Enantioselective synthesis of (-)-pentalenene

Article abstract of DOI:10.1021/ol702597y

A short, enantioselective synthesis of (-)-pentalenene is described. Catalytic enantioselective cyclopropenation with (R,R)-Rh₂(OAc)(DPTI) ₃ was used to set the absolute stereochemistry, and an intramolecular Pauson-Khand reaction of the resulting cyclopropenyne was used to establish the quaternary center.

Full text of DOI:10.1021/ol702597y

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5625-5628
Enantioselective Synthesis of
)-Pentalenene
(−
Mahesh K. Pallerla and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry,
UniVersity of Delaware, Newark, Delaware 19716
jmfox@udel.edu
Received October 25, 2007
ABSTRACT
A short, enantioselective synthesis of (−)-pentalenene is described. Catalytic enantioselective cyclopropenation with (R,R)-Rh2(OAc)(DPTI)3
was used to set the absolute stereochemistry, and an intramolecular Pauson
establish the quaternary center.
−Khand reaction of the resulting cyclopropenyne was used to
For the past three decades, triquinane natural products have
been considered to be classic1 targets for total synthesis
because of their biological activity and because of their
compact, structurally complex architectures.2 As the biosyn-
thetic precursor to the pentalenolactone family of antibiotics,3
pentalenene has attracted intense and consistent interest from
the synthetic community during the past 25 years, culminat-
ing in numerous total and formal syntheses.4-25 However,
all but one10 of these syntheses produced racemic pental-
enene, and an enantioselective synthesis has not been
reported previously.25 In general for the angular triquinane
(11) (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.
(12) (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.
(13) (a) Rowley, E. G.; Schore, N. E. J. Org. Chem. 1992, 57, 6853. (b)
Schore, N. E.; Rowley, E. G. J. Am. Chem. Soc. 1988, 110, 5224.
(14) Ihara, M.; Katogi, M.; Fukumoto, K.; Kametani, T. J. Chem. Soc.,
Perkin. Trans 1 1988, 2963.
(1) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; Wiley-
VCH: Weinheim, Germany, 1996; pp 221 and 381.
(2) Reviews of triquinanes: (a) Mehta, G.; Srikrishna, A. Chem. ReV.
1997, 97, 671. (b) Paquette, L. A.; Doherty, A. M. Polyquinane Chemistry;
Springer-Veriag: Berlin, Germany, 1987. (c) Paquette, L. A. Top. Curr.
Chem. 1984, 119, 1. (d) Trost, B. M. Chem. Soc. ReV. 1982, 11, 141. (e)
Paquette, L. A. Top. Curr. Chem. 1979, 79, 41.
(15) Shizuri, Y.; Maki, S.; Ohkubo, M.; Yamamura, S. Tetrahedron Lett.
1990, 31, 7167.
(3) Seto, H.; Yonehara, H. J. Antibiot. 1980, 33, 92.
(16) (a) Wu, Y.-J.; Burnell, D. J. J. Chem. Soc., Chem. Commun. 1991,
764. (b) Wu, Y.-J.; Zhu, Y.-Y.; Burnell, D. J. J. Org. Chem. 1994, 59,
104.
(17) (a) Franck-Neumann, M.; Miesch, M.; Gross, L. Tetrahedron Lett.
1992, 33, 3879. (b) Miesch, M.; Miesch-Gross, L.; Franck-Neumann, M.
Tetrahedron 1997, 53, 2111.
(18) Hatanaka, M.; Ueno, F.; Ueda, I. Tetrahedron Lett. 1996, 37, 89.
(19) Kim, S.; Cheong, J. H.; Yoo, J. Synlett 1998, 981.
(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. K.; 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.
(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. (c)
Paquette, L. A.; Geng, F. Org. Lett. 2002, 4, 4547.
(5) (a) Pattenden, G.; Teague, S. J. Tetrahedron Lett. 1984, 25, 2621.
(b) Pattenden, G.; Teague, S. J. Tetrahedron 1987, 43, 5637. (c) Harrington-
Frost, N. M.; Pattenden, G. Tetrahedron Lett. 2000, 41, 403. (d) De Boeck,
B.; Harrington-Frost, N. M.; Pattenden, G. Org. Biomol. Chem. 2005, 3,
340.
(6) Morimoto, T.; Horiguchi, T.; Yamada, K.; Tsutsumi, K.; Kurosawa,
H.; Kakiuchi, K. Synthesis 2004, 753.
(7) (a) Piers, E.; Karunaratne, V. J. Chem. Soc., Chem. Commun. 1984,
959. (b) Piers, E.; Karunaratne, V. Can. J. Chem. 1989, 67, 160.
(8) Crimmins, M. T.; Deloach, J. A. J. Am. Chem. Soc. 1986, 108, 800.
(9) (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.
(10) Hua, D. H. J. Am. Chem. Soc. 1986, 108, 3835.
(23) Lange, G. L.; Gottardo, C. J. Org. Chem. 1995, 60, 2183.
(24) Seo, J.; Fain, H.; Blanc, J.-B.; Montgomery, J. J. Org. Chem. 1999,
64, 6060.
10.1021/ol702597y CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/22/2007

natural products, there are a large number of total syntheses
but relatively few enantioselective syntheses.26 Especially rare
are syntheses of angular triquinine natural products that
utilize enantioselective catalysis to establish the absolute
stereochemistry.26a,b Integral to the challenge of an enantio-
selective synthesis of the angular triquinanes is the asym-
metric installation of the central, quaternary carbon.27
The Pauson-Khand reaction is a multicomponent reaction
that has found particular utility for the stereocontrolled
construction of triquinane natural products.28 In seminal
work, Schore utilized an intramolecular, diastereoselective
Pauson-Khand reaction as the key step for the synthesis of
pentalenene.13 In the only nonracemic synthesis of pental-
enene, Hua utilized a Pauson-Khand reaction to prepare 7,7-
dimethylbicyclo[3.3.0]-2-octen-3-one, which was obtained
in enantiomerically enriched form via kinetic resolution.10
More recently, Krafft utilized a tandem Pauson-Khand/aldol
sequence to construct an angular triquinine skeleton,29 and
Pericas utilized chiral auxiliaries to control the asymmetry
of the Pauson-Khand reaction in the synthesis of (+)-15-
nor-methylpentalenene.30 The angular triquinane framework
has also been constructed by Malacria and co-workers with
a Conia-ene/intramolecular Pauson-Khand sequence,31 and
by Serratosa and co-workers, who utilized an intermolecular
Pauson-Khand reaction.32
Recently, our group described intermolecular Pauson-
Khand reactions of chiral cyclopropenes33assubstrates that
are readily available in enantiomerically enriched form.34
Because cyclopropenes are exceptionally reactive in inter-
molecular Pauson-Khand reactions,33 we envisioned that an
intramolecular variant33e of the reaction could be used to set
the quaternary center of pentalenene. In a retrosynthetic
analysis (Scheme 1), it was reasoned that 1 could be derived
Scheme 1. Retrosynthetic Analysis of (-)-Pentalenene
from tricycle 2. The quaternary center of 2 could be
established from an intramolecular Pauson-Khand reaction
(25) Burnell has reported a highly enantioselective synthesis of (4R,5S)-
4-hydroxy-4,7,9,9-tetramethylspiro[4,5]dec-7-en-1-one using Baker’s yeast
reduction as the key step: Zhu, Y.-Y.; Burnell, D. J. Tetrahedron:
Asymmetry 1996, 7, 3295. Burnell had previously reported the use of a
similar derivative [7-ethyl-4-hydroxy-4,9,9-trimethylspiro[4,5]dec-7-en-1-
one] in the synthesis of racemic pentalenene.16
Scheme 2. Enantioselective Cyclopropenation with Corey’s
Rh2(OAc)(R,R-DPTI)3 Catalyst
(26) Nonracemic total syntheses have been described for the angular
triquinines (-)-pentalenolactone,26c,d,j, (-)-isocomene,26g (+)-silphenene,26a
(-)-retigeranic acid,26e,k,l,m (-)-silphiperfol-6-ene,26b,h,i,q,n,o (-)-methyl
cantabradienate,26i and (-)-subergorgic acid.26f For total or formal syntheses
that use nonenzymatic enantioselective catalysis to establish the absolute
stereochemistry, see: (a) Hu, Q.-Y.; Zhou, G.; Corey, E. J. J. Am. Chem.
Soc. 2004, 126, 13708. (b) Demuth, M.; Hinsken, W. HelV. Chim. Acta
1988, 71, 569. For syntheses in which absolute stereochemistry is established
via enzymatic desymmetrization or resolution: (c) Herrmann, E.; Gais,
H.-J.; Rosenstock, B.; Raabe, G.; Lindner, H. J. Eur. J. Org. Chem. 1998,
275. (d) Mori, K.; Tsuji, M. Tetrahedron. 1988, 44, 2835. (e) Wender, P.
A.; Singh, S. K. Tetrahedron Lett. 1990, 31, 2517. (f) Paquette, L. A.;
Meister, P. G.; Friedrich, D.; Sauer, D. R. J. Am. Chem. Soc. 1993, 115,
49. For syntheses in which chiral auxilaries are used to establish absolute
stereochemistry: (g) Rawal, V. H.; Eschbach, A.; Dufour, C.; Iwasa, S.
Pure Appl. Chem. 1996, 68, 675. (h) Meyers, A. I.; Lefker, B. A.
Tetrahedron 1987, 43, 5663. (i) Vo, N. H.; Snider, B. B. J. Org. Chem.
1994, 59, 5419. For syntheses that originate from enantiomerically enriched
natural products: (j) Testero, S. A.; Spanevello, R. A. Org. Lett. 2006, 8,
3793. (k) Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 5544. (l)
Hudlicky, T.; Fleming, A.; Radesca, L. J. Am. Chem. Soc. 1989, 111, 6691.
(m) Wright, J.; Drtina, G. J.; Roberts, R. A.; Paquette, L. A. J. Am. Chem.
Soc. 1988, 110, 5806. (n) Paquette, L. A.; Roberts, R. A.; Drtina, G. J. J.
Am. Chem. Soc. 1984, 106, 6690. (o) Sha, C.-K.; Santosh, K. C.; Lih,
S.-H. J. Org. Chem. 1998, 63, 2699.
of cyclopropenyne 3, which itself could arise from an
enantioselective cyclopropenation of diyne 4. The successful
execution of this strategy is reported herein for the synthesis
of (-)-1, the unnatural enantiomer of the natural product
pentalenene.35
(32) Montan˜a, A.-M.; Moyano, A.; Pericas, M. A.; Serratosa, F.
Tetrahedron 1985, 41, 5995.
(33) For examples of intermolecular Pauson-Khand reactions of cyclo-
propenes: (a) Pallerla, M. K.; Fox, J. M. Org. Lett. 2005, 7, 3593. (b)
Kireev, S. L.; Smit, V. A.; Ugrak, B. I.; Nefedov, O. M. Bull. Acad. Sci
USSR (Engl. Transl.) 1991, 2240. (c) Marchueta, I.; Verdaguer, X.; Moyano,
A.; Perica`s, M. A.; Riera, A. Org. Lett. 2001, 3, 3193. (d) Witulski, B.;
Go¨ssman, M. Synlett 2000, 1793. For an example of an intermolecular
Pauson-Khand reaction of a cyclopropene derivative: (e) Nu¨ske, H.; Bra¨se,
S.; de Meijere, A. Synlett 2000, 1467.
(27) Reviews for the enantioselective introduction of quaternary car-
bons: (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (b) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (c) Fuji, K. Chem.
ReV. 1993, 93, 2037. (d) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005,
347, 1473.
(28) For the seminal utilization of the Pauson-Khand reaction in
triquinane synthesis, see: (a) Magnus, P.; Exon, C.; Albaugh-Robertson,
P. Tetrahedron 1985, 41, 5861. Selected reviews of the Pauson-Khand
reaction: (b) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263.
(c) Schore, N. E. Org. React. 1991, 40, 1. (d) Schore, N. E. Chem. ReV.
1988, 88, 1081. (e) Stru¨bing, D.; Beller, M. Top. Organomet. Chem. 2006,
18, 165. (f) Blanco-Urgoiti, J.; Anorbe, L.; Perez-Serrano, L.; Dominguez,
G.; Perez-Castells, J. Chem. Soc. ReV. 2004, 33, 32.
(34) (a) Lou, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.; Corey,
E. J. J. Am. Chem. Soc. 2004, 126, 8916. (b) Lou, Y.; Remarchuk, T. P.;
Corey, E. J. J. Am. Chem. Soc. 2005, 127, 14223. (c) Weatherhead-Kloster,
R. A.; Corey, E. J. Org. Lett. 2006, 8, 171. (d) Doyle, M. P.; Protopopova,
M.; Muller, P.; Ene, D.; Shapiro, E. A. J. Am. Chem. Soc. 1994, 116, 8492.
(e) Muller, P.; Imogai, H. Tetrahedron: Asymmetry 1998, 9, 4419. (f) Davies,
H. M. L.; Lee, G. H. Org. Lett. 2004, 6, 1233. (g) Liao, L. A.; Zhang, F.;
Dmitrenko, O.; Bach, R. D.; Fox, J. M. J. Am. Chem. Soc. 2004, 126, 4490.
(h) Liao, L. A.; Zhang, F.; Yan, N.; Golen, J. A.; Fox, J. M. Tetrahedron
2004, 60, 1803.
(29) Krafft, M. E.; Kyne, G. M.; Hirosawa, C.; Schmidt, P.; Abboud,
K. A.; L’Helias, N. Tetrahedron 2006, 62, 11782.
(30) Tormo, J.; Moyano, A.; Perica´s, M. A.; Riera, A. J. Org. Chem.
1997, 62, 4851.
(31) Renaud, J.-L.; Aubert, C.; Malacria, M. Tetrahedron 1999, 55, 5113.
(35) (S,S)-Rh2(OAc)(DPTI)3 would give rise to natural (+)-pentalenene.
We synthesized the unnatural enantiomer because we had (R,R)-Rh2(OAc)-
(DPTI)3 in hand from another project.
5626
Org. Lett., Vol. 9, No. 26, 2007

The enantioselective synthesis of (-)-pentalenene was
initiated by catalytic, enantioselective cyclopropenation of
diyne 4, which can be readily synthesized on large scale from
isophorone.36 Cyclopropenation is selective for the terminal
alkyne, and leaves the silyl protected alkyne available for
subsequent cyclocarbonylation. The cyclopropenation reac-
tion of 4 with Corey’s34a-c,35 (R,R)-Rh2(OAc)(DPTI)3 (5)
proceeded with excellent enantioselectivity under optimized
reaction conditions.
Scheme 4. Cyclopropane Fragmentation/Alkylation Sequence
With enantiomerically enriched 3 in hand, the intramo-
lecular Pauson-Khand reaction to obtain 6 was attempted
with various promotors (Scheme 3). Unfortunately, these
Scheme 3. TMTU-Promoted Intramolecular Pauson-Khand
Reaction
cleanly reduced both the alkene and the cyclopropane to
provide 10 in 91% yield. Alternately, selective hydrogenation
(1 atm H2) of the alkene moiety followed by SmI2 reduction
of the cyclopropane gave 10 in 95% yield over 2 steps.
Ketalization and treatment with LDA/allyl bromide gave in
90% yield a 79:21 mixture of diastereomers 13 and 12,
respectively. It is compound 12 that has the desired stereo-
chemistry at C-9 for elaboration to pentalenene: the stereo-
chemistry of 12 was assigned by conversion into 17san
intermediate in Hudlicky’s syntheses12b of pentalenene
(Scheme 5). Although 12 was the minor kinetic product of
experiments led to decomposition and only to trace amounts
(<10%) of 6. In our experience with intermolecular Pauson-
Khand reactions of cyclopropenes, we noted that 1,2-
disubstituted cyclopropenes were the most productive
substrates.33a Accordingly, 3 was deprotonated with LiHMDS
in the presence of TMSCl to provide 7, which was treated
with Co2(CO)8 under the action of several promotors of the
Pauson-Khand reaction. Only starting materials were re-
covered from attempts to use N-oxides37a,b to promote the
production of 8. n-Butyl methylsulfide37c was a more
effective promotor: reaction of 7 with Co2(CO)8 (1 equiv)
followed by treatment with BuSMe (26 equiv) led to 8 as a
single diastereomer in 45% yield. Optimal reactivity was
achieved with tetramethylthiourea (TMTU)37dsa promotor
described recently by Yang and co-workers. This promotor
was found to be very effective even with substoichiometric
amounts of Co2(CO)8 (0.6 equiv). The product 8 was
obtained in 64% yield, along with 16% of the separable
diastereomer 9.
Scheme 5. Loss of C-9 Stereochemistry in an Initial
Construction of the Triquinane Ring System
Treatment of 8 with tetrabutylammonium fluoride removed
the silyl groups to provide 2 as a mixture of epimers (Scheme
4). Hydrogenation (1 atm H2, then 60 psi H2, 10% Pd/C)
the alkylation, it was the major thermodynamic product.
Thus, compound 13 can be equilibrated by KH38/toluene to
give a 55:45 mixture of 12:13 with high mass recovery.
Because diastereomers 12 and 13 are easily separable on
silica, it is practical to obtain 12 in 68% yield from 11 after
two recycling efforts.
(36) (a) Corey, E. J.; Sachdev, H. S. J. Org. Chem. 1975, 40, 579. (b)
Fleming, I.; De Marigorta, E. M. J. Chem. Soc., Perkin. Trans. 1 1999,
889.
(37) (a) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron
Lett. 1990, 31, 5289. (b) Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.;
Yoo, S. E. Synlett 1991, 204. (c) Sugihara, T.; Yamada, M.; Yamaguchi,
M.; Nishiizawa, M. Synlett 1991, 771. (d) Tang, Y. F.; Deng, L. J.; Zhang,
Y. D.; Dong, G. B.; Chen, J. H.; Yang, Z. Org. Lett. 2005, 7, 593.
(38) Taber, D. F.; Nelson, C. G. J. Org. Chem. 2006, 71, 8973.
Org. Lett., Vol. 9, No. 26, 2007
5627

separating 15 and 16. Accordingly, an alternate route to
pentalenene from 12 was sought.
Scheme 6. Synthesis of (-)-Pentalenene
The stereospecific synthesis of (-)-pentalenene from 12
was completed as shown in Scheme 6. Three-step conversion
(LiAlH4; MsCl, Et3N; LiEt3BH) of the ester of 12 to a methyl
group took place in 76% yield to provide 18. Reductive
ozonolysis and ketal deprotection was carried out in one pot
to give 19. Reaction of 19 with benzenesulfonyl chloride
gave 20 in 72% yield (from 18). Compound 20 is similar to
a previously described intermediate to pentalenene.18 Cy-
clization to ketone 21 was effected by treatment of 20 with
NaHMDS. Wittig olefination and acid-catalyzed isomeriza-
tion of 21 gave (-)-pentalenene (1) in 94% yield.
In summary, the first enantioselective synthesis of pen-
talenene has been described. (-)-Pentalenene was obtained
in 9% overall yield from the known diyne 4,36 and in 6%
overall yield from commercially available isophorone oxide.
The longest linear sequence from isophorone oxide was 18
steps. Keys to the success of the synthesis were the use of
catalytic enantioselective cyclopropenation and a subsequent
Pauson-Khand reaction to set the quaternary center.
It was projected that (-)-pentalenene could be accessed
via the ketone 15 (Scheme 5). Reductive ozonolysis of 12
followed by acidic workup and treatment with benzenesulfo-
nyl chloride gave 14, which cyclized upon treatment with
LiHMDS. Unfortunately, the cyclization proceeded with
epimerization to give a 7:1 mixture of 15:16 that could not
easily be separated by column chromatography. A variety
of conditions were investigated in order to avoid epimer-
ization at C-9, but these attempts were unsuccessful. After
repeated silica gel chromatography, a pure sample of 15 was
obtained that could be treated under Wittig conditions to give
the exocyclic alkene 17.
Acknowledgment. This work was supported by NIH
grant GM068640-01.
Supporting Information Available: Full experimental
1
details and H and 13C NMR spectra are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Hudlicky had previously shown that 17 could be converted
to pentalenene.12b However, the loss of stereochemistry at
C-9 was undesirable, especially given the difficulty in
OL702597Y
5628
Org. Lett., Vol. 9, No. 26, 2007