Synthesis of N-propargyl iminosugar scaffolds for compound library generation using click chemistry

Article abstract of DOI:10.1071/CH09426

We have developed an efficient synthesis of N-propargyl iminosugars for use in diversity-oriented library development. Through a common, crystalline intermediate both piperidine and azepane scaffolds can be prepared with an alkyne functional group, allowi

Full text of DOI:10.1071/CH09426

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2010, 63, 821–829
Synthesis of N-Propargyl Iminosugar Scaffolds for Compound
Library Generation using Click Chemistry
Brendan L. Wilkinson,A Laurent F. Bornaghi,A Marie Lopez,A Peter C. Healy,A
Sally-Ann Poulsen,A,C and Todd A. HoustonB,C
AEskitis Institute, Griffith University, Nathan, Qld 4111, Australia.
BInstitute for Glycomics, Gold Coast Campus, Griffith University, Qld 4222, Australia.
CCorresponding authors. Email: s.poulsen@griffith.edu.au; t.houston@griffith.edu.au
We have developed an efficient synthesis of N-propargyl iminosugars for use in diversity-oriented library development.
Through a common, crystalline intermediate both piperidine and azepane scaffolds can be prepared with an alkyne
functional group, allowing for further elaboration through reaction with azides.
Manuscript received: 6 August 2009.
Manuscript accepted: 24 September 2009.
Introduction
7-endo-tet
6-exo-tet
OMPM
O
H
Novel inhibitors of carbohydrate processing enzymes offer
potentialtherapeuticinterventioninseveraldiseasestatesandthe
biologicalactivityofiminosugarscaninmanycasesbeattributed
to their ability to act as competitive, reversible inhibitors of
glycosidases and glycosyltransferases.[1] The preparation and
evaluation of N-alkylated iminosugars is an active area of
research, withconsiderableeffortinvestedintothecombinatorial
and parallel synthesis of alkylated iminosugar libraries to enable
discovery of glycosidase and glycosyltransferase inhibitors with
improved potency and selectivity.[2] It has been shown that these
compounds possess markedly different inhibition profiles than
their non-alkylated parent structures, and so are valuable as tools
for elucidating biochemical pathways associated with protein
and lipid glycosylation.[3] The synthesis of structurally con-
served iminosugar scaffolds containing one (or more) reactive
functionalities to enable the conjugation of structurally diverse
substituents is thus desirable. This decorative approach is a
powerful means of accessing compounds for lead discovery or
optimization purposes and various groups have reported the syn-
thesis of iminosugar libraries using this ‘scaffold decoration’
strategy. More notable examples include the synthesis of an
N-alkylated fuconojirimycin library in microtitre plate format
by Wong et al.,[4] the solid phase synthesis of an N-alkylated
azafagomine library containing a variable tri-peptide sequence
by Bols et al.[5] and a C(2)-substituted tetrahydropyridoimida-
zole library reported by Vasella and coworkers.[6]
NH2
HN
O
H
O
MPMO
OH
1
MPMO
OMPM
N
N
Variable
HO
MPMO
ꢀ
HO
MPMO
OH
RN3
OH
OMPM
N
R
N
N
OMPM
2
3
Azasugar
Conserved
D-gluco-piperidine
L-ido-azepane
Scheme 1. Synthetic strategy to N-alkylated azasugar scaffolds.
(N-propargyl piperidine) and seven-membered (N-propargyl
azepane) iminosugars from a common, crystalline intermedi-
ate and subsequent ‘scaffold decoration’ by employing click
chemistry. Furthermore, the polyhydroxylated azepanes are a
relatively unexplored class of compound, and the combinato-
rial or parallel synthesis of azepane libraries is thus a viable
approach for promptly establishing compound libraries with
novel structural attributes.
We have previously applied the azide-alkyne CuI-catalyzed
azide and alkyne cycloaddition reaction (CuAAC) to carbo-
hydrate substrates to identify isozyme-selective carbonic anhy-
draseinhibitors.[7] Hereinweextendthismethodologytoprepare
N-alkylated iminosugar libraries.The modular assembly of these
libraries using click chemistry would provide both a flexible
and expedient access to novel iminosugars for use as probes of
discrete binding elements within the active site of carbohydrate-
processing enzymes. Specifically we report the development of
an efficient synthetic strategy to generate both six-membered
Results and Discussion
Our synthetic strategy to the N-alkylated iminosugar scaf-
folds is outlined in Scheme 1. Previously, Le Merrer and
colleagues examined the nucleophilic ring opening of homochi-
ral C2-symmetric bis-epoxides with benzyl amine as a key
step in the regiospecific synthesis of deoxynojirimycin and
L-ido-tetrahydroxyazepane.[8] By adopting a similar strategy,
the installation of the required N-propargyl group could be
© CSIRO 2010
10.1071/CH09426
0004-9425/10/050821

822
B. L. Wilkinson et al.
OMPM
OH
OMPM
O
O
OH
OH
O
O
O
HO
(ii)
(i)
(iii)
OH
O
O
MPMO
MPMO
O
OH
4
5
6
OMPM
OR
OR
OMPM
O
H
(vi)
(v)
N
N
TBSO
OTBS
(iv)
HO
ꢀ
MPMO
HO
MPMO
OH
O
H
MPMO
MPMO
OH
7 R ꢁ H
8 R ꢁ Ms
OMPM
OMPM
1
2
3
(vii)
(vii)
(i) NaH, p-methoxybenzyl bromide, DMF, rt
(ii) AcOH/H2O, rt, o/n
(iii) TBS-CI, imidazole, DMF, 0ꢂC, 2 h
(iv) MsCI, Et3N, DCM, 4 h
N
N
(iv) HCI, MeOH; then aq. NaOH
(vi) Propargylamine, MeOH, 45ꢂC, o/n
(vii) TFA/H2O; then Ac2O/Pyr
RO
RO
RO
OR
OR
OR
(viii) NaOMe, MeOH, rt; then IR-120 [Hꢀ]
OR
RO
9 R ꢁ Ac
11 R ꢁ H
10 R ꢁ Ac
12 R ꢁ H
(viii)
(viii)
Scheme 2. Synthesis of bis-epoxide 1 and N-alkylated azasugar scaffolds.
achieved by the nucleophilic ring opening of the structurally
rigid and crystalline C2-symmetric bis-epoxide 1 with propargyl
amine to form the N-propargyl D-gluco-piperidine 2 and the
L-ido-azepane 3 scaffolds.
the crude tetrol 6, which was used in the next step without fur-
ther purification. Selective silylation of the hydroxyl groups at
C-1 and C-6 position was achieved by immediately treating with
tert-butyldimethylsilyl chloride (2.2 equiv.) in anhydrous DMF
at 0◦C, furnishing the bis-silylether 7 in good yield (68%).
Treatment of 7 with methanesulfonyl chloride in anhydrous
dichloromethane at 0◦C facilitated the activation of C-2 and
C-5 towards the ensuing intramolecular nucleophilic attack.
Thus, the crude mesylate 8 (78%) was treated with an aque-
ous solution of 1 M HCl in methanol at 0◦C for 1 h to effect
cleavage of the silyl ether groups. This was promptly followed
by a base-promoted (addition of 20% w/v solution of potassium
hydroxide) intramolecular SN2 reaction, leading to the inver-
sion of stereochemistry at C-2 and C-5, thus the stereospecific
formation of the L-ido-configured C2-symmetric bis-epoxide 1
(55%). Pure 1 precipitated from the reaction mixture and was
obtained by vacuum filtration and recrystallization from hot
absoluteethanol.Themolecularstructureof 1hasbeensolvedby
X-ray crystallography and was in agreement with the expected
stereochemical configuration (Fig. 1).[10]
With optically pure, crystalline C2-symmetric bis-epoxide 1
in hand and available in gram quantities, we sought to opti-
mize the experimental conditions for the aminocyclization with
propargylamine. However, adaptationoftheliteraturemethod,[8]
which involved treating the substrate with excess propargyl
amine (5.0 equiv.) in refluxing chloroform, proved to be less
effective with this particular amine. The reaction was found
to be sluggish and partial decomposition of the substrate was
observed by TLC after 48 h at reflux. Microwave irradiation
(300W, 150◦C, up to 30 min) in the presence of 5 and 10 equiv.
The nucleophilic ring opening and aminocyclization of
diastereomeric, C2-symmetric bis-epoxides with benzyl amine
has been examined under different experimental conditions.[8]
The reaction conditions as well as steric influences can be mod-
ified to favour one of the two reaction pathways: the 6-exo-tet
process, which favours the formation of the D-gluco-piperidine;
or the 7-endo-tet process, which favours the formation of
the C2-symmetric L-ido-azepane (Scheme 1).[8,9] In particu-
lar, the nature of the hydroxyl protecting group at C-3 and C-4
are shown to influence the relative distribution of the piperi-
dine and azepane products. We sought a protecting group that
would impart a reasonable degree of structural rigidity lead-
ing to approximately equal product distributions, but which
could also be removed under mild and selective conditions. The
p-methoxybenzyl ether protecting group was selected because it
can be removed under orthogonal and mild oxidative conditions
as well as providing potentially crystalline synthetic interme-
diates to facilitate their purification by non-chromatographic
methods (Scheme 2).
Synthesis of the bis-epoxide 1 and N-alkylated iminosugar
scaffolds is presented in Scheme 2. Alkylation of the optically
pure and commercially available 1,2:5,6-di-O-isopropylidene-
D-mannitol (4) with p-methoxy benzyl bromide in DMF
afforded the 3,4-di-O-p-methoxybenzyl ether 5 in 74% yield.
Cleavage of the bis-acetonide was achieved by stirring 5 in aque-
ous acetic acid (70% w/v) at room temperature for 20 h affording

Synthesis of N-Propargyl Iminosugar Scaffolds
823
O42
C44
C48
C45
C47
C1
O12
C43
C2
C3
C46
O41
C42
C31
C32
C37
C36
C41
C4
C5
O31
C33
C35
O56
C38
C6
C34
O32
Fig. 1. The molecular structure of 1 as solved by X-ray crystallography.
N3
R
Scheme 3). The O-acetylated L-ido-azepane compounds 18a–d
were isolated in good yields (65–75%) following purification by
flash chromatography. Deprotection of 18a–d was achieved by
employing anhydrous methanolic sodium methoxide followed
by neutralization with acidic Amberlite IR-120 [H+] to afford
the target compounds as tetrols 19a–d in near quantitative yields.
Using an identical method, conjugation of the piperidine scaf-
fold 9 with alkyl azide 17 (building block d) was carried out to
synthesize the triazole conjugate 20d, which could be smoothly
deprotected to yield 21d.
O
N3
AcO
AcO
H
N
HN
N3
OAc
OAc
O
O
O
SO2NH2
13
14
17
N
N
O
15 R ꢁ OH
16 R ꢁ N3
Fig. 2. Azides selected to prepare N-alkylated azasugar model libraries
(13 = a, 14 = b, 16 = c, 17 = d).
Conclusion
In conclusion, the bis-epoxide 1 has been successfully syn-
thesized, its structure confirmed by X-ray crystallography and
then transformed into both N-propargyl piperidine and azepane
scaffolds. We have illustrated the utility and application of
click chemistry in preparing N-alkylated iminosugar libraries
using reaction of both scaffolds with various azide building
blocks. We believe that this synthetic methodology will provide
a powerful approach to accessing the structural diversity nec-
essary for distinguishing target enzyme selectivity and tuning
the physicochemical properties of the iminosugar. The scaffold
decoration of the iminosugar was achieved in a single, high-
yielding step using click chemistry, thus providing for flexible
and expedient access to novel iminosugars for use as probes of
discrete binding elements within the active site of carbohydrate-
processing enzymes. An extended degree of diversity can be
further achieved with the use of both a six-membered ring
and seven-membered ring scaffolds and a direct comparison
of biological activity with these counterparts will provide a
more expansive surveillance and correlation of biological and
chemical space with respect to the target enzyme.
of propargyl amine using 1,2-DCE, DMF, or acetone as sol-
vents did not lead to product formation by TLC. In an attempt
to assist epoxide opening and subsequent cyclization, the reac-
tion was next performed in a protic solvent at slightly elevated
temperature. The bis-epoxide 1 was thus treated with excess
propargyl amine (5.0 equiv.) in warm methanol (45◦C). The
formation of the 3,4-di-O-p-methoxybenzyl D-gluco-piperidine
2 and the structural isomer, C2-symmetric L-ido-azepane 3
occurred overnight. The isomers were readily separated by flash
chromatography and isolated in very good yields (2, 45%; and 3,
41%). After surveying several deprotection methods the acety-
lated iminosugars 9 and 10 were obtained by treatment of 2 and
3 with aqueousTFA (1:4TFA–H2O) at 40◦C followed by acylat-
ing the crude mixture using pyridine/Ac2O (42% and 43% from
2 and 3, respectively). Compounds 9 and 10 could be readily
converted into free tetrol iminosugars 11 and 12.
Having obtained both the N-propargyl piperidine 9 and
azepane 10 scaffolds in sufficient quantities, we proceeded to
prepare N-alkylated iminosugar model libraries containing the
structurally conserved N-methylene 1,2,3-triazole moiety. A
diverse panel of aliphatic and aryl azides were selected on the
basis of previously established structure-activity relationships
with respect to the selectivity and potency of the inhibition of
several target glycosidases (Fig. 2).[11]
Experimental
Notes on Nomenclature
Azasugars are named according to the IUPAC-IUBMB ‘Nomen-
clature of Carbohydrates’, section from 2-CARB-34[12] and
according to the literature.[8] Compound names and NMR
assignments are given with preference to the triazole ring.
The CuAAC used to prepare iminosugar libraries were per-
formed within capped scintillation vials in aqueous tert-butyl
alcohol(1:1v/v, 0.1–0.5 M)inthepresenceofsub-stoichiometric
quantities of sodium ascorbate, CuSO4 and 1.0 equiv. of the cor-
responding azide at 40◦C. The per-O-acetylated triazole series
18a–d, was prepared in an efficient manner from the L-ido-
azepane scaffold 10 and azide building blocks a–d (Fig. 2,
Preparation of N-alkylated Iminosugar-triazoles:
General Procedure 1
A mixture of the azide (1.0 equiv.) and acetylene (1.0 equiv.)
was prepared in tert-butyl alcohol and water (1:1, 0.2–0.5 M

824
B. L. Wilkinson et al.
R(a–d)
R(a–d)
N
N
N
N
CuSO4,
sodium ascorbate
N
N
NaOMe, MeOH
rt, 30 min
10 ꢀ a–d
N
N
1:1 t-BuOH/H2O,
40ꢂC, 30 min
AcO
HO
OAc
OH
AcO
HO
OH
OAc
18a–d
19a–d
Rd
Rd
N
N
N
N
CuSO4,
sodium ascorbate
N
N
NaOMe, MeOH
rt, 30 min
9 ꢀ d
N
N
HO
AcO
1:1 t-BuOH/H2O,
40ꢂC, 30 min
AcO
OAc
HO
OH
OAc
20d
OH
21d
Scheme 3. Synthesis and susbsequent deprotection of triazole azasugar analogues.
final concentration) and placed within a capped scintillation vial.
Sodium ascorbate (0.2 equiv.) and CuSO4·5H2O (0.1 equiv.) was
then added. The mixture was stirred vigorously at 40◦C and
monitored by TLC. Reactions were generally complete within
30 min at this temperature. Visualization of libraries by TLC
was performed by UV fluorescence and by charring plates with
a mixture of 10% ammonium molybdate (w/v) in 10% aqueous
H2SO4 containing 0.8% cerium sulfate.[13] Conventional aque-
ous workup using CH2Cl2 or EtOAc organic phases followed by
purification of the crude residue by silica filtration/flash chro-
matography afforded pure compound. The 1,4-regioselectivity
of the reaction was verified by 1H and 13C NMR chemical
shifts of the triazole moiety in products obtained using CDCl3,
DMSO[D6], and D2O, and are in agreement with literature
values.
was retained for deprotection according to general method 4 to
obtain tetrols 11 and 12.
Deprotection of Iminosugars: General Procedure 4
Compounds were prepared by the treating the per-O-acetate
precursors (final concentration of ∼0.1–0.2 M) with anhydrous
methanolic sodium methoxide (final pH 9–12). Full deprotection
was evident by TLC within 30 min of stirring at room tempera-
ture. The solution was neutralized by the addition of acidic ion
exchange resin (Amberlite IR-120 [H+]), filtered and washed
several times with methanol. Evaporation of the filtrates afforded
the deprotected compounds, all of which were shown to be pure
by 1H NMR.
1,2:5,6-Di-O-isopropylidene-3,4-di-O-p-methoxylbenzyl-
D-mannitol (5)[10b]
Deprotection of Iminosugar Scaffolds: General Procedure 2
A solution of 1,2:5,6-diisopropylidene-D-mannitol (25.0 g,
95.4 mmol) in anhydrous DMF at 0◦C under nitrogen was pre-
pared and a 60% mineral oil dispersion of sodium hydride
(5.0 g, 124 mmol, 2.5 equiv.) was added in three portions over
15 min. The suspension was stirred at 0◦C for 30 min and then
p-methoxybenzyl chloride (16.9 mL, 124.3 mmol, 2.5 equiv.)
was added dropwise. The suspension was then brought to room
temperature and stirred for 4 h. The reaction was quenched by
the careful addition of methanol at 0◦C. Concentration of the
mixture under reduced pressure afforded a crude oil which was
purified by flash chromatography to afford clear oil which slowly
crystallized on standing to a white crystalline solid (5: 18.6 g,
36.78 mmol, 38%). Rf 0.22 (1:4 EtOAc–hexanes); mp 43–44◦C
(Found: C 66.77, H 7.62. C28H38O8 requires C 66.91, H 7.62%).
1H NMR (400 MHz, CDCl3) δ 1.32 (6H, s, iPr CH3), 1.40 (6H,
s, iPr CH3), 3.73–3.75 (2H, m, H3), 3.78 (6H, s, PhOCH3), 3.80
A solution of the benzyl ether, 2 or 3 (∼0.1 M) was prepared
in a mixture of TFA and distilled water (1:1 v/v) and stirred at
slightly elevated temperature. The reaction was found complete
after overnight stirring by TLC (C-18 reverse phase employ-
ing 1:1 CH3CN–H2O eluent) and electrospray ionization-mass
spectrometry. Once complete, the solvent was evaporated under
reduced pressure and lyophilized to dryness. Mixtures were
used in the next step without further purification (see general
procedure 3).
Preparation of Iminosugar Scaffolds: General Procedure 3
A solution of the crude lyophilized reaction mixture (general
procedure 2) was prepared in pyridine and an equal volume of
acetic anhydride was then added (∼0.1 M final concentration).
The reaction was stirred at room temperature until found com-
plete by TLC. The solvent was removed under reduced pressure
and the resulting residue purified by flash silica chromatography
(1:2 EtOAc–CH2Cl2). A portion of the resulting pure material
2
3
2
ꢀ
ꢀ
(2H, dd, J1–1 8.4, J1–2 6.4, H1), 3.97 (2H, dd, J1 −1 8.4,
3
ꢀ
ꢀ
J1 −2 6.4, H1 ), 4.16–4.21 (2H, m, H2), 4.60 (4H, s, OCH2Ph),
6.80–7.20 (10H, m, ArH). 13C{1H} NMR (100 MHz, CDCl3)
δ 25.5 (iPr CH3), 26.9 (iPr CH3), 55.5 (PhOCH3), 67.1 (C1),

Synthesis of N-Propargyl Iminosugar Scaffolds
825
74.4 (OCH2Ph), 76.1 (C2), 79.8 (C3), 108.7 (iPr C), 114.0 (Ar
CH), 129.7 (Ar CH), 130.7 (Ar C), 159.5 (Ar C). m/z (HRMS
ESI) 525.2446, [M + Na]+ calcd for C28H38O8Na+ requires
525.2459.
6.83–7.27 (8H, m, ArH). 13C{1H} NMR (100 MHz, CDCl3) δ
−5.2 (SiCH3), −5.16 (SiCH3), 18.5 (tert-butyl C), 26.1 (tert-
butyl CH3), 38.8 (OMs CH3), 55.5 (PhOCH3), 62.2 (C1), 74.1
(CH2Ph), 78.0 (C3), 83.5 (C2), 114.1 (Ar CH), 129.8 (Ar C),
130.3 (Ar CH), 159.7 (Ar CH).
3,4-Di-O-p-methoxbenzyl-1,6-di-O-tert-butyldimethylsilyl-
D-mannitol (7)
1,2:5,6-Dianhydro-3,4-di-O-p-methoxybenzyl-L-iditol (1)
A solution of the mesylate 8 (13.2 g, 16.4 mmol) in methanol was
cooled to 0◦C and concentrated aqueous HCl (1 N, 3.47 mL,
39.2 mmol, 2.4 equiv.) was added dropwise. The solution was
stirred for an additional 1 h to effect full silyl deprotection. At
this time, an aqueous solution of potassium hydroxide (20% w/v,
28 mL, 98 mmol, 6.0 equiv.) was added dropwise. A thick white
precipitate had formed following stirring overnight at 20◦C
and was collected by vacuum filtration and washed with cold
methanol–H2O (3:7, 2 × 20 mL). A final recrystallization of the
crude white solid from hot absolute ethanol afforded the bis-
epoxide 1 as fine colourless needles (3.52 g, 9.11 mmol, 55%).
Rf 0.50 (1:1 EtOAc–hexanes); mp 108–109◦C (Found: C 68.37,
H 6.91. C22H26O6 requires C 68.38, H 6.78%), [α]2D5 +25.4 (c
A portion of pure 5 (24 g, 47.8 mmol) was dissolved in aque-
ous glacial acetic acid (70% v/v, 500 mL) and stirred at room
temperature for 24 h. At this time, TLC indicated full acetonide
deprotection. The mixture was evaporated at room temperature
under reduced pressure to afford the tetrol 6 as a pale yel-
low oil which, due to its highly hygroscopic nature, was used
in the following step without further purification or analysis.
The resulting crude 6 (12.5 g, 29.6 mmol) was azeotropically
dried with 1:1 CH3CN/toluene (3 × 50 mL) and its solution in
anhydrous DMF (30 mL) was immediately prepared under an
atmosphere of nitrogen. The solution was cooled to 0◦C and
imidazole (8.1 g, 118.3 mmol, 4.0 equiv.) was added, followed by
tert-butyldimethylsilyl chloride (11.1 g, 73.9 mmol, 2.5 equiv.)
in three equal portions. The thick suspension was stirred at
0◦C for 2 h until found complete by TLC. The reaction was
quenched with saturated, aqueous ammonium chloride (60 mL)
and extracted with CH2Cl2 (3 × 60 mL). The organic fractions
were combined, washed with brine (100 mL), dried over MgSO4,
and concentrated under reduced pressure to afford crude yellow
oil. Flash chromatography (15% EtOAc in hexanes) afforded
clear oil that slowly crystallized upon refrigeration to a white
1
0.095, CHCl3). H NMR (400 MHz, CDCl3) δ 2.48 (2H, dd,
2
3
2
3
ꢀ
ꢀ
ꢀ
J1–1 4.8, J1–2 2.8, H1), 2.69 (2H, dd, J1 –1 5.2, J1 –2 4.4,
ꢀ
H1 ), 3.15–3.17 (2H, m, H2), 3.22–3.25 (2H, m, H3), 3.79 (6H,
2
s, PhOCH3), 4.62 (4H, AB q, JAB 11.6, OCH2Ph), 6.83–7.24
(8H, m, ArH). 13C{1H} NMR (100 MHz, CDCl3) δ 43.3 (C1),
52.7 (PhOCH3), 55.48 (C2), 72.1 (OCH2Ph), 80.3 (C3), 113.9
(Ar CH), 129.8 (Ar CH), 130.2 (Ar C), 159.5 (Ar C). m/z (HRMS
ESI) 409.1620, [M + Na]+ calcd for C22H26O6Na+ requires
409.1622.
1
solid (7). Rf 0.28 (15% EtOAc in hexanes); mp 58–59◦C. H
NMR (400 MHz, CDCl3) δ 0.04 (6H, s, Me2Si), 0.05 (6H, s,
Colourless needles of 1 (C22H26O6) suitable for X-ray crys-
tallographic analysis were obtained by the slow evaporation
of an absolute ethanol–CHCl3 (1:1 v/v) solution. M = 386.43,
monoclinic, space group P21, a = 5.1245(5), b = 10.6190(9),
c = 18.513(7) Å, β = 94.320(1)◦, V = 1004.6(4) Å3, T =
0.092 mm−1, crystal size 0.50 × 0.40 × 0.30 mm; 2θmax = 50◦;
2080 reflections measured, 1860 unique (Rint = 0.0720).
r = 0.073 (1219 reflections with I > 2σ(I); wRF2 = 0.251 (all
data).
Me2Si), 0.89 (18H, s, tert-butyl CH3), 3.57 (2H, dd, 2J1–1 10,
ꢀ
3
2
3
ꢀ
ꢀ
ꢀ
J1–2 5.2, H1), 3.72 (2H, dd, J1 –1 10.0, J1 –2 3.2, H1 ), 3.77
(6H, s, PhOCH3), 3.79–3.87 (4H, m, H2, H3), 4.58 (4H, AB
2
q, JAB 11.2, OCH2Ph), 6.82–7.25 (10H, m, ArH). 13C{1H}
NMR (100 MHz, CDCl3) δ −5.1 (Me2Si), −5.09 (Me2Si), 18.5
(tert-butyl C), 26.2 (tert-butyl CH3), 55.4 (PhOCH3), 64.6 (C1),
71.0 (C2 or C3), 73.7 (OCH2Ph), 77.9 (C2 or C3), 114.0 (Ar
CH), 130.2 (Ar CH), 130.7 (Ar C), 159.5 (Ar C). m/z (HRMS
ESI) 673.3575, [M + Na]+ calcd for C34H58O8Si2Na+ requires
673.3562.
296(1) K,
Z = 2,
Dx = 1.278 Mg m−3
,
μ(Mo-Kα) =
1,5-Dideoxy-1,5-imino-3,4-di-O-p-methoxybenzyl-
N-propynyl-D-glucitol (2)
2,5-Di-O-mesyl-3,4-di-O-p-methoxybenzyl-1,6-di-O-tert-
butyldimethylsilyl-D-mannitol (8)
The bis-epoxide 1 (1.0 g, 2.6 mmol) was suspended in methanol
(25 mL) and propargyl amine (3.4 mL, 5.2 mmol, 2.0 equiv.) was
then added. Dissolution was achieved within 4 h by vigorous stir-
ring at 45◦C.The deep yellow solution was then stirred overnight
at this temperature, at which time TLC indicated reaction com-
pletion. The mixture was concentrated under reduced pressure
and the resulting orange oil purified by flash chromatography
(1:1 EtOAc–CH2Cl2 then 100% EtOAc) to afford the piperi-
dine 2 (520 mg, 1.2 mmol, 45%). Rf 0.21 (2:3 EtOAc–CH2Cl2);
mp 139–140◦C (Found: C 67.67, H 7.05, N 3.20. C25H31NO6
requires C 68.01, H 7.08, N 3.17%), [α]2D5 −1.22 (c 0.115,
To a solution of 7 (9.8 g, 15.1 mmol) in anhydrous CH2Cl2
(25 mL) at 0◦C under nitrogen, was added triethylamine
(8.67 mL, 61.9 mmol, 4.1 equiv.), followed by the dropwise
addition of methanesulfonyl chloride (3.52 mL, 45.2 mmol,
2.0 equiv.). The thick suspension was stirred at 0◦C for 15 min,
at which time TLC indicated reaction completion. The reac-
tion was quenched by the careful addition of water (20 mL)
and extracted into CH2Cl2 (30 mL). The aqueous layer was then
further extracted with CH2Cl2 (3 × 40 mL) and the combined
organic layers were washed with brine (50 mL), dried (MgSO4),
and evaporated under reduced pressure to afford the crude mesy-
late as an orange oil. Crystallization from anhydrous methanol at
0◦C afforded the mesylate 8 (9.5 g, 19.4 mmol, 78%) as a white
crystalline solid. Rf 0.22 (15% EtOAc in hexanes); mp 81–82◦C.
1H NMR (400 MHz, CDCl3) δ 0.07 (6H, s, Me2Si), 0.08 (6H, s,
Me2Si), 0.90 (18H, s, tert-butyl CH3), 2.97 (6H, s, OMs CH3),
1
4
CHCl3). H NMR (400 MHz, CDCl3) δ 2.23 (1H, t, JCH–CH
2.4, C≡CH), 2.42–2.45 (1H, m, H5), 2.53–2.58 (1H, m, H1),
2
3
ꢀ
ꢀ
ꢀ
2.89 (1H, dd, J1 –1 11.2, J1 –2 4.8, H1 ), 3.27–3.32 (1H, m,
2
4
H3), 3.36 (1H, dd, JCH–CH 18.0, JCH–CH 2.4, NCH), 3.57–
3.62 (1H, m, H4), 3.63–3.68 (2H, m, H2, H6), 3.73 (1H, dd,
2JCH–CH 18.4, 4JCH–CH 2.4, NCH), 3.79 (3H, s, PhOCH3), 3.80
3.78 (6H, s, PhOCH3), 3.90 (2H, dd, 3J1–1 11.6, 3J1–2 6.4, H1),
(3H, s, PhOCH3), 3.81–3.84 (1H, m, H6 ), 4.76 (2H, AB q, JAB
2
ꢀ
ꢀ
3.95–3.96 (2H, m, H3), 3.99 (2H, dd, 3J1 –1 11.6, 3J1 –2 3.6, H1 ),
11.2, 10.8, CH2OPh), 4.80 (2H, ABq, JAB 10.8, CH2OPh),
2
ꢀ
ꢀ
ꢀ
2
4.62 (4H, AB q, JAB 10.4, CH2Ph), 4.77–4.80 (2H, m, H2),
6.86–7.30 (8H, m, ArH). 13C{1H} NMR (100 MHz, CDCl3) δ

826
B. L. Wilkinson et al.
42.5 (NCH2), 55.5 (PhOCH3), 55.5 (PhOCH3), 56.3 (C1), 57.4
(C6), 63.5 (C5), 69.4 (C2), 75.0 (OCH2Ph), 75.1 (OCH2Ph), 75.1
(C≡CH), 76.6 (C≡CH), 77.3 (C4), 87.0 (C3), 114.2 (Ar CH),
114.3 (Ar CH), 129.8 (Ar CH), 130.0 (Ar CH), 130.5 (Ar C),
130.9 (Ar C), 159.6 (Ar C), 159.6 (Ar C). m/z (HRMS ESI)
442.2209, [M + H]+ calcd for C25H31NO+6 requires 442.2224.
(1H, m, H3), 3.27–3.31 (1H, m, H4), 3.35 (1H, dd, 2JCH–CH 18.0,
4
JCH–CH 2.4, NCH), 3.44 (1H, ddd, 3J2–1 10.4, 3J2–3 9.2, 3J2–1
ꢀ
4.8, H2), 3.73 (2H, m, H6, H6 ). 13C{1H} NMR (100 MHz, D2O)
ꢀ
δ 41.8 (NCH2), 56.0 (C1), 56.9 (C6), 63.7 (C5), 68.9 (C2), 69.7
(C4), 75.9 (C3), 76.9 (C≡CH), 78.3 (C≡CH). m/z (HRMS ESI)
202.1073, [M + H]+ calcd for C9H16NO+4 requires 202.1074.
1,6-Dideoxy-1,6-imino-3,4-di-O-p-methoxybenzyl-
N-propynyl-L-iditol (3)
1,6-Dideoxy-1,6-imino-N-propynyl-L-iditol (12)
The title compound was prepared from 10 (48 mg, 0.13 mmol)
Title compound was isolated using the identical procedure for 2
and was isolated as a pale yellow solid (47 mg, 41%). Rf 0.12
(1:4 EtOAc–CH2Cl2); mp 65–66◦C (Found: C 68.01, H 7.14,
N 3.02. C25H31NO6 requires C 68.01, H 7.08, N 3.17%), [α]D25
according to general procedure 4 and isolated as a white gum
(26 mg, 0.13 mmol, 100%). [α]2D5 −2.71 (c 0.095, MeOH). H
1
NMR (400 MHz, D2O) δ 2.58 (1H, t, 4JCH–CH 2.4, C≡H), 2.62
2
3
2
ꢀ
ꢀ
ꢀ
(2H, dd, J1–1 13.2, J1–2 7.0, H1), 2.85 (2H, dd, J1 −1 13.6,
1
3
4
+1.56 (c 0.09, CHCl3). H NMR (400 MHz, CDCl3) δ 2.31
ꢀ
J1 −2 4.0, H13), 3.31 (2H, d, JCH–CH 2.4, NCH2), 3.33 (2H,
3
3
3
dd, J3–2 6.0, J3–4 2.4, H3), 3.59–3.64 (2H, m, H2). 13C{1H}
NMR (100 MHz, D2O) δ 47.8 (NCH2), 57.9 (C1), 71.0 (C2), 75.0
(C≡CH), 75.5 (C3), 78.4 (C≡CH). m/z (HRMS ESI) 202.1072,
[M + H]+ calcd for C9H16NO+4 requires 202.1074.
3
ꢀ
(1H, t, JCH−CH 2.4, C≡CH), 2.53 (2H, dd, J1–1 12.8, J1–2
3
2
ꢀ
ꢀ
8.0, H1), 3.07 (2H, d, J1 –2 12.4, H1 ), 3.54 (2H, dd, JCH–CH
16.4, 4JCH–C≡CH 1.6, NCH2), 3.61 (2H, dd, 3J3–2 4.8, 3J3–4 1.6,
H3), 3.78 (6H, s, PhOCH3), 3.98–3.91 (2H, m, H2), 4.58 (4H,
ABq, JAB 11.2, OCH2Ph), 7.03 (8H, m, Ar). 13C{1H} NMR
2
(100 MHz, CDCl3) δ 49.0 (NCH2), 55.5 (PhOCH3), 56.8 (C1),
68.1 (C2), 73.4 (OCH2Ph), 75.4 (C≡CH), 77.6 (C≡CH), 85.1
(C3), 114.2 (Ar CH), 129.8 (Ar CH), 130.2 (Ar C), 159.6 (Ar
C). m/z (HRMS ESI) 442.2211, [M + H]+ calcd for C25H32NO+6
requires 442.2224.
5-((3-Hydroxypropylamino)methylene)-1,3-
dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (15)
A solution of 5-((diimethylamino)methylene)-1,3-dimethyl-
pyrimidine-2,4,6(1H,3H,5H)-trione (5.62 g, 26.6 mmol) in
methanol (15 mL) was cooled to 0◦C, followed by the addition
of 3-amino-1-propanol (2.1 mL, 26.7 mmol). A white precipi-
tate was formed within 2 min and the suspension was stirred
at 0◦C for an additional 15 min. The precipitate was filtered and
washedwithcoldmethanol(∼20 mL).Thecrude, off-whitesolid
was recrystallized from hot, absolute ethanol to afford the title
compound as colourless needles (4.6 g, 72%). Rf 0.22 (100%
EtOAc); mp 129–130◦C (Found: C 49.86, H 6.28, N 17.23.
2,3,4,6-Tetra-O-acetyl-1,5-dideoxy-1,5-imino-N-propynyl-
D-glucitol (9)
The title compound was prepared from 2 according to gen-
eral procedure 3 and was isolated as a colourless oil (85 mg,
0.23 mmol, 42%). Rf 0.43 (1:1 EtOAc–CH2Cl2). 1H NMR
(400 MHz, CDCl3) δ 1.98 (3H, s, OAc), 1.99 (3H, s, OAc),
4
1
2.00 (3H, s, OAc), 2.05 (3H, s, OAc), 2.28 (1H, t, JCH–CH
C10H15N3O4 requires C 49.79, H 6.27, N 17.42%). H NMR
(400 MHz, CDCl3) δ 1.89 (2H, pentet, 3JCH–CH 6.0, βCH2), 2.19
(1H, br s, OH), 3.28 (3H, s, NCH3), 3.29 (3H, s, NCH3), 3.63
(2H, m, NHCH2), 3.78 (2, t, 3JCH–CH 5.6, CH2OH), 8.17 (1H,
d, 3JCH–NH 14.4, C=CH), 10.40 (1H, br s, NH). 13C{1H} NMR
(100 MHz, CDCl3) δ 27.3 (NCH3), 28.0 (NCH3), 32.3 (βCH2),
48.2 (CH2NH), 59.6 (CH2OH), 90.8 (C=CH), 152.7 (C=O),
159.9 (C=CH), 163.9 (C=O), 165.1 (C=O).
2.4, C≡CH), 2.57–2.62 (1H, m, H1), 2.71 (1H, m, H5), 3.00
3
2
(1H, dd, 2J1–1 11.2, J1 –2 5.2, H1 ), 3.39 (1H, dd, JCH–CH 18.4,
4JCH–CH 2.4, NCH), 3.73 (1H, dd, 2JCH–CH 18.4, 4JCH–CH 2.0,
NCH), 4.10–4.20 (2H, m, H3, H4), 4.94–5.00 (1H, m, H2), 5.00–
5.10 (2H, m, H6). 13C{1H} NMR (100 MHz, CDCl3) δ 20.8
(OAc), 20.8 (OAc), 20.9 (OAc), 42.58 (NCH2), 53.9 (C1), 58.8
(C4), 60.0 (C5), 69.2 (C6 or C≡CH), 69.4 (C6 or C≡CH), 74.5
(C2), 75.3 (C3), 76.1 (C≡CH), 169.8 (OAc), 170.1 (OAc), 170.5
(OAc), 171.1 (OAc).
ꢀ
ꢀ
ꢀ
5-((3-Azidopropylamino)methylene)-1,3-
dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (16)
2,3,4,5-Tetra-O-acetyl-1,6-dideoxy-1,6-imino-N-propynyl-
L-iditol (10)
A solution of 15 (1.0 g, 4.2 mmol) and triethylamine (690 μL,
5.0 mmol, 1.2 equiv.) in anhydrous CH2Cl2 (10 mL) was pre-
pared under an atmosphere of nitrogen and cooled to 0◦C.
Methanesulfonyl chloride (390 μL, 5.0 mmol, 1.2 equiv.) was
then added dropwise. The solution was gradually brought to
room temperature and the solution was stirred for 30 min
until TLC had indicated reaction completion. The solution was
then diluted with CH2Cl2 (10 mL) and washed with distilled
H2O (10 mL) and brine (10 mL). The organic layer was dried
(MgSO4), filtered, and evaporated to afford a crude orange oil,
whichwasusedinthefollowingstepwithoutfurtherpurification.
The crude mesylate was immediately dissolved in anhydrous
DMF (15 mL) and sodium azide (810 mg, 12.5 mmol, 3.0 equiv.)
was added in a single portion. The resulting deep pink solution
was stirred overnight at room temperature. At this time, TLC
analysis indicated reaction completion. The solvent was con-
centrated under vacuum and CH2Cl2 (20 mL) was added. The
organic layer was washed with distilled H2O (10 mL) and brine
(10 mL), dried (MgSO4), filtered, and evaporated. The residue
was purified by flash chromatography (2:3 hexanes–EtOAc) and
The title compound was prepared from 3 according to general
procedure 3 and isolated as a colourless oil (220 mg, 0.60 mmol,
43%). Rf 0.45 (1:1 EtOAc–CH2Cl2). 1H NMR (400 MHz,
CDCl3) δ 2.01 (6H, s, 2 × OAc), 2.02 (6H, s, 2 × OAc), 2.26
4
2
3
ꢀ
(1H, t, JCH–CH 2.4, C≡CH), 2.83 (1H, dd, J1–1 14.0, J1–2
7.2, H1), 3.00 (1H, dd, 2J1 –1 13.6, 3J1 –2 4.0, H1 ), 3.41 (1H, dd,
2JCH–CH 17.2, 4JCH–CH 2.0, NCH), 3.49 (1H, dd, 2JCH–CH 17.2,
4JCH–CH 2.4, NCH), 5.08–5.13 (2H, m, H2), 5.26 (2H, dd, 3J3–2
ꢀ
ꢀ
ꢀ
6.0, J3–4 2.4, H3). 13C{1H} NMR (100 MHz, CDCl3) δ 20.7
3
(OAc), 21.0 (OAc), 48.6 (C1), 55.7 (NCH2), 72.0 (C2 and C3),
73.9 (C≡CH), 78.0 (C≡CH), 169.5 (OAc), 169.9 (OAc).
1,5-Dideoxy-1,5-imino-N-propynyl-D-glucitol (11)
The title compound was prepared from 9 according to general
procedure 4 and isolated as a white solid (25 mg, 100%). [α]D25
1
−77.3 (c 0.085, MeOH). H NMR (400 MHz, D2O) δ 2.21–
4
2.24 (1H, m, H5), 2.41 (1H, m, H1), 2.58 (1H, t, JCH–CH 2.4,
C≡CH), 2.82 (1H, dd, J1 –1 11.2, J1 –2 5.2, Hꢀ1), 3.11–3.15
2
3
ꢀ
ꢀ

Synthesis of N-Propargyl Iminosugar Scaffolds
827
recrystallization from hot absolute ethanol to afford the azide as
a white solid (830 mg, 3.1 mmol, 74%). Rf 0.67 (100% EtOAc);
mp 114–115◦C (Found: C 45.17, H 5.38, N 31.42. C10H14N6O3
requires C 45.11, H 5.30, N 31.56%). 1H NMR (400 MHz,
(2H, dd, 3J3–2 6.0, 3J3–4 2.0, azepane H3), 7.90–8.06 (4H, m,Ar)
8.21 (1H, br s, triazole CH). 13C{1H} NMR (100 MHz, CDCl3)
δ 20.8 (OAc), 21.1 (OAc), 53.6 (azepane C1), 60.1 (NCH2), 72.0
(azepane C2 and C3), 120.7 (Ar CH), 121.8 (triazole CH), 128.5
(Ar CH), 139.7 (Ar C), 142.6 (Ar C), 145.2 (triazole C), 169.6
(OAc), 170.1 (OAc).
3
CDCl3) δ 1.19 (2H, pentet, JCH–CH 6.5, βCH2), 3.29 (3H, s,
NCH3), 3.30 (3H, s, NCH3), 3.43 (2H, t, 3JCH–CH 6.4, N3CH2),
3.56 (2H, m, NHCH2), 8.16 (1H, d, 3JCH–NH 14.4, C=CHNH),
10.28 (1H, br s, NH). 13C{1H} NMR (100 MHz, CDCl3) δ
27.4 (NCH3), 28.1 (NCH3), 29.7 (βCH2), 47.8 (CH2N3), 48.4
(CH2NH), 91.3 (C=CH), 152.3 (C=O), 159.9 (C=CH), 163.1
(C=O), 165.3 (C=O).
1-(p-Sulfamoylphenyl)-4-(N-methylene-1,6-imino-L-iditol)-
1,2,3-triazole (19b)
The title compound was prepared from 18b according to general
procedure 4 and isolated as a pale yellow oil (38 mg, 100%).
1H NMR (400 MHz, D2O) δ 2.54 (2H, dd, 2J1–1 13.6, 3J1–2 7.6,
ꢀ
1-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-Tetra-O-acetyl-β-D-glucopyranosyl)-
4-(N-methylene-2,3,4,5-tetra-O-acetyl-1,6-dideoxy-
1,6-imino-L-iditol)-1,2,3-triazole (18a)
H1), 2.79 (2H, dd, 2J1 –1 13.6, 3J1 –2 4.4, H1 ), 3.32 (2H, dd, J3–2
5.6, 3J3–4 2.0, azepane H3), 3.54–3.58 (2H, m, azepane H2), 3.77
(2H, s, NCH2), 7.71–7.86 (4H, m, Ar CH), 8.34 (1H, s, triazole
CH). 13C{1H} NMR (100 MHz, 1:9 DMSO[D6]D2O) δ 52.8
(NCH2), 58.3 (azepane C1), 71.3 (azepane C2), 75.7 (azepane
C3), 121.3 (Ar CH), 123.6 (triazole CH), 128.0 (Ar CH), 139.4
(Ar C), 142.1 (Ar C or triazole C), 144.2 (Ar C or triazole C).
m/z (HRMS ESI) 400.1269, [M + H]+ calcd for C15H22N5O6S+
requires 400.1285.
3
ꢀ
ꢀ
ꢀ
The title compound was prepared from 10 and 13 according
to the general procedure 1 and isolated as a colourless oil
1
(87 mg, 0.11 mmol, 78%). Rf 0.32 (1:1 EtOAc–hexanes). H
NMR (400 MHz, CDCl3) δ 1.85 (3H, s, OAc), 1.99 (3H, s, OAc),
2.00 (3H, s, OAc), 2.01 (3H, s, OAc), 2.03 (3H, s, OAc), 2.04
(3H, s, OAc), 2.06 (3H, s, OAc), 2.07 (3H, s, OAc), 2.81 (2H, br
ꢀ
s, azepane H1), 3.00–3.03 (2H, m, azepane H1 ), 3.90–4.01 (2H,
br s, NCH2), 3.98 (1H, ddd, 3J5 –4 10.0, 3J5 –6 5.2, 3J5 –6 2.0,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀꢀ
ꢀꢀ
2
Glc H5 ), 4.14 (1H, dd, J6 –6 12.8, 3J6 –5 2.0, Glc H6 ), 4.29
ꢀ
ꢀꢀ
ꢀ
ꢀꢀ
ꢀ
1-(1,3-Dimethyl-5-((propylamino)methylene)pyrimidine-
2,4,6(1H,3H,5H)-trione)-4-(N-methylene-1,6-dideoxy-1,6-
imino-2,3,4,5-tetra-O-acetyl-L-iditol)-1,2,3-triazole (18c)
3
(1H, dd, 2J6 –6 12.4, J6 –5 5.2, Glc H6 ), 5.10 (2H, br s, azepane
ꢀ
ꢀꢀ
ꢀ
ꢀ
ꢀ
ꢀ
H2), 5.20–5.27 (3H, m, Glc H4 , azepane H3), 5.37–5.43 (2H,
ꢀ
ꢀ
ꢀ
m, Glc H2 , Glc H3 ), 5.81–5.83 (1H, m, Glc H1 ), 7.79 (1H, br s,
triazole CH). 13C{1H} NMR (100 MHz, CDCl3) δ 20.3 (OAc),
20.69 (OAc), 20.72 (OAc), 20.8 (OAc), 20.9 (2 × OAc), 21.0
The title compound was from 10 and 16 prepared according
to general procedure 1 and isolated as a colourless oil (98 mg,
0.15 mmol, 84%). Rf 0.28 (2:3 CH2Cl2–EtOAc). 1H NMR
(400 MHz, CDCl3) 2.01 (6H, s, 2 × OAc), 2.02 (6H, s, 2 × OAc),
2.30 (2H, pentet, 3JCH–CH 7.2, βCH2), 2.83 (2H, s, azepane H1),
ꢀ
ꢀ
(2 × OAc), 53.5 (NCH2), 55.5 (azepane C1 ), 61.8 (Glc C6 ),
ꢀ
ꢀ
ꢀ
67.9 (Glc C4 ), 70.6 (Glc C2 or Glc C3 ), 72.0 (azepane C2),
ꢀ
ꢀ
ꢀ
72.3 (azepane C3), 72.7 (Glc C2 or Glc C3 ), 75.4 (Glc C5 ), 86.0
ꢀ
3.02 (2H, s, azepane H1 ), 3.23 (2H, s, NCH3), 3.24 (3H, s,
ꢀ
(Glc C1 ), 121.0 (triazole CH), 143.5 (triazole C), 169.0 (OAc),
NCH3), 3.46–3.51 (2H, m, αCH2), 3.87 (2H, s, NCH2), 4.38–
4.51 (2H, m, γCH2), 4.98–5.03 (2H, m, azepane H2), 5.24 (2H,
dd, 3J2–3 5.6, 3J3–4 1.6, azepane H3), 7.66 (1H, s, triazole CH),
8.14 (1H, d, 3JCH–NH 14.0, C=CH), 10.24–10.30 (1H, m, NH).
13C{1H}NMR (100 MHz, CDCl3) δ 20.8 (OAc), 21.0 (OAc),
27.3 (NCH3), 28.0 (NCH3), 31.0 (βCH2), 47.2 (αCH2), 47.3
(γCH2), 53.7 (azepane C1), 55.3 (NCH2), 71.8 (C2 or C3), 72.0
(C2 or C3), 91.4 (C=CH), 123.4 (triazole CH), 152.3 (C=CH),
160.0 (C=O), 163.0 (C=O), 165.1 (C=O), 169.5 (OAc), 170.0
(OAc).
169.45 (2 × OAc), 169.54 (OAc), 169.8 (2 × OAc), 170.1 (OAc),
170.7 (OAc).
1-(β-D-Glucopyranosyl)-4-(1,6-dideoxy-1,6-imino-
L-iditol)-1,2,3-triazole (19a)
The title compound was prepared from 18a according to general
procedure 4 and isolated as a white foam (28 mg, 0.07 mmol,
100%). 1H NMR (400 MHz, D2O) δ 2.51 (2H, dd, 2J1–1 13.6,
ꢀ
3
2
3
ꢀ
ꢀ
J1–2 7.6, azepane H1), 2.76 (2H, dd, J1 –1 13.2, J1 –1 4.0,
3
azepane H1 ), 3.30 (2H, dd, J3 –2 5.6, 3J3 –4 2.0, azepane H3 ),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀꢀ
3.47–3.67 (7H, m, Glc H3 , Glc H4 , Glc H5 , Glc H6 , Glc H6
and azepane H2), 3.76 (2H, s, NCH2), 3.84–3.89 (1H, m, Glc
1-(1,3-Dimethyl-5-((propylamino)methylene)pyrimidine-
2,4,6(1H,3H,5H)-trione)-4-(N-methylene-1,6-dideoxy-
1,6-imino-L-iditol)-1,2,3-triazole (19c)
3
ꢀ
ꢀ
ꢀ
ꢀ
H2 ), 5.61 (1H, d, J1 –2 9.2, Glc H1 ), 8.10 (1H, s, triazole CH).
13C{1H} NMR (100 MHz, D2O) δ 52.8 (NCH2), 58.4 (azepane
ꢀ
ꢀ
C1), 60.6 (Glc C6 ), 69.1 (Glc C4 ), 71.3 (azepane C2), 72.5 (Glc
The title compound was prepared from 18c according to method
4 and isolated as a colourlessgum (28 mg, 0.06 mmol, 100%). 1H
NMR (400 MHz, D2O) δ 2.21 (2H, pentet, 3JCH–CH 6.4, βCH2),
ꢀ
ꢀ
ꢀ
H2 ), 76.0 (azepane C3), 76.5 (Glc C3 ), 79.1 (Glc C5 ), 87.7 (Glc
H1), 123.5 (triazole CH), 145.8 (triazole C). m/z (HRMS ESI)
407.1765, [M + H]+ calcd for C15H27N4O+9 requires 407.1773.
2.46 (2H, dd, 2J1–1 13.6, 3J1–2 8.0, azepane H1), 2.71 (2H, dd,
ꢀ
2
3
ꢀ
ꢀ
ꢀ
J1 –1 13.6, J1 –2 4.0, azepane H1 ), 3.03 (6H, s, 2 × NCH3),
3.28(2H, dd, 3J2–3 6.0, 3J3–4 2.8, azepaneH3), 3.46–3.53(4H, m,
azepane H2, γCH2), 3.63 (2H, br s, NCH2), 4.43 (2H, t, 3JCH–CH
6.0, αCH2), 7.90 (1H, s, C=CH), 7.95 (1H, s, triazole CH).
13C{1H} NMR (100 MHz, D2O) δ 27.3 (βCH2), 29.4 (NCH3),
48.04 (αCH2), 48.3 (γCH2), 52.7 (NCH2), 58.2 (azepane C1),
71.3 (azepane C2), 75.6 (azepane C3), 90.2 (C=CH), 125.2 (tri-
azole CH), 143.5 (triazole C), 153.2 (C=CH), 160.3 (2 × C=O),
164.7 (C=O). m/z (HRMS ESI) 468.2219, [M + H]+ calcd for
C19H30N7O+7 requires 468.2201.
1-(p-Sulfamoylphenyl)-4-(N-methylene-2,3,4,5-tetra-
O-acetyl-1,6-imino-L-iditol)-1,2,3-triazole (18b)
The title compound was prepared from 10 and 14 according
to the general procedure 1 and isolated as a pale yellow foam
(88 mg, 0.16 mmol, 74%). Rf 0.18 (1:4 CH2Cl2–EtOAc). 1H
NMR (400 MHz, CDCl3) δ 2.02 (6H, s, 2 × OAc), 2.02 (6H,
s, OAc), 2.92 (2H, br s, azepane H1), 3.10 (2H, br s, azepane
ꢀ
H1 ), 4.03 (2H, br s, NCH2), 5.12 (2H, br s, azepane H2), 5.30

828
B. L. Wilkinson et al.
1-(2,3-Dimethyl-N-propylbutanamide)-4-(N-methylene-
2,3,4,5-tetra-O-acetyl-1,6-dideoxy-1,6-imino-L-iditol)-
1,2,3-triazole (18d)
Acknowledgements
We wish to thank the Eskitis Institute for Cell and Molecular Therapies
and the Institute of Glycomics for support. We are grateful to Prof. Paul
Bernhardt, the University of Queensland, for the collection of X-ray data for
compound 1.
The title compound was prepared from 10 and 17 according to
the general procedure 1 and isolated as a colourless oil (89 mg,
0.16 mmol, 100%). Rf 0.31 (2:3 EtOAc–hexanes). 1H NMR
(400 MHz, CDCl3) δ 2.01 (6H, s, OAc × 2), 2.00 (6H, s, OAc,
2 × CH3), 2.97 (2H, pentet, 3JCH–CH 6.8, CH2), 2.78 (2H, br s,
References
[1] (a) M. L. Sinnott, Chem. Rev. 1990, 90, 1171. doi:10.1021/
CR00105A006
ꢀ
H1), 2.97–3.00 (2H, m, H1 ), 3.23 (3H, s, NCH3), 3.24 (3H, s,
NCH3), 3.48 (2H, dt, 3JCH–CH 13.6, 3JCH–CH 6.8, γCH2), 3.86
(2H, br s, NCH2), 4.38–5.11 (2H, m, αCH2), 4.96–5.03 (2H, m,
azepane H2), 5.22–5.27 (2H, m, azepane H3), 7.66 (1H, br s,
triazole CH), 8.14 (1H, d, 3JCH–NH 14.0, C=CH), 10.24–10.28
(1H, m, C=CHNH).
(b) V. L. Y. Yip, S. G. Withers, Org. Biomol. Chem. 2004, 2, 2707.
doi:10.1039/B408880H
[2] (a) L. Cipolla, B. La Ferla, M. Gregori, Comb. Chem. High T. Scr.
2006, 9, 571.
(b) I. Velter, B. La Ferla, F. Nicotra, J. Carbohydr. Chem. 2006, 25,
97. doi:10.1080/07328300600733020
[3] (a) V. H. Lillelund, H. H. Jensen, X. Liang, M. Bols, Chem. Rev. 2002,
102, 515 and references cited therein. doi:10.1021/CR000433K
(b) N. Asano, Glycobiology 2003, 13, 93R. doi:10.1093/GLYCOB/
CWG090
1-(2,3-Dimethyl-N-propylbutanamide)-4-(N-methylene-
1,6-dideoxy-1,6-imino-L-iditol)-1,2,3-triazole (19d)
The title compound was prepared from 18d according to gen-
(c) A. Ossor, A. D. Elbein, Carbohydrates in Chemistry and Biology
(Eds B. Ernst, G. W. Hart, P. Sinaÿ) 2000, Vol. 3, pp. 513–531 (Wiley-
VCH Verlag GmbH: Weinheim).
(d) T. A. Houston, J. T. Blanchfield, Mini Rev. Med. Chem. 2003, 3,
669. doi:10.2174/1389557033487827
(e) L. L. Johnson, Jr, T. A. Houston, Tetrahedron Lett. 2002, 43, 8905.
doi:10.1016/S0040-4039(02)02196-2
(f) R. A. Dwek, T. D. Butters, F. M. Platt, N. Zitzmann, Nat. Rev. Drug
Discov. 2002, 1, 65. doi:10.1038/NRD708
(g) P. Compain, O. R. Martin, Curr. Top. Med. Chem. 2003, 3, 541.
doi:10.2174/1568026033452474
(h) L. L. Rossi, A. Basu, Bioorg. Med. Chem. Lett. 2005, 15, 3596.
doi:10.1016/J.BMCL.2005.05.081
(i)Y. Zhao,Y. Zhou, K. M. O’Boyle, P.V. Murphy, Bioorg. Med. Chem.
2008, 16, 6333. doi:10.1016/J.BMC.2008.05.012
eral procedure 4 and isolated as an off-white foam (22 mg,
1
0.06 mmol, 100%). H NMR (400 MHz, D2O) δ 0.64 (3H, d,
3
3JCH–CH 6.4, sec-butyl CH3), 0.70 (3H, t, JCH–CH 7.6, n-Pr
CH3), 0.91 (3H, d, 3JCH–CH 6.8, sec-butyl CH3), 1.37 (2H, sextet,
3JCH–CH 7.2, n-Pr CH2), 2.37–2.46 (2H, m, sec-butyl CH), 2.57
(2H, dd, 2J1–1 13.2, 3J1–2 7.6, azepane H1), 2.80 (2H, dd, 2J1 –1
ꢀ
ꢀ
3
ꢀ
ꢀ
13.6, J1 –2 3.6, azepane H1 ), 2.98–3.12 (2H, m, n-Pr CH2),
3.33 (2H, dd, 3J2–3 5.6, 3J3–4 1.6, azepane H3), 3.54–3.60 (2H,
3
m, azepane H2), 3.82 (2H, br s, NCH2), 4.78 (1H, d, JCH–CH
10.8, sec-butyl CH), 8.09 (1H, s, triazole CH). 13C{1H} NMR
(100 MHz, D2O) δ 10.7 (n-Pr CH3), 18.0 (sec-butyl CH3), 18.4
(sec-butyl CH3), 21.8 (n-Pr CH2), 31.0 (sec-butyl CH), 41.5
(n-Pr CH2), 52.7 (NCH2), 57.9 (azepane C1), 70.7 (sec-butyl
CH), 70.9 (azepane C2), 75.7 (azepane C3), 124.7 (triazole CH),
142.6 (triazole C), 169.5 (C=O+). m/z (HRMS ESI) 386.2392,
[M + H]+ calcd for C17H32N5O5 requires 386.2398.
[4] C.-Y. Wu, C.-F. Chang, J. S.-Y. Chan, C.-H. Wong, C.-H. Lin, Angew.
Chem. Int. Ed. 2003, 42, 4661. doi:10.1002/ANIE.200351823
[5] (a) A. Lohse, J. K. Jensen, M. Bols, Tetrahedron Lett. 1999, 40, 3033.
doi:10.1016/S0040-4039(99)00317-2
(b)A. Lohse, J. K. Jensen, K. Lundgren, M. Bols, Bioorg. Med. Chem.
1999, 7, 1965. doi:10.1016/S0968-0896(99)00116-9
[6] N. Panday, Y. Canac, A. Vasella, Helv. Chim. Acta 2000, 83, 58.
doi:10.1002/(SICI)1522-2675(20000119)83:1<58::AID-HLCA58>
3.0.CO;2-K
1-(2,3-Methyl-N-propylbutanamide)-4-(N-methylene-
1,6-dideoxy-1,6-imino-D-glucitol)-1,2,3-triazole (21d)
The title compound was prepared from 20d according to general
method 4 and isolated as a pale yellow oil (12 mg, 0.03 mmol,
100%). 1H NMR (400 MHz, D2O) δ 0.64 (3H, d, 3JCH–CH 6.4,
sec-butyl CH3), 0.70 (3H, t, 3JCH–CH 7.2, n-Pr CH3), 0.92 (3H,
d, 3JCH–CH 6.4, sec-butyl CH3), 1.33–1.42 (2H, m, n-Pr CH2),
2.06–2.16 (3H, m, piperidine H1 and H5), 2.37–2.47 (1H, m, sec-
[7] (a) M. Meldal, C. T. Tornoe, Chem. Rev. 2008, 108, 2952.
doi:10.1021/CR0783479
(b) B. L. Wilkinson, A. Innocenti, D. Vullo, C. T. Supuran, S.-A.
Poulsen, J. Med. Chem. 2008, 51, 1945. doi:10.1021/JM701426T
(c) S.-A. Poulsen, B. L. Wilkinson, A. Innocenti, D. Vullo, C. T.
Supuran, Bioorg. Med. Chem. Lett. 2008, 18, 4624. doi:10.1016/
J.BMCL.2008.07.010
(d) M. Singer, M. Lopez, L. F. Bornaghi, A. Innocenti, D. Vullo,
C. T. Supuran, S.-A. Poulsen, Bioorg. Med. Chem. Lett. 2009, 19,
2273. doi:10.1016/J.BMCL.2009.02.086
butyl CH), 2.93 (1H, dd, 2J1 –1 11.6, 3J1 –2 4.8, piperidine H1 ),
3.02–3.12 (3H, m, n-pr CH2, piperidine H3), 3.32–3.37 (1H,
m, piperidine H4), 3.42–3.48 (1H, m, piperidine H2), 3.82–3.87
ꢀ
ꢀ
ꢀ
(1H, m, piperidine H6), 3.96–4.07 (3H, m, NCH2, piperidine
3
ꢀ
H6 ), 4.43 (1H, d, JCH–CH 10.4, sec-butyl CH), 8.09 (1H, s,
triazole CH). 13C{1H} NMR (100 MHz, D2O) δ 10.7 (n-Pr
CH3), 18.0 (sec-butyl CH3), 18.4 (sec-butyl CH3), 21.8 (n-
Pr CH2), 30.9 (sec-butyl CH), 41.5 (n-Pr CH2), 46.2 (NCH2),
55.3 (piperidine C1), 56.7 (piperidine C6), 64.4 (piperidine C5),
68.5 (piperidine C2), 69.5 (piperidine C4), 70.8 (sec-butyl CH),
77.9 (piperidine C3), 125.2 (triazole CH), 140.6 (triazole C),
169.5 (C=O). m/z (HRMS ESI) 386.2415, [M + H]+ calcd for
C17H32N5O+5 requires 386.2398.
(e) A. J. Salmon, M. L. Williams, A. Innocenti, D. Vullo, C. T.
Supuran, S.-A. Poulsen, Bioorg. Med. Chem. Lett. 2007, 17, 5032.
doi:10.1016/J.BMCL.2007.07.024
[8] (a) L. Poitout, Y. Le Merrer, J.-C. Depezay, Tetrahedron Lett. 1994,
35, 3293. doi:10.1016/S0040-4039(00)76888-2
(b) Y. Le Merrer, L. Poitout, J.-C. Depezay, I. Dosbaa, S. Geoffroy,
M.-J. Foglietti, Bioorg. Med. Chem. 1997, 5, 519. doi:10.1016/S0968-
0896(96)00266-0
[9] (a) J. E. Baldwin, J. Chem. Soc. Chem. Commun. 1976, 734.
doi:10.1039/C39760000734
(b) J. E. Baldwin, R. C. Thomas, L. I. Kruse, L. Silberman, J. Org.
Chem. 1977, 42, 3846. doi:10.1021/JO00444A011
[10] (a)Crystallographic data(excluding structure factors) forcompound 1
has been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC 699227. Copies of the data
Accessory Publication
1H and 13C NMR spectra of compounds 1, 2, 5, 8–10, 19a,
19b (1H only), 19c, 19d, and 21d are provided. A cif file for
compound 1 is also provided on the Journal’s website.

Synthesis of N-Propargyl Iminosugar Scaffolds
829
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: +44-(0) 1223–336033 or email:
deposit@ccdc.cam.ac.uk).
(b) For a related stereoisomer see: E. Bozo, A. Medgyes, S. Boros,
J. Kuszmann, Carbohydrate Res. 2000, 329, 25.
(e) Y. C. Zeng, Y. T. Pan, N. Asano, R. J. Nash, A. D. Elbein, Glyco-
biology 1997, 7, 297.
(f) P. B. Fischer, G. B. Karlsson, T. D. Butters, R. A. Dwek, F. M. Platt,
J. Virol. 1996, 70, 7143.
[12] (a) O. Berteau, R. Stenutz, Carbohydr. Res. 2004, 339, 929.
doi:10.1016/J.CARRES.2003.11.008 (http://www.chem.qmul.ac.uk/
iupac/2carb/34.html)
[11] (a) T. D. Butters, L. A. G. M. van den Broek, G. W. J. Fleet, T. M.
Krulle, M. W. Wormald, R. A. Dwek, F. M. Platt, Tetrahedron Asym-
metry 2000, 11, 113. doi:10.1016/S0957-4166(99)00468-1
(b)T. D. Butters, R.A. Dwek, F. M. Platt, Chem. Rev. 2000, 100, 4683.
doi:10.1021/CR990292Q
(b) A. D. McNaught, Carbohydr. Res. 1997, 297, 1. doi:10.1016/
S0008-6215(97)83449-0
(c) A. D. McNaught, Pure Appl. Chem. 1996, 68, 1919. doi:10.1351/
PAC199668101919
(c)T. D. Butters, R.A. Dwek, F. M. Platt, Glycobiology 2005, 15, 43R.
doi:10.1093/GLYCOB/CWI076
(d) R. Inmaculada, A. J. Moreno-Vargas, A. T. Carmona, P. Vogel,
Curr. Drug. Metabol. 2004, 5, 329. doi:10.2174/1389200043335513
[13] J. Spreitz, A. E. Stütz, T. M. Wrodnigg, Carbohydr. Res. 2002, 337,
183. doi:10.1016/S0008-6215(01)00291-9