Hafnium(IV) tetratriflate in selective reductive carbohydrate benzylidene acetal opening reaction and direct silylation reaction

Article abstract of DOI:10.1016/j.tetlet.2013.10.011

Hafnium(IV) tetratriflate was shown to be an effective catalyst for the regioselective reductive benzylidene ring opening with concurrent silylation reaction. The synthetic conditions were optimized, and the scope and limitations were identified. In addit

Full text of DOI:10.1016/j.tetlet.2013.10.011

Tetrahedron Letters 54 (2013) 6838–6840
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Tetrahedron Letters
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Hafnium(IV) tetratriflate in selective reductive carbohydrate
benzylidene acetal opening reaction and direct silylation reaction
a,b,
Shino Manabe a, , Yukishige Ito
⇑
⇑
a RIKEN, Synthetic Cellular Chemistry Laboratory, Hirosawa, Wako, Saitama 351-0198, Japan
b ERATO, JST, Hirosawa, Wako, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Hafnium(IV) tetratriflate was shown to be an effective catalyst for the regioselective reductive benzyli-
dene ring opening with concurrent silylation reaction. The synthetic conditions were optimized, and
the scope and limitations were identified. In addition to glucose and glycosamine derivatives, mannose
and galactose were successfully employed as substrates. Various protecting groups such as acetyl, allyl,
and benzyl were found to be stable under the reaction conditions. By using a deuterated reducing
reagent, the reaction was deduced to proceed via an SN1 mechanism.
Received 18 August 2013
Revised 25 September 2013
Accepted 3 October 2013
Available online 10 October 2013
Keywords:
Carbohydrates
Reduction
Ó 2013 Elsevier Ltd. All rights reserved.
Regioselectivity
Silylation
Regioselective ring opening of benzylidene acetals is an impor-
tant reaction in the field of carbohydrate chemistry, as such acetals
are valuable protecting groups for block 1,3-diols. Benzylidene
acetals can be opened selectively under appropriate reaction con-
ditions to yield primary or secondary alcohols (Scheme 1).1 Since
Bhattacharjee and Gorin introduced the method to the field of
carbohydrate chemistry,2 a number of effective systems for achiev-
ing reductive benzylidene acetal ring opening have been reported.
Of these, AlH3 and i-Bu2AlH have been used to obtain cleavage at
the O6 position,3,4 and Et3SiH–Lewis acid combinations have been
shown to cleave at the O4 position.5 For the reaction mediated by
Et3SiH, the amount of Lewis acid required is usually more than
stoichiometric, and the reaction takes several hours to complete.
Recently, various metal triflates such as Cu(OTf)2 and V(O)(OTf)2
have been reported to be effective Lewis acid catalysts for this
reaction.6,7 We carried out the Cu(OTf)2 (5 mol %) catalyzed benzyl-
idene cleavage reaction of methyl 2,3-di-O-benzyl-4,6-O-benzyli-
BnO
HO
BnO
TESO
PO
O
O
+
O
PO
Ph
O
O
PO
HO
BnO
PO
O
Scheme 1. Regioselective reductive benzylidene cleavage reaction and concomi-
tant silylation reaction.
Kobayashi and other groups have reported that Hf(OTf)4 is an effec-
tive Lewis acid for a variety of different reactions.9 We therefore
speculated that Hf(OTf)4 could work as an effective Lewis acid for
the regioselective benzylidene acetal cleavage reaction and con-
comitant silylation reaction.
As the opening of methyl 2,3-di-O-benzyl-4,6-O-benzylidene-
-glucopyranoside 1 has evolved into a standard reaction when
a-
D
comparing different methods for reactions of this type, we selected
this as an initial substrate for optimizing the synthesis conditions.
The reaction was completed in the presence of 2 equiv of Et3SiH
and 0.05 equiv of Hf(OTf)4 within 30 min (Table 1, entry 1). The
ratio of direct TES ether formation was increased using Hf(OTf)4.
4-alcohol 2f and its corresponding TES ether 2a were obtained in
37% and 44% yields, respectively. To facilitate the purification
process, the TES group of compound 2a was cleaved under aqueous
conditions in a one-pot reaction by the addition of 1 M HCl (entry
2). The yield of alcohol 2f was reduced after a prolonged reaction
period of up to 2 h (entry 3). When the amount of Hf(OTf)4 was
increased to 15 mol %, yield of alcohol 2f was increased (entry 4).
dene-a-D-glucopyranoside 1 using Et3SiH (2 equiv) in CH3CN
according to Hung’s procedure,7 giving 4-hydroxy alcohol 2f
(67%) and the corresponding TES ether 2a (21%). Although the
concomitant TES formation reaction was not reported by Hung,
we were interested in direct TES ether formation during the ben-
zylidene acetal cleavage reaction. As an initial attempt, we focused
on Hf(OTf)4, as it was recently found to be a good mediator of
glycosyl fluoride activation in an operationally simple manner.8
⇑
Corresponding authors. Tel.: +81 467 9432; fax: +81 462 4680 (S. Manabe); tel.:
+81 467 9430; fax: +81 462 4680 (Y. Ito).
E-mail addresses: smanabe@riken.jp (S. Manabe), yukito@riken.jp (Y. Ito).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.011

S. Manabe, Y. Ito / Tetrahedron Letters 54 (2013) 6838–6840
6839
Table 1
Regioselective benzylidene acetal cleavage reaction catalyzed by Hf(OTf)4
reducing
O
BnO
RO
BnO
HO
reagent
Ph
O
O
O
O
Lewis acid
+
BnO
BnO
BnO
BnO
BnO
2a-2e
BnO
2f
OMe
OMe
OMe
1
2a R = TES
2b R = Me2Et
2c R = TIPS
2d R = Ph3Si
2e R = TMS3Si
Entry
Reducing reagent
Lewis acid amount (mol %)
Time (h)
Solvent
Products
2a–2e (%)
2f (%)
Recovery of 1 (%)
1
2
3
4
5
6
7
8
Et3SiH
5
5
5
15
1
5
5
5
5
5
1/2
1/2
2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
Toluene
Et2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
—
44
0
37
79
28
62
33
26
0
0
0
0
0
0
Et3SiHa
Et3SiH
44
24
53
21
0
Et3SiH
Et3SiH
Et3SiH
Et3SiH
1/6
3 + 1/2
1/2
1/2
1/2
1/3
1/2
1
0
90
94
0
64
46
80
0
Et3SiH
0
0
9
Me2EtSiH
iPr3SiH
Ph3SiH
TMS3SiH
BH3ÁTHF
BH3ÁNMe3
Et3SiHg
13
11
0
0
0
58
16
23
12
0
10
11
12
13b
14b
15c
5
5
5
5
1/2
2
12
—
2a
0
0
0
77
80
0
200
2
a
b
c
After the reaction, 1 M HCl aq was added and the mixture was stirred for 0.5 h.
The reaction was carried out at room temperature.
2 equiv of BF3ÁOEt2 and 12 equiv of Et3SiH were used.
HO
HO
HO
BnO
O
O
BnO
BnO
BnO
OMe
BnO
OMe
3
4
Instead, with reduced amount of Hf(OTf)4 with 1 mol %, yield of
TES ether 2a was increased (entry 5). It is likely that the TES ether
was cleaved owing to the acidity of Hf(OTf)4 itself. In CH2Cl2, the
reaction became more complex, with 6-alcohol 3 obtained in 7%
yield together with 4-alcohol 2f and its silylated product 2a (entry
6). No reaction was observed in toluene and Et2O, and the starting
material was recovered (entries 7 and 8). When the less hindered
reducing reagent, Me2EtSiH, was employed, the efficacy of the
reaction did not change significantly (entry 9), but with hindered
reducing reagents such as Ph3SiH and TMS3SiH, the yield of alcohol
was lowered and the silyl ether was not obtained (entries 11 and
12). Although the use of a Cu(OTf)2-mediated reaction enables
the regiochemistry to be controlled to either the O4 or O6 position
by merely changing the reducing reagent, unfortunately, when
Hf(OTf)4 was used with BH3ÁTHF as the reducing reagent, the ben-
zylidene group was removed to give diol 4 in 92% yield (entry 13).
When BH3ÁNMe3 was employed, no reaction was observed and
starting material 1 was recovered in good yield (entry 14). Under
the same reaction conditions as those reported in reference 5a,
and using 12 equiv of Et3SiH and 2 equiv of BF3ÁOEt2, 2f was ob-
tained in 77% yield, together with 3 in 6% yield after 2 h (entry
15). Compared with the conventional method (entry 15), the
Hf(OTf)4-mediated reductive benzylidene cleavage reaction has
clear advantages.
11 also gave good results (entry 7). Disaccharide 12 readily under-
went the benzylidene ring opening reaction to give compounds
20a and 20b in good yield (entry 8). Although it is known that
substituents at C3 position may affect regioselectivity,1,10 our con-
ditions gave 6-benzyl products regardless the protecting groups of
the 3-hydroxy group.
To elucidate the details of the reaction mechanism, Et3SiD was
used as a deuteride source (Scheme 2).1,11,12 Hung and Ellervik re-
ported that the benzylidene acetal cleavage reaction proceeds via
either an SN1 or SN2 pathway, depending on the particular combi-
nation of solvent, reducing reagent, and Lewis acid. Using the reac-
tion conditions listed as in entry 1 in Table 1, with the deuterated
reducing reagent Et3SiD, we carried out the Hf(OTf)4-catalyzed
reaction with compound 1. Products 21 and 22 were given in
35% and 55% yields, respectively. As previously reported by Hung,
the stereochemistry at the benzylic position was found to be a
49:51 (R/S) mixture. TES ether 22 also gave mixture of (R) and (S)
compounds at the benzylic position. Treatment of 22 with TBAF
gave 21R:21S in a 53:47 ratio in 93% yield. The reason for this
slightly different R/S ratio is not currently clear, with further exper-
imentation required in order to elucidate this. Overall, these results
demonstrate that the Hf(OTf)4-catalyzed benzylidene cleavage
reaction proceeded via an SN1 mechanism.
In conclusion, Hf(OTf)4 has been shown to be an effective cata-
lyst for the regioselective benzylidene acetal cleavage reaction and
direct TES ether formation. Although the mechanism of TES ether
formation is not clear at this point, the selective protection of the
6-OH and 4-OH of pyranosides would be useful for further trans-
formation. As Hf(OTf)4 is a commercially available solid that is easy
to handle in air, the developed method has great potential in the
field of organic synthesis.
We next investigated the scope and limitations of this method.
Using the conditions as the same as in entry 1 in Table 1, (5 mol %
Hf(OTf)4, CH3CN, 4 °C, 30 min), we examined glucose 5 and 6, glu-
cosamine 7 and 8, mannose 9 and 10, galactose 11, and disaccha-
ride 12 with various protecting groups. In addition to the benzyl
group, the azide, allyl, acyl, and phthaloyl groups were all found
to be stable under these conditions (Table 2). Galactose derivative

6840
S. Manabe, Y. Ito / Tetrahedron Letters 54 (2013) 6838–6840
Table 2
O
Ph
O
O
Scope and limitations of Hf(OTf)4-catalyzed regioselective benzylidene acetal cleav-
age reaction
BnO
BnO
OMe
Et3SiD (2 equiv)
Hf(OTf)4 (0.05 equiv.)
CH3CN
Et3SiH
Hf(OTf)4
CH3CN
1
O
BnO
HO
BnO
TESO
PO
13a-20a
Ph
O
O
O
O
+
PO
PO
5-12
13b-20b
4
0.5 h
35%
H
55%
Entry
Substrate
Product
Yield (%)
Product
Yield (%)
D
H
O
D
1
2
3
4
5
6
7
8
5
6
7
8
9
10
11
12
13a
14a
15a
16a
17a
18a
19a
20a
20
43
10
39
22
24
49
64
13b
14b
15b
16b
17b
18b
19b
20b
57
43
70
56
46
42
51
33
Ph
TESO
Ph
O
O
O
HO
BnO
BnO
BnO
22R
BnO
21R
OMe
2M HCl
OMe
MeOH-dioxane
D
H
D
O
H
93%
Ph
TESO
Ph
O
HO
O
O
BnO
MP = p-methoxyphenyl.
BnO
BnO
22S
BnO
OMe
OMe
O
O
Ph
Ph
Ph
O
O
21S
O
O
SPh
OMP
BnO
AllO
22R:22S = 53:47
21R:21S = 49:51
OBz
OAc
5
7
6
Scheme 2. Stereochemistry of deuteride incorporation at the benzylic position.
O
O
O
O
Ph
O
O
OMP
SPh
AcO
BnO
N3
NPhth
Acknowledgments
8
OAc
OBn
O
O
O
O
This research was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science and
Technology (Grant No. 24590041), Yamada Science Foundation,
Takeda Foundation, and a Shiseido Female Research Grant. We
thank Ms. A. Takahashi for technical assistance and Dr. Kaori
Otsuki, Dr. Masaya Usui, and Dr. Aya Abe at the Research Resource
Center of RIKEN’s Brain Science Center for the HRMS measurement.
Ph
Ph
Ph
O
O
AcO
BnO
SPh
SPh
9
10
Ph
O
O
BnO
O
O
O
O
OMP
NPhth
AcO
AcO
O
NPhth
O
SPh
SPh
AcO
12
OAc
11
Supplementary data
BnO
RO
BnO
RO
O
O
OMP
Supplementary data (experimental, 1H NMR, 13C NMR, and
HRMS) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.10.011.
BnO
AllO
OBz
OAc
13a
14a
R = TES
R = TES
14b
R = H
13b
R = H
BnO
BnO
O
O
RO
RO
OMP
SPh
AcO
References and notes
BnO
N3
NPhth
15a R = TES
16a R = TES
1. For a review: Ohlin, M.; Johnsson, R.; Ellervik, U. Carbohydr. Res. 2011, 346,
1358.
2. Bhattacharjee, S. S.; Gorin, P. A. Can. J. Chem. 1969, 47, 1195.
3. (a) Lipták, A.; Jodál, I.; Nánási, P. Carbohydr. Res. 1975, 44, 1; (b) Fügedi, P.;
Lipták, A.; Nánási, P. Carbohydr. Res. 1982, 104, 55.
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5. (a) Debenham, S. D.; Toone, E. J. Tetrahedron: Asymmetry 2000, 11, 385; (b)
Balakumar, V.; Aravind, A.; Baskaran, S. Synlett 2004, 647.
6. Wang, C.-C.; Luo, S.-Y.; Shie, C.-R.; Hung, S.-C. Org. Lett. 2002, 4, 847.
7. Shie, C.-R.; Tzeng, Z.-H.; Kulkarni, S. S.; Uang, B.-J.; Hsu, C.-Y.; Hung, S.-C.
Angew. Chem., Int. Ed. 2005, 44, 1665.
15b
R = H
16b
R = H
OAc
OBn
BnO
BnO
O
O
RO
RO
AcO
BnO
SPh
SPh
17a R = TES
18a R = TES
17b
18b
R = H
R = H
O
OBn
BnO
BnO
O
O
RO
AcO
RO
OMP
NPhth
AcO
AcO
O
NPhth
SPh
8. Manabe, S.; Ito, Y. J. Org. Chem. 2013, 78, 4568.
OAc
9. (a) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Tetrahedron Lett. 1995, 36, 409; (b)
Hachiya, I.; Moriwaki, M.; Kobayashi, S. Bull. Chem. Soc. Jpn. 1995, 68, 2053; (c)
Kobayashi, S.; Moriwaki, M.; Hachiya, I. Tetrahedron Lett. 1996, 37, 2053; (d)
Waller, F.; Barrett, A. G. M.; Braddock, D. C.; Ramprasad, D. Tetrahedron Lett.
1998, 39, 1641; (e) Okitsu, O.; Suzuki, R.; Kobayashi, S. Synlett 2000, 989; (f)
Oohashi, Y.; Fukumoto, K.; Mukaiyama, T. Chem. Lett. 2005, 34, 190; (g)
Kawatsura, M.; Aburatani, S.; Uenishi, J. Synlett 2005, 2492; (h) Noji, M.; Konno,
Y.; Ishii, K. J. Org. Chem. 2007, 72, 5161; (i) Qin, H.; Yamagiwa, N.; Matsunaga,
S.; Shibasaki, M. Chem. Asian J. 2007, 2, 150; (j) Wu, Y.-C.; Zhu, J. J. Org. Chem.
2008, 73, 9522. and references therein.
20a R = TES
20b R = H
19a R = TES
19b R = H
Typical experimental procedure
To a solution of substrate (1.0 M) and Et3SiH (2 equiv) in CH3CN,
Hf(OTf)4 (0.05 equiv) was added at 4 °C. After consumption of the
starting material, as determined by TLC or by leaving an adequate
period of time, the reaction was quenched with satd NaHCO3, and
the aqueous layer was extracted several times with EtOAc. The
combined layers were washed with brine and dried over Na2SO4.
After concentration, the crude product was purified by preparative
TLC.
10. (a) Ek, M.; Garegg, P. J.; Hultberg, H.; Oscarson, S. J. Carbohydr. Chem. 1983, 2,
305; (b) Oikawa, M.; Liu, W.-C.; Nakai, Y.; Koshida, S.; Fukase, K.; Kusuoto, S.
Synlett 1996, 1179.
11. (a) Johnsson, R.; Ohlin, M.; Ellervik, U. J. Org. Chem. 2010, 75, 8003; (b) Lee, I.-C.;
Zulueta, M. M. L.; Shie, C.-R.; Arco, S. D.; Hung, S.-C. Org. Biomol. Chem. 2011, 9,
7655.
12. For the general acetal cleavage reaction mechanism, see: Denmark, S. E.;
Almstead, N. G. J. Am. Chem. Soc. 1991, 113, 8089.