Use of the N-tosyl-activated aziridine 1,2-dideoxy-1,2-iminomannitol as a synthon for 1-deoxymannojirimycin analogues

Article abstract of DOI:10.1016/S0040-4039(00)00130-1

1-Amino-1-deoxy-D-glucitol was converted into the selectively protected title compound 4, an N-tosyl-activated aziridine that readily underwent ring opening with various nucleophiles. Further deprotection of the 5,6-diol moiety followed by ring closure under Mitsunobu conditions afforded the corresponding 6-substituted analogues of 1-deoxymannojirimycin. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00130-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2223–2226
Use of the N-tosyl-activated aziridine 1,2-dideoxy-1,2-
iminomannitol as a synthon for 1-deoxymannojirimycin
analogues
Gert J. Joly, Koen Peeters, Hua Mao, Thierry Brossette, Georges J. Hoornaert and
Frans Compernolle ∗
Laboratorium voor Organische Synthese, Department of Chemistry, K. U. Leuven, Celestijnenlaan 200F, B-3001 Heverlee,
Belgium
Received 1 November 1999; accepted 14 January 2000
Abstract
1-Amino-1-deoxy-D-glucitol was converted into the selectively protected title compound 4, an N-tosyl-activated
aziridine that readily underwent ring opening with various nucleophiles. Further deprotection of the 5,6-diol moiety
followed by ring closure under Mitsunobu conditions afforded the corresponding 6-substituted analogues of 1-
deoxymannojirimycin. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: aziridines; Mitsunobu reactions; carbohydrates; piperidines.
Azasugars have been recognised as inhibitors of glycosidases for some time,1 thus representing
potential antiviral (including anti-AIDS)2 and antitumor3 agents. Consequently, much effort has been
devoted to the preparation of both the natural azasugars and their synthetic analogues.4 We now describe
an interesting route for the synthesis of variously substituted polyhydroxypiperidines, which proceeds
via the nucleophilic ring opening of an N-tosyl-activated aziridine intermediate.
In our previous work, divergent strategies were applied in order to transform 1-aminoglucitol 15
into various analogues of 1-deoxynojirimycin and castanospermine.6 Thus, the crystalline 3,4;5,6-di-
O-isopropylidene ammonium salt derivative 2 was isolated and subsequently converted to polyhy-
droxypiperidines modified at C-2 and C-6. The present work forms an extension of our ‘inverse chain
strategy’ concept which implies that ring closure to form the piperidine derivative occurs between the
original carbon C-6 of 1-aminoglucitol (which is to become C-1 of the iminosugar) and an amino group
introduced at C-2.
Our synthetic sequence (Scheme 1) started with protection of the 1-amino group of 2 as the N-
tosylamide and subsequent activation of 2-OH as the mesylate 3; this was isolated in 92% yield by using
∗
Corresponding author. Tel: +32 16 32.74.07; fax: +32 16 32.79.90; e-mail: frans.compernolle@chem.kuleuven.ac.be (F.
Compernolle)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00130-1
tetl 16413

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a ‘one-pot procedure’ followed by a single chromatographic purification. Upon treatment with sodium
hydride in THF, mesylate 3 was converted to the N-tosylaziridine 4 in 90% yield.
Scheme 1. Synthesis of the N-tosyl aziridine 4. (a) 4 equiv. Et3N, 1.1 equiv. p-TsCl, CH2Cl2, rt, 30 min; then 1.3 equiv. MsCl,
rt, 1 h; (b) 2 equiv. NaH, THF, rt, 1 h
1
1
The aziridine structure 4 was confirmed by H and 13C NMR data.7 In the H NMR spectrum the
absorption due to the NH–proton of the tosylamide 3 had disappeared, while the protons H-1 and H-
10 were differentiated into two doublet signals detected at 2.43 and 2.65 ppm, respectively (geminal
coupling value J›0 Hz). In the 13C NMR spectrum the values observed for the JC–H coupling
constants (171 and 179 Hz for C-1 and 171 Hz for C-2) were in agreement with those reported for
N-methylaziridine.8
2
1
Compound 4 was shown to be a highly versatile synthon for the construction of imino sugars. This
proceeded (Scheme 2) via an initial opening of the aziridine ring using the appropriate nucleophiles; the
resulting C-1-substituted 2-aminomannitols in turn could be elaborated into iminosugars of the piperidine
type. A similar approach which involved the ring opening of bis(aziridines), was applied by Depezay et
al. to prepare analogues of 1-deoxynojirimycin and 1-deoxymannojirimycin.9
Scheme 2. Conversion of the aziridine to analogues of 1-deoxymannojirimycin. (a) See Table 1; (b) Dowex, 9:1 MeOH:H2O,
rt, 30–72 h; (c) PPh3, DEAD, THF, rt, 48–72 h; (d) Py, Ac2O, rt, 2 h
Table 1 provides an overview of the reaction conditions used for the ring opening of aziridine 4 with
various nucleophiles. Except for the reaction with KOtBu, the products 5a–h were isolated in good
to excellent yields. One problem encountered when using sodium azide or potassium acetate as the
nucleophile was the formation of dimeric products. This side reaction is due to the competitive attack
of the N-tosylamide anion, i.e. the initial product generated by opening of the aziridine ring, on a second
molecule of aziridine. It could be suppressed by using 10 equivalents of the nucleophile. No dimer
formation was observed in reactions with the more nucleophilic carbanionic reagents producing 5g and
5h, and in those cases where the intermediate N-tosylamide anion could abstract an acidic proton, i.e. in
the reaction with amines, malonate, and sulfonylacetonitrile. In analogy to the copper(I)-catalyzed ring
opening of epoxides by Grignard reagents,10 the reaction with phenylmagnesium bromide only succeeded
after addition of catalytic copper(I)iodide.
The conversion of the 2-aminomannitol derivatives 5 into analogues of 1-deoxymannojirimycin was
carried out for representative examples (Nu=N3, OAc, Ph). In a first step, regioselective deprotection of
the terminal isopropylidene group was effected by treatment with an acidic ion exchange resin (Dowex

2225
Table 1
Reaction conditions for the nucleophilic ring opening of aziridine 4
50X8-200), affording the 5,6-diols 6 in good yields (azide 6a, 72%; acetate 6c, 80%; Ph-compound 6g,
82%).
Treatment of the 5,6-diols 6 with triphenylphosphine and diethylazodicarboxylate in anhydrous THF
(Mitsunobu conditions11) produced the piperidine compounds 7. At room temperature, and even at
40–60°C, the cyclisation reaction was found to proceed very slowly. After 2–3 days, TLC and mass
spectrometry confirmed that all starting material had been consumed. However, due to the presence
of co-eluting substances originating from the Mitsunobu reagent, isolation of the alcohol products 7
proved to be difficult, and therefore these were converted to the less polar acetates 8. Compounds 8 were
isolated in moderate yields (combined yields for steps c and d: 8a, 45%; 8c, 38%; 8g, 42%) and showed
spectroscopic data in accordance with the proposed piperidine structures.12
The potential offered by aziridine 4 as a synthon for various iminosugars is demonstrated by the
varying nature of the nucleophiles utilised for ring opening, i.e. nitrogen-, oxygen-, and carbon-based
reagents. In particular, the application of carbon nucleophiles may pave the way for the introduction
of more complex substituents, especially in view of the synthesis of C-azadisaccharides.13 Although
deprotection of the N-tosyl group (using the sodium–naphthalene procedure14) proceeded more readily
for the cyclised non-acidic N-tosylamides than for the acyclic NH-tosylamides, we can now also explore
the use of the recently described N-p-nitrophenylsulfonyl group which can be removed under much
milder conditions using the thiophenolate anion as a nucleophilic deprotecting agent.15
Acknowledgements
This work was supported by the FWO and by the ‘Ministerie voor Wetenschapsbeleid, IUAP’. We are
indebted to Prof. Dr. S. Toppet, R. De Boer, Dr. A. Tahri, and X. Wu for the NMR and mass spectra and
to the Janssen Pharmaceutica Company for elemental analyses. H.M. also thanks the KU Leuven for a
scholarship.

2226
References
1. (a) Legler, G.; Julich, E. Carbohydr. Res. 1984, 128, 61; (b) Saul, R.; Molyneux, R. J.; Elbein, A. D. Arch. Biochim. Biophys.
1984, 230, 668.
2. Gruters, R. A.; Neefjes, J. J.; Tersmette, M.; de Goede, R. E. Y.; Tulp, A.; Huisman, H. G.; Miedema, F.; Ploegh, H. L.
Nature 1987, 330, 74.
3. For a review, see: Olden, K.; Breton, P.; Grzegorzewski, K.; Yasuda, Y.; Gause, B. L.; Oredipe, O. A.; Newton, S. A.; White,
S. L. Pharmacol. Ther. 1991, 50, 285.
4. For monocyclic azasugars, see e.g.: Hughes, A. B.; Rudge, A. J. Nat. Prod. Rep. 1994, 11, 135; for bicyclic analogues, see
e.g.: Michael, J. P. Nat. Prod. Rep. 1995, 12, 535.
5. Kindly supplied by Cerestar, Vilvoorde.
6. (a) Kilonda, A.; Compernolle, F.; Toppet, S.; Hoornaert, G. J. Chem. Soc., Chem. Commun. 1994, 2147; (b) Kilonda, A.;
Compernolle, F.; Toppet, S.; Hoornaert, G. Tetrahedron Lett. 1994, 35, 9047; (c) Compernolle, F.; Joly, G. J.; Peeters,
K.; Toppet, S.; Hoornaert, G.; Kilonda, A.; Babady-Bila, Tetrahedron 1997, 53, 12 739; (d) Kilonda, A.; Compernolle, F.;
Hoornaert, G. J. Org. Chem. 1995, 60, 5826.
7. Selected data for 4: 1H NMR (CDCl3, 400 MHz): δ=1.26 (s, 3H, Me2C), 1.34 (s, 6H, Me2C), 1.41 (s, 3H, Me2C), 2.43 (d,
1H, J=4.5 Hz, H-1), 2.44 (s, 3H, Me tosyl), 2.65 (d, 1H, J=7.0 Hz, H-10), 3.11 (ddd, 1H, J=4.0, 4.5, 7.0 Hz, H-2), 3.74 (t,
1H, J=7.0 Hz, H-4), 3.88 (dd, 1H, J=5.5, 8.5 Hz, H-6), 3.96 (dd, 1H, J=4.0, 7.0 Hz, H-3), 3.97 (m, 1H, H-5), 4.08 (dd, 1H,
J=6.0, 8.5 Hz, H-60), 7.34 (d, 2H, CH tosyl), 7.83 (d, 2H, CH tosyl); 13C NMR (CDCl3, 100 MHz) δ=21.6 (Me tosyl), 25.2,
26.5, 26.8, 27.0 (Me2C), 30.4 (C-1), 40.1 (C-2), 67.1 (C-6) 76.4, 77.6, 79.1 (C-3,4,5), 109.8, 110.4 (Me2C), 128.2, 129.7
(CH tosyl), 134.7, 144.7 (C-ipso tosyl).
8. The values 1JC–H=161 and 171 Hz are cited for N-methylaziridine by: Kalinowski, H.-O.; Berger, S.; Braun, S. In Carbon-13
NMR Spectroscopy; John Wiley & Sons: Chichester, 1988; p. 441.
9. (a) Duréault, A.; Tranchepain, I.; Depezay, J.-C. J. Org. Chem. 1989, 54, 5324; (b) Fitremann, J.; Duréault, A.; Depezay,
J.-C. Tetrahedron Lett. 1994, 35, 1201; (c) Fitremann, J.; Duréault, A.; Depezay, J.-C. Synlett. 1995, 235; (d) McCort, I.;
Duréault, A.; Depezay, J.-C. Tetrahedron Lett. 1996, 37, 7717; (e) Fitremann, J.; Duréault, A.; Depezay, J.-C. Synlett. 1995,
235; (f) McCort, I.; Duréault, A.; Depezay, J.-C. Tetrahedron Lett. 1996, 37, 7717; (g) McCort, I.; Duréault, A.; Depezay,
J.-C. Tetrahedron Lett. 1998, 39, 4443.
10. Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G. Tetrahedron Lett. 1979, 20, 1503.
11. Mitsunobu, O. Synthesis 1981, 1.
12. Selected data for 8a: 1H NMR (CDCl3, 400 MHz): δ=1.31 (s, 3H, Me2C), 1.37 (s, 3H, Me2C), 2.07 (s, 3H, Me tosyl), 2.43
(s, 3H, MeOOC), 2.97 (dd, 1H, J=5.5, 10 Hz, H-3), 3.20 (dd, 1H, J=6.5, 15.5 Hz, H-1ax), 3.58 (dd, 1H, J=3, 12.5 Hz, H-6),
3.82 (dd, 1H, J=4.5, 12.5 Hz, H-60), 3.9 (m, 1H, H-5), 4.01 (dd, 1H, J=9, 10 Hz, H-4), 4.3 (m, 1H, H-1eq), 5.23 (ddd, 1H,
J=5.5, 6.5, 8.5 Hz, H-2), 7.37 (m, 2H, CH tosyl), 7.73 (m, 2H, CH tosyl); 13C NMR (CDCl3, 100 MHz): δ=20.6 (MeOOC),
21.4 (Me tosyl), 26.4, 26.8 (Me2C), 46.5 (C-1), 53.3 (C-6), 58.6, 64.1, 70.8, 75.5 (C-2,3,4,5), 113.2 (Me2C), 126.9, 130.0
(CH tosyl), 136.0, 144.3 (C-ipso tosyl), 169.8 (MeOOC).
13. For C-azadisaccharides, see: (a) Johnson, C. R.; Miller, M. W.; Gedebiowski, A.; Ksebati, M. B. Tetrahedron Lett. 1994, 35,
8991; (b) Martin, O. R.; Liu, L.; Yang, F. Tetrahedron Lett. 1996, 37, 1991; (c) Frerot, E.; Marquis, C.; Vogel, P. Tetrahedron
Lett. 1996, 37, 2023; (d) Johns, B.; Pan, Y.; Elbein, A.; Johnson, C. J. Am. Chem. Soc. 1997, 119, 4856.
14. (a) Ji, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson, W. D.; Wriede, P. J. Am. Chem. Soc. 1967, 89, 5311;
(b) Zhou, W.-S.; Xie, W.-G.; Lu, Z.-H.; Pan, X.-F. J. Chem. Soc., Perkin Trans. 1 1995, 2599.
15. (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373; (b) Maligres, P. E.; See, M. M.; Askin, D.;
Reider, P. J. Tetrahedron Lett. 1997, 38, 5253.