Convergent synthesis of pyrrolidine-based (1→6)- and (1→5)-aza-C-disaccharides

Article abstract of DOI:10.1016/S0040-4039(00)01005-4

A new entry to (1→6)- and (1→5)-aza-C-disaccharides featuring the pyrrolidine ring as the imino sugar component is described via Wittig condensation of polyhydroxylated 2-formylpyrrolidines with galactopyranose 6-phosphorane and ribofuranose 5-phosphorane

Full text of DOI:10.1016/S0040-4039(00)01005-4

Tetrahedron Letters 41 (2000) 6195±6199
Convergent synthesis of pyrrolidine-based (1!6)- and
(1!5)-aza-C-disaccharides
Alessandro Dondoni,* Pier Paolo Giovannini and Alberto Marra
Á
Dipartimento di Chimica, Laboratorio di Chimica Organica, Universita di Ferrara, Via L. Borsari 46,
I-44100 Ferrara, Italy
Received 12 May 2000; accepted 14 June 2000
Abstract
A new entry to (1!6)- and (1!5)-aza-C-disaccharides featuring the pyrrolidine ring as the imino sugar
component is described via Wittig condensation of polyhydroxylated 2-formylpyrrolidines with galacto-
pyranose 6-phosphorane and ribofuranose 5-phosphorane, respectively. # 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: glycomimetics; azasugars; glycosidase inhibitors; Wittig reactions.
The application of the Wittig reaction1 in synthetic routes to complex molecules is greatly
favoured by the ready preparation of the relevant reagents, the aldehyde and phosphorous ylide.
Accordingly, the access to various formyl C-glycosides by a scalable preparative method
developed in our laboratory,2 prompted us to employ these sugar aldehydes in a new synthetic
approach to (1!6)-linked C-disaccharides via Wittig-type coupling to sugar phosphoranes.3
Work is now underway to obtain higher oligomers by iterative repetition of this coupling
reaction.4 A similar Wittig-based synthesis of C-disaccharides containing an azasugar component
(aza-C-disaccharides) is reported here. This work follows our recent extension to furanoses5 of
the thiazole-based aminohomologation protocol of aldehydes through their nitrones.6
Speci®cally, d-arabinose was transformed5 into the polyhydroxylated 2-formylpyrrolidine 1, a
formyl aza-C-glycoside (Scheme 1). In contrast to our previous observation,7 the aldehyde 1
turned out to be a stable compound when generated from the corresponding thiazole precursor
by some improvements of the unmasking protocol. Also the isomer 2 which was obtained from
d-ribose by the same aminohomologation protocol proved to be a suciently stable and
manipulatable product. Hence, with the aldehydes 1 and 2 in hand, we have foreseen their Wittig-
type coupling with sugar phosphoranes as an entry to (1!6)- and (1!5)-aza-C-disaccharides
featuring the polyhydroxylated pyrrolidine ring as the azasugar component. While azasugars are
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01005-4

6196
well-known inhibitors of oligosaccharide processing enzymes,8 there is current interest in the
synthesis of aza-C-glycoconjugates since these compounds are expected to be more potent than
the parent azasugars.9 Moreover, the con®gurational stability at the anomeric carbon of the
azasugar moiety should provide increased selectivity toward a speci®c glycosidase.10 Hence aza-
C-disaccharides with di€erent (1!x)-linkages have been prepared11 although very few are
genuine isosteres of O-disaccharides. Surprisingly, methods based on Wittig-type coupling have
not been reported.
Scheme 1. Aminohomologation: (a) BnNHOH; (b) 2-lithiothiazole; (c) Zn, Cu(OAc)2; (d) Tf2O; (e) TfOMe, then
NaBH4, then AgNO3/H2O
The polyhydroxylated 2-formylpyrrolidines 1 and 2 were prepared in 10 mmol scale from
d-arabinose and d-ribose, respectively, by some improvements of the aminohomologation
protocol.12 While 1 was puri®ed and stored at low temperature for some days without appreciable
decomposition, the isomer 2 was used as crude material within 1±2 hours after preparation. The
Wittig reaction of aldehydes 1 and 2 with 1.2 equiv. of the ylide generated in situ from the d-
galactopyranose phosphonium iodide13 3 occurred smoothly at ^30ꢀC in 2:1 THF:HMPA
(Scheme 2) to give, after 2 hours, the corresponding ole®ns14 4 and 6 in 64 and 42% isolated
yield, respectively15 (¯ash column chromatography, 5:1 cyclohexane:AcOEt). Although it was
scarcely relevant in the context of the present project, we noticed that the alkene 4 was formed as
a mixture of E- and Z-isomers in ca. 1:1 ratio by NMR analysis while 6 was present exclusively as
1
E-isomer (J6,7=15.6 Hz). The H NMR data also con®rmed the stereochemistry of the a-d-
galactopyranose moiety.16 This ®nding is in line with earlier observations3,4 showing the
conservation of the con®guration at C-5 in the galactose 6-phosphorane generated from 3. Based
on our previous work on C-disaccharide synthesis,3 the subsequent elaboration of the coupling
products 4 and 6 was almost routine. The reduction of the double bond was carried out at ®rst by
in situ-generated diimide from p-toluenesulfonhydrazide (PTSH). Then the resulting alkane was
subjected to the catalytic hydrogenation over Pd(OH)2 for debenzylation and to treatment with
Amberlite IR 120 for deacetonization. The (1!6) aza-C-disaccharides 5 and 7 were released from
the resin with aqueous HCl and puri®ed as hydrochlorides by column chromatography on
Sephadex LH20 (9:1 MeOH:H2O).14 Both compounds gave consistent MALDI-TOF mass
spectra. However, it is worth noting that some condensation products were also isolated (MS
analysis), very likely arising from intermolecular glycosidation reactions.
The above reaction sequences were followed in the synthesis of the (1!5)-linked aza-C-
disaccharides 10 and 12 using the ribofuranosyl phosphonium iodide 8 as starting material17
(Scheme 3). The Wittig coupling of the aldehydes 1 and crude 2 with the in situ generated ribose
5-phosphorane derived from 8 a€orded the corresponding alkenes 9 (62%, Z-isomer, J5,6=11.2
Hz) and 11 (32%, 5:1 E:Z mixture).14,15 The relatively low yield of 11 could not be improved by

6197
Scheme 2. Reagents and conditions: (a) TsNHNH2, AcONa, DME±H2O, 85ꢀC, 5 h; (b) H2, Pd(OH)2, 8 bar, AcOH,
rt, 12 h; (c) Amberlite IR 120, H2O, 70ꢀC, 2 h
the use of puri®ed aldehyde 2 and some changes of the reaction conditions, while a substantial
decomposition of 2 was observed in all cases. The transformations of 9 and 11 to the hydroxy free
®nal products 10 and 12 were carried out using the above three-step procedure involving the diimide
reduction of the double bond, the debenzylation by hydrogenolysis, and the deacetonization by
acid hydrolysis, followed by puri®cation of the hydrochlorides by Sephadex LH20.14 Also these
compounds were characterized through their MALDI-TOF mass spectra. Special care was taken
for the assignment of the structures of these compounds since the original d-ribo con®guration of
the phosphonium salt 8 was reported as not retained in Wittig reactions.17,18 Accordingly, the J3,4
Scheme 3. Reagents and conditions as in Scheme 2

6198
of 3.6 Hz in 9 and 11 con®rmed the presence of an a-l-lyxo furanose ring.19 As already
suggested,17 a rapid epimerization of the furanose ring of the ylide should take place through an
open-chain intermediate. On the other hand, the NMR analysis con®rmed that the con®guration
at the anomeric carbon of the azasugar moiety in both products 9 and 11 was identical to that of
the aldehyde precursors 1 and 2.
A Wittig-based route to aza-C-disaccharides containing a polyhydroxylated pyrrolidine ring
linked to a pyranose or furanose residue by an ethylene bridge has been described. The scope of
this approach should be extensible for the preparation of other compounds featuring a variety of
structural diversities in both carbohydrate moieties. Other formyl aza-C-glycosides as
intermediates in the synthesis of other pyrrolidine homoazasugar are available in our laboratory
via the aminohomologation route of furanoses.20
Acknowledgements
Financial support from MURST COFIN-98 (Italy) is gratefully acknowledged. We thank Mr.
Paolo Formaglio for assistance in the NMR analysis.
References
1. (a) Maryano€, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863. (b) Kelly, S. E. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Tokyo, 1991; Vol. 1, p. 729.
2. Dondoni, A; Scherrmann, M.-C. J. Org. Chem. 1994, 59, 6404.
3. Dondoni, A.; Zuurmond, H. M.; Boscarato, A. J. Org. Chem. 1997, 62, 8114.
4. Dondoni, A.; Kleban, M.; Zuurmond, H. M.; Marra, A. Tetrahedron Lett. 1998, 39, 7991.
5. Dondoni, A.; Perrone, D. Tetrahedron Lett. 1999, 40, 9375.
6. (a) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F. L.; Merino, P.; Tejero, T.; Bertolasi, V. Chem. Eur. J.
1995, 1, 505. (b) Dondoni, A.; Perrone, D. Aldrichimica Acta 1997, 30, 35. (c) Dondoni, A. Synthesis 1998, 1691.
7. It has to be noted that the N-methyl analogue of 1 prepared by Wong and co-workers was also used as crude
material without puri®cation. See: Wong, C.-H.; Provencher, L.; Porco Jr., J. A.; Jung, S.-H.; Wang, Y.-F.; Chen,
L.; Wang, R.; Steensma, D. H. J. Org. Chem. 1995, 60, 1492.
8. (a) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem. Res. 1993, 26, 82. (b) Iminosugars as Glycosidase
Inhibitors, Nojirimycin and Beyond; Stutz, A. E., Ed.; Wiley-VCH: Weinheim, 1998.
9. Legler, G. In Carbohydrate Mimics; Chapleur, Y., Ed.; Wiley-VCH, Weinheim, 1998; p. 463.
10. This issue has been recently addressed. See: Diaz Perez, V. M.; Garcia Moreno, M. I.; Ortiz Mellet, C.; Fuentes, J.;
Diaz Arribas, J. C.; Canada, F. J.; Garcia Fernandez, J. M. J. Org. Chem. 2000, 65, 136.
11. Anzeveno, P. B.; Creemer, L. J.; Daniel, J. K.; King, C.-H. R.; Liu, P. S. J. Org. Chem. 1989, 54, 2539. Baudat, A.;
Vogel, P. J. Org. Chem. 1997, 62, 6252. Johns, B. A.; Pan, Y. T.; Elbein, A. D.; Johnson, C. R. J. Am. Chem. Soc.
1997, 119, 4856. Leeuwenburgh, M. A.; Picasso, S.; Overkleeft, H. S.; van der Marel, G. A.; Vogel, P.; van Boom,
J. H. Eur. J. Org. Chem. 1999, 1185. Zhu, Y.-H.; Vogel P. Chem. Commun. 1999, 1873.
12. The quantitative conversion of the furanose into the N-benzylhydroxylamine±nitrone equilibrium mixture was
carried out by heating the sugar and N-benzylhydroxylamine in the absence of solvent at 110ꢀC for 30 min. No
dehydrating agents were required under these conditions. The one pot thiazole-to-formyl group conversion was
carried out using AgNO3 instead of HgCl2 in the ®nal step. The aldehydes 1 and 2 were puri®ed by ®ltration
through a short column of silica gel with 8:1 cyclohexane:AcOEt. However, while 1 was stable to this treatment,
compound 2 decomposed to a large extent. Compound 1: 1H NMR (CDCl3) 9.27 (d, 1H, J1,2=1.2 Hz, H-1), 7.40±
7.19 (m, 20H, 4 Ph), 4.58 and 4.50 (2 d, 2H, J=11.4 Hz, PhCH2O), 4.56 (s, 2H, PhCH2O), 4.46 and 4.34 (2 d, 2H,
J=11.5 Hz, PhCH2O), 4.26 and 3.70 (2 d, 2H, J=13.1 Hz, PhCH2N), 4.09 (dd, 1H, J2,3=J3,4=1.2 Hz, H-3), 4.07
(dd, 1H, J4,5=4.5 Hz, H-4), 3.90 (dd, 1H, J5,6a=7.7, J6a,6b=9.1 Hz, H-6a), 3.74 (dd, 1H, J5,6b=5.1 Hz, H-6b),
3.56 (ddd, 1H, H-5), 3.34 (dd, 1 H, H-2). Compound 2: 1H NMR (CDCl3) 9.03 (d, 1H, J1,2=3.3 Hz, H-1),

6199
7.42±7.19 (m, 20H, 4 Ph), 4.66 and 4.60 (2 d, 2H, J=12.5 Hz, PhCH2O), 4.60 and 4.54 (2 d, 2H, J=11.3 Hz,
PhCH2O), 4.53 (s, 2H, PhCH2O), 4.33 and 3.75 (2 d, 2H, J=13.2 Hz, PhCH2N), 4.01 (dd, 1H, J3,4=5.2, J4,5=6.6
Hz, H-4), 3.97±3.90 (m, 2 H, 2 H-6), 3.89 (dd, 1H, J2,3=2.2 Hz, H-3), 3.79 (ddd, 1H, J5,6a=3.0, J5,6b=6.4 Hz,
H-5), 3.52 (dd, 1H, H-2).
13. Secrist III, J. A.; Wu, S.-R. J. Org. Chem. 1979, 44, 1434.
14. Compound 4: 1H NMR (CDCl3), Z-isomer: 5.78 (dd, 1H, J=10.1, 11.1 Hz), 5.65 (dd, 1H, J=8.8, 11.1 Hz).
20
.
E-isomer: 5.94 (dd, 1H, J=5.9, 15.8 Hz), 5.80 (dd, 1H, J=8.5, 15.8 Hz). Compound 5 HCl: ‰ꢀŠD =+35.6 (c 0.3,
20
1
H2O). Compound 6: ‰ꢀŠD =^42.0 (c 0.7, CHCl3); H NMR (CDCl3) 5.76 (dd, 1H, J5,6=6.5, J6,7=15.6 Hz, H-6),
20
20
.
5.60 (dd, 1H, J7,8=8.8 Hz, H-7 Hz). Compound 7 HCl: ‰ꢀŠD =+3.2 (c 0.4, H2O). Compound 9: ‰ꢀŠD =^20.8 (c 1.1,
CHCl3); 1H NMR (C6D6) 6.12 (ddd, 1H, J4,5=8.7, J5,6=11.2, J5,7=0.9 Hz, H-5), 5.84 (ddd, 1H, J4,6=1.0,
20
1
.
J6,7=9.3 Hz, H-6). Compound 10 HCl: ‰ꢀŠD =+5.5 (c 0.3, H2O). Compound 11: H NMR (CDCl3); Z-isomer:
5.82 (dd, 1H, J4,5=8.8, J5,6=11.0 Hz, H-5), 5.62 (dd, 1H, J6,7=10.5 Hz, H-6); E-isomer: 5.87 (dd, 1H, J=7.3,
20
.
15.7 Hz), 5.66 (dd, 1H, J=8.4, 15.7 Hz). Compound 12 HCl: ‰ꢀŠD =^11.5 (c 0.2, H2O).
15. The yields of 6 and 11 were calculated with respect to the thiazole precursor since the aldehyde 2 was used as crude
material.
16. This was essentially based on the almost identical values of all coupling constants, particularly that between H-4
and H-5 in the phosphonium salt 3 (J4,5=2.0 Hz) and in the disaccharides (J4,5=1.8 Hz).
17. Secrist III, J. A.; Wu, S.-R. J. Org. Chem. 1977, 42, 4084.
18. Dondoni, A.; Kleban, M.; Marra, A. Tetrahedron Lett. 1997, 38, 7801.
19. Taniguchi, M.; Koga, K.; Yamada, S. Tetrahedron 1974, 30, 3547.
20. A full report is under preparation dealing with the synthesis of various pyrrolidine homoazasugars by the thiazole-
based aminohomologation route of di€erent furanoses.