Regioselective Synthesis of Phosphonylated Sugars from Reactions of Glycals with Diphenylphosphenium Cation

Article abstract of DOI:10.1081/CAR-120025330

Reaction of methyl 4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hex-2- enopyranoside 1 with two equivalents of diphenylphosphenium cation at 0°C gave the 1-phosphonylated 2-enopyranosides 3α and 3β as major products. Similarly, reaction of diphenylphosphenium ca

Full text of DOI:10.1081/CAR-120025330

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Regioselective Synthesis of Phosphonylated Sugars
from Reactions of Glycals with Diphenylphosphenium
Cation
Akira Takano a , Hiroyuki Fukuhara a , Tadao Ohno a , Masahiro Kutsuma a , Tetsuya Fujimoto
a , Hirofusa Shirai a , Ryozo Iriye b , Akikazu Kakehi c & Iwao Yamamoto a
a Department of Functional Polymer Science , Faculty of Textile Science and Technology ,
Shinshu University , Ueda, Nagano, 386‐8567, Japan
b Department of Bioscience and Biotechnology , Faculty of Agriculture , Shinshu University ,
Minowa, Kami‐ina, Nagano, 399‐4598, Japan
c Department of Chemistry and Material Engineering , Faculty of Engineering , Shinshu
University , Wakasato, Nagano, 380‐8553, Japan
Published online: 23 Aug 2006.
To cite this article: Akira Takano , Hiroyuki Fukuhara , Tadao Ohno , Masahiro Kutsuma , Tetsuya Fujimoto , Hirofusa Shirai ,
Ryozo Iriye , Akikazu Kakehi & Iwao Yamamoto (2003) Regioselective Synthesis of Phosphonylated Sugars from Reactions of
Glycals with Diphenylphosphenium Cation, Journal of Carbohydrate Chemistry, 22:6, 443-457, DOI: 10.1081/CAR-120025330
To link to this article: http://dx.doi.org/10.1081/CAR-120025330
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, No. 6, pp. 443–457, 2003
Regioselective Synthesis of Phosphonylated Sugars from
Reactions of Glycals with Diphenylphosphenium Cation
Akira Takano,1 Hiroyuki Fukuhara,1 Tadao Ohno,1 Masahiro Kutsuma,1
Tetsuya Fujimoto,1 Hirofusa Shirai,1 Ryozo Iriye,2 Akikazu Kakehi,3
and Iwao Yamamoto1,
*
1Department of Functional Polymer Science, Faculty of Textile Science and
Technology, Shinshu University, Ueda, Nagano, Japan
2Department of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu
University, Minowa, Kami-ina, Nagano, Japan
3Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu
University, Wakasato, Nagano, Japan
ABSTRACT
Reaction of methyl 4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hex-2-enopyranoside 1
with two equivalents of diphenylphosphenium cation at 0ꢀC gave the 1-phosphony-
lated 2-enopyranosides 3 and 3 as major products. Similarly, reaction of
diphenylphosphenium cation with tri-O-acetylglycal afforded the same products in a
similar ratio. In contrast, a reaction with tri-O-benzylglucal at reflux temperature of
dichloromethane afforded the 3-phosphonylated sugar 13 as a major product. These
reactions may proceed via stable allyl cations.
*
Correspondence: Iwao Yamamoto, Department of Functional Polymer Science, Faculty of Textile
Science and Technology, Shinshu University, Ueda, Nagano 386-8567, Japan; E-mail: ganchan@
giptc.shinsu-u.ac.jp.
443
DOI: 10.1081/CAR-120025330
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

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Takano et al.
INTRODUCTION
During the last three decades, the synthesis of glycosyl phosphates and
phosphonates has become an area of intense study among organic chemists and
biochemists.[1] These compounds are important not only because they have important
biological properties, but they are chiral building blocks in the synthesis of a variety of
natural products. In regard to the biological activities of sugar phosphonates, many
reports of their synthesis have been reported. Paulsen and his research group reported
the synthesis of enopyranosyl phosphonates and their structural analysis in the
1970’s.[2–5] Vasella reported a synthesis of a phosphonic acid analogue of N-acetyl-
2,3-didehydro-2-deoxyneuramimic acid, a strong inhibitor of the Vibrio cholerae
sialidase.[6] Wightman and his co-workers reported a synthesis of D-arabino-
hexopyranosylphosphonates as an important intermediate for the shikimate pathway.[7]
In addition, synthesis of pyranosylphosphonate nucleosides was reported by El-Hamid
and Ismail.[8]
Phosphonylations of sugars are significant strategies for synthesis of chiral ligands.
Shibasaki and his co-workers reported a synthesis of 6-phosphonylated sugar
derivatives and their application for catalytic asymmetric reactions.[9,10] In this paper,
we wish to report a regio and stereoselective synthesis of C-phosphonylated sugars
from the reactions of unsaturated sugars with a phosphenium cation.
RESULTS AND DISCUSSION
Reaction of methyl 4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hex-2-enopyranoside 1
with two equivalents of diphenylphosphenium cation generated from a reaction of
chlorodiphenylphosphine with aluminum chloride in dichloromethane at 0ꢀC gave the
1-phosphonylated 2-enopyranosides 3 and 3 in 46 and 11% yields, respectively,
along with a minor product 4 in 4% yield (Scheme 1). The structures of these products
were determined from spectral data, and the stereochemistries were determined from
NOESY spectra. In particular, a correlation between the signals of H-1 and H-6 in the
product 3 was observed together with the absence of any such interaction between H-
1 and H-5, suggesting the configuration of the diphenylphosphinoyl group to be a.
Similarly, the correlations between H-1 and H-5 in the product 3 and between H-3
and H-5 in the product 4 were observed. The formation of these products (Scheme 2)
could be explained by a similar pathway that we reported previously.[11,12] This
pathway is supported by the results of Saito and his co-workers,[13] who reported that
allyl and propargyl ethers form a stable allyl and allenyl cation in the presence of
Lewis acid.
Using an equimolar amount of tri-O-acetyl-D-glucal 2 as a starting material instead
of 2-enopyranoside 1 under the same conditions, the same products, Ferrier re-
arrangementa products 3 and 3 and 4, were obtained in a similar ratio as shown in
Scheme 2. These results suggest that the reactions proceeded via the same intermediate
allyl cation A as above. The phosphenium cation, which has strong Lewis acidity, would
aRecent reports: Refs. [14,15].

Synthesis of Phosphonylated Sugars
445
Scheme 1.
attack the acetyl group at C-3 followed by elimination of acetylphosphine to form an allyl
cation A. A nucleophilic phosphorus atom then reacts with cation A at C-1 pre-
dominantly, because C-3 is somewhat protected by a neighbor acetyl group (Scheme 2).
Hiyama and his co-worker reported easy formation of allyl cations from allyl acetates in
the presence of Lewis acid.[16]
By a similar pathway, reaction of tri-O-acetyl-D-galactal 5 with diphenylpho-
sphenium cation at room temperature gave 6 , 6 , and 7 in 42%, 22%, and 7% yields,
respectively. An NOE correlation between H-1 and H-4 in compound 6 was observed,
but not between H-1 and H-4 in compound 6 , nor between H-3 and H-4 in compound
7 in the NOESY spectrum of these compounds (Scheme 3). An acid hydrolysis of the
compound 3 in methanol gave the deprotected 8, quantitatively, whose structure was
determined after conversion to di-O-tert-butyl-2-enopyranosides 9 and 9 . In contrast,
base catalyzed hydrolysis of 3 gave a rearranged product 10 in 71% yield (Scheme 4).
El-Hamid and Ismail reported a similar base catalyzed rearrangement of 2-
enopyranosylphosponate to 1-enopyranosylphosphonate.[9,10]

446
Takano et al.
Scheme 2.
Similarly, reactions of 3,4,6-tri-O-benzylglucal 11 with two equivalents of
diphenylphosphenium cation at ꢀ 78ꢀC and 0ꢀC gave phosphonylated sugars 12 ,
12 , and 13 in similar ratios compound to the products from acetylated glucal.
However, under reflux conditions in dichloromethane, the reaction gave the
3-phosphonylated 13 as a major product (Scheme 5). The structures of 12 , 12 ,
and 13 were determined from spectral data, and the stereochemistries were determined
from NOESY spectra. In addition, the structure of 13 was confirmed by X-ray crystal
analysis (Figure 1),b after hydrogenation of 13 followed by tert-butyldimethylsilylation
of the primary hydroxyl group at C-6 of compound 16 (Scheme 6). Hydrogenation over
10% Pd/C (Aldrich) at atmospheric pressure did not occur, but hydrogenation over 10%
Pd/C (Degussa type N101NE/W)c at 4.5–4.2 atm for 36 h gave deprotected saturated
bFurther details of the crystal structure determination are available on request from Cambridge
Crystallographic Centre; CCDC-190156 for compound 17.
cPd/C(Degussa type N101NE/W) was purchased from Aldrich.

Synthesis of Phosphonylated Sugars
447
Scheme 3.
sugar 16 in 64% yield along with 8% of 4-O-benzylated sugar 15 (Table 1). The X-ray
analysis of 17 (Figure 1) shows that the bulky diphenylphosphinoyl group occupies an
equatorial position.
EXPERIMENTAL
Melting points were measured with a Yanagimoto micro melting apparatus. IR
spectra were recorded as films on NaCl plates or as KBr pellets on a JASCO A-100
spectrometer. 1H NMR and 13C NMR spectra were recorded on JEOL FX-90,
BRUKER DRX-400 and BRUKER DRX-500 spectrometers. 1H and 13C chemical
Scheme 4.

448
Takano et al.
Scheme 5.
shifts are reported in (d) ppm from tetramethylsilane and coupling constants are in Hz.
DEPT-13C, HMQC, 2D-COSY, 2D-NOESY spectra were also measured on BRUKER
DRX-400 and BRUKER DRX-500 spectrometers. Mass spectra were taken with a
JEOL JMS-DX303 spectrometer.
Reaction of methyl 4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hex-2-enopyranoside
1 with diphenylphosphenium cation. General procedure. To a solution of
aluminum chloride (anhydrous) (0.27 g, 2 mmol) in dichloromethane (10 mL) was
added dropwise a solution of chlorodiphenylphosphine (0.44 g, 2 mmol) in
dichloromethane (10 mL) at 0ꢀC under a nitrogen atmosphere. After stirring at room
temperature for 1 h, to the resulting mixture was added a solution of methyl 4,6-di-O-
acetyl-2,3-dideoxy-D-erythro-hex-2-enopyranoside 1 (0.24 g, 1 mmol) in dichloro-
methane (10 mL) and the reaction mixture stirred for 1 h. Water was then added and
the mixture was extracted with dichloromethane. The solvent was evaporated and the
residue was chromatographed on silica gel to afforded diphenyl(4,6-di-O-acetyl-2,3-
dideoxy-a-D-erythro-hex-2-enopyranosyl)phosphine oxide 3a (0.19 g, 46%), diphe-
nyl(4,6-di-O-acetyl-2,3-dideoxy-b-D-erythro-hex-2-enopyranosyl)phosphine oxide 3b
(0.046 g, 11%), and 1,5-anhydro-4,6-di-O-acetyl-2,3-dideoxy-3-diphenylphosphinoyl-
D-arabino-hex-1-enitol 4 (0.018 g, 4%).

Synthesis of Phosphonylated Sugars
449
Figure 1. Ortep drawing of the compound 17.
3 ; white crystals; mp 124–125ꢀC; IR (KBr); n 3050, 2900, 1730, 1440, 1370,
1220, 1180, 1100, 1090, 1030, 970, 880, 820, 780, 720, and 690 cmꢀ 1, 1H NMR
(500.13 MHz, CDCl3): d 7.90–7.47 (m, 10H, Ph), 6.14 (br.d, 1H, J1,2 = 2.2 Hz,
J2,3 = 10.4 Hz, H2), 6.01 (dd, 1H, J2,3 = 10.4 Hz, J3,4 = 3.0 Hz, H3), 5.17 (dd, 1H,
J1,2 = 2.2 Hz, JPH = 9.3 Hz, H1), 5.08 (br.s, 1H, H4), 4.27–4.22 (m, 2H, H5 and H6),
4.08–4.04 (m, 1H, H6’), 2.00 (s, 6H, C(O)CH3); 13C NMR (125.76 MHz, CDCl3): d
3
170.6 (s, C O), 170.3 (s, C O), 132.4–128.3 (m, Ph), 126.4 (d, JPC = 9.2 Hz, C3),
2
1
3
125.4 (d, JPC = 2.4 Hz, C2), 72.4 (d, JPC = 81.5 Hz, C1), 72.2 (d, JPC = 3.5 Hz, C5),
63.8 (s, C4), 62.2 (s, C6), 20.9 (s, C(O)CH3), 20.7 (s, C(O)CH3); 31P NMR (202.46
MHz, CDCl3): d 28.8. HRMS (Fab): Calcd for C22H24O6P: M + 1, 415.1311. Found:
M++ 1, m/z, 415.1314.
3 ; white crystals; mp 135–137ꢀC; IR (KBr); n 3050, 2825, 1740, 1440, 1370,
1
1240, 1180, 1140, 1100, 1080, 1040, 950, 880, 740, and 690 cmꢀ 1; H NMR (500.13

450
Takano et al.
Scheme 6.
MHz, CDCl3): d 7.97–7.26 (m, 10H, Ph), 6.33 (br.d, J2,3 = 10.0 Hz., 1H, H2), 5.80
(br.d, J2,3 = 10.0 Hz, 1H, H3), 5.13 (br.d, JPH = 13.4 Hz, 1H, H1), 5.00 (br.s, 1H, H5),
4.20–4.19 (m, 2H, H6 and H6’), 3.71 (dd, J3,4 = 4.5 Hz, J4,5 = 8.7 Hz, 1H, H4), 2.17
(s, 6H, C(O)CH3); 13C NMR (125.76 MHz, CDCl3): d 170.5 (s, C O), 170.3 (s,
3
C
O), 132.4–128.1 (m, Ph), 127.6 (d, JPC = 8.7 Hz, C3), 125.1 (s, C2), 75.2 (d,
1JPC = 90.2 Hz, C1), 74.1 (d, JPC = 8.3 Hz, C5), 64.5 (s, C4), 63.0 (s, C6), 20.9 (s,
C(O)CH3), 20.7 (s, C(O)CH3); 31P NMR (202.46 MHz, CDCl3): d 28.8. HRMS (Fab):
Calcd for C22H24O6P: M + 1, 415.1311. Found: M++ 1, m/z, 415.1326.
3
4: white crystals mp 138–141ꢀC; IR (KBr); n 3060, 2950, 2910, 1725, 1645, 1440,
1
1360, 1205, 1165, 1070, 1040, 950, 860, 820, 760 and 690 cmꢀ 1; H NMR (500.13
MHz, CDCl3): d 7.90–7.27 (m, 10H, Ph), 6.53–6.51 (m, 1H, H1), 5.32 (m, 1H, H4),
5.17, 5.15 (m, 1H, H5), 4.41 (dd, 1H, Jgem = 12.3 Hz, J5,6 = 3.8 Hz, H6), 4.23 (dd, 1H,
Jgem = 13.1 Hz, J56’ = 1.3 Hz, H6’), 4.20 (dd, J1,2 = 8.95 Hz, J2,3 = 5.70 Hz, 1H, H2),
3.71 (dd, J2,3 = 5.70 Hz, JPH = 11.5 Hz, 1H, H3), 2.03 (s, 3H, C(O)CH3), 1.15 (s, 3H,
C(O)CH3); 13C NMR (125.77 MHz, CDCl3): d 170.7 (s, C O), 170.2 (s, C O), 146.3
3
2
(d, JPC = 9.6 Hz, C1), 134.0–128.6 (m, Ph), 92.5 (d, JPC = 7.8 Hz, C2), 71.8 (s, C5),
2
66.6 (d, JPC = 7.7 Hz, C4), 62.0 (s, C6), 35.3 (d, JPC = 76.9 Hz, C3), 20.7 (s,
1
Table 1. Hydrogenation of 13.
Hydrogen
pressure (atm)
Reaction
time (h)
Entry
Catalyst
Products (yield*)
1
2
3
4
10% Pd/C (Aldrich)
5% Pd/C (Wako)
10% Pd/C (Aldrich)
10% Pd/C (Degussa
type N101NE/W)
10% Pd/C (Degussa
type N101NE/W)
1.0
24
24
24
9
No reaction
14 (44%)
15 (48%)
5.0–4.8
5.0–4.8
4.5–4.2
15 (25%)/16 (25%)
5
4.5–4.2
36
15 (6%)/16 (64%)
*Isolated yield.

Synthesis of Phosphonylated Sugars
451
C(O)CH3), 19.5 (s, C(O)CH3); 31P NMR (202.5 MHz, CDCl3): d 26.0. HRMS (Fab):
Calcd for C22H24O6P: M + 1, 415.1311. Found: M++ 1, m/z, 415.1298.
Reactions of glucal with phosphenium cation. General procedure. To a
solution of aluminum chloride (anhydrous) (1.47 g, 11.1 mmol) in dichloromethane
(10 ml) was added dropwise a solution of chlorodiphenylphosphine (2.43 g, 11.0 mmol)
in dichloromethane (10 ml) at 0ꢀC under a nitrogen atmosphere. After stirring at room
temperature for 1 h, to the resulting mixture was added a solution of methyl 3,4,6-tri-O-
acetyl-D-glucal 2 (2.0 g, 7.35 mmol) in dichloromethane (10 ml) and the reaction
mixture was stirred for 1 h at room temperature. Water was then added and the mixture
was extracted with dichloromethane. The solvent was evaporated and the residue was
chromatographed on silica gel to afford phosphonylated sugars, 3 (1.56 g, 51%), 3
(0.64 g, 21%), and 4 (0.17 g, 6%).
Similarly, from the reaction of tri-O-acetyl galactal 5 (2.0 g, 7.33 mmol) with
chlorodiphenylphosphine (1.2 g, 8.8 mmol) in the presence of anhydrous aluminum
chloride (1.2 g, 8.8 mmol), diphenyl(4,6-di-O-acetyl-2,3-dideoxy- -D-threo-hex-2-
enopyranosyl)phosphine oxide 6 (1.27 g, 42%), diphenyl(4,6-di-O-acetyl-2,3-
dideoxy-b-D-threo-hex-2-enopyranosyl)phosphine oxide 6b (0.68 g, 22%), and 1,5-
anhydro-4,6-di-O-acetyl-2,3-dideoxy-3-dipheylphosphinoyl-D-xylo-hex-1-enitol 7
(0.21 g, 7%) were obtained.
6 ; white crystals; mp 126–128ꢀC; IR (KBr); n 2900, 1720, 1590, 1440, 1370,
1
1160, 1080, 1020, 900, 840, 810, 780, 740, and 680 cmꢀ 1; H NMR (400.13 MHz,
CDCl3): d 7.89–7.48 (m, 10H, Ph), 6.21 (m, 1H, H3), 6.14 (dd, J1,2 = 2.2 Hz,
J2,3 = 10.2 Hz, 1H, H2), 5.26 (br.d, JPH = 8.0 Hz, 1H, H1), 5.07 (br.s, 1H, H4), 4.48
(br.s, 1H, H5), 4.23–4.18 (m, 1H, H6’), 4.06–4.02 (m, 1H, H6), 2.05 (s, 3H,
C(O)CH3), 1.92 (s, 3H, C(O)CH3); 13C NMR (100.62 MHz, CDCl3): d 170.5 (s,
3
O), 170.3 (s, C O), 132.5–128.5 (m, Ph), 127.0 (s, C2), 125.6 (d, JPC = 10.1 Hz,
C
1
C3), 73.6 (d, JPC = 84.5 Hz, C1), 72.1 (s, C5), 63.4 (s, C4), 62.7 (s, C6), 21.0 (s,
C(O)CH3), 20.6 (s, C(O)CH3); 31P NMR (161.97 MHz, CDCl3): d 28.5. HRMS (Fab);
Calcd for C22H24O6P: M + 1, 415.1310. Found: M++ 1, m/z, 415.1257.
6 : white syrup; IR (neat); n 3450, 3060, 2975, 1740, 1590, 1485, 1440, 1370,
1
1240, 1120, 1090, 1040, 980, 950, 910, 860, 830, 750, 720, and 690 cmꢀ 1; H NMR
(400.13 MHz,CDCl3): d 7.94–7.43 (m, 10H, Ph), 6.49 (ddd, J1,2 = 1.96 Hz,
J2,3 = 10.32 Hz, JPH = 4.68 Hz, 1H, H2), 6.09 (ddd, J2,3 = 10.32 Hz, J3,4 = 3.52 Hz,
JPH = 6.28 Hz, 1H, H3), 5.12 (dd, J1,2 = 1.96 Hz, JPH = 15.0 Hz, 1H, H1), 5.02 (dd,
J3,4 = 3.52 Hz, J4,5 = 2.12 Hz, 1H, H4), 4.32 (dd, J56’ = 5.16 Hz, Jgem = 11.48 Hz, 1H,
H6’), 4.07 (dd, J5,6 = 7.64 Hz, Jgem = 11.48 Hz, 1H, H6), 3.95 (br.m, 1H, H5), 2.01 (s,
3H, C(O)CH3), 1.90 (s, 3H, C(O)CH3); 13C NMR (100.62 MHz, CDCl3): d 170.5 (s,
2
C
O), 170.1 (s, C O), 132.6–127.8 (m, Ph), 128.6 (d, JPC = 4.5 Hz, C2), 124.2 (d,
1
3
3JPC = 8.5 Hz, C3), 75.3 (d, JPC = 90.6 Hz, C1), 74.1 (d, JPC = 10.3 Hz, C5), 63.2 (d,
4JPC = 1.97 Hz, C4), 62.6 (s, C6), 20.7 (s, C(O)CH3), 20.6 (s, C(O)CH3); 31P NMR
(161.96 MHz, CDCl3): d 29.2; MS (Fab) m/z 415 (M++ 1).
7: white amorphous solid; IR (KBr); n 3200, 3020, 2900, 1730, 1640, 1590, 1435,
1370, 1220, 1090, 1020, 960, 890, 720, and 690 cmꢀ 1; 1H NMR (400.13 MHz, CDCl3): d
7.80–7.49 (m, 10H, Ph), 6.65 (d, J1,2 = 9.24 Hz, 1H, H1), 5.11 (br.d, J4,5 = 7.92 Hz, 1H,
H5), 4.83 (m, 1H, H4), 4.35 (dd, J1,2 = 9.24 Hz, J2,3 = 3.2 Hz, 1H, H2), 4.21–4.16 (m, 1H,
H6’), 4.09–4.04 (m, 1H, H6), 3.37 (ddd, J2,3 = 3.2 Hz, J3,4 = 1.35 Hz, J PH = 11.7 Hz, 1H,

452
Takano et al.
H3), 2.06 (s, 3H, C(O)CH3), 2.04 (s, 3H, C(O)CH3); 13C NMR (100.62 MHz, CDCl3): d
170.5 (s, C O), 170.2 (s, C O), 146.3 (d, 3JPC = 9.2 Hz, C1), 132.4–128.7 (m, Ph), 91.4
2
2
(d, JPC = 7.4 Hz, C2), 72.1 (s, C4), 65.1 (d, JPC = 15.3 Hz, C5), 62.9 (s, C6), 37.2 (d,
1JPC = 65.9 Hz, C3), 20.8 (s, C(O)CH3), 20.6 (s, C(O)CH3); 31P NMR (161.97 MHz,
CDCl3): d 27.1; MS(Fab) m/z 415 (M++ 1).
Diphenyl(4,6-di-O-benzyl-2,3-dideoxy- -D-erythro-hex-2-enopyranosyl)-
phosphine oxide 12a; white syrup; IR (neat); n 3050, 2930, 2860, 1750, 1590, 1460,
1
1440, 1260, 1180, 1120, 1090, 1020, 800, 720 and 690 cmꢀ 1; H NMR (500.13 MHz,
CDCl3): d 7.96–7.19 (m, 20H, Ph), 6.18 (br.d, J2,3 = 10.60 Hz, 1H, H2), 6.12 (dd,
J2,3 = 10.60 Hz, J3,4 = 3.00 Hz, 1H, H3), 5.12 (dd, J12 = 2.5 Hz, JPH = 10.9 Hz, 1H,H1),
4.54 (d, Jgem = 12.0 Hz, PhCH2), 4.45 (d, Jgem = 12.0 Hz, PhCH2), 4.41 (d, Jgem = 11.7
Hz, PhCH2), 4.31 (d, Jgem = 11.7 Hz, PhCH2), 3.97–3.93 (m, 2H, H4 and H5), 3.61–3.54
(m, 2H, H6 and H6’); 13C NMR (125.76 MHz, CDCl3): d 138.2–127.6 (m, Ph, C3), 124.0
(d, 2JPC = 2.1 Hz, C2), 73.8 (d, 3JPC = 3.4 Hz, C5), 73.2 (s, PhCH2), 72.8 (d, 1JPC = 82.1
Hz, C1), 69.9 (s, PhCH2), 68.8 (s, C4), 68.7 (s, C6); 31P NMR (202.46 MHz, CDCl3): d
27.3. HRMS (Fab): Calcd for C32H32O4P: M + 1 511.2038. Found: M++ 1, m/z, 511.2037.
Diphenylphosphinoyl 4,6-di-O-benzyl-1,2,3-trideoxy- -D-erythro-hex-2-enopyra-
noside 12b; white syrup; IR (neat); n 3050, 2850, 1720, 1630, 1580, 1490, 1440, 1360,
1300, 1260, 1180, 1110, 1090, 740, 720 and 690 cmꢀ 1; 1H NMR (500.13 MHz, CDCl3):d
7.94–7.22 (m, 20H,Ph), 6.16 (ddd, J1,2 = 2.60 Hz, J2,3 = 10.5 Hz, JPH = 4.25 Hz, 1H, H2),
6.01–5.99 (m, 1H, H3), 5.14 (dd, J1,2 = 2.60 Hz, JPH = 9.05 Hz, 1H, H1), 4.57–4.34 (m,
4H, PhCH2), 3.77–3.71 (m, 2H, H4, H6), 3.66–3.57 (m, 2H, H6’, H5); 13C NMR (125.76
MHz, CDCl3): d 138.4–127.5 (m, Ph), 129.3 (d, 3JPC = 9.3 Hz, C3), 123.3 (d, 2JPC = 5.3
Hz, C2), 76.5 (d, 3JPC = 7.3 Hz, C5), 75.0 (d, 1JPC = 91.9 Hz, C1), 73.3 (s, PhCH2), 71.2 (s,
PhCH2), 69.6 (d, 4JPC = 2.3 Hz, C4), 69.4 (s, C6); 31P NMR (202.46 MHz, CDCl3): d 27.8.
HRMS: Calcd for C32H31O4P: M, 510.1960. Found: M+, m/z, 510.1957.
1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-diphenylphosphinoyl-D-ribo-hex-1-
enitol 13; white crystals: mp 126–128.5ꢀC; IR (KBr); n 3050, 2900, 1640, 1440, 1370,
1
1330, 1260, 1210, 1170, 1100, 920, 890, 840,and 690 cmꢀ 1; H NMR (500.13 MHz,
CDCl3):d 7.82–7.79, 7.42–7.11, 6.79–6.78 (m, 20H, Ph), 6.48–6.46 (m, 1H, H1),
4.85–4.82 (m, 1H, H5), 4.50 (d, Jgem = 12.1 Hz, 1H, PhCH2), 4.44 (d, 1H, Jgem = 12.1
Hz, PhCH2), 4.30–4.27 (m, 1H, H2), 4.27 (d, Jgem = 12.1 Hz, 1H, PhCH2), 4.24–4.19
(m, 1H, H4), 4.14 (d, Jgem = 11.3 Hz, 1H, PhCH2), 3.78 (dd, Jgem = 10.7 Hz, J5,6 = 3.8
Hz, 1H, H6), 3.67 (dd, Jgem = 10.7 Hz, J5,6’ = 2.8 Hz, 1H, H6’), 3.59–3.55 (m, 1H,
3
H3); 13C NMR (125.77 MHz, CDCl3): d 145.9 (d, JPC = 9.8 Hz, C1), 138.1, 137.4,
2
134.6, 134.1, 133.8, 133.3, 131.3–130.9, 128.5–125.9 (m, Ph), 92.8 (d, JPC = 6.8 Hz,
3
C2), 74.5 (d, JPC = 1.9 Hz, C5), 73.5 (s, PhCH2), 72.73 (d, JPC = 6.7 Hz, C4), 72.72
2
1
(s, PhCH2), 68.7 (s,C6), 37.2 (d, JPC = 72.4 Hz, C3); 31P NMR (202.46 MHz,CDCl3):
d 27.7. HRMS: Calcd for C32H31O4P: M, 510.1960. Found: M+, m/z, 510.1958.
Acid catalyzed hydrolysis of 3. To a solution of 3 (2.07 g, 5 mmol) in methanol
(20 ml) was added one-drop of 10% hydrochloric acid and the resulting mixture was
refluxed for 18 h. After cooling, the solvent was removed in vacuo, and the residue was
extracted with dichloromethane. The organic layer was washed with brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was

Synthesis of Phosphonylated Sugars
453
chromatographed on silica gel to give quantitatively diphenyl(2,3-dideoxy-D-erythro-
hex-2-enopyranosyl)phosphine oxide 8 (1.66 g).
To a mixture of 8 (1.66 g, 5 mmol) and catalytic amounts of concentrated sulfuric
acid in dichloromethane (10 ml) was passed isobutene gas for 42 h with stirring at
room temperature. Then the resulting mixture was diluted with water and extracted
with dichloromethane. The organic layer was dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by column chromatography to give
diphenyl(4,6-di-O-tert-butyl-2,3-dideoxy- -D-erythro-hex-2-enopyranosyl)phosphine
oxide 9 (0.88 g, 40%) and diphenyl(4,6-di-O-tert-butyl-2,3-dideoxy- -D-erythro-hex-
2-enopyranosyl)phosphine oxide 9 (0.13 g, 6%).
9 : white syrup; IR (neat); n 2980, 2330, 1720, 1630, 1590, 1440, 1360, 1190,
1120, 1090, 1060, 1020, 880, 750, 720 and 690 cmꢀ 1 1H NMR (500.13 MHz,
;
CDCl3):d 8.02–7.39 (m, 10H, Ph), 6.08 (dd, J1,2 = 2.46 Hz, J2,3 = 10.58 Hz, 1H, H2),
5.97–5.93 (ddd, J2,3 = 10.58 Hz, J3,4 = 3.13 Hz, JPH = 3.13 Hz, 1H, H3), 5.05 (dd,
J1,2 = 2.46 Hz, JPH = 12.3 Hz, 1H, H1), 3.84 (br.s, 1H, H4), 3.62 (ddd, J4,5 = 5.08 Hz,
J5,6 = 4.20 Hz, J5,6’ = 5.37 Hz, 1H, H5), 3.45 (dd, 1H, J5,6 = 4.20 Hz, Jgem = 10.18 Hz,
H6), 3.39 (dd, J5,6’ = 5.37 Hz, Jgem = 10.18 Hz, 1H, H6’), 1.18 (s, 9H, CH3), 1.16 (s,
9H, CH3); 13C NMR (125.76 MHz, CDCl3): d 132.6–128.1 (m, Ph and C3), 122.0 (d,
3
1
2JPC = 2.3 Hz, C2), 75.8 (d, JPC = 3.9 Hz, C5), 74.3 (s, C(CH3)3), 73.0 (d, JPC = 83.9
Hz, C1), 72.9 (s, C(CH3)3), 62.5 (s, C4), 60.6 (s, C6), 28.4 (s, CH3), 27.4 (s, CH3); 31P
NMR (202.46 MHz, CDCl3): d 26.4. HRMS (Fab): Calcd for C26H36O4P: M + 1,
443.2351. Found: M++ 1, m/z, 443.2352.
9 : white syrup; IR (neat); n 2980, 2330, 1720, 1630, 1590, 1480, 1440, 1390, 1360,
1
1190, 1120, 1100, 1060, 1030, 890, 750, 720,and 690 cmꢀ 1; H NMR (500.13 MHz,
CDCl3): d 8.08–7.41 (m, 10H, Ph), 6.06–6.03 (m, 1H, H2), 5.81–5.79 (m, 1H, H3),
5.09–5.06 (dd, JPH = 12.7 Hz, J1,2 = 2.2 Hz, 1H, H1), 3.89 (bs, 1H, H4), 3.55–3.51 (m,
2H, H6 and H6’), 3.33–3.31 (m, 1H, H5), 1.21 (s, 9H, CH3), 1.15 (s, 9H, CH3); 13C
3
NMR (125.76 MHz, CDCl3): d 133.7 (d, JPC = 9.6 Hz, C3), 132.7–127.7 (m, Ph),
2
3
1
121.9 (d, JPC = 5.7 Hz, C2), 76.3 (d, JPC = 6.7 Hz, C5), 75.1 (d, JPC = 92.7 Hz, C1),
74.7 (s, C(CH3)3), 72.6 (s, C(CH3)3), 62.2 (s, C4), 60.1 (s, C6), 28.5 (s, CH3), 27.2 (s,
CH3); 31P NMR (202.46 MHz, CDCl3): d 26.7. HRMS (Fab): Calcd for C26H36O4P:
M + 1, 443.2351. Found M++ 1, m/z, 443.2339.
Base catalyzed hydrolysis of 3. A mixture of 3 (0.48 g, 1.16 mmol) and KOH
(1.6 g, 24 eq) in methanol was stirred for 1 h at room temperature. The mixture was
then neutralized with diluted hydrochloric acid and the solvent was evaporated in
vacuo. The residue was extracted with dichloromethane, and the organic layer was
washed with brine, dried over anhydrous Na2SO4. The solvent was evaporated in
vacuo, and the residue was chromatographed over silica gel to give quantitatively
diphenyl(2,3-dideoxy-D-erythro-hex-1-enopyranosyl)phosphine oxide 10 (0.27 g,
71%).
10: white amorphous solid; IR (Nujol); n 3400, 3050, 3000, 1640, 1440, 1270,
1180 1120, 1080, 1030, 1000, 900, 740, and 700 cmꢀ 1 1H NMR (500.13 MHz,
;
CDCl3): d 7.75–7.26 (m, 10H, Ph), 5.59–5.57 (m, 1H, H2), 4.63 (s, 1H, OH), 4.03–
4.02 (m, 2H, H4 and OH), 3.89–3.86 (m, 1H, H6), 3.77–3.74 (m, 1H, H6’), 2.46–2.41
(1H, H3), 2.21–2.16 (m, 1H, H3’); 13C NMR (125.76 MHz, CDCl3): d 147.8 (d,
2
1JPC = 132.7 Hz, C1), 132.4–128.5 (m, Ph), 114.4 (d, JPC = 20.0 Hz, C2), 80.8 (d,
3
3JPC = 5.9 Hz, C5), 63.0 (s, C4), 61.5 (s, C6), 30.0 (d, JPC = 10.3 Hz, C3); 31P NMR

454
Takano et al.
(202.46 MHz, CDCl3): d 22.0. HRMS (Fab): Calcd for C18H20O4P: M + 1 331.1099.
Found: M++ 1, m/z, 331.1119.
Hydrogenation of 13. Compound 12 (4.54 g, 8.90 mmol) was dissolved in THF/
EtOH (1/1) in a Parr flask. To this was added 2.25 g of 10% Degussa Type N101NE/W
palladium on charcoal (contains 50% H2O). The flask was placed in a medium pressure
hydrogenator at 4.5–4.2 atm of hydrogen for 38 h, after which time, the solution was
filtered through celite, and concentrated. The residue was chromatographed on silica
gel using ethyl acetate–methanol (6:1–2:1, gradient) to give 1.90 g (64%) of 1,5-
anhydro-2,3-dideoxy-3-diphenylphosphinoyl-D-ribo-hexitol 16 and 0.23 g (6%) of
1,5-anhydro-2,3-dideoxy-4-O-benzyl-3-diphenylphosphinoyl-D-ribo-hexitol 15. Hy-
drogenation using 5% Pd/C (Wako) gave 1,5-anhydro-2,3-dideoxy-4,6-di-O-benzyl-
3-diphenylphosphinoyl-D-ribo-hexitol 14 as a major product (44%), and hydrogena-
tion using 10% Pd/C (Aldrich) gave 15 in 48% yield.
16; white amorphous solid; IR (KBr) n 3360, 2925, 2330, 1640, 1428, 1160, 1105,
1
1038, 980, 885, 850, 740, and 690 cmꢀ 1; H NMR (400.13 MHz, CD3OD): d 7.95–
7.46 (m, 10H, Ph), 4.05–3.93 (m, 1H, H5), 3.86–3.62 (m, 5H, H1, H4, and H6), 3.14–
3.10 (m, 1H, H3), 2.05–1.97 (m, 1H, H2), 1.65–1.58 (m, 1H, H2); 13C NMR (100.31
3
MHz, CD3OD): d 133.96–129.69 (m, Ph), 80.38 (d, JPC = 6.1 Hz, C5), 66.93 (d,
3
1
2JPC = 6.1 Hz, C4), 63.21 (d, JPC = 8.4 Hz, C1), 61.74 (s, C6), 37.21 (d, JPC = 73.2
Hz, C3), 23.07 (s, C2); 31P NMR (161.97 MHz, CD3OD): d 39.27. HRMS (FAB):
Calcd for C18H22O4P, M + 1 333.1117. Found M++ 1, m/z, 333.1255.
15; mp 139–142ꢀC; IR (KBr) n 3440, 3090, 2950, 2900, 2350, 1660, 1655, 1450,
1
1150, 1040, 1005, 906, 875, 745, 727, and 700 cmꢀ 1; H NMR (400.13 MHz, CDCl3):
d 7.88–6.92 (m, 20H, Ph), 4.51 (dd, J = 28.7 Hz, J = 11.9 Hz, 2H, PhCH2), 4.34–4.29
(m, 2H, H6), 4.17 (d, J = 11.4 Hz, 1H, H1), 4.04–3.95 (m, 2H, H1, H4), 3.81–3.77 (m,
1H, H5), 3.12–3.09 (m, 1H, H3), 2.09–2.06 (m, 1H, H2), 1.9–1.76 (m, 1H, 2H); 13C
2
NMR (100.31 MHz, CDCl3): d 138.4–127.7 (m, Ph), 76.05 (d, JPC = 3.0 Hz, C4),
74.79 (d, JPC = 5.3 Hz, C5), 71.92, 62.02 (s, C6 and C7), 63.24 (d, JPC = 4.6 Hz, C1),
3
3
1
36.38 (d, JPC = 72.4 Hz, C3), 25.55 (s, C2); 31P NMR (161.97 MHz, CDCl3): d 32.89.
HRMS (FAB): Calcd for C25H27O4P, M + 1 423.1647. Found M++ 1, m/z, 423.1721.
14; mp 164–166ꢀC; IR (KBr) n 3400, 3050, 2860, 2350, 1450, 1430, 1170, 1110,
1
900, 730, and 690 cmꢀ 1; H NMR (400.13 MHz, CDCl3): d 7.82–6.95 (m, 20H, Ph),
4.48 (dd, J = 28.0 Hz, J = 12.0 Hz, 2H, H8), 4.31–4.29 (m, 2H, H7), 4.14 (d, J = 11.4
Hz), 4.01–3.92 (m, 2H, H1, H4), 3.79–3.74 (m, 1H, H5), 3.09–3.06 (m, 1H, 3H),
2.01–1.79 (m, 2H, H2); 13C NMR (100.31 MHz, CDCl3) d 138.1–127.3 (m, Ph), 75.0
2
3
(d, JPC = 5.3 Hz, C4), 74.3 (d, JPC = 5.3 Hz, C5), 73.5, 71.8, 69.8 (s, C6, CH2Ph),
63.2 (d, JPC = 6.9 Hz, C1), 36.8 (d, JPC = 72.0 Hz, C3), 23.9 (s, C2); 31P NMR
(161.97 MHz, CDCl3): d 32.69. HRMS (FAB): Calcd for C32H33O4P, M + 1 512.2116.
Found M++ 1, m/z, 521.2158.
3
1
1,5-anhydro-2,3-dideoxy-6-O-tert-butyldimethylsilyl-3-diphenylphosphinoyl-D-
ribo-hexitol 17. To a solution of diol 15 (0.754 g, 2.27 mmol) in DME (10 ml) was
added imidazole (0.62 g, 9.08 mmol) and tert-butyldimethylsilyl chloride (0.40 g, 2.72
mmol) at room temperature under argon atmosphere, and the mixture was stirred for 48
h. After the usual workup, the organic layer was concentrated, and the residue was
chromatographed on silica gel using ethyl acetate as eluent to give 17 as white crystals

Synthesis of Phosphonylated Sugars
455
in 75% (0.754 g) yield. For the X-ray crystal analysis, a sample recrystallized from
dichloromethane was used.
mp 146–150ꢀC; IR (KBr) n 3350, 3150, 2960, 2880, 2350, 1610, 1470, 1450,
1380, 1375, 1350, 1255, 1175, 1105, 1090, 985, 900, 845, 795, 765, 725, 715, and 705
1
cmꢀ 1; H NMR (400.13 MHz): d 7.49–7.46 (m, 10H, Ph), 4.79 (s, 1H, OH), 4.24 (d,
1H, J = 8.4 Hz, H5), 3.843.79 (m, 3H, H1 and H4), 3.75–3.72 (m, 2H, H6), 2.89–2.83
(m, 1H, 3H), 2.31–2.24 (m, 1H, 2H), 1.44–1.38 (m, 1H, 2H), 0.83 (s, 9H, t-Bu); 13C
NMR (100.31 MHz, CDCl3): d 131.97, 131.84, 131.00, 130.87, 130.78, 130.74, 130.65,
3
128.81, 128.70, 128.60, 133.04, 132.54, 77.79 (d, JPC = 7.6 Hz, C5), 66.03 (d,
3
1
2JPC = 4.6 Hz, C4), 63.64 (s, C6), 62.37 (d, JPC = 10.7 Hz, C1), 33.86 (d, JPC = 71.6
Hz, C3), 25.77 (s, C10, C11 and C12), 19.09 (s, C2), 18.09 (s, C9), 5.59–5.62 (s, C7
and C8); 31P NMR (161.97 MHz, CDCl3): d 37.97. HRMS: Calcd for C24H35O4SiP, M,
446.2042. Found M+, m/z, 446.2041.
X-Ray Crystal Analysis of 17. Data Collection
A colorless prismatic crystal of C24H35O4PSi having approximate dimensions of
0.52 ꢁ 0.84 ꢁ 0.68 mm was mounted on a glass fiber. All measurements were made on a
Rigaku AFC5S diffractometer with graphite monochromated Mo–Ka radiation. Cell
constants and an orientation matrix for data collection, obtained from a least-squares
refinement using the setting angles of 25 carefully centered reflections in the range
20.13 < 2q < 23.97ꢀ corresponded to a primitive orthorhombic cell with dimensions:
ꢂ
ꢂ
ꢂ
ꢂ
a ¼ 11:490ð5Þ A; b ¼ 19:548ð6Þ A; c ¼ 10:909ð5Þ A; V ¼ 2450ð2Þ A3
For Z = 4 and F.W. = 446.60, the calculated density is 1.21 g/cm3. The systematic
absences of: h00: h 2n, 0k0: k 2n, 00l: l 2n, uniquely determine the space group to
be: P212121 (#19).
The data were collected at a temperature of 23 + 1ꢀC using the w-2q scan
technique to a maximum 2q value of 55.0ꢀ. Omega scans of several intense reflections,
made prior to data collection, had an average width at half-height of 0.22ꢀ with a take-
off angle of 6.0ꢀ. Scans of (1.47 + 0.30 tan q)ꢀ were made at a speed of 16.0ꢀ/min (in
o). The weak reflections (I < 10.0s(I)) were rescanned (maximum of 3 scans) and the
counts were accumulated to ensure good counting statistics. Stationary background
counts were recorded on each side of the reflection. The ratio of peak counting time to
background counting time was 2:1. The diameter of the incident beam collimator was
1.0 mm, the crystal to detector distance was 258 mm, and the detector aperture was
6.0 ꢁ 6.0 mm (horizontal ꢁ vertical).
Data Reduction
A total of 3189 reflections was collected. The intensities of three representative
reflections were measured after every 150 reflections. No decay correction was applied.
The linear absorption coefficient, m, for Mo–Ka radiation is 1.9 cmꢀ 1. An
empirical absorption correction based on azimuthal scans of several reflections was
applied which resulted in transmission factors ranging from 0.71 to 1.00. The data were
corrected for Lorentz and polarization effects.

456
Takano et al.
Structure Solution and Refinement
The structure was solved by direct methods and expanded using Fourier
techniques. The non-hydrogen atoms were refined anisotropically. Hydrogen atoms
were included but not refined. The final cycle of full-matrix least-squares refinement on
F was based on 1349 observed reflections (I > 2.00s(I)) and 271 variable parameters
and converged (largest parameter shift was 0.24 times its esd) with unweighted and
weighted agreement factors of:
R ¼ SjjFoj ꢀ jFcjj=SjFoj ¼ 0:099
Rw ¼ ½SwðjFoj ꢀ jFcjÞ2=Sw Fo2ꢃ1=2 ¼ 0:081
ACKNOWLEDGMENTS
This work was supported by Grant-in Aid for Scientific Research (No. 14550823),
and by Grant-in Aid for The 21st Century COE Program by the Ministry of Education,
Science, Sports and Culture of Japan. The authors gratefully acknowledge professor
Takahisa Kanda, Department of Chemistry and Material Engineering, Faculty of
Engineering, Shinshu University, for his useful discussions.
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Received August 19, 2002
Accepted July 11, 2003