Contribution to the total synthesis of caribenolide I

Article abstract of DOI:10.1016/j.tetlet.2006.06.060

Stereoselective synthesis of C₁₃-C₂₉ fragment of caribenolide I, a potent antitumour macrolide isolated from a marine dinoflagellate Amphidinium sp. is described. The key step relies on a highly diastereoselective C-glycosylation, us

Full text of DOI:10.1016/j.tetlet.2006.06.060

Tetrahedron Letters 47 (2006) 5905–5908
Contribution to the total synthesis of caribenolide I
Gael Jalce, Xavier Franck,*,ꢀ Blandine Seon-Meniel,
¨
*
`
Reynald Hocquemiller and Bruno Figadere
Laboratoire de Pharmacognosie associe´ au CNRS (BioCIS), Faculte´ de Pharmacie, Universite´ Paris-Sud,
ˆ
rue Jean-Baptiste Cle´ment, 92296 Chatenay Malabry, France
Received 5 May 2006; revised 7 June 2006; accepted 9 June 2006
Available online 30 June 2006
Abstract—Stereoselective synthesis of C13–C29 fragment of caribenolide I, a potent antitumour macrolide isolated from a marine
dinoflagellate Amphidinium sp. is described. The key step relies on a highly diastereoselective C-glycosylation, using a bulky chiral
oxazolidin-2-thione, to control the absolute configuration of C21. The C24 and C25 stereogenic centres were controlled by the enan-
tioselective vinylogous Mukayiama aldol reaction, whereas C14 and C16 stereogenic centres were built from a chiral bis-epoxide.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Caribenolide I1 is a 26-membered macrolactone belong-
ing to the Amphidinolides family,2 a new class of marine
natural products isolated from marine dinoflagellates,
Amphidinium sp., that are symbiotic of Okinawan mar-
ine flatworm Amphiscolops sp. and possessing potent
cytotoxic property against a number of tumour cells.
Caribenolide I exhibits an impressive in vitro cytotoxi-
city against human colon tumour cells of wild type as well
as against those that have acquired a multi-drug resis-
tance phenotype (IC50 = 1.6 nM, against HCT116/WT
or HCT116/VM46). In addition, caribenolide I displays
an important in vivo activity against P388 tumour
grafted mice (T/C = 150% at a dose of 0.03 mg/kg). In
continuation of our efforts to contribute to the struc-
tural elucidation of caribenolide I, along with the desire
to possess a large quantity of this extremely cytotoxic
marine natural product, we embarked on the total
synthesis of caribenolide I.3,4 Thus we report therein
our results concerning the synthesis of the enantio-pure
C13–C29 skeleton of caribenolide I.
Our retrosynthetic strategy, described in Scheme 1,
shows that caribenolide I could be obtained by a conver-
gent approach and by a coupling reaction of C13–C29
and C1–C12 fragments. In this work we describe our
efforts towards the enantioselective preparation of one
diastereomer of the C13–C29 fragment of caribenolide
I, with a good control of the absolute configurations
HO
24
HO
25
29
HO
15
19
21 O
16
O
O
PO
24
O
24
25
25
29
29
O
O
15
19
1
11
21 O
21 O
HO
14
OP
OP
OH
6
OH
1
2
O
7
O
16
O
caribenolide I
L-arabitol
24
+
25
29
O
15
21 O
O
O
14
TMSO
OP
OP
O
3
4
Scheme 1.
*
Corresponding authors. E-mail: bruno.figadere@cep.u-psud.fr
ꢀ Present address: UMR-CNRS 6014, IRCOF/LHO, Rue Tesniere, 76131 Mont Saint Aignan Cedex, France.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.060

5906
G. Jalce et al. / Tetrahedron Letters 47 (2006) 5905–5908
of six stereogenic centres (C14, C16, C19, C21, C24 and
C25), among the 13 ones of caribenolide I, as shown in
Scheme 1, with methods that could provide either enan-
tiomer, for later comparisons with the natural product.
propargyl chain and this was tentatively performed by
addition at À20 ꢁC in CH2Cl2 of propargyl Grignard
reagent (prepared in diethyl ether) to acetate 7 derived
from lactone 5. Unfortunately, the desired product
was obtained in the presence of the allenic derivatives
and as cis/trans mixtures.10
The key reactions of this strategy rely on the use of a
vinylogous Mukayiama aldol reaction5 to control the
relative and absolute configurations of C24 and C25.
Then, the highly diastereoselective C-glycosylation with
a chiral oxazolidin-2-thione6 allows the control of the
configuration of C21. The two C14 and C16 stereogenic
centres are brought by the chiral and known bis-epox-
ide,7 while C19 is introduced by reduction of the corre-
sponding carbonyl derivative.
We thus decided to use the chiral titanium enolate of
the N-acetyl(R)-5,5-diphenyl-4-benzyloxazolidin-2-thione
(prepared from 1 equiv of iPr2NEt and 1 equiv of TiCl4
at À40 ꢁC in CH2Cl2) which reacted with acetate 7 to
afford the coupled product 8 as a single trans isomer
(as shown by NOE NMR studies).6 DIBAL treatment
of the crude adduct, followed by purification by flash
chromatography led to the pure trans aldehyde 9 in
75% yield and to the chiral (R)-oxazolidin-2-thione in
92% isolated yield. The Corey–Fuchs–MacKelvie reac-
tion11 gave, from 9, the expected alkyne 2 in two steps
and in 70% overall yield (Scheme 3), through the 1,1-
dibromovinyl derivative intermediate.
The key lactone fragment 5 could be prepared through
two different approaches: (i) vinylogous Mukayiama
aldol reaction of trimethylsilyloxyfuran (TMSOF)5 with
pentanal affords the desired threo-butenolide in 54%
and 96% ee, followed by quantitative hydrogenation;
(ii) L-glutamic acid route through the 3 steps—nitrous
deamination–acylation–diastereoselective
reduction
The required bis-epoxide was prepared from L-arabitol,
as reported,7 through slightly modified procedures
(Scheme 4). Indeed, L-arabitol was treated with ethyl
orthoacetate in dichloromethane in the presence of
PPTS, to give bicyclic orthoester 10 that was directly
treated with acetyl bromide in dichloromethane to
afford dibromo-diacetate 11. The latter, under potas-
sium carbonate treatment in methanol, gave rise to the
desired bis-epoxide 12 in 50% overall yield for the last
3 steps. Compound 12 was then protected as a benzyl
ether (NaH, BnBr, DMF) in a moderate 50% yield.
Recovery of the starting material and protection allow
us to obtain the desired benzyl ether 3 in a final 75%
yield. Then, the coupling reaction between alkyne 2
and protected bis-epoxide 3 was performed by nBuLi
metallation, followed by BF3ÆOEt2 catalyzed opening
of the epoxide.12 Under these reaction conditions, the
expected mono-coupled product 13 was obtained in
(Scheme 2).8 Then the free hydroxyl of the lactone 5
was protected as a tert-butyldimethylsilyl ether under
usual reaction conditions (TBDMSCl, DMAP, imid-
azole, DMF).9 The next step required to introduce a
Reference 5 :
1) Ti(OiPr)4, (
Et2O, -20 ºC
R
)-Binol,
O
S
S
+
2) H2, Pd/C
O
O
TMSO
OH
O
54%, >96% e.e.
TMSOF
5
L-Selectride
Reference 8 :
S
50%, 98% d.e.,
98% e.e.
2 steps
L-glutamique
O
O
O
6
Scheme 2.
1) TBDMSCl, imid., DMF
2) DIBAL, toluene, -78 ºC
3) Et3N, AcCl
O
O
O
AcO
OH
O
OTBS
Ph
5
7
MgBr
Bn
Ph
CH2Cl2, BF3.OEt2, -20 ºC
, TiCl4, iPr2NEt,
CH2Cl2, -40 ºC
O
N
O
S
OTBS
56%, 65/35(trans/cis) + allenic products
Ph
Bn
Ph
O
N
DIBAL, -78˚C
O
O
O
S
O
TBSO
OTBS
75%, 100:0 (trans/cis)
9
8
1) PPh3, CBr4
2) nBuLi
O
OTBS
70%, 100:0 (trans/cis)
2
Scheme 3.

G. Jalce et al. / Tetrahedron Letters 47 (2006) 5905–5908
5907
OEt
O
numbering), that will be oxidized to the carbonyl deriv-
ative later on.
OH OH
OAc OAc
OEt
CH3C(OEt)3
AcBr, CH2Cl2
O
O
O
PPTS, CH2Cl2
OH OH OH
L-arabitol
Br OH Br
Then, we were pleased to observe that the homo-pro-
pargylalkyne can be converted regioselectively into the
corresponding c-hydroxy ketone by palladium catalysis
(PdCl2(CH3CN)2, 5 mol %) in a 9/1 dichloromethane/
water mixture at room temperature and in a high yield
(Scheme 5).14 Regioselective hydration of the triple
bond at C19 may be rationalized by invoking a pal-
lado-dihydrofuran intermediate. Protection of the free
hydroxyl of the c-hydroxy ketone as a tri-ethylsilyl ether
was then performed under usual reaction conditions
(TESCl, DMAP, imidazole),15 to give ketone 1416 in
88% yield for the last two steps. Ketone 14 was then re-
duced into the corresponding alcohol; when L-Selectride
was used as reducing reagent, a 60:40 mixture of 15 and
16 diastereomers was obtained in 57% overall yield,
whereas with NaBH4, a 1:1 mixture of 15 and 16 was ob-
tained in 73% yield. Both C19 diastereomers (caribeno-
lide numbering) were easily separated by flash
chromatography, and absolute configurations at C19
are being determined through the NMR studies of the
corresponding Mosher’s esters.17
OH
10
11
O
O
O
O
NaH, BnBr
K2CO3, MeOH
50%, 3 steps
OH
12
OBn
3
, nBuLi
O
HO 16
18
OTBS
2
19
O
15
O
with BF3.OEt2 : < 15%
OTBS
OBn
13
with BF3.THF : 70%
Scheme 4.
trace amount. Several small-scale trials were performed
without much improvement for the chemical yield. We
thus decided to work on a larger scale and to use
BF3ÆTHF as Lewis acid, which has been reported for
improving the yield of such a reaction.13 Indeed, under
these reaction conditions the expected coupled product
13 was now obtained in a satisfying 70% yield. It is
worth noting that the mono-coupled product is obtained
as a 60:40 diastereomeric mixture due to the new stereo-
genic centre bearing the OBn group (C15, caribenolide
Both compounds 15 and 16 were then protected as para-
nitrobenzoate (para-nitrobenzoyl chloride, Et3N) in
good yields, and then hydrogenation (H2, Pd/C, tolu-
ene) removed the benzyl group and reduced the nitro
1) 5% PdCl2(CH3CN)2,
OTES
HO
18
9:1 CH2Cl2/H2O, rt
BnO
19
O
O
19
2) TESCl, imid.
CH2Cl2
O
O
OTBS
OBn
O
OTBS
13
14
88% (2 steps)
NaBH4
73%
OTES
OTES
HO
BnO
BnO
O
+
O
19
19
O
O
HO
OTBS
OTBS
16
15
1) pNO2PhCOCl, Et3N, 83%
2) H2,Pd/C, toluene, 75%
OTES
HO
O
O
O
O
OTBS
17
NH2
Scheme 5.
1) SO3, pyridine
OTES
OTES
HO
2) K2CO3, MeOH,
then H3O+
O
O
O
O
O
O
OTBS
OTBS
OTBS
OH
17
NH2
1
O
TESO
HO
O
O
O
Scheme 6.

5908
G. Jalce et al. / Tetrahedron Letters 47 (2006) 5905–5908
`
5. (a) Szlosek, M.; Figadere, B. Angew. Chem., Int. Ed. 2000,
function into the amino group, affording the free alcohol
17 in 75% yield (only product obtained from 15 is shown
in Scheme 5). Oxidation of the secondary alcohol of 17
to the carbonyl derivative and removal of the para-
aminobenzoate group will give the d-hydroxy ketone 1
which under acidic conditions should be in equilibrium
with the thermodynamic tetrahydropyran cyclized prod-
uct (Scheme 6). These transformations are now under
study in our laboratories.
39, 1799; Angew. Chem. 2000, 112, 1869; (b) Szlosek, M.;
`
´
Franck, X.; Figadere, B.; Cave, A. J. Org. Chem. 1998, 63,
5169; (c) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi,
G. Synlett 1999, 1333.
6. Jalce, G.; Seck, M.; Franck, X.; Hocquemiller, R.;
`
Figadere, B. J. Org. Chem. 2004, 69, 3240.
7. Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.;
Uehling, D. E.; Schreiber, S. L. J. Am. Chem. Soc. 1990,
112, 5583.
`
´
8. Figadere, B.; Harmange, J.-C.; Laurens, A.; Cave, A.
Tetrahedron Lett. 1991, 32, 7539.
In conclusion, we have prepared enantioselectively the
C13–C29 skeleton of caribenolide I with an excellent con-
trol of the absolute configurations of the stereogenic
centres in 15 steps. The strategy used therein will allow
us to prepare several diastereomers of the target mole-
cule by varying the reaction conditions, chiral catalysts
and starting material, for further comparisons with the
natural product. The connection with the C1–C12 frag-
ment4 is now under study in our laboratories.
9. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
94, 6190.
`
10. Franck, X.; Hocquemiller, R.; Figadere, B. J. Chem. Soc.,
Chem. Commun. 2002, 160.
11. (a) Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem.
Soc. 1962, 84, 1745; (b) Corey, E. J.; Fuchs, P. L.
Tetrahedron Lett. 1972, 13, 3769.
12. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
13. Evans, A. B.; Knight, D. W. Tetrahedron Lett. 2001, 42,
6947.
14. For a related case, see: Arcadi, A.; Cacchi, S.; Marinelli,
F. Tetrahedron 1993, 49, 4955.
15. Oppolzer, W.; Snowden, R. L.; Simmons, D. P. Helv.
Chim. Acta 1981, 64, 2002.
Acknowledgements
´
We wish to thank the Departement de la Guadeloupe
16. Spectroscopic data of ketone 14: 1H NMR (400 MHz,
CDCl3) d ppm: 0.04 (s, 6H); 0.58 (m, 6H); 0.88 (br s, 12H);
0.93 (t, 9H, J = 8.0 Hz); 1.20–1.49 (m, 8H); 1.62–2.20 (m,
6H); 2.30–2.54 (m, 3H); 2.58 (dd, 0.4 · 1H, J = 2.7,
4.7 Hz); 2.64–2.73 (m, 1H); 2.76 (m, 1H); 2.82 (t,
0.4 · 1H, J = 4.5 Hz); 2.84 (dd, 0.6 · 1H, J = 2.6,
5.5 Hz); 2.91 (t, 0.4 · 1H, J = 6.1 Hz); 3.10 (m,
0.4 · 1H); 3.18 (q, 0.6 · 1H, J = 3.1 Hz); 3.42 (t,
0.6 · 1H, J = 3.6 Hz); 3.54 (m, 0.6 · 1H); 3.58 (m,
0.4 · 1H) 3.81 (m, 1H); 3.89 (m, 1H); 4.19 (m, 0.4 · 1H);
4.26 (m, 0.6 · 1H); 4.49 (dd, 0.6 · 1H, J = 1.34, 12.0 Hz);
4.59 (d, 0.4 · 1H, J = 11.8 Hz); 4.66 (d, 0.6 · 1H,
J = 12.0 Hz); 4.83 (d, 0.4 · 1H, J = 11.8 Hz); 7.32 (m,
5H). 13C NMR (75 MHz, CDCl3) d ppm: À4.7; À4.2; 4.9;
5.0; 6.9; 14.0; 18.2; 22.8; 26.0; 26.3; 27.3; 27.5; 27.8; 29.7;
32.4; 38.4; 39.7; 43.9; 44.7; 48.7; 48.8; 51.0; 53.1; 72.1; 73.1;
74.9; 75.1; 78.2; 81.5; 82.8; 127.5; 127.6; 127.8; 128.0;
128.2, 138.3; 138.4 ; 208.7; 208.8. ESI–MS m/z: 671
(M+Na+, 100). IR (CHCl3) cmÀ1: 2955; 2925; 2875; 2855;
1715; 1460; 1415; 1360; 1250; 1090; 1005; 940; 835; 775;
735.
for a fellowship to G.J. and J. C. Jullian for his help
in the NMR experiments.
References and notes
1. Bauer, I.; Maranda, L.; Young, K. A.; Shimizu, Y.;
Fairchild, C.; Cornell, L.; MacBeth, J.; Huang, S. J. Org.
Chem. 1995, 60, 1084.
2. (a) Kobayashi, J.; Ishibashi, M.; Nakamura, H.; Ohizumi,
Y.; Yamasu, T.; Sasaki, T.; Hirata, Y. Tetrahedron Lett.
1986, 27, 5755; (b) Norcross, R. D.; Paterson, I. Chem.
Rev. 1995, 95, 2041; (c) Bauer, I.; Maranda, L.; Shimizu,
Y.; Peterson, R. W.; Cornell, L.; Steiner, J. R.; Clardy, J.
J. Am. Chem. Soc. 1994, 116, 2657; (d) Ishibashi, M.;
Ohizumi, Y.; Hamashima, M.; Nakamura, H.; Hirata, Y.;
Sasaki, T.; Kobayashi, J. J. Chem. Soc., Chem. Commun.
1987, 1127; (e) Kobayashi, J.; Ishibashi, M.; Nakamura,
H.; Ohizumi, Y.; Yamasu, T.; Hirata, Y.; Sasaki, T.; Ohta,
T.; Nozoe, S. J. Nat. Prod. 1989, 52, 1036; For an
overview of synthetic efforts, see: (f) A¨ıssa, C.; Riveiros,
17. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1968, 90,
3732; (b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc.
1973, 95, 512; (c) Dale, J. A.; Dull, D. L.; Mosher, H. S.
J. Org. Chem. 1969, 34, 2543; (d) Sullivan, G. R.; Dale, J.
A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1973, 38,
2143; (e) Tan, R. X.; Jensen, P. R.; Williams, P. G.;
Fenical, W. J. Nat. Prod. 2004, 67, 1374; (f) Seco, J. M.;
Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17.
R.; Ragot, J.; Furstner, A. J. Am. Chem. Soc. 2003, 125,
¨
15512.
3. Seck, M.; Seon-Meniel, B.; Jullian, J.-C.; Franck, X.;
`
Hocquemiller, R.; Figadere, B. Lett. Org. Chem. 2006, 3,
390.
4. Seck, M.; Franck, X.; Seon-Meniel, B.; Hocquemiller, R.;
`
Figadere, B. Tetrahedron Lett. 2006, 47, 4175.