Spirohydantoins from D-ribose as new potent enzymatic inhibitors

Article abstract of DOI:10.1211/0022357011776342

Anomeric spirohydantoin derivatives from monosaccharides are known for various biological properties. We describe herein the synthesis of the 3-spirohydantoin derivatives of D-allose and D-ribose. The key step is the stereoselective glyco-α-aminonitrile formation from ulose derivatives of D-glucose and D-xylose using titanium tetra-isopropoxide as a mild and efficient catalyst. Target compounds were synthesized from these intermediates. The glucidic moiety was partially or totally deprotected under acidic conditions. These new heterocyclic monosaccharidic derivatives are potent glycogen phosphorylase inhibitors.

Full text of DOI:10.1211/0022357011776342

Journal of
Pharmacy and Pharmacology
JPP 2001, 53: 939–943
# 2001 The Authors
Received December 19, 2000
Accepted April 4, 2001
ISSN 0022-3573
Spirohydantoins from D-ribose as new potent
enzymatic inhibitors
A. Nguyen, P. Villa, G. Ronco and D. Postel
Abstract
Anomeric spirohydantoin derivatives from monosaccharides are known for various biological
properties. We describe herein the synthesis of the 3-spirohydantoin derivatives of D-allose
and D-ribose. The key step is the stereoselective glyco-α-aminonitrile formation from ulose
derivatives of D-glucose and D-xylose using titanium tetra-isopropoxide as a mild and efficient
catalyst. Target compounds were synthesized from these intermediates. The glucidic moiety
was partially or totally deprotected under acidic conditions. These new heterocyclic mono-
saccharidic derivatives are potent glycogen phosphorylase inhibitors.
Introduction
The development of new heterocyclic derivatives of monosaccharides is of great
value for the discovery of new biologically active compounds. Modification of the
parent compound is currently effected either by introduction of an aglycone moiety
or by substitution of the pyranose or furanose ring oxygen by a nitrogen or a carbon
atom. Modification of the carbohydrate moiety has also been achieved by a spiro
ring formation; examples include various analogues (I–III; Figure 1) of hydanto-
cidin (IV) for herbicidal or enzymatic inhibitor action (Chemla 1993; Fairbanks et
al 1993; Matsumoto et al 1993; Harrington & Jung 1994; Brandstetter et al 1995).
Different routes have been described in the literature for the synthesis of
spirohydantoins. Sano & Sugai (1995) described the Bucherer-Bergs synthesis,
which gives thermodynamically controlled spiro products, and also reported the
conversion of an α-aminonitrile into a hydantoin with chlorosulfonylisocyanide
followed by acid-catalysed hydrolysis. In this work herbicidal activity was found to
be not affected when the -furanose ring oxygen atom of the natural product was
replaced with a methylene unit (Sano & Sugai 1995). Fleet and colleagues used
various α-aminolactones as key intermediates for the synthesis of epimeric
spirohydantoins of -mannofuranose and -glucopyranose derivatives which are
potent glycogen phosphorylase inhibitors (Bichard et al 1995; Estevez et al 1995).
The target compounds were synthesized from -glucose and -mannose derivatives
by oxidative ring contraction. Reaction of α-aminoesters, located at non-anonmeric
sites of the sugar, with phenylisocyanates afforded the corresponding ureas, which
were converted into the corresponding spirohydantoins under basic conditions.
In the course of our ongoing interest in the preparation of novel structures based
on glyco-α-aminonitrile derivatives (Postel et al 2000), we describe the synthesis of
non-anonmeric spirohydantoins from -allose and -ribose (V, VI) as new potent
enzymatic inhibitors.
Laboratoire des Glucides,
Universite de Picardie, F-80039
Amiens, France
A. Nguyen, P. Villa, G. Ronco,
D. Postel
Correspondence: D. Postel,
Laboratoire des Glucides,
Universite de Picardie, F-80039
Amiens, France.
939

940
A. Nguyen et al
Figure 1 Structure of analogues (I–III) of hydantocidin (IV).
Materials and Methods
by silica-gel chromatography (hexane–EtOAc, 4:1) to
25
give 3a (0.88 g, 80%) as a syrup; [α]D j5.2 (c 1.2,
CHCl3). H NMR (CDCl3) δ 5.84 (d, 1 H, J 3.6 Hz,
1
Melting points were determined on a digital melting-
point apparatus (Electrothermal) and are uncorrected.
Optical rotations were recorded at 22mC in CHCl3 or
MeOH solutions with a digital polarimeter DIP-370
1,2
H-1), 4.68 (d, 1 H, H-2), 4.29 (m, 1 H, J 8.9 Hz, H-
5), 4.10 (dd, 1 H, J
4,5
6.2 Hz, H-6a), 3.92 (dd, 1 H,
5,6a
J
5,6b 4.4 Hz, H-6b), 2.02 (s, 2 H, NH2), 1.49 (s, 3H, CH3),
(JASCO) using a 1-dm cell. H NMR and 13C NMR
1
1.38 (s, 3H, CH3), 1.29 (s, 6H, CH3), 13C NMR (CDCl3)
δ 118.6 (CN), 113.7 (CH3CCH3), 110.1 (CH3CCH3),
103.9 (C-1), 83.3 (C-2), 81.6 (C-4), 75.0 (C-5), 67.6
(C-6), 62.7 (C-3).
spectra were recorded in CDCl3, Me2SO-d or Me2CO-
d6 (internal Me4Si), respectively, at 300.13 MHz and at
'
75.47 MHz (Bruker Avance-300). TLC was performed
on Silica F254 (Merck) and detection by UV light at
254 nm or by charring with phosphomolybdic-H2SO4
reagent. Column chromatography was effected on Silica
Gel 60 (Merck, 230 mesh). Me2CO, hexane, ether and
each industrial grade were supplied by CINAS. El-
emental analyses were performed by the Service Central
de Micro-Analyse du Centre National de Recherche
Scientifique (Vernaison, France). Bases and solvents
were supplied by ACROS or ALDRICH. MeOH–NH3
is methanol saturated with ammonia gas at room tem-
perature.
3-Amino-3-C-cyano-3-deoxy-5-O-trityl-1,2-O-
isopropylidene-α--xylofuranose (3b)
Likewise, 5-O-trityl-1,2-O-isopropylidene-erythro-pen-
tofuranos-3-ulose (1b; 1 g , 2.31 mmol) gave, after 2 h,
3b (1.07 g, 98%) as a solid; mp 163–167mC; [α]D25 k29.3
(c 1.2, CHCl3). 1H NMR (CDCl3) δ 7.50–7.39 (m, 15 H,
H Tr), 5.91 (d, 1 H, J 1,2 3.6 Hz, H-1), 4.70 (d, 1 H, H-
2), 3.86 (dd, 1 H, J 4,5a 7.3 Hz, H-4), 3.80 (dd, 1 H, J 4,5b
5.4 Hz, H-5b), 3.54 (dd, 1 H, J 5a,5b 9.7 Hz, H-5a), 2.04
(s, 2 H, NH2), 1.58 (s, 3H, CH3), 1.38 (s, 3H, CH3), 13
C
NMR (CDCl3) δ 143.3 (3C, Cipso), 128.6, 128.1, 127.4
(15 C, Tr), 118.5 (CN), 113.4 (CH3CCH3), 103.9 (C-1),
87.9 (C Tr), 83.2 (C-2), 79.9 (C-4), 63.3 (C-5), 62.3 (C-3),
26.5 (CH3), 26.4 (CH3).
Synthesis
3-Amino-3-C-cyano-3-deoxy-1,2:5,6-di-O-
isopropylidene-α--allofuranose (3a)
A mixture of 1a (1g , 3.87 mmol) (Figure 2), MeOH– N-Phenyloxycarbonyl-3-amino-3-C-cyano-3-deoxy-
NH3 (7  ; 5.4 mL), Ti(OiPr)4 (1.3 g, 4.56 mmol) and 1,2:5,6-di-O-isopropylidene-α--allofuranose (4a)
dry MeOH (2.4 mL) was stirred at room temperature. Phenyl chloroformate (2.09 g; 13.4 mmol) was added to
After 5 h, TMSiCN (0.37 g; 3.8 mmol) was added and a stirred mixture of 3a (3.18 g , 11.2 mmol) and K2CO3
the solution was stirred for 5 h. Water (0.5 mL) and (2.32 g; 16.8 mmol) in acetone–H2O (56 mL; 1:1 v\v) at
EtOAc (10 mL) were added and the mixture was evapo- 0mC. After 5 h the mixture was filtered and evaporated
rated under reduced pressure. The residue was purified under reduced pressure. The residue was purified by

941
Spirohydantoins from D-ribose
Figure 2 Synthesis of the glyco-α-aminonitriles 3a and 3b and the spirohydantoin 6a. Reagents: a, NH4Cl, KCN, MeOH; b, Ti(OiPr)4, NH3–
MeOH; c, TMSCN; d, PhOC(O)Cl, K2CO3, acetone–H2O; e, NaOH, H2O–1,4-dioxane.
silica-gel chromatography (hexane–EtOAc, 4:1) to give (C ipso), 142.9 (3C, C ipso), 129.4–121.3 (20 C, trityl and
4a (2.03 g; 45%) as a solid; mp 126–129mC, [α]D25 24.8 (c Ph), 115.6 (CN), 113.8 (CH3CCH3), 104.3 (C-1), 88.6 (C
1.14, CHCl3). H NMR (CDCl3) δ 7.35–7.19 (m, 5 H, trityl), 82.1 (C-2), 77.6 (C-4), 62.9 (C-5), 62.0 (C-3), 26.6
1
Ph), 5.98 (s, 1 H, NH), 5.91 (d, 1 H, J 1,2 3.4 Hz, H-1), (CH3), 26.4 (CH3).
5.30 (d, 1 H, H-2), 4.47 (m, 1 H, J 4,5 9.1 Hz, H-5), 4.20
(dd, 1 H, J
6.4 Hz, H-6a), 4.03 (dd, 1 H, J
4.3
5,6b
5,6a
(3R)-3,3-(1,3-diazaspiro-2,4-dioxo)-1,2:5,6-di-O-
isopropylidene-α--allofuranose (6a)
Hz, H-6b), 3.84 (d, 1 H, H-4), 1.55 (s, 3H, CH3), 1.49 (s,
3H, CH3), 1.38 (s, 3H, CH3), 1.32 (s, 3H, CH3), 13C
NMR (CDCl3) δ 152.6 (CꢀO), 150.3 (C ipso), 129.3–
121.3 (5C, Ph), 115.7 (CN), 114.0 (CH3CCH3), 110.7
(CH3CCH3), 104.3 (C-1), 82.0 (C-2), 79.2 (C-4), 74.3 (C-
5), 67.5 (C-6), 62.4 (C-3), 26.7 (CH3), 26.5 (2xCH3), 24.6
(CH3).
A solution of the phenylcarbamate derivative 4a
(450 mg, 1.11 mmol) and NaOH (0.13 g, 3.33 mmol) in
25 mL 1,4-dioxane–water (1:1) was stirred at 80mC for
1 h. Then the mixture was neutralized with acetic acid
and extracted with ether. The organic layers were dried,
and evaporated. The residue was purified by silica-gel
chromatography (hexane–EtOAc, 1:1) to afford the
spirohydantoin 6a (290 mg, 80%) as a solid; mp
N-Phenyloxycarbonyl-3-amino-3-C-cyano-3-deoxy-5-
O-trityl-1,2-O-isopropylidene-α--ribofuranose (4b)
25
1
232–236mC ; [α]D j56.4 (c 0.76, CHCl3). H NMR
Likewise 3-amino-3-C-cyano-3-deoxy-5-O-trityl-1,2-O- (CDCl3) δ 8.77 (s, 1 H, NH), 6.16 (s, 1 H, NH), 5.91 (d,
isopropylidene-α--ribofuranose (3b; 3 g; 6.6 mmol) 1 H, J1,2 3.6 Hz, H-1), 4.55 (d, 1 H, H-2), 4.17 (m, 1 H,
25
gave 4b (3.14 g; 83%) as a solid; mp 196–198mC; [α]D
J4,5 9.1 Hz, H-5), 4.06 (dd, 1 H, J5,6a 3.4 Hz, H-6a), 3.96
1
k26.9 (c 1.1, CHCl3). H NMR (CDCl3) δ 7.49–7.31 (dd, 1 H, J5,6b 3.4 Hz, H-6b), 3.96 (d, 1 H, H-4), 1.54 (s,
(m, 20 H, Ph, Tr), 6.19 (s, 1 H, NH), 5.91 (d, 1 H, J 1,2 3H, CH3), 1.36 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.24 (s,
3.6 Hz, H-1), 5.25 (d, 1 H, H-2), 4.00 (dd, 1 H, J
4.7 Hz, H-4), 3.87 (dd, 1 H, J
3H, CH3), 13C NMR (CDCl3) δ 172.1 (CꢀO), 156.2
4,5a
8.3 Hz, H-5b), 3.76 (CꢀO), 113.6 (CH3CCH3), 109.9 (CH3CCH3), 104.8 (C-
4,5b
(dd, 1 H, J 5a,5b 10.2 Hz, H-5a), 1.55 (s, 3H, CH3), 1.34 1), 81.5 (C-2), 79.6 (C-4), 74.1 (C-5), 71.2 (C-3), 67.9 (C-
(s, 3H, CH3), 13C NMR (CDCl3) δ 152.6 (CꢀO), 150.5 6), 26.8 (CH3), 26.6 (CH3), 26.4 (CH3), 24.8 (CH3).

942
A. Nguyen et al
Figure 3 Synthesis of spirohydantoin derivatives 8a and 8b. Reagents: f, aqueous HCl (1 ); g, CF3COOH–H2O, 9:1.
(3R)-3,3-(1,3-diazaspiro-2,4-dioxo)-5-O-trityl-1,2-O-
isopropylidene-α--ribofuranose (6b)
Likewise the phenyl carbamate derivative 4b (0.30 g;
(3R)-3,3-(1,3-diazaspiro-2,4-dioxo)--allopyranose
(8aα and 8aβ)
A solution of the spirohydantoin 6a (360 mg,
0.5 mmol) gave 6b (0.22 g; 85%) as a solid; mp 1.09 mmol) in 3.3 mL of trifluoroacetic acid–water (9:1)
25
1
115–120mC; [α]D j10.15 (c 1.06, CHCl3). H NMR wasstirredatroomtemperaturefor1 h. Thenthesolvent
(CDCl3) δ 9.36 (s, 1 H, NH), 7.36–7.19 (m, 15 H, Tr), was co-evaporated with toluene. The residue was tri-
6.18 (s, 1 H, NH), 5.88 (d, 1 H, J 1,2 3.7 Hz, H-1), 4.36 turated with ether and filtered to afford the spiro-
(d, 1 H, H-2), 4.17 (dd, 1 H, J 4,5b 7.1 Hz, H-4), 3.58 (dd, hydantoin derivatives 8aα and 8aβ (264 mg, 97%) as a
26
1 H, J
5.2 Hz, H-5a), 3.23 (dd, 1 H, J
10.2 Hz, solid; mp 230–235mC; [α]D 89.0 (c 1.0, MeOH). 8aα :
5a,5b
4,5a
H-5b), 1.52 (s, 3H, CH3), 1.29 (s, 3H, CH3), 13C NMR 1H NMR (C5D5N) δ 12.62 (s, 1 H, NH), 8.23 (s, 1 H,
(CDCl3) δ 171.9 (CꢀO), 156.3 (CꢀO), 143.2 (3C, NH), 5.84 (d, 1 H, J 1,2 3.2 Hz, H-1), 4.82 (d, 1 H, H-4),
C ipso), 128.4–127.1 (15 C, trityl), 113.3 (CH3CCH3), 4.75 (m, 1 H, J 4,5 10.3 Hz, H-5), 4.66 (d, 1 H, H-2), 4.40
104.7 (C-1), 87.4 (C trityl), 81.2 (C-2), 77.8 (C-4), 70.7 (dd, 2 H, J 5,6a l J
4.9 Hz, H-6a, H-6b), 13C NMR
5,6b
(C-3), 61.5 (C-5), 26.7 (CH3), 26.4 (CH3).
(CDCl3) δ 178.0 (CꢀO), 160.6 (CꢀO), 93.7 (C-1), 74.4
(C-2), 73.4 (C-3), 70.0 (C-5), 68.4 (C-4), 62.7 (C-6). 8aβ :
1H NMR (C5D5N) δ 12.62 (s, 1 H, NH), 8.23 (s, 1 H,
NH), 5.76 (d, 1 H, J 1,2 8.2 Hz, H-1), 4.88 (d, 1 H, H-4),
4.68 (d, 1 H, H-2), 4.59 (m, 1 H, J 4,5 10.1 Hz, H-5), 4.50
(3R)-3,3-(1,3-diazaspiro-2,4-dioxo)-1,2-O-
isopropylidene-α--allofuranose (7a)
(dd, 2 H, J 5,6a l J
2.1 Hz, H-6a, H-6b), 13C NMR
A
solution of the spirohydantoin 6a (465 mg,
5,6b
1.41 mmol) in 23.3 mL of aqueous HCl (1 ) was stirred
at 0mC for 1 h. NaHCO3 was added and the solvent co-
evaporated with 1,4-dioxane under reduced pressure.
The residue was solubilized in THF (tetrahydrofuran),
(CDCl3) δ 178.2 (CꢀO), 161.0 (CꢀO), 97.2 (C-1), 78.1
(C-2), 73.5 (C-3), 70.8 (C-5), 69.3 (C-4), 63.0 (C-6).
filtered and evaporated to give 7a (210 mg; 52%) as a (3R)-3,3-(1,3-diazaspiro-2,4-dioxo)--ribopyranose
solid; mp 228–230mC; [α]D28 l j72,4m (c 0,2; MeOH); (8bα and 8bβ)
3.6 Hz, H-1), Likewise the spirohydantoin 6b (427 mg, 8.53 mmol)
1H (ppm) (CD3OD) δ 5.89 (d, 1 H, J
1,2
4.87 (s, 4 H, NH, OH), 4.60 (d, 1 H, H-2), 4.18 (m, 1 H, gave 8bα and 8bβ (160 mg, 86%) as a solid; mp 227–
5.5 Hz, , H-5, H- 230mC; [α]D 43.7 (c 1.0, MeOH). 8bα : 1H NMR
26
J
9.1 Hz, H-4), 3.72 (m, 2H, J
4,5
5,6a
6b), 3.54 (dd, 1 H, J
11.7 Hz, H-6a), 1.57 (s, 3H, (C5D5N) δ 12.67 (s, 1 H, NH), 8.34 (s, 1 H, NH), 5.77 (d,
6a,6b
CH3), 1.36 (s, 3H, CH3). 13C (ppm) (CD3OD) δ 174.8 1 H, J1,2 3.3 Hz, H-1), 4.77 (dd, 1 H, H-4), 4.67 (d, 1 H,
(1C, CꢀO), 158.2 (1C, CꢀO), 113.4 (1C, CH3CCH3), H-2), 4.54 (dd, 1 H, J4,5a 11.2 Hz, H-5a), 4.07 (dd, 1 H,
105.1 (1C, C-1), 82.4 (1C, C-2), 77.8 (1C, C-4), 72.0 (1C, J4,5b 5.3 Hz, J5a,5b 10.9 Hz, H-5b), 13C NMR (CDCl3) δ
C-3), 71.7 (1C, C-5), 64.3 (1C, C-6), 26.1 (1C, CH3), 25.7 178.0 (CꢀO), 160.5 (CꢀO), 93.2 (C-1), 73.4 (C-3), 69.8
1
(C-2), 68.1 (C-4), 60.1 (C-5). 8bβ : H NMR (C5D5N) δ
(1C, CH3).

943
In conclusion, the target compounds were easily syn-
Spirohydantoins from D-ribose
12.67 (s, 1 H, NH), 9.85 (s, 1 H, NH), 5.62 (d, 1 H, J1,2
8.25 Hz, H-1), 4.89 (dd, 1 H, H-4), 4.68 (d, 1 H, H-2), thesized from glyco-α-aminonitriles via an isocyanate
4.43 (dd, 1 H, J4,5a 5.2 Hz, H-5a), 4.26 (dd, 1 H, J4,5b intermediate. These new spirohydantoin derivatives are
11.0 Hz, J5a,5b 11.3 Hz, H-5b), 13C NMR (CDCl3) δ being evaluated for their herbicidal activities and gly-
177.8 (CꢀO), 160.9 (CꢀO), 97.5 (C-1), 74.2 (C-3), 73.1 cogen phosphorylase inhibition. Also, it is noteworthy
(C-2), 68.8 (C-4), 67.1 (C-5).
that spirohydantoin carbohydrates have the potential to
provide a convenient access to α,α-disubstituted glyco-
α-amino acids. Studies in this direction and the synthesis
of thio compounds are in progress.
Results and Discussion
The stereoselective synthesis of non-anonmeric glyco-α-
aminonitrile using Strecker synthesis (KCN and NH4Cl)
from the ulose derivatives 1a and 1b was unsuccessful
and only the corresponding cyanohydrines (2a and 2b)
were observed (Figure 2). In contrast, the glyco-α-
aminonitriles 3a and 3b were readily obtained from the
same intermediates, using titanium (IV) isopropoxide as
a mild Lewis acid catalyst, MeOH-NH3 and TMSCN as
cyanating agent, in 80% yield from 1a and 1b.
References
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(KCN, (NH4)2CO3, MeOH–H2O, 70mC) resulted in the
formation of 2a. We therefore turned our attention to
an alternative method via an α-carboxamidoisocyanate
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was readily achieved with PhOC(O)Cl in acetone–H2O
and K2CO3 yielding 4a in 44% yield. Treatment of 4a
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achieved with aqueous HCl at room temperature (1 h)
to give 7a in 52% yield (Figure 3). Alternatively, 6a was
treated with aqueous trifluoroacetic acid for 1 h to give
8a in 97% yield. Using a similar strategy, 6b was
obtained from the phenyloxycarbonyl derivative 4b
(83% from 3b) under basic conditions in 85% yield.
Treatment of 6b with aqueous trifluoroacetic acid gave
8b in quantitative yield.
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(1993) A novel biogenetic type synthesis of (j)-hydantocidin.
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(2000) Stereoselective synthesis of a-aminonitriles at non-anomeric
positions of monosaccharides. Tetrahedron Lett. 41: 6403–6406
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spirohydantoin nucleoside. Tetrahedron 51: 4635–4646