Polyhydroxylated N-(thio)carbamoyl piperidines: Nojirimycin-type glycomimetics with controlled anomeric configuration

Article abstract of DOI:10.1016/S0957-4166(99)00462-0

N-(Thio)carbamoyl D-xylo-nojirimycin derivatives have been prepared by intramolecular rearrangement of sugar thiourea precursors under basic conditions. The stereochemistry at the aminoketal stereocentre is under stereoelectronic control, with the diaster

Full text of DOI:10.1016/S0957-4166(99)00462-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4271–4275
Polyhydroxylated N-(thio)carbamoyl piperidines: nojirimycin-
type glycomimetics with controlled anomeric configuration
M. Isabel García-Moreno,a Carmen Ortiz Melleta,∗ and José M. García Fernández b,∗
aDepartamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, E-41071 Sevilla, Spain
bInstituto de Investigaciones Químicas, CSIC, Américo Vespucio s/n, Isla de la Cartuja, E-41092 Sevilla, Spain
Received 29 September 1999; accepted 20 October 1999
Abstract
N-(Thio)carbamoyl D-xylo-nojirimycin derivatives have been prepared by intramolecular rearrangement of
sugar thiourea precursors under basic conditions. The stereochemistry at the aminoketal stereocentre is under
stereoelectronic control, with the diastereomer having the pseudoanomericgroup in axial orientation being obtained
in all cases. © 1999 Elsevier Science Ltd. All rights reserved.
Nitrogen-in-the-ring carbohydrate mimics with glycosyl hydrolase inhibitory properties (iminosugars,
‘azasugars’) have been attracting much attention due to their great chemotherapeutic potential.1–10
However, the majority of the naturally occurring azasugars and the plethora of synthetic analogues
reported so far simultaneously inhibit several α- as well as β-glycosidases, which seriously hampers
clinical applications.11 Since many glycosidases that recognise the same glycon configuration differ only
in the type of O-glycosidic linkage (α or β), introduction of an O-anomeric group with a precise spatial
orientation in azasugars might provide greater selectivity in recognition by a targeted enzyme.
The development of aza-O-glycoside glycomimetics has been limited by the lability of the O/N acetal
function under hydrolytic conditions.12 Reducing derivatives of the nojirimycin type 1 likewise suffer
from low stability and, moreover, rapid epimerisation at the aminoketal centre occurs in water solution.13
We reasoned that replacement of the sp3 N-atom by a thiourea or urea nitrogen, with substantial
sp2 character, should significantly increase the hyperconjugative contribution to the anomeric effect
due to the favourable π symmetry of the lone-pair orbital of N-(thio)carbamoyl functionalities.14,15
Recently, this principle was applied to the synthesis of the first reducing castanospermine analogue with a
stereoelectronically controlled anomeric configuration 2.16 Validation of this concept in the nojirimycin
series was, however, prevented by the strong tendency of the transient D-glucose mimic 3 to undergo
intramolecular glycosylation involving the primary OH group to give 4.17 We describe here the synthesis
of several pentose-mimic homologues, i.e. N-(thio)carbamoyl D-xylo-nojirimycin derivatives, in which
∗
Corresponding authors. E-mail: jogarcia@cica.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00462-0

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the anomeric OH or O-glycosylic group is anchored in the axial disposition as the aglycons of the putative
substrates of α-glycosidases.
A retrosynthetic analysis revealed that the polyhydroxylated N-(thio)carbamoyl piperidine skele-
ton I can be constructed by intramolecular nucleophilic addition of the sugar-N-atom of 5-deoxy-5-
(thio)ureido substituents to the masked aldehydo group of D-xylose derivatives II, with simultaneous ge-
neration of the aminoketal stereocentre (Scheme 1). The possibility of introducing a virtually unrestricted
variety of substituents at the N0-atom is of further interest since this may provide additional interactions
with enzymes. In a first approach, the 1,2-O-isopropylidene-α-D-xylofuranose thioureas 5a–c were
considered as suitable precursors.18 However, acidic hydrolysis of the acetal protecting group resulted in
extensive dehydration reactions, probably through acid-catalysed formation of an anomeric azacarbenium
cation. To avoid this undesired side-reaction, an alternative route was devised using acetyl protecting
groups. The aza-Wittig type reaction of azide 7, obtained from the known 1,2-O-isopropylidene derivative
6,18 with CS2 provided isothiocyanate 8, which upon coupling with amines afforded the corresponding
thioureas 9a–c.19 Deacetylation of 9a–c with methanolic sodium methoxide proceeded with concomi-
tant glycosylation yielding the methyl N-thiocarbonyl-D-xylo-nojirimycin glycosides 10a,b,d as single
diastereomers having the R (α) configuration at the aminoketal centre (J1,2=3.3–3.6 Hz),20 with the
4
3
piperidine ring in a conformation close to C1, as seen from the vicinal JH,H coupling constant values
(Scheme 2).21
Scheme 1. Retrosynthetic scheme for N-(thio)carbamoyl D-xylo-nojirimycin derivatives
For the preparation of the N-carbamoyl analogues, a different synthetic strategy which avoids the use
of hazardous isocyanate reagents was devised. Condensation of azide 7 with triphenylphosphine and
further in situ aza-Wittig type reactions with isothiocyanates gave the carbodiimide adducts 11a–c,22
which readily underwent acid-catalysed nucleophilic addition of water to afford the 5-deoxy-5-ureido-
D-xylofuranoses 12a–c.23 Sodium methoxide promoted deacetylation resulted in intramolecular rear-
rangement to give the tetrahydroxypiperidine heterocycles 13a,b,d (Scheme 3) as the major reaction
products.24,25 Exclusively, the diastereomer 2R, having the aminoketal hydroxy group in axial dispo-
sition, was detected in D2O solution by NMR spectroscopy (J1,2=3.8 Hz),20 in spite of the expected
abatement of the sp2 character of the urea nitrogen atom as compared with thioureas.
The propensity of N-thiocarbonyl azasugars to undergo acid-catalysed glycosylation reactions has
been previously ascribed to the stabilisation of a transient azacarbenium species by the neighbouring
thiocarbonyl group.15,17 Remarkably, formation of the methyl glycosides 10a–c occurred under basic
conditions. The fact that the axial glycosides were obtained as the single reaction products suggests a
similar cationic intermediate, further addition of methoxide anion proceeding under strict stereoelectronic

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4273
Scheme 2. (i) TFA:water, 9:1; (ii) Ac2O–pyridine (50% overall); (iii) TPP, CS2 (95%); (iv) methylamine, aniline or 2,3,4,6-tetra-
O-acetyl-β-D-glucopyranosylamine (lit.),26 pyridine (60–98%); (v) NaMeO/MeOH (50–90%)
Scheme 3. See Scheme 2 for the identity of the R substituent in the a–d series. (i) Methyl, phenyl or 2,3,4,6-tetra-
O-acetyl-β-D-glucopyranosyl isothiocyanate (lit.),26 toluene (50–82%); (ii) acetone:water, TFA (90–95%); (iii) NaMeO/ MeOH
(55–93%)
control. This reactivity is lessened in the oxo analogues, in agreement with the decreased capability of
the carbonyl group to stabilise a vicinal positive charge as compared to the thiocarbonyl group.
In conclusion, the present results validate a concise and efficient approach to polyhydroxylated
piperidine glycomimetics bearing an axially disposed pseudoanomeric hydroxyl or O-glycosylic group.
The control of the anomeric configuration relies on a very efficient overlapping between the π-type
lone-pair orbital of the nitrogen atom in the ground-state of (thio)carbamic functionalities and the σ*
antibonding orbital of the contiguous C–O bond, fully operative in polar solvents. It is noteworthy that
the N-(thio)carbamoyl substituent imparts configurational and conformational integrity at the piperidine
ring even in the case of reducing derivatives. Thus, no equilibration to the β anomers was observed for
compounds 13a,b,d after a week in D2O solution. The enhanced anomeric effect also provides additional
stabilisation as compared with classical aminoketal azasugars. Extensions of the methodology to other
sugar configurations and evaluation of the inhibitory properties of the new structures as glycosidase
inhibitors are currently in progress.

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Acknowledgements
Support from DGICyT (grant no. PB 97/0747) is acknowledged. M.I.G.M. thanks the Fundación
Cámara for a doctoral fellowship.
References
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19. For a recent review on sugar isothiocyanates and thioureas, see: García Fernández, J. M.; Ortiz Mellet, C. Sulfur Reports
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20. For clarity of presentation, the authors chose not to use the numbers resulting from the nomenclature of piperidine
heterocycles in the notation of atoms for NMR data. Instead, the notation is kept consistent with the parent carbohydrate
compounds.
21. All new compounds gave satisfactory microanalytical, MS and spectroscopic data. Data for 10a: [α]2D2=+61.0 (c 1.0,
H2O); δH (D2O, 300 MHz) 3.08 (1H, dd, J4,5b=11.0, J5a,5b=13.0, H-5b), 3.07 (3H, s, OMe), 3.31 (3H, s, NMe), 3.50 (1H,
ddd, J4,5a=5.3, J3,4=9.3, H-4), 3.54 (1H, dd, J1,2=3.3, J2,3=9.3, H-2), 3.69 (1H, t, H-3), 4.15 (1H, dd, H-5a), 6.22 (1H, d,
H-1); δC (D2O, 75.5 MHz) 34.7, 46.8, 57.5, 71.3, 73.4, 6.2, 90.5, 184.6. Data for 10b: [α]2D2=+54.0 (c 1.0, MeOH); δH
(D2O, 500 MHz, 313K) 3.27 (1H, dd, J4,5b=11.0, J5a,5b=13.0, H-5b), 3.45 (3H, s, OMe), 3.66 (1H, ddd, J4,5a=5.5, J3,4=9.3,
H-4), 3.67 (1H, dd, J1,2=3.5, J2,3=9.3, H-2), 3.79 (1H, t, H-3), 4.44 (1H, dd, H-5a), 6.27 (1H, d, H-1), 7.30–7.50 (5H,
m, Ph); δC (D2O, 125.5 MHz, 313K) 45.9, 55.7, 69.2, 70.8, 74.0, 88.8, 126.9, 127.3, 129.4, 139.3, 183.7. Data for 10d:
[α]2D2=+25.4 (c 1.0, H2O); δH (D2O, 500 MHz, 313K) 3.06 (1H, dd, J4,5b=11.3, J5a,5b=13.5, H-5b), 3.25 (3H, s, OMe),
0
3.36 (1H, dd, J4 ,5 =8.5, J3 ,4 =9.5, H-4 ), 3.45 (1H, ddd, J5 ,6 a=2.0, J5 ,6 b=5.0, H-50), 3.45 (1H, m, H-4), 3.46 (1H, dd,
0
0
0
0
0
0
0 0
0
0 0
1,2=3.6, J2,3=9.5, H-2), 3.50 (1H, t, J1 ,2 =J =9.5, H-2 ), 3.53 (1H, t, H-3 ), 3.60 (1H, t, J3,4=9.5, H-3), 3.66 (1H, dd,
2 ,3
0
0
0
0
J
J
6a,6b=12.5, H-60b), 3.79 (1H, dd, H-60a), 4.21 (1H, bs, H-5a), 5.70 (1H, d, H-10), 6.25 (1H, d, H-1); δC (D2O, 125.5 MHz)
44.9, 55.5, 60.7, 68.7, 69.4, 70.5, 71.8, 73.9, 76.7, 77.6, 85.1, 88.8, 184.3.
22. The converse strategy using isothiocyanate 8 in reaction with azides–triphenylphosphine proved less convenient. The
reaction probably involves a sugar phosphazide instead of an iminophosphorane intermediate, as previously observed for
related transformations. See: García Fernández, J. M.; Ortiz Mellet, C.; Díaz Pérez, V. M.; Fuentes, J.; Kovács, J.; Pintér,
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4161–4164.

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24. Minor amounts of the corresponding methyl glycosides were detected in the 1H NMR spectra of the crude reaction
mixtures.
25. Data for 13a: [α]2D2=−2 (c 1, H2O); δH (D2O, 500 MHz) 3.13 (3H, s, MeN), 3.42 (1H, dd, J4,5b=10.9, J5a,5b=12.6, H-5b),
3.89 (1H, dd, J1,2 3.8, J2,3=9.4, H-2), 3.95 (1H, ddd, J4,5a=5.6, H-4), 4.07 (1H, t, H-3), 4.14 (1H, dd, H-5b), 6.03 (1H, d,
H-1); δC (D2O, 125.5 MHz, 318K) 23.0, 38.6, 65.6, 67.8, 69.5, 72.9, 159.6. Data for 13b: [α]2D2=−6.0 (c 0.5, MeOH);
δH (D2O, 500 MHz) 3.20 (1H, dd, J4,5b=11.0, J5a,5b=12.7, H-5b), 3.61 (1H, dd, J1,2=3.8, J2,3=9.7, H-2), 3.67 (1H, ddd,
J
4,5a=5.6, J3,4=9.7, H-4), 3.76 (1H, t, H-3), 4.00 (1H, dd, H-5a), 5.82 (1H, d, H-1), 7.47–7.31 (m, 5 H, Ph); δC (D2O, 75.5
MHz) 43.1, 69.8, 71.9, 73.7, 77.2, 123.3, 125.2, 129.5, 138.1, 157.8. Data for 13d: [α]2D2=+6.0 (c 1.0, H2O); δH (D2O,
0
0
0
0
0
0
0
0 0
500 MHz) 3.19 (1H, dd, J4,5b=11.0, J5a,5b=13.0, H-5b), 3.54 (1H, t, J3 ,4 =J4 ,5 =9.2, H-4 ), 3.59 (1H, t, J1 ,2 =J2 ,3 =9.2,
H-20), 3.63 (1H, dd, J1,2=3.8, J2,3=9.4, H-2), 3.64 (1H, ddd, J5 ,6 a=5.7, J6 a,6 b=12.4, H-50a), 3.67 (1H, t, H-30), 3.70 (1H,
0
0
0
0
dd, J4,5a=5.3, J3,4=9.4, H-4), 3.79 (1H, t, H-3), 3.84 (1H, dd, J5 ,6 b=5.4, H-60b), 3.99 (1H, dd, H-60a), 5.03 (1H, d, H-10),
5.8 (1H, d, H-1); δC (D2O, 125.5 MHz) 42.4, 60.6, 69.3, 69.4, 71.5, 71.6, 73.3, 76.6, 76.7, 77.3, 81.6, 158.1.
26. Babiano Caballero, R.; Fuentes Mota, J.; Galbis Pérez, J. A. Carbohydr. Res. 1986, 154, 280–288.
0
0