Tandem Staudinger-azaWittig mediated ring expansion: Rapid access to new isofagomine-tetrahydroxyazepane hybrids

Article abstract of DOI:10.1039/b610377d

New seven-membered iminosugars with potent and selective inhibition towards glycosidases have been prepared as 1-N-iminosugar homologues via a tandem Staudinger-azaWittig mediated ring expansion. The Royal Society of Chemistry.

Full text of DOI:10.1039/b610377d

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Tandem Staudinger–azaWittig mediated ring expansion: rapid access to
new isofagomine-tetrahydroxyazepane hybrids{
Hongqing Li,{a Yongmin Zhang,a Pierre Vogel,b Pierre Sinay¨a and Yves Ble´riot*a
Received (in Cambridge, UK) 21st July 2006, Accepted 10th October 2006
First published as an Advance Article on the web 24th October 2006
DOI: 10.1039/b610377d
The potency of 1-N-iminosugars 2 and 3 and the conforma-
tional flexibility of azepane 1 prompted us to combine these
structures into a new seven-membered hybrid molecule (Chart 1).
Such iminosugar can be seen as a stable (relative to its
hemiaminal function) and flexible analogue of noeuromycin with a
defined stereochemistry for the C-2 hydroxyl group.
New seven-membered iminosugars with potent and selective
inhibition towards glycosidases have been prepared as 1-
N-iminosugar homologues via a tandem Staudinger–azaWittig
mediated ring expansion.
Glycosidases, believed to increase the rate of glycosidic bond
hydrolysis by a factor of 1017, making them among the most
proficient enzymes in nature,1 are involved in many aspects of
biochemistry and metabolism. The quest for strong and selective
inhibitors of this class of enzymes has been the subject of extensive
interest in the past three decades among chemists and biochemists2
and some iminosugar-based structures have displayed great
potential in the treatment of diabetes,3 HIV infection,4 viral
infections5 or cancer6 leading in some cases to therapeutics.7 To
date, a huge number of five- and six-membered iminosugars,
mimicking their parent sugar both in terms of hydroxyl pattern
and ring size have been synthesized and evaluated.8 Much less
efforts have been put into higher ring analogs. Paulsen9 was the
first to report polyhydroxylated seven-membered iminosugars such
as 1. Later on Depezay10 developed a straightforward synthesis of
this iminoalditol and Wong11 disclosed the strong inhibition
activity of this class of compounds on glycosidases.
The desired iminoalditol can be obtained by chemical
manipulation of an aldopyranose and starts with a 6-azido-6-
deoxy-sugar. Available methyl 6-azido-6-deoxy-2,3,4-tri-O-benzyl-
a-D-glucopyranoside 415 was converted to the corresponding lactol
5. Direct transformation under acidic conditions using literature
procedures was found sluggish and gave low yields in our hands.16
A more convenient acetolysis–deacetylation sequence was thus
applied to afford azidolactol 5 in good yield (90% yield over two
steps). The ring expansion step was then examined. A cyclisation
involving a Pd-mediated reductive amination of azidolactol 5 was
first applied. Such strategy has been successfully used for the
synthesis of tetrahydroxylated azepanes11 and for the protein
kinase C inhibitor balanol.17 Treatment of azidolactol 5 under
hydrogenation conditions (20% Pd(OH)2/C in methanol) in the
presence of triethylamine to minimize debenzylation followed by
reduction of the transient imine with sodium cyanoborohydride
led to the expected b-hydroxyazepane 6 (23%) along with more
polar compounds. A more efficient route was needed and a
tandem Staudinger/intramolecular aza-Wittig approach18 was
investigated. Azidolactol 5 was treated with triphenyl phosphine
in dry THF to yield the iminophosphorane adduct which reacted
with the aldehyde via an intramolecular azaWittig reaction to
afford the corresponding imine 8. This imine, as previously
observed by Wong11 and Fuentes,19 probably exists in equilibrium
with the hemiaminal 7 and the bicyclic anhydro derivative 9.
Subsequent reduction with sodium cyanoborohydride under acidic
conditions afforded the expected b-hydroxy azepane 6 in high yield
(Scheme 1).
In a program devoted to the exploration of conformational
flexibility in the field of glycosidase inhibitors, we have previously
reported the synthesis of nojirimycin and deoxynojirimycin ring
homologues,12 some of these compounds displaying fairly potent
and selective glycosidase inhibition. These results encouraged us to
apply this ring expansion to other famous glycosidase inhibitors.
In 1994, Bols et al. reported the synthesis of a new and very potent
b-glucosidase inhibitor coined isofagomine 2.13 This 1-N-imino
sugar, protonated at physiological pH, was designed to mimic the
carbocationic form of the oxycarbenium-like transition state in
which the positive charge would be located at the anomeric
carbon. The potency of this compound was further improved by
inserting a hydroxyl group at the C-2 position to afford
noeuromycin 3, a nanomolar b-glucosidase inhibitor.14
We can notice that compound 6 is a very useful building block
to desymmetrize the C-2 symmetric tetrahydroxyazepane 1 and
introduce diversity in this class of compounds.
Completion of the synthesis consisted in the homologation of
the free hydroxyl group in 6 via an oxidation–olefination–
hydroboration–oxidation sequence. Preliminary protection of the
aEcole Normale Supe´rieure, De´partement de Chimie, UMR 8642,
Universite´ Pierre et Marie Curie-Paris 6, 75005 Paris; Institut de
Chimie Mole´culaire (FR 2769), 24 rue Lhomond, 75231, Paris Cedex
05, France. E-mail: yves.bleriot@ens.fr
bLaboratoire de glycochimie et de synthe`se asyme´trique, Swiss Federal
Institute of Technology (EPFL) BCH, CH-1015, Lausanne-Dorigny,
Switzerland
{ Electronic supplementary information (ESI) available: Experimental and
characterisation data, including NMR spectra, for compounds 6, 10–16.
See DOI: 10.1039/b610377d
{ Present address: Laboratory of Natural and Biomimetic Drugs,
Guizhou University, Guiyang, 550025, China.
Chart 1
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Chem. Commun., 2007, 183–185 | 183

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Chart 2
very weak inhibitor of amyloglucosidases from Aspergillus niger
and Rhizopus mold and jack bean a-mannosidase (less than 50% of
inhibition at 1 mM concentration) and did not inhibit a-L-
fucosidase from bovine kidney, a-galactosidases from coffee beans
and E. coli, b-galactosidases from E. coli and Aspergillus oryzae,
a-glucosidases from yeast and rice, b-mannosidase from Helix
pomatia, b-xylosidase from Aspergillus niger, b-N-acetylglucosa-
minidase from jack bean and bovine kidney. Its diastereoisomer 16
is a rather potent and selective inhibitor of jack bean a-manno-
sidase (Ki = 42 mM, uncompetitive). Interestingly, two azepane-
based structures 17 and 18 designed to mimic isofagomine have
been previously reported by Mehta20 and Martin21, respectively
(Chart 2), and displayed only moderate inhibition on glycosidases,
thus emphasizing the importance of a very accurate hydroxyl
pattern to generate strong inhibition for this class of compounds.
Finally, iminocyclitol 15 and tetrahydroxyazepane 1 both
display a similar activity toward almond b-glucosidase with Ki
of 4 and 12 mM, respectively, but iminosugar 15 is much more
selective than azepane 111 towards this enzyme thus indicating that
desymmetrisation and substituent tuning at b position to the
nitrogen is of interest to obtain more potent and selective azepane-
based glycosidase inhibitors.
Scheme 1 Reagents and conditions: (a) Ac2O, H2SO4, CH2Cl2, 0 uC then
CH3ONa, CH3OH, 90% over two steps; (b) Pd(OH)2/C, Et3N, H2,
CH3OH; (c) PPh3, anhydrous THF; (d) NaBH3CN, 1 M HCl in CH3OH,
˚
4A MS, CH3OH, 23–87% over two steps.
free NH group as its benzyloxycarbonyl derivative 10 (93% yield)
to prevent nitrogen oxidation during the forthcoming step was
accomplished and subsequent PCC oxidation of the b-hydroxyl
group afforded the corresponding ketone 11 in 94% yield.
Subsequent Wittig olefination gave the desired exoalkene 12 in a
satisfactory 78% yield. Olefin 12 was then submitted to a
hydroboration–oxidation sequence (BH3, NaOH, H2O2) and
afforded a separable mixture of two hydroxymethyl derivatives
13 and 14 in a 3 : 2 ratio. Final hydrogenolysis yielded the target
iminosugar 15 along with its diastereoisomer 16 (Scheme 2).
Iminoalditols 15 and 16 have been assayed for their inhibitory
activities towards fourteen commercially available glycosidases.
Albeit weaker than the parent isofagomine 2 and noeuromycin 3,
isofagomine homologue 15 displays potent and selective inhibition
on almonds b-glucosidase (Ki = 4 mM, uncompetitive). It is also a
In conclusion, new seven-membered iminosugars have been
prepared as 1-N-iminosugar ring homologues via a short route
including a tandem Staudinger–azaWittig mediated ring expansion
as the key step. Albeit less potent than their piperidine counter-
parts, the inhibition data obtained with these flexible iminosugars
clearly demonstrate that a fine tuning of the substituents in
tetrahydroxylated azepanes can lead to improved selectivity and
new profile of inhibition for this class of compounds.
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Scheme 2 Reagents and conditions: (a) ZCl, KHCO3, AcOEt/H2O 1:1,
˚
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