Total synthesis of (±)-hedychenone: Trimethyldecalin terpene systems via stepwise allenoate diene cycloaddition

Article abstract of DOI:10.1021/ol062456c

(Diagram presented) The total synthesis of hedychenone 1 is described. The cycloaddition of the hindered diene 2 and the allenecarboxylate 3 has been shown conclusively to proceed via the [2+2] cycloadduct 5 to give a 2:1 mixture of the desired formal Diels-Alder adducts, the exo and endo isomers 4xn and is thus a stepwise [4+2] cycloaddition. The exo isomer 4x was converted in four steps (reduction, oxidation, olefination, and desilylation) into hedychenone 1.

Full text of DOI:10.1021/ol062456c

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5857-5859
Total Synthesis of (±)-Hedychenone:
Trimethyldecalin Terpene Systems via
Stepwise Allenoate Diene Cycloaddition
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 October 5, 2006
ABSTRACT
The total synthesis of hedychenone 1 is described. The cycloaddition of the hindered diene 2 and the allenecarboxylate 3 has been shown
conclusively to proceed via the [2 2] cycloadduct 5 to give a 2:1 mixture of the desired formal Diels Alder adducts, the exo and endo
2] cycloaddition. The exo isomer 4x was converted in four steps (reduction, oxidation, olefination, and
+
−
isomers 4xn and is thus a stepwise [4
+
desilylation) into hedychenone 1.
Hedychenone 1, a labdane diterpene isolated from various
types of Zingiberaceae plants, e.g., Hedychium coronarium
Koen., has shown very strong inhibition of nitric oxide
production (IC50 of 7.9 µM), has antiinflammatory activity,
and also inhibits the release of â-hexosaminidase and thus
is antiallergic (Scheme 1).1 No total synthesis of this enone
has been reported, although a synthesis from the naturally
occurring diterpene diol larixol has appeared in the literature.2
Recently, we have shown that very hindered cyclohexene
systems can be prepared either by a direct [4+2] cycload-
dition catalyzed by a mixed Lewis acid3 or via the formal
[3,3]-sigmatropic rearrangement of 1-alkenyl-3-alkylidenecy-
Scheme 1
(1) (a) Sharma, S. C.; Tandon, J. S.; Uprety, H; Shukla, Y. N.; Dhar, M.
M. Phytochemistry 1975, 14, 1059-1061. (b) Zhao, Q.; Zou, C.; Hao, X.
J.; Chen, Y. Z. Chin. Chem. Lett. 1999, 10, 531-532. (c) Matsuda, H.;
Morikawa, T.; Sakamoto, Y.; Toguchida, I.; Yoshikawa, M. Heterocycles
2002, 56, 45-50. (d) Matsuda, H.; Morikawa, T.; Sakamoto, Y.; Toguchida,
I.; Yoshikawa, M. Bioorg. Med. Chem. 2002, 10, 2527-2534. (e) Morikawa,
T.; Matsuda, H.; Sakamoto, Y.; Ueda, K.; Yoshikawa, M. Chem. Pharm.
Bull. 2002, 50, 1045-1049. (f) Liu, X.-H.; Wang, W.; He, Z.-D.; Wang,
H.-Q.; Yang, C.-R.; Chen, B. Acta Crystallogr., Sect. C: Cryst. Struct.
Commun. 1999, 55, iii, IUC9900129. (g) Srimal, R. C.; Sharma, S. C.;
Tandon, J. S. Indian J. Pharmacol. 1984, 16, 143-147. (h) Zhao, Q.; Hao,
X. J.; Chen, Y. Z.; Zou, C. Yaoxue Xuebao 1995, 30, 119-122; Chem.
Abs. 1996, 123, 5671.
clobutyl silyl ethers.4 We report here 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 initial [2+2] cycloadduct,
the cyclobutane 5.
(2) Aslaoui, J.; Li, H.; Morin, C. Tetrahedron Lett. 2005, 46, 1713-
1716.
10.1021/ol062456c CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/15/2006

A potentially quite useful route to the trimethyldecalin unit
of diterpenes, sesterterpenes, and even triterpenes would be
the direct Diels-Alder cycloaddition of a suitably function-
alized diene having the trimethylcyclohexane moiety of the
A ring with a simple or complex dienophile thereby gen-
erating the B ring in one convergent process. There are very
few examples of such a strategy being successful, partly
because of the steric hindrance involved in such a cycload-
dition, but the existence of new methods of carrying out
Diels-Alder or Diels-Alder-type reactions argues that this
route should be reexamined. The diene for the key cycload-
dition, 2-(1-tert-butyl-dimethylsilyloxyethenyl)-1,3,3-trimeth-
ylcyclohexene 2, was readily prepared from 2,6-dimethyl-
cyclohexanone 6 in several steps (Scheme 2). Methylation
Knowing that the direct [4+2] cycloaddition was very
difficult, we decided to see if a stepwise cycloaddition
process could be induced to occur, namely an initial [2+2]
cycloaddition followed by the [3,3]-sigmatropic rearrange-
ment to produce overall the same product. This is similar to
our earlier work4 where we specifically prepared the cy-
clobutane from a silyloxydiene and an allene carboxylate.
Thus, heating a neat mixture of the allene carboxylate 3
(prepared in 58% yield by reaction of acetyl chloride with
ethoxycarbonylmethylenetriphenylphosphorane)6 with the
diene 2 at 110 °C for 14 days gave a separable mixture of
three products, the [2+2] cycloadduct 5 in 9% yield, the
desired exo [4+2] cycloadduct 4x in 23.3% yield, and the
endo adduct 4n in 11.7% yield (Scheme 3). This is yet
Scheme 2
Scheme 3
gave the trimethyl ketone (92%) which was then subjected
to a Barton vinyl iodination procedure, namely formation
of the hydrazone and treatment with iodine and base to give
the vinyl iodide 7 in 73% yield for the final two steps.
Formation of the vinyllithium with tert-butyllithium followed
by trapping with acetaldehyde, TPAP/NMO oxidation of the
resulting alcohol to the acetyl group, and kinetic silyl enol
ether formation afforded the diene 2 in 88% yield from 7.
Heating a neat mixture of the diene 2 and ethyl acrylate 8
afforded none of the desired Diels-Alder adduct giving back
only the starting diene and polymeric material. This lack of
normal [4+2] cycloaddition reactivity is not at all surprising
because theoretical calculations indicate that the diene 2
exists mainly in the noncoplanar conformation 2B rather than
in the cis-planar conformation 2A required for a concerted
[4+2] cycloaddition (Figure 1). Both molecular mechanics
another example of the use of allenes in difficult cycload-
ditions.7 In addition to the three cycloadducts, 31% of the
starting diene 2 was recovered. The structures of the two
[4+2] cycloadducts were determined by NOE experiments
on the corresponding alcohols 9xn (prepared by DIBAL
reduction). We believe that the [4+2] cycloadducts 4xn are
formed in a stepwise fashion, namely via the initial formation
of 5, for the following reasons: (1) monitoring the appear-
(3) (a) Jung, M. E.; Davidov, P. Angew. Chem. 2002, 41, 4125-4128.
(b) Jung, M. E.; Ho, D.; Chu, H. V. Org. Lett. 2005, 7, 1649-1651.
(4) Jung, M. E.; Nishimura, N.; Novack, A. R. J. Am. Chem. Soc. 2005,
127, 11206-11207.
(5) MM2 calculations using Macromodel indicate a difference of about
14 kcal/mol favoring 2B (the cis planar conformation 2A was constrained
and held for these calculations). DFT calculations using B3LYP/6-31.G*//
HF/6--1.G* indicate a 9.2 kcal/mol difference favoring 2B, and those using
just HF/6-31.G* gave a 12.8 kcal/mol difference.
Figure 1. Conformations of diene 2.
(6) Paik, Y. H.; Dowd, P. J. Org. Chem. 1986, 51, 2910.
(7) For allene cycloadditions, see: (a) Jung, M. E.; Min, S.-J. J. Am.
Chem. Soc. 2005, 127, 10834-10835. (b) Jung, M. E.; Nishimura, N. J.
Am. Chem. Soc. 1999, 121, 3529-3530. (c) Kanematsu, K. ReV. Heteroatom
Chem. 1993, 9, 231-259. (d) Aso, M.; Kanematsu, K. Trends Org. Chem.
1995, 5, 157-169. (e) Gras, J. L.; Galledou, B. S.; Bertrand, M. Bull. Soc.
Chim. Fr. 1988, 4, 757-767.
and DFT methods indicate that the ground-state twisted
conformation, e.g., 2B, is 9-14 kcal/mol more stable than
the cis-coplanar conformation 2A.5
5858
Org. Lett., Vol. 8, No. 25, 2006

ance of products with time shows that the [2+2] cycloadduct
5 is produced before any of the [4+2] cycloadducts 4xn,
and its concentration decreases with the production of 4xn;
(2) thermolysis of a solution of 5 in toluene (200 °C, µwave)
produces an identical 2:1 ratio of 4xn as does the reaction
of 2 and 3, thereby providing an additional 6% of the exo
adduct 4x; (3) the cycloaddition of the diene 2 and ethyl
acrylate 8 does not proceed under the conditions that produce
4xn; and (4) as mentioned above, theoretical calculations
indicate that the diene 2 exists mainly in the noncoplanar
conformation 2B which is unsuitable for the direct [4+2]
cycloaddition. Thus, we postulate that the diene 2 reacts via
its most stable conformation 2B with the allene ester 3 via
a stepwise mechanism to give first the zwitterion C which
then closes to the less sterically hindered cyclobutane 5 via
trapping of the cation by the unsubstituted end of the allyl
anion (Scheme 4). On further heating, 5 rearranges to the
Having successfully prepared the desired [4+2] cycload-
duct, we finished the synthesis of (()-hedychenone 1 in three
steps (Scheme 5). The primary alcohol 9x, formed by
Scheme 5
treatment of 4x with DIBAL, was oxidized to the aldehyde
with Dess Martin periodinane (DMP). Wittig reaction of this
aldehyde with the known 3-furyl ylide 109 followed by
simple desilylation and in situ conjugation of the unconju-
gated enone afforded (()-hedychenone 1. The proton NMR
data of the synthetic material matched that reported for the
natural product,1a and the carbon NMR spectrum is what
would be expected for this structure.10
Scheme 4
In summary, we have demonstrated that highly substituted
functionalized trimethyldecalin systems common to many
terpenes can be prepared directly via a stepwise diene
allenoate cycloaddition process. We have also presented
strong evidence that the key reaction proceeds via the
intermediacy of the [2+2] cycloadduct. The use of this
procedure for the synthesis of diterpene natural products is
currently under study in our labs.
Acknowledgment. We thank the National Science Foun-
dation (CHE 0314591 and CHE 0614591) for generous
support of this work. M.M. thanks Sankyo Co. Ltd. for
generous support. We thank Daniel Ess and Dr. Michael
Trzoss (UCLA) for their help with the theoretical calculations
and Professor Ken Houk (UCLA) for useful discussions.
observed [4+2] cycloadducts 4xn. Although at present we
cannot explain why the ratio of products does not more
greatly favor the exo isomer as it did in other cases,4,8 we
believe that this is the first clear example of a Diels-Alder-
like product being produced via a demonstrably nonconcerted
pathway which involves the intermediacy of a [2+2]
cycloadduct. Even though the yield of this process is
somewhat low (overall yield of ∼43% of 4x based on
unrecovered starting diene 2 and the separate rearrangement
of 5 to 4xn), the conciseness of this direct approach to
trimethyldecalin terpene systems should find use in synthesis.
Supporting Information Available: Experimental pro-
cedures and proton and carbon NMR data (including copies
of the spectra) for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL062456C
(9) (a) Okabe, M.; Tamagawa, H.; Tada, M. Synth. Commun. 1983, 13,
373-378. (b) Van Altena, I. A.; Miller, D. A. Aust. J. Chem. 1989, 42,
2181-2190. (c) Kolympadi, M.; Liapis, M.; Ragoussis, V. Tetrahedron
2005, 61, 2003-2010. (d) Tanaka, K.; Hata, T.; Hara, H.; Katsumura, S.
Tetrahedron 2003, 59, 4945-4952. (e) Grossman, R. B.; Rasne, R. M. Org.
Lett. 2001, 3, 4027-4030.
(8) Indeed, this ratio agrees well with our theoretical calculations of the
transition structures and energies for the [3,3]-sigmatropic rearrangement
of such [2+2] cycloadducts to the mixture of exo and endo [4+2]
cycloadducts. Zhao, Y.-L.; Suhrada, C. P.; Jung, M. E.; Houk, K. N. J.
Am. Chem. Soc. 2006, 128, 11106-11113.
(10) Carbon NMR of 1: δ 199.9, 157.2, 143.6, 140.2, 128.1, 126.0, 124.6,
123.8, 107.4, 63.4, 61.3, 43.3, 42.7, 40.2, 33.6, 32.5, 23.0, 21.7, 18.1, 15.7.
Org. Lett., Vol. 8, No. 25, 2006
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