Short syntheses of (±)-δ-araneosene and humulene utilizing a combination of four-component assembly and palladium-mediated cyclization

Article abstract of DOI:10.1021/ol026205p

(Matrix presented) The four components shown are assembled in two steps, and the product is converted to araneosene by a short sequence.

Full text of DOI:10.1021/ol026205p

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2441-2443
Short Syntheses of (±)-δ-Araneosene
and Humulene Utilizing a Combination
of Four-Component Assembly and
Palladium-Mediated Cyclization
Tao Hu and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received May 17, 2002
ABSTRACT
The four components shown are assembled in two steps, and the product is converted to araneosene by a short sequence.
The development of simple yet effective syntheses of
multiprenyl natural products containing rings in the 9-11
size range continues to present a challenge, especially as
more complex members of this class, such as the dollabellane
group, are discovered.1 The research that is described herein
originated from methodology developed for the synthesis
of the pentacyclic marine natural product antheliolide A,2
which involved the rapid multicomponent coupling of prenyl
units3 and facile Pd-mediated ring closure.4 Specifically,
this paper describes the incorporation of these operations
into new and effective syntheses of (()-δ-araneosene and
humulene, each of which contains an eleven-membered
ring.
The synthesis of (()-δ-araneosene (1) is outlined in
Scheme 1. The first synthesis of δ-araneosene was reported
by Mehta and co-workers.5 A second synthesis was reported
by Jenny and Borschberg.6 In the first step of our synthesis
of 1, methyl tert-butyldimethylsilyl ketone was treated with
(1) For a review, see: Rodriquez, A. D.; Gonzalez, E.; Ramirez, C.
Tetrahedron 1998, 54, 11683.
(2) (a) Green, D.; Carmely, S.; Benayahu, Y.; Kashman, Y. Tetrahedron
Lett. 1988, 29, 1605. (b) Smith, A. B., III; Carrol, P. J.; Kashman, Y.; Green,
D. Tetrahedron Lett. 1989, 30, 3363.
(3) (a) Corey, E. J.; Lin, S. J. Am. Chem. Soc. 1996, 118, 8765. (b)
Corey, E. J.; Lin, S.; Luo, G. Tetrahedron Lett. 1997, 38, 5771.
(4) See: (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96,
395. (b) Godleski, S. A. Nucleophiles with Allyl-Metal Complexes. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New
York, 1991; Chapter 3.3. (c) Trost, B. M.; Brickner, S. J. J. Am. Chem.
Soc. 1983, 105, 568. (d) Trost, B. M.; Murphy, D. J. Organometallics 1985,
4, 1143.
(5) (a) Mehta, G. Pure Appl. Chem. 1990, 62, 1263. (b) Mehta, G.;
Krishnamurthy, N.; Karra, S. R. J. Am. Chem. Soc. 1991, 113, 5765. (c)
Mehta, G.; Karra, S. R.; Krishnamurthy, N. Tetrahedron Lett. 1994, 35,
2761.
(6) Jenny, L.; Borschberg, H.-J. HelV. Chim. Acta 1995, 78, 715.
10.1021/ol026205p CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/18/2002

Scheme 1. Synthesis of (()-δ-Araneosene
2-propenyllithium in ether and then with 2-isopropylallyl
0 °C. Treatment of the allylic carbonate/silyl ether 5 with
10 mol % of Pd-dibenzylidene-acetone complex and
bisdiphenylphosphinoferrocene (dppf) in THF at reflux for
1 h effected ring closure to form the 11-membered ketone 9
in 40-48% yield.9,10 The ketone 9 could also be prepared
in somewhat higher yield (ca. 65%) by a longer alternative
route through the intermediates 6, 7, and 8.5,11 Selective
ozonolysis of 9 (ca. 0.8 equiv of O3) afforded the diketone
10, which was transformed by McMurry cyclization12 in 90%
yield into (()-δ-araneosene.
bromide in THF to give the (Z)-enolsilyl ether 2 (82%). The
sequence of reactions that leads to 2 includes (1) carbonyl
addition of 2-propenyllithium, (2) Brook rearrangement of
Si from C to O, and (3) allylation of the resulting allylic
lithium reagent.3 The silyl ether 2 was then transformed using
-
(Me2N)3S+Me3SiF2 (TAS-F)7 into the corresponding TAS
enolate, which was alkylated with bromide 38 to form the
methyl ketone 4 (90%). Thus, all carbons of δ-araneosene
were assembled from four readily available components in
just two steps in ca. 73% yield. We see no reason the
synthesis of 4 cannot be carried out without isolation of 2,
thereby allowing a direct four-component synthesis of 4.
Conversion of methyl ketone 4 into the allylic carbonate/
silyl ether 5 was effected in >99% yield using diisopropyl-
ethylamine and trimethylsilyl triflate in CH2Cl2 solution at
(9) To the best of our knowledge, the Pd(0)-catalyzed intramolecular
allylation using silyl enol ether with allylic carbonate has not been
documented before. For an intermolecular version of this type of coupling
reaction, see: (a) Tsuji, J.; Minami, I.; Shimizu, I. Chem. Lett. 1983, 1325.
(b) Tsuji, J.; Takahashi, K.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1984,
25, 4783.
(10) The use of the chelating phosphine ligand dppf retarded â-hydrogen
elimination (which gives acyclic diene) relative to ring closure; see (a)
Hartwig, J. F.; Driver, M. S. J. Am. Chem. Soc. 1996, 118, 7217. (b)
Hartwig, J. F.; Hamann, B. J. Am. Chem. Soc. 1997, 119, 12382.
(11) For the conversion of 8 to 9, see: Corey, E. J.; Chaykowsky, M. J.
Am. Chem. Soc. 1965, 87, 1345.
(7) (a) Noyori, R.; Nishida, I.; Sakata, J.; Nishizawa, M. J. Am. Chem.
Soc. 1980, 102, 1223. (b) Noyori, R.; Nishida, I.; Sakata, J. Tetrahedron
Lett. 1980, 21, 2085.
(8) For method of preparation, see Supporting Information.
2442
Org. Lett., Vol. 4, No. 14, 2002

Scheme 2. Synthesis of Humulene
The synthesis of humulene (11) was carried out by an
to a well stirred suspension of sodium sand and 14 in toluene
at 0 °C proceeded quantitatively. Reaction of this alcohol
with methanesulfonyl chloride and triethylamine in CH2Cl2
at -35 °C for 30 min and -20 °C for 30 min gave the
mesylate 15 (94% overall from 14). Elimination of meth-
anesulfonate from 15 occurred upon stirring with silica gel
in CH2Cl2 at 23 °C for 6 h to produce pure humulene (11),
identical in all respects with an authentic sample. Of the
several reported syntheses of humulene described, this is the
simplest and most efficient.14
The syntheses of (()-δ-araneosene and humulene dis-
closed herein are noteworthy for the simplicity of the C-C
bond constructions and cyclization steps, which we believe
will prove advantageous in the synthesis of related polyter-
penoids.
approach paralleling that used for araneosene (1), as outlined
in Scheme 2. Alkylation of the TBS enol ether of methyl
isopropyl ketone13 by 3 afforded the keto carbonate 12 (92%),
which could be converted cleanly into the corresponding
TMS enol ether 13. Palladium-mediated cyclization of 13,
as described above for the conversion 5 f 9, directly
generated the required cycloundecadienone 14 in ca. 50%
yield. This same compound was produced in ca. 65% yield
from 13 by a longer process analogous to the sequence 5 f
8 f 9. Reduction of ketone 14 to the corresponding
secondary alcohol by gradual addition of isopropyl alcohol
(12) (a) McMurry, J. E.; Kees, K. L. J. Org. Chem. 1977, 42, 2655. (b)
McMurry, J. E.; Lectka, T.; Rico, J. G. J. Org. Chem. 1989, 54, 3748. (c)
McMurry, J. E. Chem. ReV. 1989, 89, 1513.
(13) (a) Ohkata, K.; Mase, M.; Akiba, K. J. Chem. Soc., Chem. Commun.
1987, 1727. (b) This silyl enol ether could also be prepared from methyl
tert-butyldimethylsilyl ketone and 2-propenyllithium followed by aqueous
quench (84% yield) in a manner analogous to the preparation of 2 (Scheme
1).
(14) (a) Corey, E. J.; Hamanaka, E. J. Am. Chem. Soc. 1967, 89, 2758.
(b) Vig, O. P.; Ram, B.; Atwal, K. S.; Bari, S. S. Ind. J. Chem. 1976, 14B,
855. (c) Kitagawa, Y.; Itoh, A.; Hashimoto, S.; Yamamoto, H.; Nozaki, H.
J. Am. Chem. Soc. 1977, 99, 3864. (d) McMurry, J. E.; Matz, J. R.
Tetrahedron Lett. 1982, 23, 2723. (e) Takahashi, T.; Kitamura, K.; Tsuji,
J. Tetrahedron Lett. 1983, 24, 4695. (f) Corey, E. J.; Daigneault, S.; Dixon,
B. R. Tetrahedron Lett. 1993, 34, 3675.
Acknowledgment. We are grateful to Schering Plough
for a Fellowship to T.H.
Supporting Information Available: Experimental pro-
cedures for the reaction sequences outlined in Schemes 1
and 2, complete with physical and spectroscopic data for
each intermediate. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL026205P
Org. Lett., Vol. 4, No. 14, 2002
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