Efficient synthesis from d-lyxonolactone of 2-acetamido-1,4-imino-1,2,4-trideoxy-l-arabinitol LABNAc, a potent pyrrolidine inhibitor of hexosaminidases

Article abstract of DOI:10.1016/j.tetlet.2007.04.041

The synthesis from d-lyxonolactone of 2-acetamido-1,4-imino-1,2,4-trideoxy-l-arabinitol LABNAc proceeded in an overall yield of 25%; the enantiomer, 2-acetamido-1,4-imino-1,2,4-trideoxy-d-arabinitol DABNAc, was prepared from l-lyxonolactone. LABNAc and N-

Full text of DOI:10.1016/j.tetlet.2007.04.041

Tetrahedron Letters 48 (2007) 4287–4291
Efficient synthesis from D-lyxonolactone of
2-acetamido-1,4-imino-1,2,4-trideoxy-L-arabinitol LABNAc,
a potent pyrrolidine inhibitor of hexosaminidases
J. S. Shane Rountree,a,b Terry D. Butters,a Mark R. Wormald,a Raymond A. Dwek,a
Naoki Asano,c Kyoko Ikeda,c Emma L. Evinson,d Robert J. Nashd and
George W. J. Fleetb,*
aOxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
bChemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
cDepartment of Biochemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa 9201181, Japan
dVASTox plc, Institute of Grassland and Environmental Research, Plas Gogerddan, Aberystwyth, Dyfed, Wales SY23 3EB, UK
Received 7 March 2007; revised 29 March 2007; accepted 5 April 2007
Available online 14 April 2007
Abstract—The synthesis from D-lyxonolactone of 2-acetamido-1,4-imino-1,2,4-trideoxy-L-arabinitol LABNAc proceeded in an
overall yield of 25%; the enantiomer, 2-acetamido-1,4-imino-1,2,4-trideoxy-D-arabinitol DABNAc, was prepared from L-lyxonolac-
tone. LABNAc and N-benzyl LABNAc are potent non-competitive inhibitors of D-hexosaminidase, whereas N-benzyl DABNAc
exhibits weak competitive inhibition of the enzyme; this provides further evidence in support of Asano’s hypothesis that while D-
imino sugar mimics inhibit D-glycohydrolases competitively, their L-enantiomers show non-competitive inhibition and in the case
of iminofuranoses L-enantiomers are usually more potent inhibitors.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Specific inhibition of individual D-hexosaminidases may
lead to new strategies for the treatment of many dis-
eases, including cancer,1 arteriosclerosis2 and some lyso-
somal storage diseases;3 such compounds also have
potential as antifungal agents4 and catalysts for biomass
degradation.5 Replacement of the oxygen by nitrogen in
a sugar gives a broadly based class of both synthetic and
naturally occurring glycosidase inhibitors.6 Thus,
replacement of the ring oxygen in glucose gives the nat-
ural product deoxynojirimycin 1, which is a powerful
glucosidase inhibitor;7 derivatives of 1 have been used
in the treatment of diabetes8 and Gaucher’s disease,9
and are antiviral compounds.10 Pyrrolidine imino sugar
2, which is the furanose analogue of glucose,11 is a much
weaker inhibitor of glucosidases than 1; similarly, galac-
tofuranose analogue 3 is a much weaker galactosidase
OH
HO
OH
HO
OH
HO
OH
CH2OH
HO
OH
CH2OH
N
HO
OH
OH
CH2OH
OH
CH2OH
N
N
N
N
H
CH2OH
H
H
H
H
1
2
3
4D DAB-1
4L LAB
OH
CH3CONH
OH
CH3CONH
OH
CH3CONH
OH
CH2OH
CH3CONH
OH
CH3CONH
OH
OH
OH
CH2OH
N
N
N
N
N
H
CH2OH
H
H
R
R
CH2OH
CH2OH
5
6
7
8D R=PhCH2 9D R=H
8L R=PhCH2 9L R=H
*
Corresponding author. E-mail: george.fleet@chem.ox.ac.uk
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.041

4288
J. S. Shane Rountree et al. / Tetrahedron Letters 48 (2007) 4287–4291
inhibitor than the pyranose analogue deoxygalactonojir-
imycin.12 In contrast, the naturally occurring13 pyrrol-
idine DAB-1 4D with the shorter side chain is a
powerful competitive inhibitor of D-glucosidases, and
also has potential for the treatment of late onset diabetes
since it also inhibits glycogen phosphorylase.14 The syn-
thetic enantiomer LAB 4L is a potent and highly specific
non-competitive inhibitor of glucosidases.15
Hydrogenation and acetylation of 19D afforded the re-
quired N-benzyl-8D and DABNAc 9D.
The preparation of LABNAc 9L from D-lyxonolactone
10D, obtained by oxygenation of an alkaline solution
of D-galactose,21 is detailed in Scheme 2. Treatment of
lactone 10D with benzaldehyde and aqueous hydrochlo-
ric acid gave the highly crystalline benzylidene acetal
11D22 in 90% yield. Esterification of the free hydroxyl
group in 11D with trifluoromethanesulfonic (triflic)
anhydride afforded lyxono-triflate 12D (89% yield)23
which on reaction with sodium azide in DMF for 1 h
gave inverted xylono-azide 13D24 in 92% yield. If the
reaction mixture was left longer, xylono-azide 13D equil-
ibrated to the more stable lyxono-azide 14D.25 Epimeric
azides 13D and 14D were easily distinguished by their
Piperidine analogue 5 of N-acetylglucosamine (NAG) is
a good inhibitor of many hexosaminidases.16 There are
several good D-hexosaminidase inhibitors which are
pyranose analogues of NAG containing a piperidine
ring.17 Both the iminofuranose analogue of glucose 618
and of galactose 719 are, however, relatively weak inhib-
itors of hexosaminidases. This Letter, reports the syn-
thesis and D-hexosaminidase inhibition of both the
enantiomers of 2-acetamido-1,4-imino-1,2,4-trideoxy-L-
arabinitol, DABNAc 9D and LABNAc 9L, and their
respective N-benzyl derivatives 8D and 8L.
1
13C and H NMR spectra; it was necessary to monitor
the reaction carefully since the epimerisation of 2-azido-
lactones to the more stable azide is a well established
phenomenon.26
The synthesis of DABNAc 9D from L-lyxonolactone
10L, readily available from D-ribose,20 is outlined in
Scheme 1. Protection of the 3- and 5-hydroxyls in 10L
by formation of a benzylidene acetal allowed the intro-
duction of an azide function with inversion of configura-
tion at C-2 to give 13L. Reduction of lactone 13L to the
corresponding diol and activation of the 1- and 4-hydro-
xyl groups gave L-lyxono-dimesylate 17L from which the
pyrrolidine ring could be formed by a double nucleo-
philic displacement using benzylamine with inversion
at C-4 to afford the D-arabino-pyrrolidine 19D. The
presence of azide in 19D as the precursor to the acetam-
ido group in the target compound 9D made the com-
pound non-polar and easy to purify and manipulate.
Reduction of azidolactone 13D with lithium borohy-
dride in THF afforded diol 15D (98% yield) which was
converted into dimesylate 16D by treatment with excess
methanesulfonyl chloride in dichloromethane in the
presence of triethylamine (81% yield). Reaction of di-
mesylate 16D with benzylamine in 1,4-dioxane at 95 ꢁC
gave only displacement of the primary mesylate to give
D-xylono-amino mesylate 17D in 75% yield. There was
no detectable amount of a product arising either from
further attack by benzylamine on the secondary mesy-
late or by intramolecular nucleophilic ring closure to a
pyrrolidine. Although aminomesylates rapidly close to
pyrrolidines in general, in this case the cyclisation would
lead to a trans-benzylidene acetal fused to the new pyr-
N3
OH
CH2OH
CH3CONH
OH
CH2OH
O
OMs
O
HOH2C
O
O
OMs
O
O
N
N
N3
O
O
N3
HO
OH
CH2Ph
R
Ph
Ph
8D R=PhCH2
9D R=H
13L
17L
10L
19D
Scheme 1.
OX
O
O
O
O
HOH2C
O
(iii)
O
O
(iv)
(i)
OX
N3
O
O
O
Ph
O
O
O
OX
O
N3
O
N3
O
HO
OH
Ph
Ph
Ph
10D
11D X=H
13D
14D
15D X=H
16D X=SO2CH3
(ii)
(v)
12D X=OSO2CF3
(vi)
OMs
XHN
OX
N3
OH
CH2OH
CH3CONH
OH
(vii)
(viii)
NHCH2Ph
O
CH2OX
CH2Ph
CH2OH
N
N
N
O
N3
CH2Ph
Ph
R
(x)
8L R=PhCH2
9L R=H
19L X=H
20L X=COCH3
18L
17D
(xi)
(ix)
Scheme 2. Reagents and conditions: (i) PhCHO, HCl, 90%; (ii) (CF3SO2)2O, pyridine, 89%; (iii) NaN3, DMF, 1 h, rt, 92%; (iv) LiBH4, THF, 98%;
(v) CH3SO2Cl, Et3N, CH2Cl2, 81%; (vi) PhCH2NH2, 1,4-dioxane, 75%; (vii) Amberlyst (H+), 1,4-dioxane, H2O, 89%; (viii) H2, Pd, C, THF, 99%; (ix)
Ac2O, pyridine, 75%; (x) MeONa, MeOH, 96%; (xi) H2, Pd black, 1,4-dioxane, H2O, 99%.

J. S. Shane Rountree et al. / Tetrahedron Letters 48 (2007) 4287–4291
4289
Table 1. Inhibition constant (Ki) and concentration necessary to inhibit 50% of b-N-acetyl-D-hexosaminidase activity (IC50) for pyrrolidine inhibitors
CH3CONH
OH
CH3CONH
OH
CH3CONH
OH
CH3CONH
OH
CH2OH
N
CH2OH
CH2Ph
CH2OH
CH2OH
CH2Ph
N
N
N
H
H
8L N-benzyl LABNAc
9L LABNAc
8D N-benzyl DABNAc
9D DABNAc
β-N-acetyl-D-
hexosaminidase
potent non-competitive inhibition
weaker competitive inhibition
Bovine kidney
IC50 (lM)
Ki (lM)
0.36
0.28
0.64
0.095
41.2
16.9
326
104
Jack bean
IC50 (lM)
Ki (lM)
5.2
3.4
3.4
1.9
446
ND
Weak
ND
Human placenta
IC50 (lM)
Ki (lM)
2.8
3.7
13
15
320
180
Weak
ND
rolidine five-membered ring. There are other examples
of the failure to close to such a strained bicyclic
system.27
Interestingly, N-benzyl DABNAc 8D weakly inhibited
human b-N-acetyl-D-hexosaminidase in a competitive
manner, with a Ki value of 180 lM, whereas LABNAc
and N-benzyl LABNAc were potent non-competitive
inhibitors of the enzyme, with Ki values of 15 and
3.7 lM, respectively. LABNAc 9L and N-benzyl LAB-
NAc 8L were non-competitive inhibitors for the Jack
bean enzyme, although in this case N-benzyl LABNAc
8L was not a stronger inhibitor of the enzyme; other-
wise, introduction of the benzyl group into the imino
group in LABNAc and DABNAc tended to increase
their inhibitory potential.
Deprotection of benzylidene acetal 17D using an acid
ion exchange resin in aqueous dioxane gave an open
chain aminomesylate which spontaneously cyclised in
89% yield to L-arabino-azide 18L28 resulting from inver-
sion at C-4 in the intramolecular nucleophilic displace-
ment; 18L is a relatively apolar compound and easy to
purify. Hydrogenation of azide 18L in THF in the
presence of a palladium on carbon catalyst gave the cor-
responding amine 19L (99% yield), which was peracy-
lated using acetic anhydride in pyridine to afford
triacetate 20L (75% yield). De-O-acylation of 20L, by
treatment with sodium methoxide in methanol, resulted
in ester exchange to give N-benzyl pyrrolidine 8L29 (96%
yield), which, on hydrogenation in aqueous dioxane in
the presence of palladium black, afforded LABNAc
9L30 in 99% yield. The structure of N-benzyl LABNAc
8L was firmly established by X-ray crystallographic
analysis.31 The overall yield of LABNAc 9L from D-lyxo-
nolactone 10D was 25% in 11 steps.
It has been recognised that D-imino sugar mimics inhibit
D-glycosidases competitively, their L-enantiomers show
non-competitive inhibition and in the case of iminofura-
noses L-enantiomers are usually more potent inhibitors
than D-enantiomers.32 The present Letter suggests that
this may be a more broadly based phenomenon.
In summary, efficient and convenient syntheses of the
enantiomeric pyrrolidine analogues of NAG 9L and
9D are described. Both N-benzyl LABNAc 8L and
LABNAc 9L are potent and highly specific inhibitors
of b-N-acetyl-D-hexosaminidases. Their modes of inhibi-
tion are non-competitive, whereas N-benzyl DABNAc
8D is a weak competitive inhibitor. Introduction of the
benzyl group into the imino group in LABNAc and
DABNAc tends to increase their inhibitory potential.
This work shows that pyrrolidine analogues of NAG
may be useful inhibitors of b-N-acetyl-D-hexosaminid-
ases; further studies on whole cell systems and on other
diastereomers of 9 will be reported in due course.
The inhibition of glycosidases by LABNAc 9L and
DABNAc 9D and their N-benzyl analogues 8L and 8D
was studied. No significant inhibition of any of the fol-
lowing glycosidases was found: a-D-glucosidase (from
yeast, rice, Bacillus stearothermophilus, rat intestinal
maltase or isomaltase), b-D-glucosidase (from almond
or human placenta), a-D-galactosidase (from green cof-
fee beans), b-D-galactosidase (from Jack bean or bovine
liver), a-L-fucosidase (bovine), b-D-xylosidase (Aspergil-
lus niger), naringinase (Penicillum decumbens) or amylo-
glucosidase (A. niger). None of the compounds had any
inhibitory effect on glycogen phosphorylase b (rabbit
muscle) or on a-N-acetyl-D-galactosaminidase (Charo-
nia lampas).
References and notes
1. (a) Woynarowska, B.; Wilkiel, H.; Sharma, M.; Carpen-
ter, N.; Fleet, G. W. J.; Bernacki, R. J. Anticancer Res.
1992, 12, 161–166; (b) Mohamad, S. B.; Nagasawa, H.;
Uto, Y.; Hori, H. Comp. Biochem. Physiol. A Mol. Integr.
Physiol 2002, 132, 1–8; (c) Reddi, A. L.; Sankaranaraya-
However, both N-benzyl LABNAc 8L and LABNAc 9L
were potent inhibitors of bovine kidney b-N-acetyl-D-
hexosaminidase with sub-micromolar Ki (Table 1).

4290
J. S. Shane Rountree et al. / Tetrahedron Letters 48 (2007) 4287–4291
nan, K.; Arulraj, H. S.; Devaraj, N.; Devaraj, H. Cancer
Lett. 2000, 158, 61–64.
Borodkin, V. S.; Schimpl, M.; Shepherd, S. M.; Shpiro, N.
A.; van Aalten, D. M. F. J. Am. Chem. Soc. 2006, 128,
16484–16485; (e) Tatsuta, K.; Miura, S.; Ohta, S.; Gunji,
H. J. Antibiot. 1995, 48, 286–288.
2. (a) Liu, J. J.; Numa, M. M. D.; Liu, H. T.; Huang, S. J.;
Sears, P.; Shikhman, A. R.; Wong, C. H. J. Org. Chem.
2004, 69, 6273–6283; (b) Liu, J. J.; Shikhman, A. R.; Lotz,
M. K.; Wong, C. H. Chem. Biol. 2001, 8, 701–711.
3. Tropak, M. B.; Reid, S. P.; Guiral, M.; Withers, S. G.;
Mahuran, D. J. Biol. Chem. 2004, 279, 13478–13487.
4. (a) Horsch, M.; Mayer, C.; Sennhauser, U.; Rast, D. M.
Pharmacol. Ther. 1997, 76, 187–218; (b) Horsch, M.;
Hoesch, L.; Fleet, G. W. J.; Rast, D. M. J. Enzyme Inhib.
1993, 7, 47–53; (c) Nagahashi, G.; Tu, S. I.; Fleet, G.;
Namgoong, S. K. Plant Physiol. 1990, 92, 413–418.
5. Kato, M.; Uno, T.; Hiratake, J.; Sakat, K. Bioorg. Med.
Chem. 2005, 13, 1563–1571.
6. (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. Phytochemistry 2001, 56, 265–295; (c)
Asano, N. Glycobiology 2003, 13, 93R–104R.
7. Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojir-
imycin and Beyond; Wiley-VCH: Weinheim, 1999.
8. Mitrakou, A.; Tountas, N.; Raptis, A. E.; Bauer, R. J.;
Schulz, H.; Raptis, S. A. Diabet. Med. 1998, 15, 657–660.
9. (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Glycobiology
2005, 15, R43–R52; (b) Elstein, D.; Hollak, C.; Aerts, J.
M. F. G.; van Weely, S.; Maas, M.; Cox, T. M.;
Lachmann, R. H.; Hrebicek, M.; Platt, F. M.; Butters,
T. D.; Dwek, R. A.; Zimran, A. J. Inherit. Metab. Dis.
2004, 27, 757–766.
18. Croucher, P. D.; Furneaux, R. H.; Lynch, G. P. Tetra-
hedron 1994, 50, 13299–13312.
19. Liessem, B.; Giannis, A.; Sandhoff, K.; Nieger, M.
Carbohydr. Res. 1993, 250, 19–30.
20. Batra, H.; Moriarty, R. M.; Penmasta, R.; Sharma, V.;
Stanciuc, G.; Staszewski, J. P.; Tuladhar, S. M.; Walsh, D.
A. Org. Process Res. Dev. 2006, 10, 484–486.
21. Humphlett, W. J. Carbohydr. Res 1967, 4, 157–164.
22. (a) Zinner, H.; Voigt, H.; Voigt, J. Carbohydr. Res. 1968,
7, 38–55; (b) Behling, J. R.; Campbell, A. L.; Babiak, K.
A.; Ng, J. S.; Medich, J.; Farid, P.; Fleet, G. W. J.
Tetrahedron 1993, 49, 3359–3368.
23. Extra care must be taken in the handling of triflate 12D
since a co-worker has experienced a strong allergic
response to this compound or its decomposition products.
24
24. Selected data for xylono-azide 13D: mp 119–121 ꢁC, ½aꢀD
+143.4 (c 0.99, CHCl3); mmax (NaCl) 2117 (N3), 1776
(C@O) cmꢁ1; dH (400.2 MHz, CDCl3): 4.20 (1H, a-dt, J5;5
0
13.9 Hz, J 1.9 Hz, H-5), 4.23 (1H, s, H-2), 4.46–4.51 (2H,
m, H-3, H-4), 4.62 (1H, a-d, J5 ;5 13.9 Hz, H-50), 5.54 (1H,
0
d, J 1.1 Hz, CHPh), 7.37–7.47 (5H, m, CH(Ar)); dC
(100.6 MHz, CDCl3): 63.2 (C-2), 66.0 (C-5), 73.1 (C-3),
75.6 (C-4), 99.5 (CHPh), 126.1, 128.4, 129.6 (CH(Ar)),
136.4 (C(Ar)), 171.1 (C-1).
25. Selected data for lyxono-azide 14D: mp 121–122 ꢁC
24
(acetone); ½aꢀD +37.1 (c 1.0, acetone); mmax (KBr): 2120
10. (a) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson,
S.; Namgoong, S. K.; Jacob, G. S.; Rademacher, T. W.
Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 9229–9233; (b)
Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L. E.;
Tyms, A. S.; Petursson, S.; Namgoong, S. K.; Ramsden,
N. G.; Smith, P. W.; Son, J. C.; Wilson, F. X.; Witty, D.
R.; Jacob, G. S.; Rademacher, T. W. FEBS Lett. 1988,
237, 128–132.
(N3), 1795 (C@O, lactone) cm1; dH (500 MHz, (CD3)2CO):
4.39 (1H, dd, H-50, J5 ;5 13.9 Hz, J5 ;4 2.0 Hz), 4.48 (1H, d,
0
0
0
H-5, J5;5 13.9 Hz), 4.58 (1H, d, H-2, J2,3 4.1 Hz), 4.64 (1H,
dd, H-4, J4,3 3.4 Hz, J4;5 2.0 Hz), 5.12 (1H, dd, H-3, J3,2
0
4.1 Hz, J3,4 3.1 Hz), 5.79 (1H, s, HCPh), 7.37–7.50 (5H, m,
CH(Ar)); dC ((CD3)2CO, 50.3 MHz): 66.8 (t, C-5), 62.8,
72.3, 75.7 (3 · d, C-2, C-3, C-4), 99.5 (CHPh), 126.9,
128.9, 129.8 (3 · d, CH(Ar)), 138.5 (s, C(Ar)), 172.8
(C@O).
11. Fleet, G. W. J.; Son, J. C. Tetrahedron 1988, 44, 2637–
2648.
26. (a) Fleet, G. W. J.; Bruce, I.; Girdhar, A.; Haraldsson, M.;
Peach, J. M.; Watkin, D. J. Tetrahedron 1990, 46, 19–32;
12. Legler, G.; Pohl, S. Carbohydr. Res. 1986, 155, 119–129.
13. (a) Nash, R. J.; Bell, E. A.; Williams, J. M. Phytochemistry
1985, 24, 1620; (b) Jones, D. W. C.; Nash, R. J.; Bell, E.
A.; Williams, J. M. Tetrahedron Lett. 1985, 26, 3127.
14. (a) Oikonomakos, N. G.; Tiraidis, C.; Leonidas, D. D.;
Zographos, S. E.; Kristiansen, M.; Jessen, C. U.; Nors-
kov-Lauritsen, L.; Agius, L. J. Med. Chem. 2006, 49,
5687–5701; (b) Henke, B. R.; Sparks, S. M. Mini-Rev.
Med. Chem. 2006, 6, 845–857.
15. (a) Scofield, A. M.; Fellows, L. E.; Nash, R. J.; Fleet, G.
W. J. Life Sci. 1986, 39, 645–651; (b) Behling, J. R.;
Campbell, A. L.; Babiak, K. A.; Ng, J. S.; Medich, J.;
Farid, P.; Fleet, G. W. J. Tetrahedron 1993, 49, 3359–3368;
(c) Fleet, G. W. J.; Smith, P. W. Tetrahedron 1986, 42,
5685–5691; (d) Fleet, G. W. J.; Nicholas, S. J.; Smith, P.
W.; Evans, S. V.; Fellows, L. E.; Nash, R. J. Tetrahedron
Lett. 1985, 26, 3127–3130.
16. (a) Fleet, G. W. J.; Smith, P. W.; Nash, R. J.; Fellows, L.
E.; Parekh, R. B.; Rademacher, T. W. Chem. Lett. 1986,
1051–1054; (b) Boshagen, H.; Heiker, F.; Schuller, A.
Carbohydr. Res. 1987, 164, 141–148; (c) Fleet, G. W. J.;
Fellows, L. E.; Smith, P. W. Tetrahedron 1987, 43, 979–
988.
17. (a) Knapp, S.; Vocadlo, D.; Gao, Z.; Kirk, B.; Lou, J.;
Withers, S. G. J. Am. Chem. Soc. 1996, 118, 6804–6805;
(b) Terinek, T.; Vasella, A. Helv. Chim. Acta 2005, 88, 10–
22; (c) van den Berg, R. J. B. N.; Donker-Koopman, W.;
van Boom, J. H.; Aerts, H. M. F. G.; Noort, D. Bioorg.
Med. Chem. 2004, 12, 891–902; (d) Dorfmueller, H. C.;
(b) Krulle, T. M.; Davis, B.; Ardron, H.; Long, D. D.;
¨
Hindle, N. A.; Smith, C.; Brown, D.; Lane, A. L.; Watkin,
D. J.; Marquess, D. G.; Fleet, G. W. J. J. Chem. Soc.,
Chem. Commun 1996, 1271–1272.
27. van Ameijde, J.; Horne, G.; Wormald, M. R.; Dwek, R.
A.; Nash, R. J.; Jones, P. W.; Evinson, E. L.; Fleet, G. W.
J. Tetrahedron: Asymmetry 2006, 17, 2702–2713.
28. Selected data for arabino-azide 18L: oil; ½aꢀ2D5 +97.3 (c 0.99,
CHCl3); mmax (NaCl) 3370 (OH), 2100 (N3) cmꢁ1; dH
(400.2 MHz, CDCl3): 2.46 (2H, s, 3-OH, 5-OH), 2.63 (1H,
0
ddd, J4;5 3.8 Hz, J4,3 5.7 Hz, J4,5 2.4 Hz, H-4), 2.82 (1H,
0
0
dd, J1;1 10.9 Hz, J1,2 6.6 Hz, H-1), 3.00 (1H, dd, J1 ,1
10.9 Hz, J1 ;2 2.5 Hz, H-10), 3.42 (1H, d, J 13.2 Hz,
0
NCH2Ph), 3.71–3.76 (2H, m, H-5, H-2), 3.78 (1H, dd,
J5 ;5 11.4 Hz, J5 ;4 3.8 Hz, H-50), 3.99 (1H, d, J 13.2 Hz,
NCH2Ph), 4.28 (1H, dd, J3,4 5.7 Hz, J3,2 3.4 Hz, H-3),
7.25–7.39 (5H, m, CH(Ar)); dC (100.6 MHz, CDCl3):
56.1 (C-1), 57.7 (NCH2Ph), 59.4 (C-5), 65.4 (C-2), 71.6
(C-4), 78.4 (C-3), 127.5, 128.5, 128.6 (CH(Ar)), 137.7
(C(Ar)).
0
0
29. Selected data for N-benzyl LABNAc 8L: mp 126–128 ꢁC;
22
½aꢀD +82.1 (c 0.96, MeOH); mmax (Ge) 3312 (OH), 1651
(C@O amide band I), 1551 (N–H amide band II) cmꢁ1; dH
(400.2 MHz, D2O): 1.82 (3H, s, COCH3), 2.49 (1H, a-dt,
0
J4,3 5.7 Hz, J 4.3 Hz, H-4), 2.55 (1H, dd, J1;1 11.0 Hz, J1,2
0
0
2.9 Hz, H-1), 2.76 (1H, dd, J1 ;1 11.0 Hz, J1 ;2 7.2 Hz, H-
10), 3.36 (1H, d, J 12.7 Hz, NCH2Ph), 3.59 (1H, dd, J5;5
0
0
0
12.0 Hz, J5,4 4.0 Hz, H-5), 3.64 (1H, dd, J5 ;5 12.0 Hz, J5 ;4

J. S. Shane Rountree et al. / Tetrahedron Letters 48 (2007) 4287–4291
4291
4.6 Hz, H-50), 3.82–3.94 (3H, m, H-3, H-2, NCH2Ph),
7.21–7.32 (5H, m, CH(Ar)); dC (100.6 MHz, D2O): 22.1
(NHCOCH3), 55.5 (C-2), 56.3 (C-1), 58.5 (NCH2Ph), 60.3
(C-5), 71.1 (C-4), 77.9 (C-3), 128.1, 128.9, 130.2 (CH(Ar)),
137.3 (C(Ar)), 174.2 (C@O).
dC (100.6 MHz, D2O): 22.2 (NHCOCH3), 48.3 (C-1), 57.5
(C-2), 61.4 (C-5), 64.7 (C-4), 77.1 (C-3), 174.7 (C@O).
31. Harding, C. C.; Rountree, J. S. S.; Watkin, D. J.; Cowley,
A. R.; Butters, T. D.; Wormald, M. R.; Dwek, R. A.;
Fleet, G W. J. Acta Cryst. 2005, E61, o1683–o1685.
32. (a) 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; (b) 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; (c) 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.
22
30. Selected data for LABNAc 9L: colourless oil; ½aꢀD +3.9 (c
0.765, H2O); mmax (Ge) 3284 (OH), 1652 (C@O amide
band I), 1558 (N–H amide band II) cmꢁ1; dH (400.2 MHz,
0
D2O): 1.87 (3H, s, COCH3), 2.62 (1H, dd, J1;1 12.0 Hz,
0
J1,2 6.3 Hz, H-1), 2.89 (1H, a-dt, J4;5 4.5 Hz, J 6.3 Hz, H-
4), 3.10 (1H, dd, J1 ;1 12.0 Hz, J1 ;2 7.5 Hz, H-10), 3.51 (1H,
0
0
0
0
dd, J5;5 11.7 Hz, J5,4 6.1 Hz, H-5), 3.60 (1H, dd, J5 ;5
11.7 Hz, J5 ;4 4.5 Hz, H-50), 3.75 (1H, a-t, J3,2 6.3 Hz, J3,4
0
0
6.3 Hz, H-3), 3.97 (1H, a-dt, J2;1 7.5 Hz, J 6.3 Hz, H-2);