Enantio- and diastereocontrolled synthesis of an angular triquinane sesquiterpene (+)-arnicenone.

Article abstract of DOI:10.1021/ol006922o

[figure: see text] (+)-Arnicenone, a sesquiterpene of an angular triquinane isolated from Arnica plants, has been synthesized for the first time in an enantiocontrolled manner from a synthetic equivalent of chiral 2-hydroxymethylcyclopentadienone to deter

Full text of DOI:10.1021/ol006922o

ORGANIC
LETTERS
2001
Vol. 3, No. 2
291-293
Enantio- and Diastereocontrolled
Synthesis of an Angular Triquinane
Sesquiterpene (+)-Arnicenone
Yosuke Iura, Tsutomu Sugahara, and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
konol@mail.cc.tohoku.ac.jp
Received November 25, 2000
ABSTRACT
(+)-Arnicenone, a sesquiterpene of an angular triquinane isolated from Arnica plants, has been synthesized for the first time in an
enantiocontrolled manner from a synthetic equivalent of chiral 2-hydroxymethylcyclopentadienone to determine the absolute configuration of
the natural product as 1R,3aR,5aS,8aR.
We have recently developed an efficient route to the
R-hydroxymethylketone 2 serving as a synthetic equivalent
of chiral 2-hydroxymethylcyclopentadienone by employing
either an enzymatic1 or a catalytic2 procedure. Utilizing this
chiral building block, which exhibits inherent convex-face
selectivity, we attempted diastereoselective construction of
(+)-arnicenone3 1, an isocomene-type angular triquinane
sesquiterpene isolated from the essential oil of rhizomes and
roots of Arnica plants, to determine the absolute configura-
tion4 of this natural product unambiguously as well as to
develop a general enantio- and diastereocontrolled route to
the isocomene-type sesquiterpenes. We report here the first
diastereocontrolled synthesis of (+)-arnicenone 1 from (-)-2
which allowed determination of the absolute configuration
of the natural product unambiguously as 1R,3aR,5aS,8aR
(Scheme 1).
Scheme 1
(1) Sugahara, T.; Ogasawara, K. Synlett 1999, 419.
(2) Kanada, R. M.; Taniguchi, T.; Ogasawara, K. Chem. Commun. 1998,
1755. Iura, Y.; Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 1999, 40,
5735. Kanada, R. M.; Taniguchi T.; Ogasawara, K. Tetrahedron Lett. 2000,
41, 3631. Kanada, R. M.; Taniguchi, T.; Ogasawara, K. Synlett 2000, 1019.
(3) Schmitz, R.; Frahm, A. W.; Kating, H. Phytochemistry 1980, 19,
1477.
(4) According to Fitjer’s conclusion in the determination of the absolute
configuration of natural (-)-R-isocomene 1 (dO ) dH2), natural (+)-
arnicenone 1 should have the same absolute configuration as the latter
afforded the former on Wolff-Kishner reduction,3 see: Fitjer, L.; Monzo-
Oltra, H. J. Org. Chem. 1993, 58, 6171.
Reduction of (-)-2 with diisobutylaluminum hydride
(DIBAL) gave regio- and diastereoselectively the endo-allyl
alcohol 3, [R]30D +82.4 (c 0.2, CHCl3), as the single product
by convex-face selective 1,2-reduction. Treatment of 3 with
N-bromosuccinimide (NBS)5 allowed simultaneous discrimi-
nation and specific protection of each of the two olefins and
two hydroxy functionalities in the molecule to give rise to
the single bromo-ether 4. The Eschenmoser rearrangement
reaction6 was next carried out on the basis of the remaining
primary allylic hydroxy and olefin functionalities to furnish
(5) Takano S.; Inomata, K.; Ogasawara, K. Chem. Lett. 1989, 359.
(6) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. HelV. Chim. Acta
1964, 47, 2425.
10.1021/ol006922o CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/22/2000

diastereoselectively the exo-acetamide 5, [R]27D +57.0 (c 1.0,
CHCl3), as the single product. This was then alkylated with
propargyl bromide to give the 1,5-enyne 6 as an inseparable
3:1 mixture. The formation of a mixture at this stage was
ultimately of no consequence because this stereogenic center
disappeared later in the synthesis. We, therefore, carried out
the following conversion without separation of this epimeric
mixture. Thus, the mixture, upon a Pauson-Khand reaction7
in dichloromethane in the presence of dimethyl sulfoxide
(DMSO),8 afforded the expected polycyclic enone 7 in 66%
yield as an inseparable mixture of two epimers (Scheme 2).
Scheme 3
Scheme 2
To introduce the remaining two methyl functionalities
required for the target molecule, 14 was first transformed
into the enone 18 through a 1,3-oxygen transposition. After
considerable experimentation, the Mitsunobu reaction12 was
found to be the most appropriate for this purpose. Thus,
treatment of 14 with 4-nitrobenzoic acid13 in the presence
of diisopropyl azodicarboxylate (DIAD) and triphenylphos-
phine furnished regio- and diastereoselectively the exo-allyl
benzoate 16 as a single regioisomer, presumably by interven-
tion of the phosphonium intermediate 15 which only allows
SN2′ substitution owing to the steric congestion of the
opposite face preventing SN2 substitution. The desired enone
18 was obtained from 16 via the allylic alcohol 17 on
sequential alkaline methanolysis and oxidation (Scheme 4).
Having constructed the key enone intermediate 7 carrying
the tricyclic core and two stereogenic centers required for
the target molecule, one of the two requisite quaternary
methyl functionalities was next introduced by reaction of 7
with a cuprate reagent to give the ketone 8 by diastereo-
selective 1,4-addition. The ketone 8 was transformed into
the ketal 9 whose amide functionality was then transformed
into the benzyl ether 11 via the primary alcohol 10 by
sequential treatment with lithium triethylborohydride9 and
benzyl bromide. Exposure to zinc powder in refluxing ethanol
containing acetic acid 11 liberated the olefin and the hydroxy
functionalities by reductive cleavage of the bromo-ether
linkage to afford the hydroxyketone 12 with concurrent
deketalization under these conditions. At this point, ther-
molysis of 12 was carried out in refluxing diphenyl ether in
the presence of sodium hydrogen carbonate10 to leave the
tricyclic ketoalcohol 13 in 91% yield with removal of the
cyclopentane moiety by retro-Diels-Alder reaction. The
ketone functionality of 13 was then reduced under Wolff-
Kishner conditions11 to give the allylic alcohol 14 (Scheme
3).
Scheme 4
(7) For a recent review, see: Brummond, K. M.; Kent, J. L. Tetrahedron
2000, 56, 3263.
(8) Keum, Y.; Lee, B. Y.; Jeong, N.; Hudecek, M.; Pauson, P. L.
Organometallics 1993, 12, 220.
The quaternary methyl functionality was first introduced
diastereoselectively by treating 18 with iodomethane and
(9) Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J. Org. Chem. 1980,
45, 1.
(10) Kamikubo; T.; Ogasawara, K. Chem. Commun. 1995, 1951.
(11) Huang-Minlon, J. Am. Chem. Soc. 1949, 71, 3301
(12) Mitsunobu, O. Synthesis 1981, 1. Hughes, D. L. Org. React. 1992,
42, 335.
(13) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
292
Org. Lett., Vol. 3, No. 2, 2001

potassium tert-butoxide in THF in the presence of hexa-
methylphosphoric triamide (HMPA) to give 19. In the
absence of HMPA, the reaction proceeded very slowly and
in an incomplete manner. The tertiary methyl functionality
was then introduced in a 1,4-addition reaction by treating
19 with a cuprate reagent to give the single ketone 20,
diastereoselectively. On sequential debenzylation, phenyl
sulfide formation,14 and oxidation, 20 furnished the sulfoxide
23 via the primary alcohol 21 and the phenyl sulfide 22 in
satisfactory overall yield. Finally, 23 was refluxed with
calcium carbonate in diphenyl ether to give a mixture (1:
1.2) of the exo-methyleneketone 24 and (+)-arnicenone 1,
which was separated by silica gel column chromatography
sense. Moreover, the stereochemical determination of the
isocomene-type angular triquinane sesquiterpenes based on
the complex rearrangement pathway4 has been proven
unambiguously (Scheme 5).
Scheme 5
to give (+)-arnicenone 1, as a colorless solid, [R]27 +592
D
(c 0.7, benzene) [natural3: mp 80-85 °C, [R]20 +614 (c
D
0.1, benzene)] and the exo-olefin isomer 24, [R]27 -83.0
D
(c 0.4, benzene), as a colorless oil. The latter afforded the
former on reflux in dichloromethane in the presence of
p-toluenesulfonic acid. Spectroscopic data of (+)-arnicenone
1 thus obtained were identical with those reported for the
natural product.3 Thus, the absolute configuration was
determined as 1R,3aR,5aS,8aR by correlation with the
configuration of the starting chiral building block (-)-2.
Since natural (+)-arnicenone 1 has been transformed into
(-)-isocomene3,15,16 1 (dO ) dH2), the present synthesis
constitutes its first enantiocontrolled synthesis in the formal
In conclusion, we have achieved the first enantiocontrolled
synthesis of (+)-arnicenone on the basis of the inherent steric
nature of the chiral building block used and have determined
the absolute configuration of the natural product.
(14) Walker, K. A. M. Tetrahedron Lett. 1977, 4475.
(15) Racemic arnicenone has been synthesized as an intermediate of
Paquette’s synthesis of racemic R-isocomene (()-1 (dO ) dH2), see:
Paquette, L. A.; Han, Y.-K. J. Am. Chem. Soc. 1981, 103, 1835.
(16) Quite recently, the starting material used in the Paquette synthesis
has been synthesized in a single enantiomeric form, see: Urabe, H.; Hideura,
D.; Sato, F. Org. Lett. 2000, 2, 381.
Acknowledgment. The authors thank the Ministry of
Education, Science, Sports and Culture, Japan, for financial
support.
OL006922O
Org. Lett., Vol. 3, No. 2, 2001
293