Direct methylenation of partially benzyl-protected sugar lactones by dimethyltitanocene

Article abstract of DOI:10.1055/s-2001-18772

Mono- and disaccharidic exo-methylenesugars containing an unprotected hydroxy group were conveniently prepared by the direct methylenation of the corresponding mono- and disaccharidic lactones using dimethyltitanocene.

Full text of DOI:10.1055/s-2001-18772

LETTER
1885
Direct Methylenation of Partially Benzyl-Protected Sugar Lactones by
Dimethyltitanocene
D
irec
t
Methylenati
i
on of
P
a
artially Be
o
nzyl Protecte
l
d
Suga
i
r
L
acto
u
nes Li, Hiro Ohtake, Hideyo Takahashi, Shiro Ikegami*
School of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan
Fax +81(426)851870; E-mail: shi-ike@pharm.teikyo-u.ac.jp
Received 3 September 2001
these reagents to the methylenation of sugar lactones1a,b,6,7
gave a more direct and convenient access to exo-methyle-
nesugars. Concerning the different reactivity of the re-
agents I, II and III,12 it has been reported that the highly
reactive Tebbe’s reagent (I) could methylenate the carbo-
nyl group of aldehydes, ketones, esters, and amides. How-
ever, the reagent I must be sensitive to acidic hydrogens
such as those in hydroxy or carboxylic groups.9 Although
the reagent III can selectively react with ketones and al-
dehydes even in the presence of hydroxy12a,b or
carboxylic12c groups, it showed low reactivity to esters.13
With the consideration of the reasonable stability and the
relatively high reactivity of the reagent (II),9,11 we select-
ed dimethyltitanocene (II) as the methylenation reagent in
our attempt.
Abstract: Mono- and disaccharidic exo-methylenesugars contain-
ing an unprotected hydroxy group were conveniently prepared by
the direct methylenation of the corresponding mono- and disaccha-
ridic lactones using dimethyltitanocene.
Key words: sugar lactone, methylenation, dimethyltitanocene,
exo-methylenesugar
exo-Methylenesugars are useful precursors for synthesiz-
ing C-glycosides1 and other C-glycosyl derivatives,2 and
can also be used as glycosidase inhibitors.3 exo-Methyle-
nesugars protected with a various of groups have been
prepared by several procedures, such as a multiple step
process ultimately with an elimination reaction,4 the Mey-
ers’ variant of the Ramberg–Backlund rearrangement of
S-glycoside dioxides,5 and methylenation of sugar lac-
tones by Tebbe’s reagent (I in Figure 1)1a,6 or dimethylti-
tanocene (Cp2TiMe2, II in Figure 1).1b,7 However, few
report on the direct synthesis of the partially protected
exo-methylenesugar has been published, although 3,4,6-
tri-O-benzyl-1-exo-methylenesugars were prepared by an
indirect procedure involving multiple sequence with the
last step of dehydrohalogenation.1d,8 We disclosed in this
communication a simple preparation of partially benzyl-
protected exo-methylenesugars by the direct methylenea-
tion of sugar lactones with dimethyltitanocene.
H2
C
CH3
CH3
Cp2Ti
AlMe2
Cp2Ti
II
Zn X2CH2 TiCl4
Cl
I
III
Figure 1
The required partially benzyl-protected monosaccharidic
lactones 6 and 7 were prepared by a sequence of reactions
as shown in Scheme 1. The disaccharidic lactones 8, 12
and 13, and the tetrasaccharidic lactone 14 were synthe-
sized by the procedures shown in Scheme 2 and
Scheme 3.
Tebbe’s reagent (I) and its alternative II were effective
and useful reagents for the olefination of carbonyl com-
pounds especially for the direct conversion of carboxylic
esters to enol ethers.9–11 The successful application of
HO
BnO
BnO
HO
BnO
BnO
pMBO
BnO
BnO
O
O
O
Ph
i
O
All
All
O
O
BnO
OH
BnO
O
BnO
6
7
BnO
2
3
iii, iv
4
All
v, vi
BnO
BnO
HO
BnO
BnO
pMBO
BnO
BnO
HO
BnO
O
1
O
ii
O
O
OH
BnO
BnO
BnO
5
Scheme 1 Reagents and conditions: (i) LiAlH4, AlCl3, Et2O/CH2Cl2, reflux; (ii) BH3 NMe3, AlCl3, THF, r.t.; (iii) NaH, pMBCl (p-methoxy-
benzyl chloride), THF, r.t; (iv) PdCl2, NaOAc, HOAc/H2O, r.t.; (v) DMSO, OAc2, r.t.; (vi) DDQ, CH2Cl2/H2O, r.t.
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1885,1888,ftx,en;Y17701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1886
X. Li et al.
LETTER
HO
BnO
BnO
Table Methyleneation of Sugar Lactones with Cp2TiMe2
O
pMBO
BnO
BnO
O
i, ii, iii
Entry
Sugar
Cp2TiMe2 Reaction
exo-Methylene
BnO
O
Lactone
(equiv)
Time
14 h
14 h
14 h
14 h
24 h
24 h
24 h
24 h
Sugars (yield )
OH
pMB = p-methoxybenzyl
BnO
O
BnO
BnO
1a
2
3
4
5
6
7
8
6
6
2.4
15 (58.8%)
15 (72.6%)
15 (71.5%)
16 (70.9%)
17 (67.7%)
18 (68.6%)
19 (65.2%)
–
O
4
BnO
8
4.0
Scheme 2 Reagents and conditions: (i) CCl3CN, K2CO3, CH2Cl2,
r.t.; (ii) 6, TMSOTf (0.1 equiv), MS 4A, CH2Cl2, r.t; (iii) DDQ,
CH2Cl2/H2O, r.t.
6
5.0
7
4.0
The methylenations were performed by the reaction of the
partially benzyl-protected sugar lactones 6–8, 12, and 13
with 4.0 molar equivalent of dimethyltitanocene in tolu-
ene at 70 °C under argon and afforded the corresponding
exo-methylenesugars 15–19 in good yields14,15
(Scheme 4). The results are listed in the Table.
8
4.0
12
13
14
4.0
4.0
5.0
a The conditions used in the methylenation of per benzyl-protected
sugar lactones.2c,7
As shown in the Table, the methylenation was firstly ex-
amined with the sugar lactone 6 using 2.4 equivalents of
dimethyltitanocene (II) (entry 1). Such molar ratio has
been successfully used in the methylenation of the corre-
sponding per benzyl-protected sugar lactones.2c,7 It was
found that the reaction did not complete with remaining
unreacted starting material 6. With increasing amount of
dimethyltitanocene (II), for example, in the presence of
4.0 molar equivalent of the reagent II the reaction gave
rise to a good yield of 15 (entry 2). Furthermore, an excess
of dimethyltitanocene (5.0 equivalents) did not improve
the reaction (entry 3). Under these conditions, the mono-
and disaccharidic lactones 7, 8, 12 and 13 were methyl-
enated in good yields.14
the tetrasaccharidic lactone 14 under the same conditions
was unsuccessful (entry 8).
In summary, the methylenations of partially benzyl-pro-
tected mono- and disaccharidic lactones with dimethylti-
tanocene were achieved, providing
a direct and
convenient method for preparing the exo-methylenesug-
ars containing an unprotected hydroxy group.
Acknowledgement
This research is partially supported by the Ministry of Education,
Science, Sports and Culture of Japan. We thank Miss J. Shimode for
spectroscopic measurements. X L is grateful to the JSPS for a post-
doctoral fellowship.
It was also found that a longer reaction time was necessary
for the reactions of the disaccharidic lactones 8, 12 and 13
probably due to the lower reactivity of the lactone group
in the big molecule. In addition, an attempt to methylenate
HO
BnO
BnO
O
CH3
pMBO
BnO
BnO
HO
BnO
BnO
O
O
BnO
i, ii
O
+
+
CH2
O
O
BnO
BnO
BnO
BnO
6
O
9
BnO
12
BnO
HO
BnO
BnO
CH3
OBn
BnO
O
O
O
pMBO
HO
i, ii
BnO
BnO
BnO
CH2
O
O
O
BnO
BnO
BnO
10
7
O
BnO
13
HO
BnO
BnO
O
CH3
BnO
O
BnO
BnO
HO
BnO
BnO
O
CH3
pMBO
BnO
BnO
O
O
CH3
CH3
i, ii
BnO
O
BnO
BnO
BnO
BnO
O
O
O
BnO
BnO
CH3
+
O
O
BnO
BnO
BnO
BnO
O
O
CH2
BnO
BnO
O
11
14
12
BnO
O
BnO
Scheme 3 Reagents and conditions: (i) TfOH (0.15 equiv), MS 4A, CH2Cl2, –78 °C; (ii) DDQ, CH2Cl2/H2O, r.t.
Synlett 2001, No. 12, 1885–1888 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Direct Methylenation of Partially Benzyl Protected Sugar Lactones
1887
HO
BnO
BnO
HO
BnO
BnO
i
O
O
O
CH2
BnO
BnO
6
15
HO
BnO
BnO
HO
BnO
BnO
O
O
BnO
HO
BnO
CH3
CH3
OBn
O
BnO
BnO
BnO
BnO
HO
BnO
O
O
BnO
O
BnO
O
O
O
O
BnO
BnO
BnO
BnO
X
X
BnO
X
X
BnO
BnO
13 X = O
19 X = CH2
7
X = O
8
X = O
12 X = O
18 X = CH2
16 X = CH2
17 X = CH2
Scheme 4 Reagents and conditions: (i) Cp2TiMe2 (4.0 equiv), Toluene, 65–70 °C.
well, although this protocol has been used to the
methylenation of some esters and lactones. See:
(a) Okazoe, T.; Takai, K.; Oshima, K.; Utimoto, K. J. Org.
Chem. 1987, 52, 4410. (b) Barrett, A. G. M.;
Bezuidenhoudt, B. C. B.; Metcher, L. M. J. Org. Chem.
1990, 57, 5196.
References
(1) (a) Rajan Babu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51,
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Tetrahedron 1997, 53, 6163. (d) Vidal, T.; Haudrechy, A.;
Langois, Y. Tetrahedron Lett. 1999, 40, 5677.
(14) General procedure for the Methylenation: To a solution
of 449 mg (1.0 mmol) of 6 in 10 mL of dry toluene was
added 832 mg (4.0 mmol, 4.0 equiv) of dimethyltitanocene
under argon. The solution was heated with stirring in the
dark at 70 °C (oil bath) for 14 hours. After removing the
most part of toluene in vacuo, the residue was applied on a
silica gel column using EtOAc : Hexane (1:10) containing
1% Et3N as the eluent to afford the product 15 (324.2 mg,
72.6%).
(2) (a) Campbell, A. D.; Paterson, D. E.; Raynham, T. M.;
Taylor, R. J. K. Chem. Commun. 1999, 1599.
(b) Bartolozzi, A.; Capozzi, G.; Falciani, C.; Menichetti, S.;
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(c) Li, X. L.; Ohtake, H.; Takahashi, H.; Ikegami, S.
Tetrahedron 2001, 57, 4283. (d) Li, X. L.; Takahashi, H.;
Ohtake, H.; Shiro, M.; Ikegami, S. Tetrahedron 2001, 57,
8053. (e) Nishikawa, T.; Ishikawa, M.; Wada, K.; Isobe, M.
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(15) Characterization data: 15: 1H NMR (CDCl3): = 1.83 (dd, 1
H, J = 7.93 Hz, J = 5.49 Hz, OH), 3.68–3.77 (m, 4 H), 3.88
(dd, 1 H, J = 9.46 Hz, J = 5.18 Hz), 3.93 (d, 1 H, J = 6.51
Hz), 4.57–4.84 (m, 8 H, CH2Ph 3, CH2=), 7.26–7.35 (m,
15 H, ArH); 13C NMR (CDCl3): = 61.98, 72.35, 73.99,
74.26, 77.43, 78.23, 78.58, 84.33, 94.61, 127.71, 127.80,
127.86, 127.97, 128.39, 128.44, 137.74, 137.92, 138.15,
155.67. 16: 1H NMR (CDCl3): = 2.63 (d, 1 H, J = 6.11 Hz,
OH), 3.65 (dd, 1 H, J = 9.77 Hz, J = 6.50 Hz), 3.76 (dd, 1 H,
J = 9.77 Hz, J = 3.05 Hz), 4.14–4.22 (m, 4 H), 4.40–4.68 (m,
8 H, CH2Ph, CH2=), 7.28–7.35 (m, 15 H, ArH); 13C NMR
(CDCl3): = 67.90, 69.94, 71.72, 72.33, 73.53, 80.08, 81.15,
82.45, 86.94, 127.74, 127.81, 127.88, 128.00, 128.41,
128.48, 128.52, 137.41, 137.58, 138.00, 159.55. 17: 1H
NMR (CDCl3): = 1.69 (s, br, 1 H, OH), 3.54–3.58 (m, 2 H),
3.68 (d, br, 1 H), 3.72–3.77 (m, 3 H), 3.84–3.86 (m, 1 H),
3.88–3.94 (m, 4 H), 4.05 (t, 1 H, J = 9.35 Hz), 4.58 (d, 1 H,
J = 11.55 Hz, CH2Ph), 4.62 (s, br, 1 H), 4.67–4.77 (m, 7 H,
CH2Ph, CH2=), 4.84–4.86 (m, 2 H, CH2Ph), 4.89 (d, 1 H,
J = 11.55 Hz, CH2Ph), 4.93 (d, 1 H, J = 11.00 Hz, CH2Ph),
5.02 (d, 1 H, J = 11.00 Hz, CH2Ph), 5.09 (d, 1 H, J = 3.85
Hz, 1’-H), 7.27–7.41 (m, 30 H, ArH); 13C NMR (CDCl3):
= 61.81, 65.85, 70.85, 72.35, 72.56, 74.16, 74.40, 74.94,
75.50, 77.33, 77.41, 78.19, 78.82, 80.21, 81.47, 84.65,
94.51, 97.18, 127.50, 127.54, 127.65, 127.66, 127.68,
127.75, 127.82, 127.83, 127.88, 127.94, 127.99, 128.30,
128.34, 128.39, 128.41, 128.43, 137.80, 138.15, 138.25,
138.35, 138.74, 155.69. 18: 1H NMR (CDCl3): = 1.28 (s, 3
H, CH3), 1.68 (s, br, 1 H, OH), 3.30 (d, 1 H, J = 9.46 Hz),
3.49–3.63 (m, 4 H), 3.69–3.83 (m, 4 H), 3.90–3.93 (m, 2 H),
4.13 (s, 1 H, J = 9.46 Hz), 4.55–4.95 (m, 14 H, CH2Ph 6,
CH2=), 7.21–7.35 (m, 30 H, ArH); 13C NMR (CDCl3):
= 21.05 (CH3), 60.93, 61.89, 71.77, 72.40, 73.96, 74.06,
74.49, 75.11, 75.28, 77.42, 78.09, 78.26, 78.70, 82.55,
84.45, 84.52, 94.46, 100.58, 127.47, 127.55, 127.60, 127.65,
(3) For reviews, see: (a) Legler, G. In Adv. Carbohydr. Chem.
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Griffin, F. K.; Paterson, D. E.; Taylor, R. J. K. Tetrahedron
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1993, 1.
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(13) We found that the reaction of perbenzyl-protected sugar
lactone and the reagent III in the presence of N,N,N’,N’-
tetramethylethylenediamine (TMEDA) did not proceed
Synlett 2001, No. 12, 1885–1888 ISSN 0936-5214 © Thieme Stuttgart · New York

1888
X. Li et al.
LETTER
127.67, 127.73, 127.84, 127.91, 127.96, 128.25, 128.31,
128.36, 128.43, 137.88, 138.15, 138.17, 138.39, 138.49,
138.68, 155.69. 19: 1H NMR (CDCl3): = 1.34 (s, 3 H,
CH3), 2.47 (d, 1 H, J = 2.75 Hz, OH), 3.22 (d, 1 H, J = 9.46
Hz), 3.51 (dd, 1 H, J = 10.07 Hz, J = 4.58 Hz), 3.57 (dd, 1 H,
J = 9.77 Hz, J = 4.58 Hz), 3.64 (dd, 1 H, J = 9.46 Hz,
J = 2.75 Hz), 4.04 (s, br, 1 H), 3.92 (dd, 1 H, J = 10.37 Hz,
1.83 Hz), 3.98–4.06 (m, 4 H), 4.18 (d, 1 H, J = 12.21 Hz,
CH2Ph), 4.24–4.28 (m, 1 H), 4.32 (d, 1 H, J = 12.21 Hz,
CH2Ph), 4.33 (d, br, 1 H, J = 8.55 Hz), 4.41–4.46 (m, 3 H,
CH2Ph), 4.50–4.54 (m, 3 H, CH2Ph and CH2=), 4.61 (t, 2 H,
J = 10.99 Hz, CH2Ph), 4.74 (dd, 1 H, J = 8.85 Hz, J = 3.05
Hz), 4.88–4.95 (m, 3 H, CH2Ph), 7.00–7.03 (m, 2 H, ArH),
7.20–7.37 (m, 28 H, ArH); 13C NMR (CDCl3): = 21.23,
69.23, 69.93, 69.96, 70.44, 70.74, 71.58, 73.04, 73.31,
73.63, 75.33, 75.35, 80.16, 80.82, 81.29, 82.72, 84.54,
86.44, 101.53, 127.16, 127.21, 127.33, 127.49, 127.59,
127.60, 127.64, 127.69, 127.74, 127.78, 127.80, 127.82,
127.84, 127.87, 128.12, 128.18, 128.25, 128.33, 128.37,
128.39, 128.44, 128.46, 128.55, 137.80, 138.04, 138.20,
138.59, 138.62, 138.99, 159.82.
Synlett 2001, No. 12, 1885–1888 ISSN 0936-5214 © Thieme Stuttgart · New York