First enantiospecific synthesis of marine sesquiterpene quinol akaol A

Article abstract of DOI:10.1039/c1cc14608d

The first enantiospecific synthesis of akaol A, a marine sesquiterpene quinol, has been achieved. Key steps of the synthetic sequence are the oxidative degradation of (-)-sclareol to a dinorlabdane ketoester, mediated by the ozone-lead(iv) acetate system,

Full text of DOI:10.1039/c1cc14608d

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First enantiospecific synthesis of marine sesquiterpene quinol akaol Awz
a
a
a
a
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Enrique Alvarez-Manzaneda,* Rachid Chahboun, Esteban Alvarez, Antonio Fernandez,
Ramon Alvarez-Manzaneda, Ali Haidour, Jose Miguel Ramos and Ali Akhaouzan
b
a
a
a
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Received 27th July 2011, Accepted 27th October 2011
DOI: 10.1039/c1cc14608d
The first enantiospecific synthesis of akaol A, a marine sesquiterpene
quinol, has been achieved. Key steps of the synthetic sequence are the
oxidative degradation of (ꢀ)-sclareol to a dinorlabdane ketoester,
mediated by the ozone–lead(IV) acetate system, the diastereoselective
a-methylation of a ketoaldehyde, followed by an intramolecular
aldol condensation and the further Diels–Alder cycloaddition of a
dienol ether.
possess a tetracyclic structure, including a pyran ring.5 During
the last decade a new type of merosesquiterpene, presenting a
tetracyclic structure, including a cyclopentane ring, has been
isolated from marine sponges and terrestrial fungi. Examples
of this include pelorol (2),6 akaol A (3),2 dasyscyphin B (4),7
C (5),7 D (6)8 and E (7).8 Though the bioactivities of this
family of compounds have yet to be examined comprehensively,
recent studies have revealed that pelorol (2) is an activator of
the inositol 5-phosphatase SHIP,9 whereas dasyscyphin B (4)
and C (5) present potent cytotoxic activities in several human
cell lines,7 and dasyscyphin D (6) and E (7) exhibit antifungal
properties.8
Merosesquiterpenes are natural products of mixed biosynthetic
origin (polyketide-terpenoid) containing a sesquiterpene unit
joined to a phenolic or quinone moiety. The most important
group of this family of compounds, due to the wide variety
of structural types and to their important, potent biological
activities, are those bearing a bicyclic terpene (drimane)
moiety. Smenodiol (1)1 and siphonodictyal C,2 which exhibits
CDK4/cyclin D1 complex inhibitory activity,3 are examples of
drimenyl phenols. The sphingosine kinase inhibitor (ꢀ)-F-125094
is a representative drimenyl quinone (Fig. 1).
Many efforts have been made to synthesise drimenyl phenols
and puupehenone-related compounds.10 In most cases, the carbon
skeleton of these compounds has been elaborated through a
two-synthon strategy, involving the reaction of an aryllithium
derived from a suitably protected polyphenol with a bicyclic
sesquiterpene (drimane derivative) electrophile. However, little
work has been done concerning tetracyclic merosesquiterpenes
bearing the cyclopentane C ring, such as compounds 2–7.
Andersen et al. recently reported the first synthesis of pelorol
(2) starting from (+)-sclareolide.11 These authors utilized the
two-synthon strategy to construct the carbon skeleton of the
target compound, by condensation of an aryllithium with a
drimane hydroxy aldehyde. Andersen’s group came up against
some difficulties in creating the cyclopentane C ring, via intra-
molecular Friedel–Crafts alkylation, which required a sufficiently
activated aromatic moiety.12 As was to be expected, a tetracyclic
precursor with the appropriate configuration on C-8 was
achieved in good yield after careful selection of the aromatic
substrate and cyclization conditions.
Another important group of compounds belonging to this
family of metabolites is that of marine puupehenones, which
Continuing our research into the synthesis of bioactive mero-
sesquiterpenes, we examined the synthesis of sesquiterpene quinols
such as compounds 3–7, which have not been yet synthesized,
probably because the B/C cis fused system is unattainable
utilizing the strategies previously reported. The results reported
by Andersen’s group in their synthesis of pelorol (2), corrobo-
rated by our preliminary studies, revealed that the two-synthon
strategy followed by intramolecular Friedel–Crafts alkylation
led to the tetracyclic intermediate bearing a C8b methyl group
as the major diastereomer. Considering the above arguments,
we planned the synthetic strategy shown in Scheme 1 to achieve
akaol A (3). The cyclopentane C ring of the target compound
will be obtained through the intramolecular aldol condensation
of a ketoaldehyde. The aromatic D ring of precursor 8 will be
Fig. 1 Some representative merosesquiterpenes.
a
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Departamento de Quımica Organica, Facultad de Ciencias,
Instituto de Biotecnologıa, Universidad de Granada, 18071 Granada,
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Spain. E-mail: eamr@ugr.es; Fax: +34 958 24 80 89;
Tel: +34 958 24 80 89
b
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Departamento de Quımica Organica, Facultad de Ciencias,
Universidad de Almerıa, 04120 Almerıa, Spain
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w Electronic supplementary information (ESI) available: Full experi-
mental procedures, spectroscopic data and copies of 1H and 13C
NMR. See DOI: 10.1039/c1cc14608d
z This work is dedicated to the memory of Professor Rafael Suau.
c
606 Chem. Commun., 2012, 48, 606–608
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Scheme 1 Retrosynthesis of akaol A (3).
elaborated after the Diels–Alder cycloaddition of silyl dienol
ether 9 derived from the a,b-enone resulting from the intra-
molecular aldol condensation of ketoaldehyde 10. The C8a
methyl group of compound 3 will be introduced after the
diastereoselective C-methylation of enol derived from the
corresponding suitably protected ketoaldehyde; this will be
obtained from ketone 11, after oxidative hydroboration.
Ketone 11 will be prepared from commercial sclareol (12).
First, the preparation of ketone 11 was investigated. This
compound has been widely utilized as the key intermediate in
the synthesis of many natural products and other compounds
of interest.13 However, only a total synthesis of compound 11,
utilizing a long synthetic sequence which involves optical
resolution, has been reported.13c The most efficient methods
for preparing ketone 11 use natural products as starting
materials; the most common procedure entails the degradative
oxidation of the side chain of a diterpene labdane, which
possesses the exocyclic carbon–carbon double bond of the
target compound.13a,d,e Procedures starting from (ꢀ)-sclareol (12),
a naturally abundant, inexpensive commercial diterpene, have
also been reported; these utilize as an intermediate the corres-
ponding 8-acetyloxy ketone prepared by selective acetylation of
the 8-hydroxy group and subsequent side chain oxidation, or
otherwise the palladium catalyzed allylic rearrangement of
sclareol diacetate followed by ozonolysis.13b Even though a
moderate yield (60%) for the monoacetylation of (ꢀ)-sclareol
(12) has been reported, we encountered serious difficulties in
attaining this result.
Scheme 3 Synthesis of aldehyde 18.
directly converted into formate 14 in almost quantitative yield,
after treatment with the ozone–lead(IV) acetate system, previously
reported by our group;15 the scope and limitations of this
reaction, which can be utilized in a multigram scale, are currently
under study. Ketoester 14 underwent the regioselective elimina-
tion of formic acid to give the exocyclic ketone 11, in high yield,
by heating with collidine.
Scheme 3 shows the transformation of ketone 11 into
aldehyde 18, bearing the characteristic C8a methyl group of
the target compound. After protecting the ketone group as
ethylene ketal, the oxidative hydroboration of the exocyclic
carbon–carbon double bond proceeded with complete diastereo-
selectivity, affording alcohol 16, which was easily converted into
aldehyde 17. However, the a-methylation of the latter involved
some difficulties, because of the strong tendency of this aldehyde
to undergo O-alkylation, probably due to steric factors. This
forced us to assay the methylation of aldehyde 17 under
different reaction conditions. The use of a strong base, such
as NaH, in a polar aprotic solvent, such as DMF, considerably
favoured the O-methylation (18/19, 4 : 6). The highest propor-
tion of C-methylation product was attained utilizing t-BuOK in
benzene.
After the above-described procedures, we addressed the con-
struction of the cyclopentane C and aromatic D ring of akaol A.
Scheme 4 shows the synthesis of intermediate 8, bearing the
tetracyclic skeleton of the final sesquiterpene quinol. The ketal
aldehyde 18 after treatment with 1 M HCl in THF under reflux
Scheme 2 shows a more efficient means of preparing ketone
11 from (ꢀ)-sclareol (12). Treatment of hydroxy aldehyde 13,
obtained in high yield after the ozonolysis of diterpene 12, with
lead(IV) acetate in dichloromethane at room temperature for
30 min gave ketoester 1414 in 93% yield. Compound 12 was
Scheme 2 Synthesis of ketone 11, via formate 14.
Scheme 4 Synthesis of the sesquiterpene quinol precursor 8.
Chem. Commun., 2012, 48, 606–608 607
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This journal is The Royal Society of Chemistry 2012

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Spanish Ministry of Science and Innovation for the predoctoral
grant provided.
Notes and references
1 Y. Venkateswarlu, D. J. Faulkner, J. L. R. Steiner, E. Corcoran
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4 (a) K. Kono, M. Tanaka, T. Ogita, T. Hosoya and T. Kohama,
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5 For some reviews, including the isolation and biological activity of
this type of compound, see: (a) D. J. Faulkner, Nat. Prod. Rep.,
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6 (a) E. Goclick, G. M. Koenig, A. D. Wright and R. Kamisnky,
J. Nat. Prod., 2000, 63, 1150; (b) J. H. Kwak, F. J. Schmitz and
M. Kelly, J. Nat. Prod., 2000, 63, 1153.
Scheme 5 Synthesis of akaol A (3).
for 3 h underwent simultaneous ketone deprotection and intra-
molecular aldol condensation, affording the tricyclic a,b-enone 20.
Treatment of this with TfOTMS and Pri2NEt gave silyl dienol
ether 9, which after refluxing with methyl propiolate in xylene
and further oxidation with DDQ in dioxane under reflux
afforded the tetracyclic compound 21 together with the phenol 8.
The silyl ether 21 was transformed into hydroxy ester 8 after
treatment with 1 M HCl in MeOH.
7 V. Rojas de la Parra, V. Mierau, T. Anke and O. Sterner,
Tetrahedron, 2006, 62, 1828.
Finally, functionalization of the aromatic D ring was
tackled. Scheme 5 shows the transformation of compound 8
into akaol A (3). First, the elaboration of the catechol unit was
attempted; the treatment of compound 8 with Fremy’s salt
or benzeneseleninic anhydride gave the unaltered starting
material. This result can be attributed to the deactivation of
the aromatic ring by the ester group. In order to avoid this
inconvenience, the latter was reduced to the hydroxymethyl
group. The phenol 25, resulting from the deprotection of
benzyl ether 24, was then easily converted into o-quinone 26,
which was finally transformed into akaol A (3) by reaction
with Raney nickel. The optical rotation of synthetic akaol A
(3) ([a]D25: ꢀ13.7; c 8.0, MeOH) was similar to that reported
for the natural product ([a]D25: ꢀ12; c 0.15, MeOH); the
spectroscopic properties were identical to those previously
described.2
8 J. C. Liermann, H. Kolshorn, H. Auke, E. Thines and T. Opatz,
J. Nat. Prod., 2008, 71, 1654.
9 J. Kalesnikoff, L. M. Sly, M. R. Hughes, T. Buchse, M. J. Rauh,
L.-P. Cao, V. Lam, A. Mui, M. Huber and G. Krystal, Rev.
Physiol., Biochem., Pharmacol., 2003, 149, 87.
10 For recent examples of synthesis of drimenyl phenols and puupe-
henones, see: (a) S. Quideau, M. Lebon and A.-M. Lamidey,
Org. Lett., 2002, 22, 3975; (b) H. Ishibashi, K. Ishihara and
H. Yamamoto, J. Am. Chem. Soc., 2004, 126, 11122; (c) E. J.
Alvarez-Manzaneda, R. Chahboun, I. Barranco Perez, E. Cabrera,
´
E. Alvarez and R. Alvarez-Manzaneda, Org. Lett., 2005, 7, 1477;
(d) E. J. Alvarez-Manzaneda, R. Chahboun, E. Cabrera, E. Alvarez,
A. Haidour, J. M. Ramos, R. Alvarez-Manzaneda, M. Hmamouchi
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12 We also encountered some difficulties in the construction of the
cyclopentane B ring of taiwaniaquinoids via an intramolecular
Friedel–Crafts alkylation; this goal could only be achieved through
a very reactive intermediate aryl allyl cation. See: E. Alvarez-
Manzaneda, R. Chahboun, E. Cabrera, E. Alvarez, R. Alvarez-
In summary, the first synthesis of (ꢀ)-akaol A (3) has been
achieved starting from (ꢀ)-sclareol (12). The synthetic sequence
includes a new oxidative degradation of the latter, induced by
the ozone–lead(IV) acetate system, which affords ketoester 14 in
high yield. The suitable configuration on C-8 was attained after
the diastereoselective a-methylation of aldehyde 17. The cyclo-
pentane C ring of the target compound was obtained after
intramolecular aldol condensation and the aromatic D ring was
constructed through a Diels–Alder cycloaddition involving silyl
dienol ether 9.
Manzaneda, R. Meneses, H. Es-Samti and A. Ferna
Chem., 2009, 74, 3384.
´
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13 For examples of syntheses of natural products and related com-
pounds from ketone 13, see: (a) M. C. Costa, R. Tavares, W. B.
Motherwell and M. J. C. Curto, Tetrahedron Lett., 1994, 35, 8839;
(b) B. Waegell, Pure Appl. Chem., 1997, 69, 627; (c) H. Toshima,
H. Oikawa, T. Toyomasu and T. Sassa, Tetrahedron, 2000,
56, 8443; (d) J. Villamizar, J. Fuentes, F. Salazar, E. Tropper
and R. Alonso, J. Nat. Prod., 2003, 66, 1623; (e) J. S. Yadav,
G. Baishya and U. Dash, Tetrahedron, 2007, 63, 9896;
(f) P. Basabe, O. Bodero, I. S. Marcos, D. Diez, M. de Roma
A. Blanco and J. G. Urones, Tetrahedron, 2007, 63, 11838.
14 J. M. Castro, S. Salido, J. Altarejos, M. Nogueras and A. Sa
Tetrahedron, 2002, 58, 5941.
´
n,
´
nchez,
The authors thank the Spanish Ministry of Science and
Innovation (Project CTQ2009-09932) and the Regional Govern-
ment of Andalusia (Project P07-FQM-03101 and assistance to
the FQM-348 group) for financial support. A. F. thanks the
15 E. J. Alvarez-Manzaneda, R. Chahboun, M. J. Cano, E. Cabrera
Torres, E. Alvarez, R. Alvarez-Manzaneda, A. Haidour and
J. M. Ramos Lopez, Tetrahedron Lett., 2006, 42, 6619.
´
c
608 Chem. Commun., 2012, 48, 606–608
This journal is The Royal Society of Chemistry 2012