Total synthesis and absolute stereochemistry of plakortone E

Article abstract of DOI:10.1016/j.tetlet.2006.02.025

The absolute stereochemistry of plakortone E, a cytotoxic metabolite of the Caribbean sponge, was established to be 1, by the synthesis of the racemic C-8 epimer (±)-2 and then of (-)-1 itself, which was identical with the natural compound.

Full text of DOI:10.1016/j.tetlet.2006.02.025

Tetrahedron Letters 47 (2006) 2287–2290
Total synthesis and absolute stereochemistry of plakortone E
Megumi Akiyama, Yuichi Isoda, Masato Nishimoto, Maiko Narazaki, Hiroaki Oka,
Atsuhito Kuboki and Susumu Ohira*
Department of Biological Chemistry, Faculty of Science, Okayama University of Science,
1-1 Ridai-cho, Okayama 700-0005, Japan
Received 12 January 2006; revised 30 January 2006; accepted 6 February 2006
Available online 21 February 2006
Abstract—The absolute stereochemistry of plakortone E, a cytotoxic metabolite of the Caribbean sponge, was established to be 1,
by the synthesis of the racemic C-8 epimer ( )-2 and then of (ꢀ)-1 itself, which was identical with the natural compound.
Ó 2006 Elsevier Ltd. All rights reserved.
Plakortones, poliketide metabolites of marine sponges
of the genus Plakortis, show interesting biological
activities.1 Plakortones A–D are activators of cardiac
sarcoplasmic reticulum Ca2+ pumping ATPase1a and
plakortones B–G exhibit in vitro cytotoxicity on tumor
cell lines (Fig. 1).1b,c The relative configurations of the
core moiety in plakortones A–F were determined to be
common by NOE analysis, however, the stereochemis-
tries of the side chain in many plakortones are still
unknown. Absolute configurations of plakortones D2
and G3 were determined, respectively by total synthe-
ses.2,3 The configuration of a quaternary center in pla-
kortone G is the opposite of that of the corresponding
center in plakortone D. On the other hand, the core part
of the other bicyclic plakortones (A, B, C, E, F) was
speculated to have the same configuration as plakortone
D, based on these levorotatory characters.2
precise evidence has not yet been found. This correspon-
dence, however, is confirmed by the present work.
(ꢀ)-Plakortone E, which exhibits high cytotoxicity on a
murine fibrosarcoma cell line, was isolated from Plakor-
tis simplex in 1999.1b Lactones 1 and 2 were synthesized
in racemic form by the Kitching group and the NMR
spectra of one of the two diastereomers were identical
with those of plakortone E. Although the relative stereo-
chemistry of the core part of them was clear, the stereo-
chemistry between C-6 and C-8 was ambiguous.4a It was
presumed that the absolute structure 1 is likely for pla-
kortone E by analogy with plakortone D,4a however,
Figure 1.
Keywords: Plakortone E; Alkylidenecarbene; C–H insertion; Absolute
stereochemistry.
Recently, we completed the stereocontrolled synthesis
of ( )-methyl-3,6-epoxy-4,6,8-triethyl-2,4,9-dodecatri-
enoate (3),5 which has the same carbon framework as
*
Corresponding author. Tel./fax: +81 86 256 9425; e-mail: sohira@
dbc.ous.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.025

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M. Akiyama et al. / Tetrahedron Letters 47 (2006) 2287–2290
plakortone E. The absolute stereochemistry of 3 had
been determined as shown by chemical degradation.6
Considering the possibility that stereochemistries at C-
6 and C-8 of plakortone E are the same as those of ester
3, we started the synthesis of ( )-2 from the synthetic
intermediate of ( )-3. The relationship between C-6
and C-8 of ( )-2 should become clear with our strategy.
After some model studies, we carried out iodolactoniza-
tion of 4 to give iodide 5 under various conditions. The
yield was, however, less than 30% due to lability of the
double bond in the side chain. Also unfortunately,
attempted reduction of iodide 5 with Bu3SnH gave the
tricyclic compound 6 (Fig. 2). Thus, we turned to the
modified route where the double bond was introduced
at the final stage.
Figure 2.
Alcohol 8, derived from the racemic diol 7,5 was
oxidized with IBX to ketone 9 (Scheme 1). The reaction
between lithiotrimethylsilyldiazomethane (TMSCLiN2)7
and 9 in THF afforded dihydrofurane 10 in good yield
via C–H insertion reaction of the alkylidenecarbene.
Allylic oxidation of 10 with PCC was unsuccessful due
to instability of the trityl group, however, the use of
CrO3 and 3,5-dimethyl pyrazole in CH2Cl2 at ꢀ20 °C
produced lactone 11 cleanly. Reduction of 11 with DI-
BAL followed by treatment of the resultant hemiacetal
with methyl(triphenylphosphoranylidene)acetate gave
methyl ester 12 as a 1:1 mixture of diastereomers. With-
out separation, ester 12 was subjected to alkaline hydro-
lysis and subsequent iodolactonization to provide
bicyclic lactones 14 and 15 in good yield as readily
separable diastereomers. The stereochemistries of both
compounds were determined by NOE experiments. Lac-
tone 14, with the desired stereochemistry at the core
moiety, was exposed to Bu3SnH and AIBN in benzene.
It was delightful for us to find the product was aldehyde
16 instead of the expected iodine-free trityl ether. The
oxidoreductive reaction is rationalized by radical genera-
tion on the tetrahydrofuran ring followed by 1,5 hydro-
gen transfer and elimination of the trityl radical
(Fig. 3).8 The diastereomer 15 also gave the correspond-
ing aldehyde under the same conditions.
Scheme 1. Reagents and conditions: (a) IBX, Py, DMSO, 45 °C (97%);
(b) TMSCHN2, BuLi, THF, ꢀ78 to 0 °C (81%); (c) CrO3, 3,5-dimethyl
pyrazole, CH2Cl2, ꢀ20 °C (75%); (d) DIBAL, CH2Cl2, ꢀ78 °C; (e)
Ph3PCHCO2CH3, PhMe, reflux (72% in two steps); (f) LiOH, EtOH–
H2O, rt (94%); (g) I2, NaHCO3, CH2Cl2–H2O, rt (94%); (h) Bu3SnH,
AIBN, C6H6, reflux; (i) 17, KHMDS, THF, ꢀ78 °C to rt (60% in two
steps).
Figure 3.
not identical with those of the natural product,1b but
identical with those of another epimer synthesized by
the Kitching group.4a
Now the relative stereochemistry of plakortone E must
be as shown in structure 1. Accordingly, we immediately
set about the synthesis of l in an optically active form.
Aldehyde 16 was coupled with the anion generated from
the sulfone 179 to afford the final product ( )-210
1
accompanied by the Z isomer (10:1 ratio). The H and
The Evans asymmetric alkylation of the chiral imide 18
with crotyl bromide provided olefin 1911 with 99.9% de
13C NMR spectra of the synthetic sample of ( )-2 were

M. Akiyama et al. / Tetrahedron Letters 47 (2006) 2287–2290
2289
Additionally, the optically active diol 7, which was
obtained from 23 was converted to (ꢀ)-3 in the same
way as racemate.5 The sign of the optical rotation of
synthetic (ꢀ)-3 was identical with that of the natural
product, therefore, the absolute structure of (ꢀ)-3 was
confirmed.14 It is notable that the stereochemical rela-
tionship of (ꢀ)-1 and (ꢀ)-3 is the same as that of plakor-
tone D and plakortone G.
In summary, we determined the relative stereochemistry
of plakortone E by the synthesis of its racemic C-8 epi-
mer and confirmed the absolute configuration by its own
enantioselective synthesis.
References and notes
1. (a) Patil, A. D.; Freyer, A. J.; Bean, M. F.; Carte, B. K.;
Westley, J. W.; Johnson, R. K.; Lahouratate, P. Tetra-
hedron 1996, 52, 377–394; (b) Cafieri, F.; Fattorusso, E.;
Taglialatela-Scafati, O.; Rosa, M. D.; Ianaro, A. Tetra-
hedron 1999, 55, 13831–13840; (c) Gochfeld, D. J.;
Hamann, M. T. J. Nat. Prod. 2001, 64, 1477–1479; (d)
Rahm, F.; Hayes, P. Y.; Kitching, W. Heterocycles 2004,
64, 523–575.
2. Hayes, P. Y.; Kitching, W. J. Am. Chem. Soc. 2002, 124,
9718–9719.
3. Kowashi, S.; Ogamino, T.; Kamei, J.; Ishikawa, Y.;
Nishiyama, S. Tetrahedron Lett. 2004, 45, 4393–4396.
4. Synthetic studies on plakortones: (a) Hayes, P. Y.;
Kitching, W. Heterocycles 2004, 62, 173–177; (b) Lee, H.
K.; Wong, H. N. C. Chem. Commun. 2002, 2114–2115; (c)
Semmelhack, M. F.; Shanmugam, P. Tetrahedron Lett.
2000, 41, 3567–3571; (d) Bittner, C.; Burgo, A.; Murphy,
P. J.; Sung, C. H.; Thornhill, A. J. Tetrahedron Lett. 1999,
40, 3455–3456; (e) Paddon-Jones, G. C.; Hungerford, N.
L.; Hayes, P. Y.; Kitching, W. Org. Lett. 1999, 1, 1095–
1097.
Scheme 2. Reagents and conditions: (a) LDA, crotyl bromide, HMPA,
THF, ꢀ78 °C (94%); (b) 30% H2O2, LiOH, THF–H2O, rt (92%); (c) I2,
NaHCO3, CH2Cl2–H2O, rt (93%); (d) PivCl, Et3N, THF, ꢀ10 °C to rt;
(e) Me2NH–HCl, Et3N, CH2Cl2, rt (91% in two steps); (f) Bu3SnH,
AIBN, C6H6, reflux (quant.); (g) LiAlH4, THF, 0 °C (92%); (h) DBU,
PhMe, reflux (quant.); (i) LiOH, EtOH–H2O, rt (85%); (j) I2,
NaHCO3, CH3CN, rt (90%); (k) Bu3SnH, AIBN, C6H6, reflux; (l)
17, KHMDS, THF, ꢀ78 °C to rt (69% in two steps).
5. Akiyama, M.; Isoda, Y.; Nishimoto, M.; Kobayashi, A.;
Togawa, D.; Hirao, N.; Kuboki, A.; Ohira, S. Tetrahedron
Lett. 2005, 46, 7483–7485.
6. Schmidt, E. W.; Faulkner, D. J. Tetrahedron Lett. 1996,
37, 6681–6684.
7. (a) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem.
Commun. 1992, 721–722; (b) Shioiri, T.; Aoyama, T.
Synth. Org. Chem. Jpn. 1996, 54, 918–928, and references
cited therein.
8. Generation of aldehyde in a similar case was reported.
Curran, D. P.; Yu, H. Synthesis 1992, 123–127.
9. (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.;
Morley, A. Synlett 1998, 26–28; (b) Blakemore, P. R. J.
Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
(Scheme 2). Removal of the chiral auxiliary with lithium
hydroperoxide gave carboxylic acid 20. Iodolactoniza-
tion of 20 produced lactones 22 and 23 in a 2:1 ratio.
Under similar conditions, amide 21 gave the iodo
lactones with the reversed selectivity (22:23 = 1:10).12
Iodide 22 was separated and reduced to lactone 24,
which was treated with LiAlH4 to give diol 25. Direct
reduction of iodide 22 with LiAlH4 to diol 25 was
possible, however, a partial (ca. 10%) epimerization
occurred probably via the elimination of HI from iodide
22. Along the reaction sequence from 7 to 12, diol 25 was
converted into a 1:1 mixture of methyl esters 26 and 27.
Those diastereomers were separated at this stage by sil-
ica gel column chromatography, and the stereochemis-
try of 26 was determined by NOE experiment to be
the desired one. When ester 27 was heated with DBU
in toluene, it epimerized to a mixture of 26 and 27
through b-elimination and Michael addition. Thus,
undesired ester 27 was convertible to 26 by repeated
epimerization–separation sequence. Finally, ester 26
was transformed to the target compound (ꢀ)-113 in four
10. 1H NMR (400 MHz, CDCl3) d 0.83 (t, 3H, J = 7.4 Hz),
0.84 (t, 3H, J = 7.4 Hz), 0.97 (t, 3H, J = 7.4 Hz), 1.01 (t,
3H, J = 7.4 Hz), 1.23 (m, 1H), 1.37 (m, 1H), 1.55–1.61 (m,
4H), 1.64–1.80 (m, 2H), 1.92 (m, 1H), 2.00 (m, 2H), 2.06
(d, 1H, J = 14.4 Hz), 2.23 (d, 1H, J = 14.4 Hz), 2.63 (br d,
1H, J = 18.0 Hz), 2.69 (dd, 1H, J = 4.6, 18.3 Hz), 4.35 (br
d, 1H, J = 4.4 Hz), 5.15 (dd, 1H, J = 9.0, 15.2 Hz), 5.38
(dt, 1H, J = 6.3, 15.2 Hz); 13C NMR (100 MHz, CDCl3) d
8.4, 8.5, 11.7, 13.9, 25.5, 30.1, 30.2, 32.8, 37.6, 40.5, 43.4,
44.6, 80.8, 87.7, 97.9, 131.8, 134.2, 175.7.
20
1
11. ½aꢁD +56.6 (c 0.83, CHCl3); H NMR (400 MHz, CDCl3)
d 0.91 (t, 3H, J = 7.4 Hz), 1.50–1.62 (m, 1H), 1.64 (d, 3H,
J = 5.9 Hz), 1.67–1.78 (m, 1H), 2.23–2.29 (m, 1H), 2.36–
2.40 (m, 1H), 2.66 (dd, 1H, J = 9.9, 13.3 Hz), 3.28 (dd, 1H,
J = 3.2, 13.3 Hz), 3.77–3.85 (m, 1H), 4.12–4.20 (m, 2H),
4.70 (br dddd, 1H, J = 3.2, 6.7, 6.9 Hz), 5.41–5.58 (m,
1
steps. The optical rotation and the H and 13C NMR
spectra of the synthetic sample of (ꢀ)-1 were identical
with those of the natural product. The absolute stereo-
chemistry of plakortone E was thus determined to be
(3S,4S,6S,8R) as previously suggested.2,4a

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M. Akiyama et al. / Tetrahedron Letters 47 (2006) 2287–2290
2H), 7.22–7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) d
11.6, 17.9, 24.5, 35.3, 38.0, 44.3, 55.4, 65.8, 127.3, 127.6,
J = 7.4, 15.0 Hz), 1.87–1.94 (m, 1H), 1.97 (d, 1H, J =
14.5 Hz), 1.98–2.05 (m, 2H), 2.18 (d, 1H, J = 14.5 Hz),
2.63 (d, 1H, J = 18.2 Hz), 2.70 (dd, 1H, J = 4.8, 18.2 Hz),
4.32 (d, 1H, J = 4.3 Hz), 5.10 (dd, 1H, J = 9.2, 15.3 Hz),
5.38 (dt, 1H, J = 6.4, 15.3 Hz); 13C NMR (100 MHz,
CDCl3) d 8.3, 8.6, 11.6, 13.9, 25.5, 29.7, 30.2, 31.7, 37.5,
40.8, 43.5, 46.0, 80.0, 87.7, 98.0, 131.9, 133.9, 175.6.
127.8, 128.9, 129.4, 135.5, 153.2, 176.2.
12. (a) Tamaru, T.; Mizutani, M.; Furukawa, Y.; Kawamura,
S.; Yoshida, Z.; Yanagi, K.; Minobe, M. J. Am. Chem. Soc.
1984, 106, 1079–1085; (b) Bartlett, P. A.; Holm, K. H.;
Morimoto, A. J. Org. Chem. 1985, 50, 5179–5183.
20
25
20
20
13. ½aꢁD ꢀ9.0 (c 0.03, CHCl3), lit. ½aꢁD ꢀ10 (c 0.001,
CHCl3);1b 1H NMR (400 MHz, CDCl3) d 0.82 (t, 3H,
J = 7.4 Hz), 0.85 (t, 3H, J = 7.4 Hz), 0.97 (t, 3H, J =
7.4 Hz), 1.00 (t, 3H, J = 7.4 Hz), 1.15–1.26 (m, 1H), 1.35–
1.44 (m, 1H), 1.45 (dd, 1H, J = 9.2, 14.3 Hz), 1.51–1.65
(m, 3H), 1.70 (dq, 1H, J = 7.4, 15.0 Hz), 1.76 (dq, 1H,
14. ½aꢁD ꢀ245.9 (c 0.37, CHCl3) authentic sample15 ½aꢁD
ꢀ226.9 (c 0.93, CHCl3) and lit. [a]D ꢀ175 (c 1.4, CCl4).
15. The sample was provided by Professor Abimael D.
´
´
Rodrıguez, University of Puerto Rico; Jimenez, M. d. S.;
´
´
Garzon, S. P.; Rodrıguez, A. D. J. Nat. Prod. 2003, 66,
655–661.