Azetidine iminosugars from the cyclization of 3,5-Di- O -triflates of α-furanosides and of 2,4-Di- O -triflates of β-pyranosides derived from glucose

Article abstract of DOI:10.1021/ol300669v

Primary amines with either 3,5-di-O-ditriflates of α-furanosides or 2,4-di-O-triflates of β-pyranosides form bicyclic azetidines in high yield.

Full text of DOI:10.1021/ol300669v

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2142–2145
Azetidine Iminosugars from the
Cyclization of 3,5-Di-O-triflates of
R-Furanosides and of 2,4-Di-O-triflates of
β-Pyranosides Derived from Glucose
†
†
†,‡
†
ꢀ
´
Gabriel M. J. Lenagh-Snow, Noelia Araujo, Sarah F. Jenkinson, R. Fernando Martınez,
Yousuke Shimada,§ Chu-Yi Yu, Atsushi Kato,§ and George W. J. Fleet*,†,‡
Chemistry Research Laboratory, Department of Chemistry, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, U.K., Oxford Glycobiology Institute, University of
Oxford, South Parks Road, Oxford, OX1 3QU, U.K., Department of Hospital Pharmacy,
University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan, and Beijing National
Laboratory for Molecular Science, CAS Key Laboratory of Molecular Recognition and
Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
george.fleet@chem.ox.ac.uk
Received March 16, 2012
ABSTRACT
Primary amines with either 3,5-di-O-ditriflates of R-furanosides or 2,4-di-O-triflates of β-pyranosides form bicyclic azetidines in high yield.
Applications of azetidines1 include use in polymeric
materials2 and in a wide range of bioactive compounds.3
Natural and synthetic azetidine carboxylic acids4
are common proline substitutes and components of
nonproteinogenic amino acids and are being studied as a
new class of foldamers.5 Accordingly there is much current
(3) (a) Zhang, X.; Hufnagel, H.; Markotan, T.; Lanter, J.; Cai, C.;
Hou, C.; Singer, M.; Opas, E.; McKenney, S.; Crysler, C.; Johnson, D.;
Sui, Z. Bioorg. Med. Chem. Lett. 2011, 21, 5577–5582. (b) Sun, Y.; Gou,
S.; Yin, R.; Jiang, P. Eur. J. Med. Chem. 2011, 46, 5146–5153. (c) Smith,
G. S. T.; De Avila, M.; Paez, P M.; Spreuer, V.; Wills, M. K. B.; Jones,
N.; Boggs, J. M.; Harauz, G. J. Neurosci. Res. 2012, 90, 28–47. (d) Lu,
K.; Jiang, Y.; Chen, B.; Eldemenky, E. M.; Ma, G.; Packiarajan, M.;
Chandrasena, G.; White, A. D.; Jones, K. A.; Li, B.; Hong, S.-P. Bioorg.
Med. Chem. Lett. 2011, 21, 5310–5314. (e) Perassolo, M.; Veronica
Quevedo, C.; Maria Giulietti, A.; Rodriguez Talou, J. Plant Cell Tissue
Organ Culture 2011, 106, 153–159. (f) Quevedo, C. V.; Perassolo, M.;
Giulietti, A. M; Talou, J. R. Biotechnol. Lett. 2011, 34, 571–575.
† Chemistry Research Laboratory, Department of Chemistry, University of
Oxford.
‡ Oxford Glycobiology Institute, University of Oxford.
§ University of Toyama.
Chinese Academy of Sciences.
(1) (a) Bott, T. M.; West, F. G. Heterocycles 2012, 84, 223–264. (b)
Brando, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988–4035.
(2) Wang, S.-C.; Chen, P.-C.; Hwang, J.-Z.; Huang, C.-Y.; Yeh,
J.-T.; Chen, K.-N. J. Appl. Polym. Sci. 2012, 124, 175–181.
r
10.1021/ol300669v
Published on Web 04/05/2012
2012 American Chemical Society

Scheme 1. Strategy for the Synthesis of Azetidine 2,4-Dideoxy-2,4-iminohexitols from Glucose
interest in the different strategies for the synthesis of
azetidines.6
double displacements of ditriflates at C2 and C4, or at C3
and C5, of protected hexoses [Scheme 1]. The cis-2,4-di-O-
triflate pyranoside 2D derived from D-glucose with benzy-
lamine gave the bicyclic azetidine 1D in 80% yield as a key
intermediate in the synthesis of 3,5-dideoxy-3,5-imino-D-
altritol 5D.14 Inversion of configuration at C3 of D-glucose
toD-alloseallowedthe formation ofa ditriflate 3Din which
the C3 OH group is trans to the carbon side chain; reaction
of 3D with benzylamine afforded the cis-fused azetidine 4L
in 93% yield, as a precursor to 2,4-dideoxy-2,4-imino-L-
iditol 6L. The L-enantiomers of many iminosugars have
significant bioactivities compared to the corresponding
D-natural products.15 Accordingly, the enantiomers 5L and
6D were prepared by identical sequences from L-glucose,
readily available from D-glucoheptonolactone.16 The
amine cyclization of such sugar-derived ditriflates is likely
to provide an efficient general access to highly functiona-
lized homochiral azetidines. Preliminary studies on the
inhibition of glycosidases by 5 and 6 are described.
Five, six, and seven ring iminosugars7 as mimics of
monosaccharides are the most general class of inhibitors of
glycosidases and interact with many other enzymes and
receptors concerned with carbohydrate processing. In con-
trast there are very few examples of azetidine imino sugars;8
N-alkyl hydroxyazetidines have been designed as potent
transition state analogue inhibitors of purine nucleoside
phosphorylase with subnanomolar Ki.9 Azetidine iminosu-
gar analogues of pentoses have been found to be specific
inhibitors of nonmammalian glycosidases.10,11 DMDP, the
most common natural iminosugar, is a 2,5-dideoxy-2,5-
iminohexitol and is a bioactive mimic of fructose and
glucose.12 Reported examples of corresponding azetidine
analogues, 2,4-dideoxy-2,4-iminohexitols, are rare.13
This paper reports the syntheses of analogues in which
the azetidine ring was formed in excellent yield by amine
The β-pyranoside 12L, with only the C2 and C4 hydro-
xyl groups unprotected, was the key intermediate in the
synthesis of 2,4-dideoxy-2,4-imino-L-talitol 5L from di-
acetone-L-glucose 7L [Scheme 2]. Reaction of 7L with
benzyl bromide and sodium hydride in DMF gave the
benzyl ether 8L (88%). Hydrolysis with aqueous trifluoro-
acetic acid afforded the pyranose 9L (81%). Acetylation
with acetic anhydride in pyridine formed the tetraacetate
10Lβ (75%) with a small amount of the R-anomer 10Lr.
10L with hydrogen bromide in acetic acid, followed by
treatment of the resulting crude bromide with methanol
in the presence of silver carbonate, afforded the fully
(4) Franqois, C.; Gwilherm, E. Org. Prep. Procedure Int. 2006, 38,
427–465.
(5) Zukauskaite, A.; Mangelinckx, S.; Buinauskaite, V.; Sackus, A.;
De Kimpe, N. Amino Acids 2011, 41, 541–558.
(6) (a) Stankovic, S.; D’hooghe, M.; Tehrani, K. A.; De Kimpe, N.
Tetrahedron Lett. 2012, 53, 107–110. (b) Shimokawa, J.; Harada, T.;
Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2011, 133, 17634–
17637. (c) Bouche, L.; Reissig, H.-U. Pure Appl. Chem. 2012, 84, 23–36.
(d) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc.
2012, 134, 3–6. (e) Ye, L.; He, W.; Zhang, L. Angew. Chem., Int. Ed.
2011, 50, 3236–3239.
(7) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645–1680. (b) Watson, A. A.; Fleet,
G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochem. 2001, 56,
265–295.
(8) (a) Pandey, G.; Dumbre, S. G.; Khan, M. I.; Shababb, M.;
Puranik, V. G. Tetrahedron Lett. 2006, 47, 7923–7926. (b) Shrihari, P.;
Sanap, S. P.; Ghosh, S.; Jabgunde, A. M.; Pinjari, R.; V.; Gejji, S. P;
Singh, S.; Balu, A.; Chopadeb, B. A.; Dhavale, D. D. Org. Biomol.
Chem. 2010, 8, 3307–3315.
(9) Evans, G. B.; Furneaux, R. H.; Greatrex, B.; Murkin, A. S.;
Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2008, 51, 948–956.
€
€
(11) Kramer, B.; Franz, T.; Picasso, S.; Pruschek, P.; Jager, V. Synlett
1997, 295–297.
(12) Wrodnigg, T. M. Monatsh. Chem. 2002, 133, 393–426.
(13) Dekaris, V.; Reissig, H.-U. Synlett 2010, 42–46.
(14) The equivalence of 2,4-dideoxy-2,4-imino- and of 3,5-dideoxy-
3,5-imino-hexitols is shown in Scheme 1. IUPAC carbohydrate nomen-
clature names 5 as 3,5-dideoxy-3,5-imino-altritol and 6 as 2,4-dideoxy-
2,4-imino-iditol.
ꢀ
(10) Lenagh-Snow, G. M. J.; Araujo, N.; Jenkinson, S. F.; Rutherford,
C.; Nakagawa, S.; Kato, A.; Yu, C.-Y.; Weymouth-Wilson, A. C.; Fleet,
G. W. J. Org. Lett. 2011, 13, 5834–5837.
Org. Lett., Vol. 14, No. 8, 2012
2143

protected β-glucoside 11L (53%). Sodium methoxide in
methanol removed the acetate protecting groups in 11L to
allow subsequent protection of the primary alcohol by
treatment with trityl chloride in pyridine in the presence of
DMAP to afford the diol 12L (57%). Esterification of
the free hydroxyl groups in 12L with triflic anhydride in
dichloromethane in the presence of pyridine afforded
the ditriflate 2L (83%) which with benzylamine in aceto-
nitrile underwent a highly efficient cyclization to produce
the bicyclic azetidine 1L in 86% yield. All attempts to get
the R-anomer of 2L to undergo a similar cyclization in a
significant yield were unsuccessful; further studies are in
progress to determine the propensity of similar anomeric
pyranose ditriflates to form azetidines. Hydrolysis of 1L
with aqueous hydrochloric acid in dioxane removed both
the trityl and anomeric protecting groups; reduction of the
crude lactol with sodium borohydride in methanol and
subsequent acetylation of the resulting triol with acetic
anhydride in pyridine afforded the triacetate 13L (70%),
allowing easy purification. Removal of the acetates from
13L by sodium methoxide in methanol gave 14L (100%);
subsequent transfer hydrogenation with ammonium for-
mate in anhydrous methanol in the presence of 10%
palladium on charcoal removed both benzyl groups from
Scheme 2. Synthesis of Azetidines 5L and 5Da
14L to form the target azetidine 5L17 {100%, [R]D þ15.5
25
(c 0.49, H2O) for the hydrochloride salt} in an overall
25
a
yield of 8% from 7L. The enantiomer 5D {[R]D ꢀ13.9 (c
* = yield for enantiomers prepared from 7D.
0.44, H2O) for the hydrochloride salt} was prepared by a
similar procedure in 22% overall yield from diacetone-D-
glucose 7D.
of 16D with tert-butyldimethylsilyl chloride in DMF gave
the silyl ether17D (94%), whichonesterification ofthe free
hydroxyl groups at C3 and C5 formed the ditriflate 3D
(98%). Reaction of the ditriflate 3D with benzylamine in
the presence of diisopropylethylamine (DIPEA) gave the
fused azetidine 4L (93%). Treatment of 4L with aqueous
trifluoroacetic acid removed both the silyl and isopropyli-
dene protecting groups; reduction of the resulting lactol
with sodium borohydride in water afforded a triol 19L,
which was isolated as the nonpolar triacetate 18L [68%
overall yield from4L]. Removal of theestersfrom 18L with
sodium methoxide in methanol gave 19L (98%), which on
hydrogenolysis of the N-benzyl group by transfer hydro-
The synthesis of 2,4-dideoxy-2,4-imino-L-iditol 6L, an
epimer of 5L, via azetidine ring formation between C3 and
C5 [Scheme 3], required initial epimerization of C3 in
diacetone glucose 7D to the allose 15D.18 Selective removal
of the exocyclic acetonide in 15D by hydrolysis with
aqueous acetic acid afforded the triol 16D (81%). Reaction
(15) (a) D’Alonzo, D.; Guaragna, A.; Palumbo, G. Curr. Med. Chem.
2009, 16, 473–505. (b) Clinch, K.; Evans, G. B.; Fleet, G. W. J.;
Furneaux, R. H.; Johnson, S. W.; Lenz, D.; Mee, S.; Rands, P. R.;
Schramm, V. L.; Ringia, E. A. T.; Tyler, P. C. Org. Biomol. Chem. 2006,
4, 1131–1139. (c) Smith, S. S. Toxicol. Sci. 2009, 110, 4–30. (d) Rountree,
J. S. S.; Butters, T. D.; Wormald, M. R.; Boomkamp, S. D.; Dwek,
R. A.; Asano, N.; Ikeda, K.; Evinson, E. L.; Nash, R. J.; Fleet, G. W. J.
ChemMedChem 2009, 4, 378–392. (e) Yu, C.-Y.; Asano, N.; Ikeda, K.;
Wang, M.-X.; Butters, T. D.; Wormald, M. R.; Dwek, R. A.; Winters,
A. L.; Nash, R. J.; Fleet, G. W. J. Chem. Commun. 2004, 1936–1937. (f)
da Cruz, F. P.; Newberry, S.; Jenkinson, S. F.; Wormald, M. R.; Butters,
T. D.; Alonzi, D. S.; Nakagawa, S.; Becq, F.; Norez, C.; Nash, R. J.;
Kato, A.; Fleet, G. W. J. Tetrahedron Lett. 2011, 52, 219–223. (g) Asano,
N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.; Adachi, I.; Kato, I.;
Ouchi, H.; Takahata, H.; Fleet, G. W. J. Tetrahedron: Asymmetry 2005,
16, 223–229.
genation formed the iminoiditol 6L19 {[R]D ꢀ6.2 (c 0.5,
25
MeOH) for the hydrochloride salt} (100%). The overall
25
yield of 6L from 15D was 46%. The enantiomer 6D {[R]D
(19) Selected data for 3,5-dideoxy-3,5-imino-D-altritol 6L: mp
101ꢀ102 °C; δH (D2O, 400 MHz): 3.45ꢀ3.50 (1H, dd, H6, J6,5 6.3 Hz,
Jgem 11.9 Hz), 3.62ꢀ3.66 (1H, dd, H60, J6 ,5 3.5 Hz, Jgem 11.9 Hz),
0
(16) Weymouth-Wilson, A. C.; Clarkson, R.; Best, D.; Pino-
Gonzalez, M.-S.; Wilson, F. X.; Fleet, G. W. J. Tetrahedron Lett.
2009, 50, 6307–6310.
3.63ꢀ3.67 (1H, dd, H1, J1,2 6.3 Hz, Jgem 11.3 Hz), 3.82ꢀ3.87 (1H, dd,
H10, J1 ,2 7.0 Hz, Jgem 11.3 Hz), 3.84ꢀ3.88 (1H, dd, H4, J4,3 6.3 Hz, J4,5
0
0
8.6 Hz), 3.94ꢀ3.99 (1H, ddd, H5, J5,6 3.5 Hz, J5,6 6.3 Hz, J5,4 8.7 Hz),
(17) Selected data for a HCl salt of 3,5-dideoxy-3,5-imino-D-altritol
5D: δH (D2O, 500 MHz): 3.62ꢀ3.65 (1H, dd, H6, J6,5 5.1 Hz, Jgem 12.1
0
3.99ꢀ4.04 (1H, a-dt, H2, J2,3/J2,1 6.4 Hz, J2,1 7.0 Hz), 4.62ꢀ4.65 (1H,
a-t, H3, J3,2/J3,4 6.4 Hz); δC (D2O, 100 MHz): 60.3 (C4), 60.5 (C2), 61.0
(C1), 63.4 (C6), 68.0 (C3), 71.8 (C5). Selected data for HCl salt of 3,5-
dideoxy-3,5-imino-D-altritol 6 L: δH (D2O, 400 MHz): 3.56ꢀ3.60 (1H,
Hz), 3.68ꢀ3.71 (1H, dd, H60, J6 ,5 4.1 Hz, Jgem 12.1 Hz), 3.88ꢀ3.92 (1H,
0
dd, H1, J1,2 4.1 Hz, Jgem 13.3 Hz), 3.91ꢀ3.95 (1H, dd, H10, J1 ,2 4.8 Hz,
0
dd, H6, J6,5 5.2 Hz, Jgem 12.2 Hz), 3.68ꢀ3.72 (1H, dd, H60, J6 ,5 3.5 Hz,
0
Jgem 13.3 Hz), 4.06ꢀ4.09 (1H, a-dt, H5, J5,6 4.1 Hz, J5,6/J5,4 5.3 Hz),
0
4.30ꢀ4.32 (1H, dd, H4, J4,5 5.5 Hz, J4,3 7.2 Hz), 4.33ꢀ4.36 (1H, a-dt, H2,
Jgem 12.2 Hz), 3.95ꢀ4.00 (1H, dd, H1, J1,2 5.3 Hz, Jgem 12.7 Hz),
4.05ꢀ4.10 (1H, dd, H10, J1 ,2 7.2 Hz, Jgem 12.7 Hz), 4.28ꢀ4.32 (1H,
0
J2,1/J2,1 4.4 Hz, J2,3 7.2 Hz), 4.57ꢀ4.60 (1H, t, H3, J3,4/J3,2 7.2 Hz); δC
0
(D2O, 125 MHz): 58.4 (C1), 62.6 (C6), 64.9 (C3), 67.4, 67.6 (C2 and C4),
68.8 (C5).
0
ddd, H5, J5,6 3.5 Hz, J5,6 5.2 Hz, J5,4 8.1 Hz), 4.56ꢀ4.59 (1H, dd, H4, J4,3
6.7 Hz, J4,5 8.1 Hz), 4.63ꢀ4.67 (1H, m, H2), 4.79ꢀ4.82 (1H, a-t, H3, J3,2
/
(18) Johnson, D. D.; Widlanski, T. S. J. Org. Chem. 2003, 68, 5300–
5309.
J3,4 6.5 Hz); δC (D2O, 100 MHz): 57.2 (C1), 63.0 (C6), 64.0, 64.0 (C2 and
C4), 66.3 (C3), 67.4 (C5).
2144
Org. Lett., Vol. 14, No. 8, 2012

Scheme 3. Synthesis of Azetidines 6L and 6Da
a
* = yield for enantiomers prepared from 15L.
þ12.1 (c 0.5, MeOH) for the hydrochloride salt} was also
prepared from diacetone-L-allose 15L by a similar route in
an overall yield of 33%.
β-mannosidase (snail), R-L-rhamnosidase (P. decumbens),
R-L-fucosidase (bovinekidney), trehalase (porcine kidney),
and amyloglucosidases (A. niger, Rhizopus sp). The
N-benzyl-D-iditol 19D showed potent and specific inhibi-
tion of rice and rat intestinal maltase [IC50 27 and 71 μM,
respectively] whereas the parent D-iditol 6D showed no
inhibition. The imino-L-talitol 5L was a moderate inhibitor
of rice and rat intestinal maltase [IC50 481 and 176 μM,
respectively]. The imino-L-iditol 6L showed weak but
selective R-galactosidase inhibition [IC50 416 μM].
In summary, bicyclic azetidines may be formed by high
yielding cyclizations of ditriflates of both pyranosides and
furanosides. While this paper has illustrated the value of
this strategy in the synthesis of iminosugar azetidines, this
strategymay provide a general approach tothesynthesisof
enantiomerically pure highly functionalized azetidines
and, in particular, allow easy access to a new range of
azetidine carboxylic acids.
N-Alkylation of imino sugar mimics can affect their
biological properties significantly;20 the ring closure of
the ditriflate 3D proceeded in good yield with a number
of amines, allowing access to N-alkyl azetidines. Reaction
of the ditriflate 3D with methylamine in acetonitrile in the
presence of DIPEA formed the protected azetidine 20L
(90%); with butylamine under the same conditions 21L
was obtained (88%), illustrating the general efficiency of
the ring closure. Hydrolysis of 20L with aqueous trifluoro-
aceticacidfollowedbyreduction withsodium borohydride
gave the N-methyl azetidine 22L (47%); similar treatment
of 20L afforded the N-butyl analogue 23L (88%).
Inhibition by the azetidine iminosugars of the activity of
the following glycosidases was studied:21 R-glucosidases
(rice, yeast, rat intestinal maltase, A. niger), β-glucosidases
(almond, bovine liver), R-galactosidase (coffee beans),
β-galactosidase (bovine liver), R-mannosidase (Jack bean),
Acknowledgment. This work was supported by EPSRC
ꢀ
(G.L.S.), Junta de Extramadura (N.A.), Fundacion
Ramon Areces (R.F.M.), and a Grant-in-Aid for Scientific
(20) (a) Axamawaty, M. T. H.; Fleet, G. W. J.; Hannah, K. A.;
Namgoong, S. K.; Sinnott, M. L. Biochem. J. 1990, 266, 245–249. (b)
Rawlings, A. J.; Lomas, H.; Pilling, A. W.; Lee, M. J.-R.; Alonzi, D. S.;
Rountree, J. S. S.; Jenkinson, S. F.; Fleet, G. W. J.; Dwek, R. A.; Jones,
J. H.; Butters, T. D. ChemBioChem 2009, 10, 1101–1105.
ꢀ
Research (C) (No: 23590127) (A.K.) from the Japanese
Society for the Promotion of Science (JSPS).
(21) For details of assays, see: (a) Mercer, T. B.; Jenkinson, S. F.;
Nash, R. J.; Miyauchi, S.; Kato, A.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2009, 20, 2368–2373. (b) Best, D.; Wang, C.; Weymouth-
Wilson, A. C.; Clarkson, R. A.; Wilson, F. X.; Nash, R. J.; Miyauchi, S.;
Kato, A.; Fleet, G. W. J. Tetrahedron: Asymmetry 2010, 21, 311–319.
Tables of the glycosidase inhibition by the azetidines are shown in the
Supporting Information.
Supporting Information Available. Experimental proce-
dures and full spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
2145