Octa n d r en olon e a n d Rela ted Dip yr a n oa cetop h en on es
R. Pernin,† F. Muyard,*,† F. Be´valot,† F. Tillequin,‡ and J . Vaquette†
Laboratoire de Pharmacognosie, Faculte´ de Me´decine et de Pharmacie, Place St. J acques, F25030 Besanc¸on Cedex, France, and
De´partement de Pharmacognosie, UMR/ CNRS No. 8638, Universite´ Rene´ Descartes, 4 Avenue de l’Observatoire,
F75006 Paris Cedex, France
Received J une 9, 1999
Octandrenolone (1) was prepared in high yield by condensation of 2′,4′,6′-trihydroxyacetophenone with
3-chloro-3-methylbut-1-yne in the presence of a catalytic amount of copper(I) iodide. Methylation of 1
afforded O-methyloctandrenolone (2). Oxidation of 2 with m-chloroperoxybenzoic acid followed by
hydrolysis gave the racemic trans-(+)-1-(9,10-dihydro-9,10-dihydroxy-5-methoxy-2,2,8,8-tetramethyl-
2H,8H-benzo[1,2-b:3,4-b′]dipyran-6-yl)ethanone (3), which confirmed the structure of the natural product
previously isolated from Melicope erromangensis.
Isolation of the dimethylpyran acetophenone octandre-
nolone (1), together with four novel related compounds,
including O-methyloctandrenolone (2) and trans-(+)-1-(9,-
10-dihydro-9,10-dihydroxy-5-methoxy-2,2,8,8-tetramethyl-
2H,8H-benzo[1,2-b:3,4-b′]dipyran-6-yl)ethanone (3), from
the roots of Melicope erromangensis was reported earlier.1
Fused dimethylpyran rings biogenetically arising from
condensation of a phenol with an isoprenyl unit are
commonly encountered in Rutaceae secondary metabolites,
and the syntheses of dimethylpyranocoumarins,2,3 dimeth-
ylpyranotyramine amides,4 dimethylpyranocarbazoles,5,6
dimethylpyranoquinolones,7,8 dimethylpyranofuroquino-
lines,9 and dimethylpyranoacridones10-12 are well docu-
mented. However, the synthesis of dimethylpyranoace-
tophenones has been considerably less explored. The only
previous synthesis of octandrenolone (1), by condensation
of chloroacetophenone with 3-hydroxy-3-methylbutanal
dimethylacetal, gave only 20% yield, due to formation of
byproducts.13
We selected the Claisen rearrangement10 of dimethyl-
propargyl ethers, obtained by alkylation of a suitable
phenol with 3-chloro-3-methylbut-1-yne,17 as the most
appropriate way to obtain octandrenolone (1). Thus, reac-
tion of 3-chloro-3-methylbut-1-yne with commercially avail-
able 2′,4′,6′-trihydroxyacetophenone was first carried out
in refluxing acetone, in the presence of potassium carbonate
and potassium iodide, resulting in the formation of six
major products within 24 h (Scheme 1). The first one (25%
yield) was identified as octandrenolone (1), identical with
the natural product. The second and third products were
the propargylic ethers 4 (19%) and 5 (8%), which were
subsequently converted almost quantitatively into 1 by
refluxing in dimethylformamide for 5 h. The last three
compounds were side products with one or two fused
dimethylfuran rings, resulting from cyclization of products
of C-alkylation of 2′,4′,6′-trihydroxyacetophenone with
3-chloro-3-methylbut-1-yne.18,19 Their structures were es-
tablished as 1-(2,8-diyliden-5-hydroxy-2,3,8,9-tetrahydro-
3,3,9,9-tetramethylbenzo[1,2-b:3,4-b′]difuran-6-yl)etha-
none (6), 1-(2,3-dihydro-5-hydroxy-3,3,8,8-tetramethyl-2-
yliden-8H-benzo[1,2-b]furan-[3,4-b′]pyran-6-yl)ethanone (7),
and 1-(8,9-dihydro-5-hydroxy-2,2,9,9-tetramethyl-8-yliden-
2H-benzo[3,4-b]furan-[1,2-b′]pyran-6-yl)ethanone (8) on the
basis of their spectral data. Of particular interest was the
presence of 1H NMR signals characteristic of exo-methylene
groups, appearing as systems of two doublets (J ) 2.9 Hz),
at about δ 4.30 and 4.70.18 In 7 and 8, the relative positions
of the fused pyrano and furano rings on the acetophenone
basic core could be unambiguously deduced from 1H-13C
correlations observed in the COLOC spectra.
Several series of natural products or structural ana-
logues, including a dimethylpyran-derived system, exhibit
interesting biological activities, exemplified by the cytotoxic
and antitumor activities of acronycine14 and related pyra-
nophenanthridine15 derivatives, and by the anti-AIDS
activity of seselin derivatives.16 The potential interest of
dipyranoacetophenones prompted us to develop a conve-
nient methodology for the synthesis of octandrenolone
derivatives. We describe here an efficient synthesis of
octandrenonelone (1) and O-methyloctandrenolone (2), and
the conversion of this latter compound into the trans-diol
3, which permitted us to confirm the structure of this
natural product.
Optimization of the process by addition of a catalytic
amount of copper(I) iodide20 when alkylating 2′,4′,6′-
trihydroxyacetophenone (Scheme 1) permitted isolation of
octandrenolone (1) in 78% yield, after only 3 h of reaction.
It should be noted that intermediate propargylic ethers
could not be isolated from the reaction mixture under such
conditions.
Methylation of 1 (Scheme 1) with iodomethane in re-
fluxing acetone afforded 2 in excellent yield. Finally,
conversion of 2 to the corresponding racemic trans-dihy-
drodiol 3 gave confirmation of the structure of natural
trans-(+)-1-(9,10-dihydro-9,10-dihydroxy-5-methoxy-2,2,8,8-
tetramethyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-6-yl)etha-
none isolated from M. erromangensis.1 Thus, oxidation of
2 with m-chloroperoxybenzoic acid, followed by hydrolysis,
led to the expected racemic trans-diol 3, whose UV, IR, MS,
* To whom correspondence should be addressed. Tel.: (33)-381665537.
Fax: (33)-381665562. E-mail: frederic.muyard@univ-fcomte.fr.
† Faculte´ de Me´decine et de Pharmacie, Besanc¸on, France.
‡ UMR/CNRS No 8638, Universite´ Rene´ Descartes, Paris, France.
10.1021/np9902845 CCC: $19.00
© 2000 American Chemical Society and American Society of Pharmacognosy
Published on Web 01/14/2000

246 J ournal of Natural Products, 2000, Vol. 63, No. 2
Sch em e 1. Synthetic Routes to 1 and 2a
Notes
R Key: (i) 3-chloro-3-methylbut-1-yne, Me2CO, reflux; (ii) 3-chloro-3-methylbut-1-yne, CuI, Me2CO, reflux; (iii) CH3I, KOH, Me2CO, reflux.
1-(5-Hyd r oxy-3-3-m eth ylbu tyn -3-oxy-2H-ben zo[1,2-b]-
p yr a n -6-yl)eth a n on e (5): 1H NMR (CDCl3, 200 MHz) δ 1.51
(6H, s, 2 × CH3), 1.70 (6H, s, 2 × CH3), 2.62 (1H, s, H-1′′),
2.65 (3H, s, CH3-2′′′), 5.44 (1H, d, J ) 10.0 Hz, H-3′), 6.57 (1H,
NMR, and TLC data were identical with those of natural
trans-(+)-1-(9,10-dihydro-9,10-dihydroxy-5-methoxy-2,2,8,8-
tetramethyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-6-yl)etha-
none.
d, J ) 10.0 Hz, H-4′), 6.72 (1H, s, H-4), 13.70 (1H, s, OH); 13
C
NMR (CDCl3, 75 MHz) δ 27.8 (C-5′), 27.8 (C-6′), 29.8 (C-4′′),
29.8 (C-5′′), 32.9 (C-2′′′), 77.0 (C-2′), 78.1 (C-1′′), 83.9 (C-3′′),
98.2 (C-2′′), 104.1 (C-1), 106.1 (C-5), 115.5 (C-3), 116.6 (C-4′),
127.6 (C-3′), 155.3 (C-4), 157.4 (C-2), 168.2 (C-6), 204.3 (C-
1′′′); EIMS m/z 300 [M]+, 287, 285; HREIMS m/z 300.1359
(calcd for C18H20O4 300.1362).
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Spectra were re-
corded on the following apparatuses: UV, Shimadzu UV-160A;
MS, Nermag R10-10H in electron impact (70 eV); NMR,
1
Bruker AC200, H NMR (200 MHz) and a Bruker AC300, 13C
NMR (75 MHz). Chemical shifts are given in δ with TMS as
an internal standard. Coupling constants (J ) are given in
Hertz. Multiple-pulse experiments (1H-1H COSY and 13C-
1H HETCOR and COLOC) were performed on Bruker AC300,
using the Bruker standard microprograms.
Column chromatography was conducted with Si gel (Merck;
20-63 µm). Elution was performed either with n-hexane
containing increasing amounts of EtOAc (purification of
compounds 1, 2, 6-10) or with CHCl3 containing increasing
amounts of EtOAc (purification of compound 3).
Alk yla t ion of 2′,4′,6′-Tr ih yd r oxya cet op h en on e b y 3-
Ch lor o-3-m et h ylb u t -1-yn e. To a solution of 2′,4′,6′-tri-
hydroxyacetophenone, KI (12 g), and K2CO3 (10.5 g) in dry
acetone (180 mL) was added 3-chloro-3-methylbut-1-yne (34
g, 0.34 mol) dropwise. The reaction mixture was refluxed for
24 h and then evaporated. The solid residue was extracted with
chloroform. Concentration of the chloroform solution gave an
orange oil, the TLC analysis of which showed four major
products. The residue was purified on column chromatography
to give 1, 4, 5, 6, 7, and 8 in 25%, 19%, 8%, 22%, 20%, and 5%
yield, respectively.
1-(2,8-Diylid en -5-h yd r oxy-2,3,8,9-t et r a h yd r o-3,3,9,9-
tetr a m eth ylben zo[1,2-b:3,4-b′]d ifu r a n -6-yl)eth a n on e (6):
1H NMR (CDCl3, 200 MHz) δ 1.51 (6H, s, 2 × CH3), 1.53 (6H,
s, 2 × CH3), 2.68 (3H, s, CH3-2′′′), 4.29 (1H, d, J ) 2.9 Hz,
H-4′), 4.32 (1H, d, J ) 2.9 Hz, H-10′), 4.72 (1H, d, J ) 2.9 Hz,
H-4′), 4.74 (1H, d, J ) 2.9 Hz, H-10′), 13.17 (1H, s, OH); 13C
NMR (CDCl3, 75 MHz)_δ 28.3 (C-5′), 28.3 (C-6′), 28.3 (C-11′),
28.3 (C-12′), 31.1 (C-2′′′), 42.8 (C-4′), 42.8 (C-10′), 83.5 (C-3′ or
C-9′), 84.0 (C-3′ or C-9′), 101.0 (C-3 or C-5), 101.8 (C-3 or C-5),
115.7 (C-1), 155.8 (C-2 or C-4), 156.5 (C-2 or C-4), 161.1 (C-6),
172.9 (C-2′ or C-8′), 173.1 (C-2′ or C-8′), 201.4 (C-1′′′); EIMS
m/z 300 [M]+, 285; HREIMS m/z 300.1348 (calcd for C18H20O4
300.1362).
1-(2,3-Dih yd r o-5-h yd r oxy-3,3,8,8-tetr a m eth yl-2-ylid en -
1
8H-ben zo[1,2-b]fu r a n [3,4-b′]p yr a n -6-yl)eth a n on e (7): H
NMR (CDCl3, 200 MHz) δ 1.48 (6H, s, 2 × CH3), 1.50 (6H, s,
2 × CH3), 2.66 (3H, s, CH3-2′′′), 4.29 (1H, d, J ) 2.9 Hz, H-4′),
4.71 (1H, d, J ) 2.9 Hz, H-4′), 5.47 (1H, d, J ′ ) 10.0 Hz, H-9′),
6.66 (1H, d, J ′ ) 10.0 Hz, H-10′), 13.45 (1H, s, OH); 13C NMR
(CDCl3, 75 MHz) δ 27.8 (C-11′), 27.8 (C-12′), 28.3 (C-5′), 28.3
(C-6′), 31.3 (C-2′′′), 42.9 (C-3′), 77.9 (C-8′), 83.5 (C-4′), 101.3
(C-3), 103.1 (C-5), 112.0 (C-10′), 116.2 (C-1), 125.4 (C-9′), 155.9
(C-2), 158.3 (C-4), 159.4 (C-6), 172.3 (C-2′), 201.7 (C-1′′′); EIMS
m/z 300 [M]+, 285; HREIMS m/z 300.1371 (calcd for C18H20O4
300.1362).
Octa n d r en olon e (1). Spectral data are identical with those
previously published.36
1-(5-Hyd r oxy-1-3-m eth ylbu tyn -3-oxy-2H-ben zo[3,4-b]-
1
p yr a n -6-yl)eth a n on e(4): H NMR (CDCl3, 200 MHz) δ 1.49
(6H, s, 2 × CH3), 1.73 (6H, s, 2 × CH3), 2.65 (1H, s, H-1′′),
1-(8,9-Dih yd r o-5-h yd r oxy-2,2,9,9-tetr a m eth yl-8-ylid en -
1
2.67 (3H, s, CH3-2′′′), 5.41 (1H, d, J ) 10.0 Hz, H-3′), 6.52 (1H,
2H-ben zo[3,4-b]fu r a n [1,2-b′]p yr a n -6-yl)eth a n on e (8): H
d, J ) 10.0 Hz, H-4′), 6.70 (1H, s, H-2), 13.65 (1H, s, OH); 13
C
NMR (CDCl3, 200 MHz) δ 1.51 (6H, s, 2 × CH3), 1.52 (6H, s,
2 × CH3), 2.66 (3H, s, CH3-2′′′), 4.28 (1H, d, J ) 2.9 Hz, H-10′),
4.70 (1H, d, J ) 2.9 Hz, H-10′), 5.48 (1H, d, J ′ ) 10.0 Hz, H-3′),
6.46 (1H, d, J ′ ) 10.0 Hz, H-4′), 13.68 (1H, s, OH); 13C NMR
(CDCl3, 75 MHz) δ 27.8 (C-5′), 27.8 (C-6′), 28.3 (C-11′), 28.3
(C-12′), 32.1 (C-2′′′), 43.0 (C-10′), 76.7 (C-2′), 83.5 (C-9′), 100.9
(C-3), 102.4 (C-5), 115.3 (C-4′), 117.2 (C-1), 127.2 (C-3′), 151.1
NMR (CDCl3, 75 MHz) δ 27.8 (C-5′), 27.8 (C-6′), 29.5 (C-4′′),
29.5 (C-5′′), 33.2 (C-2′′′), 75.1 (C-2′), 77.8 (C-1′′), 84.6 (C-3′′),
98.1 (C-2′′), 104.8 (C-3), 106.1 (C-5), 117.1 (C-1), 124.6 (C-3′),
124.6 (C-4′), 156.3 (C-2), 157.4 (C-4), 165.1 (C-6), 203.4 (C-
1′′′); EIMS m/z 300 [M]+, 287, 285; HREIMS m/z 300.1372
(calcd for C18H20O4 300.1362).

Notes
J ournal of Natural Products, 2000, Vol. 63, No. 2 247
(C-2), 155.9 (C-4), 156.5 (C-6), 173.2 (C-8′), 200.6 (C-1′′′); EIMS
m/z 300 [M]+, 285; HREIMS m/z 300.1342 (calcd for C18H20O4
300.1362).
tr a n s-(+)-1-(9,10-Dih yd r o-9,10-d ih yd r oxy-5-m et h oxy-
2,2,8,8-t et r a m et h yl-2H ,8H -b en zo[1,2-b:3,4-b′]d ip yr a n -6-
yl)eth a n on e (3). Spectral data were identical with those
previously published.1
Cop p er (I) Iod id e Ca ta lyzed Alk yla tion of 2′,4′,6′-Tr i-
h yd r oxya cet op h en on e b y 3-Ch lor o-3-m et h ylb u t -1-yn e.
To a solution of 2′,4′,6′-trihydroxyacetophenone (6.4 g, 38
mmol) with KI (11.5 g) and K2CO3 (9.4 g) in dry acetone (40
mL) was added CuI (60 mg, 0.3 mmol). The reaction mixture
was stirred at reflux for 15 min. Then 3-chloro-3-methylbut-
1-yne (34.9 g, 340 mmol) was added dropwise over 1.5 h. The
reaction mixture was stirred for 3 h at reflux. After cooling,
water (150 mL) was added and the mixture extracted with
CH2Cl2 (2 × 120 mL). The organic layer was washed succes-
sively with 2 N HCl, 2 N NaOH, and H2O; dried over Na2SO4;
and concentrated under reduced pressure. The residue was
crystallized from n-hexane, yielding 1 (8.9 g, 78%) as yellow
needles.
Meth yla tion of 1. A solution of 1 (2.8 g, 9.3 mmol), KOH
(1 g), and MeI (6.2 mL, 86 mmol) in dry acetone (200 mL) was
heated under reflux for 1.5 h. After cooling, water (100 mL)
was added, and the reaction mixture was extracted with CHCl3
(3 × 150 mL). The organic layer was collected, dried over Na2-
SO4, filtered, and evaporated under reduced pressure. The
residue was purified on column chromatography to give 2 (2.8
g) as yellow oil in 95% yield. Spectral data of 2 were identical
with those previously published.1
Ack n ow led gm en t. We are grateful to Dr. G. Crini for
recording the NMR spectra on a Bruker AC200 spectrometer.
Refer en ces a n d Notes
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Oxid a tion of 2. To a solution of 2 (262 mg, 0.8 mmol) in
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was added. The reaction mixture was stirred at room temper-
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NaHCO3 and stirred again for 10 min. The mixture was
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successively washed with saturated aqueous NaHCO3 (3 × 8
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was stirred at room temperature for 30 min, then acidified
with 20% HCl, and further stirred for 1 h at room temperature.
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a solution that was extracted with EtOAc. The EtOAc layer
was dried over Na2SO4 and the solvent evaporated under
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NP9902845