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沼津工業高等専門学校研究報告
第 51 号，2017 年 1 月

Synthesis and structural analysis of 3-methoxy-1,2,4-tri-O-acetyl-5-deoxy-5C(isopropylphosphinyl)-D-pentopyranose and immobilizationof its conformation by β-cyclodextrin
Kuniaki Seo,a Tadashi Hanaya,b Takanobu Goto,a Tatsuo Oshikawa*a
Abstract: The title compound of a heterosaccharide (pseudo sugar) containing aphosphorus atom in the hemiacetal ring (phospha sugar) was synthesized. The
conformation and the configuration of the phospha sugar configuration at theanomeric carbon were then characterized by 1H NMR.
The analyzed
conformation of the title compound was an equilibrium mixture of 4C1 and 1C4 in
CDCl3 and DMSO-d6. When the phospha sugar included in β-cyclodextrin inwater, the conformation of the equilibrium mixture was immobilized in the 1C4
conformation alone.
Key Words: Phospha sugar, Synthesis and structure analysis, Immobilization of Conformation, β-Cyclodextrin
Introduction
Phospha sugar of the title compound 5 was synthesized
Various sugar analogs with the oxygen atom in thefrom D-arabinose as the starting material. The synthesis

hemiacetal ring replaced by a heteroatom are of extensive

process is shown in Scheme 1.

biochemicalinterest.1-7Here, we report the novel

synthesis of 3-methoxy-1,2,4-tri-O-acetyl-5-deoxy-5C(isopropylphosphinyl)-D-pentopyranoseasa phosphasugar derivative, along with the detailed studies of its
conformation and configuration.

Hanaya et al. havereported the synthesis of phospha sugar derivatives, andthe detailed structural analyses of their conformation by
1H

NMR were reported.8-9

We have reported that theconformation of these phospha sugar derivatives insolution (as determined by NMR analysis) is the same asthat in the solid state (as determined by X-ray
crystallographic analysis).10 In this paper we will deal
with the first case of immobilization of the conformation
by inclusion with β-cyclodextrin.

Scheme 1. Route of synthesis of phospha-sugar
derivative 5 from D-arabinose.

Iodine compound (6-deoxy-6-iodo compound) 1 wasderived from D-arabinose by using a general synthetic
process. Phosphinate 2 was easily obtained by heating a
aDepartmentof Chemistry and Biochemistry, National

mixture of compound 1 and excess amount of diethyl

Institute of Technology, Numazu College, 410-8501, Japan

isopropylphosphonite at 150 °C.

bDepartment of Chemistry, Faculty of Science, Okayama

synthesized by treating compound 2 with sodium

University, Tsushima-naka 700-8530, Japandihydrobis(2-methoxyethoxy) aluminate (SDMA).

Results and Discussion

Compound 3 wasThesubsequent opening of furanoid ring of 3 to synthesize the

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沼津工業高等専門学校研究報告

第 51 号

pyranoid ring were processed under acidic conditions as

when P = O and H-2 are axial to each other and J2,P =described in the report.10

Phospha sugar derivatives 5 of

22.7–25.3 Hz, when P = O is axial and H-2 is equatorial.9

the title compound were obtained in high yield by the

Therefore, compounds 5b and 5c should present as

acetylation of compound 4.

Diastereomers of phospha

equilibrium mixtures of 1C4 and 4C1.

The orientation ofsugar 5a, 5b, 5c and 5d were separated from the mixture

P = O was determined by the chemical shift value (δppm)of reaction products by flash chromatography.

The

for H-4 and HS-5 of compounds 5a to 5d. That is, H-2,

chemical yields of the diastereomers 5a, 5b, 5c, and 5d

which is 1,3-diaxial to the orientation of P = O, shifted tosynthesized from compound 1 were 2.0%, 23.5%, 4.0%,

the down field. Thus, in CDCl3, compounds 5a and 5c

and 13.1%, respectively.

retained the 1C4 conformation, and compounds 5b and 5d
retained equilibrium mixtures of the 1C4 and the 4C1
conformations.

In DMSO-d6,9, 11-14 the equilibrium

mixtures of 5b and 5d shifted slightly to the 1C4 enriched
conformation (Scheme 2).
Single-crystal X-ray structural analysis showed thatthe equilibrium mixture of 1C4 and 4C1 was maintained atroom temperature in the solid state. This is because theatoms constituting the phospha sugar derivative weredisordered at room temperature.10 The equilibrium
mixtures 5d and 5d’ were included in β-cyclodextrin toimmobilize the equilibrium mixture of 1C4 and 4C1 intoeither the 1C4 or 4C1 conformation.
Scheme 2. Diastereoisomers of phospha-sugar 5 andβ-Cyclodextrin is

widely used in supramolecular chemistry and in the foodtheir conformations.

and chemical industries. Inclusion of a phospha sugar
derivative in cyclodextrin may have an interesting effecton the use of the latter in drug delivery.

The detailed structures of diastereomers 5a, 5b, 5c, and 5d
were determined by their 600 and 400 MHz 1H NMR
spectra. The results of the NMR spectra analyzed aresummarized in Table 1.

Structure elucidation was

performed carefully to determine the conformations ofphospha sugar derivatives 5a to 5d.

The magnituderelationshipconstants

betweenthecoupling

(A)
OMe

H-1

HR-5

HS-5

P-C-(CH3)2

H-2
H-4
OAc

J2,P

(17.8–20.8 Hz for 5d and 5b vs. 2.9–8.5 Hz for 5a and 5c)
and J4,P (7.0–9.5Hz for 5b and 5c vs. 20–30 Hz for 5a, 5c
and 5d) corresponded to the value of the dihedral angle
H-C-C-P. As a result, compounds 5a and 5c retained theC4 conformation, and compound 5b and 5c were

1

(B)

OAc

OMe

H-2

HS-5

H-1

P-C-(CH3)2

HR-5

H-4

equilibrium mixture of 1C4 and 4C1 conformation in CDCl3.
The moderate magnitudes of J5R,P (8.8-11.0 Hz) support
the anti orientation of HR-5-C5-P=O for 5b and 5d, and thesmall long range coupling constants shown J3,5R (0.5-1.2

Fig. 1. 1H NMR spectra (400 MHz) of a solution containingHz) for 5b and 5c. In a pyranose-type phospha sugar(A) compound 5d’ (6.0 mM) and β–cyclodextrin (13.1 mM)

derivative, the coupling constant J2,P required to supportin D2O, (B) the equilibrium mixture 5d and 5d’ in CDCl3.

the value of the dihedral angle is J2,P = 5.54–5.81 Hz,a) In CDCl3.

5aa)
5ab)
5ba)
5bb)
5ca)
5cb)
5da)
5db)
5de)

9.9
11.3
0.5
3.0
1.0
2.4
12.9
11.1
10.6

J1,P

5.39
5.19
5.58
5.31
5.74
5.54
5.73
5.425
5.48

H-2

0.5
0
0
0
0.5
0
0
0
0

J1,5R

0
0
0.5
0.8
0
0
0.5
1.5
2.0

J1,5S

3.50
3.72
3.75
3.76
3.37
3.66
3.60
3.71
3.73

H-3

7.6
9.3
6.1
7.3
7.8
9.8
5.9
8.5
9.8

J2,3

5.40
5.47
5.67
5.48
5.38
5.39
5.13
5.32
5.58

H-4

8.4
4.2
17.8
13.0
8.5
2.9
20.8
8.5
4.6

J2,P

2.14
2.31
2.26
2.20
1.87
2.04
2.30
2.20
2.27

2.7
2.9
2.4
2.5
2.2
2.7
2.4
2.7
2.6

J3,4

2.12
2.065
2.16
2.09
2.17
2.05
2.13
2.13
2.12

2.115
2.05
2.15
2.05
2.16
2.005
2.11
2.02
2.04

Ac-1, 2, 4c)

0
0
1.0
0.5
0
0
1.2
0.5
0

3.2
2.9
4.4
3.4
2.7
2.7
2.4
3.2
3.2

J4,5R
7.8
5.6
10.5
9.3
7.6
6.4
11.5
7.6
6.0

J4,5S
21.5
30.6
9.5
15.6
19.5
27.1
7.0
18.1
24.2

J4,P
14.9
15.6
14.4
14.9
15.1
15.3
14.7
15.1
16.2

J5R,5S

2.10
2.00
2.09
2.02
2.08
2.00
2.105
2.02
2.01

1H NMR Chemical shifts (δ, ppm)

1H NMR Coupling constants (Hz)

J3,5R

2.51
2.48
2.29
2.31
2.62
2.36
2.53
2.34
2.55

HS-5

d
2.2
9.5
d
8.8
11.0
d
d
d

J5R,P

3.42
3.27
3.52
3.41
3.44
3.30
3.55
3.39
3.37

MeO-3

9.0
11.0
5.6
6.8
16.4
15.3
16.3
15.1
15.2

J5S,P

2JH,P
d
2.2
9.5
d
8.8
11.0
d
d
d

2.11
2.10
2.02
2.05
2.00
1.94
2.17
2.02
2.05

HC-P

3JH,H
7.1
7.1
7.1
7.1
7.1
7.1
7.1
7.1
7.1

1.33
1.23
1.25
1.095
1.24
1.035
1.34
1.12
1.08

41.7

42.2

41.2

45.7

31P

3JH,P
15.6
17.1
15.0
16.9
16.4
16.9
16.1
16.8
17.0
16.4
11.0
10.5
14.8
17.1
16.6
15.9
17.8
17.4

i-Pr

1.24
1.09
1.20
1.07
1.235
1.01
1.335
1.04
1.00

Me-C-Pb) In DMSO-d6. c) The assignment of acetyl groups may have to be interchanged. d) Uncertainly because of the overlapping with other signals. e) Inclusion complex with β-cyclodextrin.

8.4
10.7
3.4
3.2
8.3
10.5
3.7
3.2
3.0

J1,2

5.50
5.58
5.51
5.39
5.37
5.45
5.75
5.44
5.72

5aa)
5ab)
5ba)
5bb)
5ca)
5ca)
5da)
5db)
5de)

Compound

H-1

HR-5

1H and 31P NMR parameters for compounds 5a, 5b, 5c, and 5d.

CompoundTable 1.

Synthesis and structural analysis of 3-methoxy-1,2,4-tri-O-acetyl-5-deoxy-5C-(isopropylphosphinyl)-D-pentopyranose and immobilization of its conformation by β-cyclodextrin

49

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沼津工業高等専門学校研究報告

When crystals of the equilibrium mixtures 5d and 5d’

第 51 号

5-Deoxy-5-C-(ethoxyisopropylphosphinyl)-1,2-O-isopropyli

were added to a solution in which β-cyclodextrin was

dene-3-O-methyl-β-D-arabinofuranosedissolved in D2O and the suspension was ultrasonicated

5-Deoxy-5-iodo-1,2-O-isopropylidene-3-O-methyl-β-(2):

The 1HD-arabinofuranose (1) (2.514 g) was treated with diethyl

NMR spectra of the 5dd’ / β-cyclodextrin inclusion complex

isopropylphosphonite as described above, to give syrupy 2

were shown in Fig. 1.

(1.831 g, 67.2 %); Rf = 0.40 (10:1 EtOAc-MeOH); [α]D =for 5 min to become completely clear solution.

In Fig. 1 (A), the protons on the carbon atom

+33.7° (c, 2.67, CHCl3); 1H NMR (CDCl3): 1.0-1.6 (m, 15H,

composing the pyranoid ring of equilibrium mixtures 5d

iPr-P, OCMe2 P-OCMe), 1.7-2.3 (m, 2H, H-5,5’), 3.38, 3.40

and 5d’ included in β-cyclodextrin are much more clearly(2s, 3H,OMe-3), 3.6-4.4 (m, 4H, H-3,4, P-O-CH2-), 4.53 (d,identified than the spectra of 5d and 5d’ in CDCl3. For

J1,2=4.1Hz, 1H, H-2), 5.82 (d, J1,2=4.1Hz, 1H, H-1).

example, the H-1 and H-2 signals of equilibrium mixtures
5d and 5d’ overlapped at δ5.75 to 5.73 ppm (in CDCl3) but

5-Deoxy-5-C-(isopropylphosphinyl)-1,2-O-isopropylidene-3

were separated into δ5.72 and δ5.48 ppm by inclusion-O-methyl-β-D-arabinofuranose (3): Compound 2 (1.73 g)complex with the β-cyclodextrin. There were significant

was treated with SDMA (3.62 g, in 70 % toluene) as

changes in the value of J1,5S (long-range coupling) for

described above to give syrupy 3 (966 mg, 63.9 %); Rf =equilibrium mixtures 5d and 5d’ (CDCl3) from 0.5 to 2.0

0.46-0.54 (10:3 EtOAc-MeOH); [α]D =+41.5° (c, 2.41,

Hz (for 5d’); in the value of J4,P from 7.0 to 24.2 Hz (for 5d’);

CHCl3); 1H NMR(CDCl3): 1.0-1.6 (m, 13H, iPr, CMe2),

and in the value of J2,P from 20.8 to 4.6 Hz (for 5d’).

2.0-2.6 (m, 2H, H-5,5’), 3.4,3.47 (2s, 3H, Ome-3), 3.84 (d,Because of the clear change in the coupling constants,

J3,4=2.42Hz, 1H, H-3), 4.4-4.6 (m, 1H, H-4), 4.62 (d,equilibrium mixtures 5d and 5d’ completely shifted to theJ1,2=3.95Hz, 1H, H-2), 5.93 (2d, J1,2=3.95Hz, 1H, H-1), 6.8

C4 conformation of 5d’ due to the inclusion in(broad d, JP-H=456Hz, 1H, P-H).

1β-cyclodextrin.

This

indicate thatcompound 5d’contained at a nearly ideal 1C4 conformation in the

Hydrolysis of compound 3 and 1,2,4-tri-O-

molecules of β-cyclodextrin by these coupling constants.

acethyl-5-deoxy-5-C-(isopropylphosphinyl)-O-

However, compounds 5a, 5b, and 5c were not included inmethyl-D-arabino-pyranoses (5): Compound 3 (913 mg) in

β-cyclodextrin.

water (30 mL) was treated with HCl (0.3 mL) as describedabove to give syrupy 4, which was treated with acetic
anhydride (2 mL) in dry pyridine (5 mL), to afford syrupy
Experimental

mixture 5.

Synthetic procedures for compound 5 from 1 as thestarting material were shown in a previous paper.1

1H

The mixture was separated by medium

pressure column chromatography on silica gel, to give 5a㸫5d. 5-C-[(S)-isopropylphosphinyl]-α-D-arabino-

NMR spectra were measured in CDCl3 (TMS as thepyranose derivative (5a) (23 mg, 2.0 % from 1), mp

internal standard) on a Varian Unity Inova AS600 (600

178-179° (crystallized from EtOAc-hexane); [α]D = -27. 8°

MHz) and JEOL ECX-400 (400 MHz).

Melting points(c, 1.53, CHCl3). Anal. Calcd for C13H23O8P: C, 49.45; H,

were measured with a micro melting point apparatus

6.92. Found: C, 49.50; H, 6.82.5-C-[(S)-isopropylphosphin-(Yamato MP-21 Co., Ltd., Japan) and are uncorrected.

yl]-β-D-arabinopyranose derivative (5b) (269 mg, 23.5 %Column chromatography was performed by flash column

from 1), mp 123.5-124° (crystallized from EtOAc-hexane);chromatography on silica gel (silica gel : KANTO Co., LTD,[α]D = -12.4° (c, 2.42, CHCl3). Anal. Calcd for C13H23O8P: C,

20-40μm).

49.45; H, 6.92. Found: C, 49.00; H, 7.01. 5-C-[(R)-The reactions were monitored by TLC on

Kieselgel 60 F254 (Merck) with detection by H2SO4.

isopropylphosphinyl]-α-D-arabinopyranose derivative (5c)Optical rotations were determined with a digital(46 mg, 4.0 % from 1), mp 203-204° (crystallized frompolarimeter DIP-4 (JASCO Ltd.).

EtOAc-n-hexane); [α]D = -20. 6° (c, 1.58, CHCl3). Anal.
Calcd for C13H23O8P: C, 49.45; H, 6.92. Found: C, 48.21; H,
6.91. 5-C-[(R)-isopropylphosphinyl]-β-D-arabinopyranose derivative (5d): 150 mg (13.1 % from 1), mp

Synthesis and structural analysis of 3-methoxy-1,2,4-tri-O-acetyl-5-deoxy-5C-(isopropylphosphinyl)-D-pentopyranose and immobilization of its conformation by β-cyclodextrin

186-187° (crystallized from EtOAc-n-hexane), [α]D = -27.6°(c, 1.90, CHCl3). Anal. Calcd for C13H23O8P: C, 49.45; H,
6.92. Found: C, 49.62; H, 7.00.

Acknowledgement
This work financial support from National Institute ofTechnology, Numazu College.
References
1. Whistler RL, Lake WC, Methods. Carbohydr. Chem
1972, 6, 286–291.
2. Pitts MJ, Chmielewski M, Chen MS, Abd El-Rahman
MMA, Whistler RL, Arch. Biochem. Biophys 1975, 169,
384–391.
3.

Capon RJ, MacLead JK. J. Chem. Soc., Chem.

Commun 1987, 1200–1201.
4.

4. Yuasa H, Izumi M, Hashimoto H. Yuki Gosei

Kagaku Kyokai Shi 2002, 60, 774–782.
5. Paulsen H. Angew. Chem., Int. Ed. Engl 1966, 5,495– 511.
6. Legler G, Julich E. Carbohydr. Res 1984, 128, 61–72.
7. Niwa T, Tsuruoka T, Gori H, Kodama Y, Itoh J, Inoue
S, Yamada Y, Niida T, Nobe M, Ogawa Y. J. Antibiot
1984, 37, 1579–1586.
8. Seo K, Yamashita M, Oshikawa T, Kobayashi J.

Carbohydr Res 1996, 281, 307-312.
9.

Hanaya T, Imai K, Prikhod’ko YV, Yamamoto H.

Carbohydr Res 2005, 340, 31-37.
10. Oshikawa T, Seo K, Yamashita M, Hanaya T,
Hamauzu Y, Yamamoto H, Carbohydr Res 2003,
338, 283-291.
11. Hanata T, Yamamoto H, Journal of Synthetic

Organic Chemistry, Japan 1993, 51, 377-387.
12. Hanaya T, Yamamoto H. Carbohydr Res 1998, 306,
157-162.
13. Hanaya T, Sugiyama K, Kawamoto H, Yamamoto H.

Carbohydr Research 2003, 338, 1641-1650.
14. Hanaya T, Imai K, Prikhod’ko YV, Yamamoto H.

Carbohydr Res 2005, 31-37.

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