Synthesis of enol ethers from lactones using modified Julia olefination reagents: application to the preparation of tri- and tetrasubstituted exoglycals

Article abstract of DOI:10.1016/j.tetlet.2007.11.206

A new route to substituted exoglycals from the corresponding lactones is described. The enol ethers synthesis via a modified Julia olefination of sugar-derived lactones is extended to substituted benzothiazolyl sulfones to furnish tri- and tetrasubstitute

Full text of DOI:10.1016/j.tetlet.2007.11.206

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 747–749
Synthesis of enol ethers from lactones using modified Julia olefination
reagents: application to the preparation of tri- and tetrasubstituted
exoglycals
Benjamin Bourdon, Matthieu Corbet, Patrice Fontaine, Peter G. Goekjian, David Gueyrard *
ˆ
ICBMS, Universite´ Claude Bernard Lyon 1, Laboratoire de Chimie Organique 2—Glycochimie, UMR-CNRS 5246, Batiment 308, 43 Boulevard
du 11 Novembre 1918, F-69622 Villeurbanne, France
Received 23 July 2007; revised 26 November 2007; accepted 30 November 2007
Available online 5 December 2007
Abstract
A new route to substituted exoglycals from the corresponding lactones is described. The enol ethers synthesis via a modified Julia
olefination of sugar-derived lactones is extended to substituted benzothiazolyl sulfones to furnish tri- and tetrasubstituted exoglycals.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Julia olefination; Exoglycals; Lactones; Enol ethers
The synthesis of functionalized tri- and tetrasubstituted
enol ethers by olefination of lactones represents a long-
standing challenge in organic chemistry due to the low elec-
trophilicity of esters and lactones. The use of metal
carbenoids such as Tebbe reagents is most effective, but is
usually limited to the preparation of unsubstituted enol
ethers.1 Conventional methods such as the Wittig reaction
have generally been unsuccessful, although some improve-
ments have been reported by the use of non-classical
reagents.2 In the specific case of exoglycals,3 a number of
procedures have been published for the preparation of
unsubstituted methylene exoglycals: methods based on
elimination reactions,4 olefination of sugar lactones with
the Tebbe reagent5 or dimethyltitanocene,6 Ramberg–
Backlund rearrangement of glycosyl sulfones7 and recently
a Bamford–Stevens reaction of anhydroaldose tosylhydra-
zone.8 Only a few of these methods can be used to obtain tri-
and tetrasubstituted exoglycals. Wittig olefination has been
employed to prepare dichloro,9 difluoro,10 dithio11 and car-
bomethoxy12 alkenes, and an example of trimethylsilyl
substituted exoglycals obtained by reaction with tris(tri-
methylsilyl) titanacyclobutene has been described.13 How-
ever, these methodologies are not general. A general
route is provided by the Ramberg–Backlund rearrange-
ment,7 although this sequence requires a somewhat lengthy
preparation of the substituted glycosyl sulfones. Finally,
other available routes are much less direct.14
We have recently demonstrated that the use of Julia
olefination reagents can be extended to the synthesis of
methylene exoglycals from sugar-derived lactones.15 The
modified Julia olefination16 has emerged as a powerful tool
for olefin synthesis, through its application in total synthe-
sis of natural products.17 This reaction has been extended
to the preparation of vinyl ethers,18 fluoro alkenes19 and
a,b-unsaturated esters.20 In this Letter, we report the exten-
sion of our enol ether synthesis using modified Julia
reagents to the preparation of tri- and tetrasubstituted
exoglycals (Fig. 1).
enol ether
O
O
O
R
R
synthesis
n
O
n
n
OH
with Julia
olefination
reagents
RO
RO
RO
*
Corresponding author. Tel.: +33 472 44 81 83; fax: +33 472 44 83 49.
Fig. 1. Julia olefination of sugar-derived lactones.
E-mail address: david.gueyrard@univ-lyon1.fr (D. Gueyrard).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.206

748
B. Bourdon et al. / Tetrahedron Letters 49 (2008) 747–749
entry
1
1) NaH, R-X or R-OTs
DMF, 0 ºC
O
S
N
N
S
O
OBn
BnO
SH
O
BnO
O
BnO
BnO
S
R
2) (NH4)6Mo7O24.4H2O
H2O2, EtOH, 0 ºC
CH3
CH3
1
2 a-f
OBn
OBn
R
= ethyl
isopropyl
93%
87%
(77%) E/Z 8/2
3
(62%) E/Z 6/4
4
cyclopentyl 67%
heptyl
94%
(CH2)4OTHP 59%
but-3-enyl
68%
OBn
O
BnO
O
BnO
BnO
BnO
2
3
4
OBn
OBn
Scheme 1. Preparation of the benzothiazolyl sulfones.
(28%)
6
5
(61%)
CH3
OBn
O
BnO
O
BnO
Benzothiazolyl sulfones 2 were prepared from inexpen-
BnO
BnO
CH3
CH3
CH3
sive and odourless 2-mercaptobenzothiazole through a
two-step process involving S-alkylation and S-oxidation
(Scheme 1).20
OBn
(35%)
OBn
8
7
(60%)
We chose the readily available 2,3,4,6-tetra-O-benzyl-D-
glucono-1,5-lactone and 2,3,5-tri-O-benzyl-D-arabinono-
lactone as starting materials to determine the influence of
the ring size of the sugar on the olefination reaction.
Our previous results showed that the enol ether synthe-
sis requires that the coupling be done under Barbier condi-
tions, presumably due to self-condensation reactions of the
lithiated sulfones, and that a two-step procedure be used in
which the elimination step is catalyzed by DBU.15 Treating
a mixture of carbohydrate lactone and benzothiazolylsulf-
one with LiHMDS at À78 °C and treating the resulting iso-
lated hemiacetal with DBU afforded the corresponding
exoglycals in reasonable yields (28–77%).21 The reaction
was successful with both pyranose and furanose ring sug-
ars, even if in most cases D-arabino exoglycals were
obtained in better yields. We also showed that functional-
ized benzothiazolyl sulfones can be used for the enol ether
synthesis (Scheme 2, entries 5 and 6).
OBn
O
BnO
O
BnO
BnO
BnO
C6H13
C6H13
OBn
(33%) E/Z 1/1
OBn
9
(63%) E/Z 9/1
10
OBn
OTHP
O
BnO
BnO
O
BnO
BnO
BnO
OTHP
5
6
OBn
OBn
(49%) E/Z 1/1
12
14
(63%) E/Z 9/1
11
OBn
O
O
BnO
BnO
BnO
OBn
OBn
(33%) E/Z 8/2
(64%) E/Z >9/1
13
Scheme 2. Synthesis of tri- and tetrasubstituted exoglycals.
In the case of the methyl-substituted compounds 3 and
4, the two diastereoisomers were separated to determine
the alkene stereochemistry by NOE experiments. A correla-
tion was observed from H-4 to the methyl group in the case
of the E isomer, and to the H-2 proton in the Z isomer
(Fig. 2). For compounds 9–14, the E/Z stereochemistry
was determined by analogy to compounds 3 and 4, and
the ratio was measured by integration of selected NMR
peaks after isolation of the E/Z mixture by column chro-
matography. The observed E/Z selectivity is usually better
in the D-arabino series (>8/2) than in the D-gluco series (1/1
to 8/2). However, it should be noted that the exoglycals
are prone to isomerization and the E isomer in the D-gluco
series is highly hindered due to the substituent on the pyra-
nose ring. Additional studies are therefore underway to
fully address the stereochemical issue.
OBn
OBn
O
H
O
H
BnO
BnO
BnO
BnO
2
H
1
2
3
3
4
4 OBn
OBn H
1
Z isomer
E isomer
Fig. 2. Determination of the stereochemistry for compound 4 (E and Z
isomer) by NOE experiments.
rasubstituted exoglycals in good yields from carbohydrate
lactones. We are currently studying the reactivity of these
substituted exoglycals for the preparation of various fami-
lies of biologically relevant compounds.
The introduction of aromatic rings (phenyl) or electron-
withdrawing groups (esters, nitriles and ketones) on the
double bond has so far been unsuccessful using this metho-
dology, presumably due to the low reactivity of the relevant
alpha-lithiated sulfone.
Acknowledgements
The European Union as a European Integrated Project
(contract No. LSHB-CT-2004-503467) is gratefully
acknowledged. The authors would like to thank Dr. D.
Bouchu for HRMS experiments and Dr. B. Fenet for
NOE experiments.
In summary, we have demonstrated that the enol ether
synthesis can be extended to the preparation of tri- and tet-

B. Bourdon et al. / Tetrahedron Letters 49 (2008) 747–749
749
61 mg (1.2 equiv) of 2-ethanesulfonylbenzothiazole were dissolved in
1 mL of freshly distilled THF at À78 °C, then a 1 M solution of
LiHMDS in THF (574 lL, 2.4 equiv) was added dropwise over
10 min. Stirring was maintained during 30 min and then, the reaction
mixture was quenched by the addition of 3 equiv of acetic acid
(43 lL). After hydrolysis, the mixture is extracted with ethyl acetate
(Â2), dried over sodium sulfate and evaporated. The residue is
dissolved in dry THF (2 mL) and 2 equiv of DBU (71 lL) were added.
Stirring was maintained during 1 h, the mixture was concentrated by
rotary evaporation and purified by flash chromatography to afford
compound 3 (66 mg) in 77% yield. Selected data: Compound 3 (Z
isomer): 1H NMR (CD3COCD3, 300 MHz): d = 1.60 (d, 3H,
J = 6.8 Hz, CH3), 3.64 (d, 2H, J = 6.4 Hz, H-7), 4.10 (t, 1H,
J = 2.1 Hz, H-5), 4.32 (br s, 1H, H-4), 4.43 (td, 1H, H-6), 4.49–4.55
(m, 7H, 3CH2 and H-2), 7.27–7.37 (m, 15H, Har). 13C NMR
(CD3COCD3, 75 MHz): d = 10.5, 70.9, 71.0, 71.9, 73.6, 82.3, 83.3,
84.7, 97.0, 128.3, 128.5, 128.6, 128.9, 129.1, 129.2, 139.1, 139.3, 139.5,
154.9. (E isomer): 1H NMR (CD3COCD3, 300 MHz): d = 1.59 (d,
3H, J = 7.2 Hz, CH3), 3.58 (dd, 1H, J = 7.2 Hz, J = 9.8 Hz, H-7b),
3.62 (dd, 1H, J = 6.4 Hz, H-7a), 4.18 (br s, 1H, H-5), 4.39 (td, 1H,
J = 6.6 Hz, J = 1.0 Hz, H-6), 4.48–4.63 (m, 7H, 3CH2 and H-4), 4.93
(q, 1H, H-2), 7.29–7.34 (m, 15H, Har). 13C NMR (CD3COCD3,
75 MHz): d = 12.3, 70.7, 71.3, 71.6, 73.6, 79.5, 82.7, 84.2, 97.3, 128.3,
128.4, 128.6, 129.0, 129.1, 139.0, 139.1, 139.3, 155.9. HRMS (EI): m/z
[M+Å] calcd for C28H30O4: 430.2144; found: 430.2145. Compound 4 (Z
isomer): 1H NMR (CDCl3, 300 MHz): d = 1.72 (d, 3H, J = 4.2 Hz,
CH3), 3.72 (t, 1H, J = 4.2 Hz, H-5), 3.75–3.82 (m, 3H, H-7, H-8b and
H-6), 3.85 (dd, 1H, J = 6.3 Hz, J = 0.9 Hz, H-8a), 3.96 (d, 1H,
J = 4.2 Hz, H-4), 4.56–4.90 (m, 8H, 4CH2), 5.06 (q, 1H, J = 4.2 Hz,
H-2), 7.20–7.41 (m, 20H, Har). (E isomer): 1H NMR (CDCl3,
300 MHz): d = 1.57 (d, 3H, J = 4.2 Hz, CH3), 3.69–3.77 (m, 3H, H-8
and H-6), 3.94 (dd, 1H, J = 3.0 Hz, J = 1.5 Hz, H-5), 4.28 (ddd, 1H,
J = 1.2 Hz, J = 2.4 Hz, J = 6.0 Hz, H-7), 4.40 (d, 1H, J = 1.5 Hz,
H-4), 4.42–4.71 (m, 8H, 4CH2), 5.33 (q, 1H, J = 4.5 Hz, H-2), 7.20–
7.37 (m, 20H, Har). HRMS (ESI): m/z [M+Na+] calcd for
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C
38H40O5Na: 573.2617; found: 573.2618. Compound 7: 1H NMR
(CD3COCD3, 300 MHz): d = 1.64 and 1.66 (2s, 6H, 2CH3), 3.60 (dd,
1H, J = 7.5 Hz, J = 9.8 Hz, H-7b), 3.65 (dd, 1H, J = 6.2 Hz, H-7a),
4.20 (s, 1H, H-5), 4.44 (t, 1H, J = 6.9 Hz, H-6), 4.50–4.66 (m, 7H,
3CH2 and H-4), 7.29–7.39 (m, 15H, Har). 13C NMR (CD3COCD3,
75 MHz): d = 17.2, 19.2, 71.0, 71.2, 71.7, 73.6, 80.2, 83.1, 84.2, 105.9
128.3, 128.4, 128.5, 128.6, 129.1, 129.2, 139.2, 139.3, 139.5, 149.8.
HRMS (EI): m/z [M+Å
] calcd for C29H32O4: 444.2301; found:
21. Typical procedure: In a 10 mL round-bottomed flask under argon,
100 mg (0.239 mmol) of 2,3,5-tri-O-benzyl-D-arabinonolactone and
444.2304.