Intramolecular Diels-Alder cycloadditions of fulvenes. Application to the kigelinol, neoamphilectane, and kempane skeletons

Article abstract of DOI:10.1021/ol047730m

(Chemical Equation Presented) A variety of polycyclic ring skeletons (e.g., kigelinol, neoamphilectane, and kempene systems) can be prepared rapidly via intramolecular Diels-Alder cycloadditions (IMDA) of fulvenes. The length of the tethers and the diversity of the substituents on the fulvene core dictate the nature of the IMDA pathway.

Full text of DOI:10.1021/ol047730m

ORGANIC
LETTERS
2005
Vol. 7, No. 4
557-560
Intramolecular Diels−Alder
Cycloadditions of Fulvenes. Application
to the Kigelinol, Neoamphilectane, and
Kempane Skeletons
Bor-Cherng Hong,*,† Fon-Len Chen,† Shang-Hung Chen,† Ju-Hsiou Liao,† and
Gene-Hsiang Lee‡
Department of Chemistry, National Chung Cheng UniVersity,
Chia-Yi, 621, Taiwan, R.O.C., and Instrumentation Center,
National Taiwan UniVersity, Taipei, 106, Taiwan, R.O.C
chebch@ccu.edu.tw
Received November 5, 2004 (Revised Manuscript Received December 27, 2004)
ABSTRACT
A variety of polycyclic ring skeletons (e.g., kigelinol, neoamphilectane, and kempene systems) can be prepared rapidly via intramolecular
Diels Alder cycloadditions (IMDA) of fulvenes. The length of the tethers and the diversity of the substituents on the fulvene core dictate the
−
nature of the IMDA pathway.
Synthetic strategies for preparing appropriately functionalized
polycyclic ring systems remain of major interest in organic
chemistry. Among them, the intramolecular Diels-Alder
reaction (IMDA) provides a powerful tool for the construc-
tion of complex carbocycles.1 In conjunction with our
continuing efforts in fulvene chemistry,2 we embarked on a
strategy that called for the construction of a variety of
complex polycycles (e.g., the kigelinol and kempanes
skeletons) from simple acyclic fulvene molecules. The idea
stems from the well-established diversity-oriented synthetic
(DOS) strategies,3 with the exception that in this case,
variation of the functional groups and tethers around a basic
template, namely the fulvene core, followed by an IMDA
cyclization would theoretically lead to diversity in the final
products. Scheme 1 shows the retrosynthetic analysis of
several naturally occurring carbocycles that may be prepared
via the IMDA reaction of fulvenes. Kingelinol and isokigeli-
nol were isolated from the root bark of Kigelia pinnata and
show antitrypanosomal activity against Trypanosoma brucei.4
Neoamphilectane, with its 5-6-6 tricyclic system, was
(2) For previous papers in this series, see: (a) Hong, B.-C.; Wu, J.-L.;
Gupta, A. K.; Hallur, M. S.; Liao, J. S. Org. Lett. 2004, 6, 3453. (b) Hong,
B.-C.; Gupta, A. K.; Wu, M.-F.; Liao, J.-H. Tetrahedron Lett. 2004, 45,
1663. (c) Hong, B.-C.; Gupta, A. K.; Wu, M.-F.; Liao, J.-H.; Lee, G.-H.
Org. Lett., 2003, 5, 1689. (d) Hong, B. C.; Shr, Y. J.; Wu, J. L.; Gupta, A.
K.; Lin, K. J. Org. Lett. 2002, 4, 2249. (e) Hong, B.-C.; Shr, Y.-J.; Liao,
J.-H. Org. Lett. 2002, 4, 663.
(3) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Sello, J. K.;
Andreana, P. R.; Lee, D.; Schreiber, S. L. Org. Lett. 2003, 5, 4125. (c)
Burke, M. D. Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46. (d)
Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245. (e) Burke, M. D.;
Berger, E. M. Schreiber, S. L. Science. 2003, 302, 613.
† National Chung Cheng University.
‡ National Taiwan University.
(1) For recent reviews, see: (a) Nicolaou, K. C.; Snyder, S. A.;
Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41,
1668. (b) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 513. (c)
Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001, 40,
820. (d) Fallis, A. G. Acc. Chem. Res. 1999, 32, 464. (e) Fallis, A. G. Pure
Appl. Chem. 1997, 69, 495. (f) Thomas, E. J. Acc. Chem. Res. 1991, 24,
229.
10.1021/ol047730m CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/28/2005

Scheme 1
Scheme 2
isolated from the tropical marine sponge Cymbastela hooperi,
and shows potent antimalarial activity and cytotoxicity
against Plasmodium falciparum clones and KB cells.5 The
cembrene-derived tetracyclic diterpenes (e.g., kempanes and
rippertanes) were isolated from the secretions of nasute
soldier termites.6
Ozonolysis of methylcyclohexene (O3, CH2Cl2; Me2S,
CH2Cl2; 93% yield), followed by slow addition of vinyl-
magnesium bromide to keto aldehyde 9 at 10 °C gave allyl
alcohol 10 in 71% yield. Reaction of 10 with cyclopentadiene
in the presence of pyrrolidine in MeOH provided fulvene
11 in 83% yield. Oxidation of 11 (Dess-Martin periodate
or PDC in CH2Cl2, 78% yield) afforded enone 2 which
reacted smoothly with Et3N in refluxing DMF to provide
the desired intermediate 1 in 74% yield. The single-crystal
X-ray analysis of 1a confirmed the structure and stereo-
chemistry of 1, Figure 1.13 Surprisingly, treatment of 2 with
TMSCl-Et3N-DMAP in CH2Cl2 followed by an IMDA led
to the formation of 1 (50% yield) instead of the desired
synthon 7. The same result was obtained when ketone 2 was
reacted with DABCO in CH2Cl2. The regioselective syn-
addition of the diene across one of the double bonds of
cyclopentadiene on the fulvene provides the tricyclic 1H-
cyclopenta[b]naphthalene, a motif which is found in numer-
ous natural products and pharmaceutical agents, such as SP-
18904,14 treprostinil,15 bisacutifolone,16 pycnanthuquinone,17
and kigelinol.
Dauben et al. reported a 23-step synthesis of kempene-2
that included a Diels-Alder cycloaddition and a Ti-induced
McMurry cyclization of a keto aldehyde.7 Paquette et al.
described an approach to the kempane skeleton via an
efficient palladium-catalyzed [3 + 2] cycloaddition,8 and in
1993, Mertz et al. described an enantioselective approach to
this system.9 More recently, Burnell and co-workers reported
a 19-step synthesis of the kempane ring system employing
a Diels-Alder cycloaddition as the key transformation.10
Examples of intermolecular Diels-Alder reactions of ful-
venes are well-documented,11 while examples of the corre-
sponding IMDA are rare.12 We envisioned that the key
intermediate 1 for the synthesis of kigelinol could be prepared
via an IMDA reaction of fulvene enone 2a, which in turn is
generated by isomerization of fulvene 2 during the reaction.
Fulvene 2 was subsequently synthesized from methylcyclo-
hexene in four steps and 43% total yield, Scheme 2.
(4) (a) Akunyili, D. N.; Houghton, P. J. Phytochemistry, 1993, 32, 1015.
(b) Moideen, S. V. K.; Houghton, P. J.; Rock, P.; Croft, S. L.; Aboagye-
Nyame, F. Planta Med. 1999, 65, 536. (c) Weiss, C. R.; Moideen, S. V.
K.; Croft, S. L.; Houghton, P. J. J. Nat. Prod. 2000, 1306.
(5) (a) Ko¨nig, G. M.; Wright, A. D. J. Org. Chem. 1996, 61, 3259. (b)
Weiss, C. R.; Moideen, S. V. K.; Croft, S. L.; Houghton, P. J. J. Nat. Prod.
2000, 63, 1306.
(6) (a) Baker, R.; Walmsley, S. Tetrahedron 1982, 38, 1899. (b)
Prestwich, G. D. Tetrahedron 1982, 38, 1911.
(7) Dauben, W. G.; Farkas, I.; Bridon, D. P.; Chuang, C.-P.; Henegar,
K. E. J. Am. Chem. Soc. 1991, 113, 5883.
A similar approach was used in the four-step synthesis of
fulvene enone 5 from methylcyclopentene (30% overall
yield), Scheme 3. Unfortunately, heating enone 5 with Et3N
in DMF afforded the 2,4-[a]methanobenzocycloheptene 15
instead of the desired compound 4.18 The structure of 15 (a
unique tricyclic core in artesieversin, plagiospirolide E, and
biennin C) was confirmed by a single-crystal X-ray analysis
(8) Paquette, L. A.; Sauer, D. R.; Cleary, D. G.; Kinsella, M. A.;
Blackwell, C. M.; Anderson, L. G. J. Am. Chem. Soc. 1992, 114, 7375.
(9) Metz, P.; Bertels, S.; Fro¨hlich, R. J. Am. Chem. Soc. 1993, 115, 12595.
(10) (a) Liu, C.; Burnell, D. J.J. Am. Chem. Soc. 1997, 119, 9584. (b)
Bao, G.; Liu, C.; Burnell, D. J. J. Chem. Soc., Perkin Trans. 1 2001, 2657.
(11) For recent studies, see: (a) Nair, V.; Nair, A. G.; Radhakrishnan,
K. V.; Nandakumar, M. V.; Rath, N. P. Synlett 1997, 7, 767. (b) Nair, V.;
Nair, A. G. Radhakrishnan, K. V.; Sheela, K. C.; Rath, N. P. Tetrahedron
1997, 53, 17361. (c) Himeda, Y.; Yamataka, H.; Ueda, I.; Hatanaka, M. J.
Org. Chem. 1997, 62, 6529. (d) Nair, V.; Kumar, S. Tetrahedron 1996, 52,
4029. (e) Nair, V.; Kumar, S.; Antikumar, G.; Nair, J. S. Tetrahedron 1995,
51, 9155. (f) Uebersax, B.; Neuenschwander, M.; Kellerhals, H.-P. HelV.
Chim. Acta 1982, 65, 74.
(12) Wu, T.-S.; Mareda, J.; Gupta, Y. N.; Houk, K. N. J. Am. Chem.
Soc. 1983, 105, 6996.
(13) 1a was prepared from the reaction of 1 with 2,4-dinitrophenylhy-
drazine in EtOH. Crystallographic data for 1a: C20H22N4O4, M ) 382.42,
monoclinic, space group P21/c, T ) 295(2) K, a ) 8.2559(5) Å, b ) 6.0132-
(4) Å, c ) 38.196(3) Å, â ) 93.358(2)°, V ) 1893.0(2) Å3, Z ) 4, D )
1.342 g/cm3, λ (Mo KR) ) 0.71073 Å, 15220 reflections collected, 4346
unique reflections, 255 parameters refined on F2, R ) 0.0911, wR2[F2] )
0.1978 [2941 data with F2>2σ(F2)].
(14) An antihyperglycemic agent isolated from Pycnanthus angolensis,
see: Luo, J.; Cheung, J.; Yevich, E. M.; Clark, J. P.; Tsai, J.; Lapresca, P.;
Ubillas, R. P.; Fort, D. M.; Carlson, T. J.; Hector, R. F.; King, S. R. J.
Pharmacol. Exp. Ther. 1999, 288, 529.
558
Org. Lett., Vol. 7, No. 4, 2005

Scheme 3
Figure 1. ORTEP plots for X-ray crystal structures of 1a, 15a,
and 22.
of its 2,4-DNP derivative (15a), Figure 1.19 Attempts at
preparation of 3 via the IMDA of silylated 5 also resulted
in the formation of 15. This may be a direct consequence of
the shorter tether in 5 which results in a higher ring strain
energy during the IMDA cyclic transition state.
structure of 22 was confirmed by a single-crystal X-ray
analysis, Figure 1.22 The stereochemistry of the A-B-C
tricyclic core of 22 was identical to that of the kempene
systems. An efficient synthesis of 21 was also achieved in
two steps from 12 via a Wadsworth-Emmons reaction with
(EtO)2P(O)CH2CHdCHCO2Et, followed by a standard ful-
vene formation reaction. Similarly, cycloocta[cd]indene 29
and acenaphthylene 35 (the tricycle skeleton of neoamphi-
lectane, Scheme 1) were prepared from fulvenes 9 and 32,
respectively, Scheme 4.
Encouraged by these results, we embarked on an enanti-
oselective synthesis of the kempene tetracyclic carbocycles,
Scheme 5. Selective reduction of 3623 with BH3-SMe2,
followed by oxidation with PCC gave 37 and 38 in 84%
and 81% yield, respectively. Stereoselective Michael reaction
of 38 and MVK with (R)-2-benzhydrylpyrrolidine gave 39
in 73% yield and 50% diastereomeric excess.24 Wadsworth-
Emmons reaction of 39 with triethyl-4-phosphonocrotonate
afforded diene 40 in 69% yield, which was transformed into
Compounds 6 and 7 were selected as key intermediates
for the synthesis of the kempene system, and we believed
that an IMDA of fulvene 21 could potentially lead to synthon
8, Schemes 1 and 4. Based on previous observations in our
group,20 we opted to use an inverse-electron-demand Diels-
Alder reaction in this case.21 Hence, fulvene 21 was prepared
from 5-oxohexanal (12) in 5 steps and 49% total yield,
Scheme 4. Wittig reaction of 12 with Ph3PdCHCO2Et in
CH2Cl2 afforded ester 17 in 88% yield. Reaction of 17 with
cyclopentadiene and pyrrolidine in methanol afforded fulvene
18, which was reduced with DIBAL-H and oxidized with
PDC to give aldehyde 20. The Wadsworth-Emmons reaction
of 20 provided fulvene 21 in 72% yield. Heating 21 in DMF
afforded the desired benzo[cd]azulene 22 in 86% yield. The
Scheme 4
Org. Lett., Vol. 7, No. 4, 2005
559

Scheme 5
fulvene 41 under standard conditions (cyclopentadiene,
yield).26 The proposed mechanism of the Prins reaction is
pyrrolidine, MeOH; 85% yield). Heating 41 in toluene
provided tricyclic ester 42, stereoselectively, in 71% yield.
Aldehyde 43 was prepared in 71% yield by selective
reduction of the methyl ester with DIBAL-H, followed by a
Dess-Martin oxidation.25 Prins reaction of 43 with TiCl2-
(i-OPr)2 in CH2Cl2 gave the kempene tetracycle 44 (82%
depicted in Scheme 5. The stereochemistry of 44 was
1
assigned on the basis of the H, 13C, HMQC, COSY, and
NOESY spectra.27
In conclusion, we have described an efficient means to
assemble the basic skeleton of kigelinol, neoamphilectane,
and kempene using a novel diversity based intramolecular
Diels-Alder cycloaddition of fulvenes. In addition, the
tetracyclic core of kempene 44 was prepared in nine steps
from commercially available methyl (R)-(+)-3-methylglut-
arate in 12% overall yield.
(15) An epoprostenol analogue for primary pulmonary hypertension,
see: McLaughlin, V. V.; Gaine, S. P.; Barst, R. J.; Oudiz, R. J.; Bourge,
R. C.; Frost, A.; Robbins, I. M.; Tapson, V. F.; McGoon, M. D.; Badesch,
D. B.; Sigman, J. J. CardioVas. Pharmacol. 2003, 41, 293.
(16) Isolated from the Japanese liverwort Porella acutifolia, see: Hash-
imoto, T.; Irita, H.; Tanaka, M.; Takaoka, S.; Asakawa, Y. Phytochemistry,
2000, 53, 593.
(17) Isolated from the leaves and stems of the African plant Pycnanthus
angolensis, see: Fort, D. M.; Ubillas, R. P.; Mendez, C. D.; Jolad, S. D.;
Inman, W. D.; Carney,. R.; Chen, J. L.; Laniro, T. T.; Hasbun, C.; Bruening,
R. C.; Luo, J. J. Org. Chem. 2000, 65, 6534.
Acknowledgment. We are grateful to Dr. Sepehr Sarshar
for valuable discussions. Financial support from the National
Science Council is gratefully acknowledged.
Supporting Information Available: Crystallographic
information files (CIF) for 1a, 15a, and 22, along with
experimental procedures and analytical data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) This may have occurred via a type-2 IMDA process of the fulvene.
For a recent review, see: Bear, B. R.; Sparks, S. M.; Shea, K. J.; Angew.
Chem., Int. Ed. 2001, 40, 820.
(19) Crystallographic data for 15a: C19H19N4O4, M ) 367.38, mono-
clinic, space group P21/n, T ) 293(2) K, a ) 9.7950(10) Å, b ) 12.533(2)
Å, c ) 15.010(2) Å, â ) 106.890(10)°, V ) 1763.2(4) Å3, Z ) 4, D )
1.384 g/cm3, λ (Mo KR) ) 0.71073 Å, 3912 reflections collected, 3077
unique reflections, 249 parameters refined on F2, R ) 0.0719, wR2[F2] )
0.1887 [1851 data with F2>2σ(F2)].
OL047730M
(24) (a) For a recent enantioselective Michael addition of aldehydes to
vinyl ketones catalyzed by (S)-pyrrolidine derivatives, see: Melchiorre, P.;
Jørgensen, A. J. Org. Chem. 2003, 68, 4151. (b) Reaction of 38 with (S)-
2-benzhydrylpyrrolidine gave a 4:1 mixture of the (S) isomer at the R center.
(c) Reaction of 38 with Et2NH gave a 1:1 mixture of the (S) and (R) isomers
at the R center.
(20) Unpublished results: fulvene enone A, an analogue of 5, was
prepared from (-)-limonene, and the IMDA reaction gave tricycle B.
(21) Inverse-electron-demand Diels-Alder reactions usually afford a
different periselectivity. For recent reviews, see: (a) Jayakumar, S.; Ishar,
M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379. (b) Behforouz, M.;
Ahmadian, M.; Tetrahedron 2000, 56, 5259. (c) Boger, D. L. Chemtracts:
Org. Chem. 1996, 9, 149. For reaction with 1-azadiene, see: Mohammad
B.; Mohammad A. Tetrahedron 2000, 56, 5259.
(25) Various attempts at the selective DIBAL-H reduction the methyl
ester to the aldehyde in the presence of the ethyl ester failed. Reaction in
THF gave the best selectivity but afforded the alcohol instead.
(26) (a) The chloro-Prins reaction of hex-5-enal to 3-chloro-cyclohexanol
system has been reported; see: Wo¨lfling, J.; Frank, EÄ .; Mernya´k, E.;
Bunko´czi, G.; Seijo, J. A. C.; Schneidera, G. Tetrahedron 2002, 58, 6851.
(b) For a review of the Prins reaction, see: Adams, D. R.; Bhatnagar, S. P.
Synthesis 1977, 661. (c) For a recent review of the Pinacol-terminated Prins
cyclization, see: Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003,
68, 7143.
(22) Crystallographic data for 22: C17H22O2, M ) 258.35, monoclinic,
space group P21/c, T ) 295(2)K, a ) 11.6349(11) Å, b ) 9.5265(8) Å, c
) 14.2117(12) Å, â ) 112.492(2)°, V ) 1455.4(2) Å3, Z ) 4, D ) 1.179
g/cm3, λ (Mo KR) ) 0.71073 Å, 9246 reflections collected, 3340 unique
reflections, 199 parameters refined on F2, R ) 0.0718, wR2[F2] ) 0.1781
[2035 data with F2>2σ(F2)].
(27) The 44 and R-isomer of 44 (i.e., 44a) were respectively prepared
from 39 and 39a (S isomer on the R center) and characterized; all spectral
data are consistent with this structural assignment.
(23) Purchased from Fluka [63473-60-9].
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Org. Lett., Vol. 7, No. 4, 2005