Total synthesis of (±)-hedychilactone B: Stepwise allenoate diene cycloaddition to prepare trimethyldecalin systems

Article abstract of DOI:10.1021/ol062811z

The total synthesis of the diterpene hedychilactone B 1 is reported. The exo adduct 4x, the major product of the stepwise [4+2] cycloaddition of the diene 2 and the allenoate 3, has been converted into 1 via 7 steps, among them a key nonconjugative hydrol

Full text of DOI:10.1021/ol062811z

ORGANIC
LETTERS
2007
Vol. 9, No. 3
461-463
Total Synthesis of (±)-Hedychilactone
B: Stepwise Allenoate Diene
Cycloaddition To Prepare
Trimethyldecalin Systems
Michael E. Jung* 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 November 18, 2006
ABSTRACT
The total synthesis of the diterpene hedychilactone B 1 is reported. The exo adduct 4x, the major product of the stepwise [4
of the diene 2 and the allenoate 3, has been converted into 1 via 7 steps, among them a key nonconjugative hydrolysis of a
enol ether and an E-selective olefination.
+
γ
2] cycloaddition
-methylene silyl
Hedychilactone B 1 (Scheme 1), a labdane diterpene isolated
from various types of Zingiberaceae plants, e.g., Hedychium
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] cycloadduct.2 We report here the total
synthesis of hedychilactone B 1 from the exo [4+2]
cycloadduct 4x via a key nonconjugative hydrolysis of a
γ-methylene silyl enol ether and an E-selective olefination
to install the desired E-alkylidene lactone.
Scheme 1
As we reported earlier, the trimethylcyclohexenyl diene 2
was prepared from 2,6-dimethylcyclohexanone in six steps
and 51% overall yield: methylation, Barton vinyl iodide
formation3 (via the corresponding hydrazone), trapping of
coronarium Koen, has anti-inflammatory activity and has
shown strong inhibition of nitric oxide production (IC50 28
µM).1 No synthesis of this lactone has appeared in the
(2) Jung, M. E.; Murakami, M. Org. Lett. 2006, 8, 5857-5859.
(3) (a) Barton, D. H. R.; Bashiardes, G.; Fourrey, J. L. Tetrahedron Lett.
1983, 24, 1605-1608. (b) Kende, A. S.; Deng, W.-P.; Zhong, M.; Guo,
X.-C. Org. Lett. 2003, 5, 1785-1788. (c) Di Grandi, M. J.; Jung, D. K.;
Krol, W. J.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 4989-4992. (d)
Pazos, Y.; Iglesias, B.; de Lera, A. R. J. Org. Chem. 2001, 66, 8483-
8489. (e) Helliwell, M.; Thomas, E. J.; Townsend, L. A. J. Chem. Soc.,
Perkin Trans. 1 2002, 1286-1296. (f) Jung, M. E.; Duclos, B. A.
Tetrahedron 2006, 62, 9321-9334.
(1) (a) Morikawa, T.; Matsuda, H.; Sakamoto, Y.; Ueda, K.; Yoshikawa,
M. Chem. Pharm. Bull. 2002, 50, 1045-1049. (b) Matsuda, H.; Morikawa,
T.; Sakamoto, Y.; Toguchida, I.; Yoshikawa, M. Bioorg. Med. Chem. 2002,
10, 2527-2534. (c) Matsuda, H.; Morikawa, T.; Sakamoto, Y.; Toguchida,
I.; Yoshikawa, M. Heterocycles 2002, 56, 45-50.
10.1021/ol062811z CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/12/2007

the derived vinyllithium with acetaldehyde, oxidation, and
final silyl enol ether formation. Heating a neat mixture of
the diene 2 with the allene carboxylate 3 (prepared in 58%
yield by reaction of ethoxycarbonylmethylenephosphorane
with acetyl chloride)4 at 110 °C for 14 d gave a separable
mixture of three products, the [2+2] cycloadduct 5, the
desired exo [4+2] cycloadduct 4x, and the endo adduct 4n
in 9%, 23.3%, and 11.7% yield, respectively (Scheme 2),
and triphenylphosphine, by reaction with n-butyllithium and
addition of the aldehyde gave an approximately 2:1 ratio of
stereoisomers of the enol methyl ether 9 in 62% yield.
The key step of hydrolysis of the silyl enol ether without
concomitant conjugation of the exocyclic methylene unit was
first tested on a model system, namely the mixture of endo
and exo esters 10 (prepared by a formal [3,3] sigmatropic
shift of the methylene cyclobutane as we reported earlier).6
Treatment of the silyl enol ether 10 with HF-pyridine under
various conditions gave a mixture of the desired nonconju-
gated enone 11 along with the undesired conjugated enone
12 (Scheme 4). The use of acetonitrile as the solvent and
Scheme 2
Scheme 4
with 31% of the recovered starting diene 2. The cyclobutane
5 could be converted into the same 2:1 ratio of 4x and 4n,
resulting in a 43% overall yield of 4x based on recovered
starting material.
low temperature greatly favored the desired product 11 while
tetrahydrofuran (THF) and higher temperatures led to the
more stable enone 12. When these conditions were applied
to the real system, similar results were obtained in that
treatment of 9 gave a 65% yield of the desired trans-decalone
13 while the exocyclic methylene remained untouched
(Scheme 5). As expected, reduction of the decalone with
The conversion of the adduct 4x into hedychilactone B 1
required two key steps: formation of the axial cyclohexanol
without moving the exo-methylene unit into the more stable
endocyclic position and extension of the side chain to give
the E-alkylidene lactone. To hydrolyze the silyl enol ether
group and reduce the ketone functionality without disrupting
the exocyclic methylene unit and the side chain functionality,
we decided to extend the side chain and protect it in one
inclusive process. Reduction of the ester 4x with DIBAL
afforded the alcohol 6, which was oxidized under Dess-
Martin periodinane conditions to afford the aldehyde 7 in
good yield (Scheme 3). Formation of the ylide from the
Scheme 5
Scheme 3
DIBAL occurred from the less-hindered equatorial direction
to give the desired axial alcohol 14 in 94% yield. No
protection of this alcohol was required to finish the synthesis.
Very mild acidic hydrolysis of the methyl enol ether (aq HCl
in THF) afforded the aldehyde 15 in 65% yield.
(4) Paik, Y. H.; Dowd, P. J. Org. Chem. 1986, 51, 2910-2913.
(5) Jung, M. E.; Mazurek, M. A.; Lim, R. M. Synthesis 1978, 588-590.
(6) (a) Jung, M. E.; Nishimura, N.; Novack, A. R. J. Am. Chem. Soc.
2005, 127, 11206-11207. (b) Novack, A. R. Ph.D. Thesis, UCLA, 2005.
methoxymethylphosphonium salt 8,5 prepared in two steps
from methylal via reaction with trimethylsilyl iodide (TMSI)
462
Org. Lett., Vol. 9, No. 3, 2007

Formation of the E-double bond between the butyrolactone
unit and the aldehyde of the side chain was all that was
required to complete the synthesis. Here again we first looked
at this reaction in a model series (Table 1). Following the
As shown in Scheme 6 the synthesis of hedychilactone B
1 was completed by treating the aldehyde 15 with the
triphenylphosphoranylidenelactone 21 in dichloromethane to
afford a 90% yield of the desired natural product as a 15:1
E:Z ratio. The proton and carbon NMR data matched exactly
those reported in the literature for this compound.1b
Table 1. Stereoselectivity in Lactone Olefinations
Scheme 6
reagent
RCHO
base/solvent
E:Z ratio
16
16
16
21
21
17, R ) Cy
17, R ) Cy
19, R ) Pr
17, R ) Cy
19, R ) Pr
KMHDS/18-C-6/THF
KMHDS/18-C-6/THFa
KMHDS/18-C-6/THF
CHCl3
1:23
1:32
1:18
40:1
100:1
CHCl3
a KOtBu added.
work of Wiemer,7 we treated the diethylphosphono lactone
16 with KHMDS and 18-C-6 in THF in the presence of
cyclohexanecarboxaldehyde 17 and isolated a mixture of
alkenes, in which the Z-isomer 18Z predominated over the
desired E-isomer 18E. Addition of potassium tert-butoxide
gave an even greater preponderance of the Z-isomer. Since
Wiemer had used the simple acyclic aldehyde propanal, we
repeated these experiments using butanal 19 and again
obtained largely the same results, namely a preference for
the Z-isomer 20Z. Consequently we switched to the tri-
phenylphosphoranylidenelactone 218 and obtained the desired
E-isomers 18E and 20E with very good selectivity. The
structures of the products were determined by chemical shifts
of olefinic protons, namely the proton in the E-isomer
absorbs at δ ∼6.6-6.7 whereas the corresponding proton in
the Z-isomer absorbs at δ ∼6.0-6.2.9 We cannot explain
the differences in our results and those of Wiemer.
Thus, we have carried out the first total synthesis of the
biologically active diterpene hedychilactone B 1 from the
[4+2] cycloadduct 4x formed in 43% yield via a stepwise
cycloaddition of a very hindered diene and an allenoate
dienophile. The key steps involved a nonconjugative hy-
drolysis of a γ-methylene silyl enol ether and the highly
stereoselective olefination of the side-chain aldehyde to give
predominately the E-alkylidene lactone. Studies of further
uses of the stepwise [4+2] cycloaddition in terpene synthesis
are underway in our laboratories and will be reported in due
course.
Acknowledgment. We thank the National Science Foun-
dation (CHE 0614591) for generous support of this work.
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.
(7) Lee, K.; Jackson, J. A.; Wiemer, D. F. J. Org. Chem. 1993, 58, 5967-
5971.
(8) Baldwin, J. E.; Moloney, M. G.; Parsons, A. F. Tetrahedron 1992,
48, 9373-9384.
(9) Larson, G. L.; Betancourt de Perez, R. M. J. Org. Chem. 1985, 50,
5257-5260.
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