Total synthesis of (±)-kellermanoldione: stepwise cycloaddition of a functionalized diene and allenoate

Article abstract of DOI:10.1021/ol901455q

Figur Presented The total synthesis of the diterpene kellermanoldione 1 is reported. Stepwise [4 + 2] cycloaddition of the ketal diene 8 and the allenoste 3 afforded the exo adduct 10x as the major product. It was converted into 1 via six steps, among them a key nonconjugative hydrolysis of a γ-methylene silyl enol ether

Full text of DOI:10.1021/ol901455q

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3882-3885
Total Synthesis of (()-Kellermanoldione:
Stepwise Cycloaddition of a
Functionalized Diene and Allenoate
Michael E. Jung,* Jesus Cordova, and Masayuki Murakami
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
405 Hilgard AVenue, Los Angeles, California 90095
jung@chem.ucla.edu
Received June 26, 2009
ABSTRACT
The total synthesis of the diterpene kellermanoldione 1 is reported. Stepwise [4 + 2] cycloaddition of the ketal diene 8 and the allenoate 3
afforded the exo adduct 10x as the major product. It was converted into 1 via six steps, among them a key nonconjugative hydrolysis of a
γ-methylene silyl enol ether.
Kellermanoldione 1 (Figure 1) is a labdane diterpene
isolated from Brickellia kellermanii Grenm., a shrub which
is reported to have potent antidiarrhetic properties and is
used in Mexican folk medicine.1,2 No synthesis of this
hydroxydione has appeared in the literature to date. Recently
we reported the preparation of very hindered trimethyldecalin
systems, involving a novel stepwise [4 + 2] cycloaddition
of the very hindered diene 2 with the allene carboxylate 3
to give the [4 + 2] cycloadducts 4xn by a mechanism that
proceeds via the cyclobutane 5, the initial [2 + 2] cycload-
duct (Scheme 1).3 In addition, we have shown that certain
labdane diterpenes lacking functionality in the A ring can
be prepared using this exact cycloaddition, e.g., hedychilac-
tone B.4 However, for this synthetic process to be generally
useful it must be able to be performed with functional
Figure 1. Kellermanoldione.
molecules since many di- and triterpenes have functionality
in the A ring, usually oxygen at C3. We report here the total
synthesis of 1 from the exo [4 + 2] cycloadduct 10x via a
key nonconjugative hydrolysis of a γ-methylene silyl enol
ether.
(1) Ortega, A.; Salazar, I.; Gavin˜o, R.; Maldonado, E. Phytochemistry
1997, 44, 319
.
The required diene for the synthesis of these function-
alized labdane diterpenes, the ketal silyl enol ether 8, was
prepared by a direct route from 2,2,4-trimethylcyclohex-
(2) For recent syntheses of diterpenes, see: (a) Williams, D. R.; Walsh,
M. J.; Miller, N. A. J. Am. Chem. Soc. 2009, 131, 9038. (b) Schnabel, C.;
Hiersemann, M. Org. Lett. 2009, 11, 2555. (c) Boukouvalas, J.; Wang, J.-
X. Org. Lett. 2008, 10, 3397. (d) Marcos, I. S.; Castaneda, L.; Basabe, P.;
Diez, D.; Urones, J. G. Tetrahedron 2008, 64, 10860. (e) Aslaoui, J.; Li,
H.; Morin, C. Tetrahedron Lett. 2005, 46, 1713
.
(3) Jung, M. E.; Murakami, M. Org. Lett. 2006, 8, 5857
.
(4) Jung, M. E.; Murakami, M. Org. Lett. 2007, 9, 461.
10.1021/ol901455q CCC: $40.75
Published on Web 08/05/2009
 2009 American Chemical Society

hexanol without moving the exomethylene unit into the
more stable endocyclic position and installation of the
3-furyl ketone. We used the same technique that had
worked in our earlier synthesis of hedychilactone B;3
namely, reduction of the ester of 10x with DIBAL afforded
in 88% yield the alcohol 11, which was oxidized under
Dess-Martin periodinane conditions to afford the aldehyde
7 in 85% yield (Scheme 3). Formation of the ylide 13
Scheme 1
Scheme 3
ane-1,3-dione 6 via the known vinyl iodide 7 which has
been used by Danishefsky in a synthesis of taxol deriva-
tives5 (Scheme 2). The vinyllithium prepared from 7 was
Scheme 2
from methoxymethyltriphenylphosphonium iodide,7 pre-
pared in two steps from methylal via reaction with
trimethylsilyl iodide (TMSI) and triphenylphosphine, by
reaction with n-butyllithium and addition of the aldehyde
gave a mixture of stereoisomers of the enol methyl ether
14 in 51% yield. The ketal functionality survived all of
these transformations without any problems.
The key step of hydrolysis of the silyl enol ether without
concomitant conjugation of the exocyclic methylene unit
was effected by the use of conditions shown to work in
our earlier system. Thus careful treatment of 14 with HF-
pyridine in acetonitrile at low temperature afforded a 92%
yield of the desired trans-decalone 15 in which the
exocyclic methylene remained untouched (Scheme 4). As
expected, reduction of the decalone with DIBAL occurred
from the less-hindered equatorial direction to give the
desired axial alcohol 16 in quantitative yield. Very mild
acidic hydrolysis of the methyl enol ether (aq. HCl in
THF) afforded the keto aldehyde 17 in 84% yield.
Attachment of the 3-furyl ketone unit to the side chain
was all that was required to complete the synthesis. The
3-furyllithium species,8 prepared from commercially
available 3-bromofuran, was added to the keto aldehyde
17 to afford chemoselectively the aldehyde adduct in fair
yield. However, attempted selective oxidation of this
benzylic alcohol using manganese dioxide proceeded
rather poorly, and only very small amounts of keller-
manoldione 1 could be obtained. Therefore we decided
to examine a different sequence for the conversion of the
key aldehyde 12 into the desired product 1.
trapped with acetaldehyde and oxidized, and the silyl enol
ether was prepared by the standard route to give the
desired diene 8. Heating a neat mixture of the diene 8
with the allene carboxylate 3 (prepared in 64% yield by
reaction of acetyl chloride with ethoxycarbonylmethyl-
enephosphorane)6 at 110 °C for 14 days gave a separable
mixture of three products, the [2 + 2] cycloadduct 9, the
desired exo [4 + 2] cycloadduct 10x, and the endo adduct
10n in 7.2%, 26.5%, and 13.7% yield, respectively, with
32.4% of the recovered starting diene 8. The cyclobutane
9 could be converted into the same 2:1 ratio of 10x and
10n, resulting in a 39.2% overall yield of 10x based on
recovered starting material.
The conversion of the adduct 10x into kellermanoldione
1 required two key steps, formation of the axial cyclo-
(7) Jung, M. E.; Mazurek, M. A.; Lim, R. M. Synthesis 1978, 588–90.
(8) (a) Collins, M. A.; Tanis, S. P. “3-Lithiofuran,” e-EROS Encyclo-
pedia of Reagents for Organic Synthesis ( 2001). (b) Chen, C.-L.; Sparks,
S. M.; Martin, S. F. J. Am. Chem. Soc. 2006, 128, 13696.
(5) Di Grandi, M. J.; Jung, D. K.; Krol, W. J.; Danishefsky, S. J. J.
Org. Chem. 1993, 58, 4989–92.
(6) Paik, Y. H.; Dowd, P. J. Org. Chem. 1986, 51, 2910.
Org. Lett., Vol. 11, No. 17, 2009
3883

methoxyalkenes 22ab which were hydrolyzed in good yields
to the known ketones.
Scheme 4
We then applied this route to the synthesis of keller-
manoldione 1 (Scheme 6). Formation of the anion of the
Scheme 6
We decided to reduce the number of steps of the synthesis
and install the 3-furyl unit earlier. In particular, we wanted
to see if the analogue of the enol ether 14 with the 3-furyl
unit already in place could be prepared by an olefination
process, since then that enol ether would not only serve as
a protecting group for the aldehyde but also furnish the
required 3-furyl ketone on hydrolysis. Since there were few
examples of such enol ethers in the literature, we carried
out some model studies (Scheme 5).
furyl methoxy phosphonate 21b with LDA and addition to
the aldehyde 12 afforded the desired mixture of alkene
stereoisomers 24EZ in 82% yield. Careful desilylation of
the TBS enol ether using HF-pyridine at low temperature
furnished the ꢀ,γ-unsaturated ketone 25 in 66% yield. No
migration of the exocyclic double bond into the ring at either
allylic position was observed. DIBAL reduction gave solely
the axial alcohol as expected, and final hydrolysis of both
the ketal and the enol ether afforded kellermanoldione 1 in
62% yield for the two steps. The spectroscopic data of the
synthetic material, especially the proton and carbon NMRs,
were identical to that reported in the literature for the natural
product.1,11
Scheme 5
Thus, we have carried out the first total synthesis of
the labdane diterpene kellermanoldione B 1 from the [4
+ 2] cycloadduct 10x formed in good yield via a stepwise
cycloaddition of the functionalized very hindered diene 8
and the allenoate dienophile 3. The synthesis utilized a
nonconjugative hydrolysis of a γ-methylene silyl enol
ether and a novel introduction of the 3-furyl ketone unit.
This is the first indication that functionalized trimethyl-
decalin systems can be prepared by this route using a
stepwise [4 + 2] cycloaddition. Further work on terpene
synthesis is underway in our laboratories and will be
reported in due course.
To the aldehydes 20ab was added diethyl phosphite9 followed
by methylation of the alkoxide to give the methoxy phospho-
nates 21ab.10 Addition of benzaldehyde to the anion of 21ab
afforded in good yield a mixture of the E and Z isomers of the
(9) (a) Texier-Boullet, F.; Foucaud, A. Synthesis 1982, 916. (b)
Yokomatsu, T.; Yamagishi, T.; Shibuya, S. J. Chem. Soc., Perkin Trans.
1997, 1, 1527.
(10) Compound 21a is known, while 21b is not. Roeschlaub, C. A.;
Sammes, P. G. J. Chem. Soc., Perkin Trans. 2000, 1, 2243.
(11) We thank Professor E. Maldonado of the Universidad Nacional
Autonoma de Mexico for providing the spectroscopic data.
3884
Org. Lett., Vol. 11, No. 17, 2009

Acknowledgment. We thank the National Science Founda-
tion (CHE 0614591) for generous support of this work. J.C.
thanks CONACYT (#197253) for financial support in the form
of a graduate fellowship. M.M. thanks Sankyo Co. Ltd. for
support.
Supporting Information Available: Experimental pro-
cedures and proton and carbon NMR data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL901455Q
Org. Lett., Vol. 11, No. 17, 2009
3885