Synthesis of naturally occurring diosphenols and hydroxydiosphenols

Article abstract of DOI:10.1081/SCC-120003623

Syntheses of diosphenol (3), ψ-diosphenol (4), 6-hydroxydiosphenol (5) and 6-hydroxy-ψ-diosphenol (6), which are constituents of the essential oil from Barosma betulina Bartl. (mountain buchu), are discussed.

Full text of DOI:10.1081/SCC-120003623

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SYNTHESIS OF NATURALLY OCCURRING DIOSPHENOLS
AND HYDROXYDIOSPHENOLS
a
a
David F. Schneider & Murray S. Viljoen
a
Department of Chemistry , University of Stellenbosch , Stellenbosch, 7600, South Africa
Published online: 16 Aug 2006.
To cite this article: David F. Schneider & Murray S. Viljoen (2002) SYNTHESIS OF NATURALLY OCCURRING DIOSPHENOLS AND
HYDROXYDIOSPHENOLS, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:8, 1285-1292, DOI: 10.1081/SCC-120003623
To link to this article: http://dx.doi.org/10.1081/SCC-120003623
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SYNTHETIC COMMUNICATIONS, 32(8), 1285–1292 (2002)
SYNTHESIS OF NATURALLY
OCCURRING DIOSPHENOLS AND
HYDROXYDIOSPHENOLS
David F. Schneider* and Murray S. Viljoen
Department of Chemistry, University of Stellenbosch,
Stellenbosch 7600, South Africa
ABSTRACT
Syntheses of diosphenol (3), c-diosphenol (4), 6-hydroxydios-
phenol (5) and 6-hydroxy-c-diosphenol (6), which are
constituents of the essential oil from Barosma betulina Bartl.
(
mountain buchu), are discussed.
In a recent contribution from our laboratory we communicated the
synthesis of the annulated 4-alkylidenebutenolides (1) and (2) by utilizing
the natural occurring diospenols (3) and (4), respectively, as starting
1
materials.
Steam distillation of the dried leaves of Barosma betulina Bartl.
mountain buchu), which is indigeneous to the Western Cape, affords
(
buchu oil in 1–2% yield which contained a 53 : 47 equilibrium mixture of
diosphenol (3) and c-diosphenol (4) as well as limonene, pulegone and
menthone as major constituents. Buchu oil, which is of substantial com-
mercial value, is utilized for the creation of a well-accepted black currant
2
*
Corresponding author.
1
285
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1
286
SCHNEIDER AND VILJOEN
flavour and is also highly valued in the fragrance industry due to its char-
3
acteristic and powerful, fresh odour. Its scarcity prompted Lamparsky and
3
co-workers to undertake a detailed compositional analysis of buchu oil in
order to identify the organoleptically significant constituents. These investi-
gations resulted in the identification of 123 components which largely
consisted of monoterpenes and included the hydroxydiosphenols (5) and (6).
Pure, crystalline diosphenol (3) can be separated from the essential oil
1
from B. betulina Bartl. by fractional crystallization, but no convenient
method for the isolation of pure c-diosphenol (4) in useful quantities from
natural sources appears to exist. Since c-diosphenol (4) was in high demand
for our synthetic program we decided to undertake a short investigation of
1
1
viable routes towards the synthesis of (4). We have previously demonstrated
that pure diosphenol (3) can be partially isomerized under weakly basic con-
1
ditions to yield a 55 : 45 equilibrium mixture of (3) and (4). Fractional crys-
tallization eventually produced an oily mixture of c-diosphenol (4) (86%)
and diosphenol (3) (14%) which could be used for the synthesis of the bute-
1
nolide (2). In an effort to eliminate these tedious separation procedures we
decided to investigate other more selective methods for the synthesis of (4).
4
Utaka and co-workers reported a procedure for the synthesis of c-diosphe-
nol (4) via the base-catalyzed bromination of menthone (7), but these authors
provided no convincing evidence regarding the purification and isolation of
crystalline c-diosphenol (4). In our synthesis of c-diosphenol (4) the method
4
of Utaka and co-workers was largely followed but was notably improved
in various aspects. Carefully controlled bromination of menthone (7) was

DIOSPHENOLS AND HYDROXYDIOSPHENOLS
1287
1
performed at low temperature to yield an intermediate, presumably a,a -
dibromomenthone (8), as an unstable, white solid. Immediate alkaline
4
hydrolysis, followed by separation on a chromatotron and fractional crystal-
lization, furnished pure c-diosphenol (4) in 63% crystallized yield
ꢀ
(
m.p. 34.5 C). Although the mother liquor comprised a 23 : 77 mixture of
diosphenol (3) and c-diosphenol (4) in a combined yield of 16%, no
additional (4) could be crystallized. The second eluate from the chromatodisc
afforded a small quantity of 6-hydroxydiosphenol (5), a known constituent of
3
buchu oil. Our findings differ significantly from those published by Utaka
4
and co-workers who isolated a semi-solid reaction product in 94% yield
ꢀ
(
b.p. 93–98 C/5 mm Hg), and also did not notice the presence of (3) and (5)

1
288
SCHNEIDER AND VILJOEN
as byproducts. The formation of (5) under the above reaction conditions can
be rationalized as the results of alkaline hydrolysis of the corresponding
tribromo compound (9) to afford the enol epoxide (12) via the bromodiketone
(10). Base-catalyzed opening of the epoxide ring of (12) may lead to the
formation of the natural product (5).
As a result of the successful synthesis of pure, crystalline c-diosphenol
4), it was accordingly anticipated that the formation of diosphenol (3)
(
could also be accomplished in an analogous fashion by utilizing carvo-
menthone (13) as starting material. Carefully controlled bromination of
(
13) followed by alkaline hydrolysis of the expected dibromoketone (14),
indeed produced diosphenol (3) in good yield after crystallization from
hexane. Scrutiny of the reaction mixture by tlc revealed the presence of
only traces of the expected 6-hydroxy-c-diosphenol (6), which was also
3
previously identified as a constituent of natural buchu oil. Formation of
(
6) under these reaction conditions can, in analogy to the formation
of the isomer (5), be rationalized as the result of alkaline hydrolysis of
the tribromoketone (15) followed by base-catalyzed rearrangement of the
intermediate enol epoxide (16).
Both the natural products (5) and (6) were structurally identified by
3
IR, NMR and MS data but no synthetic methods were reported in the
chemical literature. In order to provide some support to the suggested
mode of formation of 6-hydroxydiosphenol (5) during our synthesis of
c-diosphenol (4), and in the process also establish a viable laboratory

DIOSPHENOLS AND HYDROXYDIOSPHENOLS
1289
method for the synthesis of (5), the preparation of the intermediate enol
epoxide (12) and its subsequent conversion to (5) was next investigated.
5
–7
Inspired by the synthetic utility of dimethyl dioxirane as a versatile
oxidant, the epoxidation of the enolate of c-diosphenol (17) was attempted
to synthesize 6-hydroxydiosphenol (5) via the formation of the intermediate
enol epoxide (12) or its corresponding enolate (18). Rapid addition of a
THF solution of the sodium enolate of c-diosphenol (17) to an excess of
dimethyl dioxirane in acetone indeed produced the desired product (5) in an
isolated yield of 65%. Similar treatment of the enolate of diosphenol
(19) with an excess of dimethyl dioxirane gave 6-hydroxy-c-diosphenol (6)
via the intramolecular nucleophilic ring opening of the intermediate
epoxyenolate (20).
EXPERIMENTAL
All operations were standard practice performed in an argon atmos-
phere. NMR spectra were recorded in deuteriochloroform on a Varian VXR
300 instrument, while mass spectra were taken on a Varian MAT 311A
spectrometer. COSY, HETCOR and DEPT experiments were performed
to interpret more complex NMR spectra. Yields refer to isolated, recrys-
tallized compounds, the purity and structures of which were accurately

1
290
SCHNEIDER AND VILJOEN
established by NMR, mass spectral and gas chromatographical techniques.
Spectral and other physical data of reaction products are reported only in
those cases where useful data could not be found in the chemical literature.
4
Synthesis of c-Diosphenol (4) from Menthone (7) . Bromine (29.09 g,
81.8 mmol) was added dropwise during 8 h to a stirred solution of
1
3
ꢀ
menthone (7) (14 g, 90 mmol) in ether (30 cm ) at ꢁ10 C and stirring was
maintained for an additional 30 min at this temperature. The reaction mix-
ture was then consecutively washed with saturated, aqueous sodium chlor-
3
3
ide (50 cm ), saturated aqueous sodium hydrogen carbonate (2 ꢂ 40 cm )
3
and finally with saturated aqueous sodium chloride (40 cm ). The unstable,
semi-crystalline residue from the dried (MgSO ) organic phase in THF
4
3
30 cm ) was treated dropwise with 3.02 M aqueous sodium hydroxide
(
(
3
300 cm , 0.91 mole) during 1 h at 0 C and stirring was continued for an
ꢀ
ꢀ
additional 4 h at 0 C. Evaporation of about one half of the THF yielded a
light brown residual liquid which was neutralized to pH 7 by the addition of
3
conc. hydrochloric acid (37% m/m, 110 cm ) and extracted with ethyl acet-
3
ꢀ
ate (3 ꢂ 100 cm ). Evaporation of the dried (MgSO ) organic extract at 40 C
4
under reduced pressure furnished an oily, brown residue which was sepa-
rated on a chromatotron (4 mm chromatodisc, Merck silica gel 60 PF254
with calcium sulphate, activated at 120 C for 5 h) with petroleum ether–
ether (4 : 1) as eluent to yield two fractions: (a) a light yellow oil which was
ꢀ
crystallized from hexane to produce pure c-diosphenol (4) (9.54 g, 63%),
ꢀ
4
ꢀ
m.p. 34.5 C (lit. b.p. 93–98 C/5 mm Hg); d 1.04 (d, J 7.0 Hz, 3H), 1.07 (d,
H
J 6.9 Hz, 3H), 1.18 (d, J 6.8 Hz, 3H), 1.64 (dddd, J 13.1, 11.9, 8.9 and 6.3 Hz,
1
4
H), 2.04 (‘‘dq’’, J 13.3, 4.5 and 4.4 Hz, 1H), 2.27 (ddd, J 14.5, 8.9 and
.5 Hz, 1H), 2.28 (ddd, J 14.5, 6.3 and 4.4 Hz, 1H), 2.43 (dqd, J 11.8, 6.8
and 4.8 Hz, 1H), 3.14 (h, J 6.9 Hz, 1H), 6.14 (s, OH); dC 15.32 (q, CH3),
1
3
1
9.54 (q, CH ), 19.82 (q, CH ), 22.26 (t, CH ), 27.89 (d, CH), 30.76 (t, CH ),
3 3 2 2
þ
9.76 (d, CH), 138.41 (s, ¼C<), 141.71 (s, ¼C-OH), 197.63 (s, >C¼O); M ,
68.1151. Calcd. for C H O : M, 168.1150; (b) 6-hydroxy-diosphenol (5)
1
0
16
2
ꢀ
(
1.53 g, 9%), m.p. 83.6 C (from hexane/ether, 9 : 1); dH 0.75 (d, J 6.8 Hz,
3
1
1
1
H), 1.02 (d, J 6.8 Hz, 3H), 1.90 (dd, J 1.5 and 1.0 Hz, 3H), 1.94 (ddd, J 13.4,
0.8 and 5.3 Hz, 1H), 1.98 (h, J 6.8 Hz, 1H), 2.20–2.30 (m, 2H), 2.45 (dddq, J
9.1, 12.1, 4.9 and 1.6 Hz, 1H), 3.22 (s, OH), 5.79 (s, OH); d 16.02 (q, CH ),
C
3
6.88 (q, 2 ꢂ CH ), 27.32 (t, CH ), 30.60 (d, CH), 32.08 (t, CH ), 76.40 (s,
3
2
2
þ
>
184.1099. calcd for C H O : M, 184.1099.
C-OH), 131.25 (s, ¼C<), 141.45 (s, ¼C-OH), 197.88 (s, >C¼O); M ,
1
0
16
3
Synthesis of Diosphenol (3) from Carvomenthone (13). Bromine
15.12 g, 94.6 mmol) was added dropwise during 8 h to carvomenthone
(
(
3
ꢀ
13) (6.8 g, 44.16 mmol) in ether (25 cm ) at ꢁ10 C and stirring of the result-
ꢀ
ing solution was continued for an additional 40 min at ꢁ10 C. The reaction
mixture was then washed as in 1, the unstable, waxy residue from the dried

DIOSPHENOLS AND HYDROXYDIOSPHENOLS
1291
3
MgSO ) organic phase in THF (25 cm ) treated with 3.1 M aqueous sodium
(
hydroxide (194 cm , 0.6 mole) during 30 min at 0 C and the reaction mixture
4
3
ꢀ
ꢀ
stirred for an additional 3 h at 0 C. The reaction mixture was eventually
worked up as in 1 to yield a semi-crystalline residue which was recrystallized
1
ꢀ
1
from hexane to afford pure diosphenol (3) (5.3 g, 72%), m.p. 82.5 C (lit.
8
ꢀ
þ
1.7 C); M , 168.1151. Calcd for C H O : M, 168.1150.
10 16 2
6
-Hydroxydiosphenol (5). c-Diosphenol (4) (0.91 g, 5.4 mmol) in dry
3
THF (4 cm ) was added dropwise during 10 min to a stirred suspension of
3
oil-free sodium hydride (0.14 g, 5.83 mmol) in dry THF (4 cm ) at 0 C.
ꢀ
ꢀ
Stirring was continued for an additional 90 min at 0 C, after which the
ꢀ
resulting solution was cooled to ꢁ78 C and rapidly added to a preformed
8
solution of 0.073 M dimethyl dioxirane in acetone (81.7 cm , 5.94 mmol)
,9
3
ꢀ
at ꢁ78 C. Stirring of the reaction mixture was maintained at room temp. for
24 h, followed by the addition of a second batch of 0.073 M dimethyl diox-
irane in acetone (37.14 cm , 2.71 mmol) and continued stirring at room
3
ꢀ
temp. for another 11 h. Evaporation of the volatile material at 25 C under
vacuum (25 mm Hg) furnished a residue which was treated with water
3
3
(
(
10 cm ) and extracted with ether (3 ꢂ 15 cm ). The residue from the dried
MgSO ) ether extract was separated on a chromatotron as in 1 to yield
4
unreacted c-diosphenol (4) (0.08 g, 9%) as the first eluate and pure, crystal-
line 6-hydroxydiosphenol (5) (0.65 g, 65%) as the second eluate.
6
-Hydroxy-c-diosphenol (6). Diosphenol (3) (1.0 g, 5.95 mmol) in dry THF
3
(
5 cm ) was added dropwise during 5 min to a stirred suspension of oil-free
sodium hydride (0.16 g, 6.66 mmol) in THF (5 cm ) at 0 C. Stirring was contin-
ued for an additional 90 min at 0 C and 15 min at room temp., the resulting grey
3
ꢀ
ꢀ
ꢀ
enolate suspension was cooled to ꢁ78 C and rapidly added to 0.043 M dimethyl
8
,9
3
ꢀ
dioxirane in acetone
(166.5 cm , 7.14 mmol) at ꢁ78 C. The reaction
mixture was worked up and extracted as in 3 to afford an oily residue which
was crystallized from hexane to give white, crystalline 6-hydroxy-c-diosphenol
ꢀ
(
6) (0.71 g, 65%), m.p. 75.1 C; dH 1.06 (d, J 6.9 Hz, 3H), 1.09 (d, J 6.9 Hz, 3H),
1
3
3
1
7
1
.34 (s, 1H), 1.99 (ddd, J 13.0, 10.6 and 5.9 Hz, 1H), 2.09 (ddd, J 13.0, 7.8 and
.0 Hz, 1H), 2.30 (ddd, J 18.7, 10.6 and 4.8 Hz, 1H), 2.41 (ddd, J 18.6, 5.9 and
.1 Hz, 1H), 3.15 (h, J 6.9, 1H), 3.30 (s, OH), 5.88 (s, OH); d 19.53 (q, CH ),
C
3
9.65 (q, CH ), 20.77 (t, CH ), 24.32 (q, CH ), 28.08 (d, CH), 35.41 (t, CH ),
3
2
3
2
þ
2.57 (s, >C-OH), 139.82 (s, ¼C<), 140.53 (s, ¼C-OH), 197.94 (s, >C¼O); M ,
84.1099. Calcd for C H O : M, 184.1099.
1
0
16
3
ACKNOWLEDGMENTS
We thank the late Mr. H. S. C. Spies for the NMR spectra and many
helpful discussions and Ms. V. Truter for recording the mass spectra.

1
292
SCHNEIDER AND VILJOEN
Financial support by the University of Stellenbosch and technical assistance
by Mr. M. C. de Jongh and his staff is gratefully appreciated.
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961, 290.
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Received in the UK April 6, 2001