First enantiospecific synthesis of marine nor-sesquiterpene (+)-austrodoral from (-)-sclareol

Article abstract of DOI:10.1016/j.tetlet.2005.06.010

A short and efficient synthesis of the rearranged nor-sesquiterpenes (+)-austrodoral (1) and (+)-austrodoric acid (2), recently isolated from the Antarctic marine mollusk Austrodoris kerguelenensis, from diterpene (-)-sclareol (4) is reported. The key step of the sequence is the pinacol rearrangement of the drimanetriol 11.

Full text of DOI:10.1016/j.tetlet.2005.06.010

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5321–5324
First enantiospecific synthesis of marine nor-sesquiterpene
+)-austrodoral from (À)-sclareol
a
(
a,
a
a
*
E. J. Alvarez-Manzaneda, R. Chahboun, I. Barranco, E. Cabrera Torres,
a
E. Alvarez and R. Alvarez-Manzaneda
b
a
Departamento de Qu ı´ mica Org a´ nica, Facultad de Ciencias, Instituto de Biotecnolog ı´ a, Universidad de Granada, 18071 Granada, Spain
b
Departamento de Qu ı´ mica Org a´ nica, Facultad de Ciencias, Universidad de Almer ı´ a, 04120 Almer ı´ a, Spain
Received 14 April 2005; revised 30 May 2005; accepted 3 June 2005
Available online 21 June 2005
Abstract—A short and efficient synthesis of the rearranged nor-sesquiterpenes (+)-austrodoral (1) and (+)-austrodoric acid (2),
recently isolated from the Antarctic marine mollusk Austrodoris kerguelenensis, from diterpene (À)-sclareol (4) is reported. The
key step of the sequence is the pinacol rearrangement of the drimanetriol 11.
Ó 2005 Elsevier Ltd. All rights reserved.
Marine organisms constitute an inexhaustible source of
new natural products exhibiting very different structural
patterns and a wide variety of biological activities.
Among these, nudibranch mollusks are known to har-
vest a variety of chemical metabolites, which are in-
volved in the defensive mechanisms of these animals.
The study of this chemical defence is an important goal
of the research from the ecological point of view and in
Moreover, the presence of 1 in the skin of the animal
seems to be related to some kind of defensive mecha-
nism. On the other hand, the increase of this metabolite
in individuals kept in an aquarium for several days sug-
2
gests a probable role as stress-metabolite.
The scarcity of 1 in its natural source, as well as the ob-
served fast degradation during work-up, have prevented
the evaluation of its biological activity, which forces us
to develop a suitable synthesis. Very recently, a first syn-
thesis of the related austrodoric acid (2) from (+)-sclareo-
1
order to achieve new bioactive compounds.
Recently, Cimino and co-workers, have reported the iso-
lation of (+)-austrodoral (1), a nor-sesquiterpene with a
new carbon skeleton, from the Antarctic nudibranch
4
lide (5) has been reported. Acid 2, also obtained during
the isolation of 1, is formed by air oxidation of the latter,
2
Austrodoric kerguelenensis. This compound is of great
interest due to its structural feature. The unusual rear-
ranged bicyclic moiety, characteristic of some spon-
and is probably a work-up product, as Cimino and co-
2
workers claimed. The reported synthesis of 2, a possible
intermediate to prepare 1, from 5 (nine steps, 6.8% global
yield) involves some low yield transformations and few
stereoselective reactions, which makes it a little laborious.
3
gian-type diterpenes, such as (+)-norrisolide (3), was
found in the sesquiterpenes series for the first time.
AcO
O
O
R
OH
O
O
OH
O
1
2
R: CHO
R: COOH
3
4
5
Keywords: Terpenes; Marine metabolites; Enantiospecific synthesis; Pinacol rearrangement; Triphenylphosphine; Iodine.
*
Corresponding author. Tel./fax: +34 958 24 80 89; e-mail: eamr@ugr.es
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.010

5322
E. J. Alvarez-Manzaneda et al. / Tetrahedron Letters 46 (2005) 5321–5324
X
OH
O
CHO
X
OH
OH
1
I
II
6
Scheme 1.
I
O
OH
(
i)
(ii)
(iii)
4
OH
OH
OH
6
7
8
(vii)
(
iv)
O
O
COOH
I
(
v)
2
10
9
(
vi)
Scheme 2. Reagents and conditions: (i) Ref. 6, four steps, 59%; (ii) MCPBA, CH
BF ÆOEt , CH Cl
2
Cl
2
, rt, 1 h (quant.); (iii) PPh , I
3
2
, CH
2
Cl
2
, rt, 30 min (quant.); (iv)
3
2
2
2
, rt, 15 min (92%); (v) Ref. 7 (70–85%); (vi) DMSO, reflux, 2days (30%); (vii) PPh
3
, I , CH
2
2
Cl
2
, rt, 20 min; reflux, 2 h (88%).
Continuing our investigation on the synthesis of bioac-
tive compounds based on homochiral synthons obtained
from natural sources, we plan the synthesis of (+)-aus-
trodoral (1) from (À)-sclareol (4), via 9,11-drimen-8a-
acids afforded complex mixtures, gave in quantitative
8
yield the crystalline iodohydrin 8, by reaction with the
PPh –I system. The treatment of 8 with BF ÆOEt gave
3
2
3
2
8
the expected iodoketone 9 in high yield. All attempts at
converting 9 into acid 2, under different haloform reac-
tion conditions were unsuccessful, affording instead
5
ol (6) (Scheme 1). Aldehyde 1 will be obtained by
degradation of a keto intermediate I, resulting from
the pinacol rearrangement of diol II derived from 6.
Obviously, the success of this synthesis will depend
strongly on the stereoselectivity for the introduction of
the hydroxyl group on C-9.
8
methylketone 10. Compound 9 was converted in low
yield into 2 after prolonged reflux in DMSO. It should
be emphasized that epoxyde 7 was directly transformed
quantitatively into 10, by treatment with PPh and I
3
2
in CH Cl under reflux. A possible mechanism is
2
2
Scheme 2 shows a first approach to this. The epoxy-
dation of 6 led quantitatively and with complete stereo-
selectivity to 7, isolated as a crystalline solid. Epoxy-
alcohol 7, which by treatment with different Lewis
depicted in Scheme 3. The pinacol rearrangement of 8
induced by the phosphonium salt, would afford the
iodoketone 9, which would be reduced by iodide anion
to give 10.
I
I
O
OH
OH
PPh3
OH
PPh3I
-HI
I
OH
O
PPh3
I
I2
8
9
7
-I
-
Ph PO
3
H
I
O
O
OH
I
-I2
I
1
0
Scheme 3.

E. J. Alvarez-Manzaneda et al. / Tetrahedron Letters 46 (2005) 5321–5324
5323
OH
OH
O
OH
(
i)
(ii)
OH
OH
11
6
12
v)
(iii)
(
OH
CHO
OH
COOH
(
iv)
1
13
2
Scheme 4. Reagents and conditions: (i) OsO
2
4
, H
2
O, t-BuOH, trimethylamine N-oxide, pyridine, reflux, 24 h (87%); (ii) BF
0 min (95%); (iii) NaBH , EtOH, rt, 15 min (97%); (iv) Pb(OAc) , CH Cl , rt, 45 min (92%); (v) NaIO , t-BuOH–H O, reflux, 12h (91%).
3
ÆOEt
2
, CH
2
Cl
2
, 0 °C to rt,
4
4
2
2
4
2
A very efficient transformation of 6 into (+)-austrodoral
1), via triol 11, was achieved (Scheme 4). Compound
1, which could not be synthesized from 7 by ring open-
J. E.; Faulkner, D. J.; Matsumoto, G. K.; Clardy, J. J. Org.
Chem. 1983, 48, 1141–1142.
(
1
4
. Kultcitki, V.; Ungur, N.; Gavagnin, M.; Carbone, M.;
Cimino, G. Tetrahedron: Asymmetry 2004, 15, 423–428.
. Alcohol 6 is a natural sesquiterpene isolated from Asper-
gillus oryzae. See: (a) Wada, K.; Tanaka, S.; Marumo, S.
Agric. Biol. Chem. 1983, 47, 1075–1078; (b) Shishido, K.;
Omodani, T.; Shibuya, M. J. Chem. Soc., Perkin Trans. 1
ing, was obtained in high yield and with complete stereo-
selectivity after cis-dihydroxylation of 6. Treatment of
5
8
1
intermediate to prepare 1 and 2. Reduction of 12 gave
1 with BF ÆOEt led to hydroxyketone 12, a suitable
3
2
diol 13, which was then easily converted into aldehyde
1
991, 2285–2287; (c) Dominguez, G.; Hueso-Rodriguez, J.
8
8
1
1
. (+)-Austrodoric acid (2) was obtained by treating
2 with NaIO . It should be remarked that aldehyde 1
A.; De la Torre, M. C.; Rodriguez, B. Tetrahedron Lett.
1991, 32, 4765–4768.
4
is easily transformed into acid 2 by exposition to air of
its solutions. This behaviour, also remarked upon by
Ciminoꢀs group, seems to support the work-up product
nature of this acid.
6. For syntheses of 6 from 4 see: (a) Alvarez-Manzaneda, E.
J.; Chahboun, R.; Barranco P e´ rez, I.; Cabrera, E.; Alvarez,
E.; Alvarez-Manzaneda, R. Org. Lett. 2005, 7, 1477–1480;
(b) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun,
R.; Gonz a´ lez D ´ı az, C. Synlett 2000, 1561–1564.
. Ketone 10 was obtained in 70–85% from 9, under different
7
In summary, the first enantiospecific synthesis of marine
nor-sesquiterpene (+)-austrodoral (1) from (À)-sclareol
haloform reaction conditions, as KI, I
NaOBr, NaBr, NaOH, H O. See: March, J. A. Advanced
2
, KOH, dioxane or
2
(
4) (eight steps, 45% overall yield) is reported. The short
Organic Chemistry: Reactions, Mechanisms and Structures,
5th ed.; Wiley Interscience: New York, 2001; pp 813–814;
For recent examples of the use of haloform reaction see: (a)
Larionov, O. V.; Kozhushkov, S. I.; de Meijere, A.
Synthesis 2005, 158–160; (b) Bolster, M. G.; Jansen, B. J.
M.; de Groot, A. Tetrahedron 2002, 58, 5275–5285.
. All new compounds were fully characterized spectroscop-
ically and had satisfactory high resolution mass spectro-
scopy data. Selected data:
synthetic sequence, involving high-yield steps and com-
pletely stereoselective processes, makes it possible to pre-
pare large amounts of 1 and thus elaborate bicyclic chiral
synthons to gain access to other interesting metabolites,
such as 3.
8
Acknowledgements
Compound 8: Crystalline solid, mp: 110 °C (dec). [a] +1.1
D
1
(0.023 M, CHCl ). H NMR (CDCl , 300 MHz): d 3.74 (d,
3 3
J = 10.7 Hz, 1H), 3.63 (d, J = 10.7 Hz, 1H), 3.16 (s, 1H),
Financial support was received from Ministerio de Cien-
cia y Tecnolog ´ı a (Project PPQ 2002-03308).
2
.54 (br s, 1H), 1.35 (s, 3H), 0.98 (s, 3H), 0.84 (s, 3H), 0.76
1
3
(
s, 3H). C NMR (CDCl
3
, 75 MHz): d 75.8 (C), 75.4 (C),
6.2(CH), 43.7 (C), 41.0 (CH ), 39.3 (CH ), 33.8 (CH ),
3.6 (CH ), 33.4 (C), 25.4 (CH ), 21.8 (CH ), 19.5 (CH ),
4
3
2
2
2
3
3
3
2
References and notes
2 3 2
19.4 (CH ), 17.7(CH ), 13.4 (CH ). IR (KBr): 3510, 2945,
À1
.
2
869, 2363, 2337, 1459, 788, 752 cm
1
. For selected reviews see: (a) Faulkner, D. J. In Biomedical
Importance of Marine Organisms; Fautin, D. G., Ed.;
Memoirs California Academy of Sciences: San Francisco,
CA, 1988; Vol. 13, pp 29–36; (b) Karuso, P. In Bioorganic
Marine Chemistry; Scheuer, P. J., Ed.; Springer: Berlin,
Compound 9: Crystalline solid, mp: 75–77 °C. [a]
D
À12.6
1
(0.012M, CHCl ). H NMR (CDCl , 300 MHz): d 4.03 (d,
3
3
J = 11.9 Hz, 1H), 3.88 (d, J = 11.9 Hz, 1H), 2.29 (m, 1H),
1
3
1.32(s, 3H), 0.88 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H).
NMR (CDCl , 75 MHz): d 208.6 (C), 62.5 (C), 52.5 (CH),
47.1 (C), 40.9 (CH ), 36.1 (CH ), 33.7 (CH ), 33.4 (C), 33.3
), 21.5 (CH ), 21.1 (CH ), 20.0 (CH ), 15.6
C
3
1987; pp 31–60; (c) Faulkner, D. J. Nat. Prod. Rep. 1984, 1,
251–280; (d) Thompson, T. E. J. Mar. Biol. Assoc. UK
1960, 39, 115–122.
2
2
3
(CH
(CH
1459, 788, 752cm
2
), 21.7 (CH
), 8.3 (CH
2
3
3
2
3
2
). IR (KBr): 2945, 2869, 2363, 2337, 1693,
.
À1
2
. Gavagnin, M.; Carbone, M.; Mollo, E.; Cimino, G.
Tetrahedron Lett. 2003, 44, 1495–1498.
. (a) Brady, T. P.; Kim, S.-H.; Wen, K.; Theodorakis, E. A.
Angew. Chem., Int. Ed. 2004, 43, 739–742; (b) Hochlowski,
1
Compound 10: [a]
NMR(CDCl , 400 MHz): d 2.15 (m, 1H), 2.04 (s, 3H), 1.13
(s, 3H), 0.83 (s, 3H), 0.82(s, 3H), 0.79 (s, 3H). C NMR
D
À1.1 (0.028 M, CHCl
3
).
H
3
3
1
3

5324
E. J. Alvarez-Manzaneda et al. / Tetrahedron Letters 46 (2005) 5321–5324
(
4
CDCl
3
, 100 MHz): d 215.2 (C), 61.7 (C), 52.4 (CH), 46.7 (C),
(CH
996, 794, 752cm
(+)-Austrodoric acid (2): Crystalline solid, mp: 172–173 °C.
3 3
), 16.1 (CH ). IR (film): 3479, 2928, 1693, 1465, 1383,
À1
.
1.0 (CH ), 35.9 (CH ), 33.7 (CH ), 33.2(C), 32.5 (CH ), 29.5
2
2
3
2
(
CH ), 21.7 (CH ), 21.5 (CH ), 20.8 (CH ), 20.1 (CH ), 15.9
2
3
2
3
3
À1
13
(
CH
3
). IR: 2929, 1694, 1465, 1234, 793, 741 cm
À9.1 (0.032M, CHCl ). H NMR
, 300 MHz): d 4.27 (d, J = 18.5 Hz, 1H), 4.18
d,J = 18.5 Hz, 1H), 3.71 (br s, 1H), 2.20 (m, 1H), 1.12 (s,
.
[a]
184.4 (C), 56.6 (C), 53.4 (CH), 46.7 (C), 41.3 (CH
(CH ), 33.8 (CH ), 33.2(C), 33.0 (CH ), 21.7 (CH
D 3 3
+4.4 (0.054 M, CHCl ). C NMR (CDCl , 400 MHz): d
1
Compound 12: [a]
(
(
D
3
2
), 35.3
CDCl
3
2
3
2
2
), 21.6
(CH ), 20.5 (CH ), 20.1 (CH ), 15.7 (CH ). IR (KBr): 3300–
3 3 2 3
1
3
1
2800, 2948, 2929, 1686, 1462, 772 cm .
3
H), 0.91 (s, 3H), 0.85 (s, 3H), 0.84 (s, 6H). C NMR
, 75 MHz): d 216.4 (C), 67.4 (CH ), 59.2(C), 5 2. 4
CH), 47.7 (C), 40.8 (CH ), 35.4 (CH ), 33.8 (CH ), 33.1
1 13
(+)-Austrodoral (1): H and C NMR data are identical to
(
(
(
CDCl
3
2
2
those reported in the literature. [a] +9.0 (0.022 M, CHCl ).
2
2
3
D
1
IR (film): 2948, 2868, 1693, 1462, 1374 cm .
3
CH
2
), 30.8 (C), 21.9 (CH
2
), 21.5 (CH
3
), 19.9 (CH
2
), 18.4