Regio- and chemoselective reductive cleavage of 4,6-O-benzylidene-type acetals of hexopyranosides using BH3·THF-TMSOTf

Article abstract of DOI:10.1016/j.tetlet.2009.03.194

Benzylidene-type cyclic acetals of carbohydrates undergo efficient reductive ring opening using BH₃·THF and a catalytic amount of TMSOTf at room temperature. 4,6-O-Benzylidene-hexopyranosides afford the corresponding 4-O-benzyl ethers exclusive

Full text of DOI:10.1016/j.tetlet.2009.03.194

Tetrahedron Letters 50 (2009) 2914–2916
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Regio- and chemoselective reductive cleavage of 4,6-O-benzylidene-type
acetals of hexopyranosides using BH3ÁTHF–TMSOTf
*
Katalin Daragics, Péter Fügedi
Department of Carbohydrate Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri út 59-67, H-1025 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzylidene-type cyclic acetals of carbohydrates undergo efficient reductive ring opening using BH3ÁTHF
and a catalytic amount of TMSOTf at room temperature. 4,6-O-Benzylidene-hexopyranosides afford the
corresponding 4-O-benzyl ethers exclusively, in high yields. Other benzylidene-type acetals, such as
naphthylmethylene and 4-methoxybenzylidene acetals are also cleaved with the same reagent. The con-
versions are highly regio- and stereoselective and afford benzyl-type ethers in excellent yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 12 February 2009
Revised 17 March 2009
Accepted 27 March 2009
Available online 2 April 2009
Keywords:
Carbohydrates
Benzylidene acetals
Reductive ring opening
Regioselective
Regioselective protection of individual hydroxy groups of
carbohydrates is an essential step for the synthesis of complex
carbohydrates. Cyclic acetals are formed regioselectively and are
commonly used for the 4,6-O-protection of hexopyranosides. In
addition, the reductive ring opening of benzylidene-type acetals
to the corresponding O-benzyl (or substituted benzyl) ethers, in a
regioselective manner, allows release of any one of the two hydro-
xy groups, while providing the other as benzyl protected. Thus,
these two steps constitute a very effective method for regioselec-
tive benzylation.
has a directing effect.2c In most of the above methods, the choice
of the reaction solvent is restricted, and the desired regioselectivity
can only be obtained in a particular solvent. Changing the solvent
sometimes not only results in loss, but also in reversal of the reg-
ioselectivity.3b,4a,5a Reaction temperature and even reagent con-
centrations have been reported to have a similar effect.9c Traces
of water13 and protic acids9c also influence the yields and reaction
2
rates. Additionally, some of these reagents such as LiAlH4–AlCl3
and DIBAL-H3 are not compatible with several of the common
protecting groups, whilst other reagents, such as BH3ÁNMe3–AlCl3
in toluene4a give only modest yields of products due to decompo-
sition of the starting materials. In most of these methods, the
hydride or Lewis acid have to be used in large excess. Some of
the latter are quite hazardous and expensive, which limit their
use in large-scale applications.
Various reagent systems have been introduced for the regioselec-
tive ring cleavage of benzylidene acetals to benzyl ethers.1 For the
preparation of 4-O-benzyl ethers these include: LiAlH4–AlCl3,2
DIBAL-H,2c,3 BH3ÁNMe3–AlCl3,4 BH3ÁHNMe2–BF3ÁOEt2,5 BH3ÁNMe3–
7a
Me2BBr,6 Et3SiH–PhBCl2,7 PS-DES –PhBCl2, polymethylhydrosi-
TM
loxane (PMHS)–AlCl3,8 and BH3ÁTHF alone2c or in combination with
Ph2BBr,9a Bu2BOTf,9b,c lanthanide triflates,9d Cu(OTf)2,9e or CoCl2.9f
Alternatively, for the preparation of 6-O-benzyl ethers, NaCNBH3–
HCl,10 NaCNBH3-MsOH,11 BH3ÁNMe3–AlCl3,4a BH3ÁHNMe2–BF3Á
OEt2,5a or silanes, such as Et3SiH12 in combination with TFA,12a
Hence, there is still the need for a generally applicable, regiose-
lective, effective, and practical method for the reductive ring
opening of 4,6-O-benzylidene-hexopyranosides to the correspond-
ing 4-O-benzyl ethers. Here we report a new method for the ring
opening of benzylidene-type acetals which provides O-benzyl
and related ethers in excellent yields and regioselectivity.14
Using compound 1 as a common substrate we have studied the
reductive ring cleavage using various borane complexes
(BH3ÁNMe3, BH3ÁSMe2, and BH3ÁTHF) as hydride donors in combi-
nation with different Lewis acids. The results of the reactions with
TMSOTf are summarized in Table 1.
9e
TfOH,7a or BF3ÁOEt2,5b,12b and Me2EtSiH–Cu(OTf)2 have been
reported.
The regioselectivities and the yields of the ring opening reac-
tions using the above reagents are influenced by several factors.
The regioselectivity often varies on changing the structure of the
substrate and the steric bulk of neighboring substituents often
Reaction with BH3ÁNMe3 in CH2Cl2 gave only the 6-O-benzyl
derivative (as a ꢀ1:1 mixture of 2a and its trimethylsilyl derivative
2b), BH3ÁSMe2 afforded 6-O- (2a) and 4-O-benzyl ethers (3) in ca.
* Corresponding author. Tel.: +36 1 438 1100; fax: +36 1 438 1145.
E-mail address: pfugedi@chemres.hu (P. Fügedi).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.194

K. Daragics, P. Fügedi / Tetrahedron Letters 50 (2009) 2914–2916
2915
Table 1
1:1 ratio. Using BH3ÁTHF, however, only the 4-O-benzyl ether (3)
was formed, which was isolated in excellent yield. Similar changes
in the regioselectivity using the same borane complexes in combi-
nation with AlCl3 have been published recently.15
Reductive ring opening of 4,6-O-benzylidene acetal
complexes and TMSOTf
1
with different borane
OH
OBn
O
Ph
Borane, TMSOTf
CH2Cl2
O
O
RO
O
BnO
BnO
O
+
BnO
BnO
These results suggest that the choice of the borane complex
plays a decisive role in determining the regioselectivity. Next, the
effect of various Lewis acids was studied in combination with
BH3ÁTHF (Table 2).
BnO
BnO
OMe
BnO
OMe
OMe
1
2a
R = H
3
2b R = TMS
Entry Borane
complex
Amount of TMSOTf Reaction
Isolated yield (%)
Irrespective of the Lewis acid used (TMSOTf, Sc(OTf)3, ZnI2,
AlCl3, and BF3ÁOEt2), in all cases, the 4-O-benzyl ether was formed
in excellent yield. On the other hand, the reaction rate was strongly
influenced by the Lewis acid.
(equiv)
time (h)
6-O-
4-O-
Benzyl 2
Benzyl 3
1
2
3
BH3ÁNMe3
BH3ÁSMe2
BH3ÁTHF
1.5
0.15
0.15
7
1
1
84
48
0
0
40
96
From the reagent combinations tested BH3ÁTHF–TMSOTf16 was
selected for further investigations and a series of 4,6-O-benzyli-
dene acetals were next reduced in CH2Cl2 (Table 3).17
In all cases, the cleavage reactions afforded the corresponding
4-O-benzyl ethers in high yields. The regioselectivity and the yields
were unaffected by the nature and steric bulk of the O-3 substitu-
ents. Also, the regioselectivity was not influenced by the type of
ring annelation, both trans- (entries 1–4) and cis-annelated sys-
tems (entries 5–7) gave the 4-O-benzyl ethers. In contrast to other
methods,3a,4a,5a the regioselectivity was not affected by changing
the solvent, essentially the same results were obtained by perform-
ing the reactions in THF instead of CH2Cl2.
Table 2
Effect of Lewis acids on the reductive cleavage of 1 with BH3ÁTHF
Entry
Lewis acid
Amount
(equiv)
Reaction
time (h)
Isolated yield
of 3 (%)
1
2
3
4
5
TMSOTf
Sc(OTf)3
ZnI2
AlCl3
BF3ÁOEt2
0.15
0.15
0.15
1.15
3
1
6
7
24
240
96
96
99
99
91
The reagent system is compatible with most common protect-
ing groups, such as benzyl (entries 1–4, 6–7) and tert-butyldimeth-
ylsilyl ethers (entries 1f and 1g), acyl groups including benzoyl
(entries 1b, 1c, 5, 7), acetyl (entries 1f and 1g), and chloroacetyl
(see Table 4), as well as benzyloxycarbonyl (entry 1d) and fluore-
nylmethoxycarbonyl (entry 3) groups. Furthermore, the reactions
could also be performed in the presence of free hydroxy (entries
1e and 5), azido (entry 2), and thioglycoside (entries 2, 3, 6, and
7) moieties. No undesired hydrolysis of the benzylidene acetals
was observed as BH3ÁTHF reacts readily with water.
Table 3
Reductive cleavage of 4,6-O-benzylidene-hexopyranosides with BH3ÁTHF and TMSOTf
Entry Substrate
Product
Isolated yield (%)
OH
O
O
Ph
O
O
BnO
R2
R2
1
R1
R1
OMe
OMe
a
b
c
d
e
f
1 R1 = OBn, R2 = OBn
4 R1 = OBz, R2 = OBz
6 R1 = OBn, R2 = OBz
3 R1 = OBn, R2 = OBn
5 R1 = OBz, R2 = OBz
7 R1 = OBn, R2 = OBz
96
87
99
8 R1 = NHCO2Bn, R2 = OBn 9 R1 = NHCO2Bn, R2 = OBn 99
10 R1 = OBn, R2 = OH
11 R1 = OBn, R2 = OH
72
12 R1 = OAc, R2 = OTBDMS 13 R1 = OAc, R2 = OTBDMS 87
14 R1 = OTBDMS, R2 = OAc 15 R1 = OTBDMS, R2 = OAc 95
Table 4
g
Reductive cleavage of 4-methoxybenzylidene and 1-naphthylmethylene acetals using
BH3ÁTHF-TMSOTf
OH
O
O
Ph
O
BnO
BnO
O
SPh
SPh
BnO
2
3
95
89
Entry
Substrate
Product
Isolated yield (%)
89a
N3
N3
16
17
OH
O
O
PMP
O
PMBO
BnO
O
OH
O
OFmoc
19
1
BnO
O
O
Ph
O
BnO
BnO
OMe
BnO
BnO
SEt
OMe
SEt
BnO
28
29
OFmoc
18
OH
O
O
BnO
PMP
O
BzO
PMBO
BnO
O
SEt
SEt
2
3
4
76
90
84
OBn
O
HO
BnO
OBn
O
O
O
Ph
BzO
31
30
4
5
91
88
BnO
BnO
OBn
OBn
OBn
20
21
1Naphth
1Naphth
OH
O
1NAPO
BnO
O
O
Ph
O
O
SEt
SEt
BnO
BnO
BzO
OH
O
SEt
SEt
BzO
32
BzO
33
O
OBn
O
OH
23
BzO
OH
OH
O
22
1NAPO
BnO
O
O
O
BnO
Ph
O
ClAcO
ClAcO
35
BnO
BnO
OH
O
34
O
SEt
6
7
91
95
O
1Naphth
SEt
OBn
25
BnO
1NAPO
BnO
OH
O
OBn
24
O
O
5
84
O
BnO
BnO
OCH3
SPh
SPh
BnO
BnO
BnO
OCH3
37
HO
O
O
36
O
O
OBz
26
OBn
27
PMB = p-methoxybenzyl; PMP = p-methoxyphenyl; 1NAP = 1-naphthylmethyl;
OBz
1Naphth = 1-naphthyl.
Ph
a
The reaction was carried out using BH3ÁTHF without TMSOTf.

2916
K. Daragics, P. Fügedi / Tetrahedron Letters 50 (2009) 2914–2916
Table 5
References and notes
Reductive cleavage of 1,3-dioxolane-type benzylidene acetals with BH3ÁTHF-TMSOTf
1. Garegg, P. J. In Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker: New York, NY, USA, 1997; pp 53–67.
Entry
Substrate
Product
Isolated yield (%)
OBn
2. (a) Bhattacharjee, S. S.; Gorin, P. A. J. Can. J. Chem. 1969, 47, 1195–1206; (b)
Lipták, A.; Jodál, I.; Nánási, P. Carbohydr. Res. 1975, 44, 1–11; (c) Fügedi, P.;
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Tanaka, N.; Ogawa, I.; Yoshigase, S.; Nokami, J. Carbohydr. Res. 2008, 343, 2675–
2679.
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305–311; (b) Fügedi, P.; Birberg, W.; Garegg, P. J.; Pilotti, Å. Carbohydr. Res.
1987, 164, 297–312.
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Synlett 1996, 1179–1180; (b) Tanaka, K.; Fukase, K. Synlett 2007, 164–166.
6. Ghosh, M.; Dulina, R. G.; Kakarla, R.; Sofia, M. J. J. Org. Chem. 2000, 65, 8387–
8390.
OBn
Me
O
O
Me
BnO
BnO
BnO
OH
1
88
O
O
Ph H
38
39
OBn
OBn
Me
BnO
O
Me
O
BnO
O
HO
2
69
O
OBn
H Ph
7. (a) Sakagami, M.; Hamana, H. Tetrahedron Lett. 2000, 41, 5547–5551; (b) Dilhas,
A.; Bonnaffé, D. Tetrahedron Lett. 2004, 45, 3643–3645.
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41
8. Chandrasekhar, S.; Reddy, Y. R.; Reddy, C. R. Chem. Lett. 1998, 1273–1274.
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Can. J. Chem. 1990, 68, 897–902; (b) Jiang, L.; Chan, T.-H. Tetrahedron Lett. 1998,
39, 355–358; (c) Hernandez-Torres, J. M.; Achkar, J.; Wei, A. J. Org. Chem. 2004,
69, 7206–7211; (d) Wang, C.-C.; Luo, S.-Y.; Shie, C.-R.; Hung, S.-C. Org. Lett.
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J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97–101.
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669–672; (b) Debenham, S. D.; Toone, E. J. Tetrahedron: Asymmetry 2000, 11,
385–387.
The BH3ÁTHF–TMSOTf reagent proved to also be effective for the
ring opening of other benzylidene-type acetals. Reactions of
p-methoxybenzylidene and 1-naphthylmethylene acetals afforded
the p-methoxybenzyl (PMB) and 1-naphthylmethyl (1NAP) ethers,
respectively, in high yields and regioselectively (Table 4). In the
case of reduction of p-methoxybenzylidene acetals, reactions could
be performed using BH3ÁTHF without TMSOTf.
The reagent system is also applicable for the reductive cleavage
of 1,3-dioxolane-type benzylidene acetals (Table 5). As with other
reagents, the regioselectivity in this case was determined by the
configuration of the acetal carbon.10b,13,18
13. Sherman, A. A.; Mironov, Y. V.; Yudina, O. N.; Nifantiev, N. E. Carbohydr. Res.
2003, 338, 697–703.
14. Daragics, K.; Fügedi, P. In 13th European Carbohydrate Symposium, Bratislava,
Slovakia, August 21–26, 2005; Abstract P20.
In conclusion, BH3ÁTHF-TMSOTf is an effective and practical
reagent which cleaves benzylidene, p-methoxybenzylidene, and
naphthylmethylene acetals regioselectively under mild condi-
tions to the corresponding 4-O-ethers in excellent yield. Further-
more the regioselectivity was not influenced by the type of ring
annelation. The conversions are highly chemo- and regioselective
and afford the corresponding ethers in excellent yields. This
method should have utility in the preparation of complex
carbohydrates.
15. (a) Johnsson, R.; Olsson, D.; Ellervik, U. J. Org. Chem. 2008, 73, 5226–5232; (b)
Johnsson, R.; Cukalevski, R.; Dragén, F.; Ivanisevic, D.; Johansson, I.; Petersson,
L.; Wettergren, E.; Yam, K. B.; Yang, B.; Ellervik, U. Carbohydr. Res. 2008, 343,
2997–3000.
16. TMSOTf is less expensive than the metal triflates9d,9e and organoboron
compounds9a–c used in combination with BH3ÁTHF recently. In contrast to
methods using Ph2BBr,9a Bu2BOTf9b,c, and CoCl29f where an excess of the Lewis
acid is required, the ring opening proceeds readily using only a catalytic
amount of TMSOTf. An additional advantage is the relative safe handling of
TMSOTf compared to the highly pyrophoric Bu2BOTf.9b,c
17. Typical experimental procedure: To a solution of the acetal (1 mmol) in dry
CH2Cl2 (10 mL) a 1 M solution of borane in THF (5 mL, 5 equiv) and TMSOTf
(0.027 mL, 0.15 equiv) were added and the mixture was stirred under argon at
room temperature. When TLC indicated the complete disappearance of the
starting material (1–4 h), Et3N (1 mL) was added, followed by careful addition
of MeOH until the evolution of H2 ceased. The mixture was concentrated, and
the residue was coevaporated with MeOH (3 Â 30 mL). Purification of the
residue by silica gel column chromatography afforded the 4-O-benzyl ethers.
Reactions on a larger scale (up to 0.05 mol) were also performed by reducing
the excess of borane to 2 equiv giving the same results. All new compounds
were analyzed and characterized by 1H-, 13C- NMR, and MS-spectroscopies.
18. (a) Lipták, A.; Fügedi, P.; Nánási, P. Carbohydr. Res. 1976, 51, C19–C21; (b)
Lipták, A.; Fügedi, P.; Nánási, P. Carbohydr. Res. 1978, 65, 209–217.
Acknowledgment
The skillful technical assistance of Ms. Katalin T. Palcsu is grate-
fully acknowledged.
Supplementary data
Supplementary data (characterization data of all new
compounds) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.03.194.