Stereocontrolled total synthesis of (+)-leucascandrolide A

Article abstract of DOI:10.1002/anie.200390112

Apparently no longer available from its natural source is the potent cytotoxic and antifungal agent leucascandrolide A (1), which was initially isolated from a New Caledonian calcareous sponge. A highly stereocontrolled total synthesis of this structurally unique macrolide commences with a Jacobsen asymmetric hetero Diels-Alder reaction to configure the tetrahydropyran ring. An efficient endgame relies on two Mitsunobu reactions, the first to generate the 18-membered macrolactone and the second to attach the oxazole-bearing side chain.

Full text of DOI:10.1002/anie.200390112

Angewandte
Chemie
[10] Abbreviations: H2tmp: meso-tetrakis(2,4,6-trimethylphenyl)-
porphyrin, H2(3,4,5-MeO-tpp): meso-tetrakis(3,4,5-trimethoxy-
phenyl)porphyrin, m-CPBA: m-chloroperoxybenzoic acid,
H2tpp: meso-tetraphenylporphyrin, H2ttp: meso-tetrakis(p-tol-
yl)porphyrin, H2tpfpp: meso-tetrakis(pentafluorophenyl)por-
phyrin, NBS: N-bromosuccinimide, Ts ¼ p-toluenesulfonyl.
[11] a) J. T. Groves, R. Quinn, J. Am. Chem. Soc. 1985, 107, 5790;
b) C. Ho, W.-H. Leung, C.-M. Che, J. Chem. Soc. Dalton Trans.
1991, 2933.
Synthesis of a marine macrolide
Stereocontrolled Total Synthesis of (þ)-
Leucascandrolide A**
Ian Paterson* and Matthew Tudge
[12] As tmp is a sterically encumbered porphyrin, whereas 3,4,5-
MeO-tpp is basically a sterically unencumbered porphyrin
ligand (the latter can not prevent formation of dinuclear m-oxo
ruthenium porphyrins), yet both of them gave nitrido ruthenium
porphyrin 1 in similar yields, the steric properties of porphyrin
Leucascandrolide A (1, Scheme 1) was isolated in 1996 from
the calcareous sponge Leucascandra caveolata, collected off
the east coast of New Caledonia, by Pietra and co-workers.[1]
This polyoxygenated 18-membered macrolide features two
trisubstituted tetrahydropyran rings, one of which has an
unusual oxazole-bearing unsaturated side chain. To date, the
true biosynthetic origin of this unique polyketide is uncer-
tain.[2] Subsequent reisolation attempts proved unsuccessful
which indicates that leucasandrolide A may be produced by
opportunistic microbial colonization of the sponge.[2] Prelimi-
nary biological studies revealed potent cytotoxic activity
ꢀ
ligands should have a minor effect on the Ru N formation from
reaction (2).
ꢀ
[13] The frequency of this new band is comparable to the Ru N
stretching frequency of 1023 cmÀ1 reported for the non-porphyr-
in nitrido ruthenium(vi) complex [RuVI(N)Cl3(AsPPh3)2] (a
neutral, six-coordinate nitrido ruthenium(vi) species, like 1a
and 2). See: D. Pawson, W. P. Griffith, Inorg. Nucl. Chem. Lett.
1974, 10, 253.
against
a
range of cancer cell lines (IC50 ¼ 0.05and
[14] CCDC-193042 (1b) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: (þ 44)1223-336-033; or deposit
@ccdc.cam.ac.uk).
0.25 mgmLÀ1 against KB oral epidermoid carcinoma and
P388 leukemia cell lines, respectively), as well as pronounced
antifungal activity. Since the natural supply of leucascandro-
lide A is unreliable, an efficient synthesis is paramount to
enable further biological studies and, furthermore, to provide
access to analogues. Consequently, leucascandrolide A has
[15] P. M. Chan, W.-Y. Yu, C.-M. Che, K.-K. Cheung, J. Chem. Soc.
Dalton Trans. 1998, 3183.
attracted considerable synthetic attention,[3 with the first
5]
[16] We treated [NnBu4][RuVI(N)Cl4] (prepared as described in W. P.
Griffith, D. Pawson, J. Chem. Soc. Dalton Trans. 1973, 1315) and
total synthesis reported by Leighton and co-workers.[3] Here-
in, we report an expedient total synthesis of (þ)-leucascan-
drolide A in which essentially complete control over all of the
stereochemistry is achieved.
[RuVI(N)(L)Cl]
(H2L ¼ 2,6-bis(2-hydroxy-2,2-diphenylethyl)-
pyridine, prepared as described in ref. [15]) with TFAA and
the silyl enol ethers shown in Table 1 under the conditions
similar to those for 1a/1b but obtained no amination products
from the reaction mixtures.
As outlined in Scheme 1, our approach relies on two
Mitsunobu reactions–the first is employed to cyclize the
seco-acid 2 and the second to append the heterocyclic side
chain 3 at C5. A double Lindlar hydrogenation should then
install the two Z-configured alkenes to provide leucascan-
drolide A directly. By exploiting the high degree of 1,3-
dioxygenation embodied within the seco-acid 2, we planned to
introduce all the oxygenated stereocenters from tetrahydro-
pyran 4 by using only substrate control. In light of the anti
configurational relationship between C7 and C11, seco-acid 2
should be accessible from the b-oxygenated ketone 4 and
aldehyde 5 by using our 1,5-anti aldol methodology.[5b,6,7]
Furthermore, the resulting C11 stereocenter could then serve,
in turn, to direct an alkylation with silyl enol ether 6 to install
the full C15side chain.
[17] Selected examples: a) R. Breslow, S. H. Gellman, J. Chem. Soc.
Chem. Commun. 1982, 1400; b) J. P. Mahy, G. Bedi, P. Battioni,
D. Mansuy, Tetrahedron Lett. 1988, 29, 1927; c) I. N‰geli, C.
Baud, G. Bernardinelli, Y. Jacquier, M. Moran, P. M¸ller, Helv.
Chim. Acta 1997, 80, 1087; d) S.-M. Au, J.-S. Huang, C.-M. Che,
W.-Y. Yu, J. Org. Chem. 2000, 65, 7858, and references therein;
e) Y. Kohmura, T. Katsuki, Tetrahedron Lett. 2001, 42, 3339.
As shown in Scheme 2, the synthesis of the trisubstituted
tetrahydropyran 4 began with a Jacobsen asymmetric hetero
[*] Prof. I. Paterson, M. Tudge
University Chemical Laboratory
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax: (þ44)1223-336-362
E-mail: ip100@cus.cam.ac.uk
[**] We thank the EPSRC (studentship to M.T. and GR/N08520), the EU
(Network HPRN-CT-2000-00018), and Merck, Pfizer, and Novartis
for support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
Mitsunobu
esterification
Me
7
O
O
O
5
O
9
O
N
H
12
Cr
Cl
TBSO
double Lindlar
hydrogenation
O
O
O
O
N
1
O
7
O
O
9
17
TBSO
+
a)
Mitsunobu
macrolactonisation
O
OTES
N
OMe
O
(80%)
H
> 20:1 d.r.,
> 98% ee
1: leucascandrolide A
OPMB
10
OPMB
(99%)
8
b)
1,5-anti
aldol
(13:1 d.r.)
reaction
Me
1'
OR1
CO2H
OTIPS
O
11
O
OTIPS
R2O
e), f)
(84%)
R
5
O
O
1
O
+
15
O
OPMB
OPMB
OH OH
N
enol silane
alkylation
11 R1 = H, R2 =TBS
12 R1 = TIPS, R2 = H
13 R = C≡CH
4 R = COMe
g)
(86%)
O
c), d)
(82%)
3
2
11'
NHCO2Me
(99%)
(17:1 d.r.)
h)
CHO
OTBS
5
O
OTIPS
5
1,5-anti
11
O
H
O
OTIPS
OTIPS
10
i)
(99%)
+
OH
OH
OH
O
O
O
1
15
OTBS
OPMB
OTBS
OR
(> 49:1 d.r.)
5 C11 – C15 subunit
4 C1 – C10 subunit
14
15 R = TBS
16 R = H
OPMB
OPMB
16
j)
OTMS
23
(79%, 2 steps) k)
6 C16 – C23 subunit
Scheme 1. Retrosynthesis of leucascandrolide A (1) leading to key
building blocks 2 6. TIPS¼triisopropylsilyl; TBS¼tert-butyldimethylsil-
yl; TMS¼trimethylsilyl; PMB¼p-methoxybenzyl.
OTIPS
17 R = H
l)
(84%)
O
OR
O
18 R = Me
O
OPMB
Diels Alder reaction of aldehyde 7 and readily available 2-
siloxydiene 8,[8] promoted by the chromium tridentate catalyst
9.[9a] This generated the corresponding [4þ2] cycloadduct,[9b]
which, upon workup with mild acid, led to isolation of 2,6-cis-
pyranone 10 in 80% yield with > 20:1 d.r. and > 98% ee.
Installation of the equatorial C5hydroxy group was achieved
by treatment with NaBH4 in MeOH to give secondary alcohol
11 in 99% yield and 13:1 d.r. Following TIPS ether formation,
selective acidic removal of the TBS group gave primary
alcohol 12 (82%). Homologation[10] to the methyl ketone 4
involved activation of alcohol 12 as its triflate derivative,
displacement with lithium trimethylsilyl acetylide and basic
methanolysis to give alkyne 13 (84%). Subsequent HgII-
mediated hydration gave the methyl ketone 4 cleanly (86%).
This efficient reaction sequence was performed to produce
multigram quantities of enantiopure 4.
Scheme 2. Preparation of advanced intermediate 18. a) 9 (10 mol%),
4 ä molecular sieves, 208C, 20 h; acidified CHCl3, 208C, 4 h;
b) NaBH4, MeOH, 208C, 2 h; c) TIPSOTf, lut, CH2Cl2, À788C, 2 h;
d) CSA, 2:1 MeOH/CH2Cl2, 208C, 1 h; e) Tf2O, pyr, CH2Cl2, À108C,
ꢀ
1 h; f) LDA, TMSC CH, HMPA, À78!208C, 1 h; K2CO3, MeOH,
208C, 12 h; g) cat. Hg(OAc)2, PPTS, wet THF, 408C, 1 h; h) cHex2BCl,
NEt3, Et2O, 08C, 30 min; 5, À788C, 2 h; À78!À308C, 24 h; i) Me4NB-
H(OAc)3, 3:1 MeCN/AcOH, À40!À208C, 24 h; j) CSA, 2:1 MeOH/
CH2Cl2, 258C, 1 h; k) TEMPO, PhI(OAc)2, CH2Cl2, 208C, 12 h;
l) Me3OBF4, proton sponge, CH2Cl2, 0!208C, 1 h. OTf¼trifluorome-
luoromethane sulfonate; lut¼2,6-lutidine; Tf2O¼trifluoromethane sul-
fonic anhydride; pyr¼pyridine; LDA¼lithium diisopropylamide;
HMPA¼hexamethyl phosphoramide; PPTS¼pyridinium p-tolunesulfo-
nate; CSA¼10-camphorsulfonic acid; TEMPO¼2,2,6,6-tetramethyl-1-
piperidinyloxyl.
The key 1,5-anti aldol coupling reaction of b-alkoxy
ketone 4 with aldehyde 5[11] proceeded smoothly under our
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Chemie
Br
18
OTMS
Me
O
a)
OTIPS
Me
O
NNMe2
O
PMBO 26
OTIPS
6
O
a), b)
O
(65%)
b)
OTBS
HO
O
27
OPMB
O
25
(81%, 2 steps)
( 50:1 d.r.)
O
OPMB
c), d)
(49%)
OAc
OPMB
20
19
OTf
O
e)
O
(76%)
(32:1 d.r.)
N
O
NH
c)
Me
O
Me
O
28
29
OR
OTIPS
O
h)
O
OPMB
OPMB
(65%)
CO2Me
O
O
O
R2
HN
f) – h)
OR1
17(S)
O
1,3-syn
17(R)
(36%, 5 steps)
30
O
HO
21 R1 = H, R2 = CH2OPMB
22 R1 = Ac, R2 = CH2OH
O
N
23 R = TIPS
24 R = H
d), e)
(99%)
f), g)
i)
(95%)
3
(71%)
2 R1 = H, R2 = CO2H
NHCO2Me
Scheme 3. Elaboration to the macrocyclic core 24. a) DIBAL, CH2Cl2,
then Ac2O, pyr, DMAP, À78!À208C, 15 h; b) ZnBr2, CH2Cl2, 208C,
4 h; c) LiAlH(OtBu)3, CH2Cl2, À78!À108C, 1.5 h; d) Ac2O, pyr,
DMAP, CH2Cl2, 0!208C, 15 h; e) DDQ, 10:1 CH2Cl2/pH 7 buffer,
208C, 1 h; f) TEMPO, PhI(OAc)2, CH2Cl2, 208C, 1 h; NaClO2, NaHPO4,
methyl-2-butene, aq. tBuOH, 0!208C, 1 h; g) K2CO3, MeOH, 208C,
18 h; h) DEAD, PPh3, PhH, 208C, 5 min; i) HF¥pyr, THF, 0!208C, 5 h.
DIBAL¼ diisobutylaluminum hydride; DMAP¼4-(dimethylamino)pyri-
dine; DDQ¼2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DEAD¼die-
diethylazodicarboxylate.
Scheme 4. Preparation of the oxazole-bearing side chain 3. a) LDA,
HMPA, THF, À78!208C, 2 h; b) TBAF, THF, 208C, 1 h;
c) Cl3CC(O)NCO, CH2Cl2, 208C, 1 h; K2CO3, MeOH, 208C, 1 h; d) 4 ä
molecular sieves, PhMe, 908C, 2 h; e) Tf2O, lut, CH2Cl2, À78!À108C,
1 h; f) [Pd(PPh3)4], 30, lut, 1,4-dioxan, 208C, 6 h; g) DDQ, 10:1
CH2Cl2/pH 7 buffer, 208C, 1 h; h) TEMPO, PhI(OAc)2, CH2Cl2, 208C,
1 h; then NaClO2, NaHPO4, methyl-2-butene, aq. tBuOH, 0!208C,
1 h. TBAF¼tetrabutylammonium fluoride.
standard conditions.[5b,6] Thus, treatment of 4 with cHex2BCl
and Et3N in Et2O generated the corresponding less substi-
tuted enolate, which on addition of aldehyde 5 provided, after
oxidative workup, aldol adduct 14 in 99% yield and 17:1
d.r.[12] With the required 11R configuration installed, efforts
were now focused towards constructing the second tetrahy-
dropyran ring and installing the C9 stereocenter. To this end,
1,3-anti reduction of b-hydroxy ketone 14 with Me4NB-
Leighton et al.[3] and Rychnovsky et al.[4] In both these cases,
however, following ozonolysis of the terminal alkene, the
addition of either an alkenyl[3] or an alkynyl[4] organozinc to
the derived aldehyde resulted in modest control over the C17
hydroxy stereocenter, that is, typically 3 3.5:1 in favor of the
1,3-anti stereochemistry (followed by a Yamaguchi macro-
lactonization). In contrast, we set about installing the full
C16 C23 side chain with concomitant generation of the C15
stereocenter. As shown in Scheme 3, suitable activation of the
anomeric position was achieved by treating d-lactone 18 with
DIBAL followed by in situ acetylation[15] to afford acetate 19.
Treatment of 19 with an excess of silyl enol ether 6[16] in the
[13]
H(OAc)3 provided diol 15 in 99% yield and ꢁ 50:1 d.r.
Next, acidic removal of the TBS group gave triol 16, which
was oxidized selectively at the primary hydroxy group by
using catalytic TEMPO and iodobenzene diacetate[14] to give
d-lactone 17 (79%); by this procedure, the 1,5,7-triol was
discriminated and the second pyran ring closed in a highly
effective manner. This constitutes one of the first examples of
a TEMPO-mediated procedure for achieving chemoselective
lactone formation from open-chain polyols. Methylation of
the isolated C9 hydroxy group with Me3OBF4 and proton
sponge gave advanced intermediate 18 (84%).
[17]
presence of catalytic ZnBr2 afforded ketone 20 cleanly in
81% yield and ꢁ 50:1 d.r. Next, a 1,3-syn reduction directed
by the C15pyran oxygen atom was envisioned to configure
the C17 stereocenter ready for the planned Mitsunobu
macrolactonization. Several reducing agents were screened
in the presence of ZnBr2 to induce metal chelation, but only
LiAlH(OtBu)3 provided a satisfactory selectivity (5:1 d.r.) in
favor of the syn isomer. However, use of LiAlH(OtBu)3 alone
gave allylic alcohol 21 with much improved syn diastereose-
Effective anomeric allylation procedures for the stepwise
installation of the C15side chain have been reported by both
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Communications
group. As detailed in Scheme 5, reaction of acid 3 and
macrocycle 24 in the presence of DEAD and PPh3 in 1.5:1
PhMe/THF resulted in the smooth formation of the axial ester
31 in 81% yield. Finally, Lindlar hydrogenation of the triple
bonds enabled the stereospecific introduction of the two Z-
alkenes to provide a 92% yield of (þ)-leucascandrolide A (1).
This had spectroscopic data[23] in full accord with those
reported by Leighton[3] and Pietra.[1]
24
+
3
a)
O
(81%)
Me
O
5
N
O
O
O
O
O
In summary, we have completed a highly stereocontrolled
synthesis of the potent cytotoxic macrolide leucascandroli-
de A, proceeding in 23 steps from 8 (longest linear sequence)
and 5.3% overall yield. Key features include a Jacobsen
asymmetric hetero Diels-Alder reaction to configure the
right-hand tetrahydropyran ring, a 1,5-anti aldol coupling,
control over the C17 hydroxy center, and two sequential
Mitsunobu reactions, to close the 18-membered macrolactone
and append the oxazole-bearing side chain, respectively.
O
O
N
H
OMe
31
(92%) b)
Me
O
O
O
5
O
Received: September 12, 2002 [Z50143]
O
O
N
O
N
O
17
[1] M. D©Ambrosio, A. Guerriero, C. Debitus, F. Pietra, Helv. Chim.
Acta 1996, 79, 5 1.
[2] M. D©Ambrosio, M. Tato, G. Pocsfalvi, C. Debitus, F. Pietra,
Helv. Chim. Acta 1999, 82, 347.
[3] K. R. Hornberger, C. L. Hamblett, J. L. Leighton, J. Am. Chem.
Soc. 2000, 122, 12894.
OMe
H
O
1: (+)-leucascandrolide A
Scheme 5. Completion of the total synthesis of leucascandrolide A.
a) DEAD, PPh3, 1.5:1 THF/PhMe, 0!208C, 18 h; b) H2, 5% Pd/CaCO3
poisoned with lead (Lindlar catalyst), quinoline, EtOAc, 208C, 2 h.
[4] For formal syntheses based on the endgame of Leighton, see:
a) D. J. Kopecky, S. D. Rychnovsky, J. Am. Chem. Soc. 2001, 123,
8420; b) P. Wipf, J. T. Reeves, Chem. Commun. 2002, 2066.
c) After submission of this manuscript, we were informed by
Professor Carreira of his completed synthesis of leucascandro-
lide A, see: A. Fettes, E. M. Carreira, Angew. Chem. 2002, 114,
4272; Angew. Chem. Int. Ed. 2002, 41, 4098.
[5] For the synthesis of fragments of leucascandrolide, see: a) M. T.
Crimmins, C. A. Carroll, B. W. King, Org. Lett. 2000, 2, 597;
b) S. A. Kozmin, Org. Lett. 2001, 3, 75 5 ; c) P. Wipf, T. H.
Graham, J. Org. Chem. 2001, 66, 3242.
[6] I. Paterson, K. R. Gibson, R. M. Oballa, Tetrahedron Lett. 1996,
37, 8585.
[7] D. A. Evans, P. J. Coleman, B. Cotÿ, J. Org. Chem. 1997, 62, 788.
[8] Diene 8 was prepared from 3-buten-1-ol [Eq. (1); DBU ¼ 1,8-
diazabicyclo[5.4.0]undec-7-ene, TES ¼ triethylsilyl].
lectivity (76%, > 32:1 d.r.) which indicates the operation of a
nonchelation pathway possibly following the Evans polar
model.[18] Acetylation of the resultant (17S)-hydroxy group
followed by oxidative removal of the PMB group gave alcohol
22 in 99% yield. Oxidation to the corresponding acid and
saponification afforded seco-acid 2 (71%) which set the stage
for the Mitsunobu macrolactonization.[19] Pleasingly, treat-
ment of 2 with DEAD and Ph3P in degassed benzene for
5min proceeded to give the desired macrocycle 23 in 65%
yield with clean inversion of configuration. Cleavage of the
equatorial C5TIPS ether was achieved by HF¥pyr in THF to
furnish macrocycle 24 in 95% yield in readiness for the
introduction of the axially oriented side chain at C5.
a) NaH, PMBCl, TBAI, THF
b) OsO4, NMO, aq. Me2CO
OTES
c) NaIO4, aq. Me2CO
As shown in Scheme 4, preparation of the bis-alkyne side
chain 3 relied on a Sonogashira coupling, in which the
required oxazolyl triflate 29 was derived from alcohol 27, the
a-alkylation product of hydrazone 25[20] and bromide 26.[21]
Treatment of 27 with trichloroacetyl isocyanate, followed by
basic hydrolysis and heating the resulting intractable mixture
to 908C, in the presence of 4 ä molecular sieves, produced the
required oxazolone 28 (49%). Reaction with triflic anhydride
provided oxazolyl triflate 29 which was treated with alkyne
30[3] under Sonogashira coupling conditions, as developed by
Panek and co-workers,[22] to provide the side-chain precursor.
Removal of the PMB group, followed by oxidation of the
resulting alcohol to the carboxylic acid, then gave the
required oxazole-bearing side chain 3.
d)
O
O
P
(1)
OH
OMe
OPMB
MeO
DBU, LiCl, MeCN
8
e) TESOTf, NEt3, Et2O
(68%)
[9] a) A. G. Dossetter, T. F. Jamison, E. N. Jacobsen, Angew. Chem.
1999, 111, 2549; Angew. Chem. Int. Ed. 1999, 38, 2398. b) This
reaction is believed to proceed through a highly ordered [4þ2]
cycloaddition in contrast to a Mukaiyama aldol/hetero-Michael
pathway. For a review, see: K. A. Jorgensen, Angew. Chem. 2000,
112, 3702; Angew. Chem. Int. Ed. 2000, 39, 3559.
[10] This homologation sequence was adapted from Evans and co-
workers: D. A. Evans, D. M. Fitch, T. E. Smith, V. J. Cee, J. Am.
Chem. Soc. 2000, 122, 10033.
With the two key fragments in hand, we were now poised
to test the Mitsunobu coupling on the equatorial C5hydroxy
346
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Angewandte
Chemie
[11] Aldehyde 5 was prepared by diastereoselective alkylation of the
Myers chiral amide I with iodide II [Eq. (2)]. A. G. Myers, L.
McKinstry, J. Org. Chem. 1996, 61, 2428.
Yttria-Zirconia Thin Films
Controlled Formation of Highly Ordered Cubic
and Hexagonal Mesoporous Nanocrystalline
Yttria Zirconia and Ceria Zirconia Thin Films
Exhibiting High Thermal Stability**
a) LDA, LiCl, THF
O
TBSO
I
Ph
H
N
II
(2)
OH Me
O
Eduardo L. Crepaldi, Galo J. de A. A. Soler-Illia,
Anne Bouchara, David Grosso,
Dominique Durand, and Clÿment Sanchez*
b) LDA, BH3·NH3, THF
c) Dess–Martin periodinane, CH2Cl2
(73%)
OTBS
I
5
Zirconia-based mixed oxides are current targets of intensive
research as a result of their applications in strategic tech-
nologies, such as yttria-stabilized zirconia (YSZ) in solid-
oxide fuel cells (SOFCs),[1] and ceria zirconia in the latest
generation of automotive exhaust three-way catalysts,[2,3] the
latter having the potential to be applied in the next generation
of compact SOFCs.[3] In view of these applications, controlling
the porosity of these systems is highly desirable. The
™supramolecular template approach∫ offers precise control
of the material porosity on the mesoscale (20 200 ä).[4] Ozin
and co-workers[5] were the first to extend this method to the
synthesis of YSZ by using cetyltrimethylammonium bromide
(CTAB) templated glycolate-modified inorganic precursors.
Gedanken and co-workers[6] reported the synthesis of meso-
porous YSZ using metallic salts or oxides as inorganic sources
and anionic surfactants as templates. All of these precipita-
tion methods yield disordered wormlike mesoporous pow-
ders. However, to the best of our knowledge, periodically
organized mesoporous ceria zirconia and even yttria zirco-
nia materials are yet to be reported.
[12] The corresponding aldol addition with achiral aldehydes led to
comparably high levels of 1,5-anti stereoinduction which in-
dicates that chiral aldehyde 5 contributed only negligibly to 1,2-
induction.
[13] D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. Soc.
1988, 110, 3560.
[14] A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancatelli,
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[15] V. H. Dahanukar, S. D. Rychnovsky, J. Org. Chem. 1996, 61,
8317.
[16] Enol silane 6 was prepared from isovaleraldehyde [Eq. (3)].
O
O
P
a)
OTMS
OMe
MeO
O
DBU, LiCl, MeCN
b) LDA, TMSCl, NEt3,
THF
(3)
H
(79%)
6
[17] I. Paterson, Tetrahedron Lett. 1979, 1519.
The present work reports the first examples of periodi-
cally organized mesoporous yttria zirconia (YZ) and ceria
zirconia (CZ) (R ¼ M/(M þ Z) ¼ 0.05 0.30, where Z is the
amount of Zr and M is the amount of Y or Ce present in the
material). Moreover, these materials are processed as thin
films. The procedure is simple and reproducibly gives highly
ordered mesoporous nonsilicate mixed oxides, which retain
their structure (order and porosity) after crystallization of the
inorganic walls and subsequent thermal treatment to temper-
atures as high as 7008C. This advantageous one-step method
can replace the usual precipitation of particles/deposition/
[18] D. A. Evans, M. J. Dart, J. L. Duffy, M. G. Yang, J. Am. Chem.
Soc. 1996, 118, 4322.
[19] O. Mitsunobu, Synthesis 1981, 1. A Mitsunobu macrolactoniza-
tion strategy was independently reported by Wipf et al.[4b] while
this manuscript was in preparation.
[20] C. W. Jefford, J.-C. Rossier, J. Boukouvalas, P. Huang, Helv.
Chim. Acta 1994, 77, 661.
[21] L. Banfi, G. Guanti, A. Basso, Eur. J. Org. Chem. 2000, 939.
[22] N. F. Langille, L. A. Dakin, J. S. Panek, Org. Lett. 2002, 4, 2485.
[23] [a]2D0 ¼ þ 40.0 (c ¼ 0.29, EtOH) [ref. [1], [a]2D0 ¼ þ 41.0 (c ¼ 0.29,
EtOH)]. For copies of 1H and 13C NMR spectra, see the
Supporting Information.
[*] Dr. C. Sanchez, Dr. E. L. Crepaldi, Dr. G. J. de A. A. Soler-Illia,
A. Bouchara, Dr. D. Grosso
Laboratoire de Chimie de la Matiõre Condensÿe
UMR7574, Universitÿ Pierre et Marie Curie (Paris VI)
4 place Jussieu, 75252 Paris CEDEX 05 (France)
Fax: (þ33)1-4427-4769
E-mail: clems@ccr.jussieu.fr
Dr. D. Durand
LURE B‚t 209D, Centre Universitaire
B.P. 34, 91898 Orsay Cedex (France)
[**] This work was financially supported by the French Ministry of
Research, CNRS, CNPq (Brazil, grant no. 200636/00-0), CONICET,
and FundaciÛn Antorchas (Argentina). Rhodia is greatly acknowl-
edged for financial support of A.B.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, No. 3
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1433-7851/03/4203-0347 $ 20.00+.50/0
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