A new route for preparation of 5-deoxy-5-(hydroxyphosphinyl)-D-mannopyranose and -L-gulopyranose derivatives

Article abstract of DOI:10.1002/1522-2675(200209)85:9<2608::AID-HLCA2608>3.0.CO;2-F

Starting from methyl 2,3-O-isopropylidene-α-D-mannofuranoside (5), methyl 6-O-benzyl-2,3-O-isopropylidene-α-D-lyxo-hexofuranosid-5-ulose (12) was prepared in three steps. The addition reaction of dimethyl phosphonate to 12, followed by deoxygenation of 5-

Full text of DOI:10.1002/1522-2675(200209)85:9<2608::AID-HLCA2608>3.0.CO;2-F

2608
Helvetica Chimica Acta Vol. 85 (2002)
A New Route for Preparation of 5-Deoxy-5-(hydroxyphosphinyl)-
d-mannopyranose and -l-gulopyranose Derivatives
by Tadashi Hanaya* a) and Hiroshi Yamamotob)
a) Center of Instrumental Analysis, Okayama University, Tsushima, Okayama 700-8530, Japan
(fax: ‡81862517853, e-mail: hanaya@cc.okayama-u.ac.jp)
b) Department of Chemistry, Faculty of Science, Okayama University, Tsushima, Okayama 700-8530, Japan
Dedicated to Professor Wolfgang Pfleiderer on the occasion of his 75th birthday
Starting from methyl 2,3-O-isopropylidene-a-d-mannofuranoside (5), methyl 6-O-benzyl-2,3-O-isopropyl-
idene-a-d-lyxo-hexofuranosid-5-ulose (12) was prepared in three steps. The addition reaction of dimethyl
phosphonate to 12, followed by deoxygenation of 5-OH group, provided the 5-deoxy-5-dimethoxyphosphinyl-
a-d-mannofuranoside derivative 15a and the b-l-gulofuranoside isomer 15b. Reduction of 15a and 15b with
sodium dihydrobis(2-methoxyethoxy)aluminate, followed by the action of HCl and then H2O2, afforded the d-
mannopyranose (17) and l-gulopyranose analog 21, each having a phosphinyl group in the hemiacetal ring.
These were converted to the corresponding 1,2,3,4,6-penta-O-acetyl-5-methoxyphosphinyl derivatives 19 and
23, respectively, structures and conformations (4C1 or 1C4, resp.) of which were established by 1H-NMR
spectroscopy.
Introduction. We have prepared various sugar analogs having a P-atom in the
hemiacetal ring (phospha sugars) [1] because of considerable interest in the
physicochemical properties and potential biological activity, as in the case of aza
sugars [2] and thia sugars [3]. Thus, a large number of phospha sugars were synthesized,
such as those of d-glucose (1a,b) [4][5], d-mannose (2) [6], d-galactose (3) [7], and
l-fucose (4) [8].
For example, the first synthesis of 5-deoxy-5-(hydroxyphosphinyl)-d-mannopyr-
anose (2) was performed starting from methyl 2,3-O-isopropylidene-a-d-mannofur-
anoside (5) by the sequence of 5 ! 6 ! 7 ! 8 ! 2 in ten steps (Scheme 1) [6]. Although
the introduction of a phosphinyl group at C(5) was accomplished by the addition of
dimethyl phosphonate to the nitro olefin 6 with relatively good diastereoselectivity
(86 :14), the conversion of the 6-NO2 group of the major isomer 7 to a 6-OH group

Helvetica Chimica Acta Vol. 85 (2002)
2609
Scheme 1
resulted in a low yield of 8 because of the simultaneous production of various by-
products.
We have recently found an alternative new procedure to introduce a phosphinyl
group into a sugar skeleton: namely, addition of a phosphonate to hexofuranos-5-ulose
derivatives and the subsequent deoxygenation of 5-OH group [5][7]. As the use of
such procedures was proved to be effective for preparation of d-glucopyranose and d-
galactopyranose analogs, 1b and 3, respectively, we have decided to employ the new
method for preparation of d-mannopyranose analogs, 2, as a series for systematic
investigation of the stereoselectivity and synthetic efficiency for dehydroxylation of
various a-hydroxyphosphonates (5-hydroxy-5-phosphinylhexofuranoses).
Results and Discussion. Methyl 2,3-O-isopropylidene-a-d-mannofuranoside (5)
served as the starting material for preparation of an important key intermediate 12 for
the introduction of a phosphinyl group at C(5) (Scheme 2). The epoxidation of 5 under
Mitsunobu×s conditions afforded the 5,6-O-anhydro derivative 91) (89%) which was
treated with BnOH and NaH in 1,2-dimethoxyethane (DME) to give the 6-O-benzyl
compound 112) in 94% yield. As an alternative way for preparation of 11, compound 5
was converted to the 6-O-Ts derivative 10 [8] in 96% yield. The treatment of 10 with
BnOH and NaH in DME afforded 11 by a one-pot procedure, without isolation of the
intermediate 9, in 93% yield.
The addition reaction of dimethyl phosphonate to 12 in the presence of DBU
afforded the (5R)-5-(dimethylphosphinyl)-d-lyxo-hexofuranoside derivative 13a
(76%) and its (5S)-epimer 13b (19%). The major (5R)-epimer 13a was converted to
the methoxalyl esters 14a with methoxalyl chloride in the presence of 4-(dimethyla-
mino)pyridine (DMAP) and then reduced with Bu3SnH in the presence of AIBN [11],
affording an 81:19 mixture of the 5-deoxy products. On structural assignment of the
1
resulting two separable diastereoisomers by H-NMR, it turned out that the major
isomer was not the expected 5-deoxy-5-(dimethylphosphinyl)-a-d-mannofuranoside
derivative 15a (16% from 13a) but the b-l-gulofuranoside isomer 15b (70%).
The a-d-manno configuration for 15a was assigned on the basis of the large J(4,5)
value (10.7 Hz) and the presence of long-range coupling, 5J(1,P) (1.5 Hz) [8][12] (Fig. 1
1
)
Compound 9 had been obtained from 5 via the 6-O-naphthalenesulfonyl derivative in 45% overall yield
[9].
2
)
Compound 11 had been obtained as a minor product (35% yield) from 5 in two-phase BnBr/aq. NaOH
system [10].

2610
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 2
and Table 1). Similarly, the b-l-gulo configuration for 15b was derived from the large
4
J(4,5) value (10.4 Hz), and the presence of 5J(2,P) (1.2 Hz) and J(3,P) (1.1 Hz).
Although 5-OH compounds 13a and 13b have no H-atom at C(5), their configurations
at C(5) were assigned by comparison to the corresponding 5-deoxy compounds 15a
and 15b, respectively, because the similar characteristic tendency of the correspond-
ing coupling constants and the chemical shifts is expected due to almost identical
conformations3). Thus, (5R)-configuration for 13a and (5S)-configuration for 13b were
5
4
derived from the presence of J(1,P) (for 13a), and 5J(2,P) and J(3,P) (for 13b).
Fig. 1. The most favorable conformations for 13a,b and 15a,b
3
)
The antiperiplanar orientation of HÀC(4) and HÀC(5) in 15a,b is due to steric interaction around
C(4)ÀC(5) bond, whereas the same orientation of HÀC(4) and HOÀC(5) in 13a,b could be explained in
terms of the intramolecular H-bond between the OH group, and O(3) and/or O(4) [13].

Helvetica Chimica Acta Vol. 85 (2002)
2611
1
Table 1. Selected H-NMR Parameters for Compounds 13a,b and 15a,b in CDCl3
d/ppm
HÀC(1)
HÀC(2)
HÀC(3)
HÀC(4)
HÀC(5)
13a
13b
15a
15b
4.91
4.97
4.81
4.88
4.57
4.49
4.54
4.48
5.00
4.85
4.77
4.59
4.32
4.32
4.29
4.29
2.71
2.62
J/Hz
J(1,2)
5J(1,P)
J(2,3)
5J(2,P)
J(3,4)
4J(3,P)
J(4,P)
J(4,5)
13a
13b
15a
15b
0
0
0
0
2.1
0
1.5
0
5.8
5.8
5.5
5.5
0
1.0
0
2.8
3.4
3.1
3.1
0
0.9
0
1.0
4.2
5.8
7.3
10.7
10.4
1.2
1.1
Similarly, the minor (5S)-epimer 13b was converted to 14b, which afforded 15a,b in
almost the same ratio and yields as those from 13a. These results, therefore, indicated
that an epimerization took place at C(5) via a radical intermediate during the reduction
of the methoxalyl esters 14a,b [5][7].
As for the predominant production of the l-gulofuranoside (15b) by the radical
reduction of 14a,b, we propose transition state A of the radical intermediate from the
viewpoint of electronic factors (Fig. 2). Namely, the opposition of the phosphinyl group
and electronegative O-atom in the furanose ring reduces intramolecular electrostatic
repulsion [14]. Moreover, the alignment of the s(C(4)ÀC(3)) bond with the radical p
orbital stabilizes the transition state [15]. Although the mechanistic proposals have
been reported for the radical-mediated reduction of a-bromo-b-alkoxycarboxylates
[16], no report seems to exist, to the best of our knowledge, for the corresponding b-
alkoxyphosphonate derivatives. Systematic mechanistic studies concerning stereo-
selectivity of the reduction for 5-phosphinylhexofuranoses are in progress.
The minor a-d-mannofuranoside 15a was then reduced with sodium dihydrobis(2-
methoxyethoxy)aluminate (SDMA) to give the 5-phosphino derivative 16, which, with
HCl in aq. i-PrOH followed by oxidation with H2O2, afforded 6-O-benzyl-5-deoxy-5-
(hydroxyphosphinyl)-a/b-d-mannopyranoses 17 (Scheme 3). For the purpose of
purification and characterization, compounds 17 were converted to the corresponding
Fig. 2. A plausible conformation for the radical intermediate A and the direction of reduction

2612
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 3
5-(methoxyphosphinyl) 1,2,3,4-tetra-O-acetates 18 by treatment with Ac2O/pyridine
and then ethereal CH2N2. As the separation of a diastereoisomeric mixture of 18 was
still difficult, unambiguous structural assignment was made by further conversion of 18
to the 1,2,3,4,6-penta-O-acetyl derivatives 194). Namely, debenzylation5) of 18 by the
catalytic hydrogenation over 20% Pd(OH)2/C, followed by acetylation, afforded the
pentaacetates 19. After chromatographic purification, 1,2,3,4,6-penta-O-acetyl-5-
deoxy-5-[(R)-methoxyphosphinyl]-a-d-mannopyranose (19a; 6.2% from 15a), its b-
anomer 19b (8.3%), the 5-[(S)-methoxyphosphinyl]-a-isomer 19c (4.7%), and its b-
isomer 19d (5.9%) were obtained6).
The similar treatment of the major b-l-gulofuranoside 15b afforded 6-O-benzyl-5-
deoxy-5-(hydroxyphosphinyl)-a/b-l-gulopyranoses (21) via the 5-phosphino com-
pound 20. The l-gulopyranose analogs 21 were also converted to 5-(methoxyphos-
4
)
Penta-O-acetates are apparently more valuable in view of synthesizing unsubstituted phospha sugars,
because it is easy to convert them to deacetylated compounds with MeONa/MeOH.
On debenzylation of crude 17 by catalytic hydrogenation, a considerable amount of starting material
remained unchanged despite many trials. However, the same reaction of 18, which had been purified by
column chromatography, proceeded with quantitative yield.
5
)
6
)
Compounds 19c/d, 23a/d, and 23b/c were obtained as inseparable mixtures. The yield of each product was
1
based on the H-NMR.

Helvetica Chimica Acta Vol. 85 (2002)
2613
phinyl) pentaacetates 23 via 22: 1,2,3,4,6-penta-O-acetyl-5-deoxy-5-[(R)-methoxy-
phosphinyl]-b-l-gulopyranose (23a; 12% from 15b), its a-anomer 23b (5.1%), the 5-
[(S)-methoxyphosphinyl]-b-isomer 23c (11%), and its a-anomer 23d (6.5%)6).
The precise parameters were obtained for these eight isomers, 19a d, 23a d by the
1
analysis of their 500-MHz H-NMR spectra (Table 2). Some characteristic features of
new products 19b and 23a d are discussed here in detail for comparison with those of
the previously reported isomers 19a,c, and d [6].
Table 2. Selected 1H-NMR Parameters for Compounds 19a d and 23a d in CDCl3
d/ppm
HÀC(1) HÀC(2) HÀC(3) HÀC(4) HÀC(5) HÀC(6) H'ÀC(6) MeOÀP
19a
19b 5.32
19c 5.35
19d 5.42
23a 5.78
23b 5.63
23c 5.49
5.45
5.36
5.61
5.42
5.67
5.40
5.45
5.57
5.67
5.34
5.14
5.25
5.11
5.44
5.37
5.53
5.52
5.63
5.62
5.52
5.56
5.30
5.46
5.36
5.49
2.65
2.47
2.74
2.49
2.83
2.99
2.71
2.81
4.49
4.50
4.58
4.58
4.40
4.41
4.40
4.43
4.41
4.47
4.31
4.33
4.35
4.38
4.40
4.39
3.75
3.82
3.85
3.95
3.94
3.86
3.79
3.87
23d 5.61
J/Hz
J(1,2)
J(1,P)
J(2,3)
J(2,P)
J(3,4)
J(4,5)
J(4,P)
J(5,P)
others
19a
19b
19c
19d
23a
23b
23c
23d
6.4
3.1
5.5
3.6
11.3
3.4
8.8
8.6
10.1
5.9
3.4
14.4
4.9
2.8
2.5
3.0
2.9
2.7
3.0
2.6
3.1
21.6
24.4
25.1
28.9
3.1
7.3
4.9
20.1
8.6
8.9
9.3
9.9
4.6
6.0
5.5
8.6
9.9
10.8
10.8
11.1
3.7
4.3
3.7
4.2
8.315.4
6.8
4.8
13.3
14.6
13.3
15.1
18.9
15.0
22.1
3.9
a
35.4
26.0
33.6
11.0
)
)
)
b
c
11.0
3.4
9.8
b
c
a) 4J(3,P) ˆ 1.8 Hz. ) 4J(1,3) ˆ 1.3Hz. ) 4J(3,P) ˆ 1.9 Hz.
The large J(4,5) values (10 11 Hz) of 19a d and the small J(4,5) values (ca. 4 Hz)
of 23a d indicate the d-mannopyranose configuration of the former and the l-
gulopyranose configuration of the latter. Conformations of these compounds (in CDCl3
solution) are derived from the magnitudes of J(2,P) (20 29 Hz for 19a d and 23d vs.
3 7 Hz for 23a c) and J(4,P) (4 11 Hz for 19a d and 23d vs. 26 3 5 Hz for23a c)
with respect to the corresponding vicinal dihedral angles. Thus, 19a d and 23d are
assigned to be predominantly in the 4C1 conformation, whereas 23a c exist in the 1C4
conformation. Compounds 19a and 23d have smaller J(2,P) (21.6 and 19.8 Hz) and
larger J(4,P) values (8.3and 11.0 Hz) than those of 19b d, indicating that they exist as
4
1
a conformational mixture of C1 and C4 forms (Fig. 3). By employing the additivity
1
rule for vicinal coupling constants [17], the equilibrium population of 4C1 and C4
conformers were estimated to be 76 :24 for 19a and 81:19 for 23d7).
7
)
The ratios of the conformers were estimated by means of the following values: 19a: J(1,2) ˆ 4.0, J(2,3) ˆ
3.1, J(3,4) ˆ 9.8, J(4,5) ˆ 11.55 for the pure 4C1 form; J(1,2) ˆ 11.3, J(2,3) ˆ 3.1, J(3,4) ˆ 3.6, J(4,5) ˆ 3.5 for
the pure 1C4 form. 23d: J(1,2) ˆ 3.5, J(2,3) ˆ 3.1, J(3,4) ˆ 9.8, J(4,5) ˆ 4.5 for the pure 4C1 form; J(1,2) ˆ 2.7,
1
J(2,3) ˆ 3.1, J(3,4) ˆ 3.6, J(4,5) ˆ 3.0 for the pure C4 form [17].

2614
Helvetica Chimica Acta Vol. 85 (2002)
Fig. 3. Conformational equiliblia for 19a and 23d
As for the d-mannopyranose derivative, the HÀC(3) and HÀC(5) signals of
19a,c appear downfield from those of 19b,d, thus indicating that the orientation of
AcOÀC(1) group of 19a,c is axial and that of 19b,d equatorial. For the l-gulopyranose
derivatives, the large magnitudes of J(1,2) indicate axial HÀC(1) orientation for 23a,c,
whereas the smaller J(1,2) value points out the equatorial HÀC(1) orientation for 23b.
A slight downfield shift of HÀC(4) signal of 19a,b compared with those of 19c,d
indicates the axial PˆO orientation for 19a,b and the equatorial PˆO orientation for
19c,d. Likewise, a similar downfield shift of HÀC(2) signal of 23c compared with those
of 23a,b indicates the axial PˆO orientation for 23c and the equatorial PˆO
orientation for 23a,b. An appreciable downfield shift observed for HÀC(2) of 23d
could be explained by its equatorial orientation (contrary to the axial HÀC(2) for
23a c).
4
The conformation of 23d in favor of C1 is most likely ascribed to the presence of
strong destabilizing interactions between 1,3-syn-diaxial PˆO and AcOÀC(4) group in
the 1C4 form as well as those between AcOÀC(1) and AcOÀC(3) group. The
electronic destabilizing effects of axial PˆO group for 23d seems to be much stronger
than those of the corresponding PÀOMe group for 23b, because the latter exists in the
1C4 form.
Such a difference in the destabilization effect between PˆO and PÀOMe group is
also observed between 19a and 19c. Namely, the repulsion between the axial PÀOMe
4
and AcOÀC(2) groups of 19c (in the C1 form) scarcely affects the inversion of the
chair conformer, while the repulsion between axial PˆO and AcOÀC(2) group of 19a
1
(in the 4C1 form) causes interconversion into the C4 form at a considerable rate (but
4
still in favor of the C1 form).
For b-d-mannopyranose 19b and b-l-gulopyranose 23c, both having the equatorial
AcOÀC(1) group, notable conformational equiliblia are not observed, although there
exist destabilizing interactions between the 1,3-syn-diaxial PˆO and AcO groups.
1
These precise H-NMR parameters of eight diastereoisomers obtained by the
present study are thought to be of high value in determining configurations and
conformations for other hexopyranose phospha sugars. Although the desired d-
mannofuranose precursor was not obtained as a major product for introduction of
phosphinyl group, total reaction steps of the present work are fewer, and yields of the
ring-transposition products were higher than by the method previously employed.
Extension of this work, including investigation of stereoselectivity of the dehydrox-
ylation for a-hydroxyphosphonates, having other hexopyranose structures, as well as
biological evaluation of d-manno- and l-gulopyranose phospha sugars, is anticipated to
be of interest.

Helvetica Chimica Acta Vol. 85 (2002)
2615
Experimental Part
General. All reactions were monitored by TLC (Merck silica gel 60F, 0.25 mm) with an appropriate solvent
system. Column chromatography (CC) was performed with Katayama silica gel 60K070. Components were
detected by exposing the plates to UV light and/or spraying them with 20% H2SO4/EtOH (with subsequent
1
heating). The NMR spectra were measured in CDCl3 with Varian VXR-500 (500 MHz for H) and VXR-200
(81 MHz for 31P) spectrometers at 228; chemical shifts are reported as d values [ppm] relative to TMS (internal
standard for 1H) and 85% phosphoric acid (external standard for 31P). The MS spectra were recorded on a VG-
70SE instrument and are given in terms of m/z (relative intensity) compared with the base peak.
Methyl 5,6-Anhydro-2,3-O-isopropylidene-a-d-mannofuranoside (9) [9]. To a soln. of 5 (1.04 g, 4.44 mmol)
and Ph3P (1.20 g, 4.57 mmol) in dry toluene (10 ml) was added diethyl azodicarboxylate (DEAD; 0.750 ml,
4.82 mmol). The mixture was refluxed for 8 h and evaporated in vacuo. The residue was purified by CC with
AcOEt/hexane 1:4 ! 1:2 to give 9 (854 mg, 89%). Colorless syrup. Rf (AcOEt/hexane 1:2) 0.48. 1H-NMR
(500 MHz): 1.32, 1.47 (2s, Me2C); 2.77 (dd, J(6,6') ˆ 5.2, J(5,6') ˆ 2.8, H'ÀC(6)); 2.90 (dd, J(5,6) ˆ 4.0,
HÀC(6)); 3.29 (ddd, J(4,5) ˆ 6.1, HÀC(5)); 3.30 (s, MeOÀC(C(1)); 3.64 (dd, J(3,4) ˆ 3.7, HÀC(4)); 4.57
(d, J(2,3) ˆ 5.8, J(1,2) ˆ 0, HÀC(2)); 4.81 (dd, HÀC(3)); 4.90 (s, HÀC(1)).
Methyl 6-O-Benzyl-2,3-O-isopropylidene-a-d-mannofuranoside (11) [10]. a) From 9. To a suspension of
NaH (60% in mineral oil, 250 mg, 6.25 mmol) and BnOH (1.30 ml, 1.26 mmol) in DME (2.0 ml), a soln. of 9
(270 mg, 1.25 mmol) in DME (1.0 ml) at 08 was added. The mixture was stirred at 608 for 5 h, diluted with sat.
NH4Cl (20 ml), and extracted with CHCl3 three times. The combined org. layers were washed with H2O, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by CC with AcOEt/hexane 1:1 to give 11
(380 mg, 94%). Colorless syrup. Rf (AcOEt/hexane 1 :2) 0.33. 1H-NMR (500 MHz): 1.32, 1.47 (2s, Me2C); 2.75
(br. s, HOÀC(5)); 3.28 (s, MeOÀC(1)); 3.65 (dd, J(6,6') ˆ 9.8, J(5,6) ˆ 5.8, H'ÀC(6)); 3.76 (dd, J(5,6) ˆ 3.7,
HÀC(6)); 3.96 (dd, J(4,5) ˆ 8.2, J(3,4) ˆ 3.7, HÀC(4)); 4.14 (ddd, HÀC(5)); 4.55 (d, J(2,3) ˆ 5.8, J(1,2) ˆ 0,
HÀC(2)); 4.57, 4.62 (2d, 2J ˆ 11.9, 1 H each, CH2OÀC(6)); 4.83( dd, HÀC(3)); 4.88 (s, HÀC(1)); 7.30 (m, Hp of
Ph); 7.35 (m, 2 Ho, 2 Hm of Ph).
b) From 10 [18]. To a soln. of 10 (4.01 g, 10.4 mmol) dissolved in DME (40 ml), NaH (60% in mineral oil,
450 mg, 11.2 mmol) at 08 was added. After stirring for 10 min, BnOH (8.60 ml, 83.1 mol) and then NaH (1.70 g,
42.5 mmol) were added. The mixture was stirred at 608 for 4 h and worked up by employing the same procedures
described above to give 11 (3.12 g, 93%).
Methyl 6-O-Benzyl-2,3-O-isopropylidene-a-d-lyxo-hexofuranosid-5-ulose (12). To a soln. of oxalyl chloride
(2.00 ml, 22.9 mmol) in CH2Cl2 (20 ml), a soln. of DMSO (3.30 ml, 46.5 mmol) in CH2Cl2 (10 ml) at À608 was
added under Ar, and then a soln. of 11 (2.91 g, 8.98 mmol) in CH2Cl2 (10 ml) was added. The mixture was stirred
at À608 for 8 h, and then Et3N (TEA; 8.0 ml, 57 mmol) was added, followed by stirring at 0 108 for 0.5 h. The
mixture was diluted with CHCl3 (30 ml) and washed with aq. NaCl soln. The aq. layer was extracted twice with
CHCl3. The combined org. layers were washed once with H2O, dried (Na2SO4), and evaporated in vacuo. The
residue was purified by CC to give 12 (2.72 g, 94%). Colorless prisms. M.p. 66 678 (AcOEt/hexane 1:2). Rf
(AcOEt/hexane 1 :2) 0.52. 1H-NMR (500 MHz): 1.27, 1.34 (2s, Me2C); 3.33 (s, MeOÀC(1)); 4.34
(s, CH2OÀC(6)); 4.54 (d, J(2,3) ˆ 5.8, J(1,2) ˆ 0, HÀC(2)); 4.61 (d, 2J ˆ 11.9, H'ÀC(6)); 4.64 (d, HÀC(6));
4.66 (d, J(3,4) ˆ 4.3, HÀC(4)); 5.01 (s, HÀC(1)); 5.07 (dd, HÀC(3)); 7.32 (m, Hp of Ph); 7.34 7.38 (m, 2 Ho and
‡
2 Hm of Ph). FAB-MS: 323 (7.8, [M ‡ 1] ), 307 (5.6), 291 (11), 233 (22), 201 (35), 181 (56), 91 (100). HR-MS:
‡
323.1480 ([M ‡ 1], C17H23O6 ; calc. 323.1495). Anal. calc. for C17H22O6 (322.36): C 63.34, H 6.88; found: C 63.22,
H 6.95.
Methyl (5R)- and (5S)-6-O-Benzyl-5-(dimethoxyphosphinyl)-2,3-O-isopropylidene-a-d-lyxo-hexofurano-
sides (13a,b). DBU (0.800 ml, 5.25 mmol) was dropwise added to a soln. of 12 (1.21 g, 3.75 mmol) in dimethyl
phosphonate (10.0 ml, 90 mmol) at 08, and the soln. was stirred at this temp. for 0.5 h under Ar. The mixture was
treated with sat. NH4Cl at 208 for 4 h and extracted with CHCl3 three times. The combined org. layers were
washed with H2O, dried (Na2SO4), and evaporated in vacuo. The residue was separated by CC with AcOEt/
hexane 1:1 ! 2 :1 to give 13a and 13b.
Data of 13a: Colorless needles (1.31 g, 76%). M.p. 85 868 (AcOEt/hexane 2 :1). Rf (AcOEt/hexane 2 :1)
0.25. 1H-NMR (500 MHz): see Table 1; additionally, 1.32, 1.48 (2s, Me2C); 3.26 (s, MeOÀC(1)); 3.76, 3.81
(2d, J(P,Me) ˆ 10.7, P(OMe)2); 3.82 (dd, J(6',P) ˆ 12.8, J(6,6') ˆ 8.6, H'ÀC(6)); 3.88 (dd, J(6,P) ˆ 26.6,
HÀC(6)); 4.45, 4.63(2 d, 2J ˆ 11.9, 1 H each, CH2OÀC(6)); 4.75 (s, HOÀC(5)); 7.24 (m, Hp of Ph); 7.30 (m, 2
‡
H
m of Ph); 7.32 (m, 2 Ho of Ph). 31P-NMR (81 MHz): 25.2. FAB-MS: 433 (35, [M ‡ 1] ), 401 (11), 201 (18), 91
‡
‡
(100). HR-MS: 433.1641 ([M ‡ 1] , C19H30O9P ; calc. 433.1628). Anal. calc. for C19H29O9P (432.41): C 52.78,
H 6.76; found: C 52.66, H 6.89.

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Helvetica Chimica Acta Vol. 85 (2002)
Data of 13b: Colorless syrup (322 mg, 20%). Rf (AcOEt/hexane 1:2) 0.18. 1H-NMR (500 MHz): see
Table 1; additionally, 1.23, 1.46 (2s, Me2C); 3.36 (s, MeOÀC(1)); 3.80, 3.85 (2d, J(P,Me) ˆ 10.7, P(OMe)2); 3.85
(dd, J(6',P) ˆ 19.8, J(6,6') ˆ 9.8, H'À(6)); 3.96 (t, J(6,P) ˆ 10.0, HÀC(6)); 4.36 (br. s, HOÀC(5)); 4.58, 4.64
(2d, 2J ˆ 11.9, 1 H each, CH2OÀC(6)); 7.28 (m, Hp of Ph); 7.33 (m, 2 Hm of Ph); 7.35 (m, 2 Ho of Ph). 31P-NMR
‡
‡
(81 MHz): 24.1. FAB-MS: 433 (24, [M ‡ 1] ), 401 (13), 201 (15), 91 (100). HR-MS: 433.1651, ([M ‡ 1] ,
‡
C19H30O9P ; calc. 433.1628).
Methyl 6-O-Benzyl-5-(dimethoxyphosphinyl)-2,3-O-isopropylidene-a-d-manno- and b-l-gulofuranoside
(15a and 15b, resp.). Methoxalyl chloride (1.00 ml, 10.9 mmol) was added to a soln. of 13a (1.19 g, 2.75 mmol)
and DMAP (1.34 g, 11.0 mmol) in dry MeCN (10 ml) at 08. The mixture was stirred at 08 for 0.5 h under Ar, and
the most of solvent was distilled off in vacuo. The residue was treated with aq. NH4Cl and extracted with CHCl3
three times. The combined org. layer was washed with H2O, dried (Na2SO4), and evaporated in vacuo to give the
(5R)-5-O-methoxalyl derivative 14a as a pale yellow syrup: Rf (AcOEt/hexane 2 :1) 0.35.
The crude 14a was co-evaporated with dry toluene and dissolved in the same solvent (10 ml). Bu3SnH
(1.10 ml, 4.09 mmol) and AIBN (80 mg, 0.49 mmol) were added under Ar. The mixture was stirred at 808 for 2 h
and then concentrated in vacuo. The residue was separated by CC with AcOEt/hexane 1 :1 ! 2 :1 to give 15a
and 15b.
Data of 15a: Colorless syrup (187 mg, 16%). Rf (AcOEt/hexane 2 :1) 0.33. 1H-NMR (500 MHz): see
Table 1; additionally, 1.31, 1.42 (2s, Me2C); 2.71 (dddd, J(5,P) ˆ 19.2, J(4,5) ˆ 10.7, J(5,6') ˆ 4.9, J(5,6) ˆ 2.8,
HÀC(5)); 3.26 (s, MeOÀC(1)); 3.71, 3.73 (2d, J(P,Me) ˆ 10.7, P(OMe)2); 3.94 (ddd, J(6',P) ˆ 29.3, J(6,6') ˆ 9.2,
H'ÀC(6)); 3.98 (ddd, J(6,P) ˆ 15.3, HÀC(6)); 4.55, 4.61 (2d, 2J ˆ 11.9, 1 H each, CH2OÀC(6)); 7.26 (m, Hp of
‡
Ph), 7.32 (m, 2 Hm of Ph), 7.35 (m, 2 Ho of Ph). 31P-NMR (81 MHz): 31.3. FAB-MS: 417 (21, [M ‡ 1] ), 401
‡
‡
(12), 385 (11), 177 (19), 137 (11), 91 (100). HR-MS: 417.1691 ([M ‡ 1] , C19H30O8P ; calc. 417.1679).
Data of 15b: Colorless syrup (803mg, 70%). Rf (AcOEt/hexane 2 :1) 0.26. 1H-NMR (500 MHz): see
Table 1; additionally, 1.25, 1.40 (2s, Me2C); 2.62 (ddt, J(5,P) ˆ 18.3, J(4,5) ˆ 10.4, J(5,6) ˆ 4.0, J(5,6') ˆ 3.7,
HÀC(5)); 3.32 (s, MeOÀC(1)); 3.74, 3.76 (2d, J(P,Me) ˆ 10.7 Hz, P(OMe)2); 3.82 (ddd, J(6',P) ˆ 28.1, J(6,6') ˆ
9.8, H'ÀC(6)); 3.88 (ddd, J(6,P) ˆ 10.6, HÀC(6)); 4.51, 4.57 (2d, 2J ˆ 11.9, 1 H each, CH2OÀC(6)); 7.28 (m, Hp
‡
of Ph); 7.33 (m, 2 Ho and 2 Hm of Ph). 31P-NMR (81 MHz): 32.4. FAB-MS: 417 (32, [M ‡ 1] ), 401 (18), 385
‡
‡
(15), 177 (15), 91 (100). HR-MS: 417.1682 ([M ‡ 1] , C19H30O8P ; calc. 417.1679).
By the same procedures described above, 13b (262 mg) was converted to 15a (38.3 mg, 15%) and 15b
(172 mg, 68%) via intermediate 14b.
1,2,3,4,6-Tetra-O-acetyl-5-deoxy-5-[(R)- and (S)-methoxyphosphinyl]-a/b-d-mannopyranoses 19a d. To a
soln. of 15a (196 mg, 0.471 mmol) in dry toluene (2.0 ml) was added, with stirring, a soln. of sodium
dihydrobis(2-methoxyethoxy)aluminate (SDMA; 70% in toluene, 2.5 ml, 0.85 mmol) in dry toluene (1.0 ml) in
small portions during 30 min at À108 under Ar. The stirring was continued at this temp. for 30 min. Then, H2O
(0.2 ml) was added to decompose excess SDMA, and the mixture was centrifuged. The precipitate was extracted
with several portions of toluene. The org. layers were combined and evaporated in vacuo to give methyl 6-O-
benzyl-5-deoxy-2,3-O-isopropylidene-5-phosphino-a-d-mannofuranoside (16) as a colorless syrup.
This syrup was immediately treated with i-PrOH/0.5m HCl 2 :1 (3.0 ml) at 908 for 2 h under Ar. After
cooling, the mixture was evaporated in vacuo. The residue was dissolved in i-PrOH (2.0 ml), treated with 35%
H2O2 (0.8 ml, 9.3mmol) at 20 8 for 12 h and then concentrated in vacuo to give crude 6-O-benzyl-5-deoxy-5-
(hydroxyphosphinyl)-a/b-d-mannopyranoses (17) as a colorless syrup. This was dissolved in dry pyridine
(2.0 ml), and Ac2O (1.0 ml, 11 mmol) was added at 08. The mixture was stirred at r.t. for 12 h, diluted with a
small amount of cold H2O, and concentrated in vacuo. The residue was dissolved in EtOH and passed through a
‡
column of Amberlite IR-120(H ) (20 ml). The eluent was evaporated in vacuo, and the residue was methylated
with ethereal CH2N2 in dry CH2Cl2 (2.0 ml) at 08. After evaporation of the solvent, the residue was separated by
CC with AcOEt/hexane 2 :1 ! AcOEt to give 1,2,3,4-tetra-O-acetyl-6-O-benzyl-5-deoxy-5-[(R)- and (S)-
methoxyphosphinyl]-a/b-d-mannopyranoses (18; 72 mg) as a colorless syrup containing a small amounts of
unidentified products (Rf (AcOEt) 0.59 0.52).
Compounds 18 dissolved in EtOH (2.0 ml) was hydrogenated in the presence of Pd(OH)2/C (25 mg) at 208
under atmospheric pressure of H2. After 12 h, the catalysts was filtered off, and the filtrate was evaporated in
vacuo. The residue was dissolved in dry pyridine (1.0 ml), and Ac2O (0.25 ml) was added. After stirring at 208
for 12 h, cold H2O was added. The mixture was evaporated in vacuo, and the residue was separated by CC with
AcOEt/hexane 2 :1 ! AcOEt into three Fractions A C.
Fraction A (Rf(AcOEt) 0.41) gave the 5-[(R)-methoxyphosphinyl]-a-d-mannopyranose 19a [6] as a
colorless syrup (13.2 mg, 6.2% from 15a; [6]: 6.1% from 8). 31P-NMR (81 MHz): 39.3.

Helvetica Chimica Acta Vol. 85 (2002)
2617
Fraction B (Rf 0.36) gave a colorless syrup (22.6 mg), which consisted of 5-[(S)-methoxyphosphinyl]-a-
isomer 19c (4.7% from 15a; [6]: 2.4% from 8) and its b-isomer 19d (5.9%; [6]: 3.6% from 8), the ratio being
1
estimated by H-NMR. 31P-NMR (81 MHz): 38.8 (for 19c), 37.7 (for 19d).
Fraction C (Rf 0.23) gave 5-[(R)-methoxyphosphinyl]-b-isomer 19b as a colorless syrup (17.7 mg, 8.3%
from 15a). 1H-NMR (500 MHz): see Table 2; additionally, 2.03, 2.07, 2.08, 2.15, 2.18 (5s, 5 AcO); 3.82
(d, J(P,Me) ˆ 11.0, MeOÀP); 4.47 (ddd, J(6',P) ˆ 13.5, J(6,6') ˆ 11.8,
J
(5,6') ˆ 6.6, H'ÀC(6)); 4.50
‡
(ddd, J(6,P) ˆ 11.1, J(5,6) ˆ 6.9, HÀC(6)). 31P-NMR (81 MHz): 38.0. FAB-MS: 453 (8.2, [M ‡ 1] ), 410 (11),
‡
393 (6), 368 (8), 351 (48), 321 (28), 309 (80), 207 (75), 188 (100), 164 (36). HR-MS: 453.1163 ([M ‡ 1] ,
‡
C17H36O12P ; calc. 453.1162).
1,2,3,4,6-Tetra-O-acetyl-5-deoxy-5-[(R)- and (S)-methoxyphosphinyl]-a/b-l-gulopyranoses (23a d). The
procedures similar to those for the preparation of compounds 19 from substrates 15a were employed. Thus,
compound 15b (210 mg, 0.504 mmol) was converted to 1,2,3,4-tetra-O-acetyl-6-O-benzyl-5-deoxy-5-[(R)- and
(S)-methoxylphosphoninyl]-a/b-l-gulopyranoses (22) via intermediates 20 and 21. The diastereoisomeric
mixture 22 was debenzylated and then acetylated again to give 23. The crude product 23 was separated by CC
into Fractions A and B.
Fraction A (Rf (AcOEt) 0.44) gave a colorless syrup (41.1 mg), which consisted of 5-[(R)-methoxyphos-
phinyl]-b-isomer 23a (12% from 15b) and 5-[(S)-methoxyphosphinyl]-a-isomer 23d (6.5%), the ratio being
estimated by 1H-NMR. 1H-NMR (500 MHz) of 23a: see Table 2; additionally, 1.98, 2.05, 2.14, 2.15, 2.175 (5s, 5
AcO); 3.84 (d, J(P,Me) ˆ 10.7, MeOÀP); 4.35 (ddd, J(6,6') ˆ 11.3, J(5,6') ˆ 9.8, J(6',P) ˆ 7.0, H'ÀC(6)); 4.40
(dt, J(6,P) ˆ 5.9, J(5,6) ˆ 5.2, HÀC(6)). 1H-NMR (500 MHz) of 23d: see Table 2; additionally, 2.04, 2.11, 2.12,
2.135, 2.17 (5s, 5 AcO); 3.87 (d, J(P,Me) ˆ 10.7, MeOÀP); 4.39 (m8), J(5,6') ˆ 5.2, H'ÀC(6)); 4.43( dt, J(6,P) ˆ
19.2, J(6,6') ˆ 11.6, J(5,6) ˆ 3.7, HÀC(6)). 31P-NMR (81 MHz): 38.4 (for 23a); 37.7 (for 23d). FAB-MS: 453(5.2,
‡
[M ‡ 1] ), 410 (9.8), 393 (6), 351 (48), 321 (18), 309 (80), 230 (39), 207 (79), 188 (100), 164 (32). HR-MS:
453.1169 ([M ‡ 1]+, C17H36O12P+; calc. 453.1162).
Fraction B (Rf 0.39) gave a colorless syrup (36.1 mg), which consisted of 5-[(R)-methoxyphosphinyl]-a-
isomer 23b (5.1% from 15b) and 5-[(S)-methoxyphosphinyl]-b-isomer 23c (11%), the ratio being estimated by
1H-NMR. 1H-NMR (500 MHz) for 23b: see Table 2; additionally, 2.06, 2.10, 2.115, 2.12, 2.175 (5s, 5 AcO); 3.86
(d, J(P,Me) ˆ 11.0, MeOÀP); 4.40 (ddd, J(6,6') ˆ 11.6, J(5,6') ˆ 8.5, J(6',P) ˆ 6.7, H'ÀC(6)); 4.41 (ddd, J(6,P) ˆ
9.9, J(5,6) ˆ 4.5, HÀC(6)). 1H-NMR (500 MHz) for 23c: see Table 2; additionally, 2.00, 2.07, 2.16, 2.18, 2.19 (5s,
5 AcO); 3.79 (d, J(P,Me) ˆ 11.0, MeOÀP); 4.40 (dd, J(6,P) ˆ J(6',P) ˆ 9.8, J(5,6') ˆ J(5,6) ˆ 7.3, CH 2(6)). 31P-
‡
NMR (81 MHz): 37.8 (for 23b); 39.1 (for 23c). FAB-MS: 453(4.2, [ M ‡ 1] ), 410 (11), 393 (10), 351 (38), 321
‡
‡
(15), 309 (69), 230 (32), 207 (68), 188 (100), 164 (39). HR-MS: 453.1173 ([M ‡ 1] , C17H36O12P ; calc.
453.1162).
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The J(6',P) value is uncertain because of overlap with other signals.

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Received May 13, 2002