Synthesis of methylene exoglycals using a modified Julia olefination

Article abstract of DOI:10.1055/s-2005-862364

A new route to exomethylene sugars is reported. The use of a two-step coupling-elimination procedure allows successful Julia olefination of sugar-derived lactones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-862364

520
LETTER
Synthesis of Methylene Exoglycals Using a Modified Julia Olefination
S
ynthesis of Methy
a
lene Exogl
v
ycals
U
sing
i
a
Modi
d
fied Julia
O
lefinati
G
on ueyrard,* Rose Haddoub, Amine Salem, Nassib Said Bacar, Peter G. Goekjian
UMR 5181, Laboratoire de Chimie Organique 2 – Glycochimie, Université Claude Bernard Lyon 1, CNRS, 43, Bd du 11 Novembre 1918,
69622 Villeurbanne Cedex, France
Fax +33(4)72448349; E-mail: david.gueyrard@univ-lyon1.fr
Received 29 November 2004
Abstract: A new route to exomethylene sugars is reported. The use
of a two-step coupling–elimination procedure allows successful
Julia olefination of sugar-derived lactones.
Key words: glycals, olefination, carbohydrate, alkenes, lactones
Scheme 2
Methylene exoglycals1 3 (Scheme 1) are known to be
This study is described in Table 1. We investigated the
nature of the base, the solvent (toluene or THF), the tem-
perature (–85 °C to r.t.) and the order of addition (Barbier
or premetalation).
glycosidase inhibitors2 as well as valuable intermediates
for the synthesis of C-glycosides,3 C-disaccharides, 4 and
natural products.5 A number of procedures have been pub-
lished for the preparation of such compounds: indirect
– None of the desired compounds is detected when the
methods based on elimination reactions,6 olefination of
sulfone is premetalated (entries 1, 3 and 5).
sugars by the Tebbe reagent7 or dimethyltitanocene,8
Ramberg–Backlund rearrangement of glycosyl sulfones,9
and recently Bamford–Stevens reaction of anhydroaldose
tosylhydrazone.10 The use of the Tebbe reagent is an effi-
cient method, yet the sensitivity and cost of this reagent,
as well as functional group compatibility considerations
call nonetheless for alternative procedures. Our plan was
to extend the modified Julia olefination conditions to sug-
ar lactones as shown in Scheme 2. There are many pub-
lished procedures for the conversion of reducing sugars
into lactones, and the Julia olefination11 has been used ex-
tensively in the last decade for the construction of C=C
bonds present in many natural products.12 Generally, this
type of reaction is carried out using a heteroarylsulfone
and an aldehyde. This reaction has recently been extended
to ketones13 and hemiacetals14 but to our knowledge, Julia
olefination has not been achieved with lactones.
– The reaction affords the methylene exoglycal in low to
moderate yields under Barbier conditions, at low temper-
ature (entries 2, 4 and 8).
– Best results using the standard modified Julia procedure
(35%) were obtained with LiHMDS as base (entry 2 vs. 8)
and THF as solvent (entry 2 vs. 4).
The observation that the expected a-heteroarylsulfonyl
hemiketal intermediate was formed cleanly, yet reverted
to starting material upon warming, led us to try a two-step
Table 1 Coupling between Methylbenzothiazoylsulfone and Tri-O-
benzyl-D-arabinolactone
Entry
Base
Solvent
Temp. Additiona
(°C)
Yield
(%)
1
2
3
4
5
6
7
8
9
KHMDS
LDA
Toluene r.t.
Premetal.
Barbier
Premetal.
Barbier
Premetal.
Barbier
Barbier
Barbier
Barbier
–
THF
THF
–78
–78
18
–
LDA
LDA
Toluene –85
7
Scheme 1 Julia olefination of sugar derived lactones
LDA
Toluene
THF
0
–
LiHMDS
LDA
0
–
In this paper, we report the first example of a modified
Julia olefination using a sugar-derived lactone to prepare
methylene exoglycals. In order to optimise the reaction
conditions, we first explored the coupling between meth-
ylbenzothiazoylsulfone and tri-O-benzyl-D-arabino-
lactone.
THF
0
–
LiHMDS
THF
–78
35
21
1) LiHMDS THF
2) NaOH THF
–78
r.t.
10
1) LiHMDS THF
2) DBU THF
–78
r.t.
Barbier
66
a Barbier: base added to a mixture of sulfone and lactone.
Premetalate: base added to sulfone and then lactone added.
SYNLETT 2005, No. 3, pp 0520–0522
Advanced online publication: 04.02.2005
DOI: 10.1055/s-2005-862364; Art ID: G44304ST
1
6.
0
2.
2
0
0
5
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Methylene Exoglycals Using a Modified Julia Olefination
Synthesis of 4; Typical Experiments
521
sequence (entries 9 and 10). The first step consists in the
addition of the sulfone on the lactone using LiHMDS in
THF at –78 °C, providing the intermediate in 78% yield.
Attempted conversion into the desired exoglycal by basic
treatment in THF using a strong base such as sodium hy-
droxide gave a low yield (21%), along with a significant
amount of the starting lactone. On the other hand, treat-
ment of the crude intermediate after aqueous work up with
DBU led to the glycal in 66% overall yield for the two
steps.
In a 10 mL round bottom flask under argon, 100 mg (0.239 mmol)
of tri-O-benzyl-D-arabinolactone and 61 mg (1.2 equiv) of 2-
methanesulfonylbenzothiazole were dissolved in 1 mL of freshly
distilled THF at –78 °C, then a 1 M solution of LiHMDS in THF
(574 mL, 2.4 equiv) was added drop-wise over 10 min. Stirring was
maintained during 30 min, and then the reaction mixture was
quenched by addition of 3 equiv of HOAc (43 mL). After hydrolysis,
the mixture was extracted with EtOAc (2 ×), dried over Na2SO4 and
evaporated. The residue was dissolved in dry THF (5 mL), and 2
equiv of DBU (71 mL) was added. Stirring was maintained during 1
h, the mixture was concentrated by rotary evaporation and purified
by flash chromatography to afford the desired product (66 mg) with
66% yield.
To evaluate the scope and limitations of this method, we
performed the modified Julia olefination between sulfone
and a variety of sugar-derived lactones under the opti-
mised reaction conditions (Scheme 3).
Acknowledgment
The authors would like to thank Data Development Designers
(3DS) for financial support (R.H.) and Dr. D. Bouchu and L. Arzel
for HRMS experiments.
References
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Scheme 3 Synthesis of methylene exoglycals in diverse sugar
series16
(7) For a recent example, see: Waldscheck, B.; Streiff, M.; Notz,
W.; Kinzy, W.; Schmidt, R. R. Angew. Chem. Int. Ed. 2001,
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Generally, the reaction affords the methylene exoglycal
with reasonable yields (46–74%). Pyranose and furanose
rings were successfully employed. The reaction was
shown to occur with diverse sugar series (D-arabino, D-
gluco, D-ribo, D-manno and D-erythro) and several types
of protective groups (benzyl ether, silyl ether and isopro-
pylidene). Only a t-butyldimethylsilyl protecting group on
the C2-hydroxyl group was found to interfere with the re-
action.
(12) For a recent review, see: Balkemore, P. R. J. Chem. Soc.,
In summary, we demonstrated that the Julia olefination
can be extended to sugar derived lactones to lead to meth-
ylene exoglycals in good yields. We are currently extend-
ing the ester Julia olefination methodology to a range of
sulfones, readily prepared through a two-step process
from commercially available and inexpensive reagents, in
order to furnish substituted exoglycals which are also of
interest.
Perkin Trans. 1 2002, 23, 2563.
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Synlett 2005, No. 3, 520–522 © Thieme Stuttgart · New York

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D. Gueyrard et al.
LETTER
(16) All compounds were characterised by NMR spectroscopy
and HRMS. Data were identical to those reported in the
literature.
J = 11.5 Hz, H-5a), 3.63 (dd, 1 H, J = 3.4 Hz, H-5b), 0.90
(m, 27 H, CH3), 0.59 (m, 18 H, CH2). 13C NMR (75 MHz,
CDCl3): d = 4.7, 5.2, 5.5, 7.1, 7.2, 7.3, 62.4, 72.7, 73.0, 82.6,
85.9, 163.4. IR: 1678 cm–1 (C=C). [a]D +15 (c 1, CHCl3).
HRMS (CI-MS): m/z calcd for C24H52O4Si3 [M + H]+:
489.3252; found: 489.3257
Data for compound 5: 1H NMR (300 MHz, CDCl3): d = 4.39
(d, 1 H, J = 4.3 Hz, H-2), 4.23 (s, 1 H, H-1¢a), 4.05 (m, 2 H,
H-3 and H-4), 3.95 (s, 1 H, H-1¢b), 3.71 (dd, 1 H, J = 3.2 Hz,
Synlett 2005, No. 3, 520–522 © Thieme Stuttgart · New York