The first total synthesis and absolute stereochemistry of plakortone G from the Jamaican sponge Plakortis sp.

Article abstract of DOI:10.1016/j.tetlet.2004.03.169

Total synthesis of plakortone G (1), a secondary metabolite of the Jamaican sponge Plakortis sp., was successfully achieved. The absolute configuration of this molecule was determined by comparison of the synthetic diastereomers with reported data to poss

Full text of DOI:10.1016/j.tetlet.2004.03.169

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4393–4396
The first total synthesis and absolute stereochemistry of plakortone
G from the Jamaican sponge Plakortis sp.
Satomi Kowashi, Takahisa Ogamino, Junichi Kamei, Yuichi Ishikawa and
Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku,
Yokohama 223-8522, Japan
Received 11 March 2004; revised 22 March 2004; accepted 26 March 2004
Abstract—Total synthesis of plakortone G (1), a secondary metabolite of the Jamaican sponge Plakortis sp., was successfully
achieved. The absolute configuration of this molecule was determined by comparison of the synthetic diastereomers with reported
data to possess the (4R,8R)-configuration 14.
Ó 2004 Elsevier Ltd. All rights reserved.
From among the secondary metabolites of marine ori-
gin, the plakortone-family1 consists of a synthetically
attractive polyketide-framework carrying peroxide and
tetrahydrofuranyl functionalities (Fig. 1).2
heart diseases. Plakortone G (1), isolated from the
Jamaican sponge Plakortis sp., was reported to exhibit
highly cytotoxic activity. The same carbon sequence of 1
as that of plakortide F, indicates that plakortide F
would be a biosynthetic precursor of 1.1e Since most
plakortones have an activity of facile calcium entry into
the sarcoplasmic reticulum, 1 might have the same
activity; however, this point is still unclear. The relative
and absolute configurations of 1 have not been revealed,
along with those of other plakortones except plakortone
In addition, plakortones A–D, isolated from the Carri-
bean sponge Plakortis halichondrioides, possessed an
activating factor of cardiac SR-Ca2þ-pumping ATPase,
which promotes relaxation of cardiac muscle. Accord-
ingly, they may be a lead of chemotherapeutic agents for
O
O
8
O
4
O
O
R
H
plakortone G 1
plakortone A: R = Et
B: R = Me
O
O
OMe
O
O
O
O
H
plakortone D
plakortide F
Figure 1. Structures of marine natural products from the marine sponge Plakortis sp.
Keywords: Plakortis sp.; a,b-Unsaturated c-lactone; Absolute stereochemistry; Plakortones.
* Corresponding author. Tel./fax: +81-45-566-1717; e-mail: nisiyama@chem.keio.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.169

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S. Kowashi et al. / Tetrahedron Letters 45 (2004) 4393–4396
D, which was synthesized in an optically active form.2g
We describe herein findings obtained in the synthesis of
optically active 1.
of 1. The first target was 2 carrying the same (4S,8R)-
configuration as that of plakortone D. Retrosynthetic
analysis of 2 was elaborated as follows; the approach to
2 was based on an intramolecular aldol reaction to
construct the a,b-unsaturated c-lactone moiety, and the
Julia olefination for selective E-olefination of 3. Intro-
duction of the asymmetric points at the C-4 and C-8
would be performed before construction of 3 by the
Julia coupling reaction between the sulfone unit 4 and
Plakortone G (1) possesses two asymmetric centers at
the C-4 and C-8 positions. In addition to construction of
the diastereomers, comparison of their spectral data and
optical rotations with those of natural 1 would be re-
quired for determination of the absolute stereochemistry
Evans asymmetric
alkylation
intramolecular
aldol reaction
SO2R
TBDPSO
Julia coupling
Julia olefination
O
O
O
RO2S
O
4
O
OHC
3
2 (4S,8R)
O
5
Sharpless asymmetric
dihydroxylation
Scheme 1. Retrosynthetic analysis of compound (4S,8R)-2.
O
O
OH
a
b
TBDPSO
TBDPSO
O
N
Bn
7
8
6
O
O
SO2Ph
c
d
TBDPSO
TBDPSO
4
9
N N
N
O
O
O
O
e
g
f
HO
S
N
O2
Ph
10
11
3
OH
OH
O
h
O
12
O
j
i
O
O
O
O
13
2
Scheme 2. Reagents and conditions: (a) i. LiBH4, ii. TBDPSCl, imidazole, MS4A (73% in two steps); (b) i. OsO4, NMO, NaIO4 (94%), ii. NaBH4
(100%); (c) i. PhSSPh, n-Bu3P (97%), ii. mCPBA (100%); (d) i. n-BuLi, 5 (72%), ii. Ac2O, Py, DMAP (97%), iii. 5% Na–Hg, Na2 HPO4 (96%); (e) i.
H2, Pd(OH)2–C (91%), ii. TBAF (95%), (f) i. TsCl, Et3N, ii. 1-phenyl-1H-tetrazole-5-thiol, t-BuOK, iii. (NH4)6Mo7O24Æ4H2O, H2O2 (73% in three
steps); (g) LHMDS, propanal, DME (74%, E:Z, 3:2); (h) 2 M HCl (81%); (i) i. SO3ÆPy, DMSO, Et3N (85%), ii. butyryl chloride, DMAP (79%); (j) i.
LHMDS, ii. MsCl, Et3N (85% in two steps).

S. Kowashi et al. / Tetrahedron Letters 45 (2004) 4393–4396
4395
the aldehyde unit 5. Fragment 4 containing the asym-
metric center at C-8 would be synthesized by the Evans
asymmetric alkylation, and 5 containing the asymmetric
center at the C-4 atom would be approached by the
Sharpless asymmetric dihydroxylation (Scheme 1).
AgNO3-coated PTLC. Acid hydrolysis of the acetal
group in (E)-11 gave diol 12 in 81% yield. Oxidation of
the primary alcohol in 12, and successive acylation
afforded 13, a precursor of the intramolecular aldol
reaction. Compound 13 was cyclized with LHMDS,
followed by dehydration with MsCl to give the a,b-
unsaturated c-lactone 27 (Scheme 2).
Synthesis of sulfone 4 commenced with the acyloxazo-
lidinone derivative 6, which was prepared by the Evans
asymmetric alkylation with excellent stereoselectivity
(94%, >99% de).3 After reductive removal of the chiral
auxiliary, protection of the primary alcohol by a TBDPS
group gave 7, which was subjected to oxidative cleavage
by the Lemieux–Johnson oxidation, and reduction with
NaBH4. Substitution of the resulting alcohol 8, followed
by oxidation with mCPBA, gave sulfone 4 in good yield.
According to the Hale protocol,4 aldehyde 5 was syn-
thesized by the Sharpless asymmetric dihydroxylation.5
In the next stage, the Julia coupling reaction was per-
formed between 4 and 5 with n-BuLi, followed by
acylation and reductive elimination to give alkene 9
(70% in three steps) as a geometrical mixture. Hydro-
genation of alkene 9, followed by deprotection of the
TBDPS group produced alcohol 10. After tosylation,
substitution reaction with a thiolate anion generated
from 1-phenyl-1H-tetrazole-5-thiol, followed by oxida-
tion afforded 3 as the precursor of the one-pot Julia
olefination.6 The modified Julia olefination of 3 with
propanal led to alkene 11 as a mixture of E and Z iso-
mers (3:2). This E/Z mixture could only be separated by
Comparison of the 1H NMR data of synthetic 2 with the
reported data indicated an obvious difference at the C-5
methylene proton {natural product: d 1.61 ppm (isolated
signal), 2: d 1.67–1.85 ppm (overlapping with other sig-
nals)}. This result indicated that natural plakortone G
(1) has a different relative stereochemistry from that of
2. Accordingly, we undertook synthesis of 14 carrying
the (4R,8R)-configuration in the next stage. The vicinal
diol 16 was synthesized by the asymmetric dihydroxyl-
ation from alkene 15. In spite of the low enantiomeric
excess of this AD reaction (78% ee), recrystallization of
the p-nitrobenzoate derivative 17, followed by hydroly-
sis and oxidation gave aldehyde 18 as a pure enantiomer
(>99% ee) (Scheme 3).
Sulfone 19 was obtained by substitution reaction of 8 by
a similar procedure to the case of 4. The modified Julia
coupling reaction of 19 with 18 gave alkene 20 in 85%
yield. Compound 20 was derivatized by essentially the
same procedure as in the case of 2 to afford (4R,8R)-14,8
1
the H NMR data and 13C NMR data of which were
superimposable to those reported. In addition, the
optical rotation of 14 was identical with the natural data
20
{syn. ½aŠ )25.3 (c 0.0083, CHCl3), nat.1e ½aŠ )25.91 (c
D
D
0.0083, CHCl3)}. Accordingly, the stereochemistry of
TBDPSO
a
b
OH
TBDPSO
OH
plakortone G (1) should be determined as 14 (Scheme
4).
15
16
In conclusion, the first total synthesis and determination
of the relative and absolute stereochemistry of plakor-
tone G (1) to possess the (4R,8R)-configuration 14 were
accomplished by comparison of the spectral data and
optical rotation of the synthetic samples with those
of the natural product. These results will contribute
toward the synthesis of more complicated congeners
carrying the same carbon-framework and the creation of
biologically more potent substances.
O
O
O
OHC
c
PNBO
O
18
17
Scheme 3. Reagents and conditions: (a) AD-mix-a (93%); (b) i.
cyclohexanone dimethylacetal, CSA (99%), ii. TBAF (100%), iii.
PNBCl, Py, iv. recrystallization (38% in two steps); (c) i. K2CO3,
MeOH (56%), ii. SO3ÆPy, DMSO, Et3N (64%).
Ph
N
O2
S
OH
a
b
TBDPSO
TBDPSO
N
N
N
8
19
14
O
c
TBDPSO
O
O
O
20
Scheme 4. Reagents and conditions: (a) i. 1-phenyl-1H-tetrazole-5-thiol, DIAD, n-Bu3P (75%), ii. (NH4)6Mo7O24Æ4H2O, H2O2 (100%); (b) LHMDS,
18 (85%); (c) i. H2, Pd(OH)2–C (92%), ii. TBAF (quant.), iii. TsCl, Et3N, iv. 1-phenyl-1H-tetrazole-5-thiol, t-BuOK (88%), v. (NH4)6Mo7O24Æ4H2O,
H2O2 (97%), vi. LHMDS, propanal, DME (77%, E:Z, 3:2), vii. 2M HCl (82%), viii. SO3ÆPy, DMSO, Et3N (64%), ix. butyryl chloride, DMAP (63%),
x. LHMDS, xi. MsCl, Et3N (40% in two steps).

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S. Kowashi et al. / Tetrahedron Letters 45 (2004) 4393–4396
3. Evans, D. A.; Rieger, D. L.; Jones, T. K.; Kaldor, S. W.
J. Org. Chem. 1990, 55, 6260.
Acknowledgements
4. (a) Hale, K. J.; Manaviazar, S.; Peak, S. A. Tetrahedron
Lett. 1994, 35, 425; (b) Hale, K. J.; Cai, J. Tetrahedron Lett.
1996, 37, 4233.
5. The enantiomer excess (89% ee) of the AD reaction was
determined by the 1H NMR analysis of the (R)-MTPA
ester, produced by esterification of a precursor of 5.4
6. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
This work was supported by Grant-in-Aid for the 21st
Century COE program ‘Keio Life Conjugate Chemis-
try’, as well as Scientific Research C from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan. The authors are grateful to the COE program for
financial support to T.O.
Synlett 1998, 2 6.
26
D
7. 2: ½aŠ +31.3 (c 0.0083, CHCl3); IR (film) m 1757, 1460,
968 cmÀ1
;
1H NMR (400 MHz, CDCl3) d 0.81 (3H, t,
References and notes
J ¼ 7:3 Hz), 0.82(3H, t,
J ¼ 7:3 Hz), 0.96 (3H, t,
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J ¼ 7:3 Hz), 1.15 (3H, t, J ¼ 7:3 Hz), 1.18 (2H, m), 1.26–
1.36 (4H, complex), 1.67–1.75 (3H, complex), 1.79 (2H,
complex), 2.00 (2H, complex), 2.30 (2H, dq, J ¼ 7:3,
1.5 Hz), 5.03 (1H, dd, J ¼ 15:1, 8.8 Hz), 5.36 (1H, dt,
J ¼ 15:1, 6.4 Hz), 6.82(1H, m); 13C NMR (100 MHz,
CDCl3) d 8.4, 12.2, 12.6, 14.8, 19.1, 21.7, 26.2, 28.7, 30.6,
35.6, 37.3, 44.7, 89.8, 132.8, 133.4, 136.3, 150.5, 173.9.
HRMS (EI) calcd for C18H30O2 (Mþ) 278.2244, found: m=z
(e) Gochfeld, D. J.; Hamann, M. T. J. Nat. Prod. 2001, 64,
1477; (f) Jimenez, M. D. S.; Garzon, S. P.; Rodriguez, A. D.
J. Nat. Prod. 2003, 66, 655.
278.2246.
20
D
8. 14: ½aŠ )25.3 (c 0.0083, CHCl3); IR (film) m 1755, 1460,
968 cmÀ1
;
1H NMR (400 MHz, CDCl3) d 0.80 (3H, t,
2. (a) Paddon-Jones, G. C.; Hungerford, N. L.; Hayes, P.;
Kitching, W. Org. Lett. 1999, 1, 1905; (b) Bittner, C.;
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J ¼ 7:3 Hz), 0.82(3H, t,
J ¼ 7:3 Hz), 0.96 (3H, t,
J ¼ 7:3 Hz), 1.15 (3H, t, J ¼ 7:3 Hz), 1.16 (4H, complex),
1.25 (1H, m), 1.32 (1H, m), 1.60 (1H, m), 1.68–1.85 (4H,
complex), 1.99 (2H, complex), 2.29 (2H, dq, J ¼ 7:3,
1.5 Hz), 5.02(1H, dd, J ¼ 15:1, 8.8 Hz), 5.35 (1H, dt,
J ¼ 15:1, 6.4 Hz), 6.83 (1H, t, J ¼ 1:5 Hz); 13C NMR
(100 MHz, CDCl3) d 8.4, 12.2, 12.6, 14.8, 19.1, 21.8, 26.2,
28.8, 30.5, 35.6, 37.4, 44.9, 89.8, 132.8, 133.4, 136.2, 150.6,
173.9. HRMS (EI) calcd for C18H30O2 (Mþ) 278.2244,
found: m=z 278.2234.