An improved synthesis of rhinocerotinoic acid

Article abstract of DOI:10.1016/S0040-4020(02)01481-3

The stereoselective synthesis of E-rhinocerotinoic acid has been achieved in five steps from (-)-sclareol in an overall yield of 32%. This constitutes a significant improvement on the previous synthesis of this anti-inflammatory compound.

Full text of DOI:10.1016/S0040-4020(02)01481-3

Tetrahedron 59 (2003) 165–173
An improved synthesis of rhinocerotinoic acid
*
Christopher A. Gray, Michael T. Davies-Coleman and Douglas E. A. Rivett
Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa
Received 13 September 2002; revised 21 October 2002; accepted 14 November 2002
Abstract—The stereoselective synthesis of E-rhinocerotinoic acid has been achieved in five steps from (2)-sclareol in an overall yield of
32%. This constitutes a significant improvement on the previous synthesis of this anti-inflammatory compound. q 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
1. Consequently, we decided to synthesize 1 from
commercially available (2)-sclareol (3) as briefly described
by Dekker et al.2 whereby 3 was first converted to methyl
13-hydroxy-7-oxolabda-8-en-15-oate (4) according to the
route described by Mangoni and co-workers in the synthesis
of grindelic acid (Scheme 1).3 Dehydration of 4 with
phosphorus oxychloride in pyridine followed by hydrolysis
in alkaline medium resulted in the formation of rhino-
cerotinoic acid and isorhinocerotinoic acid (5). Unfortu-
nately, this synthesis of 1 did not proceed smoothly in our
hands and we report here an improved version.
We required large quantities of rhinocerotinoic acid (1) as a
starting material for a projected synthesis of 6b,7a-
diacetoxylabda-8,13E-dien-15-ol (2) and its 6,7-dia-
stereomers. Compound 2 is a bioactive metabolite isolated
from the endemic South African intertidal marine mollusc,
Trimusculus costatus1 and we required more of this
compound, and its 6,7-diastereomers, for comparative
chemical ecology studies.
Rhinocerotinoic acid was originally obtained by Dekker
et al.2 from the South African medicinal plant Elytropappus
rhinocerotis (commonly known as renosterbos) and was
shown to have anti-inflammatory properties. Although this
plant grows abundantly around Grahamstown, we found
that local specimens of E. rhinocerotis did not contain any
2. Results and discussion
The degradative oxidation of 3 with potassium permanga-
nate to yield (þ)-8a-hydroxy-14,15-bisnorlabda-13-one (6)
Keywords: labdane; diterpene; rhinocerotinoic acid; synthesis.
*
Corresponding author. Tel.: þ27-46-603-8268; fax: þ27-46-622-5109; e-mail: m.davies-coleman@ru.ac.za
0040–4020/03/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01481-3

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C. A. Gray et al. / Tetrahedron 59 (2003) 165–173
Scheme 1. Mangoni et al.’s synthesis of grindelic acid via 4.3 Reagents and conditions: (a) KMnO4, acetone, ,158C; (b) I2, benzene, K, 3 h; (c) Zn,
BrCH2CO2Me, benzene–Et2O (5:2), K, 2 h; (d) CrO3, H2SO4, acetone, over-night, rt.
and the enol ether (þ)-8a,13-epoxy-14,15-bisnorlabda-12-
ene (7) was first reported by Ruzicka et al.4 Barltrop and
co-workers subsequently modified this procedure so that,
under controlled conditions, either 6 or the enol ether 7 may
be obtained as the major product of oxidation.5,6 The facile
conversion of 6 to 7 is well documented with significant
cyclization and dehydration occurring in light petroleum,5
benzene7 or pyridine8 solutions and quantitative conversion
occurring in the presence of trace acid,5 on silica gel9 or
through vacuum distillation.10
confirmed by subjecting it to the same dehydration
conditions. Similar yields of 8 (76%) and 9 (8%) were
obtained, indicating that in subsequent large-scale (5–7 g)
preparations of 8 the products obtained from the initial
permanganate oxidation step need not be separated before
continuing with the dehydration.
The iodine catalyzed dehydration procedure gave a better
yield of 8 than acid catalyzed dehydration.5 In accordance
with the observations of Wenkert et al.11 we found that
when dehydrated under acidic conditions, 6 gave a 71%
overall yield of 8 and 9 in a 3:2 ratio, and 7 gave a 67%
overall yield of 8 and 9 in a 2:1 ratio. Moreover, the
products of acid catalyzed dehydration were identical to
those obtained through iodine catalyzed dehydration,
contrary to the results reported by Mangoni and Belardini.12
With a reliable, gram scale preparation of the key
intermediate 8 in hand, we next turned our attention to the
formation of methyl 13-hydroxylabda-8-en-15-oate (10) by
Reformatsky reaction13 but, owing to the commercial
availability of ethyl bromoacetate, we instead prepared the
ethyl ester 11 in 93% yield as a 1:1 mixture (determined by
1H and 13C NMR spectroscopy) of inseparable C-13
epimers. Although the allylic oxidation of the methyl ester
10 to 4 using Jones’ reagent (Scheme 1) was reported to
proceed in 86% yield,3 we obtained a complex mixture of
products in low yield with the ethyl ester 11, presumably
because of competing allylic oxidation at C-11 and C-17.
However, when we applied the Chu and Coates modi-
fication14 of the Collins oxidation15 using 15 equiv. of
dipyridine–chromium trioxide, the desired a,b-unsaturated
ketone (12) was obtained in 80% yield.
Although both 6 and 7 may be converted to (þ)-14,15-
bisnorlabda-8-en-13-one (8) by treatment with mineral acid
in ethanol,5 this procedure has subsequently been found to
produce a mixture of the D7- and D8-unsaturated ketones.11
As the second step in our synthesis involved the iodine
catalyzed dehydration of 6, we were careful to optimize the
yield of this intermediate and avoid the formation of 7.
Accordingly, 3 was oxidized with potassium permanganate
following the established procedure5 to yield a 10:1 mixture
(by 1H NMR in benzene-d6) of the desired product 6 and the
enol ether 7 in 77% yield. Compounds 6 and 7 were
obtained pure by recrystallization from hexane and
methanol, respectively. Dehydration of 6 to 8 using iodine
in refluxing benzene gave variable yields of 7–9, and the
yield of the desired product 8 was optimized as follows.
Instead of using a small crystal of iodine,12 we standardized
the iodine concentration by adding a known volume of a
solution of iodine in anhydrous benzene. The reaction was
consequently carried out using 0.05 equiv. of iodine and
monitored by NMR spectroscopic analysis of aliquots taken
after 0, 0.5, 1, 2, 4, 6, 18 h reflux. This showed that 6 rapidly
formed the enol ether 7, which on further reaction
rearranged, initially to the kinetically favored D7-unsatu-
rated ketone 9, then to the more thermodynamically favored
8. Optimal conditions for the dehydration were 6 h reflux
with 0.05 equiv. of iodine, which gave 8 and 9 in 75 and 6%
yield, respectively, as colorless oils, easily separable by
flash chromatography. The proposed intermediacy of 7 was
The next transformation in the synthesis, dehydration of 12
with phosphorus oxychloride in pyridine,16 proceeded
regiospecifically to give a reasonable yield (76%) of
dehydration products, although the stereoselectivity of this
reaction was disappointing: the D13-E-isomer, ethyl
rhinocerotinoate (13), and the D13-Z-isomer, ethyl

C. A. Gray et al. / Tetrahedron 59 (2003) 165–173
Table 1. H (400 MHz, CDCl3), 13C (100 MHz, CDCl3) and 2D NMR data of methyl 7-oxolabda-8,13(16)-dien-15-oate (19)
167
1
Carbon
dC ppm, (mult.)
dH ppm (int., mult., J, Hz)
HMBC correlation to
COSY coupling to
1
2
3
4
5
6
7
8
35.7 (t)
18.6 (t)
41.3 (t)
33.1 (s)
50.2 (d)
35.2 (t)
200.1 (s)
130.3 (s)
167.2 (s)
40.9 (s)
27.8 (t)
34.6 (t)
141.8 (s)
41.8 (t)
171.6 (s)
114.0 (t)
11.3 (q)
32.5 (q)
21.3 (q)
18.1 (q)
51.9 (q)
1.34 (1H, bt, 11.1), 1.90 (1H, bd, 12.4)
1.58 (2H, m)
1.21 (1H, bt, 13.3), 1.46 (1H, bd, 13.1)
C-2, C-10
C-1, C-2
C-2, C-19
H2-2
H2-1, H2-3
H2-2
1.68 (1H, bd, 13.8)
2.34 (1H, bt, 13.9), 2.47 (1H, bd, 17.2)
C-4, C-6, C-7, C-10
C-5, C-7, C-8, C-9, C-10
H2-6
H-5
9
10
11
12
13
14
15
16
17
18
19
20
15-OMe
2.31 (2H, m)
2.22 (2H, bd, 7.5)
C-9, C-10, C-12, C-13,
C-13, C-16
H2-12
H2-11, H2-16
3.08 (2H, bs)
C-12, C-13, C-15, C-16
H2-16
4.95 (1H, s), 4.98 (1H, s)
1.74 (3H, s)
0.87 (3H, s)
0.90 (3H, s)
1.07 (3H, s)
3.68 (3H, s)
C-12, C-13, C-14, C-15
C-7, C-8, C-9
C-4, C-5, C-10, C-19
C-3, C-4, C-5, C-18
C-1, C-5, C-9, C-10
C-15
H2-12, H2-14
isorhinocerotinoate (14), were obtained in a 2:1 ratio and
were only separable by normal phase semi-preparative
HPLC. Repetition of this procedure using the more active
dehydrating agent thionyl chloride17 gave a complex
mixture of products in low yield, which was not investigated
further. The unsatisfactory stereoselectivity observed above
prompted us to try boron trifluoride etherate, which has been
reported to yield the thermodynamically favored
elimination products in higher yields than classical
reagents,18 but only starting material was recovered on
leaving a solution of this reagent and 12 in dichloromethane
at room temperature for 24 h. Unfortunately, neither
refluxing with catalytic amounts of iodine in benzene19
nor prolonged heating with thiophenol20 satisfactorily
converted 14 in the 2:1 mixture to 13.
conditions generally exhibit less stereoselectivity than that
obtained with 15.28–30
Having established a method of preparing the C-13–C-14
double bond stereoselectively, we turned our attention to the
hydrolysis of the ester functionality in 13 which, according
to Dekker et al.2 had been carried out under basic
1
conditions. However, H NMR examination of the crude
reaction mixture obtained by refluxing the 10:1 mixture of
esters 13 and 14 with ethanolic potassium hydroxide
suggested that significant isomerization of the C-13–C-14
double bond had occurred. The presence of two vinylic
methine singlets at dH 5.73 and 5.72 indicated that both 1
and 5 were present and additional vinylic methylene singlets
at dH 5.00 and 5.02 suggested that 7-oxolabda-8,13(16)-
dien-15-oic acid (16) had also been formed. Integration of
the vinylic proton resonances showed that the crude reaction
mixture contained these acids in a ratio of 12:3:2,
respectively. Attempts to separate this mixture by chroma-
tographic methods (normal phase and reversed phase
column chromatography and HPLC) were unsuccessful.
Crystallization from hexane allowed the isolation of
approximately half of the E-isomer 1 while crystallization
of the mother liquors from methanol–water yielded a small
quantity of the pure Z-isomer 5. The mother liquors from 5
were methylated with diazomethane and the resulting
methyl esters separated by repeated flash chromatography
(the ethyl esters were inseparable under these conditions),
followed by semi-preparative HPLC to give methyl
rhinocerotinoate (17), methyl isorhinocerotinoate (18) and
methyl 7-oxolabda-8,13(16)-dien-15-oate (19). The struc-
ture of the new ester 19 was elucidated from a combination
of NMR spectroscopic data (Table 1) and high resolution
mass spectrometry.
Accordingly, the synthesis was modified by using the
Horner–Wadsworth–Emmons (HWE) modification of
the Wittig reaction, which has been widely used in the
stereoselective preparation of both E and Z disubstituted a,b
unsaturated esters,21,22 even though the stereoselectivity is
often significantly diminished when using ketones to
prepare trisubstituted alkenes.23 To use this methodology,
we had to perform the allylic oxidation at C-7 prior to
elaboration of the side chain and rely on the HWE
olefination to proceed selectively at the more electrophilic
saturated C-13 carbonyl group in the known diketone 15.24
Such preferential reaction is well known, e.g. with the
Wieland–Miescher ketone.25–27 Accordingly, 8 was sub-
mitted to Collins’ oxidation,14 employing the optimized
procedure already described, to afford (þ)-14,15-bis-
norlabda-8-en-7,13-dione (15)24 in 81% yield. Compound
15 was then subjected to HWE reaction with triethyl
phosphonoacetate in tetrahydrofuran to give the a,b-
unsaturated esters 13 and 14 with vastly improved
stereoselectivity (10:1 E/Z) and in excellent yield (96%).
Although the chemospecificity observed in the HWE
reaction was predictable, the extent of stereoselectivity
was unexpected23 as HWE reactions performed on similar
14,15-bisnorlabda-13-one derivatives under comparable
As Dekker et al.2 did not report any isomerization resulting
from hydrolysis of the mixed methyl esters 17 and 18, nor
stipulate the base used for hydrolysis, the ethyl esters 13 and
14 were also saponified with a weaker base (potassium
carbonate) but the same products, 1, 5, and 16, were

168
C. A. Gray et al. / Tetrahedron 59 (2003) 165–173
obtained in 83% yield and a less favorable ratio of 7:2:7,
respectively. A milder method for cleaving esters was also
attempted and the mixture of the ethyl esters 13 and 14 was
refluxed with chlorotrimethylsilane and sodium iodide in
acetonitrile.31 Unfortunately, only a complex mixture of
products (from 1H NMR) resulted. A search of the literature
for the saponification of related b-methyl b-alkyl sub-
stituted a,b-unsaturated esters indicated that isomerization
of the double bond is extremely variable.32 In such systems
this transformation has been reported to proceed with no
isomerization,33 with cis–trans isomerization,34 as well as
minor a,b- to bg-isomerization35 of the double bond. We
also attempted to hydrolyze the 10:1 mixture of 17 and 18
under acidic conditions using the method of Cativela et al.36
by heating the esters with HCl in THF at 708C. No
isomerization occurred but poor yields of the acids resulted,
necessitating an investigation of other solvents and mineral
acids to facilitate hydrolysis. The best yield (82%) was
obtained on heating 13 and 14 (4 h) with H2SO4 in acetic
acid. Washing the product with hexane followed by vacuum
sublimation afforded isomerically pure (by 1H NMR)
rhinocerotinoic acid (1) in 72% overall yield. Methyl
7-oxolabda-8,13(16)-dien-15-oate (19) on similar acid
(254 nm) and developed by spraying with 10% H2SO4 in
MeOH followed by heating. Open column chromatography
was performed using Kieselgel 60 (70–230 mesh) silica gel
and flash chromatography was performed using Kieselgel
60 (230–400 mesh) silica gel. Normal phase semi-
preparative HPLC separations were performed on a
Whatman Magnum 9 Partisil 10 column with an eluent
flow rate of 4 mL min21 and reverse phase semi-preparative
HPLC separations were attempted on a Phenomenex Luna
10 mm C18 column.
3.2. Attempted isolation of rhinocerotinoic acid from E.
rhinocerotis
Dried aerial parts (312 g) of E. rhinocerotis (identified by
Mrs Estelle Brink of the Albany Museum Herbarium,
Grahamstown), collected from Burnt Kraal near
Grahamstown in early November 1999 were extracted in a
Soxhlet apparatus with acetone. The extract was concen-
trated in vacuo and the resulting green waxy solid (11.8 g)
stirred with Et2O (500 mL), left overnight at 58C and
filtered. Portions of the green filtrate (10 mL) were extracted
with either 5% NaHCO3 or Na2CO3 solutions (10 mL), the
aqueous phase acidified, extracted with Et2O, dried and
evaporated. Both acidic extracts were examined by 1H NMR
spectroscopy, but no resonances corresponding to those
reported for rhinocerotinoic acid were observed. In case 1
was present as an ester in the E. rhinocerotis extract, the
neutral material from the base extractions was refluxed with
8% ethanolic KOH for 18 h but no 1 could be detected in the
product by 1H NMR spectroscopy.
1
hydrolysis isomerized to give a 3:2 mixture (by H NMR)
of 1 and 5.
In conclusion, the overall yield of our five step synthesis of 1
from (2)-sclareol was 32%. Dekker et al.2 do not quote
yields in their six step synthesis but previous results for the
preparation of 43,12 and our own for the subsequent
dehydration and saponification suggest an overall yield for
their synthesis of not more than 12%.
3.3. Potassium permanganate oxidation of (2)-sclareol (3)
Sclareol (25.0 g, 81.2 mmol) was dissolved in a mixture of
acetone (2.5 L) and water (25 mL) in a flask previously
washed with aqueous Na2CO3, cooled (158C) and finely
powdered KMnO4 (45.0 g, 285 mmol, 3.5 equiv.) added in
portions over 2 h. The reaction mixture was stirred for a
further 5 h and left at ambient temperature overnight. The
solution was carefully siphoned from the fine MnO2
precipitate which was washed with acetone (2£600 mL).
The combined acetone extracts were concentrated to
300 mL under reduced pressure, filtered through celite,
10% aqueous NaOH (50 mL) added, and the remaining
acetone removed in vacuo. The residual semi-solid solution
was extracted with EtOAc (1£200 mL, 1£100 mL) which
was washed with H2O (3£15 mL), dried and concentrated to
afford crude 8a-hydroxy-14,15-bisnorlabda-13-one (6,
17.4 g, mp 71–758C). Washing with hexane afforded 6
(15.9 g, 56.8 mmol, 70%) and the mother liquors, on
evaporation, gave 7 (1.43 g, 5.46 mmol, 7%).
3. Experimental
3.1. General
1
The H and 13C NMR spectra were recorded on a Bruker
400 MHz Avance NMR spectrometer using CDCl3 as the
solvent, referenced at d 7.25 and 77.0, respectively. The
HRFABMS data were acquired by Professor Louis Fourie of
the University of Potchefstroom on a Micromass 70-70E
spectrometer and the LREI mass spectra (70 eV) were
obtained on a Finnegan-Matt GCQ mass spectrometer by
Mr Aubrey Sonemann of Rhodes University. The IR data
for all compounds were obtained from thin films on NaCl
discs using a Perkin–Elmer 2000 FTIR spectrometer. All
rotations were recorded on a Perkin–Elmer 141 polarimeter
as CHCl3 solutions. Melting points were determined using a
Reichert hot-stage microscope and are uncorrected.
Reactions with exclusion of moisture were performed in
flame-dried glassware under N2. Immediately prior to their
use in dry reactions, diethyl ether, tetrahydrofuran and
benzene were distilled from sodium metal/benzophenone
ketyl, and dichloromethane was distilled from calcium
hydride. Pyridine was distilled at reduced pressure from
3.3.1. (1)-8a-Hydroxy-14,15-bisnorlabda-13-one (6).
White solid (from hexane); mp 81–828C, lit.6 78–808C;
1
[a]D27¼þ5 (c 1.08), lit.7 þ6.7; IR, H and 13C NMR data
consistent with published values;7 EIMS m/z (rel. int.) 280
[Mþ] (2), 262 (77), 244 (41), 191 (56), 229 (95), 191 (56),
177 (46), 121 (63), 109 (100), 95 (91); HRFABMS obsd
280.2405 [Mþ], C18H32O2 requires 280.2402.
˚
KOH and stored over 4 A molecular sieves under nitrogen.
General laboratory solvents were distilled before use.
Reactions were monitored by analytical normal phase
(performed on DC-Plastikfolien Kieselgel 60 F254 plates)
or reverse phase (performed on DC-Ferigplatten RP18 F254
plates) thin layer chromatography visualized under UV light
3.3.2. (1)-8a,13-Epoxy-14,15-bisnorlabda-12-ene (7).
Fine white solid (from ice-cold MeOH); mp 43–458C,

C. A. Gray et al. / Tetrahedron 59 (2003) 165–173
169
1
lit.5 44–468C; [a]D26¼þ4 (c 3.53), lit.5 þ5; IR, H and 13C
NMR data consistent with published values;7 EIMS m/z (rel.
int.) 262 [Mþ] (95), 244 (45), 229 (98), 191 (67), 135 (54),
121 (67), 109 (98), 95 (100), 81 (97); HRFABMS obsd
[Mþ] 262.2294, C18H30O requires 262.2297.
(1H, m, H-2a), 1.52 (3H, s, H3-17), 1.47 (1H, m, H-2b), 1.42
(1H, m, H-3a), 1.36 (1H, m, H-6b), 1.12 (1H, m, H-3b), 1.08
(1H, dd, J¼12.5, 1.9 Hz, H-5), 1.07 (1H, m, H-1b), 0.93
(3H, s, H3-20), 0.87 (3H, s, H3-18), 0.82 (3H, s, H3-19); 13
C
NMR d 208.9 (s, C-13), 139.5 (s, C-9), 126.6 (s, C-8), 52.0
(d, C-5), 44.7 (t, C-12), 41.8 (t, C-3), 39.1 (s, C-10), 37.0
(t, C-1), 33.7 (t, C-7), 33.3 (s, C-4), 33.3 (q, C-18), 29.7 (q,
C-16), 21.7 (q, C-19), 21.6 (t, C-11), 20.0 (q, C-20), 19.4 (q,
C-17), 19.0 (t, C-6 and t, C-2); EIMS m/z (rel. int.) 262 [Mþ]
(9), 244 (58), 229 (100), 204 (32), 189 (73), 173 (71), 159
(63), 133 (67), 105 (67), 91 (60); HRFABMS obsd 262.2295
[Mþ], C18H30O requires 262.2297.
3.4. Conversion of (1)-8a-hydroxy-14,15-bisnorlabda-
13-one (6) to (1)-8a,13-epoxy-14,15-bisnorlabda-12-
ene(7)
The hydroxy ketone 6 (2.04 g, 7.29 mmol) was slowly
passed through an open column of silica gel (100 g) using
CHCl3 as eluent. Removal of the solvent in vacuo gave a
quantitative yield of the enol ether 7.
3.6. Acid catalyzed dehydration of (1)-8a-hydroxy-
14,15-bisnorlabda-13-one (6) and isomerization of
(1)-8a,13-epoxy-14,15-bisnorlabda-12-ene (7)
3.5. Iodine catalysed dehydration of (1)-8a-hydroxy-
14,15-bisnorlabda-13-one (6) and isomerization of
(1)-8a,13-epoxy-14,15-bisnorlabda-12-ene (7)
The hydroxy ketone 6 (1.43 g, 5.11 mmol) was dissolved in
EtOH (50 mL), 5 M HCl (10 mL) added and the solution
heated at 708C for 2 h. The reaction mixture was
concentrated in vacuo to 20 mL, poured into H2O
(100 mL) and extracted with EtOAc (3£50 mL). The
organic fractions were combined, washed with 5%
Na2CO3 (50 mL), dried (Na2SO4) and concentrated to
give a yellow oil (1.21 g). Silica gel flash chromatography
of the crude product in 9:1 hexane/EtOAc afforded the
unsaturated ketones 9 (0.36 g, 1.37 mmol, 27%) and 8
(0.59 g, 2.25 mmol, 44%) as light yellow oils.
The hydroxy ketone 6 (5.00 g, 17.9 mmol) was dissolved in
anhydrous benzene (500 mL), I2 (0.23 g, 0.9 mmol,
0.05 equiv.) added and the resulting pink solution refluxed
under a Dean-Stark head for 6 h. The solution was washed
with 5% Na2S2O3 (3£25 mL) and H2O (25 mL), dried
(MgSO4) and concentrated to give a dark brown oil (4.39 g)
that was purified by flash chromatography on silica gel in
9:1 hexane/EtOAc to give (þ)-14,15-bisnorlabda-7-ene-13-
one (9, 0.26 g, 0.99 mmol, 6%) and (þ)-14,15-bisnorlabda-
8-ene-13-one (8, 3.51 g, 13.4 mmol, 75%) as light yellow
oils.
The enol ether 7 (1.29 g, 4.92 mmol) was treated in the same
manner to give a light yellow oil (1.08 g) that yielded, after
flash chromatography, the unsaturated ketones 9 (0.30 g
1.15 mmol, 23%) and 8 (0.56 g, 2.18 mmol, 44%) as light
yellow oils.
The enol ether 7 (5.20 g, 19.7 mmol) was treated in the same
manner to give a dark brown oil (5.18 g), which after flash
chromatography yielded the unsaturated ketones 9 (0.41 g,
1.56 mmol, 8%) and 8 (3.91 g, 14.9 mmol, 76%) as light
yellow oils.
3.7. Preparation of ethyl 13-hydroxylabda-8-en-15-oate
(11) via the Reformatsky reaction
3.5.1. (1)-14,15-Bisnorlabda-7-ene-13-one (9). Oil;
[a]D27¼þ22 (c 1.60), lit. for enantiomer28 223.1; IR nmax
2924, 2847, 1717, 1669, 1457, 1388, 1360, 1214, 1160,
Activated zinc powder (2.10 g, 32.2 mmol, 1.2 equiv.;
washed with 10% HCl for 5 min, rinsed twice with water,
twice with acetone and dried in an oven at 1208C for 1 h
immediately prior to use) and ethyl bromoacetate (3.59 mL,
32.2 mmol, 1.2 equiv.) were stirred in a mixture of
anhydrous benzene (30 mL) and anhydrous Et2O (10 mL).
The mixture was gently warmed at 408C until reaction
between the zinc and ethyl bromoacetate caused the solvent
to reflux. When this reaction was complete, 8 (7.04 g,
26.9 mmol) in a mixture of anhydrous benzene (30 mL) and
anhydrous Et2O (10 mL) was added dropwise over 10 min
and the resulting solution gently refluxed for 2.5 h. The
solution was cooled, poured into 2 M H2SO4 (30 mL) and
extracted with Et2O (3£20 mL). The organic fractions were
combined, washed with 5 % NaHCO3 (2£20 mL) and H2O
(10 mL), dried (MgSO4) and concentrated to give a yellow
oil (10.3 g). Silica gel flash chromatography in 7:3
hexane/EtOAc afforded ethyl 13-hydroxylabda-8-en-15-
oate (11, 8.74 g, 25.0 mmol, 93%) as a 1:1 mixture of
1
983 cm21; H NMR d 5.40 (1H, br s, H-7), 2.62 (1H, m,
H-12a), 2.40 (1H, m, H-12b), 2.12 (3H, s, H3-16), 1.93 (1H,
m, H-6a), 1.88 (1H, m, H-6b), 1.85 (1H, m, H-1a), 1.79 (1H,
m, H-11a), 1.64 (3H, s, H3-17), 1.58 (1H, s, H-9), 1.52 (1H,
m, H-2a), 1.44 (1H, m, H-2b), 1.41 (1H, m, H-11b), 1.40
(2H, m, H2-3), 1.15 (1H, dd, J¼12.3, 4.9 Hz, H-5), 0.93
(1H, dd, J¼13.7, 4.3 Hz, H-1b), 0.86 (3H, s, H3-19), 0.84
(3H, s, H3-18), 0.76 (3H, s, H3-20); 13C NMR d 208.8 (s,
C-13), 134.5 (s, C-8), 123.0 (d, C-7), 54.4 (d, C-9), 50.5 (d,
C-5), 45.9 (t, C-12), 42.3 (t, C-3), 39.4 (t, C-1), 36.9 (s,
C-10), 33.2 (q, C-18), 33.0 (s, C-4), 29.9 (q, C-16), 23.8 (t,
C-6), 22.2 (q, C-17), 21.9 (q, C-19), 21.0 (t, C-11), 18.8 (t,
C-2), 13.6 (q, C-20); EIMS m/z (rel. int.) 262 [Mþ] (5), 244
(25), 229 (19), 204 (83), 189 (55), 161 (100), 147 (24), 119
(35), 105 (41); HRFABMS obsd 262.2296 [Mþ], C18H30O
requires 262.2297.
1
3.5.2. (1)-14,15-Bisnorlabda-8-ene-13-one (8). Oil;
[a]D26¼þ75 (c 1.10), lit.12 þ78; IR nmax 2938, 2867, 1716,
1463, 1387, 1360, 1273, 1159, 1070, 999 cm21; 1H NMR d
2.47 (2H, t, J¼8.3 Hz, H2-12), 2.28 (1H, m, H-11a), 2.16
(1H, m, H-11b), 2.12 (3H, s, H3-16), 1.97 (2H, m, H2-7),
1.77 (1H, br d, J¼12.2 Hz, H-1a), 1.64 (1H, m, H-6a), 1.57
C-13 diastereomers (determined from H and 13C NMR
spectroscopy; inseparable by normal phase HPLC) and
recovered starting material (8, 331 mg, 1.26 mmol, 5%).
3.7.1. Ethyl 13-hydroxylabda-8-en-15-oate (11). Oil; IR
n
max 3523 (br), 2939, 2926, 1716, 1463, 1374, 1332, 1103,

170
C. A. Gray et al. / Tetrahedron 59 (2003) 165–173
1030 cm21
;
1H NMR d 4.16 (2H,q, J¼7.1 Hz, 15-
4.1 Hz, H-3b), 1.07 (3H, s, H3-18), 0.87 (3H, s, H3-19), 0.86
(3H, s, H3-20); 13C NMR d 200.1 (s, C-7), 172.9 (s, C-15),
167.7/167.6 (s, C-9), 130.2 (s, C-8), 70.9 (s, C-13), 60.8 (t,
15-OCH2CH3), 50.3 (d, C-5), 44.7 (t, C-14), 41.3 (t, C-3),
41.1 (s, C-10), 40.2/40.1 (t, C-12), 35.9 (t, C-1), 35.2 (t,
C-6), 33.1 (s, C-4), 32.5 (q, C-20), 26.5/26.3 (q, C-16), 23.7
(t, C-11), 21.3 (q, C-19), 18.6 (t, C-2), 18.2 (q, C-18), 14.1
(q, 15-OCH2CH3), 11.2 (t, C-17); EIMS m/z (rel. int.) 364
[Mþ] (1), 346 (38), 331 (16), 285 (16), 259 (19), 240 (63),
205 (48), 161 (22), 152 (83), 135 (100); HRFABMS obsd
365.2691 [(MþH)þ], C22H37O4 requires 365.2692.
OCH2CH3), 3.53/3.52 (1H, s, 13-OH), 2.52 (1H, d, J¼
15.6 Hz, H-14a), 2.48 (1H, d, J¼15.6 Hz, H-14b), 2.08 (1H,
m, H-11a), 1.98 (1H, m, H-11b), 1.88 (1H, m, H-7b), 1.78
(1H, J¼14.0 Hz, H-1a), 1.67 (1H, m, H-2a), 1.56 (2H, m,
H2-12), 1.54/1.53 (3H, s, H3-17), 1.43 (1H, m, H-2b), 1.38
(2H, m, H2-6), 1.26 (3H, t, J¼7.1 Hz, 15-OCH2CH3), 1.24
(3H, s, H3-16), 1.14 (2H, m, H2-3), 1.11 (1H, m, H-1b), 1.07
(1H, m, H-5), 0.93 (3H, s, H3-18), 0.86 (3H, s, H3-20), 0.81
(3H, s, H3-19); 13C NMR d 173.1 (s, C-15), 139.8 (s, C-9),
125.9 (s, C-8), 71.2 (s, C-13), 60.6 (t, 15-OCH2CH3), 51.9
(d, C-5), 44.6 (t, C-14), 42.1 (t, C-3), 42.0 (t, C-12), 41.8
(t, C-6), 39.1 (s, C-10), 37.0 (t, C-1), 33.6 (t, C-7), 33.3 (q,
C-20 and s, C-4), 26.4 (q, C-16), 22.1 (t, C-11), 21.7 (q,
C-19), 20.1 (q, C-18), 19.4 (q, C-17), 19.1 (t, C-2), 14.1 (q,
15-OCH2CH3); EIMS m/z (rel. int.) 350 [Mþ] (3), 332 (12),
317 (13), 271 (31), 229 (54), 204 (100), 189 (57), 161 (46),
121 (41), 95 (27); HRFABMS obsd 350.2821 [Mþ],
C22H38O3 requires 350.2821.
3.9. Dehydration of ethyl 13-hydroxy-7-oxolabda-8-en-
15-oate (12)
Ethyl 13-hydroxy-7-oxo-labda-8-en-15-oate (12, 6.34 g,
17.4 mmol) was dissolved in anhydrous pyridine (40 mL),
cooled to 2108C and POCl3 (12.7 mL, 139 mmol, 8 equiv.)
in dry pyridine (20 mL) added dropwise. The solution was
slowly warmed to RT and allowed to stir for 16 h before the
reaction was quenched by pouring into ice (300 g) and the
resulting aqueous suspension extracted with EtOAc
(3£100 mL). The organic phases were combined, washed
with 1 M HCl (3£100 mL), 5% Na2CO3 (100 mL) and sat.
brine (1£50 mL), dried (Na2SO4) and the solvent evapo-
rated to give a brown oil (5.43 g). Silica gel flash
chromatography of the crude product (7:3 hexane/EtOAc)
yielded a 2:1 mixture (measured from integration of the
H-14 vinylic proton resonances in the 1H NMR spectrum of
the purified product) of ethyl rhinocerotinoate (13) and ethyl
isorhinocerotinoate (14) as a yellow oil (4.58 g, 13.2 mmol,
76%). The two geometrical isomers were inseparable by
column chromatography and could only be purified by
subjecting the 13/14 mixture to semi-preparative normal
phase HLPC in 9:1 hexane/EtOAc.
3.8. Allylic oxidation of ethyl 13-hydroxylabda-8-en-15-
oate (11)
CrO3 (18.9 g, 189 mmol, 15 equiv.; dried at 0.5 mm Hg and
708C over P2O5 for 8 h immediately prior to use) was stirred
vigorously in anhydrous CH2Cl2 (200 mL) and cooled in an
ice-salt bath. Pyridine (30.5 mL, 379 mmol, 30 equiv.) in
CH2Cl2 (50 mL) was then added dropwise over 30 min
taking care not to allow the temperature to rise above 08C.
The resulting deep red solution was allowed to warm to
ambient temperature over 1 h and stirred for a further
30 min before ethyl 13-hydroxylabda-8-en-15-oate (11,
4.42 g, 12.6 mmol) in CH2Cl2 (50 mL) was added dropwise
over 30 min. The solution was stirred at room temperature
for 48 h, during which time a large amount of waxy, dark
brown precipitate formed. The supernatant solution was
decanted, the precipitate thoroughly washed with EtOAc
(3£100 mL) and the washings combined with the super-
natant solution. The tarry precipitate was dissolved in sat.
NaHCO3 (500 mL) and this solution extracted with EtOAc
(2£100 mL; centrifugation helped to break the emulsions
which formed). The organic fractions were combined with
the initial supernatant, the volume of the resulting solution
reduced to approximately 200 mL in vacuo and then
thoroughly washed with 1.5 M NaOH (3£100 mL), 1 M
HCl (2£100 mL), 5% NaHCO3 (1£100 mL) and sat. brine
(1£50 mL). Drying (MgSO4) and evaporation of the solvent
gave a yellow oil (4.17 g) that, after flash chromatography in
3:2 hexane/EtOAc, afforded ethyl 13-hydroxy-7-oxolabda-
8-en-15-oate (12, 1:1 mixture of C-13 diastereomers) as a
light yellow oil (3.69 g, 10.1 mmol, 80%).
3.9.1. Ethyl rhinocerotinoate (13). Oil; [a]2D6¼þ34 (c
1.95); IR nmax 2931, 2863, 1715, 1662, 1608, 1463, 1330,
1
1222, 1147, 1036 cm21; H NMR d 5.69 (1H, br d, J¼
0.9 Hz, H-14), 4.14 (2H, q, J¼7.1 Hz, 15-OCH2CH3), 2.49
(1H, dd, J¼17.6, 3.7 Hz, H-6a), 2.34 (1H, m, J¼17.6 Hz,
H-6b), 2.32 (2H, m, H2-11), 2.24 (2H, m, H2-12), 2.21 (3H,
d, J¼0.9 Hz, H3-16), 1.90 (1H, br d, J¼12.2 Hz, H-1a), 1.75
(3H, s, H3-17), 1.69 (1H, dd, J¼8.6, 3.6 Hz, H-2a), 1.66
(1H, m, J¼6.5 Hz, H-5), 1.60 (1H, m, J¼3.6 Hz, H-2b),
1.47 (1H, br d, J¼13.3 Hz, H-3a), 1.37 (1H, td, J¼12.3,
3.8 Hz, H-1b), 1.27 (3H, t, J¼7.2 Hz, 15-OCH2CH3), 1.19
(1H, dd, J¼13.4, 4.2 Hz, H-3b), 1.07 (3H, s, H3-20), 0.90
(3H, s, H3-19), 0.87 (3H, s, H3-18); 13C NMR d 200.0 (s,
C-7), 166.6 (s, C-9), 166.3 (s, C-15), 158.4 (s, C-13), 130.5
(s, C-8), 115.9 (d, C-14), 49.6 (t, 15-OCH2CH3), 50.3 (d,
C-5), 41.3 (t, C-3), 41.0 (s, C-10), 39.6 (t, C-12), 35.9 (t,
C-1), 35.2 (t, C-6), 33.1 (s, C-4), 32.5 (q, C-18), 27.7 (t,
C-11), 21.3 (q, C-19), 18.8 (q, C-16), 18.6 (t, C-2), 18.2 (q,
C-20), 14.3 (q, 15-OCH2CH3), 11.4 (q, C-17); EIMS m/z
(rel. int.) 346 [Mþ] (42), 331 (12), 318 (32), 300 (54), 285
(31), 258 (67), 245 (30), 205 (37), 161 (21), 135 (100);
HRFABMS obsd 347.2586 [(MþH)þ], C22H35O3 requires
347.2586.
3.8.1. Ethyl 13-hydroxy-7-oxolabda-8-en-15-oate (12).
Oil; IR nmax 3437 (br), 2931, 2863, 1732, 1661, 1600,
1376, 1331, 1154, 1031 cm21; H NMR d 4.17 (2H, q, J¼
1
7.1 Hz, 15-OCH2CH3), 3.64/3.62 (1H, s, 13-OH), 2.53 (1H,
d, J¼15.9 Hz, H-14a), 2.47 (1H, d, J¼17.5 Hz, H-6a), 2.43
(1H, d, J¼15.9 Hz, H-14b), 2.33 (1H, m, H-6b), 2.30 (2H, m
H2-11), 1.19 (1H, br t, J¼11.8 Hz, H-1a), 1.74/1.73 (3H, s,
H3-17), 1.68 (1H, m, H-2a), 1.66 (1H, m, H-5), 1.62 (2H, m,
H2-12), 1.55 (1H, m, H-2b), 1.46 (1H, br d, J¼13.3 Hz,
H-3a), 1.32 (1H, m, H-1b), 1.27 (3H, t, J¼7.2 Hz, 15-
OCH2CH3), 1.27 (3H, s, H3-16), 1.20 (1H, dd, J¼13.3,
3.9.2. Ethyl isorhinocerotinoate (14). Oil; [a]2D6¼þ47 (c
0.48); IR nmax 2931, 2863, 1714, 1662, 1603, 1444, 1377,
;
1165, 1144, 1036 cm21 1H NMR d 5.67 (1H, br d,

C. A. Gray et al. / Tetrahedron 59 (2003) 165–173
171
J¼1.1 Hz, H-14), 4.14 (2H, q, J¼7.1 Hz, 15-OCH2CH3),
2.75 (2H, m, H2-12), 2.49 (1H, dd, J¼17.5, 3.8 Hz, H-6a),
2.35 (1H, dd, J¼17.6, 14.1 Hz, H-6b), 2.34 (2H, m, H2-11),
2.05 (1H, br d, J¼12.4 Hz, H-1a), 1.94 (3H, d, J¼1.3 Hz,
H3-16), 1.84 (3H, s, H3-17), 1.71 (1H, dd, J¼14.2, 3.9 Hz,
H-5), 1.69 (1H, m, H-2a), 1.62 (1H, tt, J¼12.1, 3.6 Hz,
H-2b), 1.47 (1H, br d, J¼13.4 Hz, H-3a), 1.42 (1H,
td, J¼12.6, 3.9 Hz, H-1b), 1.26 (3H, t, J¼7.1 Hz, 15-
OCH2CH3), 1.23 (1H, td, J¼13.3, 4.1 Hz, H-3b), 1.10 (3H,
s, H3-20), 0.91 (3H, s, H3-19), 0.88 (3H, s, H3-18); 13C
NMR d 200.3 (s, C-7), 167.2 (s, C-9), 166.0 (s, C-15), 157.9
(s, C-13), 130.6 (s, C-8), 117.0 (d, C-14), 59.6 (t, 15-
OCH2CH3), 50.2 (d, C-5), 41.3 (t, C-3), 41.1 (s, C-10), 35.9
(t, C-1), 35.3 (t, C-6), 33.1 (s, C-4), 32.5 (q, C-18), 32.2 (t,
C-12), 27.6 (t, C-11), 24.9 (q, C-16), 21.3 (q, C-19), 18.7 (t,
C-2), 18.3 (q, C-20), 14.3 (q, 15-OCH2CH3), 11.3 (q, C-17);
EIMS m/z (rel. int.) 346 [Mþ] (37), 301 (18), 285 (22), 258
(39), 220 (50), 205 (57), 176 (33), 135 (92), 127 (100);
HRFABMS obsd 347.2587 [(MþH)þ] C22H35O3 requires
347.2586.
resulting solution was stirred at room temperature for
30 min then the dione 15 (3.22 g, 11.7 mmol) in anhydrous
THF (20 mL) was added dropwise and the reaction mixture
stirred at ambient temperature overnight. The reaction
mixture was concentrated in vacuo and taken up in Et2O
(50 mL), washed with H2O (3£10 mL), dried (MgSO4) and
concentrated to give a light yellow oil (6.91 g). Silica gel
flash chromatography (7:3 hexane/EtOAc) of the oil yielded
a mixture of ethyl rhinocerotinoate (13) and ethyl
isorhinocerotinoate (14) as a colorless oil (3.87 g,
11.2 mmol, 96%). 1H NMR spectroscopy of the 13/14
mixture indicated that it was composed of a 10:1 mixture of
13/14.
3.12. Saponification of esterified 7-oxolabda-8,13-dien-
15-oic acid derivatives
The 10:1 13/14 mixture (3.40 g, 9.83 mmol) and 5 M KOH
(10 mL, 50 mmol, 5.1 equiv.) were refluxed in EtOH
(40 mL) for 6 h. The reaction mixture was then concentrated
in vacuo to give a cloudy aqueous solution (15 mL), which
was acidified with 1 M HCl and extracted with CHCl3
(3£25 mL). The organic fractions were combined, dried and
3.10. Preparation of (1)-14,15-bisnorlabda-8-en-7,13-
dione (15)
1
concentrated to give a 12:3:2 mixture (determined by H
Treatment of (þ)-14,15-bisnorlabda-8-en-13-one (8, 4.98 g,
19.0 mmol) with CrO3 (28.5 g, 285 mmol, 15 equiv.) and
pyridine (46.0 mL, 570 mmol, 30 equiv.) as described in
Section 3.8 gave a brown oil (4.53 g). Flash chroma-
tography of the crude product in 7:3 hexane/EtOAc afforded
(þ)-14,15-bisnorlabda-8-en-7,13-dione (15) as a colorless
oil (4.26 g, 15.4 mmol, 81%) which could be crystallized
from cold hexane to give large white needles. A small
amount of starting material (8, 156 mg, 3%) was also
recovered from the column.
NMR spectroscopy) of rhinocerotinoic acid (1), isorhino-
cerotinoic acid (5) and (þ)-7-oxolabda-8,13(16)-dien-15-
oic acid (16) as a colourless oil (2.98 g, 9.37 mmol, 95%).
Trituration of this oil with hexane and vacuum sublimation
(1508C, 0.5 mm Hg) of the resulting off-white solid allowed
1
the isolation of isomerically pure (by H NMR spectro-
scopy) 1 (1.01 g, 48% of the total 1 in the mixture) as fine
white crystals. The oil obtained from the mother-liquor was
similarly treated with cold MeOH/water (10:1) to yield
isomerically pure 5 (47 mg, 9% of the total 5 in the
mixture). The mother-liquors from the second crystal-
lization were combined to give a 3.11:1.37:1 (approxi-
mately 6:3:2, estimated from 1H NMR spectroscopy)
mixture of 1/5/16 as an oil (1.91 g, 6.01 mmol) that was
inseparable by both normal phase and reversed phase
HPLC. The acid 16 could therefore not be obtained pure and
was isolated as the methyl ester 19 as described below.
3.10.1. (1)-14,15-Bisnorlabda-8-en-7,13-dione (15).
White solid; mp 78–808C, lit.24 79.5–80.58C; [a]D26¼þ58
(c 1.89), lit.24 þ64.58; IR nmax 2931, 2870, 1716, 1661,
1607, 1417, 1366, 1330, 1162, 1071 cm21 1H NMR
;
(CDCl3, 400 MHz) d 2.56 (2H, m, H2-12), 2.51 (1H, m,
H-6a), 2.46 (2H, m, H2-11), 2.34 (1H, dd, J¼17.5, 14.3 Hz,
H-16), 2.17 (3H, s, H3-16), 1.88 (1H, br d, J¼12.4 Hz,
H-1a), 1.70 (1H, m, H-2a), 1.71 (3H, s, H3-17), 1.67 (1H, dd,
J¼14.2, 3.6 Hz, H-5), 1.57 (1H, m, H-2b), 1.47 (1H, br d,
J¼13.4 Hz, H-3a), 1.25 (1H, td, J¼12.6, 3.7 Hz, H-1b), 1.23
(1H, td, J¼13.4, 4.1 Hz, H-3b), 1.08 (3H, s, H3-20), 0.91
(3H, s, H3-19), 0.87 (3H, s, H3-18); 13C NMR (CDCl3,
100 MHz) d 206.8 (s, C-13), 199.9 (s, C-7), 166.7 (s, C-9),
130.4 (s, C-8), 50.4 (d, C-5), 42.4 (t, C-12), 41.3 (t, C-3),
41.1 (s, C-10), 35.9 (t, C-1), 35.2 (t, C-6), 33.1 (s, C-4), 32.5
(q, C-18), 29.8 (q, C-16), 22.7 (t, C-11), 21.3 (q, C-19), 18.5
(t, C-2), 17.9 (q, C-20), 11.3 (q, C-17); EIMS m/z (rel. int.)
276 [Mþ] (13), 258 (7), 233 (37), 215 (11), 205 (41), 136
(24), 135 (100), 107 (12), 91 (17); HRFABMS obsd
277.2167 [(MþH)þ], C18H29O2 requires 277.2168.
The 6:3:2 1/5/16 (1.91 g, 6.01 mmol) mixture was dissolved
in MeOH (10 mL) and treated with an ethereal diazo-
methane solution (20 mL, approximately 34 mmol,
5.7 equiv.)37 at 08C. The bright yellow solution was allowed
to stand in ice for 30 min and excess diazomethane removed
by evaporation. The residual MeOH solution was concen-
trated in vacuo to give a mixture of the methyl esters 17–19
in the same ratio of 6:3:2 as a light yellow oil (1.99 g,
5.99 mmol, 100%). A portion of the methylated mixture
(1.69 g) was purified by repeated flash chromatography in
19:1 and 9:1 hexane/EtOAc and normal phase HPLC of
mixed fractions in 17:3 hexane/EtOAc to yield methyl
rhinocerotinoate (17, 0.68 g), methyl isorhinocerotinoate
(18, 0.34 g) and methyl 7-oxolabda-8,13(16)-dien-15-oate
(19, 0.19 g) as colorless oils. It should be noted that the
masses of the methyl esters isolated are not representative of
their yields due to the losses incurred through the extensive
chromatography required to separate these isomers.
3.11. Horner–Wadsworth–Emmons reaction of
(1)-14,15-bisnorlabda-8-en-17,13-dione (15)
NaH (336 mg, 14.0 mmol, 1.2 equiv.) was stirred in
anhydrous THF (15.0 mL), whilst triethyl phosphonoacetate
(2.78 mL, 14.0 mmol, 1.2 equiv.) in anhydrous THF
(5.0 mL) was added dropwise at room temperature. The
The 2:1 13/14 mixture (5.82 g, 16.8 mmol; prepared by
POCl3 dehydration) was treated in the same manner to give

172
C. A. Gray et al. / Tetrahedron 59 (2003) 165–173
a 10:5:2 mixture (determined by 1H NMR spectroscopy) of
rhinocerotinoic acid (1), isorhinocerotinoic acid (5) and
(þ)-7-oxolabda-8,13(16)-dien-15-oic acid (16) as an orange
semi-solid residue (5.01 g, 15.8 mmol, 94%). The mixture
was taken up in hexane (60 mL) and stored overnight at 08C
when an off white solid (2.03 g) precipitated from solution.
The solid was vacuum sublimed (1508C, 0.5 mm Hg) to
give isomerically pure 1 as white needles (1.81 g, 61% of
the total 1 in the reaction mixture). The mother-liquor from
the crystallization was discarded.
(1H, dd, J¼17.5, 3.8 Hz, H-6a), 2.35 (1H, dd, J¼17.3,
14.6 Hz, H-6b), 2.32 (2H, m, H2-11), 2.06 (1H, br d,
J¼12.3 Hz, H-1a), 1.95 (3H, d, J¼1.0 Hz, H3-16), 1.84 (3H,
s, H3-17), 1.71 (1H, dd, J¼14.1, 3.7 Hz, H-5), 1.69 (1H, m,
H-2a), 1.63 (1H, tt, J¼11.1, 3.5 Hz, H-2b), 1.47 (1H, br d,
J¼13.3 Hz, H-3a), 1.42 (1H, td, J¼12.6, 3.8 Hz, H-1b), 1.23
(1H, td, J¼13.2, 4.2 Hz, H-3b), 1.10 (3H, s, H3-20), 0.91
(3H, s, H3-19), 0.88 (3H, s, H3-18); 13C NMR d 200.3 (s,
C-7), 167.1 (s, C-9), 166.4 (s, C-15), 158.4 (s, C-13), 130.6
(s, C-8), 116.5 (d, C-14), 51.0 (q, 15-OMe), 50.2 (d, C-5),
41.3 (t, C-3), 41.1 (s, C-10), 35.9 (t, C-1), 35.3 (t, C-6), 33.1
(s, C-4), 32.5 (q, C-18), 32.3 (t, C-12), 27.6 (t, C-11), 25.0
(q, C-16), 21.3 (q, C-19), 18.7 (t, C-2), 18.2 (q, C-20), 11.3
(q, C-17); EIMS m/z (rel. int.) 332 [Mþ] (45), 300 (15), 285
(26), 258 (35), 220 (55), 205 (28), 161 (39), 135 (100), 113
(58), 91 (38); HRFABMS obsd 333.2430 [(MþH)þ],
C21H33O3 requires 333.2430.
The 10:1 13/14 mixture (20 mg, 0.06 mmol) and K2CO3
(41 mg, 0.30 mmol, 5.0 equiv.) was refluxed for 14 h in
EtOH (4.0 mL) and H2O (1.0 mL). Work-up of the reaction
in the usual manner gave a 7:2:7 mixture (determined by 1H
NMR spectroscopy) of rhinocerotinoic acid (1), isorhino-
cerotinoic acid (5) and (þ)-7-oxolabda-8,13(16)-dien-15-
oic acid (16) as a colorless oil (16.3 mg, 0.05 mmol, 83%).
3.12.5. Methyl 7-oxolabda-8,13(16)-dien-15-oate (19).
Oil; [a]2D7¼þ57 (c 3.03); IR nmax 2951, 2931, 2870, 1742,
NMR data see Table 1; EIMS m/z (rel. int.) 332 [Mþ] (100),
317 (53), 299 (11), 285 (27), 259 (24), 243 (13), 231 (44),
205 (13), 135 (79), 91 (25); HRFABMS obsd 333.2420
[(MþH)þ], C21H33O3 requires 333.2430.
3.12.1. Rhinocerotinoic acid (1). Fine white needles; mp
189–1908C, lit.2 189–1908C; [a]2D7¼þ40 (c 2.52), lit.2
þ42; IR nmax 3145 (br), 2931, 2853, 1745, 1694, 1657,
1630, 1596, 1436, 1338, 1219, 1146 cm21;1H and 13C NMR
data identical to published values;2 EIMS m/z (rel. int.) 318
[Mþ] (24), 300 (26), 290 (32), 258 (31), 231 (19), 205 (54),
177 (23), 135 (100), 121 (29); HRFABMS obsd 319.2272
[(MþH)þ], C20H31O3 requires 319.2273.
1662, 1607, 1435, 1332, 1154, 1017 cm21 1H and 13C
;
3.13. Acid hydrolysis of the 10:1 ethyl rhinocerotinoate
(13)/ethyl isorhinocerotinoate (14) mixture (prepared
via the HWE reaction)
3.12.2. Isorhinocerotinoic acid (5). White crystalline solid;
mp 155–1578C, lit.2 156–1588C; [a]2D7¼þ50 (c 1.26), lit.2
þ54; IR nmax 3214 (br), 2931, 2863, 1693, 1651, 1634,
1592, 1442, 1384, 1254, 1164, 1002 cm21 1H and 13C
;
NMR identical to published values;2 EIMS m/z (rel. int.)
318 [Mþ] (24), 300 (10), 285 (13), 258 (22), 241 (9), 220
(45), 205 (44), 176 (22), 135 (100); HRFABMS obsd
319.2273 [(MþH)þ], C20H31O3 requires 319.2273.
The 10:1 13/14 mixture (719 mg, 2.08 mmol) and 5 M
H2SO4 (6.0 mL) in AcOH (7.5 mL) was heated at 1008C for
4 h. The reaction mixture was diluted with H2O (50 mL),
extracted with EtOAc (2£15 mL) and the combined organic
fractions extracted with 10% K2CO3 (6£10 mL). The
aqueous phases were combined, acidified with HCl and
extracted with EtOAc (3£15 mL). The combined acidic
organic phases were washed with H2O (5 mL), dried
(Na2SO4) and concentrated to give a mixture of 1 and 5 in
3.12.3. Methyl rhinocerotinoate (17). Oil; [a]2D7¼þ43 (c
1.65, CHCl3); IR nmax 2947, 2930, 2863, 1721, 1663, 1607,
1
1
1435, 1223, 1150, 1013 cm21; H NMR d 5.71 (1H, d,
a ratio of 10:1 (determined by H NMR spectroscopy) as a
J¼1.2 Hz, H-14), 3.69 (3H, s, 15-OMe), 2.49 (1H, dd,
J¼17.6, 3.7 Hz, H-6a), 2.37 (1H, m, J¼17.6 Hz, H-6b), 2.31
(2H, m, H2-11), 2.24 (2H, m, H2-12), 2.21 (3H, d, J¼1.3 Hz,
H3-16), 1.90 (1H, br d, J¼12.7 Hz, H-1a), 1.76 (3H, s,
H3-17), 1.69 (1H, dd, J¼14.3, 3.7 Hz, H-5), 1.65 (1H, m,
H-2a), 1.59 (1H, m, H-2b), 1.47 (1H, br d, J¼13.2 Hz,
H-3a), 1.35 (1H, td, J¼12.7, 3.7 Hz, H-1b), 1.21 (1H, td,
J¼13.5, 4.1 Hz, H-3b), 1.08 (3H, s, H3-20), 0.91 (3H, s,
H3-19), 0.87 (3H, s, H3-18); 13C NMR d 200.0 (s, C-7),
167.0 (s, C-15), 166.3 (s, C-9), 158.9 (s, C-13), 130.5 (s,
C-8), 115.5 (d, C-14), 50.9 (q, 15-OMe), 50.3 (d, C-5), 41.3
(t, C-3), 41.0 (s, C-10), 39.6 (t, C-12), 35.9 (t, C-1), 35.2 (t,
C-6), 33.1 (s, C-4), 32.5 (q, C-18), 27.7 (t, C-11), 21.3 (q,
C-19), 18.8 (q, C-16), 18.6 (t, C-2), 18.2 (q, C-20), 11.4 (q,
C-17); EIMS m/z (rel. int.) 332 [Mþ] (69), 317 (26), 304
(43), 300 (35), 285 (36), 258 (28), 245 (28), 205 (25), 135
(100), 121 (24); HRFABMS obsd 333.2420 [(MþH)þ],
C21H33O3 requires 333.2430.
light yellow solid (542 mg, 1.70 mmol, 82%). Washing with
hexane and vacuum sublimation (1508C, 0.5 mm Hg)
afforded rhinocerotinoic acid (1, 478 mg, 1.50 mmol, 72%
overall) as fine white needles (isomerically pure by 1H NMR).
Acknowledgements
We are very grateful to Mrs Estelle Brink of the Albany
Museum Herbarium, Grahamstown for the taxonomic
identification of E. rhinocerotis. Rhodes University, the
South African National Research Foundation (NRF) and the
South African Network for Coastal and Oceanographic
Research (SANCOR) are thanked for their financial support.
C. A. G. gratefully acknowledges student support in the
form of a Rhodes University Post-Graduate Scholarship.
3.12.4. Methyl isorhinocerotinoate (18). Oil; [a]2D7¼þ49
(c 1.76, CHCl3); IR nmax 2948, 2931, 2862, 1718, 1662,
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