Concise approach to pupukeanane skeleton: Synthetic study of chloropupukeananin

Article abstract of DOI:10.1021/ol100935w

A concise synthesis of a highly functionalized chloropupukeananin (1) skeleton via a reverse electron-demand Diels-Alder reaction and intramolecular carbonyl-ene reaction sequence based on our proposed biosynthetic pathway is described.

Full text of DOI:10.1021/ol100935w

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2920-2923
Concise Approach to Pupukeanane
Skeleton: Synthetic Study of
Chloropupukeananin
Takahiro Suzuki and Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo UniVersity of Science (RIKADAI), 2641
Yamazaki, Noda-shi, Chiba 278-8510, Japan
kobayash@rs.noda.tus.ac.jp
Received April 23, 2010
ABSTRACT
A concise synthesis of a highly functionalized chloropupukeananin (1) skeleton via a reverse electron-demand Diels-Alder reaction and
intramolecular carbonyl-ene reaction sequence based on our proposed biosynthetic pathway is described.
The pupukeanane family of secondary metabolites from
marine sponges1 includes 2- and 9-isocyanopupukeanane, 2-
and 9-pupukeanone, 2-thiocyanatopupukeanane, and 9-isothio-
cyanatopupukeanane. Pupukeananes possess a common
complex tricyclic skeleton, 5-isopropyl-1,3-dimethyl-
tricyclo[4.3.1.03,7]decane, which has made them attractive
synthetic targets for the last three decades.2 Recently, chloro-
pupukeananin (1) was isolated from the plant endophyte fungus
Pestalotiopsis fici, collected in the suburb of Hangzhou, China,
by Che and colleagues as a new inhibitor against HIV-1
replication in C8166 cells (IC50 ) 14.6 µM).3a,b Structurally,
chloropupukeananin possesses a highly functionalized pu-
pukeanane skeleton that includes an isoprenylated epoxy-
cyclohexenol group (Figure 1). The array of functional
groups in a rigid tricyclic structure of 1 has provided us with
a strong motive to investigate a novel strategy for an effective
construction of the pupukeanane core.
Che and colleagues also reported that iso-A82775C (2)4
and pestheic acid (3),5a also known as RES-1214-25b and
(2) For 9-isocyanopupukeanane :(a) Corey, E. J.; Behforouz, M.;
Ishiguro, M. J. Am. Chem. Soc. 1979, 101, 1608–1609. (b) Yamamoto, H.;
Sham, H. L. J. Am. Chem. Soc. 1979, 101, 1609–1611. For 2-isocyanopu-
pukeanane: (c) Corey, E. J.; Ishiguro, M. Tetrahedron Lett. 1979, 20, 2745–
2748. For 2-pupukeanone: (d) Hrater, G.; Wenger, J. HelV. Chim. Acta 1984,
67, 1702–1706. (e) Chang, N.-C.; Chang, C.-K. J. Org. Chem. 1996, 61,
4967–4970. (f) Srikrishna, A.; Vijaykumar, D.; Sharma, G. V. R. Tetra-
hedron Lett. 1997, 38, 2003–2004. (g) Kaliappan, K.; Subba Rao, G. S. R.
Tetrahedron Lett. 1997, 38, 2185–2186. For 9-pupukeanone: (h) Schiehser,
G. A.; White, J. D. J. Org. Chem. 1980, 45, 1864–1868. (i) Piers, E.; Winter,
M. Liebigs Ann. Chem. 1982, 5, 973–984. (j) Srikrishna, A.; Kumar, P. R.
Tetrahedron Lett. 2002, 43, 1109–1111.
(3) (a) Liu, L.; Liu, S.; Jiang, L.; Chen, X.; Guo, L.; Che, Y. Org. Lett.
2008, 10, 1397–1400. (b) Liu, L.; Li, Y.; Liu, S.; Zheng, Z.; Chen, X.;
Zhang, H.; Guo, L.; Che, Y. Org. Lett. 2009, 11, 2836–2839. Very recently,
several related compounds were isolated from the same extract with 1 and
4. See: (c) Liu, L.; Niu, S.; Lu, X.; Chen, X.; Zhang, H.; Guo, L.; Che, Y.
Chem. Commum. 2010, 46, 460–462.
(1) (a) Burreson, B. J.; Scheuer, P. J.; Finer, J. S.; Clardy, J. J. Am.
Chem. Soc. 1975, 97, 4763–4764. (b) Hagadone, M. R.; Burreson, B. J.;
Scheuer, P. J.; Finer, J. S.; Clardy, J. HelV. Chim. Acta 1979, 62, 2484–
2494. (c) Fusetani, N.; Wolstenholme, H. J.; Matsunaga, S. Tetrahedron
Lett. 1990, 31, 5623–5624. (d) He, H.; Salva, J.; Catalos, R. F.; Faulkner,
D. J. J. Org. Chem. 1992, 57, 3191–3194. (e) Simpson, J. S.; Garson, M. J.;
Hooper, J. N. A.; Cline, E. I.; Angerhofer, C. K. Aust. J. Chem. 1997, 50,
1123–1127.
(4) An isomer of A82775C, see; Sanson, R.; Gracz, H.; Tempesta, M. S.;
Fukuda, D. S.; Nakatsukasa, W. M.; Sands, T. H.; Baker, P. J.; Mynderse,
J. S. Tetrahedron 1991, 47, 3633–3644.
10.1021/ol100935w  2010 American Chemical Society
Published on Web 06/11/2010

Scheme 1. Proposed Biosynthetic Pathway Involving Maldoxin
Figure 1. Chloropupukeananin (1) and its related compounds.
approach to a highly functionalized pupukeanane skeleton
which involves the right half of chloropupukeananin.
dihydromaldoxin,5c were concomitantly isolated and claimed
that these compounds were possible biosynthetic precursors
of 1.3a Furthermore, they proposed a biosynthetic pathway
for chloropupukeananin from 2 and 3 involving a reverse
electron-demand Diels-Alder (REDDA) reaction. More
recently, the same group reported the isolation of chlorope-
stolide A (4),3b which is regarded as a stereoisomer in the
proposed Diels-Alder reaction.
Scheme 2. Synthetic Strategy toward Model Compond 5
These findings led us to propose an alternative biosynthetic
hypothesis involing maldoxin5c (Scheme 1). Thus, pestheic
acid is first oxidized to maldoxin which possesses a reactive
diene, known as a masked o-benzoquinone (MOB).6 REDDA
reaction of the diene of maldoxin and the terminal alkene of
iso-A82775C would furnish two bicyclo[2.2.2]octanes, cy-
cloadduct A and chloropestolide A. Then, an acid-mediated
spiroketal opening of cycloadduct A and a simultaneous
migration of the benzoyl group would afford 1,2-diketone
B, which is spontaneously transformed to a tricyclic com-
pound via an intramolecular carbonyl-ene reaction to produce
chloropupukeananin.
At the outset of our synthetic investigation on chloropu-
pukeananin, we planned a synthetic study of the model core
structure 5 starting from MOB 6 and vinylallene 7 based on
our proposed biosynthesis (Scheme 2). Tricyclic 5 contains
all the functional groups of the core moiety of chloropu-
pukeananin. Our primary concern was to realize the con-
struction of the tricyclo[4.3.1.03,7]decane core structure by
REDDA reaction of MOB 6 and vinylallene 7, followed by
carbonyl-ene reaction. We report herein a novel biomimetic
The preparation of MOB 6 and vinylallene 7 was readily
achieved (Scheme 3). Chlorination of 3-hydroxy-2,5-
dimethoxybenzoic acid7 (NaOCl aq, KOH aq, rt),8 followed
by acidic esterification, furnished benzoate 9 (40% yield over
2 steps). Oxidation of the aromatic ring with PhI(OAc)2 in
CH2Cl2/MeOH (5/1) afforded MOB 6 in 81% yield. Viny-
lallene 7 was prepared from the known 1- ethynylcyclohexyl
acetate9 with an isopropenyl-copper reagent (CuCN, isopro-
penyl-MgBr, BF3·OEt2, THF, -20 °C)10 in moderate yield.
With both precursors in hand, thermal and Lewis acid
promoted REDDA reaction of MOB 6 and vinylallene 7 was
(5) (a) Shimada, A.; Takahashi, I.; Kawano, T.; Kimura, Y. Z. Natur-
forsch. 2001, 56B, 797–803. (b) Ogawa, T.; Ando, K.; Aotani, Y.; Shinoda,
K.; Tanaka, T.; Tsukuda, E.; Yoshida, M.; Matsuda, Y. J. Antibiot. 1995,
48, 1401–1406. (c) Adeboya, M. O.; Edwards, R. L.; Lassøe, T.; Maitland,
D. J.; Shields, L.; Whalley, A. J. S. J. Chem. Soc., Perkin Trans. 1 1996,
1419–1425.
(7) Churcher, I.; Hallett, D.; Magnus, P. J. Am. Chem. Soc. 1998, 120,
10350–10358.
(8) Nicolaou, K. C.; Boddy, C. N. C. J. Am. Chem. Soc. 2002, 124,
10451–10455.
(9) Riveiros, R.; Rodr´ıguez, D.; Sestelo, J. P.; Sarandeses, L. A. Org.
Lett. 2006, 8, 1403–1406.
(6) For reviews on MOBs, see: (a) Liao, C.-C.; Peddinti, R. K. Acc.
Chem. Res. 2002, 35, 856–866. (b) Liao, C.-C. Pure Appl. Chem. 2005,
77, 1221–1234.
(10) Ibuka, T.; Taga, T.; Habashita, H.; Nakai, K.; Tamamura, H.; Fujii,
N.; Chounan, Y.; Nemoto, H.; Yamamoto, Y. J. Org. Chem. 1993, 58, 1207–
1214.
Org. Lett., Vol. 12, No. 13, 2010
2921

24 h) predominantly produced REDDA cycloadducts 8 and
10 (8:10 ) 1.0:1.6) in 34% yield (entry 5). Some typical
results are also summarized in Table 1. Other solvents
(entries 6-8) gave the cycloadducts in low yield probably
due to the low solubility of MOB 6. High concentration
conditions (0.5 M in CH2Cl2, entry 9) improved the total
yield of 8 and 10, while prolonged reaction time (entry 10)
resulted in a decrease in yield due to the competitive
decomposition of the products. Finally, we found that the
use of 2.0 equiv of vinylallene 7 (entry 11) afforded the
cycloadducts in 70% yield. We reasoned that relatively
insoluble MOB 6 precipitated under high-pressure conditions
when a large excess of vinylallene 7 was employed.
Scheme 3. Preparation of Simplified Biosynthetic Precursors
Scheme 4
.
Proposed Transition States under High-Pressure
Conditions
carried out (Table 1). Simply heating a mixture of two
precursors in toluene (entry 1, 110 °C, 48 h) gave reverse
electron-demand cycloadducts 8 and 10 (ca. 1:3 inseparable
mixture) in very low yield (14%), along with a normal
electron-demand cycloadduct 11. Most of the starting materi-
als were recovered. All attempts to perform the Lewis acid
promoted Diels-Alder reaction11 were unsuccessful. Nev-
ertheless, intriguingly the initially formed 8 underwent an
undesired carbonyl-ene reaction affording tricyclic compound
12 through a Lewis acid-promoted activation of acetal
carbon. The structures of cycloadducts 8, 10, and 12 were
determined by NMR spectroscopy (1H NMR, 13C NMR,
DEPT, HMQC, HMBC, and NOESY). Key NOESY cor-
relations of 8 and 10 are shown in Figure 2.
The predominant formation of the REDDA cycloadducts
8 and 10 over normal Diels-Alder cycloadduct 11 under
high-pressure conditions is quite interesting. Qualitative
explanation of the observed selectivity is shown in Scheme
4. Cycloadducts 8, 10, and 11 might be formed through the
transition states TS1, TS2, and TS3, respectively. The
reaction rate in high-pressure chemistry depends on the
volume of activation (∆Vq).12a-d Among them, TS3 has a
larger volume due to the extended cyclohexylidene and
R-chloroenone moiety (the arrows in Scheme 4 represent
∆∆Vq). Thus, REDDA cycloadducts 8 and 10 might pre-
dominantly be produced through compact transition states
TS1 and TS2 under high-pressure conditions. Although the
diastereoselectivity of the REDDA reaction is unsatisfactory
in favor of 10, the undesired cycloadduct 10 could be
regarded as a model compound for chloropestolide A.
Next, we examined the intramolecular carbonyl-ene reac-
tion to construct the tricyclo[4.3.1.03,7]decane skeleton
(Scheme 5). The Lewis acid-promoted carbonyl-ene reaction
of bicyclic compounds 8 and 10 was unsuccessful, resulting
in the hydrolysis of the methyl enol ether moiety. In contrast,
treatment of a mixture of 8 and 10 with 80% aqueous TFA
Figure 2. Key NOESY correlations of cycloadducts 8 and 10.
These unsuccessful results under normal conditions
prompted us to examine a REDDA reaction under high-
pressure conditions.12 Surprisingly, the intermolecular
Diels-Alder reaction under 0.8 GPa (0.1 M in CH2Cl2, rt,
(11) Using other Lewis acids (e.g., Me3Al, EtAlCl2, ZnCl2, TiCl4, etc.)
resulted in no reaction or decomposition of 6.
(12) For recent reviews on high-pressure Diels-Alder reaction, see: (a)
Jenner, G. Tetrahedron 1997, 53, 2669–2695. (b) Jenner, G. J. Phys. Org.
Chem. 2002, 15, 1–13. (c) Matsumoto, K.; Hamana, H.; Iida, H. HelV. Chim.
Acta 2005, 88, 2033–2234. (d) Kotsuki, H.; Kumamoto, K. J. Synth. Org.
Chem. Jpn. 2005, 63, 770–779. For recent examples of high-pressure
Diels-Alder reaction in natural product synthesis, see: (e) Pandey, S. K.;
Orellana, A.; Greene, A. E.; Poisson, J.-F. Org. Lett. 2006, 8, 5665–5668.
(f) Kienzler, M. A.; Suseno, S.; Trauner, D. J. Am. Chem. Soc. 2008, 130,
8604–8605. (g) Waalboer, D. C. J.; Schaapman, M. C.; van Delft, F. L.;
Rutjes, F. P. J. T. Angew. Chem. 2008, 47, 6678-6680; Angew. Chem.,
Int. Ed. 2008, 47, 6576-6578. (h) Ballerini, E.; Minuti, L.; Piermatti, O.;
Pizzo, F. J. Org. Chem. 2009, 74, 4311–4317.
13
in CH2Cl2 gave the desired tricyclo[4.3.1.03,7]decane
2922
Org. Lett., Vol. 12, No. 13, 2010

Table 1. Reverse Electron-Demand Diels-Alder Reaction
7
M
(mol/L)
8 and 10
product ratio
11
(%)
recovereda
(%)
6
entry
(equiv)
conditions
toluene, reflux
neat, 110 °C
Me2AlCl (1.5 equiv), CH2Cl2, rt
Me2AlCl (2.0 equiv), CH2Cl2, rt
0.8 GPa, CH2Cl2, rt
0.8 GPa, Et2O, rt
0.8 GPa, toluene, rt
0.8 GPa, MeOH/CH2Cl2 (10/1), rt
0.8 GPa, CH2Cl2, rt
0.8 GPa, CH2Cl2, rt
time (h)
(%)
(8:10)
1
2
3
4
5
6
7
8
9
2.0
4.8
2.0
4.0
2.5
2.5
2.5
2.5
2.5
2.5
2.0
1.5
0.1
-
48
48
48
48
24
24
24
24
24
96
24
24
14
1.0:3.0
-
11
69
-
50
0
60
90
75
61
47
42
20
25
decomposed
-
7
0.05
0.2
0.1
0.1
0.1
0.1
0.5
0.5
0.5
0.5
8
(10 only)
(10 only)b
1.0:1.6
1.0:1.4
1.0:1.6
1.0:1.6
1.0:1.6
1.0:1.6
1.0:1.6
1.0:1.6
31
34
6
12
31
48
33
70
67
11
6
trace
2
7
6
5
10
11
12
0.8 GPa, CH2Cl2,rt
0.8 GPa, CH2Cl2, rt
10
9
a Vinylallene 7 could not be recovered because of its volatility. b Tricyclic compound 12 was isolated in 11% yield.
skeleton 13 in 34% yield (88% calculated yield from 8).
HMQC, HMBC, and NOESY data for 13 confirmed the
Scheme 5
.
Acid-Promoted Carbonyl-ene Reaction and Synthesis
anticipated stereochemistry of the tricyclo[4.3.1.03,7]decane
skeleton. Under this condition, dimethyl acetal of 8 might
be initially hydrolyzed to 1,2-diketone, and the latter
underwent a simultaneous carbonyl-ene reaction to afford
13. The corresponding carbonyl-ene reaction of isomer 10
of Model Compound 5
gave
a
complex mixture of products including
tricyclo[4.3.1.03,7]decanes.14 Finally, protection of alcohol
13 with the TMS group, enol etherification,15 followed by
removal of the TMS group afforded the model compound 5
which possesses all the requisite functional groups of the
right half of chloropupukeananin. The H and 13C NMR
1
spectral data of the model compound 5 resemble those of
chloropupukeananin.
In conclusion, we were able to construct a highly func-
tionalized chloropupukeananin core skeleton based on our
proposed biosynthetic pathway. The characteristic feature of
the present study is that MOB 6 and vinylallene 7 can be
converted to the tricyclo[4.3.1.03,7]decane skeleton 13 in two
steps, i.e., the REDDA reaction under high-pressure condi-
tions followed by a TFA-promoted intramolecular carbonyl-
ene reaction. Synthetic efforts toward chloropupukeananin
by a tandem Diels-Alder/carbonyl-ene reaction under acidic
and high-pressure conditions with pestheic acid and iso-
A82775C are currently underway.
(13) Hauser, F. M.; Dorsch, W. A.; Mal, D. Org. Lett. 2002, 4, 2237–
2239.
Acknowledgment. We thank Dr. G. Hirai, Dr. T. Shimizu,
and Dr. M. Sodeoka (RIKEN) for assistance with operation
of the high-pressure apparatus.
(14) 1HNMR analysis of the crude mixture indicated the formation of
following tricyclic derivatives
Supporting Information Available: Detailed experimen-
tal proedures and characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Paquette, L. A.; Oplinger, J. A. Tetrahedron 1989, 45, 107–124.
OL100935W
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