First total synthesis of natural 6-epiplakortolide e.

Article abstract of DOI:10.1021/ol026285x

[reaction: see text] Natural 6-epiplakortolide E was first synthesized from readily available 1-bromo-10-phenyldecane in 10 steps by using singlet oxygen-mediated Diels-Alder reaction to form cyclic peroxide followed by a directed iodolactonization to give the peroxylactone core.

Full text of DOI:10.1021/ol026285x

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2763-2765
First Total Synthesis of Natural
6-Epiplakortolide E
Mankil Jung,* Jungyeob Ham,† and Jueun Song
Department of Chemistry, Yonsei UniVersity, Seoul 120-749, Korea
mkjung@alchemy.yonsei.ac.kr
Received June 3, 2002
ABSTRACT
Natural 6-epiplakortolide E was first synthesized from readily available 1-bromo-10-phenyldecane in 10 steps by using singlet oxygen-mediated
Diels−Alder reaction to form cyclic peroxide followed by a directed iodolactonization to give the peroxylactone core.
Plakortolide is a novel cyclic peroxylactone isolated in very
low yield (0.0003% for 6-epiplakortolide E 1a) from the
marine sponge Plakortis sp.1 Plakortolide E 1b shows potent
cytotoxicity against murine and human cancer cell lines1f
and a derivative is active against the AIDS opportunistic
parasite Toxoplasma gondi.2 However, limited isolation of
the peroxylactones was reported due to their instability.1
Interestingly, these compounds hold a unique cyclic per-
oxylactone skeleton connected with long aliphatic side chains
at C-6. Although the synthesis of some natural monocyclic
peroxides due to their biological importance has already been
reported,3 no synthesis of any member of the scarce bicyclic
plakortolide family of compounds has, heretofore, been
achieved. In this letter, we wish to report our results on the
preparation of natural (()-6-epiplakortolide E 1a as the first
of its kind.
Considering that plakortolides are cyclic peroxylactones,
a concise and simplified synthetic approach to their core
skeleton should arise from the biosynthetic proposal in
Scheme 1. This biosynthetic pathway involves singlet
Scheme 1. Plausible Biosynthetic Pathway for the Formation
of Plakortolides from Precursor 6a (Relative Stereochemistry
Indicated)
† Present address: Marine Biotechnology Laboratory and Research
Institute of Oceanography, School of Earth and Environmental Sciences,
Seoul National University.
(1) For isolation of the plakortolides, see: (a) Davidson, B. S. Tetrahe-
dron Lett. 1991, 32, 7167. (b) Horton, P. A.; Casapullo, A.; Minale, L.;
Zollo, F.; Lavayre, J. J. Nat. Prod. 1994, 57, 1227. (c) Kourany-Lefoll, E.;
Laprevote, O.; Sevenet, T.; Montagnac, A.; Pais, M.; Devitus, C. Tetra-
hedron 1994, 50, 3415. (d) Longley, R. E.; Kelly-Borges, M.; McConnell,
O. J.; Ballas, L. M. J. Nat. Prod. 1994, 57, 1374. (e) Kawasaki, I.;
Yamashita, M.; Ohta, S. J. Chem. Soc., Chem. Commun. 1994, 59, 6823.
(f) Varoglu, M.; Peters, B. M.; Crews, P. J. Nat. Prod. 1995, 58, 27. (g)
Qureshi, A.; Salva, J.; Harper, M. K.; Faulkner, D. J. J. Nat. Prod. 1998,
61, 1539. (h) Chen, Y.; Killday, K. B.; McCarthy, P. J.; Schimoler, R.;
Chilson, K.; Selitrennikoff, C.; Pomponi, S. A.; Wright, A. E. J. Nat. Prod.
2001, 64, 262.
oxygen-mediated Diels-Alder cyclization of the plausible
bioprecursor 6a. Although rare, there are some instances
where Diels-Alder processes have been found in nature and
(2) Perry, T. L.; Dickerson, A.; Khan, A. A.; Kondru, R. K.; Beratan,
D. N.; Wipf, P.; Kelly, M.; Hamann, M. T. Tetrahedron 2001, 57, 1483.
(3) For synthesis of the natural monocyclic peroxides, see: (a) Snider,
B. B.; Shi, Z. J. Am. Chem. Soc. 1992, 114, 1790. (b) Dussault, P. H.;
Eary, C. T.; Woller, K. R. J. Org. Chem. 1999, 64, 1789. (c) Yao, G.;
Steliou, K. Org. Lett. 2002, 4, 485.
10.1021/ol026285x CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/04/2002

biologically catalyzed Diels-Alder reactions have been
reported.4 Subsequent lactonization of the cyclic peroxyacids,
which are frequently isolated from marine sponges,5,6 may
afford plakortolide.
Starting from commercially available 1-bromo-10-phen-
yldecane 2, the corresponding (3E)-R,â-unsaturated ketone
3 was readily obtained in 69% yield (Scheme 2).7 Exclusive
precursor 6 as regioisomers (3E, 5E/3Z, 5E in 1.8:1 ratio)
in 83% yield. Diels-Alder cyclization of 6 with singlet
oxygen generated by irradiation with a 500-W tungsten lamp
in the presence of rose bengal in methylene chloride and
5% methanol at 0 °C for 4 h gave two cyclic peroxides 7a
and 7b as diastereomers in 1.8:1 ratio in 45% yield (Scheme
3). Deprotection of the alcohol group of the isolated major
Scheme 2a
Scheme 3a
a Reaction conditions: (a) Mg/ether, room tmeperature, 2 h, 69%.
(b) allylmagnesium bromide, ether, 0 °C, 1.5 h, 60%. (c) 9-BBN,
room temperature, 3 N NaOH/H2O2, 2 h, 90%. (d) TBDMS-Cl,
imidazole, DMF, room temperature, 4 h, 98%. (e) TsOH/CaCl2,
benzene, room temperature, 2 h, 80%.
a Reaction conditions: (a) O2, 500-W lamp, rose bengal, 0 °C,
6 h, CH2Cl2/MeOH (19:1), 45%. (b) 10% HCl, THF/MeOH, room
temperature, 1 h, 87%. (c) Jones’ reagent, acetone, room temper-
ature, 1.5 h, 78%. (d) NaHCO3/I2, CHCl3/H2O, room temperature,
2 days, 55%. (e) AIBN/Bu3SnH, benzene, 80 °C, 1 h, 68%.
1,2-addition of Grignard reagent, allylmagnesium bromide
controlled by the steric factor of 3 resulted in the tertiary
alcohol 4 (yield 60%). Subsequent hydroboration-oxidation
of the terminal olefin of 4 with 9-BBN and 3 N NaOH/H2O2
afforded the diol 5 in 90% yield. Selective protection of the
primary alcohol group of 5 with TBDMS-Cl and elimination
of the tertiary alcohol group of 5a gave the protected
isomer 7a with 10% HCl without destruction of the cyclic
peroxide to the cyclic peroxyalcohol 8 and subsequent Jones’
oxidation of 8 in acetone afforded plakoric acid 9 in 78%
yield. The R-face directed iodolactonization of 9 with
NaHCO3/I2 produced 5â-iodo-6-epi-plakortolide E 10, which
is a cyclic peroxylactone in 55% yield. Subsequent reduction
of 10 with Bu3SnH (3.0 equiv) in the presence of AIBN (2.0
equiv) in benzene at 80 °C for 1 h finally provided the (()-
6-epiplakortolide E 1a in natural configuration as a colorless
oil in 68% yield. Interestingly, the cyclic peroxylactone
remains untouched during the Bu3SnH-mediated reduction
of 10, which is consistent with the selective reduction in the
presence of the stable cyclic peroxide of artemisinin.8,9 Their
(4) (a) Hilvert, D.; Hill, K. W.; Nared, K. D.; Auditor, M.-T. M. J. Am.
Chem. Soc. 1989, 111, 9261. (b) Braisted, A. C.; Schultz, P. G. J. Am.
Chem. Soc. 1990, 112, 7430. (c) Rao, K. R.; Srinivasan, T. N.; Bhanumathi,
N. Tetrahedron Lett. 1990, 31, 5960. (d) Sanz-Cervera, J. F.; Glinka, T.;
Williams, R. M. J. Am. Chem. Soc. 1993, 115, 347. (e) Yli-Kauhaluoma,
J. T.; Ashley, J. A.; Lo, C.-H.; Tucker, L.; Wolfe, M. M.; Janda, K. D. J.
Am. Chem. Soc. 1995, 117, 7041.
(5) For the isolation of chondrillin as the first monocyclic peroxy
metabolite, see: Wells R. J.; et. al. Tetrahedron Lett. 1976, 2637. For the
isolation of the other monocyclic peroxy natural products, see ref 6 and
references therein.
(6) For a comprehensive review of the peroxy natural products, see:
Casteel, D. A. Nat. Prod. Rep. 1992, 289.
(7) Shea, K. J.; Haffner, C. D. Tetrahedron Lett. 1988, 29, 13.
(8) Jung, M.; Li, X.; Bustos, D. A.; ElSohly, H. N.; McChesney, J. D
Tetrahedron Lett. 1989, 30, 5973.
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relative stereochemistry was unambiguously established as
shown in the structures of 10 and 1a, using the NOESY,
ROESY, and TOCSY technique. All spectral data of
synthetic 1a are in agreement with the spectral data of natural
6-epi-plakortolide E reported in the literature.1g The same
conversion of the 7b followed by the R-face directed
iodolactonization due to the already established chirality at
C-3 will afford the plakortolide E 1b in natural configuration.
Thus, the first and concise total synthesis of natural 6-epi-
plakortolide E was achieved by using an assembly process
activated by singlet oxygen. This synthetic route finds some
applications, since many analogues of plakortolide can be
readily obtained by simply changing the long aliphatic side
chain 2 during R,â-unsaturated ketone 3 formation. Thus,
these scarce natural products can be provided in quantities
suitable for more extensive biological evaluation.
Acknowledgment. This work was supported by the
Korean Research Foundation (Grant KRF-2000-A1004-
DP0267).
Supporting Information Available: Experimental pro-
cedures for the preparation of all compounds (3-10 and 1a)
and spectral data of compounds 3-9 and those including
NOESY, ROESY, and TOCSY of compound 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Jung, M.; Li, X.; Bustos, D. A.; ElSohly, H. N.; McChesney, J. D.;
Milhous, W. K. J. Med. Chem. 1990, 33, 1516.
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