Synthesis and structure determination of iso-cladospolide B

Article abstract of DOI:10.1016/S0040-4039(01)00323-9

iso-Cladospolide B 1 was previously characterized from the fungal isolate I96S215 obtained from a marine sponge collected in Indonesia. However, neither the relative nor the absolute configurations were reported. We describe in this letter a synthetic pathway which allowed us to prepare 1 and attribute the absolute configurations of the three stereogenic centers.

Full text of DOI:10.1016/S0040-4039(01)00323-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2801–2803
Synthesis and structure determination of iso-cladospolide B†
Xavier Franck, Maria E. Vaz Araujo, Jean-Christophe Jullian, Reynald Hocquemiller and
Bruno Figade`re*
Laboratoire de Pharmacognosie, associe´ au CNRS (BIOCIS), Universite´ Paris-Sud, Faculte´ de Pharmacie,
rue Jean-Baptiste Cle´ment, 92296 Chaˆtenay-Malabry, France
Received 9 February 2001; revised 12 February 2001; accepted 22 February 2001
Abstract—iso-Cladospolide B 1 was previously characterized from the fungal isolate I96S215 obtained from a marine sponge
collected in Indonesia. However, neither the relative nor the absolute configurations were reported. We describe in this letter a
synthetic pathway which allowed us to prepare 1 and attribute the absolute configurations of the three stereogenic centers. © 2001
Elsevier Science Ltd. All rights reserved.
Terrestrial, as well as marine fungi, are an extremely
rich source of pharmaceutically interesting compounds
of various structures. Recently from a sponge collected
in Indonesia, Ireland obtained, from the fermentation
of the fungal isolate I96S215, several hexaketides.1
Among those new compounds, iso-cladospolide B 1
showed a butenolide moiety substituted at the g posi-
tion by an aliphatic chain bearing two hydroxyl groups.
Although neither the relative nor the absolute configur-
ations of the three stereogenic centers of 1 was known,
its close relationship with the fully characterized natural
product cladospolide B 22 prompted us to synthesize 1
(Fig. 1).
4-yn-1-ol 6 (Fig. 2). Both enantiomers of propylene
oxide 5 are available, but the R isomer was used in
order to prepare the 11-R isomers of 1 (the use of the S
isomer would give rise to the complementary stereoiso-
mers of 1).
11R
O
O
OH
OH
11
OH
O
O
4
5S
5
1
4S
2
3
OH
iso-cladospolide B 1
cladospolide B 2
The retrosynthetic scheme shows that the key step relies
on the use of the asymmetric vinyloguous Mukaiyama
Figure 1.
aldol reaction3 between 2-trimethylsilyloxyfuran
3
(TMSOF) and the desired aldehyde 4. The latter could
be obtained in a few steps from the commercially
available starting materials propylene oxide 5 and pent-
Pent-4-yn-1-ol 6 was protected as a benzyl ether4 by
treatment with sodium hydride and benzyl bromide in
THF in the presence of 0.1 equiv of Bu4NBr to afford
O
OTBS
O
OH
OH
11
TMSO
+
O
O
4
5
1
4
TMSOF 3
2
3
iso-cladospolide B 1
O
+
HO
6
5
Figure 2.
Keywords: polyketides; marine fungi; asymmetric aldol reaction; structure determination.
* Corresponding author. Fax: (33) 1 46 83 53 99; e-mail: bruno.figadere@cep.u-psud.fr
†
Dedicated to Professor W. H. Okamura on the occasion of his 60th birthday.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00323-9

2802
X. Franck et al. / Tetrahedron Letters 42 (2001) 2801–2803
BuLi, -78 ˚C, 1 h
NaH, BnBr, Bu4NBr, THF
then (R)- 5 (1.2 equiv),
BF3.OEt2 (1.1 equiv),
-78 ˚C, 3 h
BnO
HO
71 %
6
9
7
56%
BnO
BnO
TBDMSCl, imidazole, DMAP
DMF, R.T., 3h
8
97%
OH
OTBS
H2, Pd/C, toluene
82%
(COCl)2, DMSO,
Et3N, CH2Cl2,
OTBS
O
OTBS
- 60 ˚C
HO
81%
10
4
Figure 3.
in 1 (lCH-3 7.63, lCH-4 5.07 and lCH-5 3.77 ppm) are in
good agreement with the chemical shifts of CH-3, CH-4
and CH-5 in 12b/13b (lCH-3 7.63, lCH-4 5.07 and lCH-5
3.78 ppm), and related compounds.10 Furthermore
comparison of the coupling constants for the CH-4
signals (td, J=4.9 and 1.7 Hz for erythro and quin.
J=1.8 Hz for threo compounds) confirms the threo
relative configuration for the natural product 1.
7 in 71% yield. Then metallation of the latter with
n-butyllithium at −78°C in THF5 followed by additions
of (R)-propylene oxide 5 and BF3·OEt2, led to the
homopropargyl alcohol 8 in 56% yield. We then
decided to protect the secondary hydroxyl group of 8 as
a hindered silyl ether by usual treatment6 (TBDMSCl
and imidazole in the presence of a catalytic amount of
DMAP in DMF, to afford 9 in 97% yield), to avoid
competitive interactions of this hydroxyl with the cata-
lyst during the aldolization step. Then, treatment of 9
in toluene under a hydrogen, atmosphere in the pres-
ence of palladium on charcoal7 (Fig. 3), allowed us to
simultaneously reduce the triple bond and deprotect the
benzyl ether to give the desired saturated and depro-
tected primary alcohol 10 in 82% yield. It is noteworthy
that the silyl ether remained unchanged during the
hydrogenation step.8 Finally, Swern oxidation9 of 10
led to the desired aldehyde 4 in 81% yield.
1H NMR analysis in CDCl3 of this mixture in the
presence of Eu(hfc)3 showed that, not surprisingly, each
diastereomer was in fact a 1:1 mixture of two pseudo-
enantiomers 12a/13a and 12b/13b, the remote stereo-
genic center of
4
at C-11 (iso-cladospolide
B
numbering) being too far away from the reactive site to
induce some selectivity in the aldolization reaction. The
aldol reaction was thus performed under asymmetric
catalysis through a stepwise addition:3,10 the chiral cata-
lyst was first prepared in Et2O at room temperature by
mixing Ti(OiPr)4 (20 mol%) and either (S)- or (R)-
Binol (40 mol%) for 1 h (method B or C, respectively),
then the temperature was brought to −20°C and
TMSOF 3 with aldehyde 4 added in four portions over
a 6 h period of time. Mixtures of compounds were thus
obtained in both cases which after deprotection (HF, in
THF at rt for 12 h) afforded the products 12a,b and
Aldehyde 4 was then treated at −78°C in CH2Cl2 by
TMSOF 3 in the presence of BF3·OEt2 to afford a
mixture of erythro 12a,13a/threo 12b,13b compounds
(erythro/threo ratio=15:85) in 60% yield (Fig. 4). The
relative stereochemistry at C-4 and C-5 can be deduced
1
from the H and 13C NMR data (see Table 1). For
1
instance, H chemical shifts of CH-3, CH-4 and CH-5
O
OTBS
4
Method A , B or C
OH
OH
OH
OH
O
O
O
4S
4R
O
O
O
5R
11R
5R
11R
erythro12a
erythro 13a
threo 12b
threo 13b
OH
OH
OH
OH
4R
4S
O
O
5S
5S
11R
11R
Figure 4. Method A: (1) TMSOF 3, CH2Cl2, −78°C, BF3·OEt2; (2) HF, THF; 60%. Method B: (1) TMSOF 3, Et2O, −20°C,
Ti(OiPr)4 (20%), (S)-Binol (40%); (2) HF, THF; 50%. Method C: (1) TMSOF 3, Et2O, −20°C, Ti(OiPr)4 (20%), (R)-Binol (40%);
(2) HF, THF; 50%.

X. Franck et al. / Tetrahedron Letters 42 (2001) 2801–2803
Table 1. CD3OD H and 13C NMR dataa of 1 (500 MHz),1 and synthetic 12a/13a and 12b/13b (400 MHz)
2803
1
Atom
1
12a/13a (erythro)
12b/13b (threo)
1
− (175.75)
− (175.58)
− (175.78)
2
3
4
5
6
7
8
9
6.16 [dd, 5.8, 2.0] (122.71)
7.63 [dd, 5.8, 1.4] (157.13)
5.07 [quint., 1.8] (88.22)
3.77 (71.65)
6.18 [dd, 7.0, 2.0] (122.95)
7.72 [dd, 5.8, 1.5] (156.56)
5.01 [td, 4.9, 1.7] (88.37)
3.70 (72.28)
6.16 [dd, 5.8, 2.0] (122.69)
7.63 [dd, 5.8, 1.5] (157.11)
5.07 [quint., 1.8] (88.19)
3.78 (71.73)
1.56b (34.22)
1.56b (34.19)
1.56b (34.19)
1.36b (30.61b)
1.37b (30.59b)
1.36b (30.59b)
1.35b (26.78b)
1.37b (26.75b)
1.36b (26.75b)
1.56b (26.78b)
1.56b (26.75b)
1.56b (26.75b)
10
11
12
1.42 (40.12)
3.70 (68.54)
1.13 [d, 6.2] (23.50)
1.42 (40.09)
3.70 (68.51)
1.13 [d, 6.2] (23.50)
1.42 (40.09)
3.70 (68.51)
1.13 [d, 6.2] (23.50)
a l ppm [mult., J (Hz)] (13C NMR).
b Assignments may be interchanged.
13a,b in around 50% combined yield which were ana-
lyzed by 1H NMR in CDCl3 in the presence of
Eu(hfc)3. It is noteworthy that the pseudo-enantiomers
12a and 13a or 12b and 13b were not separable by usual
chromatography.
Acknowledgements
We thank Professor C. M. Ireland for copies of NMR
data of iso-cladospolide and cladospolide B.
B
M.E.V.A. thanks the University of Vigo for
SOCRATES fellowship.
a
The diastereomeric ratio in experiment B was in favor
of the threo isomers (d.r.=65:35) which showed fur-
thermore a 12b/13b ratio of 85:15, whereas erythro
1
isomers showed a 12a/13a ratio of 75:25 (by H NMR
analysis in CDCl3 in the presence of Eu(hfc)3). How-
ever, in experiment C the threo and erythro isomers
were obtained in a 50:50 ratio. In that case, the threo
isomers showed a 12b/13b ratio of 20:80, whereas ery-
thro isomers showed a 12a/13a ratio of 30:70.
References
1. Cameron, J. S.; Abbanat, D.; Bernan, V. S.; Maiese, W.
M.; Greenstein, M.; Jompa, J.; Tahir, A.; Ireland, C. M.
J. Nat. Prod. 2000, 63, 142–145.
2. (a) Hirota, A.; Sakai, H.; Isogai, A. Agric. Biol. Chem.
1985, 49, 731–735; (b) Fuji, Y.; Fukuda, A.; Hamasaki,
T.; Ichimoto, I.; Nakajima, H. Phytochemistry 1995, 40,
1443–1446.
3. Szlosek, M.; Franck, X.; Figade`re, B.; Cave´, A. J. Org.
Chem. 1998, 63, 5169–5172.
Absolute configurations of the products drawn on Fig.
4, were deduced from comparison of the H chemical
1
shifts in the presence of Eu(hfc)3 with those of related
compounds.10 Then specific rotations were measured in
methanol after isolation by flash chromatographies of
four erythro and threo enriched mixtures: 12amaj, [h]D=
−32 (c 0.66); 13amaj, [h]D=+15 (c 0.55); 12bmaj, [h]D=
+54 (c 0.45); 13bmaj, [h]D=−47 (c 0.75). After calcula-
tions,11 comparison of the specific rotations with those
of natural products (1, [h]D=−90;1 2, [h]D=+452b) did
not unfortunately allow us to determine unambigously
all absolute configurations of stereogenic centers of 1.
However, due to the strong influence of the butenolide
moiety on the specific rotation, we can assume that 1
has the 4S,5S configuration, identical to cladospolide
B 2.
4. Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetra-
hedron Lett. 1976, 3535.
5. Yamagushi, M.; Hirao, I. Tetrahedron Lett. 1983, 24,
391–394.
6. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
94, 6190.
7. Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971,
93, 1746.
8. Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron Lett.
2000, 41, 5711–5714.
9. Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
10. Szlosek, M.; Figade`re, B. Angew. Chem., Int. Ed. 2000,
39, 1799–1801.
11. After calculations: 12a, [h]D=−152; 13a, [h]D=+157; 12b,
[h]D=+99; 13b, [h]D=−105.
12. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1968,
90, 3732–3738; (b) Trost, B. M.; Belletire, J. L.; Godleski,
S.; McDougal, M. C.; Balkovec, J. M. J. Org. Chem.
1986, 51, 2370–2374; (c) Duret, P.; Waechter, A. I.;
Figade`re, B.; Hocquemiller, R.; Cave´, A. J. Org. Chem.
1998, 63, 4717–4720.
In conclusion, the synthesis of iso-cladospolide B 1 was
performed in seven steps and 13% overall yield. The
NMR data of the synthetic compounds, as well as the
comparison of the specific rotations allow us to propose
the absolute configuration of 1 as follows: 4S,5S and
1
11R, for close analogy with cladospolide B 2. H NMR
analysis of the Mosher esters12 of natural 1 would allow
one to conclude without ambiguity on the absolute
configuration at C-11.