Ferrier-type N-glycosylation: Synthesis of N-glycosides of enone sugars

Article abstract of DOI:10.1021/jo302619b

A mild and efficient protocol for the stereoselective synthesis of N-glycosides of enone sugars has been developed. The reaction proceeds to provide N-glycosides of enone sugars in moderate to good yields with preferential α-anomeric selectivity. Additionally, applications of the N-glycosides of enone sugar derivatives as precursor to assemble some biochemically functional derivatives have also been explored. This includes the use of N-glycosides of enone sugars as reactive dienophile in asymmetric synthesis of bicyclic adduct through Diels-Alder cycloaddition reaction.

Full text of DOI:10.1021/jo302619b

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Note
Ferrier-type N-Glycosylation: Synthesis of N-Glycosides of Enone Sugars
Feiqing Ding, Ronny William, and Xue-Wei Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo302619b • Publication Date (Web): 04 Jan 2013
Downloaded from http://pubs.acs.org on January 12, 2013
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Ferrier-type N-Glycosylation: Synthesis of
N-Glycosides of Enone Sugars
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Feiqing Ding, Ronny William and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link,
Singapore 637371, Email: xuewei@ntu.edu.sg
Abstract: A mild and efficient protocol for the stereoselective synthesis of
N-glycosides of enone sugars has been developed. The reaction proceeds to provide
N-glycosides of enone sugars in moderate to good yields with preferential α-anomeric
selectivity. Additionally, the applications of the N-glycosides of enone sugar
derivatives as precursor to assemble some biochemically functional derivatives have
also been explored. This includes the use of N-glycosides of enone sugars as reactive
dienophile in asymmetric synthesis of bicyclic adduct through Diels-Alder
cycloaddition reaction.
Structurally-defined nucleosides with N-glycosidic linkage have attracted a great
deal of interest academically in view of their extensive applicability as
pharmacological agents including antibiotic, antineoplastic and antiviral compounds.1
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Specifically, N-glycosides of enone sugars have emerged with potential applications
in the development of antitumor-cancer oriented ketonucleosides2 and optically active
bicyclic lactams (Fig.1).3 It is well established that oligosaccharides and
glycoconjugates containing O-glycosidic bonds are prone to chemical or enzymatic
hydrolysis leading to cleavage of glycosyl linkage and degradation. To address this
issue, tremendous efforts have been directed towards structural modification of
naturally occurring carbohydrates over the past few decades.4 Needless to say, the
development of more convenient method to access to structurally modified
N-glycosides of enone sugars which are more biologically stable is highly desirable.
Although 2,3-unsaturated glycals, which are traditionally obtained by Ferrier
rearrangement,5 have inspired many studies, the structural diversity and approaches
toward N-pseudoglycals remain limited.6 Moreover, there are only few methods
available for the synthesis of enoside O-glycosides or N-glycosides of enone sugars.7
Nevertheless, the stereoselective synthesis of N-glycosides of enone sugars is still
inadequate by virtue of the lack of advancement in methodological development for
N-glycosides. Recently, we derived a strategy for ready access to
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Fig. 1 Structures of cancer oriented ketonucleosides and optically active bicyclic
lactams.
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3-arylsulphonamino-2,3-dideoxysugars via regio- and stereoselective tandem
hydroamination/glycosylation of glycal (Fig. 2, eqn (1)).8 During our efforts to
extend the method to include 2-OAc substituted glycal, serendipitious formation of
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N-glycosides
of
enone
sugars
instead
of
the
anticipated
3-arylsulphonamino-2,3-dideoxy product was observed. In conjunction with our
previous work, herein, we report a novel design for the stereoselective synthesis of
N-glycosides of enone sugars through BF3·Et2O-promoted glycal rearrangement (Fig.
2, eqn (2)).
Fig. 2 Our previous work and new design of quick access to N-glycosides of enone
sugars.
Initially, a systematic screening was executed using 1a and p-toluenesulfonamide 2a
(TsNH2) in the presence of BF3·Et2O to establish the ideal reaction conditions (Table
1). The first evaluation was conducted with different concentration of BF3·Et2O as
promoter at room temperature, whereby DCM was employed as reaction solvent. We
found that 4.4 equiv. of BF3·Et2O was required to promote the reaction and achieve
excellent selectivity for the formation of N-glycoside of enone sugar 3ab with 89%
yield (Table 1, entry 5). It is notable that when promoter loading as low as 0.5-2.2
equivalent was used, the reaction favored the Ferrier rearranged 2,3-unsaturated
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glycosides 4 as the major product (Table 1, entries 1-3). Furthermore, 4.4 equivalence
of BF3·Et2O led to a promising anomeric selectivity with α:β ratio of 84:16.
Subsequently, the use of other Lewis acids as promoter (TMSOTf, TESOTf, SnCl4,
TiCl4 and Sc(OTf)3) also afforded the desired products of N-glycosides of enone
sugars 3ab and 2,3-unsaturated glycosides 4, albeit with incomplete conversion and
poor selectivity (Table 1, entries 6-9, 11). In contrast, treatment of the reaction with
Cu(OTf)2 exhibited no reaction whereas with TfOH complex mixture of products
were obtained (Table 1, entries 10, 12). Next, screening was performed in various
solvents namely THF, toluene, CH3CN and DMF. It is found that when DCM was
used as solvent, the desired product was produced in the highest yield and selectivity
(Table 1, entries 13-16). A decrement in reaction temperature adversely affected the
yield and selectivity after prolonged reaction time. Thus, the optimized conditions
were found to include the employment of 4.4 equivalence of BF3·Et2O with DCM as
the solvent and stirring at room temperature under nitrogen atmosphere for 20
minutes.
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Under the optimized conditions obtained, the scope and generality of stereoselective
synthesis of N-glycosides of enone sugars 3a-3m promoted by BF3·Et2O was
examined extensively. A range of nitrogen derived nucleophiles with various
substituent (R) groups was screened and the results were summarized in Table 2. To
our delight, the pure α isomer can be easily separated by purification with flash
column chromatography and the isolated yields of the pure isomer ranged from
moderate to good. In general, aromatic sulfonamides (2a, 2c to 2f) afforded the
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Table 1 Optimization for synthesis of N-glycosides of enone sugars
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yieldb(%)
promoter
α/βc
(3ab)
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entry
solvent
DCM
DCM
DCM
DCM
DCM
(equiv.)
3ab
4
BF3·OEt2 (0.5)
1
2
3
4
5
20
63
NDd
BF3·OEt2 (1.1)
BF3·OEt2 (2.2)
BF3·OEt2 (3.3)
BF3·OEt2 (4.4)
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31
57
89
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48
NDd
NDd
24
NDd
trace
84: 16
6
7
TMSOTf (4.4)
TESOTf (4.4)
DCM
DCM
44
55
NDd
NDd
60 : 40
56 : 44
8
9
DCM
DCM
DCM
52
NDd
83
-
58 : 42
NDd
-
SnCl4 (4.4)
TiCl4 (4.4)
trace
NRe
Cu(OTf)2 (4.4)
Sc(OTf)3 (4.4)
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11
12
13
DCM
DCM
THF
72
NDd
72 : 28
TfOH (4.4)
complex
NRe
-
-
-
-
BF3·OEt2 (4.4)
14
15
16
CH3CN
toluene
DMF
78
67
NDd
NDd
-
75 : 25
78 : 22
-
BF3·OEt2 (4.4)
BF3·OEt2 (4.4)
BF3·OEt2 (4.4)
complex
a Isolated yield of anomeric mixtures after purification. b The anomeric ratio was determined on
the crude 1H NMR spectra. c ND = no data. d NR = no reaction.
corresponding N-glycosides of enone sugars (3a, 3c to 3f) in moderate yield and good
anomeric selectivity (Table 2, entries 1 and 2). The only exception is aromatic
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sulfonamides bearing nitro group (2b and 2g) which have shown relatively lower
reactivity with moderate α to β anomeric selectivity. Interestingly, halogen bearing
aromatic sulfonamides (2c and 2d) provided good yield and superior anomeric
selectivity with α to β ratio of ~90:10. Subsequently, methanesulfonamide 2h
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Table 2. Scope of the synthesis of N-glycosides of enone sugars
O
AcO
AcO
BF3 OEt2
O
NHR
O
AcO
RNH2
OAc
DCM
rt, 20 min
OAc
2
1a
3
entry
RNH2
productb
yieldc
(%)
α/βd
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74/26
90/10
78/22
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75/25
89/11
68/32
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CbzNH2
2j
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FmocNH2
2k
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1
b
aAll products were characterized by IR, HRMS, H NMR and 13C NMR. Isolated yields of
pure isomer after purification. c The anomeric ratio was determined on the crude H NMR
1
spectra.
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(MsNH2) and trichloromethane-sulfonamide 2i (TecNH2) were also exploited as
viable nucleophile. Reaction of 2-acyloxy glycols with alkylsulfonamide which
provides the desired glycoside with moderate yield and high anomeric selectivity
illustrated the extended feasibility of our reaction (Table 2, entries 3 and 4).
Encouraged by the results, we further investigated the scope of carbamates (2j to 2l)
that can serve as efficient nucleophiles (Table 2, entries 5-7). The enone N-glycoside
3j represent a crucial example as benzyloxycarbonyl (Cbz) group could be
transformed into amines easily following simple protective group chemistry.8a
Likewise, we have attempted the reaction with allyl-substituted aromatic sulfonamide
2m which furnished the corresponding N-glycoside of enone sugar 3m with moderate
yield and selectivity (Table 2, entry 8). The presence of easily functionalized allyl
group allows promising application of the resulting N-glycosides as precursor in
asymmetric synthesis. Overall, this novel synthetic method provides a straightforward
access to a wide range of N-glycosides of enone sugar derivatives, with potential
biochemical applications.
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In our initial attempt to probe the reaction mechanism, we found that when C-4
epimer of 2,3,4,6-tetra-O-acetyl-2-hydroxy-D-glactal (from the corresponding
D-glactal) was reacted under the same reaction conditions, the N-glycoside of enone
sugar formed was of the similar results as that obtained from the corresponding
D-glucal. This observation implies that both acetyl protected D-glucal and D-glactal
led to a common reactive intermediate that eventually converged to the resulting
N-glycoside of enone sugar. Additionally, reaction with p-toluenesulfonamide 2a and
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2,3-unsaturated glycosides 4, similar α/β ratio of 3ab was observed. A plausible
mechanism for the formation of N-glycosides of enone sugars 3 was depicted in
Scheme 1.9 The selectivity for the α isomer in the formation of 3 can be explained by
taking into account the steric course of the glycosylation of 1a combined with
anomeric effect. Our proposed mechanism involves formation of intermediary
allyloxocarbenium ion І as a result of expulsion of acetoxy group. Assuming that 1a
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4
reacts in the preferred H1 conformation, the quasiaxial allylic acetoxy group can be
readily eliminated by coordinating with the Lewis acid. Simultaneous migration of the
double bond (Ferrier’s rearrangement) generates a cation at C-1 that can be stabilized
by participation of the oxygen-ring lone pair. The quasiaxially oriented alkoxy group
at C-4 should induce the attack of the sulfonamide from the opposite face to give the
2-enopyranoside with the α-anomeric configuration. This intermediate ІI undergoes a
β-elimination affording the dihydropyranones 3a.
Scheme 1. Proposed mechanism.
To demonstrate the application of N-glycosides of enone sugars 3 as precursor to
potentially biological active derivatives, compound 3 was subjected to a sequence of
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reactions that consisted of the reduction of ketone functionality followed by
dihydroxylation of the unsaturated double bond (Scheme 2).10 It is noteworthy that
there was a remarkable diastereoselectivity in the reduction of 3a to 5, probably due
to steric hindrance imposed by anomeric substituent adjacent to the carbonyl group.11
Chemical structure determination and stereochemical characterization of 5a were
achieved by extensive and detailed 1D and 2D NMR studies.12 The subsequent
dihydroxylation13 of 5 occurred smoothly by diastereofacial selective addition of
osmium tetroxide to the double bond from the same side of the ring as the existing
allylic hydroxy group to afford N-sulfonamidotalose 6.14
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Scheme 2. Synthesis of N-sulfonamidotalose 6.
In similar manner, we have prepared the 6-deoxy enone N-glycoside derivative 3n
which has various possible synthetic and biochemical applications. The starting
Scheme 3. Synthesis of 6-deoxy enone N-glycoside 3n.
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2,3,4-tri-O-acetyl-6-deoxy-L-rhamnal 1b was synthesized from L-rhamnose according
to a literature reported procedure (Scheme 3).12, 15
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Optically active dihydropyranones derived from common sugars are useful chiral
templates for the synthesis of natural products and their analogues.16 To explore the
reactivity of N-glycoside of enone sugar derivative 3o as dienophile, optically active
pure 2,6-dihydropyran-3-one 7 has been prepared through Diels-Alder cycloaddition
with 2,3-dimethylbutadiene (Scheme 4).9c, 9d, 17 As expected, the presence of chiral
centre at the anomeric position which induces asymmetry during the cycloaddition
reaction led to preponderant formation of a diastereomer. The high diastereofacial
selectivity in the cycloaddition provides reliable entry to optically active
tetrahydrobenzopyranones possessing a number of contiguous stereogenic centers
established in a desired manner. However, the Diels-Alder cycloaddition with
C5-substituted N-glycosides of enone sugars 3a and 3n, no desired cycloproducts
were obtained as well.
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Scheme 4. Synthesis of 2,6-dihydropyran-3-one 7.
In conclusion, we have developed a new protocol for stereoselective synthesis of
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N-glycosides of enone sugars with a wide range of nitrogen nucleophiles utilizing
BF3·Et2O as promoter. This method would allow the application of N-glycosides of
enone sugar derivatives to expeditiously assemble a wide pool of biologically active
derivatives through a straightforward manner. N-glycosides of enone sugar derivatives
also served as dienophile which underwent Diels-Alder cycloaddition with excellent
diastereofacial selectivity providing a landmark access to optically active bicyclic
adduct, where the multiple stereogenic centered compound could serve as chiral
building block for potential synthesis of complex natural products.
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Experimental Section
General Methods. All solvents were distilled under nitrogen from the following
drying agents immediately before use: tetrahydrofuran (THF) was distilled from
sodium/benzophenone ketyl; dichloromethane and 1,2-dichloroethane were distilled
from calcium hydride. BF3·OEt2 was distilled from calcium hydride before use.
2,3,4,6-tetra-O-acetyl-2-hydroxy-D-glucal
(1a),
2,3,4-tri-O-acetyl-2-hydroxy-L-
rhamnal (1b) and 2,3,4-tri-O-acetyl-2-hydroxy-D-xylal (1c) were prepared from
L-fucose according to literature reported procedure.18 The promoters were purchased
from commercial suppliers and used without further purification. High resolution
mass spectra (HRMS) were recorded on Q-Tof premier mass spectrometer.
General procedure for the synthesis of N-glycisides of enone sugars 3a-3o. To a
solution of 2,3,4,6-tetra-O-acetyl-2-hydroxy-D-glucal 1a (40 mg, 0.12 mmol) and
nitrogen nucleophiles 2 (0.132 mmol, 1.1 equiv) in DCM (4.0 mL) was added
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BF3·OEt2 (62 μL, 0.53 mmol, 4.4 equiv) under N2 atmosphere. The reaction mixture
was stirred at room temperature for 20 min, subsequently quenched with saturated
NaHCO3 (3 mL) and extracted with DCM (3 x 10 mL). The extract was then washed
with brine (2 x 20 mL), dried over Na2SO4 and was concentrated. The residue was
separated using column chromatography (silica gel, hexane/EtOAc system) to obtain
pure N-glycosides of enone sugars 3a-3o.
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Spectroscopic Data for 3a-3o. N-(p-Methylphenylsulfonamido)-6-O-acetyl-3,4-
dideoxy-α-D-glycero-hex-3-eno-pyranoside-2-ulose (3a). Following the general
procedure, the crude product was purified over a silica gel column using
hexane/EtOAc system (8:1 to 4:1) to give a gummy liquid, 30 mg, 75% yield: [α]D
=
21
-9.16 (c 0.5 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 8.0 Hz, 2H), 7.31 (d,
J = 8.0 Hz, 2H), 6.95 (dd, J = 10.4, 2.0 Hz, 1H), 6.17 (dd, J = 10.8, 2.4 Hz, 1H), 5.46
(d, J = 7.2 Hz, 1H), 4.45–4.48 (m, 1H), 4.27 (dd, J = 11.6, 5.2 Hz, 1H), 4.05 (dd, J =
12.0, 4.4 Hz, 1H), 2.43 (s, 3H), 2.06 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 187.8,
170.6, 148.2, 144.1, 137.4, 129.7, 126.6, 80.7, 68.4, 63.8, 21.6, 20.7; IR (CHCl3)
3429, 1739, 1701, 1327, 1153, 1041, 976 cm-1; HRMS (ESI) m/z [M + Na]+ calcd for
C15H17NO6SNa 362.0674, found 362.0681.
N-(p-nitrophenylsulfonamido)-6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-eno-pyrano
side-2-ulose (3b). Following the general procedure, the crude product was purified
over a silica gel column using hexane/EtOAc system (8:1 to 4:1) to give a gummy
liquid, 25 mg, 56% yield: [α]D21 = -7.80 (c 0.5 CHCl3); 1H NMR (CDCl3, 400 MHz) δ
8.39 (d, J = 8.8Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H), 6.99 (dd, J = 10.4, 2.8 Hz, 1H), 6.24
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(dd, J = 10.4, 2.0 Hz, 1H), 5.80 (br, 1H), 5.65 (s, 1H), 4.56–4.60 (m, 1H), 4.41 (dd, J
= 12.0, 4.8 Hz, 1H), 4.22 (dd, J = 12.0, 4.0 Hz, 1H), 2.11 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 187.2, 170.4, 147.7, 145.4, 128.5, 126.6, 124.4, 80.0, 70.0, 63.3, 30.9,
20.7; IR (CHCl3): 3422, 1643, 1350, 1169, 1042, 945cm-1; HRMS (ESI) m/z [M +
Na]+ calcd for C14H14N2O8SNa 393.0369, found 393.0370.
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N-(o-nitrophenylsulfonamido)-6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-eno-pyrano
side-2-ulose (3c). Following the general procedure, the crude product was purified
over a silica gel column using hexane/EtOAc system (8:1 to 4:1) to give a gummy
liquid, 37 mg, 83% yield: [α]D21 = -6.35 (c 0.4 CHCl3); 1H NMR (CDCl3, 400 MHz) δ
8.21 (d, J = 10.0 Hz, 1H), 7.91 (d, J = 10.0 Hz, 1H), 7.78–7.82 (m, 2H), 7.00 (dd, J =
10.4, 2.4 Hz, 1H), 6.44 (d, J = 7.2 Hz, 1H), 6.24 (dd, J = 10.4, 2.4 Hz, 1H), 5.58 (d, J
= 8.4 Hz, 1H), 4.55–4.58 (m, 1H), 4.25 (dd, J = 12.0, 5.2 Hz, 1H), 4.05 (dd, J = 12.0,
4.4 Hz, 1H), 2.06 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 187.7, 170.5, 163.3, 147.9,
131.8, 129.5, 126.6, 114.3, 80.6, 68.7, 63.8, 55.7, 20.7; HRMS (ESI) m/z [M + H]+
calcd for C14H15N2O8S 371.0549, found 371.0529.
N-(p-chlorophenylsulfonamido)-6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-eno-pyran
oside-2-ulose (3d). Following the general procedure, the crude product was purified
over a silica gel column using hexane/EtOAc system (8:1 to 4:1) to give a gummy
liquid, 37 mg, 86% yield: [α]D21 = -45.0 (c 0.5 CHCl3); 1H NMR (CDCl3, 400 MHz) δ
7.87 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 6.97 (dd, J = 10.4, 2.4 Hz, 1H),
6.21 (dd, J = 10.4, 2.0 Hz, 1H), 5.53 (d, J = 7.2 Hz, 1H), 4.52–4.55 (m, 1H), 4.34 (dd,
J = 12.0, 4.8 Hz, 1H), 4.16 (dd, J = 12.0, 4.4 Hz, 1H), 2.09 (s, 3H); 13C NMR (CDCl3,
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100 MHz) δ 187.5, 170.5, 147.8, 139.7, 139.0, 129.4, 128.7, 126.7, 80.3, 69.2, 63.6,
20.7; IR (CHCl3): 3020, 1744, 1701, 1215, 1088 cm-1; HRMS (ESI) m/z [M + Na]+
calcd for C14H14NO6SClNa 382.0128, found 382.0125.
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N-(p-fluorophenylsulfonamido)-6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-eno-pyran
oside-2-ulose (3e). Following the general procedure, the crude product was purified
over a silica gel column using hexane/EtOAc system (8:1 to 4:1) to give a gummy
liquid, 31 mg, 76% yield: [α]D21 = -17.0 (c 0.5 CHCl3); 1H NMR (CDCl3, 400 MHz) δ
7.94-7.97 (m, 2H), 7.21 (t, J = 8.4 Hz, 2H), 6.97 (dd, J = 10.4, 2.4 Hz, 1H), 6.20 (dd,
J = 10.4, 2.4 Hz, 1H), 5.52 (d, J = 7.2 Hz, 1H), 4.50–4.54 (m, 1H), 4.33 (dd, J = 12.0,
5.6 Hz, 1H), 4.14 (dd, J = 12.0, 4.4 Hz, 1H), 2.08 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 187.6, 170.5, 147.9, 140.4, 130.1, 130.0, 126.6, 116.8, 116.3, 80.4, 69.0, 63.6,
20.7; IR (CHCl3): 3429, 1740, 1697, 1339, 1157, 1042, 841 cm-1; HRMS (ESI) m/z
[M + Na]+ calcd for C14H14NO6SFNa 366.0424, found 366.0415.
N-(p-methoxyphenylsulfonamido)-6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-eno-py
ranoside-2-ulose (3f). Following the general procedure, the crude product was
purified over a silica gel column using hexane/EtOAc system (8:1 to 4:1) to give a
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gummy liquid, 31 mg, 73% yield: [α]D21 = -28 (c 0.5 CHCl3); H NMR (CDCl3, 300
MHz): δ 7.88 (d, J = 9.0 Hz, 2H), 6.90–7.02 (m, 3H), 6.21 (dd, J = 10.5, 2.4Hz, 1H),
5.48–5.52 (m, 2H), 4.53–4.56 (m, 1H), 4.36 (dd, J = 11.7, 5.1 Hz, 1H), 4.14 (dd, J =
11.7, 4.5 Hz, 1H), 2.10 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 187.2, 170.4, 147.7,
145.4, 128.5, 126.6, 124.4, 80.0, 70.0, 63.3, 30.9, 20.7; IR (CHCl3): 3422, 1728,
1643, 1339, 1157, 1034 cm-1; HRMS (ESI) m/z [M + Na]+ calcd for C15H17NO7SNa
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378.0623, found 378.0632.
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N-(phenylsulfonamido)-6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-eno-pyranoside-2-
ulose (3g). Following the general procedure, the crude product was purified over a
silica gel column using hexane/EtOAc system (8:1 to 4:1) to give a gummy liquid, 17
mg, 44% yield: [α]D21 = -9.16 (c 0.5 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.94 (d, J
= 4.0 Hz, 2H), 7.54–7.63 (m, 3H), 6.95 (dd, J = 10.4, 2.4 Hz, 1H), 6.19 (dd, J = 10.4,
2.0 Hz, 1H), 5.69 (d, J = 6.8 Hz, 1H), 4.47–4.49 (m, 1H), 4.31 (dd, J = 12.0, 4.8 Hz,
1H), 4.09 (dd, J = 12.0, 4.0 Hz, 1H), 2.07 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
187.6, 170.5, 147.9, 140.4, 133.2, 129.1, 127.2, 126.6, 80.5, 68.8, 63.7, 20.7; IR
(CHCl3): 3429, 1740, 1701, 1450, 1165, 1042cm-1; HRMS (ESI) m/z [M + Na]+ calcd
for C14H15NO6SNa 348.0518, found 348.0514.
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N-(methylsulfonamido)-6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-eno-pyranoside-2-
ulose (3h). Following the general procedure, the crude product was purified over a
silica gel column using hexane/EtOAc system (8:1 to 4:1) to give a gummy liquid, 21
mg, 68% yield: [α]D21 = -11.0 (c 0.5 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.02 (dd,
J = 10.4, 2.8 Hz, 1H), 6.27 (dd, J = 10.4, 2.0 Hz, 1H), 5.63 (d, J = 6.8 Hz, 1H), 5.51
(d, J = 6.0 Hz, 1H), 4.80–4.84 (m, 1H), 4.49 (dd, J = 12.0, 6.0 Hz, 1H), 4.35 (dd, J =
12.0, 4.4 Hz, 1H), 2.11 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 187.8, 170.5, 147.4,
126.8, 80.0, 70.1, 63.5, 43.3, 20.7; IR (CHCl3): 3418, 1732, 1697, 1327, 1153, 1042,
976 cm-1; HRMS (ESI) m/z [M + Na]+ calcd for C9H13NO6SNa 286.0361, found
286.0360.
N-(2’,2’,2’-trichloroethylsulfonamido)-6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-eno
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-pyranoside-2-ulose (3i). Following the general procedure, the crude product was
purified over a silica gel column using hexane/EtOAc system (8:1 to 4:1) to give a
gummy liquid, 32 mg, 71% yield: [α]D21 = -27.7 (c 0.5 CHCl3); 1H NMR (CDCl3, 400
MHz) δ 7.05 (dd, J = 10.4, 2.4 Hz, 1H), 6.29 (dd, J = 10.4, 2.0 Hz, 1H), 5.66 (d, J =
6.8 Hz, 1H), 4.85–4.90 (m, 1H), 4.67–4.77 (m, 1H), 4.51 (dd, J = 12.0, 4.8 Hz, 1H),
4.33 (dd, J = 12.0, 4.0 Hz, 1H), 2.12 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 187.5,
170.5, 147.8, 126.6, 80.2, 78.8, 73.3, 70.5, 63.5, 20.8; IR (CHCl3): 3163, 1732, 1701,
1377, 1188, 1045, 961 cm-1; HRMS (ESI) m/z [M + Na]+ calcd for C10H12NO6SCl3Na
401.9349, found 401.9350.
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N-(benzyloxycarbonylamino)-6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-eno-pyranosi
de-2-ulose (3j). Following the general procedure, the crude product was purified over
a silica gel column using hexane/EtOAc system (8:1 to 4:1) to give a gummy liquid,
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21 mg, 54% yield: [α]D21 = -37.0 (c 0.5 CHCl3); H NMR (CDCl3, 400 MHz) δ
7.33–7.37 (m, 5H), 6.99 (dd, J = 10.4, 2.4 Hz, 1H), 6.25 (dd, J = 10.4, 2.0 Hz, 1H),
5.71 (d, J = 8.0 Hz, 1H), 5.15 (s, 2H), 4.75–4.79 (m, 1H), 4.51 (dd, J = 12.0, 5.2 Hz,
1H), 4.27 (dd, J = 12.0, 4.0 Hz, 1H), 2.09 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
189.2, 170.6, 147.5, 135.6, 128.6, 128.4, 128.3, 127.6, 127.1, 78.6, 70.1, 67.7, 63.9,
20.8; IR (CHCl3): 3418, 1732, 1697, 1369, 1169, 1042, 988 cm-1; HRMS (ESI) m/z
[M + Na]+ calcd for C16H17NO6Na 342.0954, found 342.0959.
N-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-O-acetyl-3,4-dideoxy-α-D-glycero-
hex-3-eno-pyranoside-2-ulose (3k). Following the general procedure, the crude
product was purified over a silica gel column using hexane/EtOAc system (8:1 to 4:1)
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to give a gummy liquid, 22 mg, 46% yield: [α]D21 = -9.56 (c 0.5 CHCl3); H NMR
(CDCl3, 400 MHz) δ 7.77 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 4.4 Hz, 2H), 7.41 (t, J =
7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 2H), 6.99 (dd, J = 10.4, 2.8Hz, 1H), 6.25 (dd, J =
10.4, 2.0 Hz, 1H), 5.69 (d, J = 6.8 Hz, 1H), 4.75–4.82 (m, 1H), 4.47 (d, J = 6.8 Hz,
1H), 4.32 (dd, J = 12.0, 4.8 Hz, 1H), 4.24 (dd, J = 12.0, 4.0 Hz, 1H), 2.10 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 189.2, 170.6, 147.5, 143.6, 141.3, 127.8, 127.1, 125.1,
125.0, 120.0, 78.6, 67.6, 63.9, 47.0, 20.8; IR (CHCl3): 3418, 1694, 1636, 1450, 1161
cm-1; HRMS (ESI) m/z [M + Na]+ calcd for C23H21NO6Na 430.1267, found 430.1270.
N-(ethoxycarbonylamino)-6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-eno-pyranoside-
2-ulose (3l). Following the general procedure, the crude product was purified over a
silica gel column using hexane/EtOAc system (8:1 to 4:1) to give a gummy liquid, 17
mg, 55% yield: [α]D21 = -20.0 (c 0.5 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 6.98 (dd,
J = 10.4, 2. 4Hz, 1H), 6.27 (dd, J = 10.4, 2.8 Hz, 1H), 5.68 (d, J = 8.0 Hz, 1H),
4.76–4.79 (m, 1H), 4.51 (dd, J = 12.0, 4.8 Hz, 1H), 4.34 (dd, J = 12.0, 4.0 Hz, 1H),
4.15–4.28 (m, 2H), 2.11 (s, 3H), 1.27 (t, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 170.7, 170.6, 155.6, 147.5, 127.7, 127.1, 78.6, 73.1, 64.6, 63.9, 61.9, 20.8, 14.2; IR
(CHCl3): 2924, 1736, 1373, 1242, 1034 cm-1; HRMS (ESI) m/z [M + Na]+ calcd for
C11H15NO6Na 280.0797, found 280.0798.
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N-(N-allyl-p-methylphenylsulfonamido)-6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-
eno-pyranoside-2-ulose (3m). Following the general procedure, the crude product was
purified over a silica gel column using hexane/EtOAc system (8:1 to 4:1) to give a
gummy liquid, 19 mg, 42% yield: [α]D21 = -64.4 (c 0.5 CHCl3); 1H NMR (CDCl3, 400
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MHz) δ 7.79 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.96 (dd, J = 10.4, 2.4 Hz,
1H), 6.29 (dd, J = 10.4, 2.0 Hz, 1H), 5.58–5.68 (m, 1H), 5.13 (dd, J = 17.2, 1.6 Hz,
1H), 5.05 (dd, J = 14.4, 1.6 Hz, 1H), 4.82–4.85 (m, 1H), 4.46 (dd, J = 12.0, 5.2 Hz,
1H), 4.25 (dd, J = 12.0, 4.0 Hz, 1H), 3.79–3.86 (m, 1H), 2.43 (s, 3H), 2.11 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 188.8, 170.3, 146.4, 143.9, 136.5, 133.2, 129.5, 128.3,
127.9, 118.8, 84.4, 70.4, 64.3, 49.1, 21.6, 20.8; ; IR (CHCl3): 1730, 1705, 1311, 1183,
1045, 956 cm-1; HRMS (ESI) m/z [M + Na]+ calcd for C18H21NO6SNa 402.0987,
found 402.0988.
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N-(p-methylphenylsulfonamido)-6-methyl-3,4-dideoxy-D-rhamnal-hex-3-eno-pyranosi
de-2-ulose (3n and 3nb). Compounds 3n (gummy liquid, 48 mg, 68% yield) and 3nb
(gummy liquid, 13 mg, 19% yield) were prepared according to the general procedure
from 2,3,4-tri-O-acetyl-2-hydroxy-L-rhamnal 1b (68 mg, 0.25 mmol),
p-toluenesulfonamide 2a (47 mg, 0.275 mmol, 1.1 equiv) and BF3·OEt2 (138 μL, 1.1
mmol, 4.4 equiv), and the crude product was purified over a silica gel column using
hexane/EtOAc system (8:1 to 4:1). 3n: 1H NMR (CDCl3, 400 MHz) δ 7.81 (d, J = 8.0
Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.91 (dd, J = 10.4, 1.6 Hz, 1H), 6.03 (d, J = 10.4 Hz,
1H), 5.90 (br, 1H), 5.36 (d, J = 8.0 Hz, 1H), 4.34–4.38 (m, 1H), 2.43 (s, 3H), 1.24 (d,
J = 6.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 188.3, 153.4, 143.9, 137.6, 129.6,
127.3, 124.3, 80.2, 65.8, 21.6, 18.6; IR (CHCl3): 3023, 1746, 1715, 1334, 1176, 1042,
954 cm-1; HRMS (ESI) m/z [M + Na]+ calcd for C13H15NO4SNa 304.0619, found
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304.0614. 3nb: H NMR (CDCl3, 400 MHz) δ 7.81 (d, J = 8.4 Hz, 2H), 7.28 (d, J =
8.0 Hz, 2H), 6.90 (dd, J = 10.0, 1.6 Hz, 1H), 6.10 (dd, J = 10.0, 2.4 Hz, 1H), 5.92 (d,
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J = 6.0 Hz, 1H), 5.26 (dd, J = 6.0, 1.6 Hz, 1H), 4.63–4.69 (m, 1H), 2.41 (s, 3H), 1.32
(d, J = 6.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 189.3, 153.4, 143.7, 138.1, 129.5,
127.2, 125.2, 82.1, 70.9, 21.5, 20.3; HRMS (ESI) m/z [M + Na]+ calcd for
C13H15NO4SNa 304.0619, found 304.0617.
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(S)-4-methyl-N-(3-oxo-3,6-dihydro-2H-pyran-2-yl)benzenesulfonamide(3o).
Compound 3o was prepared according to the general procedure from
2,3,4-tri-O-acetyl-2-hydroxy-D-xylal 1c (64.5 mg, 0.25 mmol), p-toluenesulfonamide
2a (47 mg, 0.275 mmol, 1.1 equiv) and BF3·OEt2 (138 μL, 1.1 mmol, 4.4 equiv), and
the crude product was purified over a silica gel column using hexane/EtOAc system
(8:1 to 4:1) to give a gummy liquid, 54 mg, 78% yield: 1H NMR (CDCl3, 400 MHz) δ
7.81 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 6.90 (dq, J = 10.4, 2.4 Hz, 1H),
6.10 (dq, J = 10.4, 1.6 Hz, 1H), 5.87 (d, J = 6.4 Hz, 1H), 5.27 (dd, J = 6.4, 1.6 Hz,
1H), 4.39–4.54 (m, 2H), 2.42 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 188.7, 149.2,
143.9, 137.8, 129.7, 127.1, 125.6, 82.3, 63.9, 21.6; IR (CHCl3): 3033, 1748, 1356,
1201, 1056 cm-1; HRMS (ESI) m/z [M + Na]+ calcd for C13H15NO4SNa 304.0619,
found 304.0617.
Synthetic procedure and characterization for 5 and 6. To a solution of compound
3a (50 mg, 0.15 mmol) in dry MeOH (1 mL) was added CeCl3·7H2O (15 mg, 0.04
mmol). After stirring for 10min at room temperature, the solution was cooled down to
0oC, and NaBH4 (6 mg, 0.15 mmol) was added with stirring for 30 min. After the
workup, the crude syrup, which showed a main product by TLC (Rf = 0.3,
DCM/MeOH = 10:1), was purified by flash chromatography (DCM/MeOH = 10:1) to
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afford the corresponding alcohol 5 (40 mg, yield: 84%). Compound 5 (40 mg, 0.12
mmol) was dissolved in a mixture of tert-butyl alcohol (250 μL) and water (25 μL)
and N-methylmorpholine N-oxide was added (12 mg, 0.12 mmol). The resulting
solution, cooled to 0°C, was treated with 2% (w/v) OsO4 in tert-butyl alcohol (10 μL).
After stirring at room temperature for 16 h, the mixture was diluted with tert-butyl
alcohol and stirred with NaHSO3. After filtration, the residue was washed with
tert-butyl alcohol, and the filtrate was concentrated to give the 8:1 mixture of isomers,
determined from the 1H NMR spectrum. The crude syrup was purified by flash
chromatography (DCM/MeOH = 10:1) to afford the pure major isomer 6 (14 mg,
yield of pure 6: 64%). 5: 1H NMR (CDCl3, 400 MHz) δ 7.83 (d, J = 8.0 Hz, 2H), 7.29
(d, J = 8.0 Hz, 2H), 6.95 (dq, J = 10.4, 2.4 Hz, 1H), 6.17 (dq, J = 10.4, 0.8 Hz, 1H),
5.30-5.33 (m, 1H), 4.19–4.21 (m, 1H), 4.09–4.13 (m, 2H), 4.03 (dd, J = 12.0, 4.0 Hz,
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1H), 2.42 (s, 3H), 2.08 (s, 3H), 1.67 (br, 1H); C NMR (CDCl3, 100 MHz) δ 170.6,
143.6, 138.5, 129.5, 128.8, 127.9, 127.2, 78.7, 70.6, 64.4, 63.0, 21.6, 20.8; HRMS
(ESI) m/z [M + Na]+ calcd for C15H19NO6SNa 364.0831, found 364.0833. 6: 1H NMR
(CDCl3, 400 MHz) δ 7.82 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.78 (d, J =
9.2 Hz, 1H), 5.37 (t, J = 1.6 Hz, 1H), 4.33 (d, J = 11.6 Hz, 1H), 4.27 (d, J = 0.8 Hz,
1H), 3.76 (t, J = 2.4 Hz, 1H), 3.36–3.41 (m, 3H), 3.23 (br, 3H), 2.43 (s, 3H), 2.08 (s,
13
3H); C NMR (CDCl3, 100 MHz) δ 170.6, 143.7, 138.5, 129.6, 129.5, 127.3, 127.2,
81.3, 72.0, 66.5, 65.8, 62.6, 29.7, 21.5, 20.8; HRMS (ESI) m/z [M + Na]+ calcd for
C15H21NO8SNa 398.0886, found 398.0884.
Synthetic procedure and characterization for cycloadducts 7. The compound 3o
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(50 mg, 0.18 mmol) was weighed into a vial equipped with a magnetic stirrer and
septum seal. The anhydrous solvent (0.5 mL) was added, and the vial was flushed
with dry argon and sealed. The mixture was cooled to -18°C, and BF3·OEt2 (27 mg,
0.18 mmol) was added. The mixture was stirred at -18°C for 5 min, and the flask was
placed in a bath at the temperature desired for the cycloaddition. A solution of the
2,3-dimethyl-1,3-butadiene (26 mg, 0.32 mmol) in the dry solvent (0.6 mL) was then
slowly injected, and the temperature was maintained for 20 min. The reaction mixture
was diluted with ethyl ether (10 mL), except for the reaction in CH2Cl2 in which case
the same solvent was used for the dilution. The resulting solution was washed with
satd aq NaHCO3, satd aq NaCl, dried (MgSO4), and concentrated. The residue was
purified by flash chromatography (10-30% EtOAc in hexane) to afford the pure
cycloadducts 7 (41 mg, yield of pure 7: 67%): 1H NMR (CDCl3, 400 MHz) δ 7.79 (d,
J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 5.97 (d, J = 8.0 Hz, 1H), 5.13 (d, J = 6.8 Hz,
1H), 4.10 (dd, J = 12.0, 2.4 Hz, 1H), 3.77 (d, J = 12.0 Hz, 1H), 2.97 (t, J = 6.4 Hz,
1H), 2.44–2.48 (m, 2H), 2.41 (s, 3H), 2.44–2.48 (m, 2H), 2.01–2.14 (m, 3H), 1.79 (dd,
J = 12.8, 4.8 Hz, 1H), 1.64 (s, 3H), 1.55 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 201.2,
143.5, 138.3, 129.5, 127.0, 123.4, 122.3, 83.9, 69.4, 47.3, 39.3, 31.3, 29.0, 21.5, 19.1,
18.6; HRMS (ESI) m/z [M + Na]+ calcd for C18H23NO4SNa 372.1245, found
372.1241.
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Acknowledgements
We gratefully acknowledge Nanyang Technological University (RG50/08) and the
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Ministry of Education, Singapore (MOE 2009-T2-1-030) for the financial support of
this research.
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Supporting Information
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Copies of NMR spectra of novel compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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