Synthesis of 2-acetamido-1,2-dideoxy-d-galacto-nojirimycin [DGJNAc] from d-glucuronolactone: the first sub-micromolar inhibitor of α-N-acetylgalactosaminidases

Article abstract of DOI:10.1016/j.tetlet.2010.02.063

2-Acetamido-1,2-dideoxy-d-galacto-nojirimycin [DGJNAc], prepared in 20% overall yield from d-glucuronolactone, is the first potent competitive sub-micromolar inhibitor of α-N-acetyl-galactosaminidases (K_i 0.081 μM from chicken liver, K_i 0.136 μM from Charonia lampas). DGJNAc is a good competitive-whereas the enantiomer l-DGJNAc is a very weak but non-competitive-inhibitor of β-hexosaminidases.

Full text of DOI:10.1016/j.tetlet.2010.02.063

Tetrahedron Letters 51 (2010) 2222–2224
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2-acetamido-1,2-dideoxy-D-galacto-nojirimycin [DGJNAc] from
D-glucuronolactone: the first sub-micromolar inhibitor
of a-N-acetylgalactosaminidases
Daniel Best a, Phoom Chairatana a, Andreas F. G. Glawar a,b, Elizabeth Crabtree a,b, Terry D. Butters b,
Francis X. Wilson e, Chu-Yi Yu d, Wu-Bao Wang d, Yue-Mei Jia d, Isao Adachi c,
Atsushi Kato c, George W. J. Fleet a,
*
a Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
b Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
c Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
d CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
e Summit PLC, 91, Milton Park, Abingdon, Oxon OX14 4RY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Acetamido-1,2-dideoxy-
D
-galacto-nojirimycin [DGJNAc], prepared in 20% overall yield from
-N-acetyl-galactosaminidases
M from Charonia lampas). DGJNAc is a good competitive—
D-glucu-
Received 24 December 2009
Revised 2 February 2010
Accepted 12 February 2010
Available online 23 February 2010
ronolactone, is the first potent competitive sub-micromolar inhibitor of
(Ki 0.081 M from chicken liver, Ki 0.136
whereas the enantiomer
a
l
l
L
-DGJNAc is a very weak but non-competitive—inhibitor of b-hexosaminidases.
Ó 2010 Published by Elsevier Ltd.
Iminosugars—in which the ring pyranose or furanose oxygen has
been replaced by nitrogen—are the archetypes for interaction with
carbohydrate processing enzymes.1 However, among the myriad of
sugar mimics reported, there is not a single example of efficient inhi-
diseases such as Tay-Sachs and Sandhoff diseases,14 and of plant
regulation.15 The synthetic piperidine analogue of N-acetylglucosa-
mine DNJNAc 316 and its N-alkyl derivatives17 are potent inhibitors
of b-hexosaminidases. The natural product nagstatin 4,18 with a
galacto-configuration, is not reported to inhibit GalNAcases even
bition of
reports DGJNAc [2-acetamido-1,2-dideoxy-
1D as the first potent, specific and competitive inhibitor of GalNA-
a
-N-acetyl-galactosaminidases (GalNAcases). This Letter
D-galacto-nojirimycin]
though it is a
potent inhibitor of b-hexosaminidases.19 The
synthetic analogue with a gluco-configuration 520 together with
PUG derivative 621 and GlcNAc–thiazoline 722 are very potent
inhibitors of b-hexosaminidases. A rare example of a potent
pyrrolidine hexosaminidase inhibitor is LABNAc 8;23 the first pyrr-
olizidine b-hexosaminidase inhibitor, pochonicine 9 [or its enan-
tiomer], was isolated from a fungal strain Pochonia suchlasporia
var. suchlasporia TAMA 87 (Fig. 1).24 Some seven-membered ring
iminosugars also display potent inhibition.25
cases; D-glucuronolactone 2D, a well-established chiron for the syn-
thesis of many homochiral targets including amino acids2 and
iminosugars,3 is the starting material for an efficient synthesis of
DGJNAc1Dinanoverallyieldof 20%. The
nosugars have surprising biological activities compared to their
-natural products.4 The synthesis of
-DGJNAc 1L from the readily
available5
-glucuronolactone 2L is also reported. The only previous
L-enantiomers ofmanyimi-
D
L
L
synthesis of 1D starts from 1-deoxynojirimycin6 and a racemic mix-
ture of 1D and 1L has also been prepared;7 no investigations of the
glycosidase inhibitory properties of 1D have hitherto been reported.
The synthesis of DGJNAc 1D requires introduction of nitrogen at C5
of the glucuronolactone with inversion of configuration (Scheme 1),
epimerization of the hydroxygroup at C3 and formation of the piper-
idine ring by introduction of nitrogen between C6 and C2 (with
inversion of configuration).
In contrast to the diversity of structure of b-hexosaminidase
inhibitors, there are no compounds which show significant inhibi-
tion of GalNAcases. Studies on reversible binding to exo-GalNA-
cases may allow the design of chaperones for the treatment of
Schindler–Kanzaki disease.26 Inhibition of exo-GalNAcases pro-
vides a strategy for the treatment of cancer by the protection of
macrophage activating factor.27 endo-GalNAcases may have che-
motherapeutic potential in the modification of a number of
pathogens.28
Selective inhibition of b-hexosaminidases has potential in the
study of osteoarthritis,8 allergy,9 Alzheimer’s disease,10 O-GlcNA-
case inhibition,11 cancer metastasis,12 type II diabetes,13 genetic
For the synthesis of DJGNAc 1D from D-glucuronolactone 2D,
the acetonide 105 was esterified with trifluoromethanesulfonic
(triflic) anhydride in dichloromethane in the presence of pyridine
and the resulting crude triflate was treated with sodium azide in
* Corresponding author.
E-mail address: george.fleet@chem.ox.ac.uk (G.W.J. Fleet).
DMF to give the ido-azide 11, mp 112–114 °C; ½a D25
ꢀ
+261.4 (c 1.0,
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.02.063

D. Best et al. / Tetrahedron Letters 51 (2010) 2222–2224
2223
OH
4
3
OH
OH
O
O
HO
OH
3
AcHN
OH
HO
NHAc
AcHN
OH
6
O
O
5
2
6
5
HO
OH
1
O
O
N
H
CH2OH
1
HOH2C
N
H
N
H
CH2OH
OH
HO
2D
2L
1L
3
1D
Scheme 1. Strategy for the synthesis of DGJNAc 1 enantiomers – numbering of C in DGJNAc derived from that in glucuronolactone 2.
OH
N
OH
N
OH
OH
HO
OH
AcHN
OH
CH2OH
AcHN
N
OH
AcHN
N
OH
AcHN
N
OH
N
S
OH
HO
Me
N
CH2OH
CH2OH
N
H
CH2OH
N
H
CH2OH
N
H
AcHN
CH2OH
HO2C
HO2C
PhHN
O
O
4
5
6
7
8
9
Figure 1. Potent b-hexosaminidase inhibitors.
CHCl3) [lit.29 mp 114–116 °C, ½a 2D0
ꢀ
+243 (c 1.1, CHC13)], in 99% yield
(Scheme 2). Direct conversion of the azidolactone 11 by a number
16 (97%); reaction of 16 with triflic anhydride in dichloromethane
in the presence of pyridine gave the ditriflate 17 which, with ben-
of hydrides to the diol 12 gave only low yields; such
a-azidolac-
zylamine in THF, gave the bicyclic pyrrolidine 18 as an oil, ½a D25
ꢀ
tones are extremely sensitive to base and commonly a two step
reduction is necessary with initial reduction to the lactol. Accord-
ingly DIBALH reduction of the azidolactone 11 in dichloromethane
gave the corresponding lactol which was further reduced by so-
dium borohydride in methanol to afford the diol 12, mp 120–
+22.8 (c 1.11, CHCl3), as the a-anomer only in an overall yield of
61%. Formation of a piperidine ring by cyclization of a ditriflate
was thus efficient; examples of successful cyclizations of a ditri-
flate, such as the formation of a pyrrolidine,30 are very rare.
Acetolysis of the furanoside 18 with boron trifluoride diethyl
etherate in acetic anhydride gave a 4:1 mixture of the epimers
19 in 93% yield. The OMe group in 19 was reductively removed
by sequential treatment with DIBALH in dichloromethane, fol-
lowed by sodium borohydride in methanol; acetylation of the
resulting diol allowed easy isolation of the diacetate 20 as an oil,
122 °C, ½a 2D5
ꢁ69.6 (c 0.94, CHCl3), in 72% yield. Selective protection
ꢀ
of the primary alcohol in 12 by reaction with tert-butyldimethylsi-
lyl (TBDMS) chloride gave the corresponding TBDMS ether 13 as an
oil, ½a 2D5
ꢁ12.7 (c 1.1, CHCl3) in 99% yield; the overall yield of 13
ꢀ
from glucuronolactone 2D was 72% on a multigram scale and with-
out any need for chromatographic purification until the final stage.
The synthesis of DGJNAc 1D required inversion and subsequent
protection of the remaining unprotected C3 OH in the silyl ether 13.
Oxidation of 13 with pyridinium chlorochromate in dichlorometh-
ane in the presence of molecular sieves afforded the corresponding
ketone, which on reduction from the least hindered face of the car-
½
a 2D5
+79.8 (c 0.43, CHCl3), in 83% overall yield from 19. Rapid
reduction of the azide in 20 by zinc powder in the presence of cop-
per(II) sulfate in acetic acid–acetic anhydride–THF31 with concur-
rent acylation of the corresponding amine gave the crystalline
ꢀ
triacetate 21, mp 112–114 °C, ½a D25
ꢀ
+26.2 (c 1.1, Me2CO) in 79%
yield. Selective removal of the O-acetate protecting groups by
treatment of 21 with catalytic sodium methoxide in methanol, fol-
lowed by hydrogenolysis of the benzyl groups by palladium (10%
on carbon) in 1,4-dioxane/aqueous hydrochloric acid gave, after
purification by ion exchange chromatography, DGJNAc 1D,32 mp
bonyl gave the inverted alcohol 14, oil, ½a D25
ꢀ
+74.9 (c 0.94, CHCl3), in
79% yield. Treatment of 14 with benzyl bromide and sodium hy-
dride in DMF formed the fully protected benzyl ether 15, oil, ½a D25
ꢀ
+101.5 (c 0.56, CHCl3) in 97% yield. Both the acetonide and silyl pro-
tecting groups in 15 were removed by treatment with HCl in meth-
150–154 °C, ½a 2D5
ꢀ
+41.9 (c 0.67, H2O) [lit.6 oil, ½a D20
ꢀ
+37 (c 1, MeOH)],
anol to give a 5:1
a/b mixture of anomers of the methyl furanoside
in 98% yield. Unlike many iminosugars, the free base DGJNAc is
O
O
OH
OR
OBn
CH2OR
O
O
O
O
RO
MeO
(ii)
(i)
(vi)
(iv)
O
O
CH2OR
N3
CH2O[Si]
N3
O
O
O
O
O
O
O
O
O
OH
N3
N3
14 R = H
16 R = H
12 R = H
(v)
(vii)
(iii)
11
10
13 R = SiMe2tBu
15 R = Bn
17 R = SO2CF3
[Si] = SiMe2tBu
(viii)
N3
N
OH
OAc
OAc
OAc
AcHN
OH
CH2OH
AcHN
OBn
CH2OAc
N3
OBn
N3
OBn
OAc
OMe
BnO
(xii)
(x)
(xi)
(ix)
OAc
O
Bn
N
H
N
N
N
Bn
Bn
Bn
MeO
1D
21
20
19
18
Scheme 2. Reagents and conditions: (i) (CF3SO2)2O, CH2Cl2, pyridine; then NaN3, DMF, 99%; (ii) DIBALH, CH2Cl2, ; then NaBH4, MeOH, 72%; (iii) tBuMe2SiCl, pyridine, 99% [72%
from 10]; (iv) PCC, CH2Cl2, molecular sieves; then NaBH4, EtOH, H2O, 79%; (v) PhCH2Br, NaH, DMF, 97%; (vi) MeOH, HCl, 97%; (vii) (CF3SO2)2O, CH2Cl2, pyridine; (viii)
PhCH2NH2, THF, 61% from 16; (ix) Et2OꢂBF3, Ac2O, 93%; (x) DIBALH, CH2Cl2; then NaBH4, MeOH; then Ac2O, pyridine, 83%; (xi) Zn, CuSO4 (aq), THF/AcOH/Ac2O, 79%; (xii)
MeONa, MeOH; then H2, Pd (10% on C), HCl, 1,4-dioxane, H2O, 98% [20% overall yield from 10].

2224
D. Best et al. / Tetrahedron Letters 51 (2010) 2222–2224
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readily crystallized; the overall yield of DJNAc 1D from
D
-glucuron-
olactone acetonide 10 was 20%. The enantiomer
L-DGJNAc 1L, mp
152–156 °C, ½a 2D5
ꢀ
ꢁ46.6 (c 0.73, H2O), was prepared by an identical
procedure from
L-glucuronolactone 2L.
DGJNAc 1D was a highly potent competitive inhibitor of GalNA-
cases (Ki 0.081 M from chicken liver, Ki 0.136 M from Charonia
lampas), and a good but much less potent competitive inhibitor
l
l
of b-hexosaminidases (IC50 1.8
l
M from Jack bean, IC50 4.2
M from human placenta, IC50
-DGJNAc 1L, showed no inhi-
-N-acetylgalactosaminidases but was a very weak but
non-competitive inhibitor of b-hexosaminidases [Ki 1100 M—
compared with Ki 2.2 M for DGJNAc 1D—from human placenta].
This result was in accord with Asano’s hypothesis33 that
-enanti-
omers show non-competitive inhibition whereas -iminosugars
usually are competitive inhibitors. DGJNAc 1D showed modest
inhibition of coffee bean -galactosidase (IC50 64 M), whereas
-DGJNAc 1L showed no inhibition of this enzyme. Both enantio-
lM
from bovine kidney, IC50 8.3
l
2.2
lM from HL-60). The enantiomer L
bition of
a
l
l
L
D
a
l
L
mers of DGJNAc 1 were screened as inhibitors of a number of other
glycosidases and neither enantiomer showed any significant inhi-
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bition [less than 50% inhibition at 1000
(rice, yeast), b-glucosidases (almond, bovine liver), b-galactosidase
(bovine liver), -mannosidase (Jack bean), b-mannosidase (snail),
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lM] against a-glucosidases
a
a-L
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D
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tive—whereas L-DGJNAc 1L is a very weak non-competitive—inhib-
itor of b-hexosaminidases. It is likely that ready access to DGJNAc
1D as a potent and specific inhibitor of GalNAcases will allow use-
ful investigation of a number of diseases.
Acknowledgements
Support from a Nuffield Foundation Undergraduate Research
Bursary [to P.C.] and Summit plc is gratefully acknowledged.
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32. Selected data for DGJNAc 1D: HRMS (ESI +ve): C8H16N2NaO4 found 227.1001;
(M+Na+) requires 227.1002; +41.9 (c 0.67, H2O); mp 150–154 °C; vmax (thin
film, Ge): 3287 (br s, OH/NH), 1637 (s, amide I), 1561 (s, amide II); dH (D2O,
400 MHz): 2.00 (3H, s, Me), 2.37 (1H, dd, H1a Jgem 12.9, J1a,2 11.6), 2.76 (1H, dt,
H5 J5,4 1.3, J5,6a = J5,6b 6.6), 3.08 (1H, dd, H1b Jgem 12.9, J1b,2 5.1), 3.58 (1H, dd, H3
J3,2 10.6, J3,4 3.0), 3.61 (1H, dd, H6a Jgem 11.1, J6a,5 6.3), 3.65 (1H, dd, H6b Jgem
11.1, J6b,5 6.6), 3.96 (1H, dt, H2 J2,1a 11.1, J2,1b 5.1, J2,3 11.1), 4.01 (1H, dd, H4 J4,3
3.0, J4,5 1.4); dC (D2O, 100 MHz): 22.7 (Me), 47.7 (C1), 49.1 (C2), 59.4 (C5), 61.9
(C6), 68.9 (C4), 73.2 (C3), 175.2 (COMe); LRMS (ESI +ve): 205 (77%, M+H+), 431
(100%, 2 M+Na+).
33. (a) Kato, A.; Kato, N.; Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto, T.; Banba,
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Asano, N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.; Adachi, I.; Kato, I.; Ouchi,
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