Expeditious total syntheses of natural allenic products via aromatic ring umpolung

Article abstract of DOI:10.1021/ol801921d

(Chemical Equation Presented) Concise diastereoselective syntheses of the marine (±)-panacene and terrestrial (±)-desbromopanacene have been achieved in a few steps based on a concept of aromatic ring umpolung . The synthetic avenue to the (±)-panacene involved a novel oxymercuration strategy to produce the correct configuration of the bromoallene moiety.

Full text of DOI:10.1021/ol801921d

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4629-4632
Expeditious Total Syntheses of Natural
Allenic Products via Aromatic Ring
Umpolung
Cyrille Sabot, Didier Be´rard, and Sylvain Canesi*
Laboratoire de Me´thodologie et Synthe`se de Produits Naturels, UniVersite´ du Que´bec
a` Montre´al, C.P. 8888, Succ. Centre-Ville, Montre´al, H3C 3P8 Que´bec, Canada
canesi.sylVain@uqam.ca
Received August 16, 2008
ABSTRACT
Concise diastereoselective syntheses of the marine (()-panacene and terrestrial (()-desbromopanacene have been achieved in a few steps
based on a concept of “aromatic ring umpolung”. The synthetic avenue to the (()-panacene involved a novel oxymercuration strategy to
produce the correct configuration of the bromoallene moiety.
Electron-rich aromatic compounds, such as phenols, anilines,
and their derivatives, normally express nucleophilic reactiv-
ity. However, oxidative activation1,2 can convert these
aromatics into reactive electrophilic intermediates, which may
be intercepted with appropriate nucleophiles in synthetically
useful yields. This is exemplified in Figure 1. Thus, oxidative
(1) A key aspect of the potential of DIB is well defined in the work of
Kita et al.: (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem.
1987, 52, 3927. (b) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita,
S.; Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684. (c)
Kita, Y.; Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.; Eichhorn, J. J.
Org. Chem. 1996, 61, 5854. (d) Kita, Y.; Gyoten, M.; Ohtsubo, M.; Tohma,
H.; Takada, T. Chem. Commun. 1996, 1481. (e) Takada, T.; Arisawa, M.;
Gyoten, M.; Hamada, R.; Tohma, H.; Kita, Y. J. Org. Chem. 1998, 63,
7698. (f) Arisawa, M.; Utsumi, S.; Nakajima, M.; Ramesh, N. G.; Tohma,
H.; Kita, Y. Chem. Commun. 1999, 469. (g) Dohi, T.; Maruyama, A.;
Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.; Caemmerer, S. B.;
Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787 (outstanding asymmetric
version)
(2) (a) Pelter, A.; Drake, R. A. Tetrahedron Lett. 1988, 29, 4181. (b)
Quideau, S.; Looney, M. A.; Pouyse´gu, L. J. Org. Chem. 1998, 63, 9597.
(c) Quideau, S.; Looney, M. A.; Pouyse´gu, L. Org. Lett. 1999, 1, 1651. (d)
Ozanne-Beaudenon, A.; Quideau, S. Angew. Chem., Int. Ed. 2005, 44, 7065.
(e) Ciufolini, M. A.; Canesi, S.; Ousmer, M.; Braun, N. A. Tetrahedron
2006, 62, 5318. (f) Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria, G. S.
Angew. Chem. 2007, 119, 4016. (g) Ciufolini, M. A.; Braun, N. A.; Canesi,
S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis 2007, 24, 3759. (h) Be´rard,
D.; Racicot, L.; Sabot, C.; Canesi, S. Synlett 2008, 1076. (i) Be´rard, D.;
Giroux, M. A.; Racicot, L.; Sabot, C.; Canesi, S. Tetrahedron 2008, 7537.
(j) Pouyse´gu, L.; Chassaing, S.; Dejugnac, D.; Lamidey, A. M.; Miqueu,
K.; Sotiropoulos, J. M.; Quideau, S. Angew. Chem., Int. Ed. 2008, 47, 3552
(outstanding asymmetric version). (k) Special issue: Tetrahedron (Symposium-
Figure 1. Aromatic ring umpolung.
attack of a phenol3 or an N-arylsulfonamide4 with iodoben-
zene diacetate (DIB), an environmentally benign and inex-
pensive reagent, in the presence of, e.g., furan, promotes an
oxidative annulation process5 that furnishes products 4 (Z
) O) in 38-69% yield. The erstwhile electron-rich aromatic
substrate has expressed electrophilic character in this reaction.
The overall transformation may thus be thought of as
involving “aromatic ring umpolung” (Figure 1).6
The concept of aromatic ring umpolung provides new
strategic opportunities in synthetic chemistry. In this paper,
we illustrate an initial application of the new technique in
connection with a fully stereocontrolled total synthesis of
in-Print) 2001, 57, 2
.
10.1021/ol801921d CCC: $40.75
Published on Web 09/19/2008
2008 American Chemical Society

(()-desbromopanacene, 5, (()-panacene, 6,7 and its un-
natural isomer, (()-epipanacene, 7 (Figure 2). Compound 5
1). A more selective route evolves from derivative 13, which
is readily accessed from 8 in three steps.13 The TMS group
blocks position 6 of the phenol and forces the subsequent
oxidative annulation sequence to occur exclusively at position
2. Thus, the core of panacene is assembled in a single step.
It is worthy of note that the silyl substituent survives the
DIB oxidation step largely unscathed. Indeed, the desired
14 was accompanied by only a small amount (∼5%) of 9
and 10, which clearly arise through partial loss of the TMS
group during the reaction. Without separation, this crude
mixture was treated with TBAF and CsF in DMF to induce
desilylation.
Figure 2. Natural allenic products.
is a plant metabolite isolated in 1915 from Panax ginseng
and Panax quinquefolius.8 No synthesis of this substance
has been reported as of this writing. A marine variant of 5
was isolated in 1977 by Meinwald and co-workers from
Aplysia brasiliana,9 a sea hare indigenous to the gulf coast
of Florida, and christened as panacene. For this reason, we
refer to 5 as desbromopanacene. Panacene has shark anti-
feedant properties, and it is thus believed to protect the sea
hare from predatory fish.
Scheme 1. Dihydrofurano[2,3-b]benzofuran Core
The unusual architecture of 6 has elicited substantial
interest in the synthetic arena.10,11 This has led to total
syntheses of the racemate,10a,b and of the natural (-)-form10c
in 17 and 9 steps (from ethyl 6-ethylsalicylate; in 0.7% and
1.5% overall yield, respectively) and 15 steps (from 2-meth-
oxy-6-methylbenzoic acid; 8.3% overall yield), respectively.
Our approach, which is based on aromatic ring umpolung,
starts with inexpensive 3-ethylphenol 8. This material may
be directly converted into a mixture (1:1.3)12 of 9 and 10 in
46% yield by DIB oxidation in presence of furan (Scheme
Compound 9 thus emerged in 44% overall yield. Although
this route is longer than direct oxidation, it produced 9 with
a global yield of 31.1% instead of 20.2% (Scheme 1).
Compound 9 was subsequently converted into 15 by an
oxymercuration-demercuration sequence. The advantage of
the present approach is apparent when considering that
intermediate 15, a known precursor to panacene, was
previously synthesized in nine steps from 2-methoxy-6-
methylbenzoic acid.10c The unsubstituted allene present in
“terrestrial” panacene analog 5 was efficiently introduced
through a Sakurai reaction14 of 15 with propargyltrimeth-
ylsilane. Compound 5 emerged in 63% yield (Scheme 2).
The first total synthesis of this compound was thus achieved
in three steps and in 13% global yield from 8, or in seven
steps and 20% yield from 8 via 13.
(3) Phenols activation: (a) Gates, B. D.; Dalidowicz, P.; Tebben, A.;
Wang, S.; Swenton, J. S. J. Org. Chem. 1992, 57, 2135. (b) Braun, N. A.;
Ciufolini, M. A.; Peters, K.; Peters, E. M. Tetrahedron Lett. 1998, 39, 4667.
(c) Braun, N. A.; Bray, J.; Ousmer, M.; Peters, K.; Peters, E. M.; Bouchu,
D.; Ciufolini, M. A. J. Org. Chem. 2000, 65, 4397. (d) Scheffler, G.; Seike,
H.; Sorensen, E. J. Angew. Chem., Int. Ed. 2000, 39, 4593. (e) Ousmer,
M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem.
Soc. 2001, 123, 7534. (f) Quideau, S. In Modern Arene Chemistry; Astruc,
D., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 539. (g) Canesi, S.;
Belmont, P.; Bouchu, D.; Rousset, L.; Ciufolini, M. A. Tetrahedron Lett.
2002, 43, 5193. (h) Drutu, I.; Njardarson, J. T.; Wood, J. L. Org. Lett.
2002, 4, 493. (i) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Angew. Chem.,
Int. Ed. 2004, 43, 4336. (j) Quideau, S.; Pouyse´gu, L.; Deffieux, D. Curr.
Org. Chem. 2004, 8, 113. (k) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Org.
Lett. 2005, 7, 175. (l) Quideau, S.; Pouyse´gu, L.; Deffieux, D. Synlett 2008,
467. (m) Liang, H.; Ciufolini, M. A. J. Org. Chem. 2008, 4299.
(4) N-Arylsulfonamide activation: (a) Akai, S.; Kawashita, N.; Morita,
N.; Nakamura, Y.; Iio, K.; Kita, Y. Heterocycles 2002, 58, 75. (b) Jean,
A.; Cantat, J.; Be´rard, D.; Bouchu, D.; Canesi, S. Org. Lett. 2007, 9, 2553.
(5) Be´rard, D.; Jean, A.; Canesi, S. Tetrahedron Lett. 2007, 48, 8238.
(6) The concept of “umpolung“ chemistry has been discovered by E. J.
Corey and D. Seebach: (a) Seebach, D.; Corey, E. J. J. Org. Chem. 1975,
40, 231. (b) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239.
(7) Bromoallene moieties are present in marine natural products:
Hoffmann-Ro¨der, A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196.
(8) (a) Kondo, H.; Tanaka, G. Yakugaku Zasshi (Japan) 1915, 401, 779.
(b) Min, P. Folia Pharmacol. Jpn. 1931, 11, 256. (c) Dembitsy, V. M.;
Takashi, M. Prog. Lipid Res. 2007, 46, 328.
The elaboration of 15 to panacene required a method for
the stereoselective construction of bromoallene moiety. We
focused on a ring opening/ring closing strategy15 for that
(9) Kinnel, R.; Duggan, A. J.; Eisner, T.; Meinwald, J.; Miura, I.
Tetrahedron Lett. 1977, 18, 3913.
(13) Details of the preparation of 13 are provided as Supporting
Information. We note that release of the THP ether from 12 was best effected
with CAN in acetonitrile as described by: (a) DattaGupta, A.; Singh, R.;
Singh, V. K. Synlett 1996, 69. (b) Marko, I. E.; Ates, A.; Augustyns, B.;
Gautier, A.; Quesnel, Y.; Turet, L.; Wiaux, M. Tetrahedron Lett. 1999, 40,
5613. Other acidic methods lead to a partial loss of the TMS group.
(14) (a) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295. (b)
Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem.
Soc. 1999, 121, 12208.
(10) (a) Feldman, K. S.; Mechem, C. C.; Nader, L. J. Am. Chem. Soc.
1982, 104, 4011. (b) Feldman, K. S. Tetrahedron Lett. 1982, 23, 3031. (c)
Boukouvalas, J.; Pouliot, M.; Robichaud, J.; MacNeil, S.; Snieckus, V. Org.
Lett. 2006, 8, 3597
(11) Stuart, J. G.; Nicholas, K. M. Heterocycles 1991, 32, 949
(12) Estimated within the resolution limit of 1H NMR analysis (Varian
600 MHz).
.
.
4630
Org. Lett., Vol. 10, No. 20, 2008

Scheme 2
.
Total Synthesis of (()-Desbromopanacene
Table 1. Solvent Influence and Synthesis of (()-Epipanacene
solvent
time (h)
6
7
acetonitrile
ethyl acetate
tert-butyl alcohol
chloroform
cyclohexane
benzene
0.5
1
1
1
5
0.5
0.4
0.3
0.1
trace
trace
0.5
0.6
0.7
0.9
>0.95
>0.95
purpose. Accordingly, reaction of 15 with Wittig reagent 1616
proceeded with good selectivity (9:1) in favor of (E)-isomer
17,17 which was then desilylated (TBAF) to afford 18 in
high yield (Scheme 3).
1.5
with an appropriate electrophilic reagent. To that end,
treatment of 17 with silver nitrate and NBS produced 1920
in essentially quantitative yield. Exposure of the latter to
Hg(OAc)2 in benzene induced diastereoselective formation
of 20, which was demercurated in situ, with retention of
allene configuration, upon contact with ethanedithiol.
Totally synthetic (()-panacene 6 was thus obtained in
good yield (Scheme 4).
Scheme 3. Ring-Opening/Ring-Closing Strategy
Scheme 4. Synthesis of (()-Panacene
The action of 2,4,4,6-tetrabromo-2,5-cyclohexadienone
(TBCD)18 on compound 18 resulted in formation of a
mixture of panacene 6 and epipanacene 7 in high yield.19
The product ratio12 proved to be solvent dependent (Table
1): a high degree of diastereoselectivity in favor of epipan-
acene 7 was attained in apolar solvents such as cyclohexane
or benzene. Epipanacene is produced in this manner in only
five steps via a direct oxidation of 3-ethyl phenol 8 with a
global yield of 8.9% or in nine steps with an overall yield
of 14.3%. We note that TBCD appears to be a more selective
reagent than N-bromosuccinimide, which promoted aromatic
ring bromination as a side reaction. Although this method
led to an unnatural epimer of panacene, it also signaled that
the inherent facial bias present in 18 enables the execution
of highly diastereoselective cyclization.
We emphasize that thiols are known to promote
protiodemercuration of R-mercurio carbonyl compounds
under mild conditions.21 However, their application to the
stereoselective demercuration of allenylmercury organo-
metallics with retention of configuration is unprecedented
to the best of our knowledge. This could have significant
ramifications in the total synthesis of allenic natural
products. (()-Panacene has been reached, by this strategy,
for the first time, by a substrate-controlled diastereose-
lection without using any external asymmetric reagent.
In summary, concise and fully diastereoselective syn-
theses of “marine” and “terrestrial” (()-panacenes were
accomplished via a formal oxidative [2 + 3] cycloaddition
between a substituted phenol and furan. One may thus
reach panacene and desbromopanacene in an unprec-
edented five steps and three steps, respectively, from
inexpensive 3-ethylphenol. A more highly regioselective
variant of the same approach proceeds in nine and seven
steps, respectively, via 13. Finally, a novel oxymercuration-
We thus reasoned that the correct relative configuration
of the bromoallene moiety could be secured by orchestrat-
ing the cyclization of a bromoacetylene derivative of 18
(15) (a) Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L.
Angew. Chem., Int. Ed. 1999, 38, 3175. (b) Crimmins, M. T.; Tabet, E. A.
J. Am. Chem. Soc. 2000, 122, 5473.
(16) Corey, E. J.; Ruden, R. A. Tetrahedron Lett. 1973, 14, 1495.
(17) The small amount of (Z)-isomer was readily removed by flash
chromatography.
(18) Tsubota, M.; Iso, M.; Suzuki, K. Bull. Chem. Soc. Jpn. 1972, 45,
1252.
(19) For an article on the stereochemical course of bromoetherification
of enynes, see: Braddock, D. C.; Bhuva, R.; Perez-Fuertes, Y.; Pouwer,
R.; Roberts, C. A.; Ruggiero, A.; Stokes, E. S. E.; White, A. J. P. Chem.
Commun. 2008, 1419.
(20) Nishikawa, T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett 1994,
485.
(21) (a) Gouzoules, F. H.; Whitney, R. A. Tetrahedron Lett. 1985, 26,
3441. (b) Gouzoules, F. H.; Whitney, R. A. J. Org. Chem. 1986, 51, 2024.
Org. Lett., Vol. 10, No. 20, 2008
4631

demercuration process has been devised for the construc-
tion of the bromoallene segment of panacene. These
syntheses demonstrate the potential of “aromatic ring
umpolung”, further applications of which are under study
in our laboratories.
Natural Sciences and Engineering Research Council of
Canada (NSERC) and to the provincial government of
Quebec (FQRNT).
Supporting Information Available: Experimental pro-
cedures and spectral data of key compounds. This material
is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment is made to the donors of the American
Chemical Society Petroleum Research Fund (ACS PRF) for
support of this research. We are also very grateful to the
OL801921D
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Org. Lett., Vol. 10, No. 20, 2008