Synthesis of L-pyranosides from 5-enopyranosides by diastereoselective hydroboration/oxidation

Article abstract of DOI:10.1055/s-2004-834889

Improved synthesis of L-pyranosides utilizing diastereoselective hydroboration/oxidation of 5-enopyranosides was investigated. A unique phenomenon in the diastereoselectivity of the hydroboration was incidentally found. The method was successfully applied to the synthesis of L-iduronic acid.

Full text of DOI:10.1055/s-2004-834889

PAPER
2991
Synthesis of L-Pyranosides from 5-Enopyranosides by Diastereoselective
Hydroboration/Oxidation
Synthesis of
L-Pyr
i
anoside
d
s
eyo Takahashi, Namisa Miyama, Haruhiko Mitsuzuka, Shiro Ikegami*
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan
Fax +81(426)853729; E-mail: shi-ike@pharm.teikyo-u.ac.jp
Received 2 August 2004; revised 1 September 2004
enogalactoside 1b and 5-enomannoside 1c. The results are
summarized in Tables 2 and 3, respectively.
Abstract: Improved synthesis of L-pyranosides utilizing diastereo-
selective hydroboration/oxidation of 5-enopyranosides was investi-
gated. A unique phenomenon in the diastereoselectivity of the
hydroboration was incidentally found. The method was successful-
ly applied to the synthesis of L-iduronic acid.
Table 1 Hydroboration/Oxidation of Methyl a-5-Enoglucoside 1a
Key words: carbohydrates, diastereoselectivity, glycosides, hy-
droboration, synthesis
L-Sugars, which are typical components of bioactive nat-
ural products, play important roles in various biological
processes.1 Numerous studies have been performed on the
synthesis of L-pyranose and L-furanose.2 In previous pa-
pers, we described the novel synthesis of L-idose, L-al-
trose, L-gulose,3 and L-ribose.4 Our strategy was based on
the Mitsunobu reaction,5 which epimerizes the critical C-
5 stereocenter and enables the efficient conversion of
readily available D-sugars into L-sugars. Along this line,
we herein report an alternative approach to L-pyranoside
synthesis utilizing the diastereoselective hydroboration/
oxidation of 5-enopyranosides.
Entry
BH3·THF (equiv)a Yield (%)b
Ratio of 2a:3ac
2.1: 1
1
2
3
4
5
6
2.0
3.0
73
82
87
88
85
85
2.9: 1
4.0
3.4: 1
5.0
3.8: 1
Several reports have focused on the study of hydrobora-
tion/oxidation of 5-enopyranosides,6 specifically on the
conversion of D-glucoside into L-idose or L-iduronic acid,
which is a typical component of mammalian glycosami-
noglycans.7 However, there appeared to be no previous
systematic investigation of various pyranosides. We
therefore examined the diastereoselective hydroboration/
oxidation of methyl 5-enoglucoside, 5-enogalactoside,
and 5-enomannoside.
7.0
7.3: 1
10.0
11: 1
a All reactions were carried out in THF (0.1 M).
b Isolated yield of products (2a + 3a).
c Ratios were determined by 1H NMR spectroscopy.
Table 2 Hydroboration/Oxidation of Methyl a-5-Enogalactoside
1b
Initially, methyl a-5-enoglucopyranoside 1a8 was reacted
with 2 equivalents of BH3·THF at 0 °C and then oxidized
to provide predominantly L-idoside (73% yield,
2a9:3a10 = 2.1:1, Table 1, entry 1). To obtain a satisfacto-
ry yield, the amount of the reagent BH3·THF was gradual-
ly increased.11 Interestingly, an increase in BH3·THF
resulted in a high stereoselectivity of 2a (Table 1). The re-
action with 10 equivalents of BH3·THF gave the remark-
ably high ratio of 2a:3a = 11:1 (entry 6). It should be
noted that the amount of the reagent significantly modi-
fied the distribution of the products. Such unusual results
prompted us to examine the hydroboration/oxidation of 5-
Entry
BH3·THFa
2.0
Yield (%)b
1
2
3
46
66
76
5.0
10.0
a All reactions were carried out in THF (0.1 M).
b Isolated yield.
SYNTHESIS 2004, No. 18, pp 2991–2994
x
x.
x
x
.
2
0
0
4
Advanced online publication: 22.10.2004
DOI: 10.1055/s-2004-834889; Art ID: F10804SS
© Georg Thieme Verlag Stuttgart · New York

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H. Takahashi et al.
PAPER
Table 3 Hydroboration/Oxidation of Methyl a-5-Enomannoside 1c
Table 4 Hydroboration/Oxidation of Methyl a-5-Enoglucoside 1d
and 1e
Entry
BH3·THF
5.0
Time (h)
Yield (%)a 2c:3cb
Entry
R
BH3·THF Time
Yield
(%)
2:3a
1
2
5
3
51
73
2.0: 1
2.4: 1
(equiv)
(h)
10.0
1
2
3
4
5
6
H
2.0
1
49b
79b
74b
81c
98c
92c
3.5: 1
4.2: 1
5.2: 1
1.4: 1
1.5: 1
2.1: 1
a Isolated yield of products (2c + 3c).
b Ratios were determined by 1H NMR spectroscopy.
H
5.0
1
H
10.0
2.0
1
Interestingly, 5-enogalactoside 1b gave contrasting re-
sults: only D-galactoside 3b12 was obtained and no L-altro-
side was observed. While the yield of 3b increased with
the addition of an excess amount of BH3·THF, there was
no change in the diastereoselectivity. The axial benzyloxy
group at the C-4 position might cover the b-face of the
double bond between C-5 and C-6 in galactoside. There-
fore the borane reagent could attack only from the a-face
to provide 3b selectively. In contrast, the hydroboration/
oxidation of 5-enomannoside 1c with 5.0 equivalents of
BH3·THF gave predominantly L-guloside (51% yield,
2c:3c13 = 2.0:1, Table 3, entry 1). The production of 2c
was slightly increased when 10 equivalents of the reagent
was used (entry 2).
TBDMS
TBDMS
TBDMS
4.5
3
5.0
10.0
1.5
a Ratios were determined by 1H NMR spectroscopy.
b Isolated yield of products (2d14 +3d15).
c Isolated yield of products (2e + 3e14).
BH3·THF afforded methyl b-L-idoside 2a with high dia-
stereoselectivity, we applied this method to the synthesis
of L-iduronic acid (Scheme 1). As mentioned, the hydro-
boration of 1a gave methyl b-L-idoside 2a in good yield.16
Oxidation of 2a and successive esterification gave L-
idopyranosiduronate 4. Finally, O-debenzylation of 4
gave the desired methyl L-iduronic acid ester 5.17
From these results, it is possible that the hydroboration of
5-enoglucoside 1a is an exceptional case, in which the
amount of the reagent dramatically controls the diastereo-
selectivity in the reaction. To the best of our knowledge,
this is a unique phenomenon observed in hydroboration
reactions. We therefore investigated this further. For the
moment, we focussed on the effect of the protective group
at the C-4 position of 5-enoglucoside. The hydroboration/
oxidation of 5-enoglucoside derivatives 1d14 and 1e was
examined (Table 4).
In the case of methyl a-5-enoglucoside 1d bearing the 4-
hydroxyl, the ratio of 2d was increased based on the
amount of borane reagent (Table 4, entries 1–3). Howev-
er, a slight increase in the ratio was observed in the case
of methyl a-5-enoglucoside 1e bearing hindered TBDMS
protection at the 4-position. Overall, it appears that the
differences in the stereochemistry and in the protection of
the carbohydrate somehow give rise to this unique phe-
nomenon. Although our information on these interesting
results is still limited, a detailed analysis of the reaction is
underway in our laboratory and an extended discussion
will be presented in the future.
Scheme 1 Reagents and conditions: (a) BH3·THF, THF, 0 °C, then
H2O2, NaOH, 0 °C; (b) CrO3, H2SO4, r.t.; (c) CH2N2, Et2O, 0 °C; (d)
Pd(OH)2/C, H2, MeOH, r.t.
In conclusion, we examined the hydroboration/oxidation
of 5-enoglycopyranosides and developed an efficient
method for the synthesis of L-idoside and L-guloside. This
simple route to L-sugar was applied to the synthesis of L-
iduronic acid. In the course of our study, we also found a
unique form of diastereoselectivity controlled by the
amount of reagent.
After we established that the hydroboration/oxidation of
methyl a-5-enoglucoside 1a with excess amounts of
Synthesis 2004, No. 18, 2991–2994 © Thieme Stuttgart · New York

PAPER
Synthesis of L-Pyranosides
IR (neat): 3457 cm–1 (OH).
2993
Melting points were determined with a Yanagimoto micro melting
point apparatus and are uncorrected. IR spectra were measured with
a JASCO FT/IR-8000 spectrometer. HRFAB-MS were recorded
with a JEOL SX-102A. 1H NMR and 13C NMR spectra were record-
ed at 600 MHz with a JEOL GSX-600 spectrometer using TMS as
the internal standard. Chemical shifts were reported in ppm down-
field from TMS. Optical rotations were measured with a JASCO
DIP-370 in a 1 dm cell. Analytical and preparative TLC was con-
ducted on precoated TLC plates (silica gel 60 F254, Merck). Column
chromatography was performed using Merck silica gel 60 N (100–
210 mm). All anhydrous solvents were purified according to stan-
dard methods.
1H NMR (600 MHz, CDCl3): d = 7.35–7.09 (15 H, m, C6H5), 4.85
(1 H, d, J = 12.1 Hz, PhCH2), 4.76 (1 H, d, J = 8.0 Hz, H-1), 4.74 (1
H, d, J = 12.1 Hz, PhCH2), 4.58 (1 H, d, J = 12.1 Hz, PhCH2), 4.54
(1 H, d, J = 12.1 Hz, PhCH2), 4.36 (1 H, d, J = 11.8 Hz, PhCH2),
4.22 (1 H, d, J = 11.8 Hz, PhCH2), 3.95 (1 H, ddd, J = 1.4, 4.7, 7.2
Hz, H-5), 3.82 (1 H, dd, J = 7.2, 11.3 Hz, H-6), 3.79 (1 H, dd,
J = 3.3, 3.6 Hz, H-3), 3.59 (1 H, dd, J = 3.3, 8.0 Hz, H-2), 3.56 (1
H, dd, J = 4.7, 11.3 Hz, H-6¢), 3.55 (3 H, m, CH3), 3.38 (1 H, dd,
J = 1.4, 3.6 Hz, H-4).
13C NMR (150 MHz, CDCl3): d = 138.7, 138.2, 137.5, 128.4, 128.3,
128.1, 128.0, 127.9, 127.8, 127.7, 127.5 (C6H5), 102.0 (C-1), 76.4
(C-3), 75.0 (C-2), 74.5 (C-4), 73.5, 73.4, 73.1 (PhCH2), 72.2 (C-5),
62.4 (C-6), 56.7 (CH3).
The TBDMS ether 1e was prepared from 1d by the usual silylation
procedure.
HRMS (EI): m/z calcd for C28H32O6: 464.2198; found: 464.2184.
Methyl 2,3-Di-O-benzyl-4-O-[tert-butyl(dimethyl)silyl]-6-
deoxy-a-D-threo-hex-5-enopyranoside (1e)
[a]D26 +2.23 (c = 0.73, CHCl3).
IR (neat): 1667 cm–1 (C=C).
Methyl 2,3-Di-O-benzyl-4-O-[tert-butyl(dimethyl)silyl]-b-L-
idopyranoside (2e)
[a]D21 +20.5 (c = 0.47, CHCl3).
1H NMR (600 MHz, CD3OD): d = 7.33–7.23 (10 H, m, C6H5), 4.86
(1 H, d, J = 11.3 Hz, PhCH2), 4.80 (1 H, d, J = 1.7 Hz, H-6), 4.78 (1
H, d, J = 3.3 Hz, H-1), 4.76 (1 H, d, J = 11.3 Hz, PhCH2), 4.67 (1
H, d, J = 11.6 Hz, PhCH2), 4.66 (1 H, d, J = 1.7 Hz, H-6¢), 4.63 (1
H, d, J = 11.6 Hz, PhCH2), 4.00 (1 H, d, J = 8.3 Hz, H-4), 3.66 (1
H, dd, J = 3.3, 9.3 Hz, H-2), 3.63 (1 H, dd, J = 8.3, 9.3 Hz, H-3),
3.40 (3 H, s, CH3), 0.94 (9 H, s, t-C4H9), 0.06 (3 H, s, CH3), 0.04 (3
H, s, CH3).
13C NMR (150 MHz, CD3OD): d = 157.7 (C-5), 140.2, 139.5, 129.4,
129.2, 129.1, 128.9, 128.5 (C6H5), (100.0) (C-1), (97.6) (C-6),
(82.9) (C-3), (81.3) (C-2), (76.5) (C-4), 74.2, 73.6 (PhCH2), 55.7
(CH3), 26.4 [C(CH3)3], 19.0 [C(CH3)3], –4.29 [Si(CH3)2].
IR (neat): 3451 cm–1 (OH).
1H NMR (600 MHz, CDCl3): d = 7.33–7.24 (10 H, m, C6H5), 4.79
(1 H, d, J = 11.3 Hz, PhCH2), 4.70 (1 H, d, J = 12.1 Hz, PhCH2),
4.69 (1 H, d, J = 11.3 Hz, PhCH2), 4.59 (1 H, d, J = 12.1 Hz,
PhCH2), 4.52 (1 H, d, J = 3.8 Hz, H-1), 3.94–3.89 (1 H, m, H-5),
3.88–3.84 (3 H, m, H-3, H-6, H-6¢), 3.81 (1 H, dd, J = 5.5, 7.7 Hz,
H-4), 3.47 (3 H, s, CH3), 3.45 (1 H, dd, J = 3.8, 7.9 Hz, H-2), 0.86
(9 H, s, t-C4H9), 0.05 (3 H, s, CH3), 0.02 (3 H, s, CH3).
13C NMR (150 MHz, CDCl3): d = 138.6, 138.2, 137.5, 128.5, 128.4,
128.3, 128.2, 128.1, 128.0, 127.9 (C6H5), 100.1 (C-1), 78.5 (C-3),
78.0 (C-2), 74.8 (C-5), 74.8, 73.7 (PhCH2), 71.9 (C-4), 62.9 (C-6),
57.0 (CH3), 25.8 [C(CH3)3], 18.0 [C(CH3)3], –4.67 [Si(CH3)2].
HRMS (EI): m/z calcd for C27H38O5Si: 470.2489; found: 470.2480.
HRMS (FAB-NBA + NaI): m/z calcd for C27H40O6SiNa: 511.2492;
found: 511.2492.
Hydroboration/Oxidation; Methyl 2,3,4-Tri-O-benzyl-b-L-
idopyranoside (2a) and Methyl 2,3,4-Tri-O-benzyl-a-D-glucopy-
ranoside (3a); Typical Procedure
Dimethyl 2,3,4-Tri-O-benzyl-b-L-idopyranosiduronate (4)
To a solution of 2a (120 mg, 0.26 mmol) in anhyd acetone (3 mL)
was added a solution of CrO3 (69.7 mg, 0.70 mmol) in 3.5 M H2SO4
(1 mL) at 0 °C. The solution was stirred at 0 °C for 10 min and then
at r.t. for 1 h. After filtration, the filtrate was extracted with CHCl3,
and the extract was dried (Na2SO4) and evaporated. The crude car-
boxylic acid (104.5 mg, 0.22 mmol) thus obtained was dissolved in
CH2Cl2 (2 mL), and an excess amount of diazomethane in Et2O was
added to the mixture. After stirring the mixture at 0 °C for 90 min,
the solvent was evaporated. The residue was purified by silica gel
chromatography (hexane–EtOAc, 10:1) to give 76.3 mg of 4 (60%);
[a]D26 +29.0 (c = 1.10, CHCl3).
To a solution of 1a (32.0 mg, 0.07 mmol) in anhyd THF (1 mL) was
added a 1.08 M solution of borane in THF (0.66 mL, 0.72 mmol) at
0 °C, and the mixture was stirred at 0 °C for 1 h. Then, 30% H2O2
(1 mL) and aq 2 N NaOH (1 mL) were successively added and the
mixture was stirred for 30 min and extracted with EtOAc. The
EtOAc extract was washed with aq sat. NH4Cl, dried (Na2SO4), and
evaporated. Purification by chromatography on silica gel (hexane–
EtOAc, 2:1) gave 28.4 mg of the product (85%, 2a:3a = 11:1).
Methyl O-2,3,4-Tri-O-benzyl-a-D-galactopyranoside (3b)
[a]D24 +10.8 (c = 0.76, CHCl3).
IR (neat): 3436 cm–1 (OH).
IR (neat): 1688 cm–1 (C=O).
1H NMR (600 MHz, CDCl3): d = 7.26–7.15 (15 H, m, C6H5), 4.68
(1 H, d, J = 12.7 Hz, PhCH2), 4.58 (1 H, d, J = 12.7 Hz, PhCH2),
4.57 (1 H, d, J = 12.1 Hz, PhCH2), 4.50–4.48 (3 H, m, H-5, PhCH2),
4.41 (1 H, d, J = 12.1 Hz, PhCH2), 4.23 (1 H, d, J = 3.6 Hz, H-1),
3.97–3.95 (1 H, dd, J = 5.5, 7.6 Hz, H-3), 3.65 (3 H, s, CH3), 3.61
(3 H, dd, J = 3.6, 5.5 Hz, H-2), 3.41–3.39 (4 H, m, H-4, CH3).
13C NMR (150 MHz, CDCl3): d = 169.5 (C=O), 138.5, 138.0, 137.9,
128.5, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6
(C6H5), 100.9 (C-1), 75.7 (C-3), 74.5 (C-4), 73.7, 73.5, 72.9
(PhCH2), 56.9 (CH3), 51.9 (COCH3).
1H NMR (600 MHz, CDCl3): d = 7.42–7.25 (15 H, m, C6H5), 4.97
(1 H, d, J = 11.7 Hz, PhCH2), 4.89 (1 H, d, J = 11.7 Hz, PhCH2),
4.84 (1 H, d, J = 12.0 Hz, PhCH2), 4.75 (1 H, d, J = 11.7 Hz,
PhCH2), 4.71–4.68 (2 H, m, PhCH2, H-1), 4.63 (1 H, d, J = 12.0 Hz,
PhCH2), 4.05 (1 H, dd, J = 3.7, 10.0 Hz, H-2), 3.94 (1 H, dd, J = 2.7,
10.0 Hz, H-3), 3.87 (1 H, d, J = 2.7 Hz, H-4), 3.74–3.68 (2 H, m, H-
6, H-6¢), 3.45–3.52 (1 H, m, H-5), 3.36 (3 H, s, CH3).
13C NMR (150 MHz, CDCl3): d = 138.5, 138.2, 138.0, 128.4, 128.3,
128.2, 127.9, 127.8, 127.7, 127.4 (C6H5), 98.8 (C-1), 79.1 (C-3),
76.5 (C-2), 75.1, 74.4, 72.9 (PhCH2), 73.6 (C-4), 70.3 (C-5), 62.4
(C-6), 55.4 (CH3).
HRMS (EI): m/z calcd for C29H32O7: 492.2148; found, 492.2132.
HRMS (EI): m/z calcd for C28H32O6: 464.2199; found: 464.2204.
Dimethyl b-L-Idopyranosiduronate (5)
To a solution of 4 (71.9 mg, 0.15 mmol) in anhyd MeOH (1.5 mL)
was added Pd(OH)2/C (14.4 mg). After stirring the mixture under a
H2 atmosphere for 22 h, the catalyst was removed by filtration. The
Methyl 2,3,4-Tri-O-benzyl-b-L-gulopyranoside (2c)
[a]D23 +21.1 (c = 0.77, CHCl3).
Synthesis 2004, No. 18, 2991–2994 © Thieme Stuttgart · New York

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H. Takahashi et al.
PAPER
(3) Takahashi, H.; Hitomi, Y.; Iwai, Y.; Ikegami, S. J. Am.
filtrate was evaporated to give 5 (31.9 mg, quant). The analytical
and spectral data are in confirmation with the reported values.17
Chem. Soc. 2000, 122, 2995.
(4) Takahashi, H.; Iwai, Y.; Hitomi, Y.; Ikegami, S. Org. Lett.
2002, 4, 2401.
Acknowledgment
(5) Review: Mitsunobu, O. Synthesis 1981, 1.
(6) (a) Lehmann, J. Carbohydr. Res. 1966, 2, 1. (b) Ichikawa,
Y.; Kuzuhara, H. Carbohydr. Res. 1983, 115, 117.
(c) Chiba, T.; Jacquinet, J.-C.; Sinaÿ, P. Carbohydr. Res.
1988, 174, 253. (d) Boger, D. L.; Honda, T. J. Am. Chem.
Soc. 1994, 116, 5647. (e) Rochepeau-Jobron, L.; Jacquinet,
J.-C. Carbohydr. Res. 1997, 303, 395.
(7) Kjellén, L.; Lindahl, U. Ann. Rev. Biochem. 1991, 60, 443.
(8) Iimori, T.; Takahashi, H.; Ikegami, S. Tetrahedron Lett.
1996, 37, 649.
(9) Alper, P. B.; Hendrix, M.; Sears, P.; Wong, C.-H. J. Am.
Chem. Soc. 1998, 120, 1965.
(10) Sakairi, N.; Kuzuhara, H. Tetrahedron Lett. 1982, 23, 5327.
(11) Other reaction conditions (e.g., temperature, time, and
solvent) were not changed.
We thank Ms J. Shimode, Ms. M. Kitsukawa, and Ms. A. Tonoki for
spectroscopic measurements. The generous financial support for
this research from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan, Fujisawa Foundation, Hayashi Me-
morial Foundation for Female Natural Scientists, and Uehara
Memorial Foundation are gratefully acknowledged.
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Synthesis 2004, No. 18, 2991–2994 © Thieme Stuttgart · New York