Homochiral carbon branched piperidines from carbon branched sugar lactones: 4-C-methyl-deoxyfuconojirimycin (DFJ) and its enantiomer-removal of glycosidase inhibition

Article abstract of DOI:10.1016/j.tetasy.2007.02.001

The value of readily available 2-C-methyl aldonic acids in short syntheses of carbon branched piperidines containing quaternary centers is demonstrated. The effect of the introduction of a 4-C-methyl group into piperidine imino sugar inhibitors of l-fucosidases and d-galactosidases is reported.

Full text of DOI:10.1016/j.tetasy.2007.02.001

Tetrahedron: Asymmetry 18 (2007) 500–512
Homochiral carbon branched piperidines from carbon branched
sugar lactones: 4-C-methyl-deoxyfuconojirimycin (DFJ)
and its enantiomer—removal of glycosidase inhibition
David J. Hotchkiss,a Atsushi Kato,b Barbara Odell,a
Timothy D. W. Claridgea and George W. J. Fleeta,*
aChemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
bDepartment of Pharmacy, Toyama University Hospital, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Received 12 January 2007; accepted 1 February 2007
Available online 27 February 2007
Abstract—The value of readily available 2-C-methyl aldonic acids in short syntheses of carbon branched piperidines containing quater-
nary centers is demonstrated. The effect of the introduction of a 4-C-methyl group into piperidine imino sugar inhibitors of L-fucosidases
and D-galactosidases is reported.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
quaternary centre from branched sugar lactones available
by environmentally friendly one pot procedures from aldo-
hexoses. 4-C-Methyl-deoxyfuconojirimycin (DFJ) 1L2and
its C-5 epimer 2D are formed by reduction of imine 3D
obtained from 2-C-methyl-D-lyxonolactone 4D; 4D is
prepared and isolated in 11% yield from D-galactose
(Scheme 1).3 Enantiomers 1D and 2L can be similarly
Although carbohydrate scaffolds are amongst the most di-
verse set of chirons available,1 the isomerisation of aldoses
to the 2-C-methyl aldonic acids [saccharinic acids] provides
a rare set of carbon branched sugars. Herein we report the
easy synthesis of piperidines bearing a carbon branch at a
OH
OH
OH
N
Me
OH
Me
OH
Me
OH
OH OH
O
HOH2C
HO
HO
HO
O
Me
CHO
HOH2C
N
H
Me
N
H
Me
Me
OH OH
HO OH
D-galactose
OH OH
2D
4D
1L
3D
OH
OH
OH
N
O
HOH2C
Me
OH
Me
OH
Me
OH
O
Me
HO
HO
HO
CHO
HOH2C
HO OH
N
H
Me
N
H
Me
Me
OH OH
D-glucose
1D
2L
3L
5D
Scheme 1.
*
Corresponding author. Tel.: +44 1865 277386; fax: +44 1865 277378; e-mail: george.fleet@chem.ox.ac.uk
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.02.001

D. J. Hotchkiss et al. / Tetrahedron: Asymmetry 18 (2007) 500–512
501
prepared from imine 3L, synthesised from 2-C-methyl-D-
ribonolactone 5D; the tandem Amadori and calcium
hydroxide rearrangements on D-glucose make 5D available
on a large scale.4 The effect of the substitution of a hydro-
gen at C-4 by a methyl group on the ability of piperidine
sugar mimics to inhibit glycosidases is reported.
ferases.18 Thus substitution by carbon at C-1 or C-5 of the
imino sugar does not substantially affect the ability of such
piperidines to inhibit a-fucosidases; as long as the absolute
stereochemistry of the secondary hydroxyl groups is the
same as that in L-fucose the structure provides significant
inhibition. No study on the effects of substitution at any
of the hydroxyl groups on fucosidase inhibition or on other
fucose related processes has been reported; the synthesis of
4-C-methyl-DFJ 1L with an equatorial methyl group at
C-4 and of other related structures is described.
Naturally occurring and synthetic polyhydroxylated piperi-
dines, analogues of carbohydrates in which the oxygen of
the pyranose ring is replaced by nitrogen, constitute a fam-
ily of efficient glycosidase inhibitors.5 The piperidine DFJ
6L, a synthetic analogue of L-fucose,6 is a potent inhibitor
of many a-fucosidases,7 with a Ki typically in the nano-
molar range.8 A N-alkyl derivative of DFJ 6L has antiviral
properties9 and has been used for the purification of an a-
fucosidase.10 N-Alkylation of imino sugar mimics can
affect their biological properties significantly.11 The natural
The piperidine analogue of D-galactose is deoxy-
galactonojirimyin (DGJ) 10, which is a nanomolar
a-D-galactosidase inhibitor (Fig. 2).19 Homo-DGJ 11 is a
potent but more specific D-galactosidase inhibitor.20
6-Deoxy-DGJ 6D [the enantiomer of DFJ 6L] still inhibits
a-galactosidases but with a Ki that is micromolar rather
than nanomolar.21 Some N-alkylated derivatives of 6D
have antiviral activity. The N-nonyl derivative of 6D dra-
matically reduced the amount of hepatitis B virus produced
by tissue cultures under conditions where cell viability
is not affected;22 the corresponding N-oxanonyl deriva-
tive blocked the protein p7 ion channels of hepatitis C
virus.23
product deoxymannojirimycin (DMJ)
7 is generally
regarded as a mannose mimic, even though it is a more
powerful inhibitor of a-L-fucosidases than of a-D-man-
nosidases;12 DMJ 7 is related to DFJ 6L by the removal
of the equatorial methyl group at C-5 and the introduction
of an equatorial hydroxymethyl group at C-1.
Homologues of the azasugars by the introduction of a
hydroxymethyl group occur in many plants;13 their biolog-
ical properties14 have caused much synthetic interest.15
The addition of an axial hydroxymethyl group to C-1 of
DFJ 6L gives a-homo-DFJ 8, which is a natural product16
and a potent a-fucosidase inhibitor (Fig. 1). The introduc-
tion of an equatorial hydroxymethyl to C-1 of DFJ 6L- or
of an equatorial methyl group to C-1 of DMJ 7- gives b-
homo-DFJ 9 (or a-methyl-DMJ 9), which is also a specific
and potent a-fucosidase inhibitor.17 These compounds
have also allowed the design of inhibitors of fucosyl trans-
Herein we report the synthesis of the 4-C-methyl analogue
1D of 6-deoxy-DGJ 6D and related analogues; the addition
of an equatorial methyl group at C-4 of 6-deoxy-DGJ 6D
removes all glycosidase inhibition. However, some of the
chemotherapeutic properties of imino sugars do not rely
on glycosidase inhibition for their mode of action.24 Thus
Zavesca,25 the N-butyl analogue of deoxynojirimycin
DNJ 12, is used for the treatment of Gaucher’s disease
although it is a mimic of ceramide rather than glucose.26
The mechanism of long term male contraception by
OH
OH
OH
OH
OH
Me
OH
OH
Me
HO
OH
Me
OH
Me
HO
OH
HO
HO
HO
N
H
HOH2C
N
H
HOH2C
N
H
HOH2C
N
H
N
H
Me
β-homo-DFJ or
α-methyl-DMJ
α-homo-DFJ
DMJ
4-C-methyl-DFJ
DFJ
Me
Me
HOH2C
Me
Me
Me
HO
HO
HO
HO
HO
HO
HO
HO
NH
OH
NH
OH
NH
OH
NH
OH
NH
OH
HO
HO
HOH2C
HOH2C
1L
6L
7
8
9
Figure 1. Piperidine analogues as a-L-fucosidase inhibitors.
OH
OH
OH
OH
OH
Me
OH
OH
Me
OH
CH2OH
OH
CH2OH
OH
HO
HO
HO
HO
HO
N
H
Me
N
H
N
H
HOH2C
N
H
N
CH2OH
Bu
1D
6D
10
11
12
Figure 2. Piperidine analogues as D-galactose mimics.

502
D. J. Hotchkiss et al. / Tetrahedron: Asymmetry 18 (2007) 500–512
N-butyl DNJ 12 is not correlated with glucosidase inhibi-
tion.27 The efficacy of imino sugars as chaperones for
protein folding may not depend on their glycosidase
inhibition.28
by treatment with azide to give lactone 14 (89% yield),
which with methyl lithium gave lactols 15 (97% yield).
Hydrogenation of 15 caused reduction of the azide to imine
16 [as an isolated intermediate], which on further reduction
afforded the ketal 17 (83% yield). Quantitative removal of
the isopropylidene protecting group in 17 by aqueous tri-
fluoroacetic acid gave DFJ 6L in an overall yield of 72%
from 13. A similar sequence on the enantiomer of 13 gave
6-deoxy-DGJ 6D;21 this route has been performed on a
multi-kilogram scale.30
2. Results and discussion
2.1. Synthesis of 4-C-methyl piperidines from the 2-C-methyl
branched lactones 4D and 5D
For the synthesis of the L-fucopyranose mimics 4-C-
methyl-DFJ 1L and D-altro-epimer 2D and related piperi-
dines, 2-C-methyl-D-lyxonolactone 4D31 was used as the
starting material (Scheme 3).
The strategy used for the C-4 branched piperidines is the
same as that used in the short and efficient synthesis of
DFJ 6L from D-lyxonolactone, as shown in Scheme 2;29
the only protecting group in the syntheses in Scheme 2 of
6L and in Schemes 3 and 4 of all the 4-C-methyl branched
piperidines is a single isopropylidene group.
Thus the branched lyxonolactone 4D was treated with ace-
tone in the presence of copper sulfate and sulfuric acid to
afford acetonide 18D in 99% yield. It is noteworthy that
this protection is far more efficient than protection of
The protected lactone 13 was converted by esterification
with trifluoromethanesulfonic (triflic) anhydride followed
OH
OH
Me
O
O
O
O
O
HOH2C
N3H2C
N3H2C
OH
Me
O
O
O
O
HO
HO
HO
O
O
O
O
O
O
N
Me
N
Me
N
H
H
6L
15
13
14
16
17
Scheme 2. Synthesis of the a-fucosidase inhibitor DFJ 6L.
O
O
OH
Me
Me
O
HOH2C
XOH2C
(i)
O
N3H2C
O
Me
(iv)
N3H2C
O
Me
O
Me
O
O
HO OH
O
O
O
O
(iii)
18D X=H
19D X=SO2CF3
4D
20D
21D
(ii)
(v)
Bu = CH3(CH2)3
OH
OH
O
O
OH
Me
Me
OH
Me
Me
O
Me
Me
O
Me
Me
HO
HO
HO
HO
(vi)
N
H
(vii)
N
N
X
N
Bu
22D
23L X=H
1L
25L
(viii)
(vi)
24L X=Bu
(vi)
OH
OH
O
OH
OH
Me
Me
OH
Me
Me
O
Me
Me
HO
HO
HO
OH
Me
Me
(vi)
HO
N
H
N
N
X
N
Bu
2D
26D X=H
3D
28D
(viii)
(vi)
27D X=Bu
Scheme 3. Reagents and conditions: (i) Me2CO, CuSO4, concd H2SO4; (ii) (CF3SO2)2O, pyridine, CH2Cl2; (iii) NaN3, DMF; (iv) MeLi, THF; (v) H2, 10%
Pd–C, MeOH; (vi) CF3COOH, H2O; (vii) H2, PtO2, dioxane–H2O; (viii) H2, MeCH2CH2CHO, Pd(OH)2, dioxane–H2O, THF.

D. J. Hotchkiss et al. / Tetrahedron: Asymmetry 18 (2007) 500–512
503
O
O
O
O
XOH2C
HOH2C
(i)
N3H2C
XOH2C
O
Me
O
Me
O
Me
O
Me
(iii)
O
O
O
O
HO OH
O
O
(v)
18L X=H
19L X=SO2CF3
5D
29 X=H
30 X=SO2CH3
20L
(iv)
(ii)
(vi)
OH
Me
Me
O
OH
O
O
O
N3H2C
OH
Me
Me
O
Me
Me
(vii)
HO
HO
HO
(viii)
Me
O
O
N
X
(ix)
N
X
Me
N
22L
23D X=H
1D X=H
21L
(x)
(viii)
(viii)
24D X=Bu
25D X=Bu
(viii)
OH
OH
Bu = CH3(CH2)3
O
OH
HO
O
HO
OH
Me
Me
HO
Me
Me
Me
N
X
Me
N
X
N
2L X=H
26L X=H
3L
(x)
(viii)
28L X=Bu
27L X=Bu
Scheme 4. Reagents and conditions: (i) Me2CO, CuSO4, concd H2SO4; (ii) MeSO2Cl, pyridine, DMAP; (iii) KOH, dioxane–H2O; then dil aqueous HCl;
(iv) (CF3SO2)2O, pyridine, CH2Cl2; (v) NaN3, DMF; (vi) MeLi, THF; (vii) H2, 10% Pd–C, MeOH; (viii) CF3COOH, H2O; (ix) H2, PtO2, dioxane–H2O;
(x) H2, MeCH2CH2CHO, Pd(OH)2, dioxane–H2O, THF.
unbranched D-lyxonolactone; in that case a significant
amount of the 3,5-ketal—as well as the 2,3-ketal 13—was
formed. Esterification of the C-5 alcohol with triflic anhy-
dride in dichloromethane gave crystalline triflate 19D in
quantitative yield and subsequent reaction with sodium
azide in DMF afforded azide 20D in 91% yield. Treatment
of azidolactone 20D with methyl lithium in THF gave lac-
tols 21D in 97% yield. Hydrogenation of 21D in the pres-
ence of 10% palladium on carbon in methanol gave the
corresponding amine, which cyclised to crystalline imine
22D in quantitative yield; the overall yield of 22D from
2-C-methyl lactone 4D was 87% with every intermediate
crystallising readily.
of ketals 23L and 26D in yields of 41% and 56%, respec-
tively. There is little diastereoselectivity in the reduction
of the imine, indicating that the isopropylidene has much
the same steric hindrance as is caused by the methyl group
in 22D; this is in contrast to the hydrogenation of 16 where
the reduction is completely stereoselective. Epimeric
amines 23L and 26D can be separated cleanly by chroma-
tography. Hydrolysis of 23L by aqueous trifluoroacetic
acid removed the isopropylidene protecting group to afford
4-C-methyl-DFJ 1L in 97%; similar treatment of 26D affor-
ded C-5 epimer 2D (100%).
NOESY experiments were used to establish the configura-
tion at C-5 of the epimeric imino sugars 1L and 2D (Fig. 3).
In 4-C-methyl-DFJ 1L, NOE enhancements were observed
between H-3 and H-5, H-10 and Me-40; enhancements were
also observed between H-5 and H-10 and Me-40. These
observations were consistent with H-10, H-3 and H-5 all
occupying axial positions (Fig. 3a). The diaxial couplings
between H-2 and H-3 of 9.5 Hz and between H-2 and H-
10 of 11.2 Hz were consistent with the chair conformation
of a sugar (Table 1); as expected the axial-equatorial cou-
pling between H-2 and H-1 was only 5.4 Hz. Conversely,
in imino sugar 2D, NOE enhancements were observed be-
tween H-3 and Me-6, H-10 and Me-40, whilst enhancements
were only observed between H-5 and Me-6 and Me-40.
These observations were consistent with H-10, H-3 and
Me-6 all occupying axial positions and H-5 being equato-
rial (Fig. 3b). The diaxial couplings between H-2 and H-3
Under the hydrogenation conditions with palladium as the
catalyst, imine 22D did not undergo further reduction; this
is in contrast to the synthesis of DFJ 6L in Scheme 2, where
imine 16 underwent complete and stereoselective hydro-
genation to 17. Imine 22D, also much more stable under
acidic conditions than 16, with aqueous trifluoroacetic acid
gave imine 3D, in quantitative yield; 3D is a piperidine ana-
logue of the pyrrolidine imine nectrisine, a potent inhibitor
of a-glucosidases32 with anti-viral properties.33 The methyl
group at the quaternary centre in 3D added considerable
stability to the imine function, presumably since an
imine–enamine equilibration is impossible.
Hydrogenation of imine 22D was successfully achieved
using platinum oxide in aqueous dioxane to give a mixture

504
D. J. Hotchkiss et al. / Tetrahedron: Asymmetry 18 (2007) 500–512
group is a well established procedure.34 Treatment of lac-
H2
H1
tone 5D with acetone in the presence of acid gave acetonide
29 in 100% yield. Mesylation of the free hydroxyl group in
29 with methanesulfonyl chloride in pyridine in the pres-
ence of N,N-dimethylaminopyridine (DMAP) gave the cor-
responding mesylate 30 (100% yield). Treatment of 30 with
potassium hydroxide in aqueous dioxane, followed by acid
work-up, caused sequential ring opening of the lactone,
formation of an epoxide intermediate and ring closure with
inversion of configuration at C-4 of the sugar to give L-lyx-
onolactone 18L in 91% overall yield. The overall yield of
18L from D-ribonolactone 29 was 91%.
OH
NH
Me6
HO
HO
H1'
Me4'
H3
H5
Figure 3a. 4-C-Methyl-DFJ 1L.
Table 1. Proton J-couplings for imino sugars 1L and 2D
J-Values (Hz)
With L-acetonide 18L an identical sequence of reactions
[Scheme 4] to those reported above for D-acetonide 18D
[Scheme 3] gave the target galactose mimics. Thus triflation
of 18L gave 19L (96%), which with azide gave 20L (92%).
Addition of methyl lithium to azidolactone 20L afforded
lactols 21L (100%), which on palladium catalysed hydro-
genation gave imine 22L (98%). The overall yield of the
protected key imine intermediate 22L from 2-C-methyl-D-
ribonolactone 5D was 78%.
Multiplicity
Proton couplings for 1L
H-1–H-2
H-10–H-2
H-10–H-1
H-3–H-2
H-5–Me-6
5.4
11.2
12.9
9.5
dd
dd
dd
d
6.6
q
Proton couplings for 2D
H-1–H-2
5.2
9.4
13.8
8.2
dd
dd
dd
d
H-10–H-2
H-10–H-1
H-3–H-2
Hydrolysis of 22L gave piperidine nectrisine analogue 3L
(91%), whereas hydrogenation of 22L in the presence of
platinum oxide (Adams’ catalyst) formed the easily sepa-
rated saturated amines 23D (51%) and 26L (46%). Hydro-
lysis of 23D gave 6-deoxy-4-C-methyl-DGJ 1D (100%) and
of 26L gave the epimeric L-iminoaltritol 2L (100%). The N-
butyl derivatives were also prepared. Reductive amination
of 23D afforded protected amine 24D (72%), which was
hydrolysed to the N-butyl deoxy-DGJ derivative 25D
(80%). Similarly 26L gave 27L (88%) and subsequent
hydrolysis formed N-butyl L-iminoaltritol 28L (85%).
H-5–Me-6
7.3
q
H2
H1
OH
NH
H5
HO
HO
H1'
Me6
Me4'
The above high yielding sequences show the value of carbon
branched carbohydrate lactones in the synthesis of piperi-
dines with quaternary centres and many functional groups.
H3
Figure 3b. Imino sugar 2D.
2.2. Enzyme inhibition assays
of 8.2 Hz and between H-2 and H-10 of 9.4 Hz were again
consistent with the chair conformation of a sugar, as was
the axial–equatorial coupling between H-2 and H-1 of
5.2 Hz.
The concentrations of the 4-C-methyl branched imino-
sugars that caused 50% inhibition of a-L-fucosidase (from
human placenta, assayed at pH 5.5), a-D-mannosidase (from
almond, assayed at pH 4.5), a-D-galactosidase (from coffee
beans, assayed at pH 6.5), and a-L-rhamnosidase (from
Penicillium decumbens) were assayed. The glycosidase activ-
ities were determined using an appropriate p-nitrophenyl
glycoside as substrate at the optimum pH of each enzyme.
The N-butyl derivatives of 1L and 2D were also prepared.
Hydrogenation of C-methyl DFJ ketal 23L and butyralde-
hyde in the presence of palladium hydroxide in aqueous
dioxane resulted in reductive amination to form tertiary
amine 24L (61%); removal of the ketal protecting group
by aqueous trifluoroacetic acid afforded N-butyl-4-C-
methyl DFJ 25L (100%). Similar reductive amination of
the epimeric amine 26D gave 27D (71%), which on depro-
tection formed C-5 epimeric altritol 28D (90%).
DFJ 6L is a very potent and specific inhibitor of fucosid-
ases. The results of the assays on the 4-C-methyl fucose
mimics are shown in Figure 4. None of the compounds
showed any inhibition of a-D-mannosidase, a-D-galactosi-
dase, or a-L-rhamnosidase (from P. decumbens). The 4-C-
methyl analogue 1L gave modest inhibition of fucosidase
with an IC50 of 50 lM, at least 1000 times weaker than
6L. The N-butyl analogue 25L still gave significant though
weak fucosidase inhibition; the nectrisine analogue 3D gave
very weak inhibition. The epimeric compounds at C-5 2D
and the butyl amine 28D gave no inhibition.
For the synthesis of enantiomeric 4-C-methyl D-galactose
mimics 1D and related piperidines, the enantiomeric 2-C-
methyl-L-lyxonolactone 18L was prepared from 2-C-
methyl-D-ribonolactone 5D, readily available from D-glu-
cose [Scheme 4]. Inversion of configuration at C-4 by base
treatment of a carbohydrate lactone with a C-5 leaving

D. J. Hotchkiss et al. / Tetrahedron: Asymmetry 18 (2007) 500–512
505
OH
OH
OH
N
OH
OH
OH
OH
CH3
CH3
OH
CH3
CH3
OH
CH3
CH3
OH
CH3
CH3
OH
CH3
CH3
OH
HO
HO
HO
HO
HO
HO
N
H
N
N
H
N
N
H
CH3
Bu
Bu
6L
1L
25L
3D
2D
28D
IC50 (μM)
50
137
839
NI
NI
Figure 4. IC50 (lM) causing 50% inhibition of a-L-fucosidase [NI = less than 50% inhibition at 1000 lM].
OH
N
OH
OH
OH
OH
OH
OH
CH3
CH3
OH
CH3
CH3
OH
OH
CH3
CH3
OH
CH3
CH3
HO
OH
HO
HO
HO
HO
HO
CH3
CH3
N
N
H
N
H
N
N
H
CH3
Bu
Bu
6D
IC50 (μM)
1D
350
25D
3L
375
2L
NI
28L
NI
NI
Figure 5. IC50 (lM) causing 50% inhibition of a-L-fucosidase [NI = less than 50% inhibition at 1000 lM].
The results of the assays on the 4-C-methyl 6-deoxy-D-
galactose mimics are given in Figure 5. None of the com-
pounds showed any inhibition of a-D-mannosidase, a-L-
fucosidase or a-L-rhamnosidase (from P. decumbens). The
4-C-methyl analogue 1D and imine 3L both gave very weak
inhibition of galactosidase with IC50 of 350 lM and of
375 lM, respectively. The N-butyl analogue 25D caused
no inhibition. The epimeric compounds at C-5 2L and
the butyl amine 28L also gave no inhibition.
to the chemical shift of the deuterated solvent. Chemical
shifts (d) are quoted in ppm and coupling constants (J)
in Hz. The following abbreviations are used to denote mul-
tiplicities: s, singlet; d, doublet; dd, double-doublet; ddd,
double-double-doublet; t, triplet; q, quartet; dt, double-
triplet; m, multiplet; br, broad; a, apparent. Nuclear Over-
hauser Effect Spectroscopy (NOESY) experiments were
performed at 500 MHz and 298 K with a mixing time of
800 ms. Infrared spectra were recorded on a Bruker Tensor
27 FT IR spectrophotometer using thin films on NaCl or
Ge plates and peaks are given in cmꢀ1. Low-resolution
mass spectra (LRMS) were recorded on a Fisons Platform
(ESI) spectrometer or a Micromass VG Autospec 500 OAT
(CI(NH3)) spectrometer. High-resolution mass spectra
(HRMS) were recorded on a Micromass LCT (ESI) spec-
trometer, a Micromass VG Autospec 500 OAT (CI(NH3))
spectrometer or a Micromass GCT (FI) spectrometer.
Optical rotations were measured on a Perkin–Elmer 241
polarimeter with a path length of 1 dm; concentrations
(c) are quoted in g/100 mL. Elemental analyses were per-
formed by the microanalysis service of the Inorganic
Chemistry Laboratory (Oxford). Melting points (mp) were
measured on a Kofler hot-block apparatus and are uncor-
rected. Thin-layer chromatography (TLC) was carried out
on aluminum sheets coated with 60F254 silica from Merck,
and plates were developed by dipping in 0.2% w/v ceriu-
m(IV) sulfate and 5% ammonium molybdate in 2 M sulfu-
ric acid with subsequent heating. Flash column
chromatography was carried out using Sorbsil C60 40/60
silica. The solvents (HPLC grade) and the commercially
available reagents were used as supplied.
Thus the introduction of a branching methyl group at C-4
of the piperidine sugar mimics significantly reduced glyco-
sidase inhibition.
3. Conclusion
Very efficient syntheses via crystalline intermediates have
shown the value of newly available branched sugar lactones
in the synthesis of highly functionalised piperidines with a
carbon branch at a quaternary centre. The introduction of
a 4-C-methyl group to very potent glycosidase inhibitors
caused a considerable loss of potency although no other
inhibition of other glycosidases was observed; the residual
inhibition still showed specific recognition of the carbo-
hydrate moiety. Other receptors that interact with sugars
may have a lipophilic cleft in the binding site; other bio-
logical assays on the fucose and galactose analogues are
in progress.
4. Experimental
Proton nuclear magnetic resonance spectra (dH) were
recorded on a Bruker AV400 (400 MHz) or a Bruker
AV500 (500 MHz) spectrometer and were calibrated
according to the chemical shift of residual protons in the
deuterated solvent. 13C NMR spectra (dC) were recorded
on a Bruker AV400 (100.6 MHz) and calibrated according
4.1. 2,3-O-Isopropylidene-2-C-methyl-D-lyxono-1,4-lactone
18D
2-C-Methyl-D-lyxono-1,4-lactone 4D (556 mg, 3.43 mmol)
was dissolved in acetone (56 mL) and stirred under argon
with anhydrous copper(II) sulfate (3.0 g) and catalytic

506
D. J. Hotchkiss et al. / Tetrahedron: Asymmetry 18 (2007) 500–512
concentrated sulfuric acid (12 drops, ꢁ0.1 mL). After 16 h,
TLC analysis (ethyl acetate) revealed the presence of no
starting material (Rf 0.19) and one major product (Rf
0.66). The reaction mixture was neutralised with excess
anhydrous sodium carbonate, filtered through Celiteꢁ with
acetone as eluent and the filtrate concentrated in vacuo to
ture under argon in the presence of sodium azide
(258 mg, 3.97 mmol). After 16 h, TLC analysis (ethyl ace-
tate/cyclohexane, 1:1) revealed the presence of one major
product (Rf 0.65). The reaction mixture was concentrated
in vacuo, the residue dissolved in dichloromethane (75
mL) and the resulting solution washed with water
(75 mL) and brine (75 mL). The combined aqueous phases
were then washed with dichloromethane (2 · 75 mL). The
organic phases were then combined, dried over magnesium
sulfate, filtered and concentrated in vacuo to afford a yel-
low oil (607 mg). Purification by flash column chromato-
graphy (ethyl acetate/cyclohexane, 1:3) afforded azide
afford acetonide 18D (690 mg, 99%) as a colourless oil,
23
which crystallised on standing; mp 64–66 ꢂC; ½aꢂD
¼
þ77:2 (c 1.8, acetone); mmax (film): 1784 (c-lactone C@O)
3447 (O–H) cmꢀ1; dH (CDCl3, 400 MHz): 1.40, 1.43
(2 · 3H, 2 · s, C(CH3)2), 1.57 (3H, s, 20-CH3), 2.43 (1H,
0
0
br s, 5-OH), 3.94 (1H, dd, J5,5 12.2 Hz, J4,5 5.0 Hz,
H-50), 4.02 (1H, dd, J5,5 12.2 Hz, J4,5 6.7 Hz, H-5), 4.47
20D (549 mg, 91%) as a white crystalline solid; mp 59–
0
20
(1H, d, J3,4 3.4 Hz, H-3), 4.52 (1H, ddd, J3,4 3.4 Hz, J4,5
60 ꢂC; ½aꢂD ¼ þ73:9 (c 0.9, acetone); mmax (film): 2106
6.7 Hz, J4,5 5.0 Hz, H-4); dC (CDCl3, 100.6 MHz): 18.2
(N3), 1788 (C@O) cmꢀ1; dH (CDCl3, 400 MHz): 1.42,
1.45 (2 · 3H, 2 · s, C(CH3)2), 1.58 (3H, s, 20-CH3), 3.64
0
(20-CH3), 26.7, 26.8 (C(CH3)2), 60.8 (C-5), 78.1 (C-4),
80.8 (C-3), 83.1 (C-2), 113.5 (C(CH3)2), 176.3 (C-1); LRMS
m/z (ESI +ve): 220.12 (M+NH4þ, 100%); HRMS m/z (ESI
+ve): found 220.1186 (M+NH4þ); C9H18NO5 requires
220.1185.
0
(1H, dd, J4,5 6.2 Hz, J5,5 12.9 Hz, H-5), 3.72 (1H, dd,
J4,5 7.0 Hz, J5,5 12.9 Hz, H-50), 4.42 (1H, d, J3,4 3.3 Hz,
0
0
0
H-3), 4.47 (1H, ddd, J4,5 6.2 Hz, J4,5 7.0 Hz, J3,4 3.3 Hz,
H-4); dC (CDCl3, 100.6 MHz): 18.1 (20-CH3), 26.7, 26.9
(2 · C(CH3)2), 49.5 (C-5), 76.1 (C-4), 80.3 (C-3), 83.0 (C-
2), 113.6 (C(CH3)2), 175.5 (C-1); LRMS m/z (ESI +ve):
286.25 (M+ CH3CN+NH4þ, 100%); HRMS m/z (ESI
+ve): found 291.1067 (M+CH3CN+Na+); C11H16N4O4Na
requires 291.1069. Found: C, 47.58; H, 5.86; N, 18.31;
C9H13N3O4 requires C, 47.57; H, 5.77; N, 18.49.
4.2. 2,3-O-Isopropylidene-2-C-methyl-5-O-trifluoro-
methanesulfonyl-D-lyxono-1,4-lactone 19D
A solution of ketal 18D (513 mg, 2.54 mmol) in dichloro-
methane (12 mL) was stirred under argon with pyridine
(0.62 mL, 7.61 mmol) at ꢀ30 ꢂC. Trifluoromethanesulfonic
anhydride (0.68 mL, 4.06 mmol) was added drop-wise to the
reaction mixture and the mixture stirred for 3 hours when
TLC analysis (ethyl acetate/cyclohexane, 1:1) revealed the
presence of no starting material (Rf 0.25) and one major
product (Rf 0.65). The reaction mixture was diluted with
dichloromethane (40 mL) and washed with dilute hydro-
chloric acid (1.0 M, 20 mL). The aqueous layer was then
washed with dichloromethane (2 · 30 mL), the organic ex-
tracts were combined, dried over magnesium sulfate and fil-
tered. The filtrate was then concentrated in vacuo to afford
4.5. 5-Azido-5-deoxy-2,3-O-isopropylidene-2-C-methyl-L-
lyxono-1,4-lactone 20L
2,3-O-Isopropylidene-2-C-methyl-5-O-trifluoromethanesul-
fonyl-L-lyxono-1,4-lactone 19L (654 mg, 1.96 mmol) trea-
ted in a similar manner gave enantiomer 20L (407 mg,
21
92%) as a white crystalline solid; mp 59–61 ꢂC, ½aꢂD
¼
ꢀ72:0 (c 0.4, acetone); the other physical data for 20L were
consistent with those of 20D.
4.6. 6-Azido-1,6-dideoxy-3,4-O-isopropylidene-3-C-methyl-
D-tagatofuranose 21D
triflate 19D (878.3 mg, quantitative) as a white crystalline
21
solid; mp 66–68 ꢂC; ½aꢂD ¼ þ60:9 (c 0.6, acetone); mmax
(film): 1783 (c-lactone C@O) cmꢀ1; dH (CDCl3, 400 MHz):
1.42, 1.45 (2 · 3H, 2 · s, C(CH3)2), 1.61 (3H, s, 20-CH3),
4.50 (1H, d, J3,4 3.1 Hz, H-3), 4.69–4.83 (3H, m, H-4,
H-5 & H-50); dC (CDCl3, 100.6 MHz): 18.1 (20-CH3), 26.6,
26.8 (C(CH3)2), 72.9 (C-5), 74.5 (C-4), 79.8 (C-3), 82.9
(C-2), 114.3 (C(CH3)2), 174.8 (C-1); HRMS m/z (FI +ve):
found 334.0480 (M+); C10H13F3O7S requires 334.0334.
Methyl lithium (1.6 M in Et2O, 0.6 mL) was added drop-
wise to a stirred solution of azidolactone 20D (197 mg,
0.87 mmol) in tetrahydrofuran (2 mL) at ꢀ78 ꢂC under
an argon atmosphere. After 4 h TLC analysis (ethyl ace-
tate/cyclohexane, 1:1) revealed the presence of one major
product (Rf 0.70) and no starting material (Rf 0.65). The
reaction mixture was carefully quenched by addition of
aqueous saturated ammonium chloride solution (1 mL)
and the mixture extracted with ethyl acetate (3 · 8 mL).
The organic extracts were combined, dried over magnesium
sulfate, filtered and concentrated in vacuo to afford a crude
white crystalline solid (215 mg). Purification by flash col-
umn chromatography (ethyl acetate/cyclohexane, 1:4)
4.3. 2,3-O-Isopropylidene-2-C-methyl-5-O-trifluoro-
methanesulfonyl-L-lyxono-1,4-lactone 19L
2,3-O-Isopropylidene-2-C-methyl-L-lyxono-1,4-lactone (969
mg, 4.80 mmol) 18L treated in a similar manner gave enan-
tiomer 19L (1.54 g, 96%) as a white crystalline solid; mp
afforded lactols 21D (203 mg, 97%) as a white crystalline
21
24
79–81 ꢂC, ½aꢂD ¼ ꢀ55:9 (c 2.0, acetone); the other physical
solid; mp 80–81 ꢂC; ½aꢂD ¼ þ7:1 (c 0.5, acetone); mmax
(film): 3443 (O–H), 2099 (N3) cmꢀ1
; dH (CDCl3,
data for 19L were consistent with those of 19D.
400 MHz): 1.37 (3H, s, 1B-CH3), 1.42, 1.45 (2 · 3H, 2 · s,
4.4. 5-Azido-5-deoxy-2,3-O-isopropylidene-2-C-methyl-D-
lyxono-1,4-lactone 20D
C(CH3)2-A), 1.46 (3H, s, 30 -CH3), 1.47 (3H, s, C(CH3)2-
B
B), 1.49, 1.49 (2 · 3H, 2 · s, 1A-CH3 & 30 -CH3), 1.54
A
(3H, s, C(CH3)2-B), 2.15 (1H, br s, 2A-OH), 3.54 (2H, d,
J5A,6A 6.5 Hz, 6A-CH2N3), 3.55 (2H, d, J5B,6B 6.6 Hz, 6B-
CH2N3), 3.70 (1H, dt, J5B,6B 6.6 Hz, J4B,5B 3.5 Hz, H-5B),
A solution of triflate 19D (885 mg, 2.65 mmol) in N,N-
dimethylformamide (30 mL) was stirred at room tempera-

D. J. Hotchkiss et al. / Tetrahedron: Asymmetry 18 (2007) 500–512
507
4.20 (1H, dt, J5A,6A 6.5 Hz, J4A,5A 3.4 Hz, H-5A), 4.33 (1H,
4.10. 2,6-Imino-3-C-methyl-1,2,6-trideoxy-D-tagatopyra-
nose [(3R,4S,5R)-5,6-dimethyl-2,3,4,5-tetrahydropyridine-
3,4,5-triol] 3D
br s, 2B-OH), 4.38 (1H, d, J4B,5B 3.5 Hz, H-4B), 4.39 (1H, d,
J4A,5A 3.4 Hz, H-4A), A:B ꢃ 3:1; dC (CDCl3, 100.6 MHz):
20.3, 20.8 (1B-CH3 & 30 -CH3), 20.5, 22.4 (1A-CH3 & 30 -
B
A
CH3), 27.1 (C(CH3)2–B), 27.3, 27.8 (2 · C(CH3)2–A &
C(CH3)2–B), 49.6 (C-6B), 49.8 (C-6A), 73.9 (C-5B), 76.4
(C-5A), 85.7 (C-4B), 86.6 (C-4A), 89.1 (C-3B), 92.3 (C-3A),
104.6 (C-2B), 106.5 (C-2A), 113.2 (C(CH3)2–A), 113.5
(C(CH3)2–B), A:B ꢃ 3:1; LRMS m/z (ESI ꢀve): 242.29
(MꢀH+, 100%); HRMS m/z (ESI +ve): found 266.1106
(M+H+); C10H17N3NaO4 requires 266.1111. Found: C,
49.62; H, 7.08; N, 17.04; C10H17N3O4 requires C, 49.37;
H, 7.04; N, 17.27.
A solution of the protected imine 22D (65 mg, 0.33 mmol)
in water (1 mL) and trifluoroacetic acid (1 mL) was stirred
for 24 h. After this time more trifluoroacetic acid (1 mL)
was added and the reaction mixture stirred for a further
24 h. The reaction mixture was then concentrated in vacuo
and co-evaporated three times with toluene. The residue
was dissolved in water (10 mL) and eluted with water
through a plug of Dowexꢁ 50WX8-100 (H+) ion exchange
resin. Subsequent elution of the resin plug with aqueous
ammonium hydroxide solution (2 M) afforded an ammoni-
acal eluate which was concentrated in vacuo to afford the
4.7. 6-Azido-1,6-dideoxy-3,4-O-isopropylidene-3-C-methyl-
L-tagatofuranose 21L
unprotected imine 3D (53 mg, quant.) as a yellow oil;
21
½aꢂD ¼ ꢀ34:7 (c 0.3, CH3OH); mmax (film): 3385 (O–H),
1663 (C@N) cmꢀ1; dH (CD3OD, 400 MHz): 1.30 (3H, s,
30-CH3), 1.93 (3H, m, 1-CH3), 3.10 (1H, m, H-6), 3.34
(1H, d, J4,5 9.7 Hz, H-4), 3.62–3.76 (2H, m, H-5 & H-60);
dC (CD3OD, 100.6 MHz): 20.4 (30-CH3), 22.5 (C-1),
53.7 (C-6), 65.9 (C-5), 72.9 (C-3), 75.5 (C-4), 173.3 (C-2);
HRMS m/z (FI +ve): found 160.0969 (M+H+);
C7H14NO3 requires 160.0974.
5-Azido-5-deoxy-2,3-O-isopropylidene-2-C-methyl-D-lyx-
ono-1,4-lactone 20L (366 mg, 1.61 mmol) treated in a sim-
ilar manner gave enantiomer 21L (402 mg, quant.) as a
24
white crystalline solid; mp 80–83 ꢂC; ½aꢂD ¼ ꢀ5:1 (c 0.5,
acetone); the other physical data for 21L were consistent
with those of 21D.
4.8. 2,6-Imino-3,4-O-isopropylidene-3-C-methyl-1,2,6-tri-
deoxy-D-tagatopyranose [(3R,4S,5R)-5,6-dimethyl-4,5-O-
isopropylidene-2,3,4,5-tetrahydropyridine-3,4,5-triol] 22D
4.11. 2,6-Imino-3-C-methyl-1,2,6-trideoxy-L-tagatopyranose
[(3S,4R,5S)-5,6-dimethyl-2,3,4,5-tetrahydropyridine-3,4,5-
triol] 3L
A solution of azidolactols 21D (544 mg, 2.24 mmol) in
methanol (150 mL) was stirred at room temperature under
an argon atmosphere. Palladium (10%) on carbon (109 mg)
was added to the stirred solution and the flask flushed twice
with argon before flushing three times with hydrogen gas.
The reaction mixture was then left to stir vigorously under
an atmosphere of hydrogen for 3 hours, when TLC analy-
sis (ethyl acetate) revealed the presence of one major prod-
uct (Rf 0.08) and no starting material (Rf 0.89). The
reaction mixture was filtered through Celiteꢁ with metha-
nol and the filtrate concentrated in vacuo to afford imine
2,6-Imino-3,4-O-isopropylidene-3-C-methyl-1,2,6-trideoxy-
L-tagatopyranose 22L (73 mg, 0.37 mmol) treated in a sim-
ilar manner gave enantiomer 3L (53 mg, 91%) as a yellow
21
oil; ½aꢂD ¼ þ30:6 (c 1.4, CH3OH); the other physical data
for 3L were consistent with those of 3D.
4.12. 1,5-Imino-3,4-O-isopropylidene-4-C-methyl-1,5,6-tri-
deoxy-D-altritol 26D and 1,5-dideoxy-1,5-imino-3,4-O-iso-
propylidene-4-C-methyl-L-fucitol 23L
A solution of the protected imine 22D (105 mg, 0.53 mmol)
in aqueous dioxane (1:1, 11.2 mL) was stirred at room tem-
perature under an atmosphere of argon. Platinum oxide
(20 mg) was added to the stirred solution and the flask
flushed twice with argon before flushing three times with
hydrogen gas. The reaction mixture was then left to stir
vigorously under an atmosphere of hydrogen for 16 h, after
which TLC analysis (10% methanol in ethyl acetate)
revealed the presence of two major products (Rf 0.05 and
Rf 0.09) and no starting material (Rf 0.37). The reaction
mixture was filtered through Celiteꢁ with water and the fil-
trate concentrated in vacuo. Purification of the residue by
flash column chromatography (chloroform/ethanol/concd
ammonium hydroxide solution, 25:3:0.3) afforded imino-
22D (445 mg, quant.) as a colourless oil which crystallised
20
on standing; mp 95–97 ꢂC; ½aꢂD ¼ þ49:0 (c 1.6, CH3OH);
mmax (film): 3175 (O–H), 1666 (C@N) cmꢀ1; dH (CD3OD,
400 MHz): 1.28, 1.40 (2 · 3H, 2 · s, C(CH3)2), 1.45 (3H,
s, 30-CH3), 2.06 (3H, m, 1-CH3), 3.60 (2H, m, 2 · H-6),
3.97 (2H, m, H-4 & H-5); dC (CD3OD, 100.6 MHz): 19.7
(C-1), 22.3 (30-CH3), 26.5, 26.6 (2 · C(CH3)2), 51.1 (C-6),
65.3 (C-5), 77.2 (C-3), 80.0 (C-4), 109.3 (C(CH3)2), 172.4
(C-2); HRMS m/z (FI +ve): found 199.1207 (M+);
C10H17NO3 requires 199.1208. Found: C, 60.08; H, 8.57;
N, 6.81; C10H17NO3 requires C, 60.28; H, 8.60; N, 7.03.
4.9. 2,6-Imino-3,4-O-isopropylidene-3-C-methyl-1,2,6-tri-
deoxy-L-tagatopyranose [(3S,4R,5S)-5,6-dimethyl-4,5-O-
isopropylidene-2,3,4,5-tetrahydropyridine-3,4,5-triol 22L
D-altritol 26D (59 mg, 56%, Rf 0.09) as a colourless oil
22
which crystallised on standing, mp 116–118 ꢂC; ½aꢂD
¼
þ17:5 (c 1.2, acetone); mmax (film): 3385 (O–H) cmꢀ1
;
6-Azido-1,6-dideoxy-3,4-O-isopropylidene-3-C-methyl-L-
tagatofuranose 21L (360 mg, 1.48 mmol) treated in a simi-
lar manner gave enantiomer 22L (290 mg, 98%) as a col-
dH (CD3OD, 400 MHz): 1.06 (3H, d, J5,6 6.8 Hz, 6-CH3),
1.26 (3H, s, 40-CH3), 1.36, 1.44 (2 · 3H, 2 · s, 2 ·
C(CH3)2), 2.82 (1H, q, J5,6 6.8 Hz, H-5), 2.86 (1H, m, H-
1), 2.94 (1H, dd, J1,1 13.9 Hz, J2,1 2.2 Hz, H-10), 3.85
(1H, d, J2,3 1.7 Hz, H-3), 3.94 (1H, a–q, J 2.3 Hz, H-2);
dC (CD3OD, 100.6 MHz): 14.0 (C-6), 17.2 (40-CH3), 26.3,
0
0
ourless oil which crystallised on standing; mp 96–98 ꢂC;
21
½aꢂD ¼ ꢀ46:0 (c 1.5, CH3OH); the other physical data for
22L were consistent with those of 22D.

508
D. J. Hotchkiss et al. / Tetrahedron: Asymmetry 18 (2007) 500–512
27.7 (2 · C(CH3)2), 48.1 (C-1), 56.0 (C-5), 66.0 (C-2), 79.3
(C-4), 81.7 (C-3), 108.0 (C(CH3)2); LRMS m/z (ESI +ve):
202.06 (M+H+, 100%); HRMS m/z (ESI +ve): found
202.1439 (M+H+); C10H20NO3 requires 202.1438. Found:
C, 59.49; H, 9.34; N, 6.83; C10H19NO3 requires C, 59.68;
H, 9.52; N, 6.96; and the imino-L-fucitol 23L (44 mg,
4.15. 1,5-Dideoxy-1,5-imino-4-C-methyl-D-fucitol 1D
1,5-Dideoxy-1,5-imino-3,4-O-isopropylidene-4-C-methyl-D-
fucitol 23D (84 mg, 0.42 mmol) treated in a similar manner
gave enantiomer 1D (67 mg, quant.) as a colourless oil;
21
½aꢂD ¼ þ33:7 (c 0.4, CH3OH); the other physical data for
41%, Rf 0.05) as a colourless oil which crystallised on
1D were consistent with those of 1L.
22
standing, mp 86–90 ꢂC; ½aꢂD ¼ þ8:2 (c 2.2, acetone); mmax
(film): 3357 (O–H) cmꢀ1; dH (CD3OD, 400 MHz): 1.11
(3H, d, J5,6 6.7 Hz, 6-CH3), 1.36 (3H, s, 40-CH3), 1.42,
1.47 (2 · 3H, 2 · s, 2 · C(CH3)2), 2.64 (1H, m, H-1), 2.85
4.16. 1,5-Imino-4-C-methyl-1,5,6-trideoxy-D-altritol 2D
A solution of ketal 26D (23 mg, 0.11 mmol) in water
(0.6 mL) and trifluoroacetic acid (0.6 mL) was stirred at
room temperature for 72 h. The reaction mixture was then
concentrated in vacuo and co-evaporated three times with
toluene. The residue was dissolved in water (10 mL) and
eluted with water through a plug of Dowexꢁ 50WX8-100
(H+) ion exchange resin. Subsequent elution of the resin
plug with aqueous ammonium hydroxide solution (2 M)
afforded an ammoniacal eluate which was concentrated in
0
0
(1H, q, J5,6 6.7 Hz, H-5), 3.16 (1H, dd, J1,1 13.7 Hz, J2,1
5.3 Hz, H-10), 3.90–3.95 (2H, m, H-3 & H-2); dC (CD3OD,
100.6 MHz): 14.3 (C-6), 25.4 (40-CH3), 26.6, 27.6
(2 · C(CH3)2), 47.9 (C-1), 54.9 (C-5), 66.9 (C-2), 80.9 (C-
4), 83.5 (C-3), 108.9 (C(CH3)2); LRMS m/z (ESI +ve):
202.08 (M+H+, 100%); HRMS m/z (ESI +ve): found
202.1438 (M+H+); C10H20NO3 requires 202.1438. Found:
C, 59.60; H, 9.43; N, 6.89; C10H19NO3 requires C, 59.68;
H, 9.52; N, 6.96.
vacuo to afford unprotected 1,5-imino-D-altritol 2D
21
(18 mg, quant.) as a pale yellow oil; ½aꢂD ¼ ꢀ3:9 (c 0.5,
CH3OH); mmax (film): 3385 (br, O–H, N–H) cmꢀ1; dH
(D2O, 500 MHz): 1.02 (3H, d, J5,6 7.3 Hz, 6-CH3), 1.13
4.13. 1,5-Imino-3,4-O-isopropylidene-4-C-methyl-1,5,6-tri-
deoxy-L-altritol 26L and 1,5-dideoxy-1,5-imino-3,4-O-iso-
propylidene-4-C-methyl-D-fucitol 23D
(3H, s, 40-CH3), 2.52 (1H, dd, J1,1 13.8 Hz, J2,1 9.4 Hz,
0
0
H-10), 2.77 (1H, q, J5,6 7.3 Hz, H-5), 2.79 (1H, dd, J1,1
0
13.8 Hz, J1,2 5.2 Hz, H-1), 3.41 (1H, d, J2,3 8.2 Hz, H-3),
3.62–3.68 (1H, m, H-2); dC (D2O, 100.6 MHz): 13.3 (C-
6), 21.7 (40-CH3), 43.9 (C-1), 56.5 (C-5), 69.8 (C-2), 74.7
(C-4), 74.9 (C-3); HRMS m/z (ESI +ve): found 162.1125
(M+H+); C7H16NO3 requires 162.1125.
2,6-Imino-3,4-O-isopropylidene-3-C-methyl-1,2,6-trideoxy-
L-tagatopyranose 22L (263 mg, 1.32 mmol) treated in a
similar manner gave enantiomer 26L (121 mg, 46%, Rf
0.09) as a colourless oil which crystallised on standing,
21
mp 117–119 ꢂC; ½aꢂD ¼ ꢀ23:1 (c 1.6, acetone); the other
physical data for 26L were consistent with those of 26D;
and enantiomer 23D (134 mg, 51%, Rf 0.05) as a colourless
4.17. 1,5-Imino-4-C-methyl-1,5,6-trideoxy-L-altritol 2L
oil which crystallised on standing, mp 86–90 ꢂC;
1,5-Imino-3,4-O-isopropylidene-4-C-methyl-1,5,6-trideoxy-
L-altritol 26L (38 mg, 0.19 mmol) treated in a similar man-
21
½aꢂD ¼ ꢀ13:0 (c 0.2, acetone); the other physical data for
23D were consistent with those of 23L.
ner gave enantiomer 2L (30 mg, quant.) as a colourless oil;
21
½aꢂD ¼ þ5:1 (c 0.4, CH3OH); the other physical data for 2L
were consistent with those of 2D.
4.14. 4-C-Methyl DFJ [1,5-dideoxy-1,5-imino-4-C-methyl-
L-fucitol] 1L
4.18. N-Butyl-1,5-dideoxy-1,5-imino-3,4-O-isopropylidene-
4-C-methyl-L-fucitol 24L
A solution of acetonide 23L (56 mg, 0.28 mmol) in water
(1.5 mL) and trifluoroacetic acid (1 mL) was stirred for
48 h. The reaction mixture was then concentrated in vacuo
and co-evaporated three times with toluene. The residue
was dissolved in water (10 mL) and eluted with water
through a plug of Dowexꢁ 50WX8-100 (H+) ion exchange
resin. Subsequent elution of the resin plug with aqueous
ammonium hydroxide solution (2 M) afforded an ammoni-
acal eluate which was concentrated in vacuo to afford 4-C-
A solution of acetonide 23L (36 mg, 0.18 mmol) in a water/
dioxane mixture (2 mL, 1:1) was stirred at room tempera-
ture with butyraldehyde (0.16 mL, 1.8 mmol). Palladium
hydroxide (3 mg) was added to the stirred solution and
the flask flushed twice with argon before flushing three
times with hydrogen gas. The reaction mixture was then
left to stir vigorously under an atmosphere of hydrogen
for 16 h. The reaction mixture was then flushed with argon.
Tetrahydrofuran (1 mL) was added followed by a second
addition of butyraldehyde (0.08 mL) and palladium
hydroxide (10 mg). The flask was flushed twice with argon
before flushing three times with hydrogen gas and was then
left to stir vigorously under an atmosphere of hydrogen for
a further 16 h. TLC analysis (ethyl acetate) revealed the
presence of one major product (Rf 0.49) and no starting
material (Rf 0.03). The reaction mixture was filtered
through Celiteꢁ with a water/tetrahydrofuran mixture
(1:1) and the filtrate concentrated in vacuo. Purification
of the residue by flash column chromatography (ethyl ace-
tate/cyclohexane, 1:1) afforded the protected N-butyl-4-C-
methyl DFJ 1L (43 mg, 97%) as a pale yellow oil;
21
½aꢂD ¼ ꢀ25:1 (c 0.7, CH3OH); mmax (film): 3384 (br, O–H,
N–H) cmꢀ1; dH (D2O, 500 MHz): 0.97 (3H, d, J5,6
6.6 Hz, 6-CH3), 1.12 (3H, s, 40-CH3), 2.30 (1H, dd, J1,1
0
12.9 Hz, J2,1 11.2 Hz, H-10), 2.50 (1H, q, J5,6 6.6 Hz, H-
0
0
5), 2.98 (1H, dd, J1,1 12.9 Hz, J2,1 5.4 Hz, H-1), 3.08
(1H, d, J2,3 9.5 Hz, H-3), 3.53 (1H, a-ddd, J 10.8 Hz, J
9.7 Hz, J 5.4 Hz, H-2); dC (D2O, 100.6 MHz): 13.6 (C-6),
21.3 (40-CH3), 48.9 (C-1), 57.3 (C-5), 69.1 (C-2), 74.6 (C-
4), 78.6 (C-3); LRMS m/z (ESI ꢀve): 192.29
(M+CH3OHꢀH+, 100%); HRMS m/z (ESI ꢀve): found
160.0974 (MꢀH+); C7H14NO3 requires 160.0968.

D. J. Hotchkiss et al. / Tetrahedron: Asymmetry 18 (2007) 500–512
509
21
methyl-DFJ 24L (26 mg, 61%) as a pale yellow oil;
yellow oil; ½aꢂD ¼ þ1:0 (c 0.7, CH3OH); the other physical
23
½aꢂD ¼ ꢀ2:4 (c 1.4, CH3OH); mmax (film): 3385 (br, O–H)
data for 25D were consistent with those of 25L.
cmꢀ1
; dH (CD3OD, 400 MHz): 0.93–0.96 (5H, m,
CH2CH2CH2CH3), 1.17–1.22 (3H, m, 6-CH3), 1.33–1.37
4.22. N-Butyl-1,5-imino-3,4-O-isopropylidene-4-C-methyl-
1,5,6-trideoxy-D-altritol 27D
(2H, m, CH2CH2CH2CH3), 1.40 (3H, s, 40-CH3), 1.43,
0
1.47 (2 · 3H, 2 · s, C(CH3)2), 2.32 (1H, dd, J1,1 12.2 Hz,
J1,2 8.1 Hz, H-1), 2.58–2.76 (3H, m, H-5
&
A solution of the protected amine 26D (43 mg, 0.21 mmol)
in a water/dioxane mixture (2.6 mL, 1:1) was stirred at
room temperature with butyraldehyde (0.20 mL, 2.10
mmol). Palladium hydroxide (4 mg) was added to the stir-
red solution and the flask flushed twice with argon before
flushing three times with hydrogen gas. The reaction mix-
ture was then left to stir vigorously under an atmosphere
of hydrogen for 16 h. The reaction mixture was then
flushed with argon. Tetrahydrofuran (1 mL) was added fol-
lowed by a second addition of butyraldehyde (0.1 mL) and
palladium hydroxide (10 mg). The flask was flushed twice
with argon before flushing three times with hydrogen gas
and then left to stir vigorously under an atmosphere of
hydrogen for a further 16 h. TLC analysis (ethyl acetate)
revealed the presence of one major product (Rf 0.59) and
no starting material (Rf 0.04). The reaction mixture was
filtered through Celiteꢁ with a water/tetrahydrofuran
mixture (1:1) and the filtrate concentrated in vacuo.
Purification of the residue by flash column chromatogra-
0
0
CH2CH2CH2CH3), 3.00 (1H, dd, J1,1 12.2 Hz, J2,1
4.5 Hz, H-10), 3.73 (1H, d, J2,3 6.0 Hz, H-3), 3.93 (1H,
0
ddd, J1,2 8.1 Hz, J2,1 4.5 Hz, J2,3 6.0 Hz, H-2); dC
(CD3OD, 100.6 MHz): 11.8 (C-6), 13.3 (CH2CH2CH2-
CH3), 20.6 (CH2CH2CH2CH3), 26.7 (40-CH3), 26.8
(CH2CH2CH2CH3), 27.9, 28.1 (2 · C(CH3)2), 53.2
(CH2CH2CH2CH3), 53.4 (C-1), 62.1 (C-5), 68.0 (C-2),
82.0 (C-4), 85.1 (C-3), 109.4 (C(CH3)2); LRMS m/z (ESI
+ve): 258.23 (M+H+, 100%); HRMS m/z (ESI +ve): found
258.2064 (M+H+); C14H28NO3 requires 258.2064.
4.19. N-Butyl-1,5-dideoxy-1,5-imino-3,4-O-isopropylidene-
4-C-methyl-D-fucitol 24D
1,5-Dideoxy-1,5-imino-3,4-O-isopropylidene-4-C-methyl-1,
5,6-trideoxy-D-fucitol 23D (37 mg, 0.19 mmol) treated in a
similar manner gave enantiomer 24D (34 mg, 72%) as a
22
pale yellow oil; ½aꢂD ¼ þ8:1 (c 0.4, CH3OH); the other
physical data for 24D were consistent with those of 24L.
phy (ethyl acetate/cyclohexane, 1:1) afforded the protected
22
altritol 27D (39 mg, 71%) as a pale yellow oil; ½aꢂD ¼ ꢀ9:9
4.20. N-Butyl-1,5-dideoxy-1,5-imino-4-C-methyl-L-fucitol
25L
(c 0.8, CH3OH); mmax (film): 3453 (br, O–H) cmꢀ1; dH
(CD3OD, 400 MHz): 0.92–0.99 (5H, m, CH2CH2-
CH2CH3), 1.15–1.20 (3H, m, 6-CH3), 1.33 (3H, s, 40-
CH3), 1.36, 1.44 (2 · 3H, 2 · s, C(CH3)2), 1.50–1.57 (2H,
m, CH2CH2CH2CH3), 2.67 (1H, ddd, Jgem 13.2 Hz, Jvic
9.4 Hz, Jvic 6.5 Hz, CH2CH2CH2CH3), 2.77 (1H, q, J5,6
6.7 Hz, H-5), 2.81–2.91 (2H, m, CH2CH2CH2CH3 & H-
A solution of N-butylamine 24L (18 mg, 0.07 mmol) in
water (0.5 mL) and trifluoroacetic acid (0.5 mL) was stirred
for 24 h. The reaction mixture was then concentrated in
vacuo and co-evaporated three times with toluene. The
residue was dissolved in water (10 mL) and eluted with
water through a plug of Dowexꢁ 50WX8-100 (H+) ion
exchange resin. Subsequent elution of the resin plug with
aqueous ammonium hydroxide solution (2 M) afforded
an ammoniacal eluate which was concentrated in vacuo
1), 3.08 (1H, dd, J1,1 12.4 Hz, J2,1 2.1 Hz, H-10), 3.88
(1H, d, J2,3 2.2 Hz, H-3), 4.05–4.10 (1H, m, H-2); dC
(CD3OD, 100.6 MHz): 11.0 (C-6), 13.2 (CH2CH2-
CH2CH3), 18.3 (40-CH3), 20.5 (CH2CH2CH2CH3), 25.7
(CH2CH2CH2CH3), 26.2, 27.5 (2 · C(CH3)2), 52.7
(CH2CH2CH2CH3), 54.4 (C-1), 61.7 (C-5), 64.7 (C-2),
80.4 (C-4), 81.0 (C-3), 108.5 (C(CH3)2); HRMS m/z (ESI
+ve): found 258.2066 (M+H+); C14H28NO3 requires
258.2064.
0
0
to afford the unprotected amine 25L (15 mg, quant.) as a
22
pale yellow oil; ½aꢂD ¼ ꢀ4:2 (c 0.2, CH3OH); mmax (film):
3423 (br, O–H, N–H) cmꢀ1; dH (D2O, 400 MHz): 0.79
(3H, t, Jvic 7.3 Hz, CH2CH2CH2CH3), 1.05 (3H, d, J5,6
6.5 Hz, 6-CH3), 1.12 (3H, s, 40-CH3), 1.13–1.21 (2H, m,
CH2CH2CH2CH3), 1.30–1.40 (2H, m, CH2CH2CH2CH3),
2.26 (1H, a–t, J 11.2 Hz, H-1), 2.40 (1H, q, J5,6 6.5 Hz,
H-5), 2.59 (2H, dd, Jvic 9.9 Hz, Jvic 6.5 Hz,
4.23. N-Butyl-1,5-imino-3,4-O-isopropylidene-4-C-methyl-
1,5,6-trideoxy-L-altritol 27L
0
0
CH2CH2CH2CH3), 2.96 (1H, dd, J1,1 11.4 Hz, J2,1
1,5-Imino-3,4-O-isopropylidene-4-C-methyl-1,5,6-trideoxy-
L-altritol 26L (33 mg, 0.17 mmol) treated in a similar man-
5.0 Hz, H-10), 3.02 (1H, d, J2,3 9.6 Hz, H-3), 3.67 (1H, a–
dt, J 10.3 Hz, J 4.9 Hz, H-2); dC (D2O, 100.6 MHz): 11.6
(C-6), 13.5 (CH2CH2- CH2CH3), 20.4 (CH2CH2CH2CH3),
ner gave the enantiomer 27L (37 mg, 88%) as a pale yellow
22
oil; ½aꢂD ¼ þ13:0 (c 0.3, CH3OH); the other physical data
22.2
(40-CH3),
24.8
(CH2CH2CH2CH3),
52.4
for 27L were consistent with those of 27D.
(CH2CH2CH2CH3), 55.6 (C-1), 62.0 (C-5), 67.7 (C-2),
74.5 (C-4), 78.5 (C-3); HRMS m/z (ESI +ve): found
240.1570 (M+Na+); C11H23NO3Na requires 240.1570.
4.24. N-Butyl-1,5-imino-4-C-methyl-1,5,6-trideoxy-D-altri-
tol 28D
4.21. N-Butyl-1,5-dideoxy-1,5-imino-4-C-methyl-D-fucitol
25D
A solution of acetonide 27D (19 mg, 0.07 mmol) in water
(0.3 mL) and trifluoroacetic acid (0.3 mL) was stirred for
72 h. The reaction mixture was then concentrated in vacuo
and co-evaporated three times with toluene. The residue
was dissolved in water (10 mL) and eluted with water
through a plug of Dowexꢁ 50WX8-100 (H+) ion exchange
N-Butyl-1,5-dideoxy-1,5-imino-3,4-O-isopropylidene-4-C-
methyl-D-fucitol 24D (21 mg, 0.08 mmol) treated in a sim-
ilar manner gave enantiomer 25D (14 mg, 80%) as a pale

510
D. J. Hotchkiss et al. / Tetrahedron: Asymmetry 18 (2007) 500–512
resin. Subsequent elution of the resin plug with aqueous
ammonium hydroxide solution (2 M) afforded an ammoni-
acal eluate which was concentrated in vacuo to afford N-
with N,N-dimethylaminopyridine (8 mg, 0.06 mmol) under
argon at 0 ꢂC. The reaction mixture was stirred for 2 h
when TLC analysis (ethyl acetate) revealed the presence
of no starting material (Rf 0.67) and one major product
(Rf 0.75). The reaction mixture was concentrated in vacuo
and co-evaporated with toluene (3 · 1 mL). The residue
was then dissolved in dichloromethane (25 mL) and
washed with water (10 mL) and brine (10 mL). The aque-
ous layers were then combined and washed with dichloro-
methane (25 mL). The combined organic extracts were
dried over magnesium sulfate and filtered. The filtrate
butyl-imino-4-C-methyl-D-altritol 28D (14 mg, 90%) as a
21
pale yellow oil; ½aꢂD ¼ ꢀ13:4 (c 0.7, CH3OH); mmax (film):
3384 (br, O–H) cmꢀ1; dH (CD3OD, 400 MHz): 1.00 (3H,
t, Jvic 7.4 Hz, CH2CH2CH2CH3), 1.30 (3H, d, J5,6 7.1 Hz,
6-CH3), 1.35 (3H, s, 40-CH3), 1.36–1.47 (2H, m,
CH2CH2CH2CH3), 1.53–1.63 (1H, m, CH2CH2CH2CH3),
1.64–1.77 (1H, m, CH2CH2CH2CH3), 2.94–3.09 (2H, m,
H-1 & CH2CH2CH2CH3), 3.11–3.18 (1H, m, CH2CH2-
CH2CH3), 3.18–3.26 (1H, m, H-10), 3.42–3.50 (2H, m, H-
3 & H-5), 4.00 (1H, ddd, Jvic 10.9 Hz, Jvic 8.9 Hz, Jvic
5.7 Hz, H-2); dC (CD3OD, 100.6 MHz): 7.0 (C-6), 12.9
(CH2CH2CH2CH3), 19.8 (CH2CH2CH2CH3), 21.9 (40-
CH3), 26.3 (CH2CH2CH2CH3), 51.4 (CH2CH2CH2CH3),
53.3 (C-1), 63.3 (C-5), 66.8 (C-2), 72.9 (C-4), 73.5 (C-3);
LRMS m/z (ESI +ve): 218.12 (M+H+, 100%); HRMS m/z
(ESI +ve): found 218.1751 (M+H+); C11H24NO3 requires
218.1751.
was then concentrated in vacuo to afford mesylate 30
24
(187 mg, quantitative) as a colourless oil; ½aꢂD ¼ ꢀ24:7 (c
1.0, CHCl3); mmax (film): 1789 (c-lactone C@O) cmꢀ1; dH
(CDCl3, 400 MHz): 1.42, 1.44 (2 · 3H, 2 · s, C(CH3)2),
1.65 (3H, s, 20-CH3), 3.06 (3H, s, SO2CH3), 4.44 (2H, d,
J4,5 3.1 Hz, 2 · H-5), 4.52 (1H, d, J3,4 0.5 Hz, H-3), 4.71
(1H, dt, J3,4 0.5 Hz, J4,5 3.1 Hz, H-4); dC (CDCl3,
100.6 MHz): 20.0 (20-CH3), 26.7, 26.8 (C(CH3)2), 37.6
(SO2CH3), 68.0 (C-5), 79.7 (C-4), 81.8 (C-3), 82.3 (C-2),
113.6 (C(CH3)2), 175.4 (C-1); LRMS m/z (ESI ꢀve):
279.28 (MꢀH+, 100%); HRMS m/z (ESI +ve): found
303.0508 (M+Na+); C10H16O7SNa requires 303.0509.
Found: C, 42.76; H, 5.86; C10H16O7S requires C, 42.85;
H, 5.75.
4.25. N-Butyl-1,5-imino-4-C-methyl-1,5,6-trideoxy-L-altri-
tol 28L
N-Butyl-1,5-imino-3,4-O-isopropylidene-4-C-methyl-1,5,6-
trideoxy-L-altritol 27L (22 mg, 0.09 mmol) treated in a sim-
ilar manner gave enantiomer 28L (16 mg, 85%) as a pale
4.28. 2,3-O-Isopropylidene-2-C-methyl-L-lyxono-1,4-lactone
18L
21
yellow oil; ½aꢂD ¼ þ22:1 (c 0.8, CH3OH); the other physical
data for 28L were consistent with those of 28D.
Solid potassium hydroxide (409 mg, 7.29 mmol) in water
(11.7 mL) was added to a solution of mesylate 30
(680.6 mg, 2.43 mmol) in dioxane (15 mL) and stirred vig-
orously. After 3 h the reaction mixture was acidified to
pH 1 with dilute hydrochloric acid (2.0 M). The reaction
mixture was then washed with dichloromethane
(3 · 40 mL) until no lactone product (Rf 0.66 in ethyl ace-
tate) remained in the aqueous phase. The organic extracts
were then combined, dried over magnesium sulfate and
filtered. The filtrate was concentrated in vacuo and the
residue purified by flash column chromatography (ethyl
acetate/cyclohexane, (2:1)) to afford C-methyl-L-lyxono-
4.26. 2,3-O-Isopropylidene-2-C-methyl-D-ribono-1,4-lactone
29
2-C-Methyl-D-ribono-1,4-lactone 5D (129 mg, 0.80 mmol)
was dissolved in acetone (13 mL) and stirred under argon
with anhydrous copper(II) sulfate (0.75 g) and catalytic
concentrated sulfuric acid (three drops (ꢁ0.03 mL)). After
16 h TLC analysis (ethyl acetate) revealed the presence of
no starting material (Rf 0.27) and one major product (Rf
0.67). The reaction mixture was neutralised with excess
anhydrous sodium carbonate and filtered through Celiteꢁ
with acetone as eluent. The filtrate was concentrated in
vacuo to afford acetonide 29 (163 mg, quantitative) as a
1,4-lactone 18L (447 mg, 91%) as a colourless oil which
22
crystallised on standing; mp 64–66 ꢂC; ½aꢂD ¼ ꢀ74:1 (c
18
colourless oil which crystallised on standing; mp 52–
0.6, acetone) {Lit.35 ½aꢂD ¼ ꢀ75 (c 2.6, CHCl3)}; mmax
19
54 ꢂC; ½aꢂD ¼ ꢀ35:6 (c 1.4, acetone); mmax (film): 1781 (c-
(film): 1784 (c-lactone C@O) 3447 (O–H) cmꢀ1; dH
(CDCl3, 400 MHz): 1.39, 1.42 (2 · 3H, 2 · s, C(CH3)2),
1.56 (3H, s, 20-CH3), 2.63 (1H, br s, 5-OH), 3.93 (1H, dd,
lactone C@O) 3490 (O–H) cmꢀ1; dH (CDCl3, 400 MHz):
1.39, 1.41 (2 · 3H, 2 · s, C(CH3)2), 1.64 (3H, s, 20-CH3),
0
0
0
0
0
2.86 (1H, br s, 5-OH), 3.81 (1H, dd, J5,5 12.5 Hz, J4,5
J5,5 12.2 Hz, J4,5 5.1 Hz, H-50), 4.01 (1H, dd, J5,5
2.5 Hz, H-50), 3.97 (1H, dd, J5,5 12.5 Hz, J4,5 2.9 Hz, H-
5), 4.54 (2H, m, H-3 & H-4); dC (CDCl3, 100.6 MHz):
19.8 (20-CH3), 26.6, 26.8 (C(CH3)2), 62.0 (C-5), 82.6 (C-
3), 82.9 (C-2), 83.7 (C-4), 112.9 (C(CH3)2), 177.1 (C-1);
LRMS m/z (ESI ꢀve): 201.18 (MꢀH+, 100%); HRMS
m/z (ESI +ve): found 225.0731 (M+Na+); C9H14O5Na
requires 225.0733. Found: C, 53.48; H, 6.98; C9H14O5
requires C, 53.46; H, 6.98.
12.2 Hz, J4,5 6.7 Hz, H-5), 4.46 (1H, d, J3,4 3.4 Hz, H-3),
0
0
4.51 (1H, ddd, J3,4 3.4 Hz, J4,5 6.7 Hz, J4,5 5.1 Hz, H-4);
dC (CDCl3, 100.6 MHz): 18.2 (20-CH3), 26.7, 26.8
(C(CH3)2), 60.7 (C-5), 78.1 (C-4), 80.8 (C-3), 83.1 (C-2),
113.5 (C(CH3)2), 176.2 (C-1); HRMS m/z (ESI +ve): found
225.0732 (M+Na+); C9H14O5Na requires 225.0733.
5. Enzyme assays
4.27. 2,3-O-Isopropylidene-5-O-methanesulfonyl-2-C-
methyl-D-ribono-1,4-lactone 30
The enzymes a-L-fucosidase (from human placenta,
assayed at pH 5.5), a-D-mannosidase (from almond, assayed
at pH 4.5), a-D-galactosidase (from coffee beans, assayed at
pH 6.5) and a-L-rhamnosidase (from P. decumbens) were
Methanesulfonyl chloride (0.06 mL, 0.77 mmol) was added
to acetonide 29 (129 mg, 0.64 mmol) in pyridine (0.9 mL)

D. J. Hotchkiss et al. / Tetrahedron: Asymmetry 18 (2007) 500–512
511
Kameda, Y.; Kato, A.; Nash, R. J.; Fleet, G. W. J.;
Molyneux, R. J.; Asano, N. J. Nat. Prod. 2002, 65, 198–202.
14. (a) Dhavale, D. D.; Mattin, M. M. Arkivoc 2005, 110–132; (b)
Pearson, M. S. M.; Mathe-Allainmat, M.; Fargeas, V.;
Lebreton, J. Eur. J. Org. Chem. 2005, 11, 2159–2191; (c)
Asano, N.; Nishida, M.; Kato, A.; Kizu, H.; Matsui, K.;
Shimada, Y.; Itoh, T.; Baba, M.; Watson, A. A.; Nash, R. J.;
Lilley, P. M. D.; Watkin, D. J.; Fleet, G. W. J. J. Med. Chem.
1998, 41, 2565–2571.
purchased from Sigma Chemical Co. The glycosidase activ-
ities were determined using an appropriate p-nitrophenyl
glycoside as substrate at the optimum pH of each enzyme.
The reaction was stopped by adding 2 mL of 400 mM
Na2CO3. The released p-nitrophenol was measured spec-
trometrically at 400 nm.
15. (a) Bruce, I.; Fleet, G. W. J.; di Bello, I. C.; Winchester, B.
Tetrahedron 1992, 48, 10191–10200; (b) Bruce, I.; Fleet, G.
W. J.; di Bello, I. C.; Winchester, B. Tetrahedron Lett. 1989,
30, 7257–7260; (c) Shilvock, J. P.; Wheatley, J. R.; Nash, R.
Acknowledgement
A generous gift of 2-C-methyl-D-ribono-1,4-lactone is
gratefully acknowledged. D.J.H. was supported by an
EPSRC studentship.
J.; Watson, A. A.; Griffiths, R. C.; Butters, T. D.; Muller, M.;
¨
Watkin, D. J.; Winkler, D. A.; Fleet, G. W. J. J. Chem. Soc.,
Perkin Trans. 1 1999, 2735–2745; (d) Shilvock, J. P.; Nash, R.
J.; Lloyd, J. D.; Winters, A. L.; Asano, N.; Fleet, G. W. J.
Tetrahedron: Asymmetry 1998, 9, 3505–3516.
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