Synthesis of 2-Amino-2,5-dideoxy-5-hydroxyphosphinyl-D-mannopyranose Derivatives: New Phospho-sugar Analogues of D-Mannosamine

Article abstract of DOI:10.1039/a804961k

3,6-Di-O-benzyl-5-deoxy-5-dimethylphosphinyi-1,2-0-isopropylidene-α- D-glucofuranose 5 was converted, in four steps, into methyl 2-acetamido-3,6-di-O-benzyl-2,5-dideoxy-5-dimethoxyphosphinyl-α-D- mannofuranoside 7, which led to 3,5-di-O-benzyl derivatives 9 of a P-in-the-ring D-mannosamine analogue.

Full text of DOI:10.1039/a804961k

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790 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 790±791$
Synthesis of 2-Amino-2,5-dideoxy-5-
hydroxyphosphinyl-D-mannopyranose Derivatives:
New Phospho-sugar Analogues of D-Mannosamine$
Tadashi Hanaya,*a Yasushi Fujiib and Hiroshi Yamamoto*b
aCenter of Instrumental Analysis, Okayama University, Tsushima, Okayama 700, Japan
bDepartment of Chemistry, Faculty of Science, Okayama University, Tsushima, Okayama 700, Japan
3,6-Di-O-benzyl-5-deoxy-5-dimethylphosphinyl-1,2-O-isopropylidene-ꢀ-D-glucofuranose 5 was converted, in four steps,
into methyl 2-acetamido-3,6-di-O-benzyl-2,5-dideoxy-5-dimethoxyphosphinyl-ꢀ-D-mannofuranoside 7, which led to
3,5-di-O-benzyl derivatives 9 of a P-in-the-ring D-mannosamine analogue.
Various sugar analogues containing a heteroatom instead of
oxygen in the ring have been prepared because of the wide
interest in their chemical and biochemical properties.1,2
Heteroatom-in-the-ring sugar analogues of 2-amino- and
2-acetamido-2-deoxyhexopyranoses, which widely occur
as a component of many natural products, have also
attracted considerable interest. Thiasugar analogues of
2-acetamido-2-deoxy-D-glucose 13 and D-mannose 2,4 for
example, are potentially useful owing to their inhibitory
activity in the biosynthesis of important constituents of
higher animal cell walls.5 In view of such a chemical modi®-
cation by heteroatoms, we have prepared various sugar
analogues having a phosphorus atom in the ring (phospho-
sugar),6,7 such as D-glucopyranose 38 and D-mannopyranose
analogues 4.9 We describe herein the ®rst synthetic route to
a new phospho-sugar of a mannosamine analogue.
Scheme 1
syrup, which was presumed by NMR spectra to be the
b-anomers of 10a and 10b.
The structural assignments of 10a,b were made by the
Treatment of the 5-phosphinyl-D-glucofuranose derivative
510 with methanol in the presence of an acidic ion-exchange
resin gave methyl a-D-glucofuranoside 6a (39%) and its
analysis of the 1H NMR spectra. Both compounds have
medium J2,P and J4,P values (14±21 Hz), indicating that they
4
1
existed as a conformational mixture of C1 and C4 forms.7,9
By employing the additivity rule11 for vicinal coupling
constants, the equilibrium populations of 4C1 and 1C4 con-
formers were estimated to be 33:67 for 10a and 42:58 for
10b.% Such equilibria were observed in the case of only the
a-anomer of D-mannopyranose phospho-sugars 4.9 A slight
down®eld shift of H-2 signal of 10b in comparison with that
b-anomer 6b (42%). The conversion of 6a into the 2-O-
tri¯ate, followed by the treatment with sodium azide,
a€orded the corresponding 2-azido-2-deoxy-a-D-manno-
furanoside; a byproduct, 5-(2-O-cyclo-methoxyphosphinyl)-
a-D-mannofuranoside 8, was present but it was separable
only after the subsequent step (see below). The treatment
of the above mixture with thioacetic acid provided, after
chromatographic separation, the 2-acetamido-2-deoxy-a-D-
mannofuranoside 7 (36% overall yield from 6a) and 8
(20%). Attempts to convert the b-anomer 6b into the
corresponding 2-C-azide (the b-anomer of 7) using similar
procedures have remained unsuccessful.
of 10a indicates an axial P O orientation for the 1C4 form
.
of 10b. A similar down®eld shift of the H-4 signal of 10a
.
compared with that of 10b shows an axial P O orientation
4
for the C1 form of 10a.
Compound 7 was then reduced with sodium dihydrobis-
(2-methoxyethoxy)aluminate (SDMA) to give its 5-phosphino
derivative, which was immediately subjected to acid hydro-
lysis and then to oxidation with hydrogen peroxide,
a€ording 5-hydroxyphosphinyl-D-mannopyranose 9. This
was characterized, after peracetylation and methylation, as
2-acetamido-5-[(R)-methoxyphosphinyl]-a-D-mannopyranose
10a (13% overall yield from 7) and its 5-[(S)-methoxy-
phosphinyl] isomer 10b (12%). A small amount of an
inseparable mixture (1.7%) was obtained as a colourless
Experimental
The general methods followed those described earlier,7 the TLC
solvent system being (A) AcOEt, (B) 1:19 (v/v) EtOH±AcOEt and
(C) 1:19 (v/v) AcOEt±CHCl3. All the products were puri®ed by
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
%The ratios of the conformers were estimated by use of the follow-
ing values, J1,2=J2,3=3.8, J3,4 9.8, J4,5 11.55 for the pure 4C1 form,
J1,2 12.1, J2,3 2.9, J3,4 3.6, J4,5 3.5 for the pure 1C4 form.

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J. CHEM. RESEARCH (S), 1998 791
column chromatography on silica gel. NMR spectra were measured
in CDCl3 with Varian VXR-500 (500 MHz for 1H) and VXR-200
(81 MHz for 31P) instruments (SC-NMR Lab., Okayama Univ.)
at 23 8C. J values are given in Hz. The mass spectra were taken on
a VG 70-SE instrument and are given as m/z (relative intensity).
Methyl 3,6-Di-O-benzyl-5-deoxy-5-dimethoxyphosphinyl-ꢀ-D-gluco-
furanoside 6a and its ꢁ-Anomer 6b.ÐA mixture of 510 (4.79 g,
was centrifuged and the precipitate was extracted with benzene. The
organic layer was evaporated in vacuo, giving the 5-phosphino
derivative as a colourless syrup; RF=0.70 (A). This syrup was im-
mediately treated with 1:1 (v/v) propan-2-ol±0.5 M HCl (3.0 cm3) at
90 8C for 2 h under argon. After cooling, 30% hydrogen peroxide
(1.0 cm3) was added. The solution was stirred at 23 8C for 18 h
and concentrated in vacuo. The residue was dissolved in MeOH
(1.5 cm3), treated with propylene oxide (0.8 ml) at 23 8C for 6 h and
evaporated in vacuo to give crude 9 as a colourless syrup. This was
dissolved in dry pyridine (1.5 cm3) and acetic anhydride (0.8 cm3)
at 23 8C for 20 h, and concentrated in vacuo. The residue was
dissolved in ethanol and passed through a column of Amberlite
‡
9.73 mmol) and Amberlite IR-120(H ) in dry methanol (96 cm3)
was stirred at 60 8C for 8 h. The resin was ®ltered o€ and the ®ltrate
was evaporated in vacuo to give 6a and 6b.
6a: Colourless prisms (1.78 g, 39%), mp 84±85 8C [Found:
‡
(M ‡ H), 467.1850. C23H32O8P requires (M ‡ 1), 467.1836];
‡
RF ˆ 0.50 (C); dH 2.81 (1 H, dddd, J5,P 20.1, J4,5 9.8, J5,6' 5.5, J5,6
3.1, H-5), 2.98 (1 H, d, J2,OH 4.9, HO-2), 3.46 (3 H, s, MeO-1),
3.67, 3.675 [3 H each, 2 d, JPOMe 10.8, P(OMe)2], 3.90 (1 H, ddd,
J6',P 27.5, J6,6' 9.5, H-6'), 3.95 (1 H, ddd, J6,P 17.1, H-6), 3.98 (1 H,
dd, J3,4 4.2, J2,3 1.8, H-3), 4.24 (1 H, td, J1,2 4.8, H-2), 4.53, 4.59
(1 H each, 2 d, J 11.9, CH2O-3 or -6), 4.55 (1 H, ddd, J4,P 6.2,
H-4), 4.54, 4.68 (1 H each, 2 d, J 11.0, CH2O-6 or -3), 5.01 (1 H, d,
IR-120(H ). The eluent was evaporated in vacuo and the residue
was methylated with ethereal diazomethane in dry CH2Cl2 (2.0 cm3)
at 0 8C. After evaporation of the solvent, the residue was separated
by chromatography into three fractions A±C.
Fraction A [RF=0.27 (B)] gave 10a as colourless needles, mp
168±169 8C (21.3 mg, 13% from 7) [Found: (M+ ‡ 1), 548.2062.
C27H34O9NP requires (M ‡ 1), 548.2051]; dH 1.73, 2.03, 1.78 (3 H
each, 3 s, Ac-1,2,4), 2.66 (1 H, ddt, J5,P 19.2, J5,6' 9.5, J4,5 6.1, J5,6
5.8, H-5), 3.73 (1 H, dd, J3,4 5.8, J2,3 3.1, H-3), 3.81 (3 H, d, JPOMe
11.0, POMe), 3.87 (1 H, q, J6,6' 9.8, J6',P 9.4, H-6'), 3.92 (1 H, dt,
J6,P 6.4, H-6), 4.45, 4.54 (1 H each, 2 d, J 11.9, CH2O-3 or -6),
4.51, 4.57 (1 H each, 2 d, J 11.9, CH2O-6 or -3), 4.79 (1 H, dtd, J2,P
14.7, J2,NH 9.8, J1,2 9.4, H-2), 5.39 (1 H, dd, J1,P 5.3, H-1), 5.63
(1 H, dt, J4,P 21.4, H-4), 5.92 (1 H, br d, NH-2), 7.25±7.36 (10 H,
m, Ph); dP 41.4; FAB m/z 548 (M+ ‡ 1, 22). 506 (8), 488 (10), 181
(14) and 91 (100).
‡
H-1) and 7.25±7.35 (10 H, m, Ph); dP 32.5; FAB m/z 467 (M ‡ 1,
23), 387 (6), 297 (12), 181 (9) and 91 (100).
6b: Colourless needles (1.93 g, 42%), mp 123±124 8C [Found:
‡
(M ‡ H), 467.1828. C23H32O8P requires (M ‡ 1), 467.1836];
RF ˆ 0.40 (C); dH 2.83 (1 H, d, J2,OH 4.0, HO-2), 2.90 (1 H, dddd,
J5,P 19.2, J4,5 9.5, J5,6' 5.5, J5,6 3.4, H-5), 3.36 (3 H, s, MeO-1), 3.62,
3.67 [3 H each, 2 d, JPOMe 10.8, P(OMe)2], 3.93 (1 H, ddd, J6',P
25.6, J6,6' 9.5, H-6'), 3.955 (1 H, ddd, J6,P 19.5, H-6), 3.96 (1 H, dd,
J3,4 4.3, J2,3 1.0, H-3), 4.17 (1 H, td, J1,2 0.8, H-2), 4.53, 4.58 (1 H
each, 2 d, J 12.2, CH2O-3 or -6), 4.55, 4.65 (1 H each, 2 d, J 11.6,
PhCH2O-6 or -3), 4.65 (1 H, ddd, J4,P 7.0, H-4), 4.80 (1 H, d, H-1)
Fraction B [RF=0.22 (B)] gave an inseparable mixture (1:1) of
(5-[(R)- and (S)-methoxyphosphinyl]-b-isomers (3.2 mg, 1.8%) con-
taining a small amount of 10a,b.
‡
and 7.23±7.36 (10 H, m, Ph); dP 32.7; FAB m/z (M ‡ 1, 24), 435
(15), 297 (39), 207 (9) and 91 (100).
Methyl 2-Acetamido-3,6-di-O-benzyl-2,5-dideoxy-5-dimethoxyphos-
Fraction C [RF=0.18 (B)] gave 10b as a colourless syrup
(20.2 mg, 12% from 7); dH 1.81, 2.03, 2.13 (3 H each, 3 s, Ac-1,2,4),
2.70 (1 H, dtd, J5,P 18.9, J4,5 7.1, J5,6 6.9, J5,6' 5.2, H-5), 3.72 (1 H,
ddd, J6'P 9.8, H-6'), 3.73 (1 H, dd, J3,4 6.0, J2,3 3.4 Hz, H-3), 3.74
(3 H, d, JPOMe 10.7, POMe), 3.84 (1 H, td, J6,P 9.6, H-6), 4.49 (2 H,
s, CH2O-6), 4.50, 4.61 (1 H each, 2 d, J 11.9, CH2O-3), 4.84 (1 H,
dtd, J2,P 14.3, J2,NH 9.2, J1,2 8.7, H-2), 5.32 (1 H, dd, J1,P 7.9,
H-1), 5.54 (1 H, ddd, J4,P 16.9, H-4), 5.63 (1 H, br d, NH-2),
7.26±7.36 (10 H, m, Ph); dP 41.3.
phinyl-ꢀ-D-glucofuranoside
7 and Methyl 3-O-Benzyl-5-deoxy-5-
[(5R,S)-2-O-cyclomethoxyphosphinyl]-ꢀ-D-mannofuranoside 8.ÐTri-
¯uoromethanesulfonic anhydride (0.54 cm3, 3.21 mmol) was added
to a solution of 6a (750 mg, 1.61 mmol) in pyridine (0.52 cm3,
6.43 mmol) in dry CH2Cl2 (25 cm3) at 40 8C. The mixture was
stirred at 40 8C for 30 min under argon, poured into water and
extracted with CH2Cl2. The organic layer was evaporated in vacuo
to give the crude 2-O-tri¯ate as a colourless syrup [RF ˆ 0.63 (A)].
A mixture of this syrup and sodium azide (520 mg, 8.00 mmol)
in dry DMF (25 cm3) was stirred at 40 8C for 3 d under argon,
poured into water and extracted with CHCl3. The organic layer was
evaporated in vacuo, giving an inseparable mixture (573 mg) of the
2-azido compound and 8. This was dissolved in thioacetic acid
(5.0 cm3, 7.0 mmol) and stirred at 23 8C for 1 d under argon. The
excess thioacetic acid was evaporated in vacuo, giving 7 and 8.
7: Colourless prisms (295 mg, 36% from 6a), mp 42±44 8C
Received, 29th June 1998; Accepted, 10th August 1998
Paper E/8/04961K
References
1 H. Paulsen, Angew. Chem., Int. Ed. Engl., 1966, 5, 495; G. Legler
and E. Julich, Carbohydr. Res., 1984, 108, 61.
2 R. L. Whistler and W. C. Lake, Methods Carbohydr. Chem.,
1972, 6, 286; M. J. Pitts, M. Chemielewski, M. S. Chen, M. M. A.
Abd El-rahman and R. L. Whistler, Arch. Biochem. Biophys.,
1975, 169, 384.
3 R. Bognar, P. Herczegh, R. L. Whistler and E. B. Madumelu,
Carbohydr. Res., 1981, 70, 138; R. D. Guthrie and K. O'Shea,
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5 P. K. Ray, Adv. Appl. Microbiol., 1971, 21, 227.
6 T. Hanaya and H. Yamamoto, Yuki Gosei Kagaku Kyokai Shi,
1993, 51, 377 and references therein.
7 T. Hanaya, K. Yasuda, H. Yamamoto and H. Yamamoto, Bull.
Chem. Soc. Jpn., 1993, 66, 2315.
8 H. Yamamoto, T. Hanaya, H. Kawamoto, S. Inokawa,
M. Yamashita, M.-A. Armour and T. T. Nakashima, J. Org.
Chem., 1985, 50, 3516; T. Hanaya, A. Akamatsu, H. Kawamoto,
M.-A. Armour, A. M. Hogg and H. Yamamoto, Bull. Chem.
Soc. Jpn., 1991, 64, 2398.
9 T. Hanaya, K. Hirose and H. Yamamoto, Heterocycles, 1993,
36, 2557; T. Hanaya, K. Ohmori, H. Yamamoto, M.-A. Armour
and A. M. Hogg, Bull. Chem. Soc. Jpn., 1990, 63, 1174.
10 T. Hanaya, Y. Fujii, S. Ikejiri and H. Yamamoto, Heterocycles,
1999, 50, in press.
‡
[Found: (M ‡ H), 508.2118. C25H35O8NP requires (M ‡ 1),
508.2102]; RF=0.18 (A); dH 1.72 (3 H, s, Ac), 2.92 (1 H, dtd, J5,P
21.7, J5,6 6.7, J4,5 6.1, J5,6' 4.3, H-5), 3.30 (3 H, s, MeO-1), 3.62,
3.70 [3 H each, 2 d, JPOMe 10.7, P(OMe)2], 3.81 (1 H, ddd, J6,P
16.5, J6,6' 10.1, H-6'), 3.98 (1 H, td, J6,P 10.1, H-6), 4.41 (1 H, dd,
J3,4 6.5, J2,3 6.0, H-3), 4.43, 4.52 (1 H each, 2 d, J 11.3, CH2O-3 or
-6), 4.44, 4.52 (1 H each, 2 d, J 11.6, CH2O-6 or -3), 4.54 (1 H,
ddd, J2,NH 8.9, J1,2 1.2, H-2), 4.60 (1 H, td, J4,P 18.0, H-4), 4.76
(1 H, d, H-1), 7.04 (1 H, br d, HN-2) and 7.25±7.35 (10 H, m, Ph);
‡
dP 32.1; FAB m/z 508 (M ‡ 1, 15), 476 (14), 368 (9), 338 (38), 248
(10) and 91 (100).
8: Yellow syrup (143 mg, 20%) [Found: (M ‡ H), 435.1560.
‡
C
22H28O7P requires (M ‡ 1), 435.1573]; RF=0.55 (A); (for the main
isomer) dH 2.79 (1 H, dddd, J5,P 19.5, J5,6 9.2, J5,6' 6.1, J4,5 3.0,
H-5), 3.50 (3 H, s, MeO-1), 3.78 [3 H, d, JPOMe 12.0, POMe], 3.88
(1 H, ddd, J6,6' 10.4, J6',P 7.9, H-6'), 3.92 (1 H, td, J6,P 11.0, H-6),
5
4.29 (1 H, ddd, J3,4 6.1, J2,3 3.1, J3,P 1.2, H-3), 4.41, 4.54 (1 H
each, 2 d, J 12.2, CH2O-3 or -6), 4.49, 4.77 (1 H each, 2 d, J 11.6,
CH2O-6 or -3), 4.51 (1 H, dd, J2,P 18.9, J1,210, H-2), 4.71 (1 H,
ddd, J4,P 31.1, H-4), 5.11 (1 H, br s, H-1) and 7.23±7.38 (10 H, m,
‡
Ph); dP 22.6; FAB m/z 435 (M ‡ 1, 16), 345 (5), 237 (5), 181 (10)
and 91 (100).
2-Acetamido-1,4-di-O-acetyl-3,6-di-O-benzyl-2,5-dideoxy-5-[(R)-
methoxyphosphinyl]-ꢀ-D-mannopyranose 10a and its 5-[(S)-Methoxy-
phosphinyl] Isomer 10b.ÐTo a solution of 7 (157 mg, 0.309 mmol)
in dry toluene (1.5 cm3) was added SDMA (0.34 M in toluene,
3.20 cm3, 1.09 mmol) at 0 8C under argon. The mixture was stirred
at 0 8C for 1 h and then water (0.12 cm3) was added. The mixture
11 C. Altona and C. A. G. Haasnoot, Org. Magn, Reson., 1980, 13,
417; T. Hanaya and H. Yamamoto, Carbohydr. Res., in press.