Diastereoselective routes towards the austrodorane skeleton based on pinacol rearrangement: synthesis of (+)-austrodoral and (+)-austrodoric acid

Article abstract of DOI:10.1016/j.tet.2007.09.016

Efficient routes towards the austrodorane skeleton from the labdane diterpene (-)-sclareol (22) are described. The processes, based on pinacol rearrangement, take place with complete diastereoselectivity. Utilizing these, the marine nor-sesquiterpenes (+)-austrodoral (1) and (+)-austrodoric acid (2) have been prepared from 22. Ketone 19, a key intermediate in the synthesis of rearranged cytotoxic diterpene lactones, such as norrisolide (3), has also been prepared in moderate yield.

Full text of DOI:10.1016/j.tet.2007.09.016

Tetrahedron 63 (2007) 11943–11951
Diastereoselective routes towards the austrodorane
skeleton based on pinacol rearrangement: synthesis
of (D)-austrodoral and (D)-austrodoric acid
a
a
Enrique Alvarez-Manzaneda,a, Rachid Chahboun, Inmaculada Barranco,
*
a
a
a
b
ꢀ
Eduardo Cabrera, Esteban Alvarez, Armando Lara, Ramon Alvarez-Manzaneda,
Mohamed Hmamouchic and Hakima Es-Samtic
aDepartamento de Quꢀımica Orgaꢀnica, Facultad de Ciencias, Instituto de Biotecnologꢀıa,
Universidad de Granada, 18071 Granada, Spain
bDepartamento de Quꢀımica Orgaꢀnica, Facultad de Ciencias, Universidad de Almerꢀıa, 04120 Almerꢀıa, Spain
c
´
´
Departement de Biologie, Unite des Substances Naturelles, Faculte de Medecine et Pharmacie,
Universite Mohammed V-Suissi, Rabat, Morocco
Received 1 August 2007; accepted 7 September 2007
Available online 12 September 2007
Abstract—Efficient routes towards the austrodorane skeleton from the labdane diterpene (ꢀ)-sclareol (22) are described. The processes,
based on pinacol rearrangement, take place with complete diastereoselectivity. Utilizing these, the marine nor-sesquiterpenes (+)-austrodoral
(1) and (+)-austrodoric acid (2) have been prepared from 22. Ketone 19, a key intermediate in the synthesis of rearranged cytotoxic diterpene
lactones, such as norrisolide (3), has also been prepared in moderate yield.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Austrodoriskerguelenensis(Fig. 1).1 Theunusual, rearranged
perhydroindane moiety of this sesquiterpene skeleton,
named ‘austrodorane’, is also present in the structure of the
rearranged diterpene lactones norrisolide (3), a cytotoxic
metabolite isolated from the nudibranch Chromodoris nor-
risi,2 chromodorolides A (4) and B (5), found in the nudi-
branch Chromodoris cavae,3 or the most recently reported
chromodorolide C (6), isolated from an Aplysillid sponge.4
Research into the chemical composition of marine organ-
isms is one of the most exciting activities in the field of nat-
ural products chemistry, because of the incessant discovery
of metabolites with novel chemical structures and potent
biological activities.
Recently, Cimino’s group reported the isolation of (+)-
austrodoral (1) and the related (+)-austrodoric acid (2),
with a new carbon skeleton, from the Antarctic nudibranch
During the last few years, chemists have studied this type
of marine metabolites not only because of their unusual
O
H
O
O
OAc
O
HO
AcO
R
AcO
O
O
AcO
O
H
H
R
O
H
H
H
H
OAc
O
5 R: OAc
6 R: OH
1 R: CHO
2 R: COOH
3
4
Figure 1. Austrodorane sesquiterpenes and structurally related spongiane diterpenes.
* Corresponding author. Tel./fax: +34 958 248089; e-mail: eamr@ugr.es
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.016

11944
E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11943–11951
structures but also due to their biological properties and eco-
logical significance. These substances, with toxic and anti-
feedant activities, are concentrated in the skin and constitute
a ‘chemical shell’ possessed by the shell-less marine mol-
luscs, named nudibranchs, against their natural predators.5
Recent studies indicate that these metabolites are acquired
from the nudibranch’s diet, which generally includes sponges
and bryozoans. Despite the still incompletely explored
biology of this class of compounds, interesting biological
properties including antifungal, antimicrobial, antifeedant,
antitumour and PLA2 inhibition, have been reported.6
On the other hand, the perhydroindane moiety of norrisolide
(3), which seems to play an important role in the biological
activity of this type of compounds, has been synthesized
through ketone 19, prepared via asymmetric Robinson annu-
lation (Scheme 2).10 This ketone could also be synthesized
starting from aldehyde 1 and/or acid 2.
O
I
O
2 steps
(60%)
13 steps
(8%)
3
+
O
O
19
20
The scarcity of these metabolites in their natural sources and
the observed fast degradation during the isolation of some
of them, such as (+)-austrodoral (1), oblige us to develop
suitable syntheses in order to study their structural and
biological features. Cimino et al. developed a synthesis of
(+)-austrodoric acid (2) starting from (+)-sclareolide (7).
The key step was the rearrangement of epoxyester 10 to
giveketoester 11in45%yield, aftertreatmentwithacomplex
Lewis acid, tris-(p-bromophenyl)-aminium-hexachloro-
antimonate; epoxidation of acetoxyalkene 8 led to a 3:1
mixture of stereoisomers 10 and 9 (Scheme 1).7 After unsuc-
cessful attempts to convert acid 2 into aldehyde 1, these
authors utilized a similar methodology to convert lactone
7 into (+)-austrodoral (1). The key step was again the isom-
erization of epoxyester 16 to ketoester 17, which took place
in good yields, under acidic conditions. In this case, epoxida-
tion of drimane alcohol 13 gave a 3:1 mixture of stereoiso-
mers 15 and 14 (Scheme 1).8
Scheme 2. Synthesis of the hydrindane core fragment of norrisolide (3).
2. Results and discussion
During our research into the synthesis of bioactive marine
metabolites from diterpenes we examined the recently iso-
lated rearranged sesquiterpenes 1 and 2, and other structur-
ally related spongiane diterpenes, such as compound 3. We
planned the synthesis of (+)-austrodoral (1) and (+)-austro-
doric acid (2) from (ꢀ)-sclareol (22), a labdane diterpene
that is very abundant in Salvia sclarea. The key step involves
the ring contraction through the pinacol rearrangement of
diol II, leading to intermediate ketone I. Compounds 1
and 2 are obtained after oxidative degradation of ketone I
(Scheme 3).
Scheme 4 shows a first approach to these compounds. The
epoxidation of 9,11-drimen-8a-ol (21)11,12 led quantita-
tively and with complete stereoselectivity to 23, isolated as
a crystalline solid. The behaviour of epoxy alcohol 23
against different Lewis acids was investigated: complex
mixtures were obtained in all cases.
O
R
R
O
O
(ii)
(i)
or (vi)
or (vii)
Crystalline iodohydrine 24 resulted by treating epoxide 23
with the PPh3/I2 system. The treatment of compound 24
with BF3$OEt2 gave the expected iodoketone 25 in high
yield. All attempts at converting ketone 25 into acid 2 under
the haloform reaction conditions, e.g., KI, I2, KOH in diox-
ane, were unsuccessful, affording instead methyl ketone 26.
Even though these results seem to indicate that compound 26
would remain unreactive under the haloform conditions, due
probably to the steric hindrance, the behaviour of this methyl
ketone against these oxidizing reagents under more drastic
conditions was assayed; methyl ketone 26 was recovered un-
altered in all cases. Iodoketone 25 was converted in low yield
into (+)-austrodoric acid (2) after prolonged reflux in
DMSO. Interestingly, epoxide 23 was directly and quantita-
tively transformed into ketone 26, by treating with PPh3 and
I2 in CH2Cl2 under reflux. Scheme 5 shows a possible mech-
anism. The pinacol rearrangement of 24 induced by the
phosphonium salt, would afford the iodoketone 25, which
would be reduced by iodide anion to give 26.
7
8 R: CH2OAc
13 R: OH
9 R: CH2OAc
14 R: OH
O
+
(v)
R
O
O
2
(iv)
R
(iii)
12
or (ix)
(x)
11 R: CH2CH2OAc
17 R: CH2OAc
10 R:CH2OAc
OH
15 R: OH
OH
16 R: OAc
(xi)
1
18
Scheme 1. Synthesis of austrodoral (1) and austrodoric acid (2) by Cimino’s
group. Reagents, conditions and yields: (i) Ref. 7, three steps (72% global
yield); (ii) MCPBA, CH2Cl2, 0 ꢁC, 1 h (90%); (iii) RSbCl6, CH2Cl2, rt,
1 h (45%); (iv) NaH, THF, ꢀ78 ꢁC/rt, 4 h (52%); (v) OsO4, NaIO4,
t-BuOH, H2O, 45 ꢁC, 12 h (70%); (vi) Ref. 8, six steps (65% global);
(vii) o-PPA, Et2O, 0 ꢁC, 12 h (75%); (viii) Ac2O, pyridine, rt, 12 h (89%);
(ix) RSbCl6, CH2Cl2, rt, 2 h (87%) or FSO3H, 2-nitropropane, ꢀ78 ꢁC,
30 min (quant.); (x) LiAlH4, Et2O, rt, 3 h (98%); (xi) NaIO4, THF, H2O,
rt, 3 h (quant.).
The hydroxyketone 28, obtained after pinacol rearrange-
ment of triol 27, resulted in a most suitable precursor of
acid 2 and also enabled us to obtain aldehyde 1 (Scheme
6). Compound 27, which could not be synthesized from ep-
oxide 23 by ring opening, was obtained in high yield and
with complete stereoselectivity after cis-dihydroxylation of
Publication of the above synthesis of (+)-austrodoric acid (2)
prompted us to report our previous results on this subject.9

E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11943–11951
11945
X
OH
O
1
OH
OH
X
OH
OH
2
I
II
21
22
Scheme 3. Retrosynthesis for 1 and 2 from (ꢀ)-sclareol (22).
I
OH
OH
OH
O
O
OH
OH
(ii)
(i)
(iii)
(i)
(ii)
OH
OH
22
OH
OH
27
23
24
21
21
28
(v)
(iii)
(iv)
(vii)
12
O
O
13
OH
COOH
I
9
CHO
OH
(v)
11
COOH
8
10
(iv)
15
14
25
2
26
1
18
2
Scheme 6. Avery efficient synthesis of compounds 1 and 2, via drimanetriol
27. Reagents, conditions and yields: (i) OsO4, H2O, t-BuOH, trimethyl-
amine N-oxide, pyridine, reflux, 24 h (87%); (ii) BF3$OEt2, CH2Cl2,
0 ꢁC/rt, 20 min (95%); (iii) NaBH4, EtOH, rt, 15 min (97%); (iv)
Pb(OAc)4, CH2Cl2, rt, 45 min (92%); (v) NaIO4, t-BuOH/H2O, reflux,
12 h (91%).
(vi)
Scheme 4. Synthesis of austrodoric acid (2) from (ꢀ)-sclareol (22).
Reagents, conditions and yields: (i) Ref. 12, four steps (59% global yield);
(ii) MCPBA, CH2Cl2, rt, 1 h (quant.); (iii) PPh3, I2, CH2Cl2, rt, 30 min
(quant.); (iv) BF3$OEt2, CH2Cl2, rt, 15 min (92%); (v) I2, KI, aq NaOH, di-
oxane, rt, 24 h (76%); (vi) DMSO, reflux, two days (30%); (vii) PPh3, I2,
CH2Cl2, rt, 20 min, reflux, 2 h (88%).
complete stereoselectivity, affording diol 30 in 83% yield.
Compound 30 underwent the expected rearrangement in
high yield, under the same mild conditions utilized for diols
24 and 27, to give the acetoxyketone 11, which was effi-
ciently converted into enone 12 after refluxing with DBU
in benzene. Oxidative degradation of ketone 12 with
OsO4/NaIO4 gave (+)-austrodoric acid (2).7
I
OH
I
OH
OH
O
O
PPh3I
-HI
I
PPh3
I2
OH
O
PPh3
I
24
-Ph3PO
-I
23
I
H
O
OAc
OAc
OH
OAc
OH
OH
I
(ii)
(i)
(iii)
I
-I2
OH
22
8
30
26
25
29
(iv)
Scheme 5. Possible mechanism for the direct transformation of 23 into 26.
O
O
COOH
hydroxy alkene 21. Treatment of triol 27 with BF3$OEt2 led
to ketone 28 in almost quantitative yield. Compound 28 was
easily converted into (+)-austrodoral (1) via diol 18. (+)-
Austrodoric acid (2) was also obtained in high yield by treat-
ing the hydroxyketone 28 with NaIO4.
OAc
(v)
(vi)
11
2
12
Scheme 7. Synthesis of acid 2 via acetoxyalkene 8. Reagents, conditions
and yields: (i) Ref. 13, three steps (60% global); (ii) Ref. 14; (iii) 0.2% aq
OsO4, Me3NO, pyridine, t-BuOH, Ar, reflux, seven days (90%); (iv)
BF3$OEt2, CH2Cl2, 0 ꢁC/rt, 30 min (94%); (v) DBU, benzene, reflux,
12 h (95%); (vi) Ref. 7 (70%).
After the successful ring contraction, via pinacol rearrange-
ment of drimanediols 24 and 27, we were interested in inves-
tigating the scope of this methodology in order to obtain
terpenoids bearing a longer side chain on the pentacyclic
moiety. Thus, we studied the behaviour of diol 30, derived
from acetoxyalkene 8, whose efficient preparation from
(ꢀ)-sclareol (22) had been previously reported by us
(Scheme 7). Treatment of acetoxyalcohol 29, obtained in
a three-step sequence (60% overall yield) from 22,13 with
PPh3/I2, utilizing a methodology recently described by our
group,14 afforded compound 8 in 87% yield. The cis-dihy-
droxylation of alkene 8 with OsO4 also proceeded with
It should be noted that the obtention of acetoxyketone 11 from
the epoxyester 10 described by Cimino’s group took place in
moderate yield, after treatment with the unusual tris-(p-bro-
mophenyl)-aminium hexachloroantimonate (Scheme 1).7
However, these authors reported a satisfactory result when
the epoxyester 16 was transformed into ketone 17, under
similar conditions. The low yield attained for the desired
rearranged product 11 could be due to cyclization side

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E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11943–11951
Table 1. Reaction of alcohol 34 under different dehydration conditions
reactions, which are most favoured in the precursor homodri-
mane epoxide 10. In contrast with this, the pinacol rearrange-
mentofthehomodrimanediol 30, reportedhere, didnotsuffer
from this disadvantage and led satisfactorily to ketone 11.
Entry
Conditions
Product(s) (%)
1
2
3
4
MsCl, Et3N, 0 ꢁC, 12 h
POCl3, Et3N, ꢀ20 ꢁC
35 (80)
35–31, 2:1 (82)
35–31, 1.25:1 (78)
36 (98)
SOCl2, Et3N, ꢀ50 ꢁC
Finally, in view of the above successful obtention of austro-
dorane derivatives, such as compounds 1, 2 and 26, we
planned a possible synthesis of ketone 19, perhydroindane
synthon of the spongiane diterpene (+)-norrisolide (3), start-
ing from aldehyde 1 or ketone 26 (Scheme 8). Ketone 19 is
obtained after oxidative degradation of exocyclic alkene 31.
Compound 31 results from the pyrolysis of formate 32 or
acetate 33, obtained after Baeyer–Villiger oxidation15 of al-
dehyde 1 or methyl ketone 26, or from the dehydration of the
corresponding alcohol 34. Scheme 9 summarizes the se-
quence from aldehyde 1 to ketone 19. Treatment of aldehyde
1 with MCPBA in CH2Cl2 at reflux for 6 h gave a 45:55 mix-
ture of formate 32 and acid 2; this result is in agreement with
the remarkable instability of aldehyde 1, whose transforma-
tion into acid 2 by exposure of its solution to air had been
reported in the previous studies.7–9 When methyl ketone 26
was treated with MCPBA, under the same reaction condi-
tions utilized for aldehyde 1, no reaction was observed, the
starting material being recovered; the same results were ob-
tained by utilizing H2O2 and trifluorocacetic anhydride as
oxidizing reagents.
Amberlyst 15, CH2Cl2, rt, 4 h
A 4:1 mixture of alkenes 35 and 31 was obtained when the
formate 32 was refluxed with collidine. It should be empha-
sized that our previous studies concerning the ring A func-
tionalization of terpenoids, through the pyrolysis of
quaternary formates similar to 32, revealed that this reaction
was biased in favour of the corresponding exocyclic al-
kene.15 The complete preference for the formation of the en-
docyclic regioisomer observed in this case must be attributed
to the higher stability of endocyclic double bond in the cy-
clopentane ring. Then, the dehydration of alcohol 34, result-
ing from the hydrolysis of ester 32, was investigated; the
most significant results are shown in Table 1. The best results
were obtained with SOCl2 at low temperature, which led to
a 1:25:1 mixture of endocyclic 35 and exocyclic alkene 31 in
good yield. Treatment of alcohol 34 with Amberlyst 15 in
CH2Cl2 at room temperature led to the rearranged alkene
36.16 Finally, ketone 19 was obtained after treatment of the
mixture 35–31 with OsO4/NaIO4. Unfortunately, although a
suitable route towards the perhydroindane synthon of spon-
giane diterpenes from (ꢀ)-sclareol (22) could be expected to
be achieved, the easy oxidation of aldehyde 1 together with
the unfavourable formation of exocyclic alkene 31 dimin-
ishes the usefulness of this method.
O
COR
OR
3
19
1
R: H
31
32 R: CHO
26 R: CH3
33 R: COCH3
34 R: H
3. Conclusions
Scheme 8. A possible synthesis of ketone 19, precursor of spongiane diter-
pene (+)-norrisolide (3) from aldehyde 1 or ketone 26.
In summary, very efficient strategies towards obtaining the
austrodorane skeleton from (ꢀ)-sclareol (22) are reported.
The processes, based on the pinacol rearrangement of the
suitable diols take place with complete diastereoselectivity.
Utilizing these, syntheses of (ꢀ)-austrodoral (1) and austro-
doric acid (2) from 22 are described. Ketone 19, a key inter-
mediate in the synthesis of rearranged diterpene lactones,
such as norrisolide (3), was also obtained in moderate yield.
COR
OCHO
COOH
(i)
or (ii)
+
2
1
R: H
32
26 R: CH3
(iv)
(iii)
4. Experimental
4.1. General
OH
(v)
+
Routinely, dry organic solvents were stored under argon,
over freshly activated molecular sieves. Dichloromethane
(DCM) was dried over calcium hydride. Tetrahydrofuran
(THF) and tert-butyl methyl ether (E) were dried over so-
dium-benzophenone ketyl. Methanol was distilled from
magnesium at 760 Torr. Dimethylsulfoxide (DMSO) and
34
(vi)
35
31
(vii)
O
˚
ethanol were dried over 4 A molecular sieves. Chromato-
graphy separations were carried out using conventional
column on silica gel 60 (230–400 mesh) using hexane/
MeOt-Bu (H/E) mixtures of increasing polarity. Infrared
(IR) spectra were obtained using Perkin Elmer Spectrum
Models 782 and 983G spectrophotometers with samples
between sodium chloride plates or as potassium bromide
pellets. Data are presented as the frequency of absorption
19
36
Scheme 9. Synthesis of ketone 19 from austrodoral (1). Reagents, conditions
and yields: (i) MCPBA, solid NaHCO3, CH2Cl2, reflux, 6 h (32–2, 45:55,
80% from 1; no reaction was observed starting from 26); (ii) 90% H2O2,
(CF3CO)2O, CH2Cl2, rt, 24 h; unaltered ketone 26 was recovered; (iii) col-
lidine, reflux, 12 h (35–31, 4:1, 98%); (iv) KOH, MeOH, rt, 1 h (92%); (v)
and (vi) see Table 1; (vii) 0.2% OsO4, NaIO4, t-BuOH, 45 ꢁC, 5 h (30%).

E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11943–11951
11947
(cmꢀ1). Proton and carbon-13 nuclear magnetic resonance
(1H NMR or 13C NMR) spectra were recorded on Varian
300, 400 and 500 spectrometers, chemical shifts are ex-
pressed in parts per million (d scale) downfield from tetra-
methylsilane. Data are presented as follows: chemical
shift, multiplicity (s¼singlet, br s¼broad singlet, d¼doublet,
t¼triplet, m¼multiplet), J¼coupling constant in hertz (Hz).
The signals of the 13C NMR spectra were assigned utilizing
DEPT experiments. HRMS were obtained on a trisector WG
AutoSpecQ spectrometer. FAB spectra acquisition was per-
formed with a 10,000 resolution and a relative error of
5 ppm.
203 (20), 177 (30), 163 (22), 137 (47), 127 (30), 123 (36),
121 (28), 119 (22), 109 (61), 97 (26), 95 (71); HRMS (FAB)
m/z calcd for C15H27IO2Na 389.0953; found 389.0961.
4.1.3. (5S,8R,10S)-9-(Iodomethyl)austrodor-9-one (25).
BF3$Et2O (0.40 mL, 3.16 mmol) was added at 0 ꢁC to
a stirred solution of compound 24 (0.58 g, 1.58 mmol) in
CH2Cl2 (15 mL) and the cooling bath was removed. After
stirring for 15 min at this temperature, TLC showed no re-
maining starting material. Then, satd aq NaHCO3 (2 mL)
was added slowly, and the mixture was extracted with ether
(2ꢂ30 mL). The organicphasewas washed with water, brine,
dried over Na2SO4 and concentrated to give pure 25 (0.51 g,
92%) as a colourless solid. Mp 75–77 ꢁC; [a]D ꢀ12.6 (c 0.14
CHCl3); IR (KBr) n 1694, 1464, 1384, 1269, 1188, 1088,
4.1.1. 9a,11-Epoxydrimane-8a-ol (23). m-Chloroperoxy-
benzoic acid (MCPBA, 75%; 663 mg, 2.68 mmol) was
added at 0 ꢁC to a stirred solution of compound 21 (0.5 g,
2.25 mmol) in CH2Cl2 (15 mL) and the reaction was allowed
to warm to room temperature for 1 h, then TLC indicated that
no starting 21 remained. The reaction was quenched with
satd aq Na2SO3 (2 mL) and stirred for an additional
30 min. Then, the mixture was poured into ether/water
(40:10 mL), and the organic phase was washed with satd
aq NaHCO3 (9ꢂ10 mL) and brine. The organic phase was
dried over Na2SO4 and concentrated to give pure 23
(535 mg, 99.9%) as a colourless oil. [a]D ꢀ22.6 (c 0.67,
CHCl3); IR (KBr) n 3521, 1775, 1729, 1465, 1386, 1173,
1016, 999, 966, 788, 751 cmꢀ1 1H NMR (300 MHz,
;
CDCl3): d 4.03 (d, J¼11.9 Hz, 1H), 3.88 (d, J¼11.9 Hz,
1H), 2.28 (m, 1H), 1.74–1.22 (m, 8H), 1.32 (s, 3H), 0.94
(ddd, J¼13.1, 13.1, 4.2 Hz, 1H), 0.88 (s, 3H), 0.85 (s, 3H),
0.83 (s, 3H); 13C NMR (75 MHz, CDCl3): d 208.6 (C),
62.5 (C), 52.5 (CH), 47.1 (C), 40.9 (CH2), 36.1 (CH2), 33.8
(CH3), 33.4 (CH2), 32.6 (C), 21.7 (CH2), 21.5 (CH3), 21.1
(CH3), 20.0 (CH2), 15.6 (CH3), 8.3 (CH2); EIMS m/z (rel
int.): 348 [M+] (1), 333 (3), 254 (8), 221 (25), 203 (18),
179 (26), 169 (10), 163 (16), 149 (8), 147 (10), 138 (18),
137 (100), 125 (14), 123 (61), 121 (21), 119 (12), 109 (54),
107 (26), 97 (20), 95 (88), 93 (24); HRMS (FAB) m/z calcd
for C15H25IONa 371.0848; found 371.0843.
1078, 1054, 1009, 975, 948, 915, 842, 789, 675, 582 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 2.82 (d, J¼4.5 Hz, 1H),
2.71 (d, J¼4.5 Hz, 1H), 2.43 (br s, 1H), 1.91 (m, 1H), 1.68
(m, 1H), 1.45–1.35 (m, 9H), 1.32 (s, 3H), 1.16 (s, 3H),
0.86 (s, 3H), 0.79 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 69.33 (C), 69.27 (C), 51.2 (CH), 45.5 (CH2), 42.1 (CH2),
41.3 (CH2), 38.1 (C), 33.6 (C), 32.9 (CH3), 31.8 (CH2),
25.7 (CH3), 21.7 (CH3), 20.4 (CH3), 20.3 (CH2), 18.0
(CH2); EIMS m/z (rel int.): 238 [M+] (10), 159 (5), 147
(6), 139 (10), 123 (12), 119 (14), 111 (16), 109 (22), 105
(23), 95 (30), 91 (39); HRMS (FAB) m/z calcd for
C15H26O2Na 261.1830; found 261.1822.
4.1.4. Treatment of ketone 25 with I2/KI in aq NaOH.
Synthesis of (5S,8R,10S)-9-methylaustrodor-9-one (26).
To a stirred mixture of 25 (125 mg, 0.36 mmol) and 4 N
aq NaOH (2 mL) in 1,4-dioxane (5 mL), were added drop-
wise at room temperature aqueous solutions of iodine
(10%; 2 mL) and KI (20%; 1 mL) for 15 min, and the reac-
tion mixture was stirred for an additional 24 h. Then, it was
quenched with 2 N HCl (4 mL) and diluted with ether
(20 mL). The organic phase was washed with water and
brine, dried over Na2SO4 and concentrated to afford a crude
product which was purified by flash column chromatography
on silica gel (H/E, 8:2) to afford pure methyl ketone 26
(61 mg, 76%) as a colourless oil. [a]D ꢀ1.1 (c 0.62,
CHCl3); IR (KBr) n 1773, 1697, 1464, 1365, 1258, 1208,
4.1.2. 11-Iododrimane-8a,9a-diol (24). Iodine (1.2 g,
4.72 mmol) was added to a solution of triphenylphosphine
(1.2 g, 4.53 mmol) in CH2Cl2 (18 mL) and the mixture
was stirred at room temperature for 5 min. A solution of ep-
oxy alcohol 23 (0.6 g, 2.52 mmol) in CH2Cl2 (15 mL) was
then added and the reaction mixture was further stirred at
this temperature for 30 min, at which time TLC showed no
23. The reaction was quenched with 10% aq NaHSO3
(2 mL) and the mixture was vigorously stirred for 5 min.
Then, the yellow mixture was diluted with ether (50 mL)
and washed with water and brine. The organic phase was
dried over Na2SO4 and concentrated to give a crude product
which was purified by flash chromatography column on sil-
ica gel (H/E, 9:1) to afford pure diol 24 (0.92 g, 99.8%) as
a white solid. Mp 110 ꢁC (dec); [a]D +1.1 (c 0.84, CHCl3);
1
1082, 966, 788, 742 cmꢀ1; H NMR (400 MHz, CDCl3):
d 2.25–2.10 (m, 2H), 2.04 (s, 3H), 1.65–1.15 (m, 8H), 1.13
(s, 3H), 0.90 (m, 1H), 0.83 (s, 3H), 0.82 (s, 3H), 0.79 (s,
3H); 13C NMR (100 MHz, CDCl3): d 215.2 (C), 61.7 (C),
52.4 (CH), 46.7 (C), 41.0 (CH2), 35.9 (CH2), 33.7 (CH3),
33.2 (C), 32.5 (CH2), 29.5 (CH3), 21.7 (CH2), 21.5 (CH3),
20.8 (CH3), 20.1 (CH2), 15.9 (CH3); EIMS m/z (rel int.):
222 [M+] (1), 165 (3), 155 (4), 145 (5), 141 (9), 135 (9),
127 (13), 121 (9), 105 (10), 95 (12), 91 (15), 83 (15), 79
(16), 69 (19), 67 (25), 55 (42); HRMS (FAB) m/z calcd for
C15H26ONa 245.1881; found 245.1877.
IR (KBr) n 3510, 1459, 788, 752 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 3.74 (d, J¼10.7 Hz, 1H), 3.63 (d,
J¼10.7 Hz, 1H), 3.16 (s, 1H), 3.14 (s, 1H), 2.54 (br s, 1H),
1.70–1.42 (m, 8H), 1.30–1.09 (m, 3H), 1.35 (s, 3H), 0.98
(s, 3H), 0.84 (s, 3H), 0.76 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 75.8 (C), 75.4 (C), 46.2 (CH), 43.7 (C), 41.0
(CH2), 39.3 (CH2), 33.8 (CH2), 33.6 (CH3), 33.4 (C), 25.4
(CH3), 21.8 (CH3), 19.5 (CH2), 19.4 (CH2), 17.7 (CH3), 13.4
(CH2); EIMS m/z (rel int.): 366 [M+] (4), 254 (15), 221 (29),
4.1.5. Treatment of 26 with I2/KI in aq NaOH. To a stirred
mixture of methyl ketone 26 (0.5 g, 2.25 mmol) and 4 N aq
NaOH (10 mL) in 1,4-dioxane (25 mL) were added drop-
wise at room temperature aqueous solutions of iodine
(10%; 10 mL) and KI (20%; 5 mL) for 15 min, and the reac-
tion mixture was stirred at reflux for an additional 36 h. Fol-
lowing the same work-up described for compound 25, the
unaltered starting material was obtained.

11948
E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11943–11951
4.1.6. Treatment of epoxy alcohol 23 with I2 and PPh3. Io-
dine (1 g, 3.93 mmol) was added to a solution of triphenyl-
phosphine (1 g, 3.77 mmol) in CH2Cl2 (15 mL) and the
mixture was stirred at room temperature for 3 min. A solu-
tion of epoxy alcohol 23 (0.5 g, 2.1 mmol) in CH2Cl2
(15 mL) was then added and the mixture was further stirred
at reflux for 30 min, at which time TLC showed no 23. The
reaction was quenched with 10% aq NaHSO3 (2 mL) and the
mixture was vigorously stirred for 10 min, and then it was
diluted with ether (50 mL) and washed with water and brine.
The organic phase was dried over Na2SO4 and concentrated
to give a crude product which was purified by flash chroma-
tography column on silica gel (H/E, 9:1) to afford pure
ketone 26 (0.41 g, 88%) as a colourless syrup.
hydroxyketone 28 (1.32 g, 95%) as a colourless oil. [a]D
ꢀ9.1 (c 0.76, CHCl3); IR (film) n 3472, 1694, 1464, 1384,
1
1284, 1233, 1164, 1093, 997, 794, 756 cmꢀ1; H NMR
(300 MHz, CDCl3): d 4.27 (d, J¼18.5 Hz, 1H), 4.18 (d,
J¼18.5 Hz, 1H), 3.10 (br s, 1H), 2.20 (m, 1H), 1.80–1.12
(m, 10H), 1.12 (s, 3H), 0.92 (m, 1H), 0.91 (s, 3H), 0.85 (s,
3H), 0.84 (s, 6H); 13C NMR (75 MHz, CDCl3): d 216.4
(C), 67.4 (CH2), 59.2 (C), 52.4 (CH), 47.7 (C), 40.8 (CH2),
35.4 (CH2), 33.8 (CH3), 33.1 (CH2), 30.9 (C), 21.9 (CH2),
21.5 (CH3), 19.9 (CH2), 18.4 (CH3), 16.1 (CH3); HRMS
(FAB) m/z calcd for C15H26O2Na 261.1830; found 261.1822.
4.1.10. (5S,8R,10S)-9-(Hydroxymethyl)austrodor-9-ol
(18). Sodium borohydride (0.32 g, 8.42 mmol) was added
to
a stirred solution of hydroxyketone 28 (1.3 g,
4.1.7. Austrodoric acid (2). A solution of iodoketone 25
(0.2 g, 0.57 mmol) in DMSO (6 mL) was stirred at reflux
for two days. Then, the reaction mixture was diluted with
ether (20 mL) and washed with water and brine. The organic
phase was dried over Na2SO4 and evaporated to give a crude
product which was purified by a chromatography column
(H/E, 7:3) to afford acid 2 (39 mg, 30%) as a white solid.
Mp 172–173 ꢁC; [a]D +4.4 (c 1.2, CHCl3) [lit.:7 ꢀ2.0 (c
5.46 mmol) in EtOH (10 mL) and the reaction mixture was
stirred at room temperature for 15 min, at which time TLC
showed no 28. The reaction mixture was quenched with wa-
ter (1 mL), the solvent was evaporated, and the crude prod-
uct was diluted with ether (30 mL) and washed with water
and brine. The organic phase was dried over Na2SO4 and
concentrated to give 18 (1.27 g, 97%) as a mixture of diaste-
reoisomers (ratio 4:1); 1H NMR (400 MHz, CDCl3) data for
the major product: d 3.84 (dd, J¼9.5, 3.1 Hz, 1H), 3.75 (dd,
J¼10.6, 3.3 Hz, 1H), 3.51 (dd, J¼10.3, 9.5 Hz, 1H), 2.72 (br
s, 2H), 2.16 (m, 2H), 1.69–1.14 (m, 8H), 1.03 (ddd, J¼16.6,
13.7, 3.7 Hz, 1H), 0.90 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H),
0.80 (s, 3H); 13C NMR (100 MHz, CDCl3) data for the major
product: d 73.6 (CH), 62.9 (CH2), 52.5 (CH), 48.9 (C), 45.8
(C), 40.4 (CH2), 33.8 (CH2), 33.3 (CH3), 32.3 (C), 31.1
(CH2), 20.6 (CH2), 20.5 (CH3), 19.1 (CH2), 16.5 (CH3),
15.3 (CH3); IR (film) data for the mixture: n 3300, 1458,
1381, 1235, 1061, 1002 cmꢀ1; EIMS m/z (rel int.) data for
the mixture: 240 [M+] (3), 235 (11), 204 (10), 189 (14),
163 (32), 133 (19), 123 (65), 119 (40), 109 (87), 107 (78),
105 (69), 95 (100), 91 (85); HRMS (FAB) m/z calcd for
C15H28O2Na 263.1987; found 263.1994.
1
0.15, CHCl3). The MS, IR, H and 13C NMR data agreed
with the literature data.7
4.1.8. Drimane-8a,9a,11-triol (27). To a solution of alco-
hol 21 (1.5 g, 6.75 mmol) in t-BuOH/H2O (45:5 mL) were
added trimethylamine N-oxide dihydrate (0.91 g,
8.19 mmol) and pyridine (0.2 mL) under argon atmosphere.
The solution was stirred for 5 min at room temperature, and
2% aq OsO4 (2.8 mL) was added and the reaction mixture
was further stirred under the inert atmosphere at reflux for
24 h, at which time TLC indicated no remaining starting ma-
terial. The solvent was evaporated to afford a crude product
that was dissolved in ether (40 mL) and washed with water
(3ꢂ10 mL) and brine. The organic phase was dried over
Na2SO4 and concentrated to give pure 27 (1.5 g, 87%) as
a white solid. [a]D +1.46 (c 0.13, CHCl3); IR (KBr) n
3427, 1460, 1389, 1130, 1094, 1059, 989, 936, 828, 771,
4.1.11. Austrodoral (1). Pb(OAc)4 (2.8 g, 6 mmol) was
added to a solution of diol 18 (1 g, 4.16 mmol) in CH2Cl2
(25 mL) and the reaction mixture was stirred at room tem-
perature for 45 min, at which time TLC showed no 18.
The reaction was quenched with 10% aq NaHSO3 (2 mL)
and the mixture was diluted with ether (50 mL) and washed
with satd aq NaHCO3 (3ꢂ10 mL), water and brine. The or-
ganic phase was dried over Na2SO4 and concentrated to give
pure 1 (0.8 g, 92%) as a colourless oil. [a]D +9.0 (c 0.4,
CHCl3) [lit.:1 +5.0 (c 0.3, CHCl3); lit.:8 +18.3 (c 0.45,
668 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 4.08 (d,
J¼11.5 Hz, 1H), 3.78 (s, 1H, –OH), 3.73 (d, J¼11.5 Hz,
1H), 3.69 (br s, 1H, –OH), 3.48 (br s, 1H, –OH), 1.72–
1.14 (m, 9H), 1.43 (s, 3H), 0.94 (s, 3H), 0.89 (s, 3H), 0.81
(s, 3H); 13C NMR (100 MHz, CDCl3): d 78.1 (C), 76.3
(C), 63.5 (CH2), 45.9 (CH), 41.6 (C), 41.3 (CH2), 38.6
(CH2), 33.7 (CH3), 33.1 (C), 32.9 (CH2), 25.5 (CH3), 21.9
(CH3), 19.6 (CH2), 18.4 (CH2), 17.3 (CH3); EIMS m/z (rel
int.): 139 [M+] (5), 128 (6), 116 (7), 111 (11), 105 (12),
96 (9), 93 (14), 91 (26), 85 (12), 81 (16), 79 (24), 77 (35),
75 (35), 65 (28), 63 (33), 56 (28), 55 (42), 54 (75), 48 (7);
HRMS (FAB) m/z calcd for C15H28O3Na 279.1936; found
279.1928.
1
CHCl3)]. The MS, H and 13C NMR data agreed with the
literature data.1,8
4.1.12. Synthesis of acid 2 from hydroxyketone 28. NaIO4
(0.54 g, 2.52 mmol) was added to a solution of compound 28
(0.7 g, 2.94 mmol) in t-BuOH/H2O (25:4 mL) and the reac-
tion mixture was stirred at reflux for 12 h, at which time TLC
showed no 28. Then, the solvent was evaporated, and the
crude product was diluted with ether (40 mL) and washed
with water and brine. The organic phase was dried over
Na2SO4 and concentrated to give pure 2 (0.6 g, 91%) as
a white solid.
4.1.9. (5S,8R,10S)-9-(Hydroxymethyl)austrodor-9-one
(28). BF3$Et2O (1.5 mL, 11.83 mmol) was added at 0 ꢁC
to a stirred solution of triol 27 (1.5 g, 5.86 mmol) in
CH2Cl2 (30 mL) and the cooling bath was removed. After
stirring for 20 min at this temperature, TLC showed no re-
maining starting material. Then, satd aq NaHCO3 (3 mL)
was added slowly, and the mixture was extracted with ether
(2ꢂ50 mL). The organic phase was washed with water,
brine, dried over Na2SO4 and concentrated to give pure
4.1.13. 12-Acetoxy-13,14,15,16-tetranorlabd-8-ene (8).
Iodine (1.8 g, 7.10 mmol) was added to a solution of

E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11943–11951
11949
triphenylphosphine (1.85 g, 7.0 mmol) in CH2Cl2 (15 mL)
and the mixture was stirred at room temperature for 5 min.
A solution of acetoxyalcohol 29 (2 g, 6.75 mmol) in
CH2Cl2 (15 mL) was then added and the reaction mixture
was further stirred at room temperature for 2.5 h, at which
time TLC showed no 29. The reaction was quenched with
10% aq NaHSO3 (2 mL) and the reaction mixture was vigor-
ously stirred for 4 min. The yellow mixture was diluted with
ether (50 mL) and washed with water and brine. The organic
phase was dried over anhydrous Na2SO4 and concentrated to
give a crude product which was purified by flash chromato-
graphy column on silica gel (H/E, 95:5) to afford 8 (1.65 g,
87%) as a colourless syrup. [a]D +92.4 (c 0.7, CHCl3) [lit.:7
+117.1 (c 1.4, CHCl3)]. The MS, IR, 1H and 13C NMR data
agreed with the literature data.7
1 M HCl, water and brine. The organic phase was dried
over Na2SO4 and concentrated under vacuum to yield ketone
12 (378 mg, 95%) as a yellow syrup. [a]D ꢀ13.5 (c 1.2,
1
CHCl3) [lit.:7 ꢀ6.4 (c 0.3, CHCl3)]. The MS, IR, H and
13C NMR data agreed with the literature data.7
4.1.17. Treatment of austrodoral (1) with MCPBA. Syn-
thesis of (5S,8R,10S)-8-formyloxy-9-nor-austrodorane
(32). m-Chloroperoxybenzoic acid (MCPBA, 75%; 1.3 g,
5.25 mmol) was added at 0 ꢁC to a stirred suspension of aus-
trodoral (1) (0.5 g, 2.40 mmol) and solid NaHCO3 (0.43 g,
5.12 mmol) in CH2Cl2 (25 mL) and the reaction was stirred
at reflux for 3 h, at which time TLC indicated no starting ma-
terial remaining. The reaction was quenched with satd aq
Na2SO3 (2 mL) and stirred for an additional 30 min. Then,
it was poured into ether/water (50:10 mL), and the organic
phase was washed with satd aq NaHCO3 (10ꢂ15 mL) and
brine, dried over Na2SO4 and concentrated to give a crude
product which was purified by chromatography column
(H/E, 75:15) to give formate 32 (194 mg, 36%) and acid 2
(236 mg, 44%). Compound 32: [a]D ꢀ16.61 (c 0.49,
CHCl3); IR (film) n 1771, 1718, 1575, 1467, 1426, 1379,
4.1.14. 12-Acetoxy-13,14,15,16-tetranorlabdane-8a,9a-
diol (30). To a solution of 8 (1 g, 3.60 mmol) in t-BuOH
(15 mL) were added trimethylamine N-oxide dihydrate
(1.11 g, 10 mmol) and pyridine (0.5 mL) under argon atmo-
sphere. After stirring for 5 min at room temperature, 2% aq
OsO4 (6 mL) was added and the reaction mixture was further
stirred under inert atmosphere at reflux for seven days. 10%
aq NaHSO3 (3 mL) was added and the solvent was evapo-
rated, then ether (40 mL) was added and the mixture was
washed with 5% HCl (2ꢂ10 mL), water and brine. The or-
ganic phase was dried over Na2SO4 and concentrated to
give a crude product which was purified by flash chromato-
graphy column on silica gel (H/E, 1:1) to give pure 30
(1.01 g, 90%). [a]D 19.9 (c 2.95, CHCl3); IR (film) n 3492,
1
1216, 1187, 1149, 1087, 1019, 804, 728 cmꢀ1; H NMR
(400 MHz, CDCl3): d 8.08 (s, 1H), 2.45 (m, 2H), 1.90–
1.70 (m, 2H), 1.69–1.03 (m, 6H), 1.48 (s, 3H), 1.10 (m,
1H), 0.91 (s, 3H), 0.90 (s, 3H), 0.81 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 161.4 (C), 94.9 (C), 51.5 (CH), 47.5
(C), 41.2 (CH2), 33.8 (CH3), 33.3 (CH2), 33.2 (C), 30.6
(CH2), 30.3 (C), 21.3 (CH3), 20.6 (CH2), 19.5 (CH2), 18.5
(CH3), 16.2 (CH3); EIMS m/z (rel int.): 224 [M+] (4), 222
(9), 163 (26), 139 (15), 111 (32), 107 (45), 105 (36), 95
(20), 93 (35), 91 (57), 85 (100), 83 (100), 77 (42); HRMS
(FAB) m/z calcd for C14H24O2Na 247.1674; found
247.1682.
1
1719, 1459, 1365, 1253, 1099, 1030, 944, 753 cmꢀ1; H
NMR (300 MHz, CDCl3): d 4.37 (m, 2H), 2.96 (br s, 1H),
2.58 (br s, 1H), 2.13 (dd, J¼14.8, 7.8 Hz, 1H), 2.06 (s,
3H), 1.90 (ddd, J¼14.8, 7.6, 6.3 Hz, 1H), 1.35 (s, 3H),
0.96 (s, 3H), 0.91 (s, 3H), 0.83 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 171.4 (C), 80.1 (C), 75.6 (C), 63.2
(CH2), 46.0 (CH), 43.3 (C), 41.5 (CH2), 39.4 (CH2), 33.9
(CH3), 33.4 (C), 32.9 (CH2), 30.2 (CH2), 25.5 (CH3), 22.0
(CH3), 21.4 (CH3), 20.0 (CH2), 18.6 (CH2), 17.3 (CH3);
EIMS m/z (rel int.): 312 [M+] (4), 294 (10), 276 (28), 179
(11), 157 (29), 123 (34), 109 (19), 97 (64), 69 (47), 55
(100); HRMS (FAB) m/z calcd for C18H32O4Na 335.2198;
found 335.2205.
4.1.18. Treatment of methyl ketone 26 with MCPBA. To
a
stirred mixture of methyl ketone 26 (100 mg,
0.45 mmol) and solid NaHCO3 (100 mg, 1.19 mmol) in
CH2Cl2 (10 mL) was added m-chloroperoxybenzoic acid
(MCPBA, 75%; 260 mg, 1.05 mmol) and the reaction was
stirred at reflux for 24 h. The reaction was quenched with
satd aq Na2SO3 (1 mL) and stirred for an additional
30 min. Following the same work-up used to prepare 32,
the unaltered starting material was obtained.
4.1.15. (5S,8R,10S)-9-(2-Acetoxyethyl)-austrodor-9-one
(11). BF3$Et2O (45%, 0.62 mL, 4.89 mmol) was added at
0 ꢁC to a stirred solution of 30 (0.67 g, 2.15 mmol) in
CH2Cl2 (20 mL) and the cooling bath was removed. After
stirring for 30 min, TLC showed no remaining starting ma-
terial. Then satd aq NaHCO3 (1 mL) was added slowly,
and the mixture was extracted with ether (2ꢂ35 mL). The
organic phase was washed with water, brine, dried over
Na2SO4 and concentrated to give 11 (0.593 mg, 94%) as
a yellow oil. [a]D ꢀ2.7 (c 1.9, CHCl3) [lit.:7 ꢀ2.4 (c 1.6,
4.1.19. Treatment of methyl ketone 26 with H2O2/
(CF3CO)2O. To a cooled (0 ꢁC) solution of trifluoroacetic
anhydride (1 mL, 7.08 mmol) in CH2Cl2 (20 mL) was added
a 90% solution of H2O2 (0.3 mL, 7.92 mmol) and the mix-
ture was stirred at this temperature for 10 min. Then a solu-
tion of 26 (0.5 g, 2.25 mmol) in CH2Cl2 (10 mL) was added
and the reaction mixture was stirred at room temperature for
24 h. Solid NaHCO3 (420 mg, 5 mmol) was added and the
reaction mixture was stirred for 15 min, then it was diluted
with ether (50 mL), washed slowly with a solution of
NaHCO3 (3ꢂ15 mL), water, brine, dried (Na2SO4) and the
solvent was evaporated to give the unaltered 26.
1
CHCl3)]. The MS, IR, H and 13C NMR data agreed with
the literature data.7
4.1.16. (5S,8R,10S)-9-Vinylaustrodor-9-one (12). 1,8-Di-
azabicyclo[5.4.0]undec-7-ene (DBU) (520 mg, 3.42 mmol)
was added to a stirred solution of acetoxyketone 11 (0.5 g,
1.70 mmol) in benzene (15 mL) and the mixture was stirred
under reflux for 12 h, at which time TLC showed no 11.
Then, it was diluted with ether (30 mL) and washed with
4.1.20. Treatment of formate 32 with collidine. A solution
of ester 32 (0.3 g, 1.34 mmol) in collidine (5 mL) was re-
fluxed for 12 h, at which time TLC showed no 32. Then,
the reaction mixture was diluted with ether (25 mL) and
washed with 2 N HCl (5ꢂ10 mL), water and brine. The

11950
E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11943–11951
1
organic phase was dried over Na2SO4 and concentrated to
give a mixture of alkenes 35 and 31 (234 mg, 98%) as a yel-
low oil (ratio 4:1).
austrodor-8(12)-ene (31) and 35 (ratio 1:2). Selected H
and 13C NMR chemical shifts (300 and 75 MHz, CDCl3)
for compound 31: d 4.52 (s, 1H), 4.53 (s, 1H) and
99.6 ppm (exocyclic methylene).
4.1.21. (5S,8R,10S)-9-Nor-austrodor-8-ol (34). KOH
(2 N) in MeOH (1 mL) was added to a solution of ester
32 (167 mg, 0.745 mmol) in MeOH (5 mL) and the mix-
ture was stirred at room temperature for 1 h. The solvent
was evaporated and the residue was diluted with ether
(20 mL) and washed with water and brine. The organic
phase was dried (Na2SO4) and the solvent was evaporated
to give alcohol 34 (135 mg, 92%) as a colourless oil. [a]D
ꢀ3.56 (c 0.71, CHCl3); IR (film) n 3169, 1697, 1462,
1H NMR (400 MHz, CDCl3): d 1.84–1.76 (m, 2H),
1.68–1.52 (m, 4H), 1.50–1.25 (m, 4H), 1.18 (s, 3H),
1.08 (ddd, J¼13.1, 13.1, 4.9 Hz, 1H), 0.90 (s, 3H), 0.89
(s, 3H), 0.79 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 82.4 (C), 51.6 (CH), 47.1 (C), 41.4 (CH2), 37.4
(CH2), 33.9 (CH3), 33.2 (C), 30.6 (CH2), 23.0 (CH3),
21.2 (CH3), 20.5 (CH2), 19.7 (CH2), 16.9 (CH3); EIMS
m/z (rel int.): 196 [M+] (4), 191 (5), 189 (5), 179 (6),
165 (9), 147 (10), 141 (12), 127 (18), 119 (16), 115
(19), 105 (21), 95 (21), 91 (75), 79 (44), 77 (48), 69
(73), 55 (100); HRMS (FAB) m/z calcd for C13H24ONa
219.1725; found 219.1719.
4.1.22.3. Treatment of alcohol 34 with thionyl chlo-
ride. SOCl2 (0.1 mL, 1.37 mmol) was added slowly to a so-
lution of 34 (170 mg, 0.858 mmol) and triethylamine (1 mL)
in dry CH2Cl2 (10 mL) at ꢀ50 ꢁC. The reaction mixture was
stirred at this temperature under argon atmosphere for 1 h, at
which time TLC showed no starting material. The reaction
mixture was quenched with satd aq NaHCO3 (1 mL) and
the cooling bath was removed. The mixture was poured
into ether/water (20:5 mL) and it was extracted with ether
(2ꢂ15 mL). The organic phase was washed with 2 N HCl
(3ꢂ10 mL), brine (3ꢂ10 mL), dried over Na2SO4 and the
solvent evaporated to give a crude product which was
purified by flash chromatography on silica gel (H/E, 95:5)
affording a mixture of regioisomers 35 and 31 (119 mg,
78%) as a colourless oil (ratio 1.25:1).
1376, 1281, 1235, 1134, 1022, 919, 788, 751, 572 cmꢀ1
;
4.1.22.4. Treatment of alcohol 34 with Amberlyst 15.
Amberlyst 15 (0.5 g) was added to a solution of alcohol 34
(113 mg, 0.57 mmol) in CH2Cl2 (10 mL) and the mixture
was stirred at room temperature for 4 h, at which time
TLC showed no 34. Then, it was filtered and the solvent
was evaporated to give 13-nor-austrodor-5(10)-ene (36)
(99 mg, 98%). IR (film) n 1693, 1463, 1379, 1359, 1261,
4.1.22. Dehydration of alcohol 34.
4.1.22.1. Treatment of alcohol 34 with mesyl chloride.
Synthesis of (5S,10S)-9-nor-austrodor-7-ene (35). Mesyl
chloride (0.2 mL) was added to a solution of compound
34 (0.1 g, 5.10 mmol) in Et3N (5 mL) and the mixture
was stirred at room temperature for 12 h, at which time
TLC showed no 34. H2O (2 mL) was added and the mix-
ture was extracted with ether (3ꢂ10 mL). The organic
phase was washed with 2 N HCl (3ꢂ10 mL), water and
brine, dried over Na2SO4 and the solvent evaporated to
give alkene 35 (73 mg, 80%). [a]D +2.36 (c 0.10,
CHCl3); IR (film) n 1722, 1560, 1464, 1378, 1260,
1190, 1097, 100, 801, 749 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d 2.09 (m, 2H), 1.72 (m, 2H), 1.51 (dt, J¼6.0,
3.1 Hz, 2H), 1.49 (t, J¼7.1 Hz, 2H), 1.31 (dt, J¼6.0,
3.0 Hz, 2H), 0.88 (s, 6H), 0.87 (s, 6H); 13C NMR
(125 MHz, CDCl3): d 139.4 (C), 138.6 (C), 38.2 (CH2),
38.0 (CH2), 30.9 (C), 29.8 (C), 27.0 (CH2), 26.8 (2CH3),
25.4 (2CH3), 20.6 (CH2), 19.1 (CH2); EIMS m/z (rel int.):
178 [M+] (4), 163 (46), 149 (12), 138 (9), 123 (92), 109
(21), 107 (23), 95 (37), 91 (30), 87 (35), 82 (51), 81 (32),
79 (23), 69 (34); HRMS (FAB) m/z calcd for C13H22Na
201.1619; found 201.1611.
1203, 1097, 1018, 856, 787, 695, 594 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 5.29 (br s, 1H), 1.97 (t, J¼2 Hz,
1H), 1.94 (t, J¼2 Hz, 1H), 1.81–1.37 (m, 6H), 1.12
(ddd, J¼13, 13, 5 Hz, 1H), 1.59 (s, 3H), 0.96 (s, 3H),
0.88 (s, 3H), 0.82 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 151.6 (C), 122.3 (CH), 99.6 (C), 60.2 (CH), 41.6
(CH2), 34.8 (CH2), 33.2 (CH3), 33.1 (C), 29.8 (C), 28.6
(CH2), 21.4 (CH3), 20.1 (CH2), 16.7 (CH3), 12.1 (CH3);
EIMS m/z (rel int.): 178 [M+] (2), 170 (5), 152 (7), 149
(10), 111 (13), 104 (16), 97 (23), 95 (22), 81 (40), 71
(51), 69 (63), 57 (80), 55 (100); HRMS (FAB) m/z calcd
for C13H22Na 201.1619; found 201.1623.
4.1.23. Synthesis of (5S,10S)-9,12-dinor-austrodor-8-one
(19). To a solution of the mixture of alkenes 35–31
(1.25:1) (0.5 g, 2.80 mmol) in t-BuOH/Water (8:1 mL) was
added under argon atmosphere 2% aqueous solution of
OsO4 (1 mL). After stirring for 5 min at room temperature,
sodium periodate (1.8 g, 8.41 mmol) was added and the mix-
ture was stirred at 45 ꢁC under an atmosphere of argon for
5 h. Water (5 mL) was added and the mixture was extracted
with ether (2ꢂ15 mL), the combined ether was washed with
water (3ꢂ10 mL) and brine. The organic phase was dried
over Na2SO4 and concentrated to give a crude product which
was chromatographed on silica gel (H/E, 9:1) to give pure 19
(150 mg, 30%) as a colourless oil. [a]D +112.4 (c 0.9,
4.1.22.2. Treatment of alcohol 34 with phosphorus
oxychloride. Phosphorus oxychloride (0.2 mL) was added
to a solution of alcohol 34 (110 mg, 0.56 mmol) and tri-
ethylamine (3 mL) in dry CH2Cl2 (5 mL) at ꢀ20 ꢁC and
the reaction mixture was stirred at this temperature for
3 h, at which time TLC showed no 34. The reaction mix-
ture was poured into ice and extracted with ether
(3ꢂ10 mL). The combined organic phase was washed
with 2 N HCl (3ꢂ7 mL), water and brine, dried
(Na2SO4) and the solvent was evaporated to give 82 mg
(82%) of a mixture of regioisomers (5S,10S)-9-nor-
1
CH2Cl2) [lit.:10b +107.0 (c 3.8, CH2Cl2)]. The MS, IR, H
and 13C NMR data agreed with the literature data.10b
Acknowledgements
The authors thank the Spanish Ministry of Science and Tech-
nology (Project CTQ2006-12697) and the ‘Junta de Andalu-
cia’ (PAI group FQM-348) for their financial support.

E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11943–11951
11951
R. A.; Nothcote, P. T.; Zubkov, O. A. Eur. J. Org. Chem.
2004, 2, 419–425; (e) Guizzunti, G.; Brady, T. P.; Malhotra,
V.; Theodorakis, E. A. J. Am. Chem. Soc. 2006, 128, 4190–
4191.
Supplementary data
Copies of 1H, 13C NMR and DEPT spectra for compounds 1,
2, 11, 12, 23–28, 30, 32 and 34–36 are included as Supple-
mentary data. Supplementary data associated with this arti-
cle can be found in the online version, at doi:10.1016/
j.tet.2007.09.016.
7. Kultcitki, V.; Ungur, N.; Gavagnin, M.; Carbone, M.; Cimino,
G. Tetrahedron: Asymmetry 2004, 15, 423–428 and references
cited therein.
8. Kultcitki, V.; Ungur, N.; Gavagnin, M.; Carbone, M.; Cimino,
G. Eur. J. Org. Chem. 2005, 1816–1822 and references cited
therein.
References and notes
9. Alvarez-Manzaneda, E. J.; Chahboun, R.; Barranco, I.; Cabrera
Torres, E.; Alvarez, E.; Alvarez-Manzaneda, R. Tetrahedron
Lett. 2005, 46, 5321–5324.
10. (a) Brady, T. P.; Kim, S. H.; Wen, K.; Theodorakis, E. A.
Angew. Chem., Int. Ed. 2004, 43, 739–742; (b) Brady, T. P.;
Kim, S. H.; Wen, K.; Kim, C.; Theodorakis, E. A. Chem.—
Eur. J. 2005, 11, 7175–7190.
11. Alcohol 21 is a natural sesquiterpene isolated from Aspergillus
oryzae. See: (a) Wada, K.; Tanak, S.; Marumo, S. Agric. Biol.
Chem. 1983, 47, 1075–1078; (b) Shishido, K.; Omodani, T.;
Shibuya, M. J. Chem. Soc., Perkin Trans. 1 1991, 2285–2287;
(c) Dominguez, G.; Hueso-Rodriguez, J. A.; De la Torre,
M. C.; Rodriguez, B. Tetrahedron Lett. 1991, 32, 4765–4768.
12. For syntheses of 21 from 22 see: (a) Alvarez-Manzaneda, E. J.;
1. Gavagnin, M.; Carbone, M.; Mollo, E.; Cimino, G. Tetrahedron
Lett. 2003, 44, 1495–1498.
2. (a) Hochlowski, J. E.; Faulkner, D. J.; Matsumoto, G. K.;
Clardy, J. J. Org. Chem. 1983, 48, 1141–1142; (b) Rudi, A.;
Kashman, Y. Tetrahedron Lett. 1990, 46, 4019–4022.
3. (a) Dumdei, E. J.; de Silva, E. D.; Andersen, R. J. J. Am. Chem.
Soc. 1989, 111, 2712–2713; (b) Morris, S. A.; Dumdei, E. J.; de
Silva, E. D.; Andersen, R. J. Can. J. Chem. 1991, 69, 768–771.
4. Rungprom, W.; Chavasiri, W.; Kokpol, V.; Kotze, A.; Garson,
M. J. Mar. Drugs 2004, 2, 101–107.
5. For selected reviews on marine invertebrates’ chemical de-
fenses see: (a) Faulkner, D. J. Nat. Prod. Rep. 1984, 1, 251–
280; (b) Karuso, P. Bioorganic Marine Chemistry; Scheuer,
P. J., Ed.; Springer: Berlin, 1987; pp 31–60; (c) Faulkner,
D. J. Biomedical Importance of Marine Organisms; Fautin,
D. G., Ed.; Memoirs California Academy of Sciences: San
Francisco, CA, 1988; Vol. 13, pp 29–36; (d) Faulkner, D. J.
Ecological Roles of Marine Natural Products; Paul, V. J.,
Ed.; Comstock Publishing Associates: Ithaca, NY, 1992;
pp 119–163; (e) Pawlick, J. R. Chem. Rev. 1993, 93, 1911–
1922; (f) Garson, M. J.; Simpson, J. S. Nat. Prod. Rep. 2004,
21, 164–179; (g) Marin, A.; Ros, J. Sci. Mar. 2004, 68, 227–
241; (h) Pohnert, G. Top. Curr. Chem. 2004, 239, 179–219.
6. (a) Kitagawa, I.; Kobayashi, M. Cancer Chemother. Rep. 1989,
16, 1–8; (b) Stingl, J.; Andersen, R. J.; Emerman, J. T. Cancer
Chemother. Pharmacol. 1992, 30, 401–406; (c) Arno, M.;
ꢀ
Chahboun, R.; Barranco Perez, I.; Cabrera, E.; Alvarez, E.;
Alvarez-Manzaneda, R. Org. Lett. 2005, 7, 1477–1480; (b)
Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.;
ꢀ
ꢀ
Gonzalez Dıaz, C. Synlett 2000, 1561–1564.
13. Barrero, A. F.; Alvarez-Manzaneda, E. J.; Altarejos, J.; Salido,
S.; Ramos, J. M. Tetrahedron 1993, 49, 10405–10412.
14. Alvarez-Manzaneda, E. J.; Chahboun, R.; Cabrera Torres, E.;
Alvarez, E.; Alvarez-Manzaneda, R.; Haidour, A.; Ramos,
J. M. Tetrahedron Lett. 2004, 45, 4453–4455.
15. Barrero, A. F.; Alvarez-Manzaneda, E. J.; Alvarez-Manzaneda,
R.; Chahboun, R.; Meneses, R.; Aparicio, M. Synlett 1999,
713–716.
16. Whitfield, F. B.; Sugowdz, G.; Hlubucek, J. R. Aust. J. Chem.
1982, 35, 2131–2144.
ꢀ
Betancur-Galvis, L.; Gonzalez, M. A.; Zaragoza, R. J.
Bioorg. Med. Chem. 2003, 11, 3171–3177; (d) Keyzers,