A Highly Abbreviated Synthesis of Pentalenene by Means of the Squarate Ester Cascade

Article abstract of DOI:10.1021/ol020208k

(Equation Presented) The sequential addition of 5-methylcyclopentyllithium and propynyllithium to diisopropyl squarate results in the efficient formation of a functionalized angular triquinane having two of its five-membered rings substituted precisely as in the target sesquiterpene. Only seven additional steps are then required to access pentalenene.

Full text of DOI:10.1021/ol020208k

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4547-4549
A Highly Abbreviated Synthesis of
Pentalenene by Means of the Squarate
Ester Cascade
Leo A. Paquette* and Feng Geng
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received October 14, 2002
ABSTRACT
The sequential addition of 5-methylcyclopentyllithium and propynyllithium to diisopropyl squarate results in the efficient formation of a
functionalized angular triquinane having two of its five-membered rings substituted precisely as in the target sesquiterpene. Only seven
additional steps are then required to access pentalenene.
Pentalenene (1), whose isolation from Streptomyces griseo-
chromogenes was reported by Seto and Yonehara in 1980,1
is the parent hydrocarbon of the pentalenone antibiotic family
of fungal metabolites. The unusual tricyclo[6.3.0.04,8]-
undecane structural motif common to 1 and its oxygenated
congeners has elicited considerable synthetic2 and biosyn-
thetic interest.3 Since the first de novo approach to pental-
enene reported by our group in 1982,4 almost 30 total5-19
and formal syntheses20-26 of 1 have been defined. Some of
the more effective means for accessing this sesquiterpenoid
(8) (a) Mehta, G.; Rao, K. S. J. Chem. Soc., Chem. Commun. 1985, 1464.
(b) Mehta, G.; Rao, K. S. J. Am. Chem. Soc. 1986, 108, 8015.
(9) Hua, D. H. J. Am. Chem. Soc. 1986, 108, 3835.
(1) Seto, H.; Yonehara, H. J. Antibiot. 1980, 33, 92.
(10) (a) Imanishi, T.; Ninbari, F.; Yamashita, M.; Iwata, C. Chem. Pharm.
Bull. 1986, 34, 2268. (b) Imanishi, T.; Yamashita, M.; Ninbari, F.; Tanaka,
T.; Iwata, C. Chem. Pharm. Bull. 1988, 36, 1371. (c) Imanishi, T.;
Yamashita, M.; Hirokawa, Y.; Tanaka, T.; Iwata, C. Chem. Pharm. Bull.
1990, 38, 1124.
(2) Reviews: (a) Mehta, G. Srikrishna, A. Chem. ReV. 1997, 97, 671.
(b) Paquette, L. A.; Doherty, A. M. Polyquinane Chemistry; Springer-
Verlag: New York, 1987. (c) Paquette, L. A. Top. Curr. Chem. 1984, 119,
1. (d) Paquette, L. A. Top. Curr. Chem. 1979, 79, 41.
(3) (a) Seemann, M.; Zhai, G.; Umezawa, K.; Cane, D. E. J. Am. Chem.
Soc. 1999, 121, 591. (b) Lesburg, C. A.; Zhai, G.; Cane, D. E.; Christianson,
D. W. Science 1997, 277, 1820. (c) Cane, D. E.; Weiner, S. W. Can. J.
Chem. 1994, 72, 118. (d) Cane, D. E.; Sohng, J. K.; Lamberson, C. R.;
Rudnicki, S. M.; Wu, Z.; Lloyd, M. D.; Oliver, J. S.; Hubbard, B. R.
Biochemistry 1994, 33, 5846. (e) Cane, D. E.; Oliver, J. S.; Harrison, P. H.
M.; Abell, C.; Hubbard, B. R.; Kane, C. T.; Lattman, R. J. Am. Chem. Soc.
1990, 112, 4513. (f) Harrison, P. H. M.; Oliver, J. S.; Cane, D. E. J. Am.
Chem. Soc. 1988, 110, 5922. (g) Cane, D. E.; Abell, C.; Lattman, R.; Kane,
C. T.; Hubbard, B. R.; Harrison, P. H. M. J. Am. Chem. Soc. 1988, 110,
4081.
(4) (a) Annis, G. D.; Paquette, L. A. J. Am. Chem. Soc. 1982, 104, 4504.
(b) Paquette, L. A.; Annis, G. D. J. Am. Chem. Soc. 1983, 105, 7358.
(5) (a) Pattenden, G.; Teague, S. J. Tetrahedron Lett. 1984, 25, 3021.
(b) Pattenden, G.; Teague, S. J. Tetrahedron 1987, 43, 5637.
(6) (a) Piers, E.; Karunaratne, V. J. Chem. Soc., Chem. Commun. 1984,
959. (b) Piers, E.; Karunaratne, V. Can. J. Chem. 1989, 67, 160.
(7) Crimmins, M. T.; DeLoach, J. A. J. Am. Chem. Soc. 1986, 108, 800.
(11) (a) Hudlicky, T.; Natchus, M. G.; Sinai-Zingde, G. J. Org. Chem.
1987, 52, 4641. (b) Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G.; Ranu,
B. C.; Papadopolous, P. Tetrahedron 1987, 43, 5685.
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5224. (b) Rowley, E. G.; Schore, N. E. J. Org. Chem. 1992, 57, 6853.
(13) Ihara, M.; Katogi, M.; Fukumoto, K.; Kametani, T. J. Chem. Soc.,
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403.
10.1021/ol020208k CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/16/2002

include thermal and photochemical cycloadditions,4,7,11,17
transannular cyclizations,5,8 tandem radical-mediated ring
closures,18,19 metal-catalyzed transformations (Zr,26 Co,12 Fe,22
Ni25), and the use of cyclopropane and cyclobutane inter-
mediates.6,10,16
Scheme 1
In making use of the extensive bond reorganization that
accompanies the so-called “squarate ester cascade”,27 we
previously found it possible to apply this deep-seated
rearrangement to the expeditious synthesis of the naturally
occurring linear triquinanes hypnophilin (2),28,29 coriolin,29
and ceratopicanol (3).29 Presently, we describe the first
successful undertaking that transforms diisopropyl squarate
(4)30 in an equally convenient and concise manner into the
alternative angularly fused architecture, as is present, for
example, in 1.
The pentalenene framework features a bridged spirane
arrangement of three cyclopentane rings. To arrive at this
carbocyclic skeleton from the direction of 4, it becomes
necessary to achieve regioselective protonation within a
strained 1,2,4,6-cyclooctatetraene intermediate such as 8. To
this end, we found it productive to treat 4 first with
5-methylcyclopentenyllithium and then propynyllithium
(Scheme 1). Under these circumstances, trans addition likely
predominates to furnish 5 as the principal bis-adduct.31 The
doubly charged nature of 5 and the strong donor character
of the two oxido anions combine to promote outward
conrotatory movement of the oxygen atoms during opening
of the cyclobutene ring.32
constituent triple bond in the second (now 8π conrotatory)
electrocyclization proceeds more slowly and delivers the
strained intermediate 8.34 Beyond that, the presence of a
methyl group on the cyclopentene subunit should sufficiently
impede the rate of ring closure in 6 because of its placement
on the interior of the coil in this case.35 Comparable kinetic
retardation should not accompany the conversion of 7 to 8,
thereby resulting in good overall stereochemical control at
this stage. At the experimental level, 10 was isolated in 76%
yield following acidification and transannular aldolization
(see 9). We note specifically that the stereoselectivity and
steric constraints operational while proceeding from 6 to 10
result in the direct, one-pot assembly of a tricycloundecane
product having rings B and C of the target pentalenene
structure completely elaborated.
Equilibration between the two helical dienolates 6 and 7
so formed was anticipated to be facile.33 Participation of the
(20) Jurlina, J. L.; Patel, H. A.; Stothers, J. B. Can. J. Chem. 1984, 62,
1159.
(21) Baker, R.; Keen, R. B. J. Organomet. Chem. 1985, 285, 419.
(22) (a) Zhao, S.; Mehta, G.; Helquist, P. Tetrahedron Lett. 1991, 32,
5753. (b) Ishii, S.; Zhao, S.; Mehta, G.; Knors, C. J.; Helquist, P. J. Org.
Chem. 2001, 66, 3449.
(23) Lange, G. L.; Gottardo, C. J. Org. Chem. 1995, 60, 2183.
(24) Zhu, Y.-Y.; Burnell, D. J. Tetrahedron: Asymmetry 1996, 7, 3295.
(25) Seo, J.; Fain, H.; Blanc, J.-B.; Montgomery, J. J. Org. Chem. 1999,
64, 6060.
(26) Agnel, G.; Negishi, E. J. Am. Chem. Soc. 1991, 113, 7424.
(27) Review: Paquette, L. A. Eur. J. Org. Chem. 1998, 1709.
(28) Geng, F.; Liu, J.; Paquette, L. A. Org. Lett. 2002, 4, 71.
(29) Paquette, L. A.; Geng, F. J. Am. Chem. Soc. 2002, 124, 9199.
(30) Liu, H.; Tomooka, C. S.; Moore, H. W. Synth. Commun. 1997, 27,
2177.
The chemical modification of ring A began by activation
of the hydroxyl group in 10 as the acetate (Scheme 2). When
(33) (a) Paquette, L. A.; Doyon, J.; Kuo, L. H. Tetrahedron Lett. 1996,
37, 3299. (b) Paquette, L. A.; Hamme, A. T., II; Kuo, L. H.; Doyon, J.;
Kreuzholz, R. J. Am. Chem. Soc. 1997, 119, 1242.
(34) (a) Morwick, T.; Doyon, J.; Paquette, L. A. Tetrahedron Lett. 1995,
36, 2369. (b) Paquette, L. A.; Morwick, T. M. J. Am. Chem. Soc. 1997,
119, 1230.
(31) Diastereoselective cis addition would also give rise to 8 via dianionic
oxy-Cope rearrangement.
(32) (a) Kirmse, W.; Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc.
1984, 106, 7989. (b) Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc. 1985,
107, 2099. (c) Niwayama, S.; Kallel, E. A.; Spellmeyer, D. C.; Sheu, C.;
Houk, K. N. J. Org. Chem. 1996, 61, 2813. (d) Dolbier, W. R., Jr.; Koroniak,
H.; Kouk, K. N.; Sheu, C. Acc. Chem. Res. 1996, 29, 471.
(35) Carefully executed experiments and quantitation of chromatographic
fractions following workup have shown 10 to dominate over its diastereomer
(formed analogously from 6) by a ratio of 8.8:1. Since racemic 5-methyl-
cyclopentenyllithium was employed in this study and the other reagents
are achiral, the enantiomeric representations of 6-10 are also involved.
4548
Org. Lett., Vol. 4, No. 25, 2002

guarding against possible overreduction. With rapid arrival
at 13, it was now possible to undertake the R,R-dimethylation
of its enolate anion. This transformation was best achieved
with potassium tert-butoxide and methyl iodide in that
contamination involving the difficultly separable monomethyl
derivative was not seen.
Scheme 2
The doubly neopentylic nature of the carbonyl group in
14 brought an assortment of challenges to the fore. For
example, no reaction was observed whenever nucleophilic
attack at the sp2-hybridized carbon was a matter of consid-
eration. Two such processes include attempted Wolff-
Kishner and LiAlH4/THF reduction at elevated temperature.
In contrast, dissolving metal reduction was well suited to
the task, providing alcohol 15 in near-quantitative yield. Once
its derived acetate 16 was reached, recourse to C-O bond
cleavage with sodium metal in HMPA37 gave pentalenene
(1), which was spectroscopically identical to an authentic
sample.38
The use of the squarate ester cascade as a device for rapid
assembly of a naturally occurring angular triquinane has thus
been demonstrated. The hydrocarbon nature of the target also
provided a forum for evaluating the power of dissolving
metal reduction. Three distinctively different transformations
involving Li/NH3 can be identified at various stages of the
synthesis, this routing making possible an economic eight-
step sequence to arrive at 1 from 4.
11 was reduced with approximately 50 mol equiv of lithium
metal in liquid ammonia at -78 °C and excess methanol
was slowly added over 1 h, the transfer of six electrons was
made possible and 12 was formed in 68% yield.36 Although
conditions for cleavage of the second isopropoxy substituent
in this step were not found, the independent dissolving metal
reduction of 12 did lead efficiently to ketone 13. Sodium
benzoate was invariably introduced prior to workup for the
purpose of quenching the excess lithium reagent, thus
Acknowledgment. Financial support was provided by the
National Science Foundation whom we thank.
Supporting Information Available: Experimental details
and characterization data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL020208K
(36) Although a single isomer of 12 was produced in this manner, the
relative orientation of its isopropoxy group was not definitively established,
although it is expected that it is on the â-face.
(37) Deshayes, H.; Pete, J.-P. J. Chem. Soc., Chem. Commun. 1978, 567.
(38) All compounds are considered to be of >97% purity on the basis
of NMR and TLC analyses.
Org. Lett., Vol. 4, No. 25, 2002
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