Synthesis of the C1-C13 fragment of (+)-callipeltoside A

Article abstract of DOI:10.1055/s-2007-980367

The synthesis of the C1-C13 fragment of (+)-callipeltoside A has been achieved in 12 steps with an overall yield of 11%. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-980367

LETTER
1461
Synthesis of the C1–C13 Fragment of (+)-Callipeltoside A
S
ynthesis of the
u
C
1–C13
F
ra
c
gment of (+
i
)-Calli
e
peltoside
A
Boulard,a Samir BouzBouz,*a,1 Jean Marc Paris,b Janine Cossy*a
a
Laboratoire de Chimie Organique, ESPCI, CNRS, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(0)140794660; E-mail: janine.cossy@espci.fr
b
Laboratoire de Chimie Organique de Synthèse, ENSCP, CNRS, 11 Rue Pierre et Marie Curie, 75230 Paris Cedex 05, France
Received 5 March 2007
figurations of the stereogenic centers has been established
by total synthesis. Up to now, four total syntheses4 of the
aglycon part of callipeltoside A have been published and
synthetic efforts towards the aglycon part of callipeltoside
A5 have also been reported.
Abstract: The synthesis of the C1–C13 fragment of (+)-callipelto-
side A has been achieved in 12 steps with an overall yield of 11%.
Key words: callipeltoside, crotyltitanation, vinyllithium
When this work was started, only the synthesis of the
aglycone of callipeltoside A had been published and later
on, it was revealed to be the aglycone of (+)-callipeltoside
A.4a Here, we would like to report the synthesis of the C1–
C13 fragment of (+)-callipeltoside A based on the addi-
tion of the vinyllithium reagent C to aldehyde B, which
possesses 4 of the 9 stereogenic centers present in the
macrolactone of (+)-callipeltoside A. The control of the
stereogenic center at C5 was envisaged by addition of the
vinyl silylenol ether D to an aldehyde of type E according
to Felkin–Anh control. This latter aldehyde of type E
would be issued from an enantioselective crotyltitanation6
applied to an aldehyde of type F, which would in turn be
synthesized from the Roche ester (Scheme 1).
Callipeltoside A (Figure 1) is a polyketide isolated from
the shallow water sponge Callipelta sp. collected off the
east coast of New Caledonia.2,3 This marine natural prod-
uct was found to inhibit the proliferation of NSCLC-N6
(15.26 mg·mL–1) and P388 (11.26 mg·mL–1) cell lines in
vitro. This compound consists of a 14-membered
macrolide, containing a six-membered hemiacetal ring
and a unique deoxyamino sugar, callipeltose, which is
attached glycosidically at C5. Furthermore, a pendant
dienyne side chain terminated by a trans-chlorocyclopro-
pane ring is present at C13. The relative stereochemical
relationship between the sugar moiety and the macro-
lactone has been proposed on the basis of 2D-NMR stud-
ies. However, due to the small amount of callipeltoside A,
isolated from the natural source (3.5 mg from 2.5 kg of
freeze-dried sponge, 1.4 × 10–4% yield), its full structural
determination and biological evaluation were limited.
Thus, the synthesis of callipeltoside A was imperative to
establish the absolute configuration of all the stereogenic
centers and to further examine its anticancer properties.
O
O
OR OR OMe
1
9
13
MeO
OR
A
(fragment C1–C13)
O
O
O
OR OR
O
O
8
Li
9
1
5
NH
13
OR
O
MeO
10
C
B
O
O
5
O
OR OR
O
O
O
OH
O
8 H
OH
8
8
5
1
R3SiO
O
O
MeO
E
D
F
13
Scheme 1 Retrosynthetic analysis of the C1–C13 fragment of
(+)-callipeltoside A
Cl
(+)-callipeltoside A
Figure 1 Structure of (+)-callipeltoside A
The synthesis (Scheme 2) began with the preparation of
aldehyde 1 from the Roche ester in three steps. After pro-
tection of the primary hydroxy group using chloro-tert-
butyldiphenylsilane (TBDPSCl, imidazole, CH2Cl2, r.t.,
95%), DIBAL-H reduction of the ester (DIBAL-H,
CH2Cl2, –78 °C, 99%) and a Swern oxidation, aldehyde 1
was isolated in 94%, the stereogenic center of which
corresponds to the C8 stereogenic center present in
The relative stereochemistry of the chlorocyclopropyl
side chain to the rest of the molecule and the absolute con-
SYNLETT 2007, No. 9, pp 1461–1463
0
1.
0
6.
2
0
0
7
Advanced online publication: 23.05.2007
DOI: 10.1055/s-2007-980367; Art ID: G04907ST
© Georg Thieme Verlag Stuttgart · New York

1462
L. Boulard et al.
LETTER
1. TBSPDCl , imidazole
CH2Cl2, r.t., 95%
O
O
OH
(R,R)-I
8
8
6
8
5
OR
7
OR
MeO
H
OH
2. DIBAL-H, –78 °C
CH2Cl2, 99%
3. Swern, quant.
Et2O, –78 °C
77%
2
Roche ester
1
dr > 95:5
R = TBPDS
R = TBPDS
1. TBSOTf, 2,6-lutidine
CH2Cl2, –78 °C, 76%
2. OsO4, NMO
H2O–acetone (1:3.5)
then NaIO4, quant.
O
O
D
O
OTBS
O
O
OH OTBS
OSiMe3
BF3·Et2O
8
9
5
1
H
OR
O
OR
CH2Cl2, –78 °C
95%
4
3
R = TBPDS
R = TBPDS
dr > 95:5
1. TBSOTf, 2,6-lutidine
CH2Cl2, –78 °C, 61%
2. NH4F, MeOH, 65 °C, 69%
3. Swern, quant.
OR
O
O
O
OR
OH
Li
8
9
O
O
OR
OR
OTBS
O
O
OR OR
O
C
6'
+
9
Et2O, –105 °C
then –78 °C
1
O
H
O
OR RO OH
5
8
9
75%
R = TBS
6/6' 1:1
6
R = TBS
Ph
*
MeOTf
Cp
Ti
O
Ph
O
O
2,6-tBu-pyridine
CH2Cl2, r.t.
67%
*
O
Ph
Ph
O
O
OR OR OMe
(R,R)-I
13
9
1
OR
MeO
7
R = TBS
Scheme 2 Synthesis of the C1–C13 fragment
callipeltoside A. In order to control the C6 and C7 stereo- between aldehyde 5 with vinyllithium C was investigated.
genic centers, aldehyde 1 was treated with the highly face- An ethereal solution of vinyllithium was added to a solu-
selective crotyltitanium complex (R,R)-I6 (Et2O, –78 °C) tion of aldehyde 5 (1 equiv) in Et2O at –78 °C which pro-
to produce the anti/syn-triad 2 in 77% yield and with a vided the coupling products 6 and 6¢ in an equimolar ratio
diastereomeric ratio superior to 95:5. The latter product with a global yield of 75%. These two compounds were
was then protected with TBSOTf (2,6-lutidine, CH2Cl2, separated by flash chromatography on silica gel and the
–78 °C, 76%) and an oxidative cleavage of the terminal syn,anti,syn,anti-stereopentad 6 was isolated. We have to
double bond using OsO4, NMO [H2O–acetone (1:3.5)] point out that vinyllithium C was prepared from the cor-
followed by the addition of NaIO4, led to aldehyde 3 in responding vinyliodide 10 by an iodide–metal exchange
quantitative yield. The addition of the vinyl silylenol ether (n-BuLi, Et2O, –78 °C), and the vinyliodide was obtained
D on the previously prepared aldehyde 3, in the presence in two steps from but-3-ynol 8 (Scheme 3). Compound 6
of BF3·OEt2 (3 equiv, CH2Cl2, –78 °C), resulted in the ex- was then converted into 77 in 67% yield in a one-pot pro-
clusive formation of the aldol condensation product 4 in tection–deprotection reaction using four equivalents of
95% yield and with an excellent Felkin–Anh control (dr > MeOTf [2,6-tert-butylpyridine (6 equiv), CH2Cl2, r.t.].
95:5). Protection of the hydroxy group of 4 (TBSOTf, 2,6-
lutidine, CH2Cl2, –78 °C, 61%) followed by the deprotec-
The C1–C13 fragment of (+)-callipeltoside A was synthe-
sized in 12 steps with an overall yield of 11% (Scheme 2).
tion of the primary hydroxy group using NH4F (MeOH,
Due to the versatility of the reactions used, the total
65 °C, 69% yield) and a Swern oxidation (quantitative
synthesis of (+)- as well as (–)-callipeltoside A will be
yield) afforded aldehyde 5. In order to synthesize the C1–
reported in due course.
C13 fragment of callipeltoside A, the coupling reaction
Synlett 2007, No. 9, 1461–1463 © Thieme Stuttgart · New York

LETTER
Synthesis of the C1–C13 Fragment of (+)-Callipeltoside A
1463
Cp2ZrCl2, AlMe3
H2O, I2
TBSOTf
2,6-lutidine
I
I
13
13
13
OH
OH
OTBS
CH2Cl2, –78 °C
~quant.
CH2Cl2, –23 °C
43%
10
9
8
E > 98%
Scheme 3 Synthesis of the C10–C13 fragment
(5) (a) Hoye, T.; Zao, H. Org. Lett. 1999, 1, 169.
Acknowledgment
(b) Velazquez, F.; Olivo, H. F. Org. Lett. 2000, 2, 1931.
(c) Olivo, H. F.; Velazquez, F.; Trevisan, H. C. Org. Lett.
2000, 2, 4055. (d) Olivo, H. F.; Romero-Ortega, M.; Colby,
D. A. Tetrahedron Lett. 2002, 43, 6439.
One of us (L.B.) thanks Rhodia and the CNRS for a grant and we
also thank Rhodia for financial support.
(6) Hafner, A.; Duthaler, R.; Marti, R.; Rihs, G.; Streit, P. R.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
(7) Compound 7: Rf = 0.75 (eluent: hexane–EtOAc, 80:20);
[a]D20 –3.5 (c 1.0, CHCl3). IR: 2940, 1750, 1720, 1630,
1470, 1460, 1250, 1090 cm–1. 1H NMR: d = 4.82 (d, J = 9.9
Hz, 1 H), 4.21 (d, J = 5.5 Hz, 1 H), 3.99 (m, 1 H), 3.70–3.52
(m, 6 H), 3.50 (s, 2 H), 3.11 (s, 3 H), 2.80 (dd, J = 15.8, 5.1
Hz, 1 H), 2.72 (dd, J = 15.8, 4.8 Hz, 1 H), 2.22 (t, J = 7.0 Hz,
2 H), 1.69 (m, 1 H), 1.62 (s, 3 H), 1.42 (m, 1 H), 0.87 (d,
J = 7.0 Hz, 3 H), 0.86–0.79 (3 s, 27 H), 0.68 (d, J = 6.6 Hz,
3 H), 0.08–0.02 (6 s, 18 H) ppm. 13C NMR: d = 201.2 (s),
167.4 (s), 137.6 (s), 126.5 (d), 78.5 (d), 70.4 (d), 70.1 (d),
62.0 (t), 55.1 (q), 52.0 (q), 50.4 (t), 48.7 (t), 45.2 (d), 43.0 (t),
39.6 (d), 25.9 (3 q), 25.8 (3 q), 25.6 (3 q), 18.2 (s), 18.1 (s),
18.0 (s), 17.1 (q), 11.3 (q), 10.5 (q), –4.0 (q), –4.3 (q), –4.5
(q), –4.6 (q), –4.8 (q), –5.5 (q) ppm.
References and Notes
(1) Current address: Laboratoire de Chimie Pharmaceutique,
UFR Médecine et Pharmacie, CNRS, 22 Bd Gambetta,
76183 Rouen, France
(2) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.;
Roussakis, C. J. Am. Chem. Soc. 1996, 118, 11085.
(3) Zampella, A.; D’Auria, M. V.; Minale, L. Tetrahedron 1997,
53, 3243.
(4) (a) Paterson, I.; Davies, R. D.; Marquez, R. Angew. Chem.
Int. Ed. 2001, 40, 603. (b) Trost, B. M.; Gunzner, J. L. J.
Am. Chem. Soc. 2001, 123, 9449. (c) Evans, D. A.; Burch, J.
Org. Lett. 2001, 3, 503. (d) Evans, D. A.; Hu, E.; Burch, J.;
Jaeschke, G. J. Am. Chem. Soc. 2002, 124, 5654. (e) Trost,
B. M.; Dirat, O.; Gunzner, J. L. Angew. Chem. Int. Ed. 2002,
41, 841. (f) Trost, B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y.
H. J. Am. Chem. Soc. 2002, 124, 10396. (g) Paterson, I.;
Davies, R. D. M.; Heimann, A. C.; Marquez, R.; Meyer, A.
Org. Lett. 2003, 5, 4477. (h) Huang, H.; Panek, J. S. Org.
Lett. 2004, 6, 4383.
Synlett 2007, No. 9, 1461–1463 © Thieme Stuttgart · New York