3804
Z.-X. Zhang et al. / Tetrahedron Letters 52 (2011) 3802–3804
Figure 2. Single crystal X-ray structure of DNJÁHCl.
As depicted in Scheme 2, the synthesis commenced from
Acknowledgments
2,3,4,6-tetra-O-benzyl-D-glucopyranose 4 that could be easily
obtained from either glucose12 or sucrose13 on the basis of the lit-
erature precedents. Subsequent reduction of hemi-acetal 4 to diol
5 was conducted using NaBH4 as a reductant which, among many
other reductants screened, was found to be best in terms of reac-
tion yield and efficiency. Without isolation of the reduced diol,
direct regioslective pivolylation (PivCl/pyridine) at the primary
OH furnished the desired product 6 in 95% yield over two reaction
steps. Next, complete inversion of the C5 configuration of 6 was
effected by Mitsunobu reaction when treated with benzoic acid
in the presence of Ph3P and DEAD in toluene, affording the benzo-
ate 7 in 93% yield. Zemplén deacylation of 1,5-diacyl groups
followed by the mesylation using methanesulfonyl chloride in
presence of pyridine afforded 1,5-di-mesylate 9 in nearly quantita-
tive yield.
With the key electrophilic dimesylate 9 in hand, subsequent
cyclization reactions enroute to the final iminosugars were
conducted conveniently using various amines as neucleophiles,
furnishing the corresponding benzylated DNJ, Miglustat and
Miglitol when employing benzyamine, 1-butylamine, and
2-hydroxyethylamine, respectively. Such an easy-to-handle meth-
od obviously confers multiple advantages over the traditional
counterparts: (1) it provided an efficient access to various imino-
sugar analogs while allowing flexible and maximum modifications
of substitution patterns on the endocyclic nitrogen simply by
choosing different easily available amines as annulation compo-
nents; (2) the stereochemistry at C5 position could be unequivo-
cally secured by a simple double inversion mechanism, which is
usually problematic as to literature protocols; (3) it is readily appli-
cable to scale up of the synthesis due to the excellent overall yields.
Finally, hydrogenolysis of benzyl protecting groups by Pearlman’s
catalyst under hydrogen atmosphere cleanly afforded the target
DNJ, Miglustat and Miglitol, respectively, in excellent yields with
their respective spectroscopic data consistent with those reported
in literatures14 (Scheme 2).
This work was supported by the National Basic Research Pro-
gram of China (973 Program: No. 2007CB914403) and Natural Sci-
ence Foundation of China (No. 20802037).
Supplementary data
Supplementary data (experimental procedure, spectral data and
copies of 1H and 13C NMR spectra of all new compounds) associ-
ated with this article can be found, in the online version, at
References and notes
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The absolute configuration of 1ÁHCl salt was also further unam-
biguously confirmed by a single crystal X-ray analysis, from which
it can be clearly seen that C5 configuration retains as the glucose-
type, namely, C5–C6bondorientingasanequatorialone, furthercor-
roborating our designed double-inversion strategy for the exquisite
controlofthedesired stereochemistryduringthesynthesis(Fig. 2).15
In summary, we have developed a highly efficient and stereo-
specific access to prepare DNJ, Miglustat and Miglitol in short
reaction steps with the astonishing overall 50–60% yield. The
methodology developed here will bode well for its application on
the synthesis of relevant iminosugar analogs which are of
potentially biological significance.
14. (a) Takahat, H.; Banda, Y.; Sasatani, M.; Nemoto, H.; Kato, A.; Adachi, I.
Tetrahedron 2004, 60, 8199–8205; (b) Concia, A. L.; Lozano, C.; Castillo, J. A.;
Parella, T.; Joglar, J.; Clapés, P. Chem. Eur. J. 2009, 15, 3808–3816; (c) Wennekes,
T.; Meijer, A. J.; Groen, A. K.; Boot, R. G.; Groener, J. E.; van Eijk, M.; Ottenhoff,
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Aerts, J. M. J. Med. Chem. 2010, 53, 689–698.
15. The crystal structure has been deposited at the Cambridge Crystallographic
Data Centre and allocated the deposition number CCDC 799141.