The 3-hydroxycineoles

Article abstract of DOI:10.1071/CH05144

Data concerning the 3-hydroxycineoles 1 and 2 are provided to enable the ready identification of these metabolites and to determine their enantiomeric excess in mixtures. An unusual S_N2-type inversion at a tertiary center is observed during one synthetic approach. CSIRO 2005.

Full text of DOI:10.1071/CH05144

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2005, 58, 785–791
The 3-Hydroxycineoles
Raymond M. Carman,A,C Ward T. Robinson,B and Craig J. WallisA
A Chemistry, University of Queensland, Brisbane QLD 4072, Australia.
B Department of Chemistry, University of Canterbury, Christchurch, New Zealand.
C Corresponding author. Email: carman@chemistry.uq.edu.au
Data concerning the 3-hydroxycineoles 1 and 2 are provided to enable the ready identification of these metabolites
and to determine their enantiomeric excess in mixtures. An unusual SN2-type inversion at a tertiary center is
observed during one synthetic approach.
Manuscript received: 20 June 2005.
Final version: 21 September 2005.
Introduction
Discussion and Results
The two 3-hydroxycineoles, the α-isomer 1 and the β-isomer
2, have been frequently reported[1–14] as metabolites of the
commonly occurring cineole 3, arising by either animal or
microbial ingestion or cell-culture biotransformation. Com-
pounds 1 and 2 have often been obtained in low yield and
reported only as gas chromatography peaks, sometimes of
unspecified stereochemistry. Recently, the compounds have
been tentatively identified in human urine.[15] Cineole 3 is
achiral, but alcohols 1 and 2 are chiral. Optical rotations of
isolated material, when recorded, vary considerably, and it
is clear that enzymatic metabolism of cineole 3 need not be
enantioselective. It seems likely in many systems that the
prime aim of metabolic hydroxylation is simply to water-
solubilize the somewhat toxic cineole in order to eliminate
it. However, in some animals such as possums and koalas,
where cineole may constitute a considerable portion of the
diet and where cineole metabolites are then major compo-
nents in the urine, the animal may also use these compounds
as pheromones. The advantages in using an enantiomeric
mixture, rather than the pure isomer, as a pheromone have
already been discussed.[16]
Since starting this synthetic project in 1990 we have
supplied samples of synthetic alcohols 1 and 2 to several
workers[11,12,14,15] to assist in their identifications. We now
report our syntheses in this area. To enable enantiomeric
excesses to be examined gas-chromatographically on a small
scale, we include both the racemic and enatiomerically pure
form, with detail of their chromatographic behavior on a
chiral column.
Syntheses in this area have recently been reported by
others,[17] but these workers have misnamed some of their
compounds (e.g. 3-ketocineole) and misdrawn others, mak-
ing their work very difficult to follow. Other syntheses in the
field are noted.[18–23]
Racemic alcohols 1 and 2 are readily available as shown in
Scheme 1. Chromic oxidation of cineole 3 affords racemic
3-ketocineole 4. Hydride reduction of the carbonyl group
from the less-hindered side yields the β-alcohol 2, while
reduction with aluminum isopropoxide under equilibrating
conditions provides predominately the more stable α-alcohol
1. Details of some of these steps are provided below.
The chiral alcohols 1 and 2 were synthesized by the route
shown in Scheme 2. α-Terpineol 5 of known chirality, with
N-bromosuccinimide in acetone, provides an equilibrating
mixtureofbromides6and 7 (∼4:1).Treatmentofthismixture
with potassium tert-butoxide affords the mixture of olefins 8,
9, and 10 (∼60:20:10). While these olefins can be separated
by chromatography, in most runs the reaction sequence was
O
O
OH
H
3
3
H
OH
1
2
9
10
8
O
O
O
OH
HϪ
4
CrO3
O
3
1
5
2
HOAc
H
6
7
3
4
2
(PriO-)3Al
O
H
OH
1
Scheme 1.
© CSIRO 2005
10.1071/CH05144
0004-9425/05/110785

786
R. M. Carman, W. T. Robinson, and C. J. Wallis
O
O
O
NBS
H
H
OH
H
Br
Br
H
Br
5
6
7
ButOK
O
O
O
O
O
H
ϩ
ϩ
B2H6
ϩ
H
H2O2
Hg(OCOCF3)2
OH
H
H
OH
11
1
8
9
10
Scheme 2.
by others.[17,23] Since there appears to be good evidence
that this oxidant acts via a radical mechanism,[24–27] where
tertiary hydrogen atoms are abstracted very much faster
than secondary than primary atoms, we suggest the mech-
anism depicted in Scheme 4, although the exact nature of
the complex involved in the hydrogen atom transfer is not
known. In support of this mechanism, we now find that
4-hydroxycineole 14,[28] with no tertiary hydrogen atom,
is completely stable under comparable oxidative conditions.
The equilibrium in Scheme 4 involving the hydrogen migra-
tion is driven in the forward direction by removal of the
right-hand product through further oxidation.
8
2
O
O
O
H
H
Peracid
LiAlH4
H
160Њ
OH
O
8
12
1
ϩ
O
O
H
3
1
2
H
OH
H
H
H
H
OH
13
Scheme 3.
As reported by Catalan,[20] we also obtained over-oxidized
material from the oxidation of cineole 3, including up to 10%
of the symmetrical 3,5-diketone 15.
taken a step or two further when the resultant alcohols can be
more readily separated. Diborane treatment of compound 8
provides chiral alcohol 1 together with the 2-hydroxycineole
11(∼3:1;withtracesofα-terpineol 5[18]). Olefin 8isresistant
to mercuric acetate,[18] but treatment with mercuric trifluoro-
acetate gives the required alcohol 1 as major product.Alcohol
1 can then be oxidized to the ketone 4 and reduced with
hydride to provide the other required chiral alcohol 2. Alter-
natively, olefin 8 can be epoxidized with 100% attack from
the less-hindered side of the double bond to afford epox-
ide 12 (Scheme 3). This epoxide is considerably hindered
to hydride attack at either C2 or C3. However, lithium alu-
minum hydride at 160◦C provides alcohol 1 together with the
rearranged alcohol 13 (see below).
Thebehaviorofcompounds1, 2, and 4onachiralgaschro-
matography column is listed in the Experimental section, and
allows determination of the chirality and enantiomeric excess
of any given GC sample. The acetates of both alcohols 1 and
2 were prepared for comparison purposes as these derivatives
are also reported[10] to be naturally occurring. 13C NMR data
are provided in Table 1.
Hydride Reduction of Epoxide 12
The highly hindered approach of hydride to the top (β) face of
epoxide 12, protected at C3 by the methyl group on C8 and at
C2 by the electrons of the cineole ether oxygen, requires forc-
ing conditions[18] with lithium aluminum hydride in a bomb
at 160◦C. The major product is then the required alcohol 1.
The minor product was not the expected 2-hydroxycineole 11,
formed by hydride attack at C3 at the back of the epoxide,
but rather the novel rearranged alcohol 13, a 3-hydroxypinol.
Compound 13 provided consistent NMR spectra. H3 is a
dd, with almost identical couplings to H2 and H4 consistent
with the similar H2–C2–C3–H3 and H3–C3–C4–H4 torsion
angles. Rather surprisingly, H2 is a sharp doublet, coupled
only to H3 and not to H1, with which it makes a torsion
angle approaching ∼70◦. The key element in the H spec-
1
trum is the C1-Me, which appears as a doublet (J 6.7 Hz)
requiring the presence of the C1 proton. The secondary alco-
hol 13 could be oxidized to the corresponding ketone 16,
whichonhydridereductionregeneratedalcohol13.Thestruc-
ture 13 was confirmed by X-ray crystallographic analysis
(Fig. 1).
Interesting aspects of these reactions are now discussed.
Oxidation of Cineole 3 to Ketone 4
The mechanism required for the formation of the rear-
ranged alcohol 13 is intriguing. A suggested pathway is
provided in Scheme 5. This involves a rare[29,30] example
The remote oxidation of cineole 3 by using chromyl acetate
was first discussed by Catalan[19,20] and subsequently used

The 3-Hydroxycineoles
787
Table 1. 13C chemical shifts
CDCl3 solution, cineole carbon numbering throughout
Compound
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
1
70.9
70.5
70.1
72.7
69.1
73.5A
73.0
68.7
71.0
138.5
150.5
72.7
74.1
18.9
75.9
77.6
59.2
61.4
72.3
42.9
40.0
43.2
40.1
31.7
49.0
52.3
83.0
135.3A
76.6
80.6
71.0
52.3A
80.9
49.4
77.3
79.1
80.9
82.6A
65.3
69.3
70.8
69.9
23.0
213.0
37.0
36.7
135.1A
30.3
40.4
37.1
40.7
37.3
33.1
51.8
34.6
41.0
39.4
41.8
42.5
34.3
36.4
45.1
74.4
44.7
41.1
41.6
41.3
13.9
14.8
21.4
20.9
23.0
18.2
21.7
24.3
20.3
34.5
27.2A
22.2
17.4
19.4
202.5
17.1
30.7
26.2A
24.3
31.0
30.8
30.1
30.0
31.7
30.3
26.0
36.7
31.2
120.1
27.0A
25.0
30.2
26.0
49.4
32.6
57.6
36.5
33.1
27.1
26.9
26.8
26.6
27.4
26.8
26.0
32.9
24.6
21.3A
105.2
24.1
25.2
23.9
25.2
32.6
18.8
52.0
28.7
73.2
73.2
73.4
73.0
73.0
73.5A
74.1
83.5
74.2
82.7
82.1
73.5
72.7
80.2
73.9
80.6
81.8
82.7
82.4A
28.3
28.4
30.4
30.0
28.8
30.5
28.1A
29.9
28.9B
30.4
30.4
28.6
28.5B
30.9
29.1
30.7
30.0
30.2
33.1
28.9
28.7
30.7
30.3
28.8
26.2
28.7A
22.5
28.8B
25.3A
23.0
29.0
28.9B
28.2
29.1
28.7
25.8
22.8
23.4
1-Acetate
2
2-Acetate
3
4
6
7
8
9
10
11
12
13
15
17
18
19
20
38.7
34.7
52.1A
71.1
202.5
73.3
27.6
25.5A
31.9
A,B Values within a row may be reversed.
H
O
H
O
CrV
C •
O
H• migration
Cr(OAc)2O2
Ac2O/AcOH
H
C•CrV
3
O
O
O
O
O
Cr
O
Hϩ
ϩ
ϩ
AcO-CrO2
OAc
4
H
OH
O
O
O
O
O
H
O
H
14
15
16
Scheme 4.
O
O
H
1
OϪ Liϩ
2
H
O
H
Li
AlH3
O
O
O
O
3
H
H
H
H
H
H
H
H
H
O
OH
OH
OH
H
O
H
17
18
19
20
Scheme 5.

788
R. M. Carman, W. T. Robinson, and C. J. Wallis
C11
more carbocation character. Compound 17 provided H3 in
the NMR spectrum as a dd, with couplings to H2 and H4
similar to those observed for compound 13.
C10
Epoxy-Pinols 18 and 19
C7
The formation of ‘pinol’ 9 and ‘isopinol’ 10 from a bromo-
cineole mixture has already been observed.[31] We have now
also epoxidized these two olefins 9 and 10 to form epoxides
18 and 19, respectively. In each case epoxidation occurred
from the under (α) side. While epoxide 18 is well known,[33]
epoxide 19 has not been previously reported. Both epoxides
are then opened with hydride to give the same known[32,34]
alcohol 20.
O6
C1
C2
C3
Experimental
C5
1H and 13C NMR spectra in CDCl3 solution at ambient temperature
were recorded upon a Jeol GX400 spectrometer. 13C assignments were
made using the DEPT pulse sequences. Gc analyses were performed
upon a BP5 capillary column with helium carrier gas and flame ion-
ization detection. Mass spectra were obtained upon a Hewlett Packard
MSD 5970 spectrometer using a GC inlet (BP5 column). Column
chromatography was performed over Kieselgel 60, 230–400 mesh.
C9
H8
C4
C8
H4
O12
H12
Ketone 4
In an adaptation of the method of Catalan[19,20] which we found to
often lead to spontaneous fires, chromium trioxide (96 g) was added
portionwise over 30 min to a mixture of acetic acid (200 mL) and
acetic anhydride (380 mL) kept at 0◦C. This mixture was then added
over 90 min to cineole 3 (10 g) in dichloromethane (300 mL) at 10◦C.
The mixture was allowed to warm to room temperature, and after 24 h
the green solution was poured onto ice (∼300 g) and neutralized with
sodium carbonate. The organic layer was decanted, washed with brine,
dried (MgSO4), and taken to dryness to give a mobile oil compris-
ing cineole 3 (15%), 3-ketocineole 4 (56%), and 3,5-diketocineole
15 (13%). Chromatography (30% ether in hexane) provided the three
separated compounds in the above order.
(1RS,4RS)-3-Ketocineole 4 was a colorless oil (Found: C 71.3, H 9.5.
Calc. for C10H16O2: C 71.4, H 9.6%). δH 2.31 (dd, H2β), 2.18 (d, H2α),
2.16 (ddt, H5β), 2.09 (dd, H4), 1.80 (dddd, H6β), 1.68 (dddd, H5α),
1.55 (ddd, H6α), 1.24, 1.16, 1.07 (s, 3× Me), with J2α,2β −18.8, J2β,6β
3.0, J4,5α 1.9, J4,5β 3.3, J5α,5β −13.5, J5α,6α 11.5, J5α,6β 6, J5β,6α 3.3,
J5β,6β 10.8, J6α,6β −13.5 Hz, consistent with the literature[20] but show-
ing considerably more dispersion. δC see Table 1. m/z consistent with
the literature.[20] νmax/cm−1 1733.
Fig. 1. The X-ray structure of alcohol 13 (crystallographer’s
numbering).
of SN2 type attack at a tertiary center, involving inversion
of stereochemistry at C1. In this instance there are several
factors favouring this unusual and high-energy mechanism.
(a) Alternative pathways are unfavorable due to the steric
and electronic hindrance described above. (b) The conditions
are extreme and excess hydride was employed. (c) Hydride
is a very small nucleophile, and it is normally the size of
the nucleophile which debars SN2 attack at tertiary cen-
ters. (d) The cineole ether oxygen is known[31,32] to be an
excellent participant in the displacement of α-C2 leaving
groups. (e)The possibility of a six-membered transition state,
with lithium attracted to the epoxide oxygen as shown in
Scheme 5, which will deliver hydride to the appropriate
site.
While the pathway in Scheme 5 is drawn as concerted, it
is possible that there has been prior approach of the ether
oxygen toward C2, assisted by the presence of lithium ion
on the epoxide oxygen and by the high temperature involved.
This trend toward a three-membered oxirane ring (O,C1,C2)
will both increase the carbocation nature of C1 and open up
the angle at the back of C1, allowing more facile approach of
hydride.∗
3,5-Diketocineole 15 (Found: C 65.9, H 7.7. Calc. for C10H14O3: C
65.9, H 7.7%). mp, δH, νmax, and m/z consistent with the literature.[20]
δC see Table 1.
4-Hydroxycineole 14[28] when oxidized under the same chromic
conditions provided only recovered starting material in ∼95% yield.
Hydride Reduction of Ketone 4
Sodium borohydride (0.4 g) was added to a stirred solution of racemic
ketone 4 (0.5 g) in methanol (20 mL). After 2 h the mixture was diluted
with ether (50 mL), washed with hydrochloric acid (5%, 20 mL) and
water (20 mL), dried, and evaporated. Chromatography (30% ether in
hexane) gave racemic 3β-hydroxycineole 2 (400 mg). Reduction of
ketone 4 with lithium aluminum hydride afford the same product 2.
To provide a reference compound for the NMR examina-
tions of compound 13, epoxide 12 was treated with aqueous
acid to afford the diol 17. The mechanism for the formation
of compound 17 is similar to that shown in Scheme 5, except
that now the nucleophile is water, the epoxide is protonated
for more-facile opening, and the transition state has much
(1RS,3RS,4SR)-3-Hydroxycineole
2
{(1RS,4SR,5RS)-1,3,3-
trimethyl-2-oxabicyclo[2.2.2]octan-5-ol} was an oil (lit.[1,17] oil, lit.[20]
mp 40◦C) (Found: C 70.4, H 10.7. Calc. for C10H18O2: C 70.5, H
10.7). δH 4.10 (ddd, H3α), 2.02 (dd, H2α), 1.99 (m, H5β), 1.65 (ddd,
H2β), 1.52 (2H, m), 1.39 (3H, s, H9), 1.33 (2H, m), 1.20 (3H, s, H10),
1.07 (3H, s, H7), with J2α,2β −13.8, J2α,3α 10.3, J2β,3α 6.1, J2β,6β 3.2,
J3α,4 2.1 Hz, consistent with the literature[20] but showing considerably
∗ We thank a referee for discussion on this point.

The 3-Hydroxycineoles
789
more dispersion. δC see Table 1. m/z consistent with the literature.[20]
νmax/cm−1 3422, 1458, 1363.
9, and isopinol 10 (67:19:7 by GC). Repeated flash chromatography
(3% diethyl ether in hexane, poor resolution using 100:1 ratio of silica
to sample) gave dehydrocineole 8, followed by pinol 9 and isopinol 10.
(1S,4R)-Dehydrocineole 8 {(1S,4R)-1,3,3-trimethyl-2-oxabicyclo
[2.2.2]oct-5-ene} was a colorless minty-smelling oil (Found: C 78.8,
H 10.5. C10H16O requires C 78.9, H 10.5%). δH 6.40 (dd, H3), 6.04 (dd,
H2), 2.23 (dddd, H4), 1.97 (dddd, H5β), 1.68 (ddd, H6β), 1.28 (s, Me7),
1.22 (s, Me10), 1.20 (ddd, H6α),1.15 (dddd, H5α), 0.93 (s, Me9); with
J2,3 8, J2,4 1.0, J3,4 6.5, J4,5α 4.5, J4,5β 2.5, J5α,5β −10, J5α,6α 7, J5α,6β
3.5, J5β,6α 4, J5β,6β 9.5, J6α,6β −11.5 Hz; consistent with the literature
but now with better resolution. δC see Table 1. m/z 152 (M+, 4), 137
(M-CH3, 1), 124 (13), 109 (100), 94 (121), 79 (45), 77 (14), 43 (48),
41 (15), 39 (22). νmax/cm−1 3045, 2967, 2928, 2853, 1456, 1375, 1367,
1360, 1308. This compound is naturally occurring.[35,36]
Pinol9{(1S,4R)-2,6,6-trimethyl-7-oxabicyclo[3.2.1]oct-2-ene}was
a colorless minty-smelling oil. δH consistent with the lit.[37] δC see
Table 1. m/z 152 (M+, 12), 137 (M-CH3, 25), 95 (10), 94 (35), 93 (56),
91 (18), 81 (10), 79 (100), 77 (25), 69 (9), 67 (10), 53 (12), 51 (11), 45
(17), 43 (87), 41 (32), 39 (35).
Isopinol 10 {(1S,4R)-2,6,6-trimethyl-7-oxabicyclo[3.2.1]oct-2(8)-
ene} was a colorless ‘fruity’-smelling oil. δH 4.57 and 4.49 (2× br
s, C=CH2), 4.41 (d, H2 with J2,3α 6.4, J2,3β ∼0 Hz), 1.36 and 1.18
(2× s, Me). δC see Table 1. m/z 152 (M+, not observed), 138 (5), 137
(M-CH3, 51), 109 (12), 95 (9), 94 (31), 93 (54), 91 (16), 79 (84), 77
(20), 67 (12), 55 (16), 53 (13), 43 (100), 41 (33), 39 (32). νmax/cm−1
3070, 2966, 2929, 2864, 1457, 1379, 1364, 1309.
The acetate of alcohol 2, racemic (1RS,3RS,4SR)-3-acetoxycineole,
was a mobile oil (Found: C 63.7, H 10.6. C12H20O3 requires C 63.8, H
10.7). δH 4.90 (ddd, H3α), 1.97 (3H, s, OAc), 1.28 and 1.16 (s, 2× 3H,
H9 and H10), 1.03 (3H, s, H7). δC see Table 1, with additional acetate
peaks at 170.2 and 21.1. m/z 212 (M+, 0.3), 197 (7), 137 (7), 109 (13), 93
(15), 83 (11), 55 (8), 43 (100), 41 (15), 39 (8). νmax/cm−1 (neat) 3440,
2925, 2850, 1738, 1646, 1463, 1455, 1365, 1242, 1089, 1036, 1023.
Racemic Alcohol 1
Aluminum isopropoxide was prepared from dry aluminum foil (2.75 g),
anhydrous isopropyl alcohol (30 mL) and mercuric chloride (0.05 g)
with carbon tetrachloride (three drops) at reflux. This mixture was then
diluted to 500 mL with dry isopropyl alcohol. Racemic 3-ketocineole
4 and aluminum isopropoxide (200 mL of the above mixture) were
distilled slowly until the acetone test on the distillate was weakly pos-
itive (2.5 h). Analysis (GC) showed compounds 1, 2, and 4 in the ratio
20:73:7. Heating was continued under total reflux for 150 h. The reac-
tion mixture was evaporated under vacuum, diluted with water (20 mL),
neutralized with hydrochloric acid (1%), and extracted with ether. The
organic extracts were dried (MgSO4), and evaporated to give a mixture
(2 g, 55:45) of alcohols 1 and 2. Repeated flash chromatography (30%
ether in hexane, poor resolution) gave pure racemic alcohol 1 followed
by racemic alcohol 2.
Racemic (1RS,3SR,4SR)-3-hydroxycineole
1 {(1RS,4SR,5SR)-
1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-5-ol} had mp 55◦C (hexane).
(lit.[1] 55–55.5◦C, lit.[20] oil) (Found: C 70.5, H 10.7. Calc. for
C10H18O2: C 70.5, H 10.7%). δH 4.43 (dddd, H3β), 2.09 (ddd, H2β),
2.02 (dddd, H5α), 1.75 (ddddd, H5β), 1.60 (dddd, H6β), 1.51 (ddd, H4),
1.47 (ddd, H6α), 1.28 (dd, H2α), 1.7 (s, OH), 1.27 and 1.19 (2× 3H,
s, H9 and H10), 1.04 (3H, s, H7), with J2α,2β −14.3, J2α,3β 2.8, J2β,3β
9.5, J2β,6β 3.3, J3β,4 3.6, J3β,5β 1.6, J4,5α 2.3, J4,5β 3.5, J5α,5β −13.6,
J5α,6α 11.8, J5α,6β 6.1, J5β,6α 3.5, J5β,6β 11.3, J6α,6β −13.3 Hz, consis-
tent with the literature[20] but showing considerably more dispersion.
δC see Table 1. m/z consistent with the literature.[20] νmax/cm−1 3417,
1462, 1376, 1363.
The acetate of alcohol 1, racemic (1RS,3SR,4SR)-3-acetoxycineole,
was an oil (Found: C 63.6, H 10.7. C12H20O3 requires C 63.8, H 10.7%).
δH 5.27 (ddd, H3β), 2.02 (3H, s, OAc), 1.24 and 1.23 (2× 3H, s, H9 and
H10), 1.03 (3H, s, H7). δC see Table 1, with additional acetate peaks at
170.7 and 21.3. m/z 212 (M+, 1), 197 (3), 137 (14), 109 (19), 93 (18),
83 (10), 55 (8), 43 (100), 41 (14), 39 (7).
Oxymercuration of Dehydrocineole 8
Mercuric trifluroacetate (2.1 g, 4.9 mmol) was added to a rapidly stirred
solution of dehydrocineole 8 (250 mg, 1.6 mmol) in tetrahydrofuran
(20 mL) in water (10 mL). The mixture was stirred for 24 h although the
reaction was essentially complete after 4 h (disappearance of starting
material by GC). Sodium hydroxide (10%, 5 mL) was added followed
by sodium borohydride (0.2 g, in 5 mL 10% NaOH). The solution was
diluted with tetrahydrofuran (50 mL) and salted out with solid sodium
chloride. The organic layer was decanted, washed with water and brine,
dried (MgSO4), and evaporated to give a gum (230 mg). Chromatogra-
phy (30% ether in hexane) gave initially 2α-hydroxycineole 11 followed
by 3α-hydroxycineole 1 {(1S,3R,4R)-3-hydroxycineole, (1S,4R,5R)-
1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-5-ol}, 150 mg, mp 68–69◦C
(lit.[3,5,18] 55–56◦, 68–69◦C), [α]D −18.5◦ (c, 2.5 in EtOH) (lit.[3,5,18]
−6, −19, +5.4◦ (for the enantiomer?)), with spectra identical to those
of the racemic compound 1.
The enantiomers of alcohol 1 did not separate cleanly on a β-
cyclodextrin GC column, and the alcohols were converted into their tri-
fluroacetates with trifluroacetic anhydride. The (1S,3R,4R)-enantiomer
1 was then the second enantiomer eluted when compared with the
two peaks available from the trifluroacetate of racemic 1 (baseline
resolution).
Reaction of α-Terpineol with N-Bromosuccinimide
N-Bromosuccinimide (50.85 g) was added to a stirred solution of
R-(+)-α-terpineol 5 (40 g) in dry acetone (350 mL) and stirring con-
tinued for 0.5 h. The mixture was evaporated to dryness, and the residue
taken into hexane (100 mL). Succinimide was filtered off, and the
organic solution was washed with brine (30 mL), dried over MgSO4,
and evaporated to give 55.8 g (93%) of a 83:17 mixture (by 13C
NMR) of 2α-bromocineole 6 {(1S,4R,6S)-6-bromo-1,3,3-trimethyl-2-
oxabicyclo[2.2.2]octane} and 1α-bromopinol 7 {(1R,2R,5R)-2-bromo-
2,6,6-trimethyl-7-oxabicyclo[3,2,1]octane}.
Hydroboration—Oxidation of Dehydrocineole 8
Dehydrocineole 8 (1 g) in anhydrous tetrahydrofuran (30 mL) was
treated with an excess of borane–methyl sulfide complex at 15◦C and
stirred at room temperature for 1 h. Excess hydride was decomposed
with water and the organoborane was oxidized with hydrogen peroxide
(30%, 4 mL) and sodium hydroxide (6 mol, 4 mL), with stirring (1 h) at
60◦C. The mixture was salted out with solid sodium chloride, extracted
with ether (100 mL), and the ether extracts were washed with brine.
Removal of solvent gave a viscous oil (1.1 g) comprising three compo-
nents, α-terpineol 5, 3α-hydroxycineole 1, and 2α-hydroxycineole 11 in
the ratio 10:65:25 (GC). Chromatography (30% diethyl ether in hexane,
poor resolution), gave initially α-terpineol 5, followed by impure 2α-
hydroxycineole 11, and finally impure 3α-hydroxycineole 1. Fractions
containing 3α-hydroxycineole 1 were recrystallized (hexane–ether) to
give pure compound with mp 68–69◦C.
2α-Bromocineole 6 had δC consistent with the literature,[31] with
peaks at 74.1 (C8), 73.0 (C1), and 52.3 (C2) valuable for integration
and characterization purposes.
1α-Bromopinol 7 had δC consistent with the literature,[32] with peaks
at 83.5 (C8), 83.0 (C2), and 68.7 (C1) valuable for integration and
characterization purposes.
This mixture 6 + 7 was used in the next step without purification.
Dehydrobromination of the Mixture 6 + 7
Bromide mixture 6 + 7 (48 g) in dimethyl sulfoxide (20 mL) was added
dropwise to potassium tert-butoxide (66 g) in dry dimethyl sulfoxide
(200 mL) and stirred for 1 h. Water (100 mL) was added, and the black
solution was extracted with hexane (2 × 100 mL). The organic extracts
were washed with water, brine, dried over MgSO4, and evaporated
to give 25 g (79%) of a mixture comprising dehydrocineole 8, pinol
Chiral Ketone 4
Alcohol 1 (850 mg), 3 Å sieves (2 g), and pyridium chlorochromate
(3.2 g) were stirred in dichloromethane (20 mL) for 2 h. Diethyl ether

790
R. M. Carman, W. T. Robinson, and C. J. Wallis
(50 mL) was added and the mixture stirred for 10 min. The solution
was filtered through celite, and evaporated. Flash chromatography
(20% diethyl ether in hexane) gave (1S,4S)-3-ketocineole 4 {(1S,4S)-
1,3,3-trimethyl-2-oxabicyclo[2.2.2]-octane-5-one}, 650 mg (78%) as a
colorless oil. Spectral data (NMR, IR, and m/z) were identical to that of
the racemate.
This (1S,4S)-enantiomer 4 was the second enantiomer eluted when
compared with the two peaks available when racemic 4 was passed
through a β-cyclodextrin GC column (baseline resolution).
δH (cineole numbering) 4.60 (dd appearing as a t, H3), 3.75 (sharp d,
H2), 1.90 (1H, m), 1.84 (1H, m), 1.75 (dt, H4), 1.49 (2H, m), 1.47 and
1.22 (2× s, Me9, and Me10), 1.27 (1H, m), 0.82 (d, J 6.9 Hz, Me7);
with J1,2 ∼0, J2,3 6.1, J3,4 5.8, J4,5α ∼ J4,5β 2.9 Hz. δC see Table 1. m/z
170 (M+, 0.6), 155 (73), 137 (11), 112 (19), 109 (12), 97 (21), 95 (16),
94 (12), 93 (45), 85 (41), 84 (12), 83 (13), 82 (12), 81 (29), 79 (19), 71
(13), 70 (13), 69 (25), 67 (18), 59 (16), 57 (23), 55 (28), 53 (12), 45
(11), 43 (100), 41 (61), 39 (26).
Small scale oxidation of this compound 13 (chromium trioxide in
acetone) gave a more volatile product (GC) with complete removal
of starting material. Reduction of this product (sodium borohydride)
regenerated compound 13 (GC and GC/MS).
Chiral Alcohol 2
Lithium aluminum hydride (50 mg) was added to a stirred solution of
(1S,4S)-3-ketocineole 4 (250 mg) in anhydrous ether. After 1 h, excess
hydride was decomposed by the cautious addition of MeOH (10 mL),
water (10 mL), followed by KOH (1 mol, 10 mL). The mixture was
filtered and the residue washed with ether. The filtrate was dried, evap-
orated (190 mg), and placed directly onto the top of a chromatography
column filled with silica. Flash chromatography (30% ether in hexane)
gave 3β-hydroxycineole 2 {(1S,3S,4R)-3-hydroxycineole, (1S,4R,5S)-
1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-5-ol} as transparent crystals,
mp 91◦C (lit.[17,18] 90–92◦), [α]D +50.0◦ (c, 2.5 in EtOH) (lit.[3,17,18]
2.8◦, 49.8◦, 50.5◦, −45.3◦ for the enantiomer) (Found: C 70.5, H 10.9.
Calc. for C10H18O2: C 70.5, H 10.7%). The spectral data (NMR, IR,
and m/z) were identical to that of the racemate.
It is possible that this compound 13 is the same compound as that
uncharacterized material previously reported[18] in ∼5% yield from the
hydride reduction of epoxide 12.
Diol 17
Epoxide 12 (100 mg) in acetone (5 mL), water (1 mL), and sulfuric acid
(15% aq, 2 mL) was stirred for 24 h. Ether extraction of this solution
gave (1R,2R,5R,8S)-2,6,6-trimethyl-7-oxabicyclo[3.2.1]octan-2,8-diol
17 {1α,3α-dihydroxypinol} as a gum (100 mg) which failed to crystallize
even after chromatography (Found: C 64.4, H 9.7. C10H18O3 requires
C 64.5, H 9.8%). δH (cineole numbering) 4.78 (t, H3), 3.61 (d, H2),
2.12 (dddd, H5α), 1.90 and 1.57 (2× m, H4, H5β, H6α, and H6β), 1.33
and 1.24 (2× s, Me9 and Me10), 1.18 (s, Me7); with J2,3 5.9, J3,4 ∼5.9,
J4,5α 2.9, J5α,6α 11.0, J5α,6β 5.2 Hz. δC see Table 1. m/z 186 (M+, not
observed), 111 (11), 110 (100), 97 (19), 95 (46), 69 (16), 55 (13), 43
(78), 41 (36), 39 (19). νmax/cm−1 3352, 2932, 1454, 1371, 1289, 1225,
1030, 964.
Reduction of ketone 4 (250 mg) with sodium borohydride afforded
the same alcohol 2 (200 mg crude yield).
The enantiomers of alcohol 2 did not separate cleanly on a
β-cyclodextrin GC column, and the alcohols were converted into
their trifluroacetates with trifluroacetic anhydride. The (1S,3S,4R)-
enantiomer 2 was then the second enantiomer eluted when compared
with the two peaks available from the trifluroacetate of racemic 2 (poor
resolution). If enantiomeric identification of alcohol 2 is required by
using a β-cyclodextrin column, it might be better to first oxidize alcohol
2 to ketone 4 when the separation of enantiomers is baseline (see above).
Epoxypinol 18
Pinol 9 (0.5 g) and m-chloroperbenzoic acid (1.25 g, 50%) were stirred
(3 h) in dichloromethane (20 mL).The solution was washed with sodium
hydroxide (5%), water and brine, and dried (MgSO4) to give epox-
ide (0.5 g, 91%). Flash chromatography (30% ether in hexane) gave
pure 1,6α-epoxypinol 18 {(1R,2R,3R,5R)-2,3-epoxy-2,6,6-trimethyl-7-
oxabicyclo[3.2.1]octane} as a colorless oil (lit.[34] oil) (Found: C 71.2,
H 9.5. C10H16O2 requires C 71.4, H 9.6%). δH 4.11 (d, H2), 2.83 (d,
H6) 1.96–1.75 (5H, m), 1.31 (s, Me7), 1.22 and 1.13 (2× s, Me9 and
Me10); with J2,3α 5 Hz, J2,3βα ∼0, J5α,6β 4.8 Hz, consistent with the
lit.[34,37] but with better dispersion. δC see Table 1. m/z 168 (M, not
observed), 153 (5), 109 (10), 97 (20), 95 (12), 82 (19), 71 (14), 69 (34),
67 (16), 55 (13), 43 (100), 41 (37), 39 (25). νmax/cm−1 2969, 2878, 1450,
1435, 1380, 1365, 1305, 1259, 1223, 1213, 1184, 1124, 1103, 1062,
967, 909.
Epoxide 12
(1S,4R)-Dehydrocineole 8 (10 g) and m-chloroperbenzoic acid (25 g,
50%) were stirred in dichloromethane (250 mL) for 24 h. The solution
was washed with NaOH (5%), water, and brine, and dried (MgSO4) to
give oily α-epoxide 12 (10.1 g, 90%). Flash chromatography (30% ether
in hexane) gave pure (1S,2S,3S,4R)-2-epoxycineole 12 {(1S,4R,5S,6S)-
5,6-epoxy-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane} as a colorless oil
(Found: C 71.3, H 9.5. C10H16O2 requires C 71.4, H 9.6%). δH 3.33 (t,
H3), 3.08 (d, H2), 1.86 (dt, H4), 1.63–1.42 (3H, m), 1.33–1.23 (1H, m),
ꢀ
1.17, 1.16 and 1.13 (3× s, Me); with J2,3 4.8, J3,4 4.7, J4,5 = J4,5 3.0 Hz,
consistent with the 60 MHz lit.[18] δC see Table 1. m/z 168 (M+, 2), 153
(M-CH3, 2), 150 (M-H2O, 6), 138 (10), 110 (17), 109 (13), 95 (41), 83
(11), 82 (22), 81 (19), 79 (11), 69 (10), 67 (12), 55 (13), 53 (12), 43
(100), 41 (31), 39 (28). νmax/cm−1 2971, 2928, 1458, 1376, 1364, 1244,
1226, 1179, 1164, 1156, 982, 934.
Epoxypinol 19
Isopinol 10 (0.5 g) and m-chloroperbenzoic acid (1.25 g, 50%) were
stirred in dichloromethane. Normal workup gave 0.5 g (91%) of
oily product. Flash chromatography (30% ether in hexane) gave
pure 1,7α-epoxypinol 19 {(1R,2S,5R)-2,9-epoxy-2,6,6-trimethyl-7-
oxabicyclo[3.2.1]octane} as a colorless oil (Found: C 71.3, H 9.6.
C10H16O2 requires C 71.4, H 9.6%). δH 3.59 (d, H2), 2.54 (ABq, H7
Reduction of Epoxide 12
Epoxycineole 12 (10 g) and lithium aluminum hydride (5.0 g) in dry
tetrahydrofuran (100 mL) were sealed in an autoclave tube and heated
(3 h, occasional shaking) to 165◦C. After cooling overnight, excess
hydride was decomposed with careful addition of methanol (20 mL) fol-
lowed by water (20 mL) and potassium hydroxide (1 mol, 20 mL). The
mixture was filtered, the organic phase separated, washed with brine,
dried (MgSO4), and evaporated to give 8.0 g (80%) of a mixture of two
alcohols (20:1). Flash chromatography (chloroform followed by 30%
diethyl ether in hexane) gave initially the minor product 3-hydroxypinol
13 followed by (1S,3S,4R)-3α-hydroxycineole 1. No reduction was
observed with lithium aluminum hydride in refluxing tetrahydrofu-
ran or 1,4-dioxan, or with lithium triethylborohydride in refluxing
tetrahydrofuran or toluene.
and H7ꢀ, with ꢀ7,7 0.08 ppm), 2.45 (dddd, H5β), 2.36 (m, H6β), 1.95
ꢀ
(dt, H4), 1.89 (m, H3β), 1.55 (2H, m, H5α and H6α), 1.38 and 1.18
(2× s, Me), 1.28 (dd, H3α); with J2,3α 6.7, J3α,3β −14.0, J3β,4 ∼ J4,5α
ꢀ
2.9, J4,5β 3.2, J5α,5β −13.8, J5β,6α 10.0, J5β,6β 4.7, J6β,7H 1.5 Hz, and
ꢀ
J7,7 4.7 Hz. δC see Table 1. m/z 168 (M, not observed), 153 (33), 110
(19), 109 (16), 95 (29), 93 (15), 83 (11), 81 (19), 80 (10), 79 (49), 77
(17), 69 (26), 67 (26), 55 (40), 53 (16), 43 (1000), 41 (60), 40 (14),
39 (37). νmax/cm−1 2936, 2867, 1460, 1382, 1366, 1295, 1208, 1137,
1107, 1076, 1019, 914, 890, 850.
Reduction of Epoxides 18 and 19
Lithium aluminum hydride (50 mg) was added to a stirred solution
of epoxide 18 (0.5 g) in anhydrous ether (50 mL). After 3 h excess
hydride was destroyed by careful addition of methanol (10 mL), fol-
lowed by water (10 mL) and KOH (1 mol, 10 mL). The solution
(1S,2S,5R,8S)-2,6,6-Trimethyl-7-oxabicyclo[3.2.1]octan-8-ol 13
(‘3-hydroxypinol’) was obtained as colorless needles, mp 102◦C (from
hexane) (Found: C 70.5, H 10.7. C10H18O2 requires C 70.5, H 10.7%).

The 3-Hydroxycineoles
791
was filtered and taken to dryness. Flash chromatography (20% ether
in hexane) gave 2α-hydroxypinol 20 {(1R,2R,4R)-2,6,6-trimethyl-7-
oxabicyclo[3.2.1]octan-2-ol} as transparent needles, mp 76◦C (lit.[34]
75–76◦). δH consistent with the lit.[34] δC see Table 1.
[10] K. Kubota, Y. Someya, R. Yoshida, A. Kobayashi, T. Morita,
H. Koshino, J. Agric. Food Chem. 1999, 47, 685. doi:10.1021/
JF9807465
[11] M. T. Fletcher, L. M. Lowe, W. Kitching, W. A. Konig, J. Chem.
Ecol. 2000, 26, 2275. doi:10.1023/A:1005518625764
[12] R. Boyle, S. McLean, N. W. Davies, Xenobiotica 2000, 30, 915.
doi:10.1080/004982500433336
The same product 20 was formed by similar reduction of epoxide 19.
Crystallographic Data for Alcohol 13
[13] Y. Someya, A. Kobayashi, K. Kubota, Biosci. Biotechnol.
Biochem. 2001, 65, 950. doi:10.1271/BBB.65.950
C
10H18O2: M 170.24, mp 102◦C, colorless needles, crystal dimen-
sions 0.82 mm × 0.30 mm × 0.30 mm, monoclinic, space group P21,
a 6.811(7), b 10.159(8), c 7.763(8) Å, β 98.753(14)◦, V 530.9(9) Å3,
Z 2, F(000) 188, Dc 1.065 g cm−3, linear absorption coefficient
0.072 mm−1, θ-range for data collection 2.65 to 25.00◦, index
ranges −7 ≤ h ≤ 8, −4 ≤ k ≤ 10, −9 ≤ l ≤ 9, data/restraints/parameters
941/1/113, goodness of fit on F2 1.03, final R indices [I > 2σ(I)] R1
0.0670, wR2 0.1841, R indices (all data) R1 0.0746, wR2 0.1695, largest
[14] I. A. Southwell, M. F. Russell, C. D. A. Maddox, G. S. Wheeler,
J. Chem. Ecol. 2003, 29, 83. doi:10.1023/A:1021976513603
[15] M. Duisken, personal communication, July 2004.
[16] R. M. Carman, Tetrahedron Asymmetry 1993, 4, 2327.
doi:10.1016/S0957-4166(00)80094-4
[17] F. A. Luzzio, D. Y. Duveau, Tetrahedron Asymmetry 2002, 13,
1173. doi:10.1016/S0957-4166(02)00313-0
difference peak and hole 0.439 and −0.366 e Å−3
.
[18] F. Bondavalli, P. Schenone, A. Ranise, S. Lanteri, J. Chem. Soc.
Perkin Trans. 1 1980, I, 2626. doi:10.1039/P19800002626
[19] M. V. de Martinez, F. G. de Venditti, I. J. S. de Fenik,
C. A. N. Catalan, An. Asoc. Quim. Argentina 1982, 70, 137.
[20] M. V. de Boggiatto, C. S. de Heluani, I. J. S. de Fenik,
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JO00384A023
[21] Y. Asakawa, R. Matsuda, M. Tori, Y. Hashimoto, Phytochemistry
1988, 27, 3861. doi:10.1016/0031-9422(88)83033-4
[22] J.A. S. Cavaleiro, G. M. S. F. C. Nascimento, M. G. P. M. S. Neves,
M. T. Pinto, A. J. D. Silvestre, M. G. H. Vicente, Tetrahedron Lett.
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doi:10.1039/JR9600000215
Intensity data were collected at 158(2) K on an Siemens P4 diffrac-
tometer, equipped with a Siemens SMART 1K charge-coupled device
(CCD) area detector using the program SMART ver 5.045 (Bruker AXS
1998) and a graphite monochromated MoKα radiation (λ 0.71073 Å).
Of the 2151 reflections obtained, 1261 were unique (Rint 0.1802). Pro-
cessing used Siemens XSCANS data collection, Siemens SHELXTL data
reduction, SiemensXSCANS cellrefinement, SHELXS-97 directmethod
structure solution, and SHELXL-97 structure refinement by full-matrix
least-squares on F2 hydrogen atoms were fixed in geometrically cal-
culated positions and treated as riding. All non-hydrogen atoms were
refined with anisotropic atomic displacement parameters. The atomic
nomenclature is defined in Fig. 1. Crystallographic data are deposited
with the Cambridge Crystallographic Data Base (CCDC Deposition
number 267911).
Acknowledgment
[26] Oxidation in Organic Chemistry PartA (Ed. B. K. Wilberg) 1965,
pp. 119 (Academic: New York, NY), and references therein.
[27] (a) G. Cianelli, G. Cardillo, in Chromium Oxidations in Organic
Chemistry 1984, p. 11 (Springer: New York, NY).
(b) F. A. Luzzio, in Organic Reactions (Ed. L. A. Paquette) 1998,
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We thank Tommy Karoli for early investigations into these
systems.
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