Efficient construction of the oxatricyclo[6.3.1.00,0]dodecane core of komaroviquinone using a cyclization/cycloaddition cascade of a rhodium carbenoid intermediate

Article abstract of DOI:10.1021/ol0513589

(Chemical Equation Presented) The rhodium(II)-catalyzed cyclization/cycloaddition cascade of a o-carbomethoxyaryl diazo dione is described as a potential route to the oxatricyclo[6.3.1.0^0.0]dodecane substructure of the icetexane diterpene komar

Full text of DOI:10.1021/ol0513589

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3725-3727
Efficient Construction of the
Oxatricyclo[6.3.1.00,0]dodecane Core of
Komaroviquinone Using a Cyclization/
Cycloaddition Cascade of a Rhodium
Carbenoid Intermediate
Albert Padwa,* Jutatip Boonsombat, Paitoon Rashatasakhon, and Jerremey Willis
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received June 10, 2005
ABSTRACT
The rhodium(II)-catalyzed cyclization/cycloaddition cascade of a o-carbomethoxyaryl diazo dione is described as a potential route to the
oxatricyclo[6.3.1.00,0]dodecane substructure of the icetexane diterpene komaroviquinone. The initially formed carbonyl ylide dipole prefers to
cyclize to an epoxide at 25 °C but can be induced to undergo cycloaddition across the tethered π-bond at higher temperatures.
Dracocephalum komaroVi Lipsky (Labiatae) is a perennial
semishrub1 that is called “buzbosh” in Uzbekistan, and local
people use the aerial parts in a tea to treat various inflam-
matory diseases. Dried whole plants of D. komaroVi were
extracted and fractionated to give several icetexane diterpenes
whose structures were elucidated by extensive analysis of
their NMR data.2 The major fraction isolated from the plant
was assigned structure 1 and was named komaroviquinone.
This compound showed strong in vitro trypanocidal activity
against epimastigotes of Trypanosoma cruzi, the causative
agent of Chagas’ disease in Central and South America.3
diterpene 2 was also isolated from the same plant, and since
it possessed a novel spiro-octahydroindene skeleton, it was
named komarovispirone (2).6 Biogenetically, komaro-
vispirone (2) may be derived from komaroviquinone (1)
through a novel ring-contraction sequence as outlined in
Scheme 1. The stereochemistry of 2 was tentatively assigned
as indicated in Scheme 1.
On the basis of previous work in our laboratory using the
intramolecular dipolar-cycloaddition reaction of carbonyl
ylides for the synthesis of various natural products,7-10 we
(5) Fernandez Villamil, S. H.; Perissinotti, L. J.; Stoppani, O. M.
Biochem. Pharm. 1996, 52, 1875.
(6) Uchiyama, N.; Ito, M.; Kiuchi, F.; Honda, G.; Takeda, Y.; Khodzhi-
matov, O. K.; Ashurmetov, O. A. Tetrahedron Lett. 2004, 45, 531.
(7) (a) Padwa, A.; Carter, S. P.; Nimmesgern, H. J. Org. Chem. 1986,
51, 1157. (b) Padwa, A.; Carter, S. P.; Nimmesgern, H., Stull, P. D. J. Am.
Chem. Soc. 1988, 110, 2894.
Several types of natural quinones have been reported to
show trypanocidal activity, and their activities have been
partly ascribed to the production of reactive oxygen species
in the parasite.4,5 In addition to compound 1, a minor
(8) (a) Padwa, A.; Fryxell, G. E.; Zhi, L. J. Org. Chem. 1988, 53, 2875.
(b) Padwa, A.; Fryxell, G. E.; Zhi, L. J. Am. Chem. Soc. 1990, 112, 3100.
(9) (a) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263. (b)
Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223. (c) Padwa, A.
Top. Curr. Chem. 1997, 189, 121.
(10) (a) Padwa, A.; Sandanayaka, V. P.; Curtis, E. A. J. Am. Chem. Soc.
1994, 116, 2667. (b) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org.
Chem. 1996, 61, 73.
(1) Vvedenski, A. I. In Flora Uzbekistana; Editio Academiae Scientiarum
UzSSR; Tashkent, 1961; Vol. 5, p 313.
(2) Uchiyama, N.; Kiuchi, F.; Ito, M.; Honda, G.; Takeda, Y.; Khodzhi-
matov, O. K.; Ashurmetov, O. A. J. Nat. Prod. 2003, 66, 128.
(3) Bastien, J. W. The Kiss of Death, Chagas’ Disease in the Americas;
The University of Utah Press: Salt Lake City, 1998.
(4) Sepu´lveda-Boza, S.; Cassels, B. K. Planta Med. 1996, 62, 98.
10.1021/ol0513589 CCC: $30.25
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diazoacetate in the presence of tin(II) chloride. In our hands,
a modest (but unoptimized) yield of 8 (ca. 40%) was obtained
from the reaction of 7 with hex-5-enal. A subsequent Regitz
diazo transfer reaction12 using nosyl azide and Et3N furnished
diazo dione 9 in 98% yield. Treating a sample of 9 with
Rh2(OAc)4 in benzene at 80 °C afforded cycloadduct 10 in
75% yield (Scheme 3).
Scheme 1
Scheme 3
felt that the Rh(II)-catalyzed reaction of a diazo dione
precursor (i.e., 3) might allow for a facile entry to the
icetexane core of komaroviquinone (1). The eventual forma-
tion of the oxatricyclo[6.3.1.00,0]dodecane skeleton of 1 was
envisioned to come about from cyclization of the rhodium
carbenoid intermediate 4 with the adjacent carbomethoxy
group.9 The ensuing dipole 5 was expected to undergo an
intramolecular [3 + 2]-cycloaddition across the tethered
π-bond. The resulting cycloadduct 6 would then be converted
to komaroviquinone in several steps by sequential reduction
of the keto groups, oxidation to the benzoquinone core, and
acid hydrolysis of the ketal moiety (Scheme 2).
Scheme 2
Interestingly, when the Rh(II)-catalyzed reaction was
carried out at room temperature, the major product isolated
corresponded to epoxyindanone 12 (71%) with only a small
amount (<10%) of cycloadduct 10 being formed. Heating a
sample of 12 at 100 °C in benzene gave 10 in 78% isolated
yield. This reaction presumably occurs by thermal C-C bond
cleavage of the epoxide ring to generate dipole 11, which
undergoes a subsequent intramolecular [3 + 2]-cycloaddition
to give 10.
Many studies support the intermediacy of carbonyl ylides
in reactions involving the interaction of a metallo carbenoid
with a carbonyl oxygen.13 The great majority of literature
reports on carbonyl ylides are dominated by 1,3-dipolar
cycloaddition reactions rather than cyclization of the dipole
to produce the oxirane ring system.7-10 Huisgen was the first
to report the formation of an epoxide from the reaction of
dimethyl diazomalonate with benzaldehyde, but in only 7%
yield when the reaction was carried out at 125 °C in the
presence of 1 mol % of Cu(acac)2.14 More recently, the
Doyle15 and Davies16 groups have reported stereospecific
To test the feasibility of the retrosynthetic strategy outlined
in Scheme 2, our initial efforts were focused on some model
substrates. According to our design, we hoped to employ a
tandem cyclization/cycloadddition reaction of a rhodium
carbenoid intermediate to rapidly generate the 9,10-benzo-
12-oxatricyclo[6.3.1.00,0]dodecanedione skeleton from a rela-
tively simple precursor (i.e., 9). Our synthesis of the key
diazo dione 9 commenced with o-carbomethoxy diazo ketone
7, which is readily available in high yield from phthalic acid
monomethyl ester. We anticipated that under suitable reaction
conditions 7 would react with hex-5-enal to give diketone 8
following a protocol developed by Holmquist and Roskamp
for â-keto esters.11 These authors have found that aldehydes
can be converted into â-keto esters by the addition of ethyl
(12) (a) Regitz, M. Chem. Ber. 1966, 99, 3128. (b) Regitz, M.; Hocker,
J.; Liedhegener, A. Org. Synth. 1973, 5, 179.
(13) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; John Wiley and Sons: New
York, 1998.
(11) (a) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258.
See also: (b) Padwa, A.; Hornbuckle, S. F.; Zhang, Z.; Zhi, L. J. Org.
Chem. 1990, 55, 5297.
(14) de March, P.; Huisgen, R. J. Am. Chem. Soc. 1982, 104, 4952.
(15) Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933.
(16) Davies, H. M. L.; DeMeese, J. Tetrahedron Lett. 2001, 42, 6803.
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Org. Lett., Vol. 7, No. 17, 2005

epoxide formation from rhodium acetate catalyzed reactions
of aryl, heteroaryl, and vinyl diazoacetates with R,â-
unsaturated aldehydes or ketones. Later, a similar epoxidation
process was used to prepare spiro-indoloxiranes with cyclic
diazoamides by the Mathusamy group.17 When dimethyl
diazomalonate was used as the carbenoid source, a competi-
tion between dioxolane and epoxide formation was noted.
Doyle was able to direct the decomposition of the diazoma-
lonate system to produce either epoxide or dioxolane by
influencing the stability of the intermediate carbonyl ylide
dipole.18 When the electron-rich p-anisaldehyde was used
as the trapping reagent, only epoxide formation was ob-
served. Stabilization of the intermediate ylide was suggested
to account for its diminished reactivity toward cycloaddition
with a second molecule of the added aldehyde. The fact that
we were able to isolate epoxide 12 in 71% yield from the
cyclization of dipole 11 is perfectly consistent with the Doyle
observations (Scheme 3). Thus, stabilization of the positive
center of the dipole by interaction with the adjacent methoxy
group diminishes the rate of the dipolar cycloaddition
reaction and promotes cyclization of the ylide to the epoxide
ring.
The Rh(II)-catalyzed reaction of the related dimethyl
substituted diazo ester 13 was also studied since this system
contained the appropriate substituent groups needed for the
eventual synthesis of komaroviquinone (1). The rate of an
intramolecular reaction is often increased when alkyl groups
are placed on a chain between the two reacting centers.19
This is known as the gem-dialkyl effect and is often exploited
to promote difficult cyclization reactions.20 Indeed, the
reaction of diazo dione 13, prepared in a manner similar to
that outlined in Scheme 3, gave cycloadduct 14 in 92% yield.
Most importantly, when 14 was treated with aqueous acid it
was readily converted to 15 in essentially quantitative yield
(Scheme 4). The conversion of 13 to 15 via this method
Scheme 4
suggests that a similar approach could be used in our planned
synthesis of komaroviquinone (1).
In summary, an efficient approach to the core skeleton of
komaroviquinone was accomplished by an intramolecular [3
+ 2]-cycloaddition reaction of a carbonyl ylide dipole
obtained by the interaction of a metallo carbenoid with an
adjacent carbomethoxy group. Application of this strategy
to the synthesis of komaroviquinone is currently underway
and will be reported at a later date.
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM 059384)
and the National Science Foundation (CHE-0450779).
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Muthusamy, S.; Gunanathan, C.; Nethaji, M. Synlett. 2004, 4, 639.
(18) Russell, A. E.; Brekan, J.; Gronenberg, L.; Doyle, M. P. J. Org.
Chem. 2004, 69, 5269.
(19) Bruice, T. C.; Pandit, U. K. J. Am. Chem. Soc. 1960, 82, 5858.
(20) (a) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224. (b)
Jung, M. E.; Trifunovich, I. D.; Lensen, N. Tetrahedron Lett. 1992, 33,
6719.
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