Enantiospecific synthesis of the antituberculosis marine sponge metabolite (+)-puupehenone. The arenol oxidative activation route.

Article abstract of DOI:10.1021/ol026855t

[formula: see text] The total synthesis of the marine sesquiterpene quinone (+)-puupehenone, a promising new antituberculosis agent, was achieved in 10 steps starting from commercially available (+)-sclareolide. The key feature of this synthesis is the construction of the heterocycle via an intramolecular attack of the terpenoid-derived C-8 oxygen function onto an oxidatively activated 1,2-dihydroxyphenyl unit.

Full text of DOI:10.1021/ol026855t

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3975-3978
Enantiospecific Synthesis of the
Antituberculosis Marine Sponge
Metabolite (+)-Puupehenone. The Arenol
Oxidative Activation Route
Ste´phane Quideau,* Marjolaine Lebon, and Anne-Marie Lamidey
Laboratoire de Chimie des Substances Ve´ge´tales, Centre de Recherche en
Chimie Mole´culaire, UniVersite´ Bordeaux 1, 351 Cours de la Libe´ration,
F-33405 Talence Cedex, France
s.quideau@lcsV.u-bordeaux1.fr
Received September 5, 2002
ABSTRACT
The total synthesis of the marine sesquiterpene quinone (+)-puupehenone, a promising new antituberculosis agent, was achieved in 10 steps
starting from commercially available (+)-sclareolide. The key feature of this synthesis is the construction of the heterocycle via an intramolecular
attack of the terpenoid-derived C-8 oxygen function onto an oxidatively activated 1,2-dihydroxyphenyl unit.
(+)-Puupehenone (1)1 belongs to a family of marine ses-
quiterpene-quinones and quinols that today has more than a
hundred members.2 First isolated by Scheuer and co-workers
from a yellow encrusting sponge, which was collected off
the island of Lanai and tentatively identified as Chondrosia
chucalla,3 this naturally occurring quinone methide has since
been found in many sponge specimens such as Heteronema,
Hyrtios, and Strongylophora sp.4 The special chemical
reactivity of the quinone methide moiety of 15 engenders
the formation of numerous other puupehenone-derived
metabolites such as puupehedione (2),6 15-cyanopuupehenol
(3),7 15-oxopuupehenol (4),4c and the halopuupehenones 5a
and 5b,3 as well as dimers such as the most recently
discovered dipuupehedione (6)4d (Figure 1). All of these
compounds display a wide range of biological properties as
antitumor, antiviral, antimalarial, antibiotic, and immuno-
modulatory agents. Most remarkably, (+)-puupehenone (1)
was recently reported to fully inhibit the growth of Myco-
bacterium tuberculosis at a concentration of 12.5 µg/mL (i.e.,
MIC ) 38 µM).8 This remarkable antituberculosis activity
is perhaps today the most promising biological property of
(1) Urban, S.; Capon, R. J. J. Nat. Prod. 1996, 59, 900-901.
(2) Capon, R. J. In Studies in Natural Products Chemistry; Atta-ur-
Rahman, Ed.; Elsevier Science: New York, 1995; Vol. 15, pp 289-326.
(3) Ravi, B. N.; Perzanowski, H. P.; Ross, R. A.; Erdman, T. R.; Scheuer,
P. J.; Finer, A.; Clardy, J. Pure Appl. Chem. 1979, 51, 1893-1900.
(4) (a) Okuda, R. K.; Scheuer, P. J. Experientia 1985, 41, 1355-1356.
(b) Kohmoto, S.; McConnell, O. J.; Wright, A. D.; Koehn, F.; Thompson,
W.; Lui, M.; Snader, K. M. J. Nat. Prod. 1986, 50, 336. (c) Nasu, S. S.;
Yeung, B. K. S.; Hamman, M. T.; Scheuer, P. J.; Kelly-Borgues, M.; Goins,
K. J. Org. Chem. 1995, 60, 7290-7292. (d) Bourguet-Kondracki, M. L.;
Debitus, C.; Guyot, M. Tetrahedron Lett. 1996, 37, 3861-3864. (e)
Bourguet-Kondracki, M.-L.; Lacombe, F.; Guyot, M. J. Nat. Prod. 1999,
62, 1304-1305.
(5) Zjawiony, J. K.; Bartyzel, P.; Hamann, M. T. J. Nat. Prod. 1998,
61, 1502-1508.
(6) Hamann, M. T.; Scheuer, P. J.; Kelly-Borges, M. J. Org. Chem. 1993,
58, 6565-6569.
(7) Hamann, M. T.; Scheuer, P. J. Tetrahedron Lett. 1991, 32, 5671-
5672.
(8) El Sayed, K. A.; Bartyzel, P.; Shen, X. D.; Perry, T. L.; Zjawiony,
J. K.; Hamann, M. T. Tetrahedron 2000, 56, 949-953.
10.1021/ol026855t CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/05/2002

Scheme 1
presence of an oxygen function at C-8 of (+)-sclareolide
(9). This drimane unit precursor already possesses the correct
chirality for three of the four (+)-puupehenone (1) stereo-
genic centers, i.e., C-5, C-9, and C-10. It can be purchased
from commercial sources or conveniently prepared from
labdane (-)-8.12 In our synthesis scenario, the nucleophilic
character of the terpenoid 8-oxygen will serve to mediate
the desired heterocyclization by attacking an oxidatively
activated 1,2-dihydroxyphenyl moiety (Scheme 1).
The first task to surmount in our synthesis plan is inversion
of the configuration at C-8. Indeed, the 8-oxygen is
R-oriented in terrestrial plant-derived (+)-9, whereas it is
â-oriented in marine metabolite (+)-1. The prerequisite
epimerization was achieved in the first step of our synthesis
via simple acid treatment (Scheme 2). The ease of this
Figure 1. Examples of puupehenone (1)-derived marine sponge
metabolites.
(+)-1 in view of the current re-emergence of tuberculosis
coinciding with the AIDS epidemic, a dramatic event that
has resulted in the development of new multidrug-resistant
strains of M. tuberculosis.
Scheme 2
The sesquiterpene moiety of 1 features a normal drimane
skeleton annelated to a shikimate-derived hydroxyquinone
unit. Only two total syntheses of 1 have been described. The
first one was reported by Trammel9 in 1978 and started from
a phenol-bearing polyene that was subjected to an initial
cationic bicyclization to construct the drimane unit. This
reaction was followed by an acid-catalyzed electrophilic
addition of the phenol to the remaining drimane olefin. An
ultimate oxidation furnished racemic 1. Despite the lack of
reproducibility of this synthesis noted by Barrero and co-
workers, the electrophilic addition approach to the oxygen
heterocycle probably inspired these authors, who reported
twenty years later the second synthesis of 1 via an orga-
noselenium-induced heterocyclization step.10 This latter
synthesis proceeded in an enantiospecific manner in 15 steps
starting from (-)-sclareol [8, lab-14-en-8,13-(S)-diol], the
main constituent of the flowerheads of SalVia sclarea L.
(clary sage).
In both of these syntheses, the heterocyclic oxygen is
delivered from a 1,2,4-trihydroxyphenyl unit. This strategy
is common to all reported syntheses of puupehenone-related
metabolites and analogues (Scheme 1).10,11 Whether or not
such an approach has some biogenetic relevance, we decided
to proceed in a different and reverse way by exploiting the
inversion of configuration at C-8 is attributed to the release
of the 1,3-diaxial interaction between the 13- and 16-methyl
groups in (+)-9 (Scheme 2).
The γ-lactone unit of the resulting levorotatory isosclar-
eolide 10 was then R-hydroxylated using Vedejs’ MoO5‚
3976
Org. Lett., Vol. 4, No. 22, 2002

pyridine‚HMPA (MoOPH)-based protocol13 to furnish 11 in
good yield as the sole diastereoisomer. Of particular note is
the intriguing inefficiency of LDA in promoting initial
deprotonation. The success of this apparently trivial trans-
formation relied on the use of magnesium bis(diisopropyl-
amide) [(DA)2Mg],14 whose divalent cation advantageously
expressed its chelating properties to facilitate access of the
nitrogen base to the most labile R-proton. In addition to the
formation of the desired acyloin 11 and the recovery of some
unreacted (-)-10 (7.5%), the MoOPH-mediated hydroxyla-
tion reaction gave rise to crystalline side-product 12,15
resulting from the competitive nucleophilic addition of the
enolate intermediate onto R-hydroxylactone 11. This aldol
type side-reaction was also observed in Vedejs’ earlier
work.13b An X-ray crystal structure of 12 established its
stereochemistry, which is consistent with the expectation that
both MoOPH and the drimane carbonyl should preferentially
approach the enolate from its least hindered face.13b The
synthesis of the sesquiterpenoid unit of 1 continued with a
hydride reduction of the lactone ring of 11 into a mixture of
lactol 13 and the desired triol 14 in a modest but unoptimized
yield of 45%. Surprisingly, reduction using LiAlH4 (LAH)
only gave lactol 13 and attempts to further reduce it into 14
with either DIBALH or LAH were to no avail. The triol
14 was then subjected to a nearly quantitative oxidative
cleavage of its 1,2-diol moiety into â-hydroxy aldehyde 15
(Scheme 2).
unit toward intramolecular attack by the drimane 8-oxygen.
This activation relied on the use of [bis(trifluoroacetoxy)-
iodo]benzene (BTI) in CH2Cl2 at -25 °C. Such λ3-iodane
reagents17 constitute today a convenient alternative to the
use of toxic heavy metal-based reagents for activating arenols
(i.e., any hydroxylated arene rings) toward oxidative nu-
cleophilic substitution reactions.18
The hypervalent iodine(III)-mediated transformation of 20
led to a 3:1 diastereomeric mixture (unassigned) of spirocycle
21 as the only heterocyclic system produced despite the
presence of two phenolic hydroxyl groups in starting 20. The
mechanistic consensus about such a phenolic activation
process implies passage through an arenoxenium ion inter-
mediate or a transient equivalent thereof.18a,g The C-16, C-17,
and C-21 centers are positioned either para or ortho to one
of the phenolic hydroxy groups in 20 and hence are all
available for nucleophilic attack. It thus appears that the
drimane unit exhibits an electron-releasing effect sufficient
to impose the heterocyclization regiochemistry in favor of
an exclusive 5-exo-trig spiroannulation process. Rearrange-
ment of spirocycle 21 into the targeted fused heterocyclic
system was achieved by exploiting the acidity of its enol
function (Scheme 3). An anionic rearrangement was thus
performed by gently heating 21 in anhydrous dioxane in the
presence of KH and 18-crown-6. This reaction did not stop
at the expected catecholic benzopyran (not shown), and we
were very pleased to observe that it had been oxidized in
situ to furnish (+)-1 in 27% yield (unoptimized) over the
last two one-pot transformations. This completed the syn-
The shikimate unit was elaborated from catechol 16
through bromination and benzylation to give bromide 18.
Coupling of this bromide with aldehyde 15 was achieved
via a standard halogen-metal exchange protocol. A subse-
quent hydrogenolysis under standard conditions allowed
removal of both benzyl protective groups, and the benzylic
C-15 hydroxy group that was unveiled at the previous
coupling reaction (Scheme 3), to afford catechol 20 in good
yield. This remarkable deprotection-deoxygenation step16
set the stage for the key oxidative activation of the catechol
(9) Trammel, G. L. Tetrahedron Lett. 1978, 18, 1525-1528.
(10) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R. Tetrahedron
Lett. 1997, 38, 2325-2328.
(11) (a) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.;
Armstrong, V. Tetrahedron 1999, 55, 15181-15208. (b) Barrero, A. F.;
Alvarez-Manzaneda, E. J.; Herrador, M. M.; Chahboun, R.; Galera, P.
Bioorg. Med. Chem. Lett. 1999, 9, 2325-2328. (c) Arjona, O.; Garranzo,
M.; Mahugo, J.; Maroto, E.; Plumet, J.; Sa´ez, B. Tetrahedron Lett. 1997,
38, 7249-7252. (d) Maiti, S.; Sengupta, S.; Giri, C. A., B.; Banerjee, A.
K. Tetrahedron Lett. 2001, 42, 2389-2391. (e) Takao, K.; Sasaki, T.;
Kozaki, T.; Yanagisawa, Y.; Tadano, K.; Kawashima, A.; Shinonaga, H.
Org. Lett. 2001, 3, 4291-4294.
(12) (a) Moulines, J.; Lamidey, A.-M.; Desvergnes-Breuil, V. Synth.
Commun. 2001, 31, 749-758. (b) Ruzicka, L.; Seidel, C. F.; Engel, L. L.
HelV. Chim. Acta 1942, 25, 621-630.
Scheme 3
(13) (a) Vedejs, E. J. Am. Chem. Soc. 1974, 96, 5944-5946. (b) Vedejs,
E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43, 188-196. (c)
Vedejs, E.; Larsen, S. Org. Synth. 1986, 64, 127-137.
(14) Lesse`ne, G.; Tripoli, R.; Cazeau, P.; Biran, C.; Bordeau, M.
Tetrahedron Lett. 1999, 40, 4037-4040.
(15) CCDC 179 441 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via the Internet at
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK. Fax: +44 1223 336033. E-mail:
deposit@ccdc.cam.ac.uk).
(16) Ueki, Y.; Itoh, M.; Katoh, T.; Terashima, S. Tetrahedron Lett. 1996,
37, 5719-5722.
(17) (a) Varvoglis, A. HyperValent Iodine in Organic Synthesis; Aca-
demic Press: San Diego, 1997. (b) Varvoglis, A. Tetrahedron 1997, 53,
1179-1255. (c) Stang, P. J.; Zhdankin, V. V. Chem. ReV. 1996, 96, 1123-
1178. (d) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523-
2584. (e) Koser, G. F. Aldrichimica Acta 2001, 34, 89-102.
(18) (a) Quideau, S.; Pouyse´gu, L. Org. Prep. Proc. Int. 1999, 31, 617-
680. (b) Quideau, S.; Pouyse´gu, L.; Oxoby, M.; Looney, M. A. Tetrahedron
2001, 57, 319-329. (c) Quideau, S.; Feldman, K. S. Tetrahedron
Symposium-in-Print 2001, 57, ix-x. (d) Liao, C.-C. In Modern Methodology
in Organic Synthesis; Shono, T., Ed.; Kodansha: Tokyo, 1992; p 409. (e)
Moriarty, R. M.; Prakash, O. Org. React. 2001, 57, 327-415. (f) Tamura,
Y.; Yakura, T.; Haruta, J.-i.; Kita, Y. J. Org. Chem. 1987, 52, 3927-3930.
(g) Pelter, A.; Ward, R. S. Tetrahedron 2001, 57, 273-282.
Org. Lett., Vol. 4, No. 22, 2002
3977

thesis of (+)-1 in only 10 steps. The identity of synthesized
(+)-puupehenone (1) was confirmed by comparison of H
NMR data with those of an authentic sample and by
comparison of 13C NMR data and optical rotation with
published data.
(+)-puupehenone (1), and Ce´cile De´bitus (Institut de Re-
cherche pour le De´veloppement, New Caledonia) for provid-
ing lyophilized specimens of the sponge, Hyrtios sp., from
which the sample was isolated.
1
Supporting Information Available: Detailed descrip-
1
tions of experimental procedures, H and 13C NMR spectra
Acknowledgment. The authors thank the French Ministry
of Research for M.L.’s research assistantship, Biolandes for
the gift of a multigram quantity of (+)-sclareolide, Marie-
Lise Bourguet-Kondracki (Muse´um National d’Histoire Na-
turelle, Paris, France) for a gift of an authentic sample of
of compounds 10-15, 17-21, and (+)-1, and an ORTEP
diagram of the X-ray structure of 12. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL026855T
3978
Org. Lett., Vol. 4, No. 22, 2002