Synthesis and absolute configuration of the supposed structure of cladocoran A and B

Article abstract of DOI:10.1055/s-2002-19318

The proposed structures of cladocoran A and B, sesterterpenoid γ-hydroxybutenolides, were synthesized from ent-halimic acid.

Full text of DOI:10.1055/s-2002-19318

LETTER
105
Synthesis and Absolute Configuration of the Supposed Structure of
Cladocoran A and B
S
ynthesi
.
s
and absolut
S
e
Configuratio
.
n
of Cladoc
M
oran A
a
nd B arcos,*a A. B. Pedrero,a M. J. Sexmero,a D. Diez,a P. Basabe,a F. A. Hernández,a H. B. Broughton,b
J. G. Uronesa
a
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5,
37008 Salamanca, Spain
Fax +34(923)294574; E-mail: ismarcos@usal.es
b
Merck Sharp and Dohme, Harlow, Essex, UK
Received 25 June 2001
tion. Dysidiolide inhibits the growth of A-549 human lung
carcinoma and P388 murine leukemia cell lines at low mi-
cromolar concentrations.3
Abstract: The proposed structures of cladocoran A and B, sestert-
erpenoid -hydroxybutenolides, were synthesized from ent-halimic
acid.
Because of its atypical structure and its potentially impor-
tant physiological activity, dysidiolide has attracted con-
siderable attention as a target for total synthesis, ten total
syntheses having been reported to date.3–11
Key words: cladocoran A and B, ent-halimic acid, dysidiolide,
diterpenes, sesterterpenes
The proposed structures of cladocoran A and B, sesterter-
penoid -hydroxybutenolides, were synthesized from ent-
halimic acid (Figure 1), the major component of Halimi-
um viscosum (Villarino de los Aires). Interestingly, since
our synthetic compounds 1 and 2 are not identical to cla-
docoran A or B, the structures of these marine sesterterpe-
noids must be revised.
Cladocoran
A
and B have a -hydroxybutenolide
group previously associated with phospolipase A2 inhibi-
tion,12–15 but no total synthesis has yet been reported.
In this work we describe the synthesis of the supposed
structure for cladocoran A and B, compounds 1 and 2.
Physical properties of the compounds synthesized by us
do not correspond with those reported for cladocoran A
and B. Compounds 1 and 2 are sesterterpenes structurally
considered as “isopropenyl-ent-halimanes” with the ste-
reogenic centers that match the decalin fragment plus an
additional isopropenyl group. The synthesis for com-
pounds 1 and 2 was planned starting from ent-halimic
acid16 methyl ester 3, of known absolute configuration,
due to its structural analogy. At present, ent-halimic acid
is being employed in the synthesis of natural ent-haliman-
olides.17
The synthesis of 1 and 2 from ent-halimic acid methyl es-
ter 3 presented two main problems: manipulation of side
chains on C18 (south chain) and on C9 (north chain) to
achieve the introduction of the -hydroxybutenolide
group, and control of stereochemistry for the hydroxyl
group to be placed at C12 of ent-halimic acid methyl ester
3.
The retrosynthetic route for 1 and 2 from ent-halimic acid
methyl ester 3 is presented in Scheme 1.
Figure 1
The -hydroxybutenolide moiety of 1 and 2 was to be ob-
tained from A following Faulkner18 methodology. A
could be obtained by addition of furyllithium to an alde-
hyde such as B. The elongation of the south chain of 3 by
an isoprene unit was to be done in two steps: adding one
carbon by Wittig condensation to give an intermediate
such as B and then the four remaining carbons by SN2 sub-
stitution, due to the difficulty of achieving substitution at
a neopentyl carbon.
Cladocoran A and B, isolated from the mediterranean cor-
al Cladocora cespitosa by Fontana et al.1 in 1998, are nov-
el sesterterpenoids possessing an unprecedented skeleton.
Both of them occur in the organic extract as a mixture of
- and -epimers at C20.
Cladocoran A and B share more than one analogy with
dysidiolide,2 a natural inhibitor of protein phosphatase cdc
25A (IC50 = 9.4 M), which is essential for cell prolifera-
Degradation of the north chain had to take account of the
annular double bond of 3, so the oxidation on 13 would
have to be chemoselective. Initially, attention was focused
on degradation of 3 to obtain a compound such as B.
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0105,0109,ftx,en;D15401ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

106
I. S. Marcos et al.
LETTER
Scheme 1
In Scheme 2 the route followed for the synthesis of the chain by one carbon atom was accomplished by reaction
north side chains of 1 and 2 is shown, together with the ex- of 4 with Ph3P=CHOMe,21 acid hydrolysis of the resulting
tension of the south side chain by one carbon atom.
enol ether and reduction with LAH to give 5. North side
chain degradation was done by oxidation with OsO4 and
treatment with LTA,22 to give methyl ketone 6 in an excel-
lent yield.
Methylation of the hydroxy group19 of 3 followed by re-
duction at C18 and subsequent oxidation with TPAP20 led
very satisfactorily to aldehyde 4. Extension of the south
Scheme 2 a) NaH, Mel, THF, 3 h, (90%); b) LAH, Et2O, 1 h, (97%); c) TPAP, NMO, CH2Cl2, 30 min, (85%); d) (MeOCH2PPh3)+Cl–, HMDS-
Na, THF, –78 °C, 20 min, (92%), e) p-TsOH, acetone, 0.03 M, 4 h, (98%), f) LAH, Et2O, 30 min, (96%); g) OsO4, NMO, t-BuOH/THF/H2O
(7:2:1), 24 h, (99%); h) LTA, C6H6, 20 min, (95%); i) MeMgBr, Et2O, –78 °C, 1 h 30 min, (91%); j) Ac2O, pyridine, 5 h, (95%); k) POCl3,
pyridine, 0 °C to r.t., 30 min, (75%); l) m-CPBA, CH2Cl2, 0 °C to r.t., 1 h 30 min, (90%); m) H5lO6, THF, H2O, 15 min, (91%); n) 3-Bromo-
furane, BuLi, THF, –78 °C, 20 min, (90%), R/S: 3/7; o) TsCl, pyridine, 4 h, (92%); p) CH2=C(CH3)-CH2MgCl, THF, 12 h, (93%); q) TPAP,
NMO, CH2Cl2, 45 min, (90%); r) LAH, Et2O, 30 min, (81%), R/S:3/1.
Synlett 2002, No. 1, 105–109 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis and absolute Configuration of Cladocoran A and B
107
1
Scheme 3 a) Ac2O, pyridine, 8 h (93%); b) O2, h , Rose Bengal, DIPEA, Cl2CH2, -78 °C, 2 h 30 min, (84%); c) NaBH4, EtOH, 10 min,
(88%).
Since the Baeyer–Villiger reaction was not suitable for the The undesired C18 epimer 14 may be recycled, via oxida-
removal of two more carbon atoms from the north chain tion to the ketone 15 and subsequent reduction to the de-
without effecting the annular double bond, an indirect sired stereoisomer 13. The reduction of ketone 15 with
strategy was required. Addition of MeMgBr to methyl ke- LAH gives a mixture (R/S: 3/1) of C18 diastereomers 13
tone 6 gave a crystalline diol; the primary alcohol in this and 14 that were separated and recycled. (Scheme 2).
structure was then protected as its acetate. This was fol-
Compound 13 has the required south chain and a north
chain with adequate functionality for subsequent transfor-
lowed by dehydration of the tertiary alcohol by POCl3,23
to give a mixture of tri- and disubstituted olefins 7 and 8
mations. Acetylation of 13, (Scheme 3) followed by appli-
in a ratio of 7:3. Selective oxidation of the side chain dou-
cation of the Faulkner18 furan oxidation methodology for
ble bond of 7 and 8 with m-CPBA and subsequent cleav-
age of the epoxide with H5IO624 led to a mixture 9 and 10
(7:3). Compound 10 can be recycled to give 9, by the same
sequence as before. Compound 9 is the equivalent of alde-
hyde B (Scheme 1); as can be appreciated, this compound
can easily be transformed into analogues with both side
chains interchanged. This will give rise to a synthesis of
dysidiolide analogues, useful compounds for SAR stud-
ies.
North side chain transformation was started with addition
of 10 equivalents of 3-furyllithium to 9, to give a good
yield of a mixture of 11 and 12 in a 3:7 ratio, which was
separable by column chromatography. The structure was
determined by NMR studies and the 12R absolute config-
uration in 11 was corroborated by X-ray analysis.25 (mp:
115–116 °C, hexane/AcOEt) (Figure 2).
Chemoselective esterification of 11 and 12 with TsCl in
pyridine permitted the synthesis of the monotosyl deriva-
tives which, upon reaction with 2-methylallylmagnesium
Figure 2 ORTEP view of compound 11
chloride, gave 13 and 14 respectively.
Synlett 2002, No. 1, 105–109 ISSN 0936-5214 © Thieme Stuttgart · New York

108
I. S. Marcos et al.
LETTER
(15) De Rosa, S.; De Stefano, S.; Zavodnik, N. J. Org. Chem.
the synthesis of -hydroxybutenolides, gave 1. Reaction
of 13 with 1O2 under the same conditions gave 2. Both, 1
and 2, were obtained as epimeric mixtures at C20 in a ratio
of 3:1.
1988, 53, 5020.
(16) Urones, J. G.; Pascual Teresa, J.; Marcos, I. S.; Díez, D.;
Garrido, N. M.; Guerra, R. A. Phytochemistry 1987, 26,
1077.
(17) (a) Marcos, I. S.; González, J. L.; Sexmero, M. J.; Díez, D.;
Basabe, P.; Williams, D. J.; Simmonds, M. S. J.; Urones, J.
G. Tetrahedron Lett. 2000, 41, 2553. (b) Marcos, I. S.;
Sexmero, M. J.; Pedrero, A. B.; Hernández, F. A.; González,
E.; Urones, J. G. Chimia 1999, 53, 368.
(18) Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53, 2773.
(19) Urones, J. G.; Marcos, I. S.; Basabe, P.; Garrido, N. M.;
Jorge, A.; Moro, R. F.; Lithgow, A. M. Tetrahedron 1993,
49, 6079.
Physical properties of these synthesized compounds, 1
and 2,26 are not identical to those described for the natural
products cladocoran A and B. Initially it was thought that
the difference could be at the stereogenic centre of the -
hydroxybutenolide, so this centre was eliminated by
NaBH4 reduction of lactones 1 and 2 to give the buteno-
lides 16 and 17, but the physical properties of these deriv-
atives were also not coincident with the analogues
obtained by reduction of cladocoran A and B.1
(20) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
Due to these facts, similar transformations were carried
out on 14 to give 18 and 19 (epimers of 1 and 2), but the
physical properties of these compounds also do not coin-
cide with those of Cladocoran A and B, and therefore the
structure of these natural products should be revised.
(21) (a) Liu, H. J.; Shia, K.-S. Tetrahedron 1998, 54, 13449.
(b) Levine, S. J. J. Am. Chem. Soc. 1958, 80, 6150.
(c) Wittig, G.; Schlosser, M. Chem. Ber. 1961, 94, 1383.
(d) Wittig, G.; Böll, W.; Krück, K.-H. Chem. Ber. 1962, 95,
2514. (e) Wittig, G. Angew. Chem. 1956, 68, 505.
(22) Marcos, I. S.; Moro, R. F.; Carballares, S.; Urones, J. G.
Synlett 2000, 4, 541.
(23) Giner, J. L.; Margot, C.; Djerassi, C. J. Org. Chem. 1989, 54,
369.
(24) Marcos, I. S.; Moro, R. F.; Carballares, S.; Urones, J. G.
Tetrahedron 2001, 57, 713.
Spectroscopic studies of cladocorans A and B, 1, 2, 18 and
19 show that the side chains are indeed present in the nat-
ural products, so the difference might be in the decalin,
which would then not correspond to that of ent-halimic
acid methyl ester 3.
(25) Crystal data for 11: C21H32O3, M = 332.47, orthorhombic,
space group P212121 (nº 19). a = 7.6504(15), b = 8.771(2),
c = 28.694(6) Å, V = 1925.4(7) Å3, Z = 4, Dc = 1.147 mg/
m3, m (Cu-K ) = 0.075 mm–1, F(000) = 728. Data (3609
collected reflections, and 3331 unique reflections [I >
2sigma (I)]) were measured on a Seifert 3003 SC rotating
anode diffractometer with Cu-K radiation (graphite
monochromator) using 2 - scans at 268 K. The structure
was solved by direct methods and the non-hydrogen atoms
were refined anisotropically by full-matrix least squares
based on F2 to give the agreement factors R1 =&
nbsp;0.0669, R2 = 0.1527. Computations were carried on a
Digital Alphastation 500 using the SHELXTL program.
Crystallographic data for the structure of 11 in this paper
have been deposited at the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 163376.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
(UK), (fax: +44(1223)336033 or e-mail:
Acknowledgement
The authors thank the CICYT for financial support (PB98-0257)
and Junta de Castilla and León for a doctoral fellowship to A.B.P.
References
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Lobkovsky, E.; Clardy, J. J. Am. Chem. Soc. 1996, 118,
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Lett. 2000, 41, 911. (b) Miyaoka, H.; Kajiwara, Y.; Hara,
Y.; Yamada, Y. J. Org. Chem. 2001, 66, 1429.
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(8) (a) Takahashi, M.; Dodo, K.; Hashimoto, Y.; Shirai, R.
Tetrahedron Lett. 2000, 41, 2111. (b) Takahashi, M.; Dodo,
K.; Sugimoto, Y.; Aoyagui, Y.; Yamad, Y.; Hashimoto, Y.;
Shirai, R. Bioorg. Med. Chem. Lett. 2000, 10, 2571.
(c) Blanchard, J. L.; Epstein, D. M.; Boisclair, M. D.;
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deposit@ccdc.cam.ac.uk).
(26) The assignments for the spectra, 1H NMR and 13C NMR for
1 and 2 were done by bidimensional experiments HMQC
and HMBC. Spectroscopic and physical data for the mixture
of - and -epimers at C20 in 1: Rf = 0.41 (hexane–EtOAc,
7:3, v/v); [ ]D: +20.0 (c 0.47, CHCl3); UV/Vis (EtOH):
max
= 207 nm ( 8500); IR(film): max 3422, 3071, 3051, 2938,
2870, 1794, 1771, 1719, 1653, 1458, 1373, 1250, 1123,
1038, 939, 885 cm–1; MS (EI): m/z (%) = 444(1) [M+],
384(8), 340(13), 301(25), 259(44), 173(58), 105(62),
81(57); HRMS: m/z calcd for C27H40O5: 444.2876; found:
444.2911. Data for major epimer: 1H NMR (CDCl3, 400
MHz): = 5.99 (1 H, d, J = 9.4 Hz, H-20), 5.92 (1 H, s, H-
21), 5.46 (1 H, m, H-10), 5.29 (1 H, dd, J = 3.0, 7.0 Hz, H-
18), 4.94 (1 H, d, J = 9.4 Hz, OH), 4.70 (1 H, s, HA-3), 4.66
(1 H, s, HB-3), 2.56 (1 H, dd, J = 7.0, 15.2 Hz, HA-17), 2.01
(3 H, s, -OOCMe), 1.97 (2 H, t, J = 7.2 Hz, H-4), 1.88 (2 H,
m, H-13), 1.87 (1 H, m, H-12), 1.82 and 1.37 (1 H, m ea, H-
14), 1.71 (3 H, s, Me-1), 1.60 (1 H, dd, J = 3.0, 15.2 Hz, HB-
17), 1.57 (2 H, m, H-9), 1.56 (1 H, m, H-15), 1.41 and 1.19
(1 H, m ea, H-8), 1.35 and 1.23 (1 H, m ea, H-5), 1.28 and
(11) Demeke, D.; Forsyth, C. J. Org. Lett. 2000, 2, 3177.
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Mayol, L. Tetrahedron 1994, 50, 849.
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(14) Sullivan, B.; Faulkner, D. J. Tetrahedron Lett. 1982, 23, 907.
Synlett 2002, No. 1, 105–109 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis and absolute Configuration of Cladocoran A and B
109
1.21 (1 H, m ea, H-6), 0.97 (3 H, s, Me-25), 0.84 (3 H, d,
(CDCl3, 400 MHz): = 6.06 (1 H, d, J = 6.8 Hz, H-20), 6.02
(1 H, br s, H-21), 5.66 (1 H, m, H-10), 4.80 (1 H, dd,
J = 7.2 Hz, Me-24), 0.80 (3 H, s, Me-23); 13C NMR (CDCl3,
100 MHz): = 22.4 (C-1), 146.0 (C-2), 109.7 (C-3), 38.5 (C-
4), 21.5 (C-5), 40.2 (C-6), 34.2 (C-7), 31.7 (C-8), 21.7 (C-9),
121.8 (C-10), 140.1 (C-11), 41.7 (C-12), 22.7 (C-13), 28.4
(C-14), 38.6 (C-15), 42.4 (C-16), 43.1 (C-17), 67.7 (C-18),
168.8 (C-19), 97.7 (C-20), 117.9 (C-21), 169.5 (C-22), 21.5
(C-23), 15.5 (C-24), 23.8 (C-25), 171.2 (-OOCMe), 21.0 (-
OOCMe). Data for minor epimer: 1H NMR (CDCl3, 400
MHz): = 6.20 (1 H, br s, H-20), 5.96 (1 H, s, H-21), 5.46
(1 H, m, H-10), 5.44 (1 H, dd, J = 3.0, 8.0 Hz, H-18), 4.70 (1
H, s, HA-3), 4.66 (1 H, s, HB-3), 4.38 (1 H, br s, OH), 2.38 (1
H, dd, J = 8.0, 15.2 Hz, HA-17), 2.03 (3 H, s, -OOCMe), 1.97
(2 H, t, J = 7.2 Hz, H-4), 1.92 (1 H, m, H-12), 1.88 (2 H, m,
H-13), 1.88 and 1.42 (1 H, m ea, H-14), 1.83 (1 H, dd,
J = 3.0, 15.2 Hz, HB-17), 1.71 (3 H, s, Me-1), 1.57 (2 H, m,
H-9), 1.56 (1 H, m, H-15), 1.33 and 1.09 (1 H, m ea, H-8),
1.35 and 1.23 (1 H, m ea, H-5), 1.28 and 1.21 (1 H, m ea, H-
6), 0.97 (3 H, s, Me-25), 0.84 (3 H, d, J = 7.2 Hz, Me-24),
0.80 (3 H, s, Me-23); 13C NMR (CDCl3, 100 MHz): = 22.4
(C-1), 146.0 (C-2), 109.7 (C-3), 38.5 (C-4), 21.5 (C-5), 40.2
(C-6), 34.2 (C-7), 31.9 (C-8), 21.7 (C-9), 121.1 (C-10),
140.1 (C-11), 41.4 (C-12), 22.7 (C-13), 28.2 (C-14), 38.6 (C-
15), 42.4 (C-16), 42.4 (C-17), 67.3 (C-18), 167.8 (C-19),
97.9 (C-20), 118.8 (C-21), 169.5 (C-22), 21.5 (C-23), 15.5
(C-24), 23.5 (C-25), 171.2 (-OOCMe), 21.0 (-OOCMe).
Spectroscopic and physical data for the mixture of - and -
epimers at C20 in 2: Rf = 0.45 (hexane–EtOAc, 6:4, v/v);
[ ]D: +98.9 (c 0.64, CHCl3); UV/Vis (EtOH): max = 205 nm
( 8600); IR(film): max 3378, 3074, 3052, 2938, 1753, 1649,
1451, 1377, 1263, 1136, 953, 885, 739 cm–1; MS (FAB) m/z
(%) = 403(6) [M+ +1], 385(12), 367(16), 259(34), 154(100),
91(58); HRMS (FAB) m/z calcd for [C25H38O4 + H]+:
403.2848; found: 403.2823. Data for major: 1H NMR
J = 10.0, 1.8 Hz, H-18), 4.71 (1 H, s, HA-3), 4.67 (1 H, s, HB-
3), 4.50 (1 H, d, J = 6.8 Hz, OH), 2.81 (1 H, d, J = 1.8 Hz,
OH), 2.56 (1 H, dd, J = 10.0, 14.0 Hz, HA-17), 2.16 (1 H, m,
H-12), 2.06 (2 H, m, H-9), 1.97 (2 H, m, H-4), 1.71 (3 H, s,
Me-1), 1.59 (2 H, m, H-13), 1.58 (1 H, m, H-15), 1.42 (2 H,
m, H-5), 1.39 and 1.16 (1 H, m ea, H-8), 1.35 (2 H, m, H-14),
1.34 (1 H, d, J = 14.0 Hz, HB-17), 1.23 and 1.18 (1 H, m ea,
H-6), 1.11 (3 H, s, Me-25), 0.83 (3 H, d, J = 7.0 Hz, Me-24),
0.82 (3 H, s, Me-23); 13C (CDCl3, 100 MHz): = 22.3 (C-1),
146.4 (C-2), 109.6 (C-3), 38.5 (C-4), 21.3 (C-5), 39.4 (C-6),
34.1 (C-7), 31.3 (C-8), 22.8 (C-9), 122.7 (C-10), 143.6 (C-
11), 41.1 (C-12), 22.7 (C-13), 28.3 (C-14), 40.5 (C-15), 42.7
(C-16), 44.9 (C-17), 66.8 (C-18), 171.1 (C-19), 97.3 (C-20),
117.1 (C-21), 170.6 (C-22), 21.3 (C-23), 15.4 (C-24), 22.1
(C-25). Data for minor: 1H NMR (CDCl3, 400 MHz):
=
6.20 (1 H, d, J = 6.8 Hz, H-20), 5.96 (1 H, br s, H-21), 5.66
(1 H, m, H-10), 4.76 (1 H, dd, J = 10.0, 1.8 Hz, H-18), 4.69
(1 H, s, HA-3), 4.65 (1 H, s, HB-3), 4.50 (1 H, d, J = 6.8 Hz,
OH), 2.86 (1 H, d, J = 1.8 Hz, OH), 2.56 (1 H, dd, J = 10.0,
14.0 Hz, HA-17), 2.11 (1 H, m, H-12), 2.06 (2 H, m, H-9),
1.97 (2 H, m, H-4), 1.69 (3 H, s, Me-1), 1.59 (2 H, m, H-13),
1.58 (1 H, m, H-15),1.57 (1 H, d, J = 14.0 Hz, HB-17), 1.42
(2 H, m, H-5), 1.46 and 1.23 (1 H, m ea, H-8), 1.40 (2 H, m,
H-14), 1.23 and 1.18 (1 H, m ea, H-6), 1.09 (3 H, s, Me-25),
0.83 (3 H, d, J = 7.0 Hz, Me-24), 0.82 (3 H, s, Me-23); 13
C
NMR (CDCl3, 100 MHz): = 22.3 (C-1), 146.1 (C-2), 109.7
(C-3), 38.5 (C-4), 21.3 (C-5), 39.5 (C-6), 34.1 (C-7), 31.3
(C-8), 22.8 (C-9), 122.6 (C-10), 143.8 (C-11), 41.4 (C-12),
22.7 (C-13), 28.3 (C-14), 40.4 (C-15), 42.5 (C-16), 44.2 (C-
17), 66.3 (C-18), 169.8 (C-19), 97.8 (C-20), 117.5 (C-21),
170.7 (C-22), 21.4 (C-23), 15.4 (C-24), 22.2 (C-25).
Synlett 2002, No. 1, 105–109 ISSN 0936-5214 © Thieme Stuttgart · New York