A convergent hetero-diels-alder strategy for asymmetric access to a lactone containing two lipidic chains

Article abstract of DOI:10.1002/ejoc.201200513

Eu(fod)₃-catalyzed heterocycloaddition of chiral β-alkyl-N-vinyl-1,3-oxazolidin-2-ones with a heterodiene bearing a lipidic chain led to heterocycloadducts in high yield with excellent endo and facial selectivities. An original lipidic lactone, a potent precursor of a ceramide analog, was obtained in seven steps from the adduct in a convergent manner after appropriate functionalization. Eu(fod)₃-catalyzed heterocycloaddition of chiral β-alkyl-N-vinyl-1,3-oxazolidin-2-ones with a heterodiene bearing a lipidic chain led to heterocycloadducts in high yield with excellent endo and facial selectivities. An original lipidic lactone, a potent precursor of a ceramide analog, was obtained in seven steps from the adduct in a convergent manner after appropriate functionalization. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Full text of DOI:10.1002/ejoc.201200513

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200513
A Convergent Hetero-Diels–Alder Strategy for Asymmetric Access to a
Lactone Containing Two Lipidic Chains
Cong S. Vu,[a] Nicolas Guisot,[a] Stéphane Guillarme,*[a] Arnaud Martel,[a]
Gilles Dujardin,[a] Muriel Pipelier,[b] Didier Dubreuil,[b] and Christine Saluzzo*[a]
Keywords: Lactones / Asymmetric synthesis / Chiral auxiliaries / Cycloaddition / Diastereoselectivity
Eu(fod)3-catalyzed heterocycloaddition of chiral β-alkyl-N-
vinyl-1,3-oxazolidin-2-ones with a heterodiene bearing a li-
pidic chain led to heterocycloadducts in high yield with ex-
cellent endo and facial selectivities. An original lipidic lact-
one, a potent precursor of a ceramide analog, was obtained
in seven steps from the adduct in a convergent manner after
appropriate functionalization.
program devoted to the synthesis of galactosylceramide an-
alogs,[6] we focused our attention on conformationally rigid
galactosylceramide (Figure 2). Some constrained ceramide
analogs such as 3 and 4 have already been described and
have shown potent biological activities.[2] During the time
of this study, Vasella et al. reported an efficient synthesis
of constrained ceramide analogs 5 (Figure 1) that showed
biological activities as inhibitors of sphingosine kinase or
as iNKT cells ligands.[7] Compound 5a (R = H) inhibited
SPHK1 with an IC50 of 9.8 μm. Interestingly, only com-
pounds 5 containing the two alkyl chains (R and RЈ) in a
trans relationship proved to activate iNKT cells (Figure 1).
We describe herein the synthesis of lactone 7, which is a
potential precursor to access ceramide analogs 6, and the
corresponding constrained galactosylceramide (Figure 2).[8]
Introduction
Sphingolipids are important membrane constituents of
eukaryotic cells that are involved in biological processes
such as cell proliferation, differentiation, adhesion, and sig-
nal transduction.[1] The study of sphingolipid metabolism
and function is an important field of biochemistry. Many
research groups have focused their interest on ceramides
due to their important role in sphingolipid metabolism.[2]
Ceramides are potent lipid mediators of many cellular
functions including proliferation, differentiation, and
apoptosis.[3] For example, induction of apoptotic cell death
has been observed with two aromatic ceramide analogs,
MAPP (1)[4] and B13 (2, Figure 1).[5] As part of an ongoing
Figure 1. Structures of some ceramide analogs.
[a] IMMM: Institut des Molécules et Matériaux du Mans-UMR
CNRS 6283, Université du Maine, Faculté des Sciences et
Techniques,
Figure 2. General strategy to access targeted constrained ceramides
and their corresponding constrained galactosylceramides.
Avenue Olivier Messiaen 72085 Le Mans, France
Fax: +33-2-43833902
E-mail: stephane.guillarme@univ-lemans.fr
christine.saluzzo@univ-lemans.fr
[b] CEISAM-UMR CNRS 6230, Université de Nantes,
2 rue de la Houssinière BP 92208, 44322 Nantes, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200513.
Results and Discussion
The key step of our synthetic strategy involved an asym-
metric inverse-electron-demand (IED) heterocycloaddition
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S. Guillarme, C. Saluzzo et al.
SHORT COMMUNICATION
between heterodiene 10 and dienophile 11 (Scheme 1). Con-
trary to the normal-electron-demand [4+2] pathway, the
IED [4+2] one displays optimal convergence, as it involves
two cycloreactants each incorporating a lipidic chain. To
the best of our knowledge, the formation of dihydropyranes
by [4+2] cycloaddition of oxadiene has never been extended
to cycloreactants bearing two lipidic chains. Dujardin et al.
reported that (4R)-4-ethyl-3-vinyl-1,3-oxazolidin-2-one[9]
was an efficient dienophile partner in Eu(fod)3-catalyzed
asymmetric [4+2] cycloaddition with β,γ-unsaturated α-keto
esters, leading to heterocycloadducts with high endo and
facial selectivities.[10] Furthermore, it has been shown that
the use of chiral β-substituted N-vinyl-1,3-oxazolidin-2-
ones afforded heterocycloadducts with three controlled con-
tiguous stereogenic centers with a similar level of dia-
stereocontrol.[11] Although valuable methods involving
asymmetric catalyzed Diels–Alder reactions have been de-
Scheme 2. Preparation of heterodiene 10 and dienophiles 11. Rea-
gents and conditions: (a) CSA, toluene, 110 °C. (b) BF3·OEt2,
CH2Cl2, 0 °C, 95%. (c) Silica, toluene, 110 °C, 99%.
veloped in the last decade, their efficiency towards the par- 1.5 equiv. of the heterodiene, the yield of the reaction
ticular case of an (E)-β-substituted dienophile has not yet reached 91%. This difference in yield is due to the partial
fully demonstrated.[12]
decomposition of the heterodiene under the reaction condi-
tions. In both cases, the reaction proceeded with high endo
and facial selectivities (Table 1, Entry 1). The endo control
was fully established by analysis of the NMR spectroscopic
data. Only trace amounts of the exo cycloadducts derived
1
from dienophile 11a were detected in the H NMR spec-
trum of the crude product. It is noteworthy that the same
range of selectivities and high yields were observed on
larger scale (up to 40 mmol, Table 1). Under the same con-
ditions, dienophiles 11b and 11c also provided excellent re-
sults in terms of yields and selectivities (Table 1, Entries 2
and 3).
Scheme 1. Retrosynthetic strategy.
When the reaction between dienophiles 11a–c and
To the best of our knowledge, the synthesis of heterodi- heterodiene 10 was performed with SnCl4, a reverse facial
ene 10 and N-vinyl-1,3-oxazolidin-2-ones of type 11 and selectivity was observed that agreed with a previous re-
their use in [4+2] cycloaddition have not been described to port.[11a,11b] However, yields remained significantly low (40–
date. We first explored the synthesis of β-alkyl-N-vinyl-1,3- 46%) due to poor solubility of one or both lipidic partners
oxazolidin-2-ones 11a–c and their reactivity towards β,γ- in dichloromethane at low temperature (Table 1, Entries 4–
unsaturated α-keto ester 10 under Lewis acid conditions. β- 6). Neither the dilution of the reaction mixture by addition
Alkyl-N-vinyl-1,3-oxazolidin-2-ones 11a–c were conve- of dichloromethane or a less polar solvent (heptane), nor
niently prepared in a straightforward manner by a one-step the replacement of dichloromethane by toluene, were able
reaction of the corresponding aldehydes 12a–c with (R)-5- to improve significantly the yield of the heterocycloaddi-
ethyl-1,3-oxazolidin-2-one (13) under acidic conditions.[13] tion.
(E)-Isomer dienophiles 11a–c were then isolated in good to
Both cycloadducts 17a and 18a displayed a NOESY cor-
high yields (68–97%, Scheme 2). Heterodiene 10 was pre- relation between Hc and Hd confirming an endo approach
pared in two steps from acetal 14. Reaction between acetal during the cycloaddition. Furthermore, only diastereoiso-
14 and freshly prepared methyl pyruvate derived silyl enol mer 17a displayed a NOESY correlation between Ha and
ether 15 furnished compound 16 in 95% yield. Heating of Hb confirming the absolute configuration of the cycload-
16 in the presence of silica in toluene at 110 °C afforded duct in accordance with the previously observed selectiv-
(E)-isomer γ-tridecanyl-β,γ-unsaturated α-keto ester 10[14] ity[11a] (Figure 3). The oxazolidinone moiety adopts a con-
in 94% yield (Scheme 2). It is noteworthy that a prolonged formation that places the carbonyl group orthogonal to the
heating time led to unidentified degradation products.
average plane of the dihydropyran ring.[15] The ethyl group
Having both partners in hand, we then investigated the of the oxazolidinone moiety is thus located in the less bulky
key heterocycloaddition between chiral β-substituted N- position, that is, below the molecule placing Ha in a posi-
vinyl-1,3-oxazolidin-2-one 11a and γ-tridecanyl-β,γ-unsatu- tion close to Hb.
rated α-keto ester 10 by using Eu(fod)3 as a catalyst or
Further functionalization of cycloadduct 17a was per-
SnCl4 as a promoter. With Eu(fod)3 in cyclohexane at formed to obtain lactone 7. Reduction by using a DIBAL-
80 °C, the corresponding cycloadduct was isolated in 51% H solution in the presence of BF3·OEt2 furnished allylic
yield when using only 1 equiv. of the heterodiene. With alcohol 19 (Scheme 3). The addition of BF3·OEt2 to the
2
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Asymmetric Access to a Lactone Containing Two Lipidic Chains
Table 1. Heterocycloaddition reaction between 10 and 11a–c.
Entry
11
Lewis acid
Yield[a] [%]
17+18/17Ј+18Ј
17/18[b]
[d]
1[c]
2
3
4
5
11a
11b
11c
11a
11b
11c
Eu(fod)3[d]
91
92
94
46
45
40
97:3[d]
96:4
95:5
98:2
5:95
2:98
3:97
Eu(fod)3[d]
Eu(fod)3
SnCl4
96:4[d]
95:5[d]
85:15
86:14
75:25
SnCl4
SnCl4
6
1
[a] Isolated yield after purification. [b] Determined from the H NMR spectrum of the crude product. [c] Scale of 40 mmol: 17/18 = 93:7.
[d] This ratio refers to endo/exo ratio (concerted mechanism).
The next challenging step was the removal of the chiral
auxiliary, 1,3-oxazolidin-2-one, as only few examples have
been reported.[18] Classical orthogonal protection was first
performed leading to 21 in 77% yield (Scheme 3). The for-
mation of the corresponding lactol was first envisaged by
carrying out the reaction of compound 21 in a 20% aque-
ous sulfuric acid solution in the presence of silica. However,
bicyclic compound 22 was isolated in 35% yield along with
remaining compound 21.
Figure 3. NOESY correlation observed with 17a and 18a.
The structure of acetal 22 was assessed on the basis of
2D NMR spectroscopic data (Figure 4). The NMR signals
of the acetal proton and carbon could be unambiguously
reaction mixture is crucial to avoid the concomitant re-
duction of the oxazolidinone function.[16] The hydrobor-
ation/oxidation sequence by using trimethylamine N-oxide
identified from their chemical shifts. This assignment was
(TAO) as the oxidant[17] was then performed on the allylic
confirmed by an HMBC experiment, which showed a corre-
alcohol to furnish diol 20 in 81% over two steps (Scheme 3).
lation of acetal proton Ha with the carbon atoms of the
1
Only one diastereoisomer was detected by H NMR spec-
CH2O group and the ring junction carbon atom (Cf and
troscopy, and the overall trans relationship between all vici-
Cd). Then, the corresponding proton was clearly identified
nal protons of the THP ring was assigned subsequently
and positioned in the molecule on the basis of COSY and
HSQC results.
1
from the H NMR spectroscopic data of derivative 21.
Figure 4. 2D NMR spectroscopic data of bicyclic compound 22.
The chiral auxiliary of diol 20 was then removed under
mild conditions (acetyl chloride in methanol at 65 °C) to
furnish compound 23 as a mixture of anomers in 68% yield.
Scheme 3. Synthesis of bicyclic compound 22. Reagents and condi-
Diol 23 was then protected with benzyl groups under usual
tions: (a) DIBAL-H, BF3·OEt2, CH2Cl2, –78 °C, 90%.
conditions. However, the direct obtention of lactone 26 by
(b) BH3·Me2S, THF, r.t. then TAO, THF, 65 °C, 91%. (c) 1. PivCl,
oxidation of resulting protected acetal 24 under Grieco’s
conditions[19] failed. Finally, treatment of compound 24
pyr., CH2Cl2, r.t.; 2. NaH, TBAI, BnBr, THF/DMF, r.t., 77%.
(d) Silica, H2SO4 (aq.), CH2Cl2, 40 °C, 35%.
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S. Guillarme, C. Saluzzo et al.
SHORT COMMUNICATION
in dichloromethane (1.0 m, 0.5 equiv.). The solution was stirred at
–78 °C for 3 h, quenched with a saturated aqueous NaHCO3 solu-
tion (5 mL), and then warmed up to room temperature. The aque-
ous layer was extracted with dichloromethane and the combined
organic extracts were washed with brine (20 mL), dried (MgSO4),
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (CH2Cl2/EtOAc,
99:1Ǟ95:5).
with an aqueous sulfuric acid solution led to 25 as a mix-
ture of the two desired anomeric lactols in 76% yield, which
was converted into lactone 26 by oxidation with TPAP and
NMO in dichloromethane in the presence of molecular si-
eves (76% yield). Hydrogenolysis of 26 over palladium hy-
droxide on charcoal led to targeted lactone 7 in 41% yields
(Scheme 4).
Typical Procedure for the Removal of the Oxazolidinone: To a solu-
tion of diol 20 (511 mg, 1.00 mmol) in dry methanol (10 mL) at
0 °C was added dropwise acetyl chloride (5 mL). The solution was
stirred at 0 °C for 0.5 h, at room temperature for 2 h, and then
under reflux for 2 h. After cooling to room temperature, a saturated
aqueous NaHCO3 solution (15 mL) was added, and the mixture
was stirred for 30 min. The layers were separated, and the aqueous
phase was extracted with ethyl acetate (3ϫ 30 mL). The combined
organic extracts were dried (MgSO4) and concentrated under re-
duced pressure. The residue was purified by column chromatog-
raphy on silica gel (cyclohexane/EtOAc, 95:5Ǟ90:10) to lead to
acetal 23 as a mixture of anomers (291 mg, 0.680 mmol, 68%) as
a white solid.
Scheme 4. Access to lactone 7. Reagents and conditions: (a) AcCl,
MeOH, r.t. to 65 °C, 68%. (b) NaH, TBAI, BnBr, DMF, r.t., 92%.
(c) H2SO4 (aq.), acetone, 85 °C, 76%. (d) TPAP, NMO, 4 Å MS,
CH2Cl2, r.t., 76%. (e) m-CPBA, BF3·OEt2, CH2Cl2, r.t. (f) H2, 20%
Pd(OH)2/C, MeOH, r.t., 41%.
Supporting Information (see footnote on the first page of this arti-
cle): General methods, experimental procedures, characterization
1
data, and copies of the H NMR and 13C NMR spectra.
Acknowledgments
The authors thank the Centre National de la Recherche Sci-
entifique (CNRS), the Ministère de l’Enseignement Supérieur et de
la Recherche, and the Region Pays de la Loire for their financial
support. We also thank the Agence Nationale de la Recherche
(ANR-08-PCVI-0024, Galcerdeo) for financial support. Acknowl-
edgments are also made to F. Legros, P. Gangnery, and A. Durand
for their technical assistance.
Conclusions
In conclusion, we have successfully performed a hetero-
Diels–Alder reaction between a β-alkyl-N-vinyl-1,3-oxazol-
idin-2-one and a heterodiene each containing a lipidic
chain. When Eu(fod)3 was used as the catalyst, the hetero-
cycloaddition occurred with high yield and diastereoselec-
tivities independently of the nature of the dienophile. The
Lewis acid catalyzed conditions used [Eu(fod)3 in refluxing
cyclohexane] were fully suitable with the lipophilic nature
of the two substrates, permitting the reaction to take place
in homogeneous medium. Moreover, the use of SnCl4 al-
lows for practical facial stereodivergence. The whole process
takes advantage of the availability of enamide 11 as a dieno-
phile.[20] After appropriate transformations of cycloadduct
17a, efficient conditions for removal of the chiral auxiliary
were developed to allow access to key lactone 7 featuring
the two lipidic chains in a trans relationship. Further studies
on the synthesis of conformationally rigid ceramide analogs
and galactosylceramides are currently underway.
[1] T. Kolter, K. Sandhoff, Angew. Chem. 1999, 111, 1632; Angew.
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Experimental Section
Typical Procedure for Cycloaddition with [Eu(fod)3]: A solution of
dienophile 11 (1 equiv.), heterodiene 10 (1.5 equiv.), and Eu(fod)3
(0.05 equiv.) in cyclohexane (1 mL/mmol) was heated under reflux
for 1 d. After cooling to room temperature, the solvent was re-
moved, and the crude product was purified by column chromatog-
raphy on silica gel (CH2Cl2/EtOAc, 99:1Ǟ95:5).
Typical Procedure for Cycloaddition with SnCl4: To a solution of
dienophile 11 (1 equiv.) and heterodiene 10 (2 equiv.) in dry dichlo-
romethane (7 mL/mmol) at –78 °C was added a solution of SnCl4
4
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Asymmetric Access to a Lactone Containing Two Lipidic Chains
[9] C. Gaulon, P. Gizecki, R. Dhal, G. Dujardin, Synthesis 2003,
2269–2272.
[10] C. Gaulon, R. Dhal, T. Chapin, V. Maisonneuve, G. Dujardin,
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[11] a) F. Gohier, K. Bouhadjera, D. Faye, C. Gaulon, V. Maison-
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M. Y. Laurent, V. Stocker, V. M. Temgoua, G. Dujardin, R.
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sion to β-substituted difluorodienophiles, see T. B. Nguyen, A.
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[12] A. Barba, S. Barroso, G. Blay, L. Cardona, M. Melegari, J. R.
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4069–4072.
[14] The configuration of the double bonds for compounds 10 and
11 is (E) and their coupling constants are in accordance with
the values already described in the literature: For type-11 en-
amides a coupling constant of 14.5 Hz for the (E) geometry is
generally observed (see Z. Song, T. Lu, R. Hsung, Z. Al-Ra-
shid, C. Ko, Y. Tang, Angew. Chem. Int. Ed. 2007, 46, 4069)
instead of 8.5 Hz for the (Z) configuration (see X. Zhang, Y.
Zhang, J. Huang, R. P. Hsung, K. C. M. Kurtz, J. Oppenhei-
mer, M. E. Petersen, I. K. Sagamanova, L. Shen, M. R. Tracey,
J. Org. Chem. 2006, 71, 4170–4177). For heterodiene 10, we
observed a coupling constant of 15.9 Hz, which is similar to
those found by Alexakis (L. Gremaud, A. Alexakis, Angew.
Chem. Int. Ed. 2012, 51, 794–797), by Lassaletta (R. P. Herrera,
D. Monge, E. Martín-Zamora, R. Fernández, J. M. Lassaletta,
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Outurquin, C. Paulmier, Tetrahedron 1997, 53, 16767–16782)
for such (E)-β,γ-insaturated α-oxo-esters.
See the Supporting Information.
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[15]
[16]
[17]
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[20] Independent of the stereochemistry, practical access to en-
amide 11 compares well with that of the corresponding vinyl
ether derivative.
Received: April 19, 2012
Published Online: ᭿
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S. Guillarme, C. Saluzzo et al.
SHORT COMMUNICATION
Cycloaddition
C. S. Vu, N. Guisot, S. Guillarme,*
A. Martel, G. Dujardin, M. Pipelier,
D. Dubreuil, C. Saluzzo* ................... 1–6
A Convergent Hetero-Diels–Alder Strategy
for Asymmetric Access to a Lactone Con-
taining Two Lipidic Chains
Eu(fod)3-catalyzed heterocycloaddition of
chiral β-alkyl-N-vinyl-1,3-oxazolidin-2-
ones with a heterodiene bearing a lipidic
chain led to heterocycloadducts in high
yield with excellent endo and facial selec-
tivities. An original lipidic lactone, a potent
precursor of a ceramide analog, was ob-
tained in seven steps from the adduct in a
convergent manner after appropriate func-
tionalization.
Keywords: Lactones
/ Asymmetric syn-
thesis / Chiral auxiliaries / Cycloaddition /
Diastereoselectivity
6
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