Total synthesis of cladocorans A and B: A structural revision

Article abstract of DOI:10.1021/jo020743y

Cladocorans A and B, isolated from the Mediterranean coral Cladocora cespitosa, are novel sesterterpenoids whose structures were initially proposed as 1 and 2, respectively. These designations, however, subsequently came under doubt. In the present study,

Full text of DOI:10.1021/jo020743y

Tota l Syn th esis of Cla d ocor a n s A a n d B: A Str u ctu r a l Revision
Hiroaki Miyaoka, Makoto Yamanishi, Yasuhiro Kajiwara, and Yasuji Yamada*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji,
Tokyo 192-0392, J apan
yamaday@ps.toyaku.ac.jp
Received December 16, 2002
Cladocorans A and B, isolated from the Mediterranean coral Cladocora cespitosa, are novel
sesterterpenoids whose structures were initially proposed as 1 and 2, respectively. These
designations, however, subsequently came under doubt. In the present study, the synthesis of
compounds 5 and 6 was undertaken. The physical properties of 5 and 6 were found to be identical
to those of natural cladocorans A and B, whose structures were thus concluded to be 5 and 6,
respectively. Cladocoran B is thus clearly shown to be an olefinic regioisomer of dysidiolide and
cladocoran A as its acetate.
Cladocorans A and B, isolated from the Mediterranean
coral Cladocora cespitosa by Fontana et al. in 1998, are
novel sesterterpenoids each with a unique carbon skel-
eton (Figure 1).1 Cladocorans A and B are regarded as
analogues of dysidiolide, a natural inhibitor of protein
phosphatase cdc25A that is essential for cell prolifera-
tion.2 The biological activity of cladocoran has not been
reported, but the compound may likely be an inhibitor
of protein phosphatase and phospholipase A2 in consid-
eration of its structural characteristics.3-6 The relative
configuration (C-7, C-12, C-15 and C-16) of the decalin
ring system in cladocoran A was determined on the basis
of coupling constants and NOEs of a derivative compound
obtained from cladocoran A. The absolute configuration
of the secondary hydroxy group at C-18 was determined
by the modified Mosher method,7 though the relative
configurations of the hydroxy group at C-18 and decalin
ring remain to be elucidated. Fontana et al. have pre-
sented the structural formulas 1 and 2 for cladocorans
A and B, respectively.
out by the authors using intramolecular Diels-Alder
reaction as the key reaction.11 But the total synthesis of
cladocoran has not yet been reported. The total synthesis
of cladocorans A and B was thus conducted in the present
study so as to clarify their structures and establish a
method for synthesis.
Recently, Marcos et al. reported the chemical conver-
sion of ent-halimic acid to compounds 1 and 2 proposed
by Fontana et al., but the physical properties of the
synthesized compounds did not match those of natural
cladocorans.18 It was thus apparent that the structures
of cladocorans A and B should be revised. We considered
the absolute configurations at the C-7 and C-16 positions
of cladocorans to be identical with those of dysidiolide,
in that these compounds bear close connection with
biogenesis, and their structures were consequently as-
sumed to be 3 and 4. The authors synthesized compounds
3 and 4 whose physical properties were clearly found to
differ with those of natural cladocorans. It was then
anticipated that actual structures of cladocorans A and
B would be 5 and 6, both epimers at C-15 of 3 and 4,
based on analysis of NMR data of natural cladocorans 3
Numerous attempts have been made to conduct the
total synthesis of dysidiolide, prompted by its unique
structure features and potential biological significance.8-17
The total synthesis of dysidiolide was previously carried
(11) (a) Miyaoka, H.; Kajiwara, Y.; Yamada, Y. Tetrahedron Lett.
2000, 41, 911-914. (b) Miyaoka, H.; Kajiwara, Y.; Hara, Y.; Yamada,
Y. J . Org. Chem. 2001, 66, 1429-1435.
(12) (a) Takahashi, M.; Dodo, K.; Hashimoto, Y.; Shirai, R. Tetra-
hedron Lett. 2000, 41, 2111-2114. (b) Takahashi, M.; Dodo, K.;
Sugimoto, Y.; Aoyagi, Y.; Yamada, Y.; Hashimoto, Y.; Shirai, R. Bioorg.
Med. Chem. Lett. 2000, 10, 2571-2574.
(13) Piers, E.; Caille´, S.; Chen, G. Org. Lett. 2000, 2, 2483-2486.
(14) Demeke, D.; Forsyth, C. J . Org. Lett. 2000, 2, 3177-3179.
(15) Paczkowski, R.; Maichle-Mo¨ssmer, C.; Maier, M. E. Org. Lett.
2000, 2, 3967-3969.
(16) (a) J ung, M. E.; Nishimura, N. J . Am. Chem. Soc. 1999, 121,
3529-3530. (b) J ung, M. E.; Nishimura, N. Org. Lett. 2001, 3, 2113-
2115.
(17) (a) Brohm, D.; Waldmann, H. Tetrahedron Lett. 1998, 39, 3995-
3998. (b) Brohm, D.; Metzger, S.; Bhargava, A.; Mu¨ller, O.; Lieb, F.;
Waldmann, H. Angew. Chem., Int. Ed. 2002, 41, 307-311. (c) Brohm,
D.; Philippe, N.; Metzger, S.; Bhargava, A.; Mu¨ller, O.; Lieb, F.;
Waldmann, H. J . Am. Chem. Soc. 2002, 124, 13171-13178.
(18) Marcos, I. S.; Pedrero, A. B.; Sexmero M. J .; Diez, D.; Basabe
P.; Herna´ndez, F. A.; Broughton H. B.; Urones J . G. Synlett 2002, 105-
109.
(1) Fontana, A.; Ciavatta, M. L.; Cimino, G. J . Org. Chem. 1998,
63, 2845-2849.
(2) Gunasekera, S. P.; McCarthy, P. J .; Kelly-Borges, M.; Lobkovsky,
E.; Clardy, J . J . Am. Chem. Soc. 1996, 118, 8759-8780.
(3) Conte, M. R.; Fattorusso, E.; Lanzotti, V.; Magno, S.; Mayol, L.
Tetrahedron 1994, 50, 849-856.
(4) Lombardo, D.; Dennis, E. A. J . Biol. Chem. 1985, 260, 7234-
7240.
(5) Sullivan, B.; Faulkner, D. J . Tetrahedron Lett. 1982, 23, 907-
910.
(6) De Rosa, S.; De Stefano, S.; Zavodnik, N. J . Org. Chem. 1988,
53, 5020-5023.
(7) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am. Chem.
Soc. 1991, 113, 4092-4096.
(8) Corey, E. J .; Roberts, B. E. J . Am. Chem. Soc. 1997, 119, 12425-
12431.
(9) Boukouvalas, J .; Cheng, Y.-X.; Robichaud, J . J . Org. Chem. 1998,
63, 228-229.
(10) Magnuson, S. R.; Sepp-Lorenzino, L.; Rosen, N.; Danishefsky,
S. J . J . Am. Chem. Soc. 1998, 120, 1615-1616.
10.1021/jo020743y CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/09/2003
3476
J . Org. Chem. 2003, 68, 3476-3479

Total Synthesis of Cladocorans A and B
docoran, was constructed in such a way that lactone C
would be produced by intramolecular Diels-Alder reac-
tion of diene ester D obtained from allylic alcohol E via
esterification. It was considered that stereoselective
hydrogenation and alkylation at C-1619 of lactone C
would take place so as to provide lactone B, knowing the
R-face of lactone C to be the less hindered side. Lactone
B would undergo conversion to aldehyde A by elimination
of the oxygenated functional group at C-10, deoxygen-
ation at C-25, and elongation of the side chain. The highly
functional γ-hydroxybutenolide would be obtained by
addition of 3-lithiofuran to aldehyde A and photochemical
oxidation of the furan moiety to give compounds 3 and
4.
The synthesis of compounds 3 and 4 was initiated from
optically active allylic alcohols 7a 11b and 7b,11b both
synthetic intermediates for dysidiolide (Scheme 2). The
secondary hydroxy group of sulfoxide 7a was acylated
with 2-butynoic acid, DCC, and DMAP in toluene to
afford ester 8. Allylic alcohol 7b was converted to ester
8 via Mitsunobu reaction20 using 2-butynoic acid, DEAD,
and Ph3P. A solution of ester 8 in toluene was refluxed
in the presence of ethyl propiolate and pyridine to
construct the diene by elimination of phenyl sulfoxide.
Subsequent intramolecular Diels-Alder reaction gave
decalin 9 corresponding to lactone C in the synthetic
strategy as the sole product. In the absence of ethyl
propiolate, there were many byproducts, and decalin 9
was obtained in only low yield. The relative configuration
of 9 was confirmed on the basis of the NOESY spectrum.
NOESY correlations were noted between the methine
proton at C-11 and one of the methylene protons at C-6
and between the olefinic proton at C-13 and the methyl
protons at C-23. The relative configuration of 9 is thus
that shown in Scheme 2.
F IGURE 1. Chemical structures proposed for cladocorans and
that of dysidiolide.
SCHEME 1. Syn th etic Str a tegy for Com p ou n d s 3
a n d 4
Stereoselective hydrogenation of two carbon-carbon
double bonds in lactone 9 was carried out in the presence
of PtO2 and acetic acid at medium pressure of H2 (4.0
atm) to afford 15â-methyl lactone. Removal of the TB-
DMS group with tetrabutylammonium fluoride (TBAF)
provided alcohol 10 as the sole product. The relative
configurations of C-12, C-15, and C-16 in 10 were
determined from NOESY correlations between both
methylene protons at C-6 and the methine proton at
C-12, between the methine proton at C-10 and the
methine proton at C-16, and between the methine proton
at C-12 and methine proton at C-15. Stereoselectivety of
hydrogenation in 9 may possibly be due to approach of
the hydrogenation catalyst from the convex face.
The hydroxy group in lactone 10 was converted to the
phenylsulfanyl group by treatment with N-phenylthio-
succinimide, Bu3P, and pyridine. Stereoselective alkyla-
tion at C-16 was carried out by treatment with LDA and
then 1-iodo-2-(tetrahydro-2-pyranyloxy)ethane11 in the
presence of HMPA to give lactone 11, corresponding to
lactone B in the synthetic strategy, as the sole product.
The relative configuration at C-16 in 11 was determined
from the NOESY spectrum of alcohol 11′, prepared from
11 by acid catalytic methanolysis of the THP group with
PPTS. NOESY correlations were evident between the
and 4. The synthesis of compounds 5 and 6 was carried
out and their physical properties were seen to be identical
with those of natural cladocorans. The structures of
cladocorans A and B were thus revised as 5 and 6. This
paper reports in detail the total synthesis of cladocorans
A and B and the structural revision is presented.
The synthetic strategy for compounds 3 and 4 as
cladocorans A and B is presented in Scheme 1. The
method of synthesis may be considered essentially the
same as that for synthesis of dysidiolide, as previously
reported.11 Optically active allylic alcohol E, the synthetic
intermediate for dysidiolide, was used as starting mate-
rial. The decalin framework, the core structure of cla-
(19) Numbering of compounds is in accordance with that for
cladocoran in this paper.
(20) Mitsunobu, O. Synthesis 1981, 1-28.
J . Org. Chem, Vol. 68, No. 9, 2003 3477

Miyaoka et al.
SCHEME 2a
SCHEME 3a
a
Reagents and conditions: (a) H2 (4.4 atm), PtO2, AcOH, rt,
89%; (b) (i) N-phenylthiosuccinimide, Bu3P, pyridine, 60 °C, 86%,
(ii) LDA, HMPA, THPOCH2CH2I, THF, 0 °C, 94%; (c) PPTS,
MeOH, rt, 26%; (d) (i) DIBALH, toluene, -78 °C, (ii) LiBH4, THF,
40 °C, 91% (two steps), (iii) TBDMSCl, imidazole, DMF, rt, quant,
(iv) SOCl2, pyridine, 0 °C, 93%, (v) TPAP, NMO, CH2Cl2, 98%; (e)
(i) BuLi, 4-iodo-2-methyl-1-butene, THF, 50 °C, 89%, (ii) Na-Hg,
Na2HPO4, MeOH, rt, 91%; (f) (i) TBAF, THF, 50 °C, 85%, (ii) TPAP,
NMO, CH2Cl2, rt, 82%, (iii) H2NNH2, KOH, diethylene glycol, 200
°C, 70%, (iv) PPTS, MeOH, rt, 94%, (v) TPAP, NMO, CH2Cl2, rt,
80%; (g) 3-bromofuran, BuLi, THF, -78 °C, 95%; (h) for 5: (i) Ac2O,
pyridine, rt, quant., (ii) O2, hν, Rose Bengal, i-Pr2NEt, CH2Cl2,
-78 °C, 83%; (i) O2, hν, Rose Bengal, i-Pr2NEt, CH2Cl2, -78 °C,
83%.
a
Reagents and conditions: (a) 2-butynoic acid, DCC, DMAP,
toluene, rt, 93%; (b) 2-butynoic acid, DEAD, Ph3P, THF, rt, 91%;
(c) pyridine, ethyl propiolate, toluene, reflux, 84%; (d) (i) H2 (4.0
atm), PtO2, AcOH, rt, (ii) TBAF, THF, rt, 92% (two steps); (e) (i)
N-phenylthiosuccinimide, Bu3P, pyridine, 60 °C, 79%, (ii) LDA,
HMPA, THPOCH2CH2I, THF, 0 °C, 97%; (f) PPTS, MeOH, rt, 77%;
(g) (i) DIBALH, toluene, -78 °C, (ii) LiBH4, THF, 40 °C, quant
(two steps), (iii) TBDMSCl, imidazole, DMF, rt, 92%, (iv) SOCl2,
pyridine, 0 °C, 97%, (v) TPAP, NMO, CH2Cl2, 95%; (h) (i) BuLi,
4-iodo-2-methyl-1-butene, THF, 50 °C, 94%, (ii) Na-Hg, Na2HPO4,
MeOH, rt, 86%; (i) (i) TBAF, THF, 50 °C, 92%, (ii) TPAP, NMO,
CH2Cl2, rt, 72%, (iii) H2NNH2, KOH, diethylene glycol, 200 °C,
71%, (iv) PPTS, MeOH, rt, 92%, (v) TPAP, NMO, CH2Cl2, rt, 91%;
(j) 3-bromofuran, BuLi, THF, -78 °C, 89%; (k) for 3: (i) Ac2O,
pyridine, rt, 91%, (ii) O2, hν, Rose Bengal, i-Pr2NEt, CH2Cl2, -78
°C, 37%; (l) for 4: O2, hν, Rose Bengal, i-Pr2NEt, CH2Cl2, -78 °C,
68%.
protected by treatment with TBDMSCl and imidazole as
TBDMS ether as the sole product. Elimination of the
secondary hydroxy group was carried out by treatment
with SOCl2 in pyridine and oxidation of sulfide with
tetrapropylammonium perruthenate (TPAP) and 4-
methylmorpholine N-oxide (NMO) produced sulfone 12.
Elongation of the side chains and deoxygenation of the
C-25 position were carried out to produce the compounds
3 and 4. Reaction of the lithio derivative of sulfone 12
with 4-iodo-2-methyl-1-butene at 50 °C gave the coupling
product and subsequent removal of the benzenesulfonyl
group with Na-Hg in the presence of Na2HPO4 provided
silyl ether 13. Silyl ether 13 was converted to aldehyde
14, corresponding to aldehyde A in the synthetic strategy,
in five steps: (1) removal of the TBDMS group in 11 with
TBAF, (2) TPAP-oxidation of the hydroxy group to
provide aldehyde, (3) Wolff-Kishner reduction21 of the
methine proton at C-10 and one of the methylene protons
at C-17, between the methine proton at C-11 and both
methylene protons at C-17, and between the methine
proton at C-11 and both methylene protons at C-18.
Following deoxygenation of the C-10 and C-25 posi-
tions, lactone 11 was reduced with DIBALH to give the
hemiacetal, the reduction of which with LiBH4 afforded
the diol. The primary hydroxy group in the diol was
3478 J . Org. Chem., Vol. 68, No. 9, 2003

Total Synthesis of Cladocorans A and B
formyl group with H2NNH2 and KOH in diethylene glycol
at 200 °C, (4) methanolysis of the THP group with PPTS
to give alcohol, and (5) TPAP-oxidation of the primary
hydroxy group with NMO. Treatment of aldehyde 14 with
3-lithiofuran, prepared from 3-bromofuran and BuLi,
gave a mixture of â-alcohol 15a and its epimer 15b (15a /
15b ) 3:1), which was readily separatable by silica gel
chromatography. The absolute configuration of the sec-
ondary hydroxy group in 15a was determined to be the
R configuration by the modified Mosher method.7 Fol-
lowing acetylation of alcohol 15a , photochemical oxida-
tion22 of the obtained acetate in the presence of excess
dine to give phenyl sulfide and treatment with LDA, and
then 1-iodo-2-(tetrahydro-2-pyranyloxy)ethane11 in the
presence of HMPA provided lactone 18 as the sole
product. The relative configuration of C-16 in 18 was
determined from the NOESY spectrum of alcohol 18′
prepared from 18 by methanolysis of the THP group.
NOESY correlations were observed between the methine
proton at C-10 and both methylene protons at C-17,
between the methine proton at C-11 and both methylene
protons at C-17, and between both methylene protons at
C-18 and the methyl protons at C-24.
Lactone 18 was converted to aldehyde 21 via sulfone
19 and silyl ether 20 in a similar manner as above.
Treatment of aldehyde 21 with 3-lithiofuran gave a
mixture of â-alcohol 22a and the epimer 22b (22a /22b
) 3:1). The absolute configuration of the secondary
hydroxy group in 22a was determined as the R config-
uration by the modified Mosher method.7 Alcohols 22a
and 22b were acetylated, and photochemical oxidation22
of the acetates thus obtained afforded compounds 5,
i-Pr2NEt afforded 3, [R]26 ) -17.9 (c 0.56, CHCl3).
D
Photochemical oxidation22 of 15a in the presence of excess
i-Pr2NEt afforded 4, [R]23 ) -31.0 (c 1.04, CHCl3).
D
Spectral data of synthesized 3 and 4 were not identical
with those reported for natural cladocoran A, [R]20
)
D
-25.8 (c 0.4, CHCl3),1 and cladocoran B, [R]20 ) -59.9
D
(c 0.6, CHCl3).1 18-epi-3 (ent-1), [R]26 ) -7.2 (c 0.25,
D
CHCl3), and 18-epi-4 (ent-2), [R]23 ) -64.3 (c 0.28,
D
CHCl3), were thus synthesized from R-alcohol 15b in
essentially the same way. None of spectral data for these
compounds was identical to the data reported for natural
cladocorans, and so consequently, structural revision of
cladocorans A and B was considered necessary. The
actual structures for cladocorans A and B may be
concluded to be 5 and 6, respectively, on the basis of the
spectral data of natural cladocorans A and B, synthesized
3, 18-epi-3, 4, and 18-epi-4. The synthesis of 5 and 6 was
subsequently carried out.
Compounds 5 and 6 were synthesized from lactone
16,11b the intermediate synthesized by the authors for
dysidiolide (Scheme 3). Stereoselective hydrogenation of
olefin in lactone 16 was done in the presence of PtO2 and
acetic acid at medium pressure of H2 (4.4 atm) to afford
cis-decalin 17 as the sole product. The relative configu-
ration of C-12 in 17 was determined from its NOESY
correlations between the methylene proton at C-6 and
methine proton at C-12 and between the methine proton
at C-12 and the methyl proton at C-24. Lactone 17 was
treated with N-phenylthiosuccinimide, Bu3P, and pyri-
[R]26 ) -30.0 (c 0.20, CHCl3), and 18-epi-5, [R]26
)
D
D
-34.5 (c 0.29, CHCl3). Photochemical oxidation22 of 22a
and 22b afforded compounds 6, [R]26 ) -63.8 (c 0.26,
D
CHCl3), and 18-epi-6, [R]24 ) -22.4 (c 0.25, CHCl3).
D
Spectral data and signs of optical rotation of 5 and 6 were
identical to those of reported natural cladocoran A,
[R]20 ) -25.8 (c 0.4, CHCl3) and cladocoran B, [R]20
)
D
D
-59.9 (c 0.6, CHCl3), respectively.
From the present results, the structures of cladocorans
A and B are clearly indicated to be those presented as 5
and 6, respectively, and cladocoran B is thus clearly
shown to be an olefinic regioisomer of dysidiolide and
cladocoran A as its acetate.
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and
Technology of J apan.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and product characterizations of all new compound
synthesized. Copies of 1H and 13C NMR spectra for compounds
3, 18-epi-3, 4, 18-epi-4, 5, 18-epi-5, 6, 18-epi-6, 8-14, 15a ,b,
17-21, and 22a ,b. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) Cram, D. J .; Sahyum, M. R. V.; Knox, G. R. J . Am. Chem. Soc.
1962, 84, 1734-1735.
(22) Kernan, M. R.; Faulkner, D. J . J . Org. Chem. 1988, 53, 2773-
2776.
J O020743Y
J . Org. Chem, Vol. 68, No. 9, 2003 3479