A general approach to the synthesis of 1-deoxy-L-iminosugars

Article abstract of DOI:10.1021/ol7014847

A stereoselective procedure for the preparation of non-naturally occurring deoxy iminosugars belonging to L-series has been developed. The synthesis involves the construction of the key intermediate bicycle pyperidine 8, available in few steps by the coup

Full text of DOI:10.1021/ol7014847

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3473-3476
A General Approach to the Synthesis of
1-Deoxy- -iminosugars
L
Annalisa Guaragna,* Stefano D’Errico, Daniele D’Alonzo, Silvana Pedatella, and
Giovanni Palumbo
Dipartimento di Chimica Organica e Biochimica, UniVersita` di Napoli Federico II,
Via Cynthia, 4 I-80126 Napoli, Italy
guaragna@unina.it
Received June 21, 2007
ABSTRACT
A stereoselective procedure for the preparation of non-naturally occurring deoxy iminosugars belonging to
L
-series has been developed. The
synthesis involves the construction of the key intermediate bicycle pyperidine 8, available in few steps by the coupling of the heterocyclic
synthon 3 and the readily available Garner aldehyde 4.
Polyhydroxylated piperidines (commonly known as imino-
sugars or azasugars) represent sugar analogues with the
nitrogen atom in place of the ring oxygen of the correspond-
ing carbohydrate. Since their first discovery over 40 years
ago, iminosugars have gained a great deal of attention as
inhibitors of carbohydrate-processing enzymes glycosidases
and glycosyltransferases. As extensively described,1 their
inhibitory aptitude has been linked with their structural
resemblance to the glycone moiety of glycosides that interact
with such enzymes.
a result, R-glucosidase inhibitors 1-deoxynojirimycin (DNJ,
1) and N-butyl-1-deoxynojirimycin (NB-DNJ, Zavesca 2)
(Figure 1) have been shown to inhibit human immunodefi-
Figure 1. Bioactive iminosugars DNJ and NB-DNJ.
As alterations in biosynthesis and function of these
enzymes are implicated in a wide variety of diseases, the
significant inhibitory properties of iminosugars make them
excellent targets for medical intervention. Their prospective
therapeutical uses range from diabetes2 through cancer3 and
viral diseases4 to metabolic and neurological disorders.5 As
ciency virus (HIV) replication and HIV-mediated syncytium
formation in vitro.6 Moreover, NB-DNJ has been the first
iminosugar medicine to receive approval, in 2002 in the
European Union and in 2003 in the United States, for use in
patients with mild to moderate type 1 Gaucher disease.
The principal advances in total and stereoselective syn-
theses of such compounds have recently been reviewed.7 As
reported, most syntheses have focused attention on the
* To whom correspondence should be addressed. Phone: + 39 081 674
118. Fax: + 39 081 674 119.
(1) (a) Stu¨tz, A., Ed. Iminosugars as Glycosidase Inhibitors; Wiley-
VCH: Weinheim, Germany, 1999. (b) Lillehund, V. H.; Jensen, H. H.;
Liang, X.; Bols, M. Chem. ReV. 2002, 102, 515-553.
(2) Somsak, L.; Nagya, V.; Hadady, Z.; Docsa, T.; Gergely, P. Curr.
Pharm. Des. 2003, 9, 1177-1189.
(3) Weiss, M.; Hettmer, S.; Smith, P.; Ladish, S. Cancer Res. 2003, 63,
3654-3658.
(4) Greimel, P.; Spreitz, J.; Stu¨tz, A. E.; Wrodnigg, T. M. Curr. Topics
Med. Chem. 2003, 3, 513-523.
(5) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. ReV. 2000, 100,
4683-4696.
(6) Ficher, P. B.; Collin, M.; Karlsson, G. B.; Lames, W.; Butters, T.
D.; Davis, S. J.; Gordon, S.; Dwek, R. A.; Platt, F. M. J. Virol. 1995, 69,
5791-5797.
10.1021/ol7014847 CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/20/2007

preparation of iminosugars with D-configuration, whereas few
routes are available for the synthesis of their corresponding
L-analogues.8 This fact is evidently due to the larger
commercial availability of D-series sugars as starting materi-
als, as well as to the fact that glycosides belonging to D-series
are the natural substrates of almost all glycosidases. However,
it is worth recalling that iminosugars mimicking the sugar
moiety structure of the natural substrate are not always
inhibitors of the corresponding glycosidase. D-manno-DNJ
(DMJ) is known as a much better inhibitor of R-L-fucosidase
than R-D-mannosidase; on the other hand L-allo-DNJ is a
better inhibitor of R-D-mannosidase than D-DMJ.9 As recently
shown,10 an explanation of this behavior could be found
considering that D-enantiomers are competitive inhibitors of
D-glycosidases, whereas their L-enantiomers are noncompeti-
tive inhibitors of the same enzymes.
devoted to the preparation of several polyhydroxylated
compounds.12
The synthesis began with the coupling of the in situ
prepared C-3 lithiated carbanion of 3 with the Garner13
aldehyde 4 (Table 1) to afford a syn/anti diastereomeric
Table 1. Three-Carbon Homologation
solvent
catalyst (20%)
(anti/syn) dr
yield(%)
THF
THF
THF
Et2O
Et2O
Et2O
none
60:40
60:40
60:40
70:30
82:18
91:9
83
80
85
49
73
72
Ti(O-i-Pr)4
Cp2TiCl2
Cp2TiCl2
ZnBr2
In the context of our ongoing program directed toward
the achievement of a new synthetic methodology for the
preparation of polyhydroxylated molecules, we have devel-
oped a versatile strategy for the synthesis of non-naturally
occurring deoxy-iminopyranoses belonging to L-series, through
a non-carbohydrate based route.
none
mixture of alcohols 5. As highlighted in Table 1, the best
stereoselectivity was achieved by the use of Et2O without
catalyst, providing anti-5 in good stereoselectivity (91:9 dr).
Interestingly, the stereochemical outcome of the reaction
seemed to be mainly influenced by the nature of the solvent,14
whereas any significant stereoselective induction was not
observed in the presence of the catalysts.15
Scheme 1. Retrosynthetic Path
The secondary alcohol16 anti-5, obtained by the coupling
reaction, was separated from its diastereomer by flash
chromatography; the stereochemical assignment at the newly
generated C-4 was clearly deduced by X-ray analysis (Figure
2).
As outlined in Scheme 1, the synthesis involves the use
of an heterocyclic synthon, the 5,6-dihydro-1,4-dithiin-2-yl-
[(4-methoxybenzyl)oxy]methane11 (3), a reagent capable of
three-carbon homologation of electrophiles by the introduc-
tion of a fully protected allylic alcohol moiety, already
(7) For comprehensive reviews see: (a) Afarinkia, K.; Bahar, A.
Tetrahedron: Asymmetry 2005, 16, 1239-1287. (b) Pearson, M. S. M.;
Allaimat, M. M.; Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159-
2191. Carbohydrate-based routes to DNJ and congeners: (c) Asano, N.;
Oseki, K.; Kizu, H.; Matsui, K. J. Med. Chem. 1994, 37, 3701-3706. (d)
O’Brien, J. L.; Tosin, M.; Murphy, P. V. Org. Lett. 2001, 3, 3353-3356.
(e) Spreidz, J. S.; Stu¨tz, A. E.; Wrodnigg, T. M. Carbohydr. Res. 2002,
337, 183-191 and references cited therein. Non-carbohydrate based routes
to DNJ and congeners: (f) Haukaas, M. H.; O’Doherty, G. A. Org. Lett.
2001, 3, 401-404. (g) Ruiz, M.; Ojea, V.; Ruanova, T. M.; Quintela, J. M.
Tetrahedron: Asymmetry 2002, 13, 795-799. (h) Takahata, H.; Banba,
Y.; Sasatani, M.; Nemoto, H.; Kato, A.; Adachi, I. Tetrahedron 2004, 60,
8199-8205 and literature cited therein.
Figure 2. X-ray analysis of anti-5.
With the educt 5 in hand, our interest was focused on the
achievement of key intermediate 9 (Scheme 2). To this
purpose, we converted the alcohol 5 in its diacetate 6 by
deprotection of the oxazolidine ring and acetylation of the
(8) Meyers, A. I.; Andres, C. J.; Resek, J. E.; Woddall, C. C.;
McLaughlin, M. A.; Lee, P. H.; Price, D. A. Tetrahedron 1999, 55, 8931-
8952.
(11) Guaragna, A.; Palumbo, G.; Pedatella, S. In e-Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; John Wiley & Sons:
New York, 2007. In press.
(9) Kato, A.; Kato, N.; Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto,
T.; Banba, Y.; Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005,
48, 2036-2044.
(10) Asano, N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.; Adachi,
I.; Kato, I.; Ouchi, H.; Takahata, H.; Fleet, G. Tetrahedron: Asymmetry
2005, 16, 223-229.
(12) (a) Caputo, R.; Guaragna, A.; Palumbo, G.; Pedatella, S. J. Org.
Chem. 1997, 62, 9369-9371. (b) Caputo, R.; De Nisco, M.; Festa, P.;
Guaragna, A.; Palumbo, G.; Pedatella, S. J. Org. Chem. 2004, 69, 7033-
7037. (c) Guaragna, A.; Napolitano, C.; D’Alonzo, D.; Pedatella, S.;
Palumbo, G. Org. Lett. 2006, 8, 4863-4866.
(13) Garner, P.; Park, J. M. Org. Synth., Collected Vol. IX 1998, 300.
3474
Org. Lett., Vol. 9, No. 17, 2007

Scheme 2. Synthesis of the Key Intermediate 9
Scheme 3. Syn Dihydroxylation of 9
crude residue (86% overall yield). Removal of MPM group
by treatment of 6 with DDQ in a CH2Cl2/H2O (9:1) emulsion
gave the primary alcohol 7 with an excellent yield (95%).
Intramolecular cyclization was then carried out under mild
conditions by treatment of 7 with Ag2O/TsCl in THF at 40
°C (85%). Finally, removal of the dithioethylene bridge on
intermediate 8 was achieved by treatment with Raney-Ni in
ethanol at 0 °C for 2 h leading to the olefin 9. Moreover,
when the reaction was carried out with a Raney-Ni excess
in THF, at room temperature, the over-reduction product was
obtained with a satisfactory yield (83%), affording the 1,2,3-
trideoxy-L-iminosugar 10.
With the promising olefin 9 in hand our interest was
directed to the stereoselective double-bond dihydroxylation
(Scheme 3). Exposure of 9 to the common Upjohn conditions
(OsO4/NMO) followed by acetylation of the crude residue
yielded a fully separable mixture of the protected L-manno-
DNJ 11 and L-allo-DNJ 12 in low diastereomeric ratio
(6:4). Both diastereomers were deprotected by means of
refluxing aq 6 N HCl solution, obtaining deoxy-L-mannojiri-
mycin (13) and deoxy-L-allonojirimycin (14) in remarkable
yields (91% and 90%, respectively). Further attempts to
improve the stereoselectivity of dihydroxylation reaction (i.e.,
using the bidentate complex OsO4/TMEDA17 and the Sharp-
less catalysts18) showed no significant effects.19 The observed
low selectivity in the above dihydroxylation reactions might
be attributed to the relatively small size of the C-4 acetyl
group and thus both faces of the double bond were almost
equally hindered. As a matter of fact, the replacement of
the Ac groups of 9 with the much bigger TBDPS ethers (15,
88% overall yield, Scheme 3), afforded after dihydroxylation
of 15, under Upjohn conditions, the protected L-manno-DNJ
16 with a high stereoselectivity (97:3 dr). Then, treatment
with aq 6 N HCl allowed removal of all protective groups
to obtain deoxy-L-mannojirimycin (13) in 93% yield.
It is noteworthy to recall that the stereochemistry of
compounds 13 and 14 is consistent with X-ray analysis of
the anti-5 compound and with the spectroscopic data.
1
However, observing the coupling constant values in the H
NMR spectra (Scheme 4), it is evident that the N-Boc
Scheme 4. Preferred Conformations for Compounds 11, 12
(14) The solvent-dependent stereoselective effect should be related to
the nature of the organolithium intermediate: as already reported (see farther
on), a “nude” and more reactive ionic couple prevails in THF, while a less
reactive non-ionized species is formed in Et2O, driving the reaction towards
a better stereoselective outcome: (a) Seyferth, D.; King, R. B. Annual
SurVeys of Organometallic Chemistry, Vol. 1-3, Elsevier Publishing Co.:
Amsterdam, 1965-1967. (b) Maercker, A.; Roberts, J. D. J. Am Chem.
Soc. 1966, 88, 1742-1759.
(15) In all our experiments the reported syn stereoselection [Liang, X.;
Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2001, 2136-2157]
was never observed. Because of the chemical characteristics of compound
5, such discrepancy could be rationalized assuming that in the reaction
medium the catalyst does not complex Garner aldehyde, but it can be
sequestrated by the negatively-charged heterocyclic system, without induc-
tion of stereoselectivity.
(16) An alternative numbering reported on the carbon skeleton has been
employed to identify carbon atoms that will belong to the carbohydrate-
like ring (see Table 1).
1
compounds 11 and 12 do not conform to the expected C4
chair conformation, typical of L-sugars adopting a conforma-
3
tion close to S1.20
(17) Donohoe, T. J.; Blades, K.; Moore, P. R.; Waring, M. J.; Winter, J.
J. G.; Helliwell, M.; Newcombe, N. J.; Stemp, G. J. Org. Chem. 2002, 67,
7946-7956.
Org. Lett., Vol. 9, No. 17, 2007
3475

The above successes led us to consider the anti dihydroxy-
lation of the key olefin 9. Treatment of this latter with in
situ generated21 DMDO (oxone/trifluoroacetone) afforded
exclusively the anti-epoxide 17 in 90% yield (Scheme 5).
refluxing HClO4 gave the deoxy-L-altronojirimycin (18) in
94% yield.
In summary, a versatile pathway for the synthesis of
L-deoxyiminosugars belonging to L-series has been opened
up in this paper. Together with L-manno-, L-allo-and L-altro-
deoxyiminosugars 13, 14, and 18, whose synthesis has been
described, this path will be profitably employed for the
synthesis of all the epimers with galacto configuration,
simply applying the same procedure on the syn-5 diastere-
omer. Furthermore, the whole synthetic procedure so far
described, carried out from 3 and the ent-4 (prepared from
D-serine) enables the preparation of D-series iminosugars as
well.
Scheme 5. Anti Dihydroxylation of 9
Acknowledgment. This research has been supported by
1
a Regione Campania grant to A.G. (L.R. 5/2002). H and
13C NMR spectra and X-ray analysis were performed at
Centro Interdipartimentale di Metodologie Chimico-Fisiche
(CIMCF), Universita` di Napoli Federico II. Varian Inova
500 MHz instrument is property of Consorzio Interuniver-
sitario Nazionale La Chimica per l’Ambiente (INCA) and
was used in the frame of a project by INCA and M.I.U.R.
(L. 488/92, Cluster 11-A). We are grateful to Dr Umberto
Ciriello (ICI International Chemical Industry S.p.A.) for his
collaboration to this work. We also thank Prof. Angela Tuzi
(Dept. of Chemisty, University of Napoli) for X-ray analysis
of anti-5 compound.
Ring opening22 of the 2,3-anhydro derivative 17 along
with the removal of all protecting groups by means of
(18) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(19) Wu, X.-D.; Khim, S.-K.; Zhang, X.; Cederstrom, E. M.; Mariano,
P. S. J. Org. Chem. 1998, 63, 841-859.
(20) In the 1C4 chair form, a downward orientation is imposed on the
N-Boc substituent owing to the nature of the ring nitrogen atom, resulting
in a strong repulsive interaction with the nearly coplanar C-6 methylene
group. An upward movement of the ring nitrogen relieves such repulsion
leading to a 3S1 conformation. For similar results see: (a) Kilonda, A.;
Compernolle, F.; Hoornaert, G. J. J. Org. Chem. 1995, 60, 5820-5824.
(b) Kazmaier, U.; Grandel, R. Eur. J. Org. Chem. 1998, 1833-1840.
(21) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887-
3889.
Supporting Information Available: Experimental pro-
cedures, analytical data, X-ray crystallographyc data (cif file)
for anti-5, 1H and 13C NMR spectra of all the new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
(22) On the basis of H NMR coupling constant values we established
that also 17 essentially exists in a 3S1 conformation and that the formation
of trans-diaxial ring opening product 18 could be explained assuming that
the HClO4 first removes the N-Boc group, allowing the chair inversion from
1
3S1 to C4, and then leads to the epoxide cleavage.
OL7014847
3476
Org. Lett., Vol. 9, No. 17, 2007