Synthesis of (+)-drim-9(11)-en-8α-ol from sclareol

Article abstract of DOI:10.1023/B:RUCB.0000030822.72251.ea

A drimane-type sesquiterpenoid, (+)-drim-9(11)-en-8α-ol, was synthesized from sclareol in four steps. The ozonolysis product of sclareol diacetate reacts with Cu(OAc)₂·H₂O to give 8α-acetoxy-14,15-bisnorlabdan-13-one. Photolysis of this compound followed by alkaline hydrolysis results in the target compound belonging to the normal steric series. (+)-Drim-9(11)-en-8α-ol acetate is highly unstable and decomposes during chromatography on SiO₂.

Full text of DOI:10.1023/B:RUCB.0000030822.72251.ea

Russian Chemical Bulletin, International Edition, Vol. 53, No. 2, pp. 443—446, February, 2004
443
Synthesis of (+)ꢀdrimꢀ9(11)ꢀenꢀ8αꢀol from sclareol
P. F. Vlad,ꢀ A. N. Aryku, and A. G. Chokyrlan
Institute of Chemistry, Academy of Sciences of the Moldova Republic,
ul. Akademiei 3, MDꢀ2028 Kishinev, the Republic of Moldova
Fax: +7 (373 2) 73 9775. Eꢀmail: vlad_p@mail.md
A drimaneꢀtype sesquiterpenoid, (+)ꢀdrimꢀ9(11)ꢀenꢀ8αꢀol, was synthesized from sclareol
in four steps. The ozonolysis product of sclareol diacetate reacts with Cu(OAc)2•H2O to give
8αꢀacetoxyꢀ14,15ꢀbisnorlabdanꢀ13ꢀone. Photolysis of this compound followed by alkaline
hydrolysis results in the target compound belonging to the normal steric series. (+)ꢀDrimꢀ
9(11)ꢀenꢀ8αꢀol acetate is highly unstable and decomposes during chromatography on SiO2.
Key words: (+)ꢀdrimꢀ9(11)ꢀenꢀ8αꢀol, synthesis, ozonolysis, photolysis, absolute configuꢀ
ration, sclareol.
Sesquiterpenoid drimaneꢀtype alcohols, namely,
(–)ꢀdrimꢀ9(11)ꢀenꢀ8αꢀol (1) and its dextrorotatory
C(8)ꢀepimer (2), were isolated1 from the culture filtrate
of the fungi Aspergillus oryzae used in breadmaking and in
the production of some beverages (sake and so on) in
Japan (Scheme 1). The racemic alcohol 1 was synthesized
starting from farnesol, which ultimately confirmed its
structure.
To establish the absolute configurations of compounds
1 and 2, sesquiterpenes 3 and 4 were synthesized2 from
manool (5). Manool was converted in three steps into a
mixture of C(8)ꢀepimeric 14,15ꢀbisnorlabdanꢀ8ꢀolꢀ13ꢀ
ones 6 and 7, whose photolytic cleavage produced a mixꢀ
ture of (+)ꢀdrimꢀ9(11)ꢀenꢀ8αꢀol (3) and (–)ꢀdrimꢀ9(11)ꢀ
enꢀ8αꢀol (4) and it was concluded that A. oryzae meꢀ
tabolites refer to the enantiomeric series. Later, a mixꢀ
ture of the same alcohols 3 and 4 was obtained3 from
royleanone (8), a natural product of the same stereochemiꢀ
cal series as manool (5). However, these researchers conꢀ
cluded that the metabolites of A. oryzae correspond to the
normal steric series. It was also found2,3 that the specific
optical rotation value reported previously1 for alcohol 1 is
markedly overestimated.
sclareol (10), is difficult to prepare in a pure state, as it
is unstable and is easily converted into cyclic vinyl
ether 12.5—7
It is noteworthy that acetoxy ketone 11 is an imporꢀ
tant intermediate for the synthesis of products with amber
odor valuable for the fragrance industry.7—11 The develꢀ
opment of methods for its preparation from sclareol (10)
has received considerable attention. This compound was
first synthesized6 from hydroxy ketone 7 in a low yield
(25—27%) by a complex, multistage route. It is also
formed12 upon Pb(OAc)4/I2ꢀ or PhI(OAc)2/I2ꢀinduced
radical cleavage of dihydrosclareol 8ꢀmonoacetate (13).
Acetoxy ketone 11 was obtained in a high yield (95%)
upon oxidation of sclareol 8ꢀmonoacetate (14) on treatꢀ
ment with RuCl3•3H2O and NaIO4 9,10 (the overall yield
based on sclareol (10) was 51%). However, the most effiꢀ
cient method for the preparation of acetoxy ketone 11
from sclareol (10) includes quantitative isomerization of
sclareol diacetate (15) induced by the PdCl2•(MeCN)2
complex to give isosclareol diacetate (16)8,10,13 and its
oxidative ozonolysis (the yield of acetoxy ketone 11 was
90%)8,10 or scission with KMnO4 (85% yield).10
Of course, it would be of interest to accomplish direct
oxidative transformation of sclareol diacetate (15) into
acetoxy ketone 11. To this end, we performed a detailed
investigation of its reactions with oxidants such as KMnO4,
CrO3, and O3 under various conditions. Sclareol diacetate
(15) was prepared by a known procedure.14 The oxidation
of diacetate 15 with KMnO4 was carried out under stanꢀ
dard conditions in acetone, acetic acid, acetone in the
presence of MgSO4•7H2O (see Ref. 2), or in benzene in
the presence of CuSO4•5H2O (see Ref. 15). However,
under these conditions, acetoxy ketone 11 either formed
in a yield of no more than 25—27% (in acetone and
acetic acid) or was not formed at all. The oxidation of
Enantioselective synthesis of crystalline alcohol 3 in
which drimaneꢀ8α,11ꢀdiol (9) served as the key comꢀ
pound has been described.3,4 The conclusions drawn are
in keeping with those reported in a previous publication.2
In view of the above contradictory data, to solve defiꢀ
nitely the problem of the absolute configuration of the
metabolites of the fungi A. oryzae, we carried out directed
partial synthesis of alcohol 3 from sclareol (10) (see
Scheme 1).
8αꢀAcetoxyꢀ14,15ꢀbisnorlabdanꢀ13ꢀone (11) was choꢀ
sen as the key intermediate compound, because 14,15ꢀbisꢀ
norlabdanꢀ8αꢀolꢀ13ꢀone (7), formed upon oxidation of
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 423—426, February, 2004.
1066ꢀ5285/04/5302ꢀ0443 © 2004 Plenum Publishing Corporation

444
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 2, February, 2004
Vlad et al.
Scheme 1
diacetate 15 with the Jones reagent or CrO3 in AcOH
did not result in acetoxy ketone 11 either. Ozonolysis
of diacetate 15 in CH2Cl2—Et3N (see Ref. 16),
MeOH—CH2Cl2—Py, or CH2Cl2 followed by oxidative
cleavage of the ozonide with H2O2 gave acetoxy ketone
11 in a yield ranging from 10 to 17%. The desired comꢀ
pound was not formed at all upon ozonolysis of diacetate
15 in a MeOH—CH2Cl2 mixture in the presence of NaOH
(see Ref. 17) or in MeOH in the presence of HCl (see
Ref. 18). Better results were obtained by ozonization of
diacetate 15 in a MeOH—CH2Cl2 mixture followed by
anomalous decomposition of the resulting hydroperꢀ
oxides by treatment with a mixture of FeSO4•7H2О and
Cu(OAc)2•H2О (see Ref. 19). The neutral fraction of
the ozonolysis product was a mixture of the target acetoxy
ketone 11 and a small amount of a more polar comꢀ
pound, which was not studied further. However, in this
case, too, the yield of acetoxy ketone 11 proved to be
relatively low (38%). A reasonable yield of acetoxy keꢀ
tone 11 (52%) was obtained upon decomposition of
the ozonolysis product of sclareol diacetate (15) by
Cu(OAc)2•H2O in toluene with heating, carried out acꢀ
cording to a previously described procedure.20 Comꢀ
pound 11 was identified by comparing the physicochemiꢀ
cal and spectroscopic characteristics obtained with pubꢀ
lished data.11

Synthesis of (+)ꢀdrimꢀ9(11)ꢀenꢀ8αꢀol
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 2, February, 2004
445
CHCl3. Photolysis was performed using a Heraeus TQꢀ150 UV
lamp, 150 W (a highꢀpressure mercury lamp). Acros silica gel
(60/200 µm) was used for column chromatography and Sorbfil
plates were used for TLC (visualization by H2SO4 with heating).
Ozonolysis of sclareol diacetate (15). A. A flow of ozonized
oxygen was passed at –60 °C through a solution of 100 mg
(0.255 mmol) of sclareol diacetate (15)14 in a mixture of 3 mL of
anhydrous MeOH and 3 mL of dry CH2Cl2 until a persistent
blue color appeared. Excess ozone was removed by purging the
solution with nitrogen. Then the reaction mixture was warmed
to ≈20 °C and the solvent was evaporated in vacuo. A solution of
Cu(OAc)2•H2O (51 mg, 0.255 mmol) in 5 mL of methanol was
added to the residue, and FeSO4•7H2O (71 mg, 0.255 mmol)
was added to the resulting solution (see Ref. 19). The mixture
was stirred for 40 h at ∼20 °C, diluted with 20 mL of ethyl
acetate, washed successively with 1% HCl (2×20 mL) and water
(2×20 mL), and extracted with 1% NaOH (2×20 mL). The
organic layer was washed with water (3×20 mL), dried with
anhydrous Na2SO4, and filtered, and the solvent was evaporated
in vacuo. The resulting neutral fraction (53 mg) was chromatoꢀ
graphed on a column with 1.6 g of SiO2. Elution with a petroꢀ
leum ether—Et2O mixture (98 : 2) gave 32 mg (yield 38%) of
8αꢀacetoxyꢀ14,15ꢀbisnorlabdanꢀ13ꢀone (11), m.p. 119—120 °C
The acidic fraction of the ozonization product is
sclareolic acid diacetate (17) as indicated by the data
from spectral and elemental analysis and was confirmed
by the preparation of the known sclareolic acid (18)5 by
saponification of the product by ethanolic alkali.
For preparing 8αꢀacetoxydrimꢀ9(11)ꢀene (19), acetoxy
ketone 11 was subjected to photolytic cleavage according
to the Norrish II reaction. Note that this reaction has
been studied previously,21 and a diene, drimꢀ7,9(11)ꢀ
diene (20), has been isolated as the only reaction product.
In view of the mechanism and mild conditions of the
Norrish II reaction, this result was difficult to explain and
we suggested that the primary reaction product, unsaturꢀ
ated acetate 19, decomposes during chromatography, as
tertiary alcohol acetates are known to be highly labile
compounds.22 Indeed, by photolysis of acetoxy ketone 11,
we obtained a mixture of the starting compound (the
reaction did not proceed to completion) and a less polar
compound; during chromatography on a SiO2 column,
the latter compound was quantitatively transformed into
another product with even a lower polarity, which was
found to be diene 20. The obtained spectroscopic characꢀ
teristics were fully consistent with published data.21 Alcoꢀ
hol 3 was also found to decompose during chromatoꢀ
graphy on silica gel Acros. This fact was confirmed exꢀ
perimentally: the photolysis product was hydrolyzed with
an ethanolic solution of alkali; the mixture of alcohol 3
and sclareol oxide (12) was separated into two portions,
one of which was chromatographed on a column with
SiO2 and the other, on а column with neutral Al2O3. On
the SiO2 column, alcohol 3 dehydrated to give hydrocarꢀ
bon 20. Chromatography on Al2O3 gave the crystalline
target product 3 and sclareol oxide (12), which was idenꢀ
tified by comparison with an authentic sample. The meltꢀ
ing point of alcohol 3 coincided with the reported value4
and the spectral characteristics were also identical to those
reported in the literature.1,2
22
(from a hexane—Et2O mixture, 98 : 2), [α]D –26.5 (c 2.17)
(Ref. 11: m.p. 118—121 °C, [α]D –22.2). IR, ν/cm–1: 1245,
1735 (OAc), 1700 (COMe). 1H NMR, δ: 0.77 (s, 3 H, C(20)H3);
0.83 and 0.85 (both s, 3 H each, C(4)(CH3)2); 1.46 (s, 3 H,
C(17)H3); 1.92 (s, 3 H, OAc); 2.12 (s, 3 H, C(16)H3).
The alkaline extract from the ozonolysis product was acidiꢀ
fied with 15 mL of 10% H2SO4 and extracted with ether
(3×20 mL), the extract was washed with water to neutral pH,
dried with anhydrous Na2SO4, filtered, and concentrated in
vacuo to give 26 mg (24.9%) of sclareolic acid diacetate 17, m.p.
83—85 °C (from a hexane—Et2O mixture, 96 : 4). Found (%):
C, 67.5; H, 8.97. C23H38O6. Calculated (%): C, 67.29; H, 9.33.
IR, ν/cm–1: 1230, 1725 (OAc), 1710, 3340 (COOH). 1H NMR,
δ: 0.78 (s, 3 H, C(20)H3); 0.84 (s, 3 H, C(18)H3); 0.86 (s, 3 H,
C(19)H3); 1.42 (s, 3 H, C(17)H3); 1.60 (s, 3 H, C(16)H3); 1.93,
2.07 (both s, 3 H each, OAc).
B. Sclareol diacetate (15) (100 mg, 0.255 mmol) was ozoꢀ
nized as described above. After evaporation of the solvent in
vacuo, the residue was dissolved in 2 mL of toluene, and the
resulting solution was added to a solution of Cu(OAc)2•H2O
(102 mg, 0.51 mmol) in 5 mL of methanol heated to 70 °C. The
mixture was stirred at the same temperature for 20 h and filꢀ
tered. Ether (20 mL) was added to the filtrate and the solution
was washed with 1% NaOH (2×20 mL) and H2O (3×20 mL).
The solution was dried with anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue (57 mg) was chromatoꢀ
graphed on a column with 15 g of SiO2 to give 43 mg (52%) of
acetoxy ketone 11, m.p. 119—120.5 °C (from a hexane—Et2O
mixture, 98 : 2) and 4 mg of a more polar compound, which was
not further studied. The yield of sclareolic acid diacetate (17)
was 16 mg (15.3%).
Thus, we accomplished a fourꢀstep synthesis of
(+)ꢀdrimꢀ9(11)ꢀenꢀ8αꢀol (3) from sclareol (10) in an
overall yield of 45% (taking into account the recovered
acetoxy ketone 11 at the stage of photolysis), which addiꢀ
tionally proves the fact that natural products 1 and 2
belong to the enantiomeric steric series.
Experimental
Melting points were determined on a Boetius hot stage.
IR spectra were recorded on a Specordꢀ74 spectrophotometer in
CCl4. 1H and 13C NMR spectra were run in CDCl3 on a Bruker
ACꢀE 200 spectrometer (200.13 and 50.32 MHz). The chemical
shifts are given in the δ scale and referred to CHCl3 as the
internal standard (δ 7.24, δ 77.00). The 13C NMR signals
Saponification of sclareolic acid diacetate (17). Sclareolic
acid diacetate (17) (70 mg, 0.169 mmol) was refluxed for 3 h
with 5 mL of 10% КOH in ethanol. Ethanol was evaporated in
vacuo, the residue was dissolved in 20 mL of ether, and
the ethereal solution was washed with water to neutral pH
(4×10 mL), dried with anhydrous Na2SO4, filtered, and conꢀ
centrated in vacuo to give 45 mg (80.8%) of sclareolic acid (18),
H
C
were assigned using DЕРТ technique and comparison with the
spectra of known related compounds. Mass spectra (EI, 70 eV)
were run on a AEI MS 902 mass spectrometer. The specific
rotation was measured on a JASCO DIP 370 polarimeter in

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Russ.Chem.Bull., Int.Ed., Vol. 53, No. 2, February, 2004
Vlad et al.
m.p. 152—153 °C (from a hexane—Et2O mixture, 96 : 4), which
was identified by comparison with an authentic sample (Ref. 5:
m.p. 153—154 °C).
Italian National Research Council, Pozzuoli, Naples,
Italy) for assistance in determining specific optical rotaꢀ
tion and spectrometric measurements.
Photolysis of 8αꢀacetoxyꢀ14,15ꢀbisnorlabdanꢀ13ꢀone (11).
A. A solution (110 mg, 0.34 mmol) of acetoxy ketone 11 in
60 mL of anhydrous hexane was irradiated in a Pyrex vessel with
a Heraeus TQꢀ150 UV lamp (150 W) under a flow of dry nitroꢀ
gen for 2 h at 5 °C. The solvent was evaporated in vacuo and the
residue representing, according to TLC, a mixture of the startꢀ
ing compound and a less polar product was chromatographed on
a column with 11 g of SiO2. Elution with light petroleum gave
32 mg of a lowꢀpolar liquid differing from the compound applied
onto the column (TLC data), and elution with a light petroꢀ
leum—Et2O mixture (98 : 2) afforded 59 mg of the starting
acetoxy ketone 11. According to spectral data, the lowꢀpolar
product represented known21 drimꢀ7,9(11)ꢀdiene (20) (the yield
with allowance for the recovered acetoxy ketone 11 was 99%).
IR, ν/cm–1: 821, 3103 (>C=C<H), 884 (>C=CH2), 1651 (conꢀ
jugated double bonds). 1H NMR, δ: 0.76 (s, 3 H, C(15)H3); 0.81
(s, 3 H, C(13)H3); 0.85 (s, 3 H, C(14)H3); 1.72 (s, 3 H,
C(12)H3); 4.72, 4.76 (both s, 1 H each, C(11)H2); 5.59 (br.s,
C(7)H). 13C NMR, δ: 19.06 (C(2)); 20.61 (C(15)); 21.11
(C(13)); 22.16 (C(12)); 24.29 (C(6)); 32.94 (C(14)); 33.37
(C(4)); 37.69 (C(1)); 37.78 (C(10)); 42.16 (C(3)); 48.64 (C(5));
103.75 (C(11)); 126.52 (C(7)); 131.19 (C(8)); 158.17 (C(9)).
B. Acetoxy ketone 11 (85 mg, 0.264 mmol) was subjected to
photolysis under conditions described above and the product
was refluxed with a solution of КOH (79 mg, 1.4 mmol) in
10 mL of ethanol for 3 h. Ethanol was evaporated in vacuo, the
residue was extracted with ether (10 mL), the extract was washed
with water (3×10 mL), dried with anhydrous Na2SO4, filtered,
and concentrated in vacuo. The reaction product consisting,
according to TLC, of a nonpolar compound and sclareol
oxide (12) was separated into two portions. The first portion
(20 mg) was chromatographed on a column with 4 g of SiO2.
The product was eluted with light petroleum, which gave 13 mg
of diene 20.
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The second portion of the hydrolysis product (45 mg) was
chromatographed on a column with 0.9 g of neutral Al2O3 (acꢀ
tivity III). Elution by light petroleum gave 18 mg (43.9%) of
drimꢀ9(11)ꢀenꢀ8αꢀol (3), m.p. 50—51 °C (from hexane),
23
[α]D +15.2 (c 0.45) (Ref. 4: m.p. 52—53 °C, [α]D +28.6
(c 0.28, CHCl3)). IR (film), ν/cm–1: 907, 1630, 3102 (>C=CH2),
1
1074, 3403 (band) (OH). H NMR, δ: 0.77 (s, 3 H, C(15)H3);
0.80 (s, 3 H, C(13)H3); 1.02 (s, 3 H, C(14)H3); 1.34 (s, 3 H,
C(12)H3); 4.77, 5.15 (both s, 1 H each, C(11)H2). 13C NMR, δ:
19.06 (C(2)); 20.20 (C(6)); 21.63 (C(15)); 22.40 (C(14)); 30.52
(C(12)); 33.26 (C(13)); 33.80 (C(4)); 39.01 (C(1)); 40.03
(C(10)); 41.77 (C(3)); 44.20 (C(7)); 53.48 (C(5)); 73.38 (C(8));
103.66 (C(11)); 166.64 (C(9)). MS, m/z (Irel (%)): 222 [M]+
(4.5), 204 [M – H2O]+ (100), 189 [M – H2O – Me]+ (84), 161
[M – H2O – Me – C2H4]+ (30); ion peaks typical of the bicyclic
system of labdane diterpenoids were also present,23 m/z 135
(27), 133 (27), 119 (28), 109 (28), 108 (27), 95 (37), 43 (34).
Further elution with a mixture of light petroleum and Et2O
(99 : 1) gave 19 mg of sclareol oxide (12), which was identified
by comparison with an authentic sample.
The authors are grateful to G. Scognamiglio and
S. Zambardino (Institute of Biomolecular Chemistry,
Received April 22, 2003;
in revised form October 23, 2003