9,10-Dihydroxy-1,8-cineole (1,3,3-Trimethyl-2-oxabicyclo[2.2.2]octane-10,11-diol)

Article abstract of DOI:10.1071/CH01168

The title compound (3) has been synthesized and its presence sought in the urinary metabolites of the brushtail possum.

Full text of DOI:10.1071/CH01168

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Aust. J. Chem. 2001, 54, 769–776
9,10-Dihydroxy-1,8-cineole
(1,3,3-Trimethyl-2-oxabicyclo[2.2.2]octane-10,11-diol)
Raymond M. CarmanA,B and Paul N. HandleyA
A Department of Chemistry, The University of Queensland, Brisbane, Qld. 4072, Australia.
B Author to whom correspondence should be addressed (e-mail: carman@chemistry.uq.edu.au).
The title compound (3) has been synthesized and its presence sought in the urinary metabolites of the brushtail
possum.
Manuscript received: 2 November 2001.
Final version: 20 March 2002.
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Introduction
Discussion and Results
Previous work[1–7] on the metabolism of achiral 1,8-cineole
(1) by the brushtail possum (Trichosurus vulpecula:
Marsupialia) has provided a range of monohydroxylated 1,8-
cineoles as urinary metabolites. All CH bonds within the
cineole structure can be hydroxylated by the possum, with
the exception of the bridgehead C4, and 4-hydroxy-1,8-
cineole has not yet been observed as a natural product. Both
enantiomers of chiral products may be formed, and
pheromonal advantages of enantiomerically impure
compounds have been discussed.[8]
This biological oxidation appears to prefer the less hin-
dered positions in the molecule. In the urine, hydroxymethyl
primary alcohols, derived by oxidation at C7, C9 and C10,
normally predominate over secondary alcohols derived by
oxidation at C2, C3, C5 and C6. Further oxidation of the
primaryalcoholstoprovidecineolicacidsalsooccurs.[2–3,9–11]
A range of diols have also been isolated. Again, oxidation
by the possum is preferably at the methyl group, and the bis-
primary diol (2) (both enantiomers) is a major contributor[7]
to the diol fraction. The other possible bis-primary diol
structure (3) has not yet been observed. A large range of
overlapped peaks are available in the diol region of a gas–
chromatography mass spectrum (GCMS) chromatogram of
an extract of possum urine, but no conclusive evidence could
be found for the unknown structure (3). We therefore
determined to synthesize structure (3) and then to search for
its presence within possum urine.
Based upon our previous syntheses in the hydroxylated
cineole area,[2–7,12] the most attractive approach to structure
(3) appeared to be through ring closure of triol (4). However,
it was unclear how much steric hindrance the triol system
might provide towards ring closure. It was also unclear
whether the two primary hydroxy groups in structure (4)
would participate in ring-closure reactions, a possibility
which would require their protection before attempted ring
closure, thus leading to even greater steric impedance.
Various approaches were made towards the synthesis of
novel triol (4), but the most efficient method involved the
steps from limonene (5) as shown in Scheme 1. Compound
(3) has a plane of symmetry, but the convenient starting
source (5) is chiral, so all the compounds shown in Scheme
1 before the final one (3) are chiral.
Metallation of limonene, followed by reaction of the
anion with oxygen, and sulfite reduction of the resultant
peroxide afforded the allylic alcohol (6). The sequence was
low-yielding but highly reproducible, consistent with the
7
1
4
OH
OH
OH
HO
OH
8
O
(5)
(6)
O
(7)
(4)
HO
OH
HO
OH
O
SePh
(8)
(3)
Scheme 1
10.1071/CH01168
© CSIRO 2001
0004-9425/01/120769

770
R. M. Carman and P. N. Handley
likely to prove troublesome due to the highly reactive nature
of 2-bromocineoles[19] caused by the positioning of the ether
oxygen close to the back of the bromine leaving group, gave
the by-products discussed later.
OH
1
The H nuclear magnetic resonance (NMR) spectrum of
triol (4) showed evidence for extensive hydrogen bonding,
with the consequent restricted rotation of the hydroxymethyl
groups the probable cause of the chemical non-equivalence
of the protons on C9 and C10. Thus, it is unclear how much
electron density remains available on the C8 oxygen to attack
the C1 of an activated double-bond complex.
OH
(10)
(9)
(11)
In a model trial, α-terpineol (11) was treated with
phenylselenyl chloride. No ring-closed product was isolated,
and it is likely in this system that chloroselenation of the
double bond proceeded faster than intramolecular
selenoetherification.
O
N
HO
OH
O
O
Se
O
SePh
(13)
Br
(14)
We therefore turned to N-phenylselenophthalimide
(12),[20] which provides a source of the phenylselenyl cation
in the absence of an effectively participating nucleophile. In
a model reaction, α-terpineol (11) cleanly gave the stable
cineole phenyl selenide (13), whose stability clearly showed
that the phenylselenyl anion is a poorer leaving group than is
the bromide ion. The solvent employed for this reagent is
always quoted in the literature to be dichloromethane, but
triol (4) is insoluble in this solvent. However, a mixture
containing tetrahydrofuran allowed the selenoetherification
to proceed for triol (4), leading to compound (8). The
reaction can be followed by NMR spectroscopy, with loss of
the vinyl proton leading to formation of a peak at δ 3.5 due
to the C2 proton geminal to the selenium atom. The
regioselectivity of the reaction was good, with little
participation of the unprotected primary hydroxy groups.
Raney nickel cleavage of the C–Se bond is well
established,[21] and selenide (8) with Raney nickel in dry
ethanol provided the required diol (3). The product
crystallized readily from ether, giving aesthetically pleasing,
opalescent flakes, and providing completely consistent
spectroscopic data that confirmed the plane of symmetry in
the compound.
With authentic diol (3) in hand, preliminary attempts have
been made determine whether this compound is a natural
component of possum urine; thus far without success. Stored
extract[6] from a male possum showed no 9,10-dihydroxy-
cineole (3) by GCMS analysis. A female possum, after
ingestion of cineole (1), provided a spectrum of hydroxylated
cineoles in the neutral extract different from that of previous
possums examined.[1–7] No mono-ols were present, but large
amounts of the 2α,4-, 2α,9- and 2α,10-diols[4–6] were
identified by GCMS. This animal apparently has an enzyme
system capable of facile oxidation of mono-ols into diols.
However, again, no 9,10-dihydroxycineole was detected. The
urine from this animal was refluxed with alkali to hydrolyse
conjugate esters, and this treatment did provide several
monohydroxycineoles, with 9-hydroxycineole the major
product, but, again, no 9,10-dihydroxycineole (3) could be
detected.
(12)
literature.[13] A small amount of the isomeric perillyl alcohol
(9) was also isolated from this reaction, resulting from
abstraction of the second most acidic proton of limonene at
the C7 methyl. A further impurity, dimer (10), also a known
compound,[14]
was
readily
removed
by
flash
chromatography.
Direct dihydroxylation of the relevant double bond in
alcohol (6) would lead directly to triol (4), but osmium
tetraoxide is expected[15] to react with the more substituted
∆
1,2 double bond even in the presence of a directing hydroxy
group. Therefore the conversion of alcohol (6) into triol (4)
involved two steps. In vanadium-based Sharpless epoxida-
tions, the allylic hydroxyl group allows epoxidation ca. 103
faster than at an unactivated olefin.[16,17] Under these
conditions, the product from compound (6) was the epoxide
(7), in almost quantitative yield as a ca. 50 : 50 mixture of
two diastereomers. Since the new C8 stereogenic centre is
removed by subsequent hydrolysis, the use of asymmetric
epoxidation[18] is unwarranted in this instance.
Amberlite cation-exchange resin in the protonated form
provided slow conversion of epoxide (7) into triol (4). The
reaction was complete after several days and then simple
filtration allowed the recovery of triol (4) without the need
for alkaline washes and the consequential losses due to the
solubility of this compound (4) in water. The compound (4)
was normally gummy, with crystals obtained from solvents
at –18°C reverting to gums at room temperature, but on one
occasion slow crystallization from evaporating diethyl ether
of a freshly chromatographed sample provided beautiful
crystals with an acceptable elemental composition.
The cyclization of triol (4) into the required diol (3)
proved troublesome. In similar cases we have previously
used[1–7,12] the mercuric cation, the bromonium cation, or the
proton to ring-close C8 hydroxyls onto C1 to form the
cineole system. In this present case, the proton is unlikely to
be expedient due to the possibility of pinacol-type
rearrangements. The mercuric cation failed to give ring
closure, either by using mercuric acetate or mercuric
trifluoroacetate. The bromonium ion, which in any case was
This lack of detection of diol (3) in possum urine was
somewhat surprising, given the range of mono-ols and diols

9,10-Dihydroxy-1,8-cineole
771
previously isolated.[1–11] It remains possible that the diol (3)
is in fact formed in the animal but is then excreted as an
undetected derivative, or, alternatively, that it undergoes
facile further oxidation within the possum to provide a
hydroxy acid[11] or diacid, followed by further conceivable
metabolism from the malonic acid system. Further work with
larger numbers of animals is required.
thermodynamically less-stable, C11 diastereomer may be
present as a by-product in this mixture, but was not isolated.
The conversion of compound (4) into compound (15)
with electrophilic bromine requires three discrete steps: a
bromoetherification, acetonide formation, and bromination
of the acetonide methyl group, and the precise order for this
sequence is not known. However, we did observe the
following results. When the reaction was conducted with a
large (10 equiv.) excess of NBS, the crude mixture was
strongly lachrymatory, consistent with the presence of free
bromoacetone. However, a solution of NBS in acetone alone
showed no reaction (by NMR spectrocopy). Therefore,
bromination of acetone is not the first step. The literature
shows that acetonides may be rapidly (‘instantaneously’)
brominated through a ring-opened species.[22,23] Protection
of the diol as the acetonide may occur before or after the
bromocyclization. However, when the cyclization was
attempted with NBS in tetrahydrofuran, where no acetonides
could form, the reaction was slow with many products
present by TLC. Attempted cyclization with NBS in acetone
in the presence of a base to remove any acid catalyst required
for acetonide formation gave similar results. Thus, reversible
acetonide formation to give structure (16) is a likely first
step, and this may in fact assist the subsequent
bromocyclization by removing intramolecular hydrogen
bonding between hydroxy groups, so leaving the C8 hydroxy
group more available for nucleophilic attack upon the
bridged bromonium ion. Bromination of the acetonide (16)
can then occur rapidly to give compound (17) which cyclizes
[(17) → (18) → (15), Scheme 2].
Alternate Synthetic Approaches
During the attempts at ether ring closure discussed above,
triol (4) was treated with N-bromosuccinimide (NBS) in the
hope of producing structure (14). The reaction in acetone
solvent was fast, with much of the starting material
consumed after a few hours. Thin-layer chromatography
(TLC) analysis showed the presence of one major product
and several minor ones, as well as unreacted triol (4).
Increased amounts of reagent or prolonged reaction times
only increased the yields of the minor products. The major
compound decomposed somewhat during chromatography
and was isolated in low yield, but subsequent
recrystallization gave a stable solid. The product was clearly
not the anticipated structure (14), but rather showed the
incorporation of acetone and an additional bromine atom,
with only two methyls, with an unexpected bromomethyl
group and with no free hydroxyls. X-Ray crystallographic
analysis confirmed the structure (15) (Fig. 1) and allowed
assignment of stereochemistry to the acetonide carbon. We
note that structure (15) is the C11 diastereomer with the
bromomethyl equatorial to the 1,3-dioxan moiety. The other,
Br+
Br
11
O
O
O
H
O
OH
O
H
O
OH
H
O
OH
O
O
CH2Br
CH2Br
Br
(16)
(17)
(18)
(15)
Scheme 2
Compound (15), like 2α-bromocineole (19), is unstable in
polar solvents due to the facile participation of the cineole
ether oxygen in the SN1 cleavage of the C2–Br bond.[17,24]
This participation greatly hinders SN2 attack at the back of
the C2 bromine, and the model compound (19) was
completely unchanged [gas chromatography (GC) analysis]
after reflux with lithium aluminium hydride in
tetrahydrofuran, or after reflux (5 days) with Superhydride.
Attempts to remove the bromine atom from model
compound (19) with tri-n-butyltin hydride in ether provided
cineole (1) as the major product by GC analysis. However,
application of this procedure to dibromide (15) did not
proceed smoothly. The least polar TLC spot, which was
assumed to contain monoterpenoid acetonides, could not be
Fig. 1. Plot of dibromide (15) showing the atom labelling scheme.

772
R. M. Carman and P. N. Handley
separated from tin salts after normal workup[25] and
chromatographic procedures. Attempted hydrolysis of this
material with acetic acid gave, after extensive
chromatography, a very poor yield of an acetate (20),
presumably formed by attack of acetate on the protonated
acetonide. This route was abandoned due to poor yields, the
difficulties of removing residual tin, and the unstable nature
of compounds (15) and (19).
O
O
O
O
O
O
(26)
The halide (21; R = Br)[30] was prepared by Birch
reduction of p-methylanisole (27) (Scheme 5) followed by
reduction of the ketone (28) to alcohol (29). Conversion into
the homoallylic bromide (21) proved more difficult but could
be achieved without too much elimination to methylcyclo-
hexadiene by using home-made triphenylphosphine
dibromide with imidazole,[31] followed by non-aqueous
work-up. Unfortunately, we were then unable to find
conditions to couple the Grignard reagent from (21; R = Br
or I) with ketone (25). Only small amounts of Wurtz-type
dimer (30) could be isolated, along with unreacted ketone,
and it appeared that the Grignard reagent was undergoing
facile β-elimination to form methylcyclohexadiene.
CH2OCOCH3
HO
O
O
Br
(19)
Br
(20)
We have also investigated the synthesis of triol (4) from
the seven-carbon fragment (21) and the protected dihydroxy
acetone (22) (Scheme 3), where it was expected that a
Grignard or similar coupling would achieve the formation of
the C4–C8 bond of the product triol. The required alkyl
halide (21; R = Br, I) has been reported,[26] but no mention of
any corresponding organometallic compounds could be
found in the literature. The addition of a Grignard reagent to
a
protected dihydroxyacetone does have literature
precedence.[27]
OMe
(27)
O
OH
R
O
(28)
(29)
(21)
+
Scheme 5
P O
O P
OH
R
(21)
(22)
OH OH
(4)
P
= protecting group
(30)
Scheme 3
To avoid these difficulties with homoallylic Grignard
reagents, a brief attempt was made to synthesize triol (34), a
compound which we were confident[12] would also be
cyclizable to diol (3) (Scheme 6). Ketone (31)[32] was
reduced to the alcohol (32), converted into the bromide (33)
and, in a model reaction, the resultant organolithium reagent
was condensed with dry acetone to provide authentic
δ-terpineol (36). However, attempted condensation with
dioxanone (25) (ammonium chloride workup) gave a poor
yield of a mixture which could not be separated by flash
chromatogaphy but which appeared (by NMR analysis) to be
a mixture of the expected product (35) and its rearranged
acetonide (37). This sequence was discontinued due to the
poor yields.
Dihydroxyacetone, protected as the acetonide (25), was
synthesized from the readily available biochemical buffer
(23) by the method shown in Scheme 4. Compound (25) was
volatile and unstable even under refrigeration, and the
compound was always used immediately after purification
through a column of basic alumina, when no hydrated
species could be detected by infrared spectroscopy. One of
the products of the decomposition of compound (25) was the
crystalline dimer (26), a product previously known to both
sugar[28] and polymer[29] chemists.
HO
H2N
HO
H2N
O
MeO
OMe
NaIO4
Conclusion
H+
DMF
buffer
OH OH
(23)
O
O
O
O
The novel diol 9,10-dihydroxy-1,8-cineole (3), predicted to
be a urinary metabolite of the brushtail possum after
ingestion of cineole, has been synthesized in five steps from
limonene. Further work is required to explore the incidence
of this compound as a naturally occurring material.
(24)
Scheme 4
(25)

9,10-Dihydroxy-1,8-cineole
773
hexane) gave two compounds. First, (4R)-p-mentha-1,8(10)-dien-9-ol
(6) was obtained as a pale yellow oil (3.35 g, 32% based on n-
butyllithium) (Found: C, 79.1; H, 10.9. Calc. for C10H16O: C, 78.9; H,
10.6%). 1H NMR δ 1.48, dddd, J 5.6, ≈ 11.2, ≈ 11.2 and 12.7 Hz, H5ax;
1.63, br s, 3H, H7; 1.81, dddd, J ≈ 2.6, 4.8, 5.6 and 12.7 Hz, H5eq; 1.85–
1.98, m, 2H, H3ax and H6ax; 1.98–2.40, m, 3H, H4, H3eq and H6eq;
4.11, br s, 2H, H9; 4.88, m, J ≈ 1, 1, 1 and 1.3 Hz, H10a; 5.02, m, J ≈
1.5, 1.5 and 1.3 Hz, H10b; 5.38, br m, H2 (providing more data than the
literature).[14] 13C NMR spectrum consistent with the literature.[14]
Later fractions yielded perillyl alcohol (9) (0.3 g, 3% based on
n-butyllithium) contaminated with alcohol (6). 1H NMR δ 1.4–2.2, m,
7H; 1.72, br s, 3H, H10; 3.97, d, 2H, J ≈ 0.7 Hz, H7; 4.68–4.72, m, 2H,
H9; 5.67, m, H2. 13C NMR spectrum consistent with the literature.[33]
The method of Chastain[14] did not give an improved yield of
alcohol (6).
OH
(36)
O
OH
Br
(31)
(32)
(33)
+
OH
O
OH
O
O
O
(4R,8RS)-8,10-Epoxy-p-menth-1-en-9-ol (7)
Alcohol (6) (0.76 g, 5 mmol) and vanadyl acetoacetonate (5 mg) were
stirred in benzene (20 mL) to give a pale red solution. t-Butylhydro-
peroxide (70%, 0.96 g, 7.5 mmol) in benzene (20 mL) was dried briefly
(Na2CO3) before dropwise addition (20 min) to the alcohol solution.
The red colour darkened during the addition, then faded to brownish-
yellow. Stirring was continued (3 h), whereupon potassium hydroxide
(0.42 g, 7.5 mmol) in brine (20 mL) was added. The mixture was
extracted (ether) and the organic layer was washed with brine before
drying (MgSO4) and evaporation. Flash column chromatography (20%
ether/hexane) gave the (4R,8RS)-8,10-epoxy-p-menth-1-en-9-ols (7) as
a pale yellow oil (0.8 g, 95%) giving two very similar peaks (47 : 53)
upon GCMS analysis. Baseline resolution of the two peaks was not
achieved; the mass spectrometric data for the two compounds were very
similar. 1H NMR δ 1.14–1.25, m, 2H, two H5ax; 1.34–1.44, m, 2H, two
H5eq; 1.60, br s, 6H, H7; 1.7–2.1, m, 10H, four H3, two H4 and four
H6; 2.76, two overlapping d, 2H, two H10; 2.83, d, 1H, J 4.6 Hz, H10;
2.87, d, 1H, J 4.6 Hz, H10; 3.66, six lines, 2H, width 29 Hz, two H9;
3.81, two overlapping d, 2H, J ≈ 12, ≈ 12 Hz, two H9; 5.33, m, 2H, two
H2. 13C NMR δ 23.33, 23.37, two C7; 23.6, 25.1, two C5; 26.4, 27.8,
29.9, 30.1, two C3 and two C6; 35.4, 35.8, two C4; 47.9, 48.6, two C10;
61.0, 61.4, two C9; 61.9, 62.2, two C8; 119.6, 119.7, two C2; 133.9,
134.2, two C1. GCMS data for the first eluting isomer: m/z 132 (C10H12,
M – 2H2O, 20%), 122 (13), 120 (12), 119 (11), 117 (24), 109 (10), 107
(13), 105 (23), 95 (23), 94 (67), 93 (74), 92 (60), 91 (54), 79 (100), 77
(42), 67 (66), 55 (40), 53 (36), 41 (66), 39 (61).
(35)
(37)
(3)
OH
OH
OH
(34)
Scheme 6
Experimental
1H and 13C NMR spectra were recorded in CDCl3 solution, unless
otherwise indicated, upon a Bruker AV 400 spectrometer. 13C
multiplicities were assigned by the DEPT (distortionless enhancement
by polarization transfer) pulse sequence. GC analyses were performed
upon a capillary column (Alltech Econocap EC-5) with helium carrier
gas and flame ionization detection in a Varian 3300 instrument. Mass
spectra were recorded upon a Hewlett Packard MSD 5970 spectrometer
with a gas chromatographic inlet (Alltech Econocap EC-5 column),
with high-resolution mass spectrometric data from Kratos MS 25 RFA
or Finnigan 2001 spectrometers. Infrared (IR) data were measured by
using a Perkin Elmer 1600 FT-IR. Flash chromatography was
performed over Silica 60, using distilled solvents. HPLC (high-pressure
liquid chromatography) separations were run on Dynamax silica
columns with refractive index detection.
p-Menth-1-ene-8,9,10-triol (4)
Amberlite cation-exchange resin (5 g) in a chromatography column was
washed with sulfuric acid (5% aqueous, 150 mL) and then with water
until the washings were neutral. The resin was transferred to an
Erlenmeyer flask with the aid of distilled water (50 mL). The epoxides
(7) (2.5 g, 15 mmol) in tetrahydrofuran (THF) (50 mL) were added in
one portion, and the stoppered flask was stirred for three days whereupon
TLC analysis showed complete disappearance of the starting material.
The resin was removed by filtration, and the solution extracted with ethyl
acetate to provide a colourless oil. The oil crystallized from ethyl acetate/
hexane after prolonged storage at –20°C, and the resulting gummy solid
could be sublimed under high vacuum (80°C, 0.1 Torr) to give triol (4)
as a gummy solid (Found: C, 64.2; H, 9.6. C10H18O3 requires C, 64.5;
H, 9.7%). Alternatively, the crude product could be purified by column
chromatography (ether), where it spontaneously crystallized on one
occasion after slow evaporation of the solvent. Crystalline p-menth-1-
ene-8,9,10-triol (4) (1.75 g, 70%) gave needles, m.p. 76–79°C (ether)
(Found: C, 64.9; H, 10.1. C10H18O3 requires C, 64.5; H, 9.7%). 1H NMR
[(D6)acetone] δ 1.34, dddd, J 5.5, ≈ 11.8, ≈ 11.8, 12.3 Hz, H5ax; 1.59,
br s, 3H, H7; 1.76, dddd, J 2.2, 7.0, 9.4, 12.3 Hz, H5eq; 1.85–2.02, m,
5H, two H3, H4 and two H6; 3.52–3.62, m, 4H, two H9 and two H10;
5.34, m, H2. Further peaks were present in various samples, due to the
(4R)-p-Mentha-1,8(10)-dien-9-ol (6)
Butyllithium (15% in hexane, 32 mL, 0.075 mol) was stirred under
nitrogen during the dropwise addition of tetra-N-methylethylene-
diamine (11.25 mL, 8.77 g, 0.075 mol). Following the literature
procedure,[13] (+)-(R)-limonene (5) (25.0 mL, 21.0 g, 0.154 mol) was
added dropwise and the resultant solution became dark red
overnight. The solution was cooled (dry ice/acetonitrile bath), and a
stream of air (dried by passage through concentrated sulfuric acid) was
introduced below the surface. The temperature of the solution was kept
below –20°C by regulating the air flow. When the solution had
completely decolorized, the reaction was brought to room temperature,
and water (15 mL) was added followed by sodium sulfite (25%
aqueous, 70 mL). The mixture was extracted with ether, and the organic
layer washed (5% sulfuric acid containing 5% potassium iodide, then
5% sulfuric acid, then water), and dried (Na2SO4). GC analysis of the
resulting orange oil showed unreacted limonene (5), alcohol (6), perillyl
alcohol (9) and an unknown compound (22 : 10 : 1 : 3 by GC). Rapid
chromatographic separation (hexane to 20% ether/hexane) removed
non-polar compounds. Careful chromatography (silica; 20% ether/
presence of hydrogen-bonded hydroxyls and contaminating water. 13
C
NMR[(D6)acetone] δ23.5, C7; 23.8,C5;26.5and 31.6,C3and C6;38.3,
C4; 65.1 and 65.2, C9 and C10; 75.1, C8; 121.9, C2; 134.0, C1. GCMS:
m/z 168 (M – H2O, 17%), 155 (37), 150 (15), 137 (17), 132 (39), 120

774
R. M. Carman and P. N. Handley
(22), 119 (21), 117 (22), 109 (35), 107 (13), 96(11), 95(100), 94 (73),
93 (100), 92 (51), 91 (43), 87 (32), 81 (36), 79 (60), 77 (32), 61 (42), 55
(63), 53 (30), 43 (63), 41 (95), 39 (52).
77.1, C1 and C8. GCMS: m/z 156 (M – CH2O, 11%), 155 (100), 137
(13), 119 (13), 109 (37), 95 (68), 93 (38), 81 (23), 67 (41), 55 (47), 43
(63), 41 (40), 39 (26).
2-(Phenylseleno)-1,8-cineole (13)
2-Bromo-9,10-dihydroxy-1,8-cineole Bromoacetonide (15)
α-Terpineol (11) (10 mg, 65 µmol), N-(phenylseleno)phthalimide (12)
(20 mg, 66 mmol) and a crystal of p-toluenesulfonic acid were stirred
overnight in dichloromethane (2 mL). The resulting white suspension
was transferred with a pipette onto a small plug of silica, and the yellow
compound washed out with hexane. Further elution (10% ether in
hexane) gave 2-(phenylseleno)-1,8-cineole (13) as a pale yellow oil
(9 mg, 45%). 1H NMR δ 1.04, s, 3H, H7; 1.16 and 1.18, two s, 6H, H9
and H10; 1.40–1.62, m, 3H, H4 and H5α and H6β; 1.67, ddd, J 2.6, 5.9
and 14.5 Hz, H3α; 1.90–2.03, m, 2H, H5β and H6α; 2.56, dddd, J ≈ 3.6,
≈ 3.6, 10.8 and 14.5 Hz, H3β; 3.47, ddd, J 2.7, 5.9 and 10.8 Hz, H2;
7.19, m, 3H, and 7.49, m, 2H, phenyl group. 13C NMR δ 22.3, C5; 26.9,
C7; 27.8, C6; 28.5 and 28.9, C9 and C10; 34.0, C3; 34.5, C4; 45.7, C2;
73.8 and 74.0, C1 and C8; 127.2, 129.0 and 133.9, aromatic CH; 130.6,
quaternary aromatic C.
Triol (4) (0.6 g, 3.2 mmol) and NBS (0.6 g, 3.4 mmol) in acetone (5 mL)
were stirred (4 h) until most of the starting triol had disappeared (by
TLC). Evaporation of the solvent and flash column chromatography
(basic alumina; 10% ether/hexane) gave the major product as a white
solid which crystallized to give 2-bromo-9,10-dihydroxy-1,8-cineole
bromoacetonide (15) (50 mg, 2.7%) as colourless needles, m.p. 81°C
1
(10% ether/hexane). H NMR [(D6)benzene] δ 1.13, s, 3H, H7; 1.19,
dddd, J 2.4, 6.7, 11.6 and 14.1 Hz, H5α; 1.29, s, 3H, acetonide Me;
1.31, dddd, J 2.5, 6.8, 11.6 and 14.1 Hz, H6β; 1.51, m, H5β; 1.77,
obscured m, H4; 1.78, overlapped ddd, J 4.5, 2.9 and ≈15.9 Hz, H3α;
2.02, ddd, J 3.0, 11.5 and 14.1 Hz, H6α; 2.22, dddd, J 2.9, 4.4, 10.3 and
15.9 Hz, H3β; 3.13, s, 2H, CH2Br; 3.35, d, J 11.8 Hz, H9ax or H10ax;
3.41, dd, J 1.8 and 11.8 Hz, H9eq or H10eq; 3.45, d, J 11.8 Hz, H10ax
or H9ax; 3.60, ddd, J 2.4, 4.5 and 10.3 Hz, H2; 3.61, dd, J 1.72 and 11.8
Hz, H10eq or H9eq. 13C NMR [(D6)benzene] δ 18.0, C13; 20.6, C5;
25.7, C7; 27.2, C6; 28.1, C4; 35.7 and 37.0, C3 and C12; 51.8, C2;
66.4 and 66.8, C9 and C10; 71.6 and 73.3, C1 and C8; 97.5, C11.
GCMS: m/z 371 (M – Me, 8%), 369 (12), 367 (7), 291 (30), 289 (30),
234 (53), 232 (52), 218 (11), 216 (13), 153 (25), 151 (15), 149 (11), 137
(18), 109(19), 93 (49), 79 (23), 43 (100), 41 (30).
9,10-Dihydroxy-2-(phenylseleno)-1,8-cineole (8)
N-(Phenylseleno)phthalimide (12) (579 mg, 1.92 mmol) in
dichloromethane (5 mL) containing p-toluenesulfonic acid (2 mg) was
added to a solution of triol (4) (276 mg, 1.48 mmol) in THF (5 mL). The
reaction mixture was stirred overnight whereupon the solvent was
evaporated and replaced with ether (20 mL). The solution was washed
with sodium hydroxide solution (5%, 5 mL) and the solvent evaporated
to provide a yellow oil. Flash column chromatography (50% ether/
hexane, then neat ether) gave 9,10-dihydroxy-2-(phenylseleno)-1,8-
cineole (8) as a pale yellow oil (200 mg, 40%). 1H NMR [(D6)acetone]
δ 1.01, sharp s, 3H, H7; 1.46–1.69, m, 3H, H4, H5α and H6β; 1.69, ddd,
J2.5,6.2,14.5Hz,H3α;1.96–2.14,m,H5βandH6α;2.68,dddd,J ≈ 3.4,
≈ 3.4, 10.8, 14.5 Hz, H3β; ca. 3.6, obscured, H2β; 3.61, ABq, JAB –10.9
Hz, ∆AB 19 Hz, two H9 or two H10; 3.62, ABq, JAB –10.8 Hz, ∆AB 18
Hz; two H10 or two H9; 7.29, m, 3H, and 7.59, m, 2H, aromatic CH.
13C NMR [(D6)acetone] δ 22.6, C5; 26.9, C4; 27.7, C7; 29.3, C6; 34.4,
C3; 46.7, C2; 66.1 and 66.2, C9 and C10; 74.1 and 77.4, C1 and C8;
128.0 and 130.0 and 134.4, aromatic CH; 132.0, quaternary aromatic C.
Attempts to force the reaction to completion by the use of the
stoichiometric quantity of NBS and longer reaction times yielded many
more side products that interfered with the purification of compound
(15). Large excesses of NBS resulted in a crude mixture that was
strongly lachrymatory, consistent with the presence of free
bromoacetone.
Crystallographic Data for Compound (15) (with Ward T. Robinson)
C13H20Br2O3, M 384.11, m.p. 81°C (ether), colourless needles, crystal
dimensions 0.17 by 0.6 by 0.4 mm, orthorhombic, a 7.704(2), b
9.847(2), c 19.482(2) Å, V 1477.9(5) Å3, space group P212121, Z 4,
F(000) 768, Dc 1.726 g cm–3, absorption coefficient 5.483 mm–1,
θ-range for data collection 2.32–27.65°, index ranges –9 ≤ h ≤ 3, –11
≤ k ≤ 12, –25 ≤ l ≤ 25, data/restraints/parameters 3151/0/165, goodness
of fit on F2 0.995; final R indices [I > 2σ(I), n = 2841] R1 0.0460, wR2
0.1171; R indices (all data): R1 0.0522, ωR2 0.1212, largest difference
peak and hole 0.812 and –1.155 e Å–3.
X-Ray crystallographic data were collected at 168 K by using a
Siemens P4 difractometer, equipped with a CCD detector using the
program SMART (Version 5.045, Bruker AXS 1998) and graphite
monochromatized Mo Kα radiation (λ 0.71073 Å). Of the 7829
reflections obtained, 3151 were unique (Rint 0.0856). The structure was
solved by using direct methods with SHELXTL (Siemens) and refined
by full-matrix least squares with anisotropic refinement for all non-
hydrogen atoms. The absolute configuration was determined (Flack
parameter 0.04[2], Flack 1983). The structure and atomic labelling is
shown in Fig. 1. Bond lengths (Table 1) and angles (Table 2) are
Raney Nickel
Raney nickel was synthesized in an adaptation of the literature[34,35]
methods, which were modified to allow preparation on a small scale.
Nickel/aluminium powder [50% Ni, 50% Al (5 g)] was added
cautiously to NaOH solution (20%, 100 mL). The rate of addition was
controlled so that excessive foaming did not occur. The resulting hot
suspension was stirred for 4 h, and then a flow of distilled water was
introduced (20 min) at such a rate that the grains of catalyst were not
washed out of the flask. The water was decanted and the black powder
washed with ethanol (95%, 100 mL) and with dry ethanol (× 2,
100 mL). The active catalyst was transferred to a storage vial filled to
the brim with dry ethanol before sealing so that minimal amounts of
oxygen were present.
9,10-Dihydroxy-1,8-cineole (3)
Diol selenide (8) (50 mg) in dry ethanol (2 mL) was stirred overnight
with Raney nickel powder (200 mg). The mixture was filtered (Celite)
and the filtrate evaporated. Flash column chromatography (50% ether/
hexane) gave a white solid which was recrystallized (ether) to yield
9,10-dihydroxy-1,8-cineole (3) (18 mg, 64%) as opalescent flakes, m.p.
109–110°C (ether) (Found: C, 64.6; H, 10.0. C10H18O3 requires C, 64.5;
H, 9.7%). 1H NMR δ 1.05, s, 3H, H7; 1.48–2.01, m, 9H, two H2, two
H3, H4, two H5 and two H6; 1.76, br, 2H, CH2OH; 3.65 and 3.75, ABq,
4H, J 10.9 Hz, two H9 and two H10. 1H NMR [(D6)acetone] δ 0.95, s,
3H, H7; 1.46–1.63, m, 6H, two H2, H3α, H5a and two H6; 1.90, dddd,
J 2.36, 2.36, 3.76, 3.76 Hz, H4; 1.96–2.06, m, 2H, H3β and H5β; 2.85,
br, CH2OH and water; 3.59, br s, 4H, two H9 and two H10. 13C NMR δ
22.4, C3 and C5; 25.5, C7; 27.1, C4; 32.2, C2 and C6; 65.8, C9 and
C10; 70.1 and 76.4, C1 and C8. 13C NMR [(D6)acetone] δ 23.0, C3 and
C5; 25.8, C7; 27.5, C4; 32.9, C2 and C6; 66.4, br, C9 and C10; 69.9 and
Table 1. Bond lengths for compound (15)
Atoms
Distance (Å)
Atoms
Distance (Å)
Br(2)–C(2)
O(2)–C(9)
O(3)–C(10)
O(6)–C(1)
C(1)–C(2)
C(1)–C(7)
C(3)–C(4)
C(4)–C(8)
C(8)–C(9)
1.951(5)
1.428(6)
1.424(6)
1.442(6)
1.542(8)
1.519(7)
1.533(7)
1.529(6)
1.525(7)
Br(12)–C(12)
O(2)–C(11)
O(3)–C(11)
O(6)–C(8)
C(1)–C(6)
C(2)–C(3)
C(4)–C(5)
C(5)–C(6)
C(8)–C(10)
C(11)–C(13)
1.940(5)
1.410(6)
1.406(6)
1.456(5)
1.523(8)
1.533(7)
1.522(8)
1.539(8)
1.515(7)
1.515(7)
C(11)–C(12) 1.518(7)

9,10-Dihydroxy-1,8-cineole
775
2,2-dimethoxypropane and p-toluenesulfonic acid by the literature
method.[36] Distillation onto a cold finger (bath 85°C, 0.1 Torr) gave
compound (24) as colourless crystals (3.98 g, 39%), m.p. 50°C (Found:
C, 52.3; H, 9.6; N, 8.7. Calc. for C7H15NO3: C, 52.2; H, 9.4; N, 8.7%).
1H and 13C NMR spectra were consistent with the literature.[37]
2,2-Dimethyl-1,3-dioxan-5-one (25) was prepared from compound
(24) with sodium periodate in potassium dihydrogen phosphate buffer
(0.1 M) by the literature[36] method. The pale yellow oil (25) (92%) had
1H and 13C NMR data consistent with the literature.[37] GCMS m/z 115
(M – Me, 17%), 100 (11), 72 (30), 43 (95), 42 (100), 41 (24). IR
(dichloromethane): νmax1752, 1237, 1218, 1093 cm–1 (no OH bands
due to hydrated species present).
Table 2. Bond angles (degrees) for compound (15)
Atoms
Angle
Atoms
Angle
C(11)–O(2)–C(9)
C(1)–O(6)–C(8)
O(6)–C(1)–C(7)
O(6)–C(1)–C(2)
C(7)–C(1)–C(2)
C(3)–C(2)–Br(2)
C(4)–C(3)–C(2)
C(8)–C(4)–C(5)
C(4)–C(5)–C(6)
O(6)–C(8)–C(10)
C(10)–C(8)–C(4)
C(10)–C(8)–C(9)
O(2)–C(9)–C(8)
O(2)–C(11)–O(3)
O(3)–C(11)–C(13)
O(3)–C(11)–C(12)
114.1(4)
115.2(4)
105.2(4)
103.5(4)
114.5(5)
111.1(4)
107.3(4)
110.1(4)
108.3(4)
106.2(4)
113.2(4)
107.0(4)
110.3(4)
111.4(4)
110.9(4)
106.4(4)
C(11)–O(3)–C(10) 114.8(4)
O(6)–C(1)–C(6)
C(6)–C(1)–C(7)
C(6)–C(1)–C(2)
C(3)–C(2)–C(1)
C(1)–C(2)–Br(2)
C(8)–C(4)–C(3)
C(3)–C(4)–C(5)
C(1)–C(6)–C(5)
O(6)–C(8)–C(4)
O(6)–C(8)–C(9)
C(4)–C(8)–C(9)
O(3)–C(10)–C(8)
108.9(5)
114.5(5)
109.4(4)
111.5(4)
112.1(3)
109.5(4)
107.0(4)
111.6(4)
109.2(4)
106.8(4)
114.0(4)
110.2(4)
The product (25) was unstable, and was normally used in Grignard
or organolithium condensations immediately after preparation. When
the oil (25) (120 mg) wasstored (2 weeks, room temperature) itdeposited
a
solid. The material was triturated (ether/hexane, 50%) and
recrystallized (× 3, acetone/water) to give 2,2,10,10-tetramethyl-
1,3,6,9,11,13-hexaoxadispiro[4.2.4.2]tetradecane (26) as a white solid
(60 mg, 50%) (Found: m/z 260.1248. Calc. for C12H20O6: 260.1259). 1H
NMR data were consistent with the literature.[29] 13C NMR δ 26.3 and
26.7, four CH3; 65.4 and75.0, four CH2; 100.4, two acetonidequaternary
C; 112.1, two spiroketal C (similar to the literature spectrum[29] except
that assignments of the two lowest-field peaks are reversed in this work).
GCMS: m/z 245 (M – Me, 12%), 185 (13), 127 (44), 115 (16), 114 (35),
99 (22), 95 (14), 72 (21), 71 (47), 59 (17), 56 (17), 43 (100), 42 (33). IR
(Nujol mull): νmax 1373, 1197, 1061, 573 cm–1.
O(2)–C(11)–C(13) 112.9(5)
O(2)–C(11)–C(12) 105.9(4)
C(13)–C(11)–C(12) 108.9(4)
C(11)–C(12)–Br(12) 113.6(3)
provided. Atomic coordinates, displacement parameters and observed
and calculated structure factors have been deposited and are available,
upon request, until 31 December 2006, from Australian Journal of
Chemistry—an International Journal for Chemical Science, P.O. Box
1139, Collingwood, Vic. 3066, Australia (website: http://www.pub-
lish.csiro.au/journals/ajc/AccessMat.cfm).
Acknowledgments
We thank Ward T. Robinson for X-ray data, Nicholas Kanizaj
and Bernadine Flanagan for preliminary synthetic
explorations, and Margaret Brimble for helpful comment.
(8RS)-9-Acetoxy-10-hydroxy-1,8-cineole (20)
The crude products from triol (4) (0.87 g), after treatment with NBS
(1.7 g) as described above, were fractionated by column
chromatography (basic alumina; 10% ether/hexane). The fraction (ca.
200 mg) containing dibromide (15) was refluxed overnight with excess
tri-n-butyltin hydride in THF (20 mL). The reaction was quenched with
iodine in ether, and the solvent was evaporated. The solid residue was
triturated with ether, and tin salts were filtered off. The ethereal solution
was extracted with saturated sodium fluoride solution (× 5, 20 mL), and
again filtered to remove tin compounds. Repeated column
chromatography did not successfully remove all tin residues, and the
products were hydrolysed with 80% acetic acid (5 mL, overnight) to
give two new spots on TLC analysis. The mixture was neutralized with
solid sodium carbonate, and extracted with ether. Column
chromatography (50% ether/hexane) gave two fractions which still
precipitated small amounts of tin residues on standing, and which were
subjected to preparative HPLC purification (silica; 30% THF/hexane).
The more-polar fraction, which contained one compound by analytical
HPLC, decomposed on preparative-scale HPLC. The remaining less-
polar fraction contained three similar compounds by analytical HPLC,
of which only the major product could be resolved and isolated by
preparative HPLC. (8RS)-9-Acetoxy-10-hydroxy-1,8-cineole (20) (ca.
3 mg, 0.3%) was contaminated with an unknown impurity, giving
additional peaks upon NMR spectroscopic analysis. 1H NMR
[(D6)acetone] δ 0.97, sharp s, 3H, H7; 1.49–1.7, m; 1.75, m; 1.98, sharp
s, 3H, COCH3; 2.80 and 2.83, br s, hydroxyl and contaminating water;
3.46, br d, J 10.9 Hz, H10a; 3.64, br d, J 10.9 Hz, H10b; 4.02, d, J 10.9
Hz, H9a; 4.24, d, J 10.9 Hz, H9b. 13C NMR [(D6)acetone] δ 20.8,
acetate CH3; 23.0 and 23.1, C3 and C5; 26.6, C7; 27.4, C4; 32.5 and
32.6, C2 and C6; 64.2 and 64.3, C9 and C10; 70.1 and 76.9, C1 and C8;
170.9, acetate carbonyl.
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