A novel synthesis of deoxy phospha sugar-sugar disaccharides

Article abstract of DOI:10.1016/j.tetlet.2003.12.134

A novel and facile synthetic method is described in the synthesis of several deoxy phospha sugar-sugar disaccharides, analogs of normal sugar disaccharides by treatment of (±)-2-bromo-3-methoxy-1-phenylphospholane 1-oxide with several pentose and hexose s

Full text of DOI:10.1016/j.tetlet.2003.12.134

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1923–1927
A novel synthesis of deoxy phospha sugar–sugar disaccharidesq
Buchammagari Haritha,a Valluru Krishna Reddy,b Tatsuo Oshikawac
and Mitsuji Yamashitaa,*
aDepartment of Materials Chemistry, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan
bSatellite Venture Business Laboratory, Shizuoka University, Hamamatsu 432-8561, Japan
cDepartment of Chemistry and Biochemistry, Numazu College of Technology (NCT), Numazu 410-8501, Japan
Received 4 November 2003; revised 21 December 2003; accepted 24 December 2003
Abstract—A novel and facile synthetic method is described in the synthesis of several deoxy phospha sugar–sugar disaccharides,
analogs of normal sugar disaccharides by treatment of ( )-2-bromo-3-methoxy-1-phenylphospholane 1-oxide with several pentose
and hexose sugar acetonides.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The biological importance of carbohydrates and gly-
cosylated natural products1 has resulted in an increased
focus on the development of synthetic methods for the
procurement of pure oligosaccharides and glycoconju-
gates. Thus, preparation of sugar derivatives such as
glycosides and nucleosides is an interesting field in the
hetero sugar chemistry as in the carbohydrate chemis-
try.2 This letter deals with a novel synthesis and struc-
ture of phospha sugar–sugar disaccharides.
starting materials. Therefore, it would be interesting to
establish facile synthetic approaches and newer concepts
in the synthesis and development of phospha sugar
molecules. Hence, we wished to develop efficient pro-
tocols and reported the successful synthesis of several
tetrofuranose analogs in high yields via simple reaction
methods.6 However, our aim to develop potential bio-
active compounds of phospha sugars led us to synthesize
phospha sugar–sugar disaccharides. Therefore, we now
report our preliminary synthesis and structural analysis
of deoxy phospha sugar–sugar disaccharides.
The term Ôphospha sugarÕ belongs to the class of hetero
sugars and denotes the replacement of hemiacetal oxy-
gen of normal sugar by phosphorus moiety. In recent
years, phospha sugar molecules have attracted consid-
erable synthetic interest in view of their physicochemical
properties as well as potential biological activity.3
Though several routes are available for the synthesis of
carba-, aza-, and thia-sugar disaccharides in racemic
or enatiomerically pure form,4 no method has been
described hitherto in the synthesis of phospha sugar–
sugar disaccharides.
In developing the synthesis of phospha sugar–sugar
disaccharides, we first started from the bromohydrin
derivatives I, II (Fig. 1), which were prepared from the
corresponding 2-phospholene 1-oxides, because intro-
duction of sugar moiety at C-2 position was expected to
be relatively easy through its 2-bromophospholane
derivative.7 We previously reported the preparation of
threo-bromohydrin derivatives I and II obtained via
bromohydrination of 1-phenyl-2-phospholene 1-oxides.8
However, using such bromohydrin derivatives I and II,
we obtained epoxides9 instead of desired disaccharides.
To avoid b-elimination reactions, we tried to protect
Moreover, synthesis of phospha sugars was rather dif-
ficult due to long reaction sequences and low yields,5
and preparations generally were normal sugars as
Ph
Ph
Ph
Ph
Br
Br
Br
Br
OH
P
O
P
O
P
O
P
O
Keywords: Phospha sugars; Hetero sugars; Phospha sugar–sugar
disaccharides.
OMe
OH
OMe
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.12.134
* Corresponding author. Tel./fax: +81-53-478-1144; e-mail: tcmyama@
ipc.shizuoka.ac.jp
I I I
I V
I
I I
Figure 1. Different type of 2-bromo-3-hydroxy/methoxy-phospholane
based glycosyl donors.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.134

1924
B. Haritha et al. / Tetrahedron Letters 45 (2004) 1923–1927
Ph
P
Ph
P
were separated by column chromatography on silica gel
using ethyl acetate, n-hexane and methanol (25:10:1)
and obtained as liquids.
Br
(major)
(minor)
MeO
R
+
O
O
Ph
H
OMe
Br
R
2a-b
(threo)
3a-b
(erythro)
P
Br2, MeOH
CHC
Furthermore, detailed spectral analysis of compounds
3a–b showed that00the presence of minor regiodiastereo-
mers 30a–b and 3 a–b, attempts to separate 30a–b and
300 a–b from 3a–b were remained unsuccessful, and hence
isomeric ratios were determined by 31P NMR spectro-
scopy. The isomeric ratios were given in Table 1. All of
these compounds were structurally confirmed from their
1H, 13C, and 31P NMR spectral data. The stereochem-
istry of these compounds was ascertained by comparison
O
l , R
T, 3
d
3
R
Ph
Ph
1a-b
OMe
P
P
a: R
b: R
=H
=Me
R
Br
R
O
+
O
OMe
Br
3'a-b
3"a-b
Scheme 1. Preparation of bromomethoxy derivatives from 1-phenyl-2-
phospholene 1-oxides (1a–b).
1
of H NMR spectral data, that is, the chemical shift
values of H-2 and H-4, long range coupling constants of
4
2
3-hydroxy group of bromohydrin derivative of I and II
via acylation and methylation reactions using mild base
K2CO3, but the reactions led us to obtain same epoxides
instead of –OH group protected compounds. Then we
decided to prepare 1-phenyl-2-bromo-3-methoxyphos-
pholane 1-oxides from starting 2-phospholenes using
methanol in place of water in bromohydrination
(Scheme 1).
H-2 and H-4 ð JHHÞ, and JPH coupling constant values
with the previously reported bromohydrin derivatives.8
These bromohydrin derivatives are very useful inter-
mediates for the synthesis of disaccharides.
To obtain the desired disaccharides, further reactions
were performed on major isomers 2a–b and 3a–b.
Treatment of compound 2a with glucosediacetonide
[1,2,5,6-di-O-isopropylidene-a-D-(+)-glucofuranose] in
Bromination of 1-phenyl-2-phospholene 1-oxides (1a–b)
in methanol, afforded the diastereomeric mixture of
( )-2-bromo-3-methoxyphospholane derivatives, 2a–b
(threo) and 3a–b (erythro) (Scheme 1) as major isomers
in addition to the minor regiodiastereomers, 30a–b and
300 a–b. Preliminary TLC analysis of the reaction mixture
showed only two spots, suggesting the formation of two
major isomers, 2a–b [( )-threo-1-phenyl-2-bromo-3-
methoxy-phospholane 1-oxide (2a) and ( )-threo-1-
phenyl-2-bromo-3-methoxy-3-methylphospholane 1-oxide
(2b)] and 3a–b [( )-erythro-1-phenyl-2-bromo-3-meth-
oxyphospholane 1-oxide (3a) and ( )-erythro-1-phenyl-
2-bromo-3-methoxy-3-methylphospholane 1-oxide (3b)].
However, HPLC analysis revealed that each compound
consists of four isomers. The isomers 2a, 2b and 3a, 3b
dry DMF at room temperature for 3 h using sodium
hydride, afforded disaccharide (4a) in 42% yield.10
Among the four major bromomethoxy intermediates
obtained, only one compound that is, compound III (2a)
gave desired product, whereas, the other isomer IV (2b)
gave b-eliminated compound (5d) instead of disacchar-
ide. It is expected due to the presence of electron-
donating (+I) natured methyl group at C-3 position,
which facilitates b-elimination reaction rather than
substitution. The other isomers 3a–b were remained
unreactive toward sugar diacetonides due to the pres-
ence of regiodiastereomers. Later, we tested compound
III with different types of hexose and pentose acetonide
derivatives in the same reaction conditions. Product
structures and yields are given in Figure 2 and Table 2,
respectively. However, in case of mannose diacetonide
(entry 6), no disaccharide was obtained, because com-
pound III was found to be unreactive toward free ano-
meric hydroxyl group. All other reactions underwent
smoothly in dry DMF. When the reactions were per-
formed in dry THF, yields were very low and in some
cases there was no product at all. To control the b-
elimination reaction, mild base K2CO3 was used instead
of NaH but reaction yields were very low. Therefore,
the optimized general reaction conditions were given
in Scheme 2. It is noteworthy to state that only
Table 1. Isomeric ratios and yields of bromomethoxy phospholane
oxides
Sub-
strate
Isomeric ratioa
Yield (%)b
2a–b 3a–b
2a–b
3a–b
30a–b
300a–b
1a
1b
6
6
4
3
1
1
1
1
45
47
44
45
a Determined by 31P NMR spectroscopy.
b Isolated yield.
O
O
O
O
O
O
O
O
O
OMe
O
O
O
O
O
OBn
O
O
O
O
O
O
O
O
OBn
Ph
O
O
Ph
Ph
Ph
P h
P
O
P
O
P
O
P
P
O
O
OMe
4e
OMe
4d
OMe
OMe
4c
OMe
4b
4a
Figure 2. Product structures of 4a–e.

B. Haritha et al. / Tetrahedron Letters 45 (2004) 1923–1927
Table 2. Preparation of deoxy phospha sugar–sugar disaccharides
1925
Entry
Donor
Acceptor
Disaccharide
Yield (%)a
42
O
O
O
1
III
4a
OH
O
O
D-(+)-Glucosediacetonide
OH
O
O
O
O
2
3
4
5
6
7
8
9
III
III
III
III
III
I
4b
4c
4d
44
42
39
41
91
88
92
95
O
D-(+)-Galactosediacetonide
HO
O
OMe
O
O
D-(-)-Riboseacetonide
O
O
O
HO
OBn
L-(-)-Xyloseacetonide
O
O
O
4e
OBn
HO
L-(-)-Arabinoseacetonide
O
O
O
Ph
O
OH
O
5a
P
Br
O
D-(+)-Mannosediacetonide
O
O
Ph
P
O
O
OH
5b
O
O
O
D-(+)-Glucosediacetonide
O
O
Ph
O
OH
P
O
II
5c
O
O
O
D-(+)-Glucosediacetonide
O
O
Ph
P
O
OH
Br
IV
5d
O
O
O
D-(+)-Glucosediacetonide
a % of yields of 4a–e was calculated after purification by column chromatography and recycle GPC analysis.
bromohydrin III (2a) gave desired compounds and the
other bromohydrins I, II, and IV gave corresponding
eliminated compounds in high yields, given in Table 2.
afforded in 39–45% yields. Endeavors to improve the
reaction yields of disaccharides 4a–e failed due to lack of
optical purity in the substrate III (2a) [racemate, ( )-
threo-1-phenyl-2-bromo-3-methoxyphospholane 1-oxide],
that means 650% yield should be theoretically achieved.
The unreacted sugar diacetonide (ꢀ40%) was recovered
by column chromatography, whereas, bromophospho-
lane oxide was converted to its b-eliminated compound
(i.e., compound 5a). The structures of products 4a–e
Purification of compounds 4a–e on silica gel column
chromatography and also using recycle GPC analysis
Deoxyphospha sugar-sugar
Acetonideprotected
sugar
NaH, DMF
0 oC-RT, 3 h
1
were thoroughly investigated by H, 13C, and 31P NMR
disaccharide
+
and mass spectral analyses.11 In 31P NMR spectra of
compounds 4a–e showed a single peak, which represents
the formation of a single isomer. In proton NMR
+
Bromophospholane
Eliminated compound
Scheme 2. Preparation of deoxy phospha sugar–sugar disaccharides.

1926
B. Haritha et al. / Tetrahedron Letters 45 (2004) 1923–1927
Table 3. Chemical shift value of H-2, JPH coupling constant and 31P
NMR chemical shift values of 4a–e
Nippon Soda Co. Ltd. B.H. is thankful for the financial
support as scholarship from Amano Kogyo Co. Ltd.
Compound
d value of H-2
(ppm)
2JPH
(Hz)
,
3JHH ðvicÞ
31P NMR
(d in ppm)
4a
4b
4c
4d
4e
3.52
3.46
3.42
3.57
3.55
11.5, 4.1
10.7, 4.0
11.1, 4.0
11.3, 4.2
10.8, 4.0
56.2
61.7
52.4
59.5
62.7
References and notes
1. For reviews, see: (a) Varki, A. Glycobiology 1993, 3, 97; (b)
Lee, Y. C.; Lee, R. T. Acc. Chem. Res. 1995, 28, 322.
2. Bochkov, A. F.; Zaikov, G. E. Chemistry of the O-Gly-
cosidic Bond; Pargamon: Oxford, 1979; Chapter 2.
3. For a review, see: Yamamoto, H.; Inokawa, S. Adv.
Carbohydr. Chem. Biochem. 1984, 42, 135.
4. (a) Anzeveno, P. B.; Creemer, L. J.; Daniel, J. K.; King,
C.-H. R.; Liu, P. S. J. Org. Chem. 1989, 54, 2539–2542; (b)
Liu, P. S. J. Org. Chem. 1987, 52, 4717; (c) Ferritto, R.;
Vogel, P. Tetrahedron Lett. 1995, 36, 3517–3518; (d)
Campanini, L.; Dureault, A.; Depezay, J. C. Tetrahedron
Lett. 1996, 37, 5095–5098.
5. Yamashita, M.; Yamada, M.; Sigiura, M.; Nomoto, H.;
Oshikawa, T. Nippon Kagaku Kaishi 1987, 1207–1213.
6. (a) Yamashita, M.; Yabui, A.; Suzuki, K.; Kato, Y.;
Uchimura, M.; Iida, A.; Mizuno, H.; Ikai, K.; Oshikawa,
T.; Parkanayi, L.; Clardy, J. J. Carbohydr. Chem. 1997, 16,
499–519; (b) Yamashita, M.; Uchimura, M.; Iida, A.;
Parkanayi, L.; Clardy, J. J. Chem. Soc., Chem. Commun.
1988, 569–570, and references cited therein.
spectra of compounds 4a–e, H-2 proton resonated as
double doublet (dd) due to P–C–H and H–H (vicinal)
coupling. The orientation of the P@O group of phos-
pholane ring in compounds 4a–e was established from
the JPH coupling constants (Table 3). The larger JPH
coupling constant suggests the cis (or gauche) relation-
ship of H-2–C-2–P@O.12 The 31P NMR chemical shift
values of 4a–e were shifted to downfield (by ꢀ5 ppm)
from the corresponding bromomethoxyphospholane
oxides, it may be due to the replacement of bromine
atom by sugar moiety.
2
2
On the other hand, the retention of configuration at C-2
1
was achieved via SN reaction mechanism, which led us
formation of a single isomer. The generated secondary
carbonium ion intermediate is presumably stabilized by
the adjacent partial )ve charge on oxygen atom of P@O
and thus the nucleophile of sugar molecule is facilitated
to attack preferably through opposite side of P@O
group, it is assumed due to the electron repulsive
interaction between Pþ–Oꢁ and attacking nucleophile.6a
The SN reaction is also supported by the solvent effect,
where the reactions were promoted by using higher
polar solvent, DMF rather than THF.
7. Yamashita, M.; Iida, A.; Mizuno, H.; Miyamoto, Y.;
Morishita, T.; Sata, N.; Kiguchi, K.; Yabui, A.; Oshi-
kawa, T. Heteroat. Chem. 1993, 4, 553–557.
8. (a) Yamashita, M.; Suzuki, K.; Kato, Y.; Iida, A.;
Mizuno, H.; Ikai, K.; Reddy, P. M.; Oshikawa, T.
J. Carbohydr. Chem. 1999, 18, 915–935; (b) To prepare
starting phospholene oxides, see: Quin, L. D.; Gratz, J. P.;
Barker, T. P. J. Org. Chem. 1968, 33, 1034–1041.
9. The epoxide structures (5b, 5c) were shown in Table 2, and
structurally confirmed from NMR (1H, and 13C) spectral
analyses.
1
Moreover, in our preliminary studies, the configuration
at C-2 of compounds 4a–e was determined by calcula-
tion of the heat of formation (DHf ) of R and S forms
using MOPAC AM1 analysis data. The calculated data
showed that the heat of formation of S (for 4a,
DHf ¼ ꢁ349:41 kcal) configuration at C-2 is lower than
R (for 4a, DHf ¼ ꢁ347:27 kcal), and thus the formation
of S configuration isomer is favored and stable than R
configuration. Therefore, the resultant configuration
obtained at P-1, C-2, and C-3 of 4a–e is (1SP,2S,3S) for
the favored formation (Fig. 2).
10. (a) The general experimental procedure for the prepara-
tion of compounds 4a–e is as follows: To a 0 ꢁC suspension
of sodium hydride (60–72% in oil, 0.036 g, 1.52 mmol) in
dry DMF (3 mL) was added the readily prepared solution
of protected sugar diacetonide (0.76 mmol) in dry DMF
(2 mL) and the resultant reaction mixture was stirred for
40 min at room temperature. After 40 min, reaction
mixture was cooled to 0 ꢁC and added the solution of
bromomethoxyphospholanes (0.8 mmol) in dry DMF
(2 mL) and allowed to stir for additional 2 h at room
temperature and then DMF was distilled off under
diminished pressure and residue was dissolved in chloro-
form (20 mL), washed with NH4Cl solution (5 mL · 2),
water, and brine. The organic layer was dried over sodium
sulfate, filtered, and concentrated under vacuum. The
residues were purified on silica gel column chromatogra-
phy (20:1 chloroform/methanol) and also using recycle
GPC analysis to get pure disaccharides 4a–e as oily
liquids.
In conclusions, we established
a novel synthetic
approach in the synthesis of deoxy phospha sugar–sugar
disaccharides. Further synthesis of these compounds,
for example, use of optically pure phospholane oxides,
determination of optical rotation, phosphate esters of
phospholanes as glycosyl donors, and bioactive studies
are currently under progress in our laboratory and will
be reported in due course.
11. All compounds were structurally characterized by spectral
1H NMR (JEOL JNM-300 at 300.40 MHz), 13C
NMR (JEOL JNM-300 at 75.0 MHz), 31P NMR (JEOL
JNM EX-90 at 36.18 MHz), mass (Kompact MALDI-
TOF MS using a-cyano-4-hydroxycinnamic acid as a
matrix, reflectron flight path and 100 profiles per sample)
analyses.
1
Acknowledgements
Compound 4a: H NMR (CDCl3): d 1.11–1.55 (4s, 12H,
CH3 · 4), 2.00–3.15 (m, 4H, H-4,5), 3.52 (dd, 1H,
3
2JPH ¼ 11:5 Hz and JHH ðvicÞ ¼ 4:1 Hz, H-2), 3.63 (m, 1H,
The authors acknowledge the financial support by
Shizuoka Science and Technology Foundation and
H-3), 3.82 (s, 3H, OMe), 3.95–4.52 (m, 1H, 6H), 4.57 (d,

B. Haritha et al. / Tetrahedron Letters 45 (2004) 1923–1927
1927
2H, J ¼ 3:5 Hz), 5.93 (d, J ¼ 3:6 Hz, 1H), 7.45–7.82 (m,
5H, Ph); 13C NMR (CDCl3): d 23.15, 26.56, 26.68, 26.81,
29.32, 29.34, 57.68, 67.41, 73.25, 74.79, 81.19, 85.15, 89.17,
90.32, 105.21, 109.32, 111.62, 128.38, 128.51, 128.55,
128.66, 130.54, 130.68; 31P NMR (CDCl3, H3PO4): d
56.2. MS ðm=zÞ: 468.42 (Mþ) for C23H33O8P.
12. Hanaya, T.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1989,
62, 2320–2327.