Glycosidase inhibition by all 10 stereoisomeric 2,5-dideoxy-2,5- iminohexitols prepared from the enantiomers of glucuronolactone

Article abstract of DOI:10.1021/jo301243s

The enantiomers of glucuronolactone are excellent chirons for the synthesis of the 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols by formation of the pyrrolidine ring by nitrogen substitution at C2 and C5, with either retention or inversion of configurat

Full text of DOI:10.1021/jo301243s

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Glycosidase Inhibition by All 10 Stereoisomeric 2,5-Dideoxy-2,5-
iminohexitols Prepared from the Enantiomers of Glucuronolactone
Benjamin J. Ayers,† Nigel Ngo,† Sarah F. Jenkinson,†,‡ R. Fernando Martínez,† Yousuke Shimada,§
Isao Adachi,§ Alexander C. Weymouth-Wilson,∥ Atsushi Kato,*,§ and George W. J. Fleet*,†,‡
†Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
‡Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
§Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
∥Dextra Laboratories Ltd., The Science and Technology Centre, Whiteknights Road, Reading RG6 6BZ, U.K.
S
* Supporting Information
ABSTRACT: The enantiomers of glucuronolactone are
excellent chirons for the synthesis of the 10 stereoisomeric
2,5-dideoxy-2,5-iminohexitols by formation of the pyrrolidine
ring by nitrogen substitution at C2 and C5, with either
retention or inversion of configuration; the stereochemistry at
C3 may be adjusted during the synthesis to give seven
stereoisomers from each enantiomer. A definitive side-by-side
comparison of the glycosidase inhibition of a panel of 13
glycosidases showed that 8 of the 10 stereoisomers showed
significant inhibition of at least one glycosidase.
(DGDP) 2D with I5−R3−I2 from the D-glucuronolactone 1D.
DGDP 2D can also be formed by a longer sequence R5−R3−
R2 from the same acetonide, 1D. This pyrrolidine is not
available from the L-enantiomer 1L. Similarly, the L-gluco
enantiomer 2L is accessible via identical sequences from the
readily available acetonide of L-glucuronolactone 1L.14 In
contrast, there is a single sequence for the syntheses from the
acetonide 1D of the two C2-symmetric stereoisomers, D-manno
(DMDP) 3D [by R5−R3−I2] and L-ido 4L [I5−R3−R2]. The
enantiomers L-manno (L-DMDP) 3L [by R5−R3−I2] and D-
ido 4D [I5−R3−R2] are thus identically available from the
acetonide 1L. The D-altro isomer 5D is obtained in the same
number of steps from either 1D [R5−I3−I2] or from 1L [I5−
I3−R2]; the L-altro isomer 5L is similarly accessible from both
1L and 1D. The meso-diastereomer galacto 6 [I5−I3−I2] was
obtained in identical sequences from 1D and 1L. meso-allo 7
[R5−I3−R2] was similarly accessed from both enantiomers of
acetonide 1. Thus, the D-acetonide 1D forms seven stereo-
isomers, whereas another seven are formed with the epimeric
configuration at C4 from the L-enantiomer 1L.
INTRODUCTION
■
The chemotherapeutic potential of iminosugars is due to the
inhibition of glycosidases and interaction with other sugar
receptors and metabolizing enzymes.1−4 Glucuronolactone 1D
has been used as the starting material for many homochiral
targets,5−12 including iminosugars.13 This paper reports the
synthesis from the enantiomers of glucuronolactone of all 10
stereoisomeric 2,5-dideoxy-2,5-iminohexitols, three of which
have been isolated from plants. Intermediates in the syntheses
also allow access to any of 16 stereoisomeric lactones as
precursors to a wide range of hydroxylated prolines and their
derivatives. A side-by-side comparison showed that 8 of the 10
stereoisomers gave significant inhibition of varying glycosidases.
The strategy for the synthesis of the 10 stereoisomeric 2,5-
dideoxy-2,5-iminohexitols is shown in Figure 1. There are four
pairs of enantiomers and two meso forms. For all of them, the
exocyclic primary alcohols result from reduction of C1 and C6
of glucuronolactone. The acetonide 1D has a single
unprotected hydroxyl group at C5 that allows introduction of
nitrogen by azide at C5 with either inversion (I5) or retention
(R5) of configuration. The stereochemistry at C3 (R3, I3) and
C2 can be adjusted, with subsequent nucleophilic displacement
of leaving groups at C2 (R2, I2), by nitrogen derived from the
azide at C5 forming the pyrrolidine ring. Access to C4 is not
possible; however, identical sequences starting from the
acetonide of L-glucuronolactone 1L allow access to epimers at
C4.
RESULTS AND DISCUSSION
■
The diols 8L and 9D are the key intermediates in the synthesis
of all 2,5-dideoxy-2,5-iminohexitol stereoisomers. Compounds
8L and 9D are formed by the introduction of nitrogen as azide
at C5 with inversion (I5) or retention (R5) of configuration,
Since the ring is formed by nucleophilic displacements at C2
Received: June 15, 2012
and C5, the shortest synthesis is that of the D-gluco isomer
© XXXX American Chemical Society
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Figure 1. Ten stereoisomeric 2,5-dideoxy-2,5-iminohexitols showing the configurational changes R (retention) or I (inversion) required at C5−C3−
C2 of the enantiomers of glucuronolactone acetonide 1D and 1L.
Scheme 1. Synthesis of Diols 8L and 9D as Key Intermediates for All 10 Stereoisomers of 2,5-Dideoxy-2,5-iminohexitols
reduction of C6 to a primary alcohol, and inversion (I3) or
retention (R3) of the hydroxyl group at C3 (Scheme 1). The
acetonide 1D, with only the C5 OH group unprotected, is
formed in 96% yield from D-glucuronolactone. Nucleophilic
substitution α to a carbonyl group, even when β-oxygens are
present, generally proceeds in high yield; thus, esterification of
the free alcohol in 1D with trifluoromethanesulfonic (triflic)
anhydride affords the corresponding triflate ester, which on
treatment with sodium azide in DMF forms the azido-lactone
10L in 92% yield with inversion of configuration at C5 (I5).15
Reaction of the triflate of 1D with trifluoroacetate as an
oxygen nucleophile gives the epimeric ido-acetonide 11L with
inversion of configuration at C5.16 Triflation of 11L followed
by azide displacement affords the azide 12D with overall
retention of configuration at C5 from 1D (R5) in an overall
yield of 84%.17 Both of the epimeric azido-lactones 10L and
12D are stable, but highly base sensitive. Nonetheless, efficient
two-step reductions of 10L and 12D by DIBALH followed by
sodium borohydride afford the epimeric diols 13L and 9D in
overall 70% and 71% yields, respectively, from D-glucurono-
lactone acetonide 1D on a multigram scale. The piperidine ring
in a large scale synthesis of DNJ 14 was formed from reduction
of the azide at C5 in the diol 9D followed by intramolecular
reductive amination with an aldehyde at C1.17 The
configuration at C3 in 13L may be inverted by oxidation of
C3 to the corresponding ketone followed by reduction with
sodium borohydride to afford diol 8L (I3).18 Diol 8L is a key
intermediate in the scalable synthesis of the potent α-
galactosaminidase inhibitor DGJNAc 15,19 in which the
nitrogen at C5 forms the exocyclic NHAc group and the
piperidine ring is formed by linking with nitrogen between C2
and C6.
The diol 13L, formed from 1D in 70% yield by I5-R3, was
converted into the triflate 19L as a common intermediate for
the synthesis of D-gluco (DGDP) 2D and L-ido 4L isomers
(Scheme 2). Reaction of 13L with benzyl bromide and sodium
hydride in DMF gave the dibenzyl ether 16L (73%). Hydrolysis
of the acetonide 16L with tosic acid in aqueous dioxane
afforded the lactols 17L (97%) which on oxidation with iodine
in 2-methyl-2-propanol in the presence of potassium carbonate
formed the lactone 18L (72%). Esterification of the only free
hydroxyl group in 18L with triflic anhydride in the presence of
pyridine in dichloromethane gave the stable triflate 19L (95%).
The overall yield of 19L from 13L was 48%.
The triflate α to the carbonyl group in 19L is susceptible to
easy intra- or intermolecular nucleophilic substitution. Thus,
catalytic hydrogenation of the azide 19L in ethanol in the
presence of 10% palladium on charcoal gave the corresponding
amine which spontaneously cyclized to the unstable bicyclic
lactone 20L; reduction of 20L by sodium borohydride in
ethanol, followed by further hydrogenation in the presence of
hydrochloric acid, gave DGDP20 2D in 80% yield [39% from
diol 13L, 27% from 1D].
For the L-ido isomer 4L, treatment of the triflate with sodium
trifluoroacetate gave the inverted alcohol 21L in 90% yield.
Mesylation of 21L with methanesulfonyl chloride in pyridine
formed the mesylate 22L (93%) which with sodium
borohydride in ethanol/dioxane gave the open chain azido-
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a
Scheme 2. Synthesis of ido- and gluco-2,5-Dideoxy-2,5-iminohexitols from Diols 13 Derived from Glucuronolactone by I5−R3
a
Reagents and conditions: (i) NaH, PhCH2Br, DMF, 73%; (ii) TsOH, dioxane/water, 7:1, 97%; (iii) I2, K2CO3, t-BuOH, 72%; (iv) (CF3SO2)2O,
pyridine, CH2Cl2, 95%; (v) 10% Pd/C, H2, EtOH; (vi) NaBH4, EtOH, then 10% Pd/C, H2, HCl, EtOH, 80% from 19L; (vii) (CF3SO2)2O, pyridine,
CH2Cl2, then CF3CO2Na, DMF, 90%; (viii) MsCl, pyridine, 93%; (ix) NaBH4, EtOH/dioxane, 8:1, 82%; (x) 10% Pd/C, H2, CH3CO2Na, dioxane,
then add HCl, 92%
mesylate 23L (82%). Initial hydrogenation of 23L in ethanol in
the presence of 10% palladium and sodium acetate caused
reduction to the amine, cyclization to the pyrrolidine, and
partial removal of the benzyl groups; further hydrogenation
with the addition of hydrochloric acid gave the L-ido27 isomer
4L (92%) in 32% overall yield from 13L (23% from 1D). The
L-gluco 2L and D-ido 4D isomers were prepared by identical
sequences from L-glucuronolactone 1L.
The synthesis of DGDP 2D from 13L in Scheme 2 required
I5−R3−I2. An alternative approach to 2D from diol 9D, with
R5−R3−R2, is shown in Scheme 3. The diol 9D was first
converted to the lactone 24D as previously described in an
overall yield of 70%.17 Esterification of the C2 hydroxyl group α
to the lactone carbonyl in 24D gave the corresponding triflate
which underwent a clean SN2 reaction with sodium
trifluoroacetate in DMF to afford the epimeric alcohol 26D
(85%). Treatment of 26D with mesyl chloride formed the
mesylate 27D (99%) which on reduction with sodium
borohydride in methanol gave the diol 28D (50%). Catalytic
hydrogenation of the azido-mesylate 28D with 10% palladium
in dioxane, initially in the presence of sodium acetate to ensure
facile cyclization to the pyrrolidine, and subsequently in the
presence of hydrochloric acid to hydrogenolyze the benzyl
protecting groups, gave D-gluco 2D (100%). The overall yield of
2D was 29% from the diol 9D and 21% from glucuronolactone
1D.
The lactone 24D was a divergent intermediate for both the
synthesis of DGDP 2D and DMDP32 3D. 24D was converted
to DMDP 3D via the relatively stable bicyclic lactone 25D as
previously reported17 in an overall yield of 56% from the diol
9D [40% from glucuronolactone 1D]. The enantiomeric L-gluco
2L and L-manno 3L were similarly prepared from L-
glucuronolactone 1L.
An inversion of configuration at C3 of 9D was required for
the synthesis of the lactone 35D as a divergent intermediate in
the synthesis of the D-altro38 5D and meso-allo41 7 isomers
(Scheme 4). Nucleophilic substitution of the secondary triflate
from 29D, which lacks an α-carbonyl group, was not efficient
due to the steric hindrance of the isopropylidene protecting
group being on the same side as the incoming nucleophile.
Accordingly, the primary alcohol group in 9D was selectively
protected by reaction with tert-butyldimethylsilyl (TBDMS)
chloride in pyridine to give the silyl ether 29D (92%) which, on
oxidation with Dess−Martin periodinane, gave the ketone 30D
(95%). Reduction of 30D by sodium borohydride in ethanol
was completely stereoselective, with hydride attack from the
less hindered side, to give the epimeric silyl ether 31D (93%).
Removal of the silyl protecting group in 31D with
tetrabutylammonium fluoride (TBAF) in THF gave 32D
(98%); subsequent protection of both the C3 and C6 hydroxyl
groups with benzyl bromide and sodium hydride in DMF
afforded the dibenzyl ether 33D (88%). Hydrolysis of the
isopropylidene protecting group in 33D by tosic acid in
C
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diol 13L was converted to the C3 epimer 8L in 66% yield as
previously reported (I5−I3) (Scheme 5).18 The diol 8L with
benzyl bromide and sodium hydride in DMF gave the dibenzyl
ether 42L (99%). Hydrolysis of the isopropylidene protecting
group in 42L by tosic acid in aqueous dioxane afforded the
lactols 43L (95%) in which C1 was protected by oxidation with
iodine in 2-methyl-2-propanol in the presence of potassium
carbonate to give the lactone 44L (80%); 44L, a common
intermediate for the synthesis of both targets 5L and 6, was
prepared in overall yield of 50% from 13L.
Scheme 3. Synthesis of gluco- and manno-2,5-Dideoxy-2,5-
iminohexitols from Diols 9 Derived from Glucuronolactone
a
by R5−R3
For the synthesis of the meso-galacto isomer 6, initial
conversion of 44L to the triflate 47L (80%) followed by
reduction of the azide to the amine produced a complex
mixture. Accordingly, conversion of 44L by mesyl chloride in
pyridine to the mesylate 45L (95%), followed by reduction
with sodium borohydride in ethanol/dioxane formed 46L
(65%). Hydrogenation of 46L in dioxane in the presence of
10% palladium and sodium acetate, followed by addition of
hydrochloric acid to the hydrogenation mixture, gave the meso-
galacto analogue 6 (91%) in 28% overall yield from 13L (20%
from 1D). Inversion of configuration at C2 of the lactone 44L
was necessary for access to the L-altro isomer 5L. The triflate
47L, formed by esterification with triflic anhydride, with
sodium trifluoroacetate in DMF gave the epimeric alcohol 48L
(72%). Mesylation of 48L to give 49L (78%), followed by
reduction by sodium borohydride, afforded 50L (89%) which
on catalytic hydrogenation formed L-altro 5L (92%); the overall
yield of 5L from the diol 13L was 23% (16% from 1D). The D-
altro 5D and meso-galacto 6 isomers were also prepared by
identical sequences from L-glucuronolactone 1L.
a
Reagents and conditions: (i) 24D from 9D, 70%;17 (ii) 3D from 9D,
56%;17 (iii) (CF3SO2)2O, pyridine, CH2Cl2, then CF3CO2Na, DMF,
85% from 24D; (iv) MeSO2Cl, pyridine, 99%; (v) NaBH4, EtOH/
dioxane, 8:1, 50%; (vi) 10% Pd/C, H2, CH3CO2Na, dioxane, then add
HCl, 100%.
The overall number of steps and yields for the syntheses of
seven DMDP stereoisomers from the azido-diols are
summarized in Table 1; the epimeric diols 13L and 9D were
prepared in overall 70% and 72% yields, respectively, from D-
glucuronolactone acetonide 1D on a multigram scale. The
stereochemistry required (R or I) at C5, C3, and C2 for the
individual synthetic routes are shown. The general procedures
are scalable, robust and reliable for the synthesis of all the
stereoisomers. While the yields for the different steps after the
formation of diols 13L and 9D have not been optimized, the
overall yields indicate that these are practicable sources of any
stereoisomer. Both the 13C NMR shifts and the specific
rotations [α]D of each diastereomer are also compared in Table
1; of the six diastereoisomers 2−7 only two (gluco 2 and altro
5) have six nonequivalent 13C signals. Full NMR analysis of
each diastereomer is given in the experimental procedures.
Glycosidase inhibition. In piperidine pyranoside mimics
aqueous dioxane afforded the lactols 34D (93%); C1 was then
protected by oxidation with iodine in 2-methyl-2-propanol in
the presence of potassium carbonate to give the lactone 35D
(79%); 35D, a common intermediate for the synthesis of both
targets 5D and 7, was prepared in overall yield of 52% from 9D.
For the synthesis of D-altro 5D, initial conversion of 35D to
the triflate 38D (80%), followed by reduction of the azide to
the amine, produced a complex mixture. Accordingly,
esterification of 35D by mesyl chloride in pyridine gave 36D
(70%); subsequent reduction with sodium borohydride in
ethanol/dioxane formed 37D (51%). Hydrogenation of 37D in
ethanol in the presence of 10% palladium and sodium acetate,
followed by addition of hydrochloric acid to the hydrogenation
mixture, produced the D-altro analogue 5D (99%) in 18%
overall yield from 9D (13% from 1D). Inversion of
configuration at C2 of the lactone 35D was necessary for
access to the meso-allo isomer 7. The triflate 38D, formed by
esterification with triflic anhydride, with sodium trifluoroacetate
in DMF, gave the epimeric alcohol 39D (75%). Mesylation of
39D to give 40D (84%) was followed by reduction by sodium
borohydride to afford 41D (93%); catalytic hydrogenation of
41D formed meso-allo 7 (95%); the overall yield of 7 was 29%
from the diol 9D and 21% from 1D. The L-altro 5L and meso-
allo 7 isomers were prepared by identical sequences from L-
glucuronolactone 1L.
(such as DNJ and DGJ), there is usually, but not always,49
a
good overlap between the structure of the glycoside and
inhibition by the corresponding iminosugar mimic. Prediction
of glycosidase inhibition by pyrrolidine analogues is far less
reliable. A comparison of inhibition of a panel of glycosidases
by all 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols was
obtained by assays as previously described (Table 2).50 Three
of the stereoisomers are natural products. DGDP 2D was
isolated from the Thai traditional crude drug “Non tai yak”
(Stemona tuberosa),51 D-altro 5D was extracted from the roots
of Adenophora triphylla52 and DMDP 3D is the most widely
naturally occurring iminosugar.53
The preceding synthesis of D-altro 5D from 9D, and of L-altro
5L from 9L, involves R5−I3−I2. An alternative strategy of I5−
I3−R2 leads to D-altro 5D from 13D and of L-altro-5L from
13L and also to the meso-galacto analogue 6 from both
enantiomers of 13 (Scheme 5).
Both DGDP 2D and DMDP 3D are modest α-glucosidase
inhibitors; DMDP is a much more potent inhibitor of β-
glucosidase54,55 and β-galactosidase. DGDP 2D, but not
DMDP 3D, is an inhibitor of xylose isomerase.56 Enantiomers
For the synthesis of the lactone 44L, a divergent intermediate
in the synthesis of the L-altro 5L and meso-galacto45 6 isomer,
D
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Scheme 4. Synthesis of meso-allo- and altro-2,5-Dideoxy-2,5-iminohexitols from Diols 9 Derived from Glucuronolactone by R5−
a
I3
a
Reagents and conditions: (i) t-BuMe2SiCl, pyridine, 92%; (ii) Dess−Martin periodinane, CH2Cl2, 95%; (iii) NaBH4, EtOH, 93%; (iv) TBAF, THF,
98%; (v) NaH, PhCH2Br, DMF, 88%; (vi) TsOH, dioxane/water, 7:1, 93%; (vii) I2, K2CO3, t-BuOH, 79%; (viii) MeSO2Cl, pyridine, 70%; (ix)
NaBH4, EtOH/dioxane, 8:1, 51%; (x) 10% Pd/C, H2, CH3CO2Na, EtOH, then add HCl, 99%; (xi) (CF3SO2)2O, pyridine, CH2Cl2, 80%; (xii)
CF3CO2Na, DMF, 75% from 35D; (xiii) MeSO2Cl, pyridine, 84%; (xiv) NaBH4, EtOH/dioxane, 8:1, 93%; (xv) 10% Pd/C, H2, CH3CO2Na,
dioxane, then add HCl, 95%.
of iminosugars frequently inhibit the same enzymes as the
natural product.57−62 Thus, L-gluco 2L is a better, and more
specific, α-glucosidase inhibitor than the natural product
DGDP 2D. L-manno 3L shows potent α-glucosidase and
trehalase inhibition. The meso-galacto 6 is an excellent inhibitor
of both α-D-galactosidase and α-L-fucosidase; 6 contains both D-
galacto and L-fuco motifs (Figure 2); the equivalence of α-D-
galactosidase and α-L-fucosidase inhibition is well estab-
lished.63,64 The natural product D-altro 5D is a good inhibitor
of α-galactosidase and a weak inhibitor of β-glucosidase; 5D has
shown promise as a pharmacological chaperone alternative to
DGJ for the treatment of Fabry’s disease. The L-altro
enantiomer 5L is a moderate inhibitor of both α-galactosidase
and α-L-rhamnosidase and a weak inhibitor of α-L-fucosidase
(Table 2). meso-allo 7 is also good inhibitor of α-galactosidase.
Neither of the ido 4 enantiomers showed any significant
inhibition of any glycosidase. None of the stereoisomers
showed any significant inhibition of β-mannosidase or of β-
glucuronidases.
only D-altro 5D showed modest inhibition against α-
mannosidase with IC50 value of 421 μM (Table 2), whereas
its enantiomer L-altro 5L gave good inhibition of α-L-
rhamnosidase (IC50 91 μM) but no inhibition of Jack bean α-
mannosidase; pyrrolidine mimics of D-mannofuranose inhibit
α-mannosidase,65,66 whereas pyrrolidine mimics of L-mannofur-
anose inhibit α-L-rhamnosidase.67
CONCLUSION
■
The synthesis of all 10 stereoisomers of 2,5-dideoxy-2,5-
iminohexitols from the enantiomers of glucuronolactone shows
the versatility of the acetonides 1D and 1L as chirons. Of the 10
2,5-dideoxy-2,5-iminohexitol stereoisomers, eight are good
inhibitors of varying glycosidases, with only the ido enantiomers
4D and 4L failing to significantly inhibit at least one glycosidase
(IC50 >100 μM). The main features of the inhibition are as
follows. (a) The natural products DGDP 2D and DMDP 3D
are weakand their enantiomers 2L and L-DMDP 3L more
specific and potentinhibitors of α-glucosidases; the other six
stereoisomers show no inhibition of α-glucosidases; (b) both
meso isomers (meso-galacto 6 and meso-allo 7) and D-altro 5D
are excellent inhibitors of α-galactosidase; (c) DMDP 3D is the
only isomer that exhibits good inhibition of β-glucosidases; (d)
none of the stereoisomers show any significant inhibition of α-
mannosidase. Biological properties, including glycosidase
A recent paper reported that L-gluco 2L, L-manno 3L, L-altro
5L, and meso-allo 7, synthesized from chiral tri-O-benzyl cyclic
nitrones,33 are all good inhibitors of Jack bean α-mannosidase
with IC50 values of 98, 88, 94, and 52 μM, respectively. In our
present study, none of these stereoisomers caused 50%
inhibition for the same Jack bean α-mannosidase even at
concentrations as high as 1000 μM. Of all 10 iminohexitols,
E
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Scheme 5. Synthesis of altro- and meso-galacto-2,5-Dideoxy-2,5-iminohexitols from Diols 13 Derived from Glucuronolactone by
a
I5−I3
a
Reagents and conditions: (i) 8L from 13L, 66%;18 (ii) NaH, PhCH2Br, DMF, 99%; (iii) TsOH, dioxane/water, 7:1, 95%; (iv) I2, K2CO3, t-BuOH,
80%; (v) MeSO2Cl, pyridine, 95%; (vi) NaBH4, EtOH/dioxane, 8:1, 65%; (vii) 10% Pd/C, H2, CH3CO2Na, dioxane, then add HCl, 91%; (viii)
(CF3SO2)2O, pyridine, CH2Cl2, 80%; (ix) CF3CO2Na, DMF, 72% from 44L; (x) MeSO2Cl, pyridine, 78%; (xi) NaBH4, EtOH/dioxane, 8:1, 89%;
(xii) 10% Pd/C, H2, CH3CO2Na, dioxane, then add HCl, 92%.
Table 1. 13C NMR, [α]25D, Overall Yields, and Number of Steps from Diols 9D and 13L Derived from D-Glucuronolactone
Acetonide 1D for 2,5-Dideoxy-2,5-iminohexitols
δC (ppm)
2,5-dideoxy-2,5-iminohexitol
from diol
steps
yield (%)
C1
C2
C3
C4
C5
C6
[α]25 (H2O)
D
D-gluco 2D
D-gluco 2D
D-manno 3D
L-ido 4L
I5−R3−I2
R5−R3−R2
R5−R3−I2
I5−R3−R2
R5−I3−I2
I5−I3−R2
I5−I3−I2
13L
9D
6
8
39
29
56
32
18
23
28
29
57.4
63.7
75.0
76.5
67.3
59.8
+22.2 (c 1.2)
a
9D
6
62.5
57.9
58.0
62.2
63.4
62.8
78.3
75.1
70.6
+50.4 (c 0.9)
13L
9D
8
+7.25 (c 0.3)
+31.0 (c 1.1)
−25.5 (c 0.9)
0 (c 1.5)
D-altro 5D
L-altro 5L
10
12
10
12
71.7
62.2
58.6
13L
13L
9D
meso-galacto 6
meso-allo 7
60.4
58.5
60.5
64.5
71.9
71.0
R5−I3−R2
0 (c 1.0)
a
[α]21
.
D
Hz. Residual signals from the solvents were used as an internal
reference, except in the case of deuterium oxide, where acetonitrile was
used as the reference. HRMS measurements were made using a time-
of-flight (TOF) mass analyzer.
5-Azido-3,6-di-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-L-ido-
furanose (16L). Sodium hydride (60% min oil suspension, 118 mg,
4.89 mmol) was added portionwise to a solution of diol 13L (410 mg,
1.67 mmol) and benzyl bromide (0.60 mL, 4.89 mmol) in DMF (5
mL) at −10 °C under argon. The reaction mixture was allowed to
warm to rt and stirred for 17 h, after which TLC analysis (2:1,
cyclohexane/ethyl acetate) indicated the complete consumption of the
starting material (Rf 0.07) and the formation of a major product (Rf
0.68). The reaction was quenched with methanol (0.5 mL), diluted
with ethyl acetate (60 mL), and washed with a 1:1 brine/water
inhibition, are likely to lead to commercial exploitation of
stereoisomers of DMDP.
EXPERIMENTAL SECTION
■
General Experimental Procedures. All commercial reagents
were used as supplied. Thin-layer chromatography (TLC) was
performed on aluminum sheets coated with 60 F254 silica. Plates
were visualized using a spray of 0.2% w/v cerium(IV) sulfate and 5%
ammonium molybdate solution in 2 M aqueous sulfuric acid. Flash
chromatography was performed on Sorbsil C60 40/60 silica. Melting
points were recorded on a Kofler hot block and are uncorrected.
Optical rotation concentrations are quoted in g·100 mL−1. 1H and 13
C
NMR spectra were assigned by utilizing 2D COSY and HSQC spectra.
All chemical shifts (δ) are quoted in ppm and coupling constants (J) in
F
dx.doi.org/10.1021/jo301243s | J. Org. Chem. XXXX, XXX, XXX−XXX

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Table 2. Concentration of 2,5-Dideoxy-2,5-iminohexitols Giving 50% Inhibition (IC50) of Various Glycosidases
Figure 2. D-galacto- and L-fuco-stereochemical motifs in altro-5D and 5L and in meso-galacto 6.
solution (5 × 60 mL). The organic phase was dried (MgSO4), filtered,
and concentrated in vacuo. The crude residue was purified by flash
chromatography (24:1 to 1:1, cyclohexane/ethyl acetate) to afford the
(1H, dd, H4A, J4,3 5.0, J4,5 6.6), 4.38 (1H, d, OCH2PhA, Jgem 11.6), 4.45
(1H, d, OCH2PhA, Jgem 11.9), 4.46 (1H, d, OCH2PhB, Jgem 11.9), 4.52
(1H, d, OCH2PhA, Jgem 11.9), 4.54 (1H, d, OCH2PhB, Jgem 11.9), 4.62
(1H, d, OCH2PhB, Jgem 11.6), 4.70 (1H, d, OCH2PhA, Jgem 11.6), 5.15
(1H, d, H1B, J1,2 10.6), 5.53 (1H, d, H1A, J1,2 4.6), 7.28−7.39 (20H, m,
ArHA, ArHB); δC (CDCl3, 100 MHz) 60.9 (C5A), 61.8 (C5B), 69.4
(C6B), 69.8 (C6A), 71.9, 73.4 (OCH2PhA), 72.6, 73.5 (OCH2PhB),
75.4 (C2A), 77.6 (C4A), 78.5 (C2B), 80.4 (C4B), 82.4 (C3B), 82.9
(C3A), 95.7 (C1A), 103.5 (C1B), 127.8, 127.9, 128.0, 128.0, 128.2,
128.5, 128.5, 128.7 (ArCHA, ArCHB), 137.2 (ArCCB), 137.6 (ArCCA);
dibenzyl ether 16L (519 mg, 73%) as a yellow oil: [α]25 −30.7 (c
D
0.93, CHCl3); νmax (thin film) 2097 (s, N3); δH (CDCl3, 400 MHz)
1.34, 1.51 (2 × 3H, s, C(CH3)2), 3.38 (1H, dd, H6, J6,5 5.8, J6,6′ 10.0),
3.45 (1H, dd, H6′, J6′,5 3.3, J6′,6 10.0), 3.81 (1H, d, H3, J3,4 3.3), 3.92
(1H, ddd, H5, J5,6′ 3.3, J5,6 5.8, J5,4 8.9), 4.25 (1H, d, OCH2Ph, Jgem
11.6), 4.27 (1H, dd, H4, J4,3 3.3, J4,5 8.9), 4.39 (1H, d, OCH2Ph, Jgem
12.1), 4.51 (1H, d, OCH2Ph, Jgem 11.9), 4.60 (1H, d, OCH2Ph, Jgem
11.9), 4.62 (1H, d, H2, J2,1 3.8), 5.97 (1H, d, H1, J1,2 3.8), 7.24−7.38
(10H, m, ArH); δC (CDCl3, 100 MHz) 26.3, 26.8 (C(CH3)2), 60.8
(C5), 69.2 (C6), 71.6, 73.4 (OCH2Ph), 79.9 (C4), 81.5 (C3), 81.9
(C2), 104.8 (C1), 112.0 (C(CH3)2), 127.8, 127.9, 128.0, 128.2, 128.5,
128.6 (ArCH), 136.8, 137.6 (ArCC); LRMS (ESI +ve) 448 (34, M +
Na+), 873 (100, 2M + Na+); HRMS (ESI +ve) found 448.1827 [M +
Na+], C23H27N3NaO5 requires 448.1843.
+
LRMS (ESI +ve) 403 (59, M + NH4 ), 408 (73, M + Na+), 739 (100,
2M + Na+); HRMS (ESI +ve) found 408.1520 [M + Na+],
C20H23N3NaO5 requires 408.1530.
For the enantiomer 17D: [α]25 −34.6 (c 0.95, CHCl3).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-L-idono-1,4-lactone (18L). Po-
tassium carbonate (337 mg, 2.44 mmol) and iodine (620 mg, 2.44
mmol) were added to a solution of lactol 17L (464 mg, 1.20 mmol) in
2-methyl-2-propanol (5 mL) at 100 °C. The reaction was stirred for 2
h, after which TLC analysis (1:1, cyclohexane/ethyl acetate) indicated
complete consumption of the starting material (Rf 0.33) and the
formation of a major product (Rf 0.60). The reaction mixture was
allowed to cool to rt and diluted with ethyl acetate (35 mL). Saturated
aqueous sodium thiosulfate (15 mL) was added slowly and the
biphasic mixture stirred until the iodine was visibly quenched. The
phases were separated, and the aqueous layer was extracted with ethyl
acetate (3 × 35 mL). The organic fractions were combined, dried
(MgSO4), filtered, and concentrated in vacuo. The crude residue was
purified by flash chromatography (9:1 to 1:1, cyclohexane/ethyl
acetate) to afford the lactone 18L (317 mg, 72%) as a yellow oil:
For the enantiomer 16D: [α]25 +38.2 (c 1.00, CHCl3).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-L-idofuranose (17L). p-Toluene-
sulfonic acid (1.04 g, 5.5 mmol) was added to a solution of
isopropylidene-protected 16L (1.05 g, 2.5 mmol) in 7:1 1,4-dioxane/
water (6.4 mL) at 80 °C. Water (2 mL) was added over 30 min to
maintain a homogeneous reaction mixture. The reaction was stirred for
2.5 h, after which TLC analysis (2:1, cyclohexane/ethyl acetate)
indicated the complete consumption of the starting material (Rf 0.68)
and the formation of a major product (Rf 0.07). The reaction mixture
was allowed to cool to rt, quenched with saturated aqueous sodium
bicarbonate (32 mL), and extracted with ethyl acetate (3 × 32 mL).
The organic fractions were combined, dried (MgSO4), filtered, and
concentrated in vacuo to afford lactol 17L (917 mg, 97%) as a yellow
oil, in an anomeric mixture (A:B, 3:1). Lactol 17L was reacted without
[α]25 +39.1 (c 1.26, CHCl3); νmax (thin film) 1794 (s, CO), 2116
D
(s, N3), 3424 (br s, OH); δH (CDCl3, 400 MHz) 3.21 (1H, br s,
OH2), 3.62 (1H, dd, H6, J6,5 6.6, J6,6′ 9.5), 3.69 (1H, dd, H6′, J6′,5 7.6,
J6′,6 9.5), 4.07 (1H, ddd, H5, J5,4 1.5, J5,6 6.6, J5,6′ 7.6), 4.41 (1H, dd,
H3, J3,2 7.8, J3,4 8.2), 4.55 (1H, d, OCH2Ph, Jgem 11.9), 4.59 (1H, d,
OCH2Ph, Jgem 11.9), 4.65 (1H, dd, H4, J4,5 1.5, J4,3 8.2), 4.67 (1H, d,
OCH2Ph, Jgem 11.9), 4.84 (1H, dd, H2, J2,OH 2.5, J2,3 7.8), 4.88 (1H, d,
OCH2Ph, Jgem 11.9), 7.32−7.39 (10H, m, ArH); δC (CDCl3, 100
further purification: [α]25 +23.2 (c 0.83, CHCl3); νmax (thin film)
D
2101 (s, N3), 3417 (br s, OH); δH (CDCl3, 400 MHz) 3.48 (1H, dd,
H6A, J6,5 6.6, J6,6′ 10.1), 3.51−3.56 (3H, m, H6B, H6′A, H6′B), 3.84
(1H, td, H5A, J5,6′ 4.2, J5,6 = J5,4 6.6), 3.88−3.91 (2H, m, H3B, H5B),
3.93 (1H, dd, H3A, J3,2 3.3, J3,4 5.0), 4.30 (1H, dd, H2A, J2,3 3.3, J2,1 4.9),
4.33−4.35 (2H, m, H2B, H4B), 4.36 (1H, d, OCH2PhB, Jgem 11.6), 4.38
G
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Featured Article
MHz) 59.4 (C5), 69.4 (C6), 72.0 (C2), 72.8, 73.6 (OCH2Ph), 76.1
(C4), 79.7 (C3), 127.7, 128.0, 128.2, 128.5, 128.6 (ArCH), 136.8,
J5,6′ 4.8, J5,6 8.3), 3.82 (1H, dd, H6, J6,5 8.3, J6,6′ 12.1), 3.87 (1H, dd,
H2, J2,3 3.7, J 7.6), 3.88 (1H, dd, H6′, J6′,5 4.8, J6′,6 12.1), 3.85−3.93
(2H, m, H1, H1′), 4.07 (1H, dd, H4, J4,3 2.3, J4,5 3.5), 4.24 (1H, dd,
H3, J3,4 2.3, J3,2 3.7); δC (D2O, 100 MHz) 57.4 (C1), 59.8 (C6), 63.7
(C2), 67.3 (C5), 75.0 (C3), 76.5 (C4); LRMS (ESI +ve) 164 (100, M
+ H+); (ESI −ve) 162 (100, [M − H]−), 325 (57, [2M − H]−);
HRMS (ESI +ve) found 162.0765 [M − H]−, C6H12NO4 requires
162.0772.
+
137.3 (ArCC), 174.8 (C1); LRMS (ESI +ve) 401 (15, M + NH4 ),
406 (100, M + Na+), 438 (28, M + MeOH + Na+), 789 (74, 2M +
Na+); (ESI −ve) 418 (100, M + 35Cl−), 420 (39, M + 37Cl−); HRMS
(ESI +ve) found 406.1360 [M + Na+], C20H21N3NaO5 requires
406.1373.
For the enantiomer 18D: [α]25 −35.2 (c 1.15, CHCl3).
D
For the enantiomer 2L: [α]25 −19.1 (c 1.80, H2O).
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-trifluoromethanesulfonyl-
L-idono-1,4-lactone (19L). Trifluoromethanesulfonic anhydride (0.13
mL, 0.76 mmol) was added dropwise to a solution of lactone 18L (220
mg, 0.58 mmol) and pyridine (0.14 mL, 1.74 mmol) in dichloro-
methane (2.5 mL) at −40 °C under argon. The reaction was stirred for
1 h, after which TLC analysis (2:1, cyclohexane/ethyl acetate)
indicated complete consumption of the starting material (Rf 0.39) and
the formation of a major product (Rf 0.59). The reaction was diluted
with dichloromethane (11 mL), washed with 2 M aqueous
hydrochloric acid (3 × 11 mL), dried (MgSO4), filtered, and
concentrated in vacuo. The crude residue was purified by flash
chromatography (19:1 to 4:1, cyclohexane/ethyl acetate) to afford the
D
5-Azido-3,6-di-O-benzyl-5-deoxy-L-gulono-1,4-lactone (21L). Tri-
fluoromethanesulfonic anhydride (0.35 mL, 2.07 mmol) was added
dropwise to a solution of lactone 18L (610 mg, 1.59 mmol) and
pyridine (0.39 mL, 4.77 mmol) in dichloromethane (6 mL) at −40 °C
under argon. The reaction was stirred for 1 h, after which TLC analysis
(2:1, cyclohexane/ethyl acetate) indicated the complete consumption
of the starting material (Rf 0.39) and the formation of a major product
(Rf 0.59). The reaction mixture was diluted with dichloromethane (8
mL), washed with 2 M aqueous hydrochloric acid (3 × 8 mL), dried
(MgSO4), filtered, and concentrated in vacuo to afford crude triflate
19L as a yellow oil. The crude triflate 19L was reacted on without
further purification.
triflate 19L (280 mg, 95%) as a yellow oil: [α]25 +56.9 (c 0.84,
D
CHCl3); νmax (thin film) 1813 (s, CO), 2119 (s, N3); δH (CDCl3,
400 MHz) 3.60 (1H, dd, H6, J6,5 6.7, J6,6′ 9.5), 3.69 (1H, dd, H6′, J6′,5
7.4, J6′,6 9.5), 4.01 (1H, dd, H5, J5,6 6.7, J5,6′ 7.4), 4.53 (1H, d,
OCH2Ph, Jgem 11.8), 4.57 (1H, d, OCH2Ph, Jgem 11.3), 4.58 (1H, d,
H3, J3,2 8.0), 4.59 (1H, d, H4, J4,2 5.3), 4.60 (1H, d, OCH2Ph, Jgem
11.6), 4.84 (1H, d, OCH2Ph, Jgem 11.8), 5.82 (1H, dd, H2, J2,4 5.3, J2,3
8.0), 7.30−7.42 (10H, m, ArH); δC (CDCl3, 100 MHz) 58.9 (C5),
68.9 (C6), 73.8, 73.8 (OCH2Ph), 76.2 (C3), 76.7 (C4), 81.4 (C2),
127.8, 128.1, 128.2, 128.6, 128.9 (ArCH), 135.5, 137.0 (ArCC), 165.7
(C1); LRMS (ESI +ve) 456 (100), 538 (18, M + Na+), 570 (54, M +
MeOH + Na+); HRMS (ESI +ve) found 538.0858 [M + Na+],
C21H20F3N3NaO7S requires 538.0866.
Sodium trifluoroacetate (362 mg, 2.66 mmol) was added to a
solution of crude triflate 19L in DMF (3 mL) at rt under argon. The
reaction was stirred for 2 h, after which TLC analysis (2:1,
cyclohexane/ethyl acetate) indicated the complete consumption of
the starting material (Rf 0.59) and the formation of a major product
(Rf 0.27). The reaction mixture was diluted with ethyl acetate (30 mL)
and washed with saturated aqueous sodium bicarbonate (30 mL). The
aqueous phase was extracted with ethyl acetate (2 × 30 mL), and the
organic fractions were combined, dried (MgSO4), and concentrated in
vacuo. The crude residue was purified by flash chromatography (9:1 to
2:1, cyclohexane/ethyl acetate) to afford lactone 21L (444 mg, 90%)
as a yellow oil: [α]25D +11.7 (c 0.81, CHCl3); νmax (thin film) 1785 (s,
CO), 2099 (s, N3), 3410 (br s, OH); δH (CD3CN, 400 MHz) 3.42
(1H, dd, H6, J6,5 5.6, J6,6′ 10.4), 3.54 (1H, dd, H6′, J6′,5 2.9, J6′,6 10.4),
3.94 (1H, ddd, H5, J5,6′ 2.9, J5,6 5.6, J5,4 9.1), 4.09 (1H, br d, OH2, JOH,2
6.1), 4.20 (1H, dd, H3, J3,4 3.3, J3,2 4.4), 4.37 (1H, d, OCH2Ph, Jgem
11.6), 4.39 (1H, d, OCH2Ph, Jgem 11.6), 4.44 (1H, dd, H4, J4,3 3.3, J4,5
9.1), 4.47 (1H, d, OCH2Ph, Jgem 11.6), 4.63 (1H, br dd, H2, J2,3 4.8,
J2,OH 6.1), 4.88 (1H, d, OCH2Ph, Jgem 11.4), 7.30−7.39 (10H, m,
ArH); δC (CD3CN, 100 MHz) 61.8 (C5), 69.2 (C6), 72.9 (C2), 74.0,
74.9 (OCH2Ph), 77.3 (C3), 79.3 (C4), 128.9, 129.0, 129.2, 129.5
(ArCH), 138.8, 139.0 (ArCC), 175.5 (C1); LRMS (ESI +ve) 406 (70,
[M + Na]+), 789 (100, [2M + Na]+); HRMS (ESI +ve) found
406.1362 [M + Na+], C20H21N3NaO5 requires 406.1373.
For the enantiomer 19D: [α]25 −63.4 (c 0.98, CHCl3).
D
2,5-Dideoxy-2,5-imino-D-glucitol (2D). Palladium (10% on C, 28
mg) was added to a solution of triflate 19L (106 mg, 0.21 mmol) in
ethanol (1.2 mL). The reaction vessel was evacuated and flushed with
hydrogen and stirred for 1 h. TLC analysis (2:1, cyclohexane/ethyl
acetate) indicated the complete consumption of starting material (Rf
0.59) and the formation of a major product (Rf 0.19). The reaction
mixture was filtered through glass microfiber (GF/B) to afford the
bicyclic lactone 20L. LRMS indicated the absence of a peak
corresponding to the triflate 19L (m/z 538 [M + Na+]) and the
presence of a peak corresponding to the bicyclic lactone 20L (m/z 340
[M + H+]). The crude bicyclic lactone 20L was reacted without
further purification.
Partial data for bicyclic lactone 20L: νmax (thin film) 1822 (s, C
O); δH (CDCl3, 500 MHz) 3.78 (1H, dd, H6, J6,5 7.6, J6,6′ 10.1), 3.85
(1H, dd, H6′, J6′,5 7.0, J6′,6 10.1), 4.36 (1H, d, H3 or H4, J 2.2), 4.39
(1H, dd, H5, J5,6′ 7.0, J5,6 7.6), 4.51 (1H, d, OCH2Ph, Jgem 12.0), 4.54
(1H, d, OCH2Ph, Jgem 12.0), 4.58 (1H, d, OCH2Ph, Jgem 11.7), 4.78
(2H, m, H2, H3 or H4), 4.84 (1H, d, OCH2Ph, Jgem 12.0), 7.25−7.37
(10H, m, ArH); δC (CDCl3, 125 MHz) 59.4 (C5), 60.3 (C2), 63.9
(C6), 72.9, 73.7 (OCH2Ph), 79.1, 79.5 (C3 or C4), 127.9, 128.0,
128.2, 128.3, 128.4, 128.5, 128.7, 128.8 (ArCH), 135.4, 136.9 (ArCC),
165.5 (C1); LRMS (ESI +ve) 362 (60, M + Na+), 394 (100, M +
MeOH + Na+), 701 (24, 2M + Na+).
For the enantiomer 21D: [α]25 −11.2 (c 0.95, CHCl3).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-L-gulono-
1,4-lactone (22L). Methanesulfonyl chloride (133 μL, 1.72 mmol) was
added dropwise to a solution of lactone 21L (444 mg, 1.15 mmol) in
pyridine (2 mL) at 0 °C under argon. The reaction was allowed to
warm to rt and stirred for 2 h, after which TLC analysis (2:1,
cyclohexane/ethyl acetate) indicated the complete consumption of the
starting material (Rf 0.27) and the formation of a major product (Rf
0.55). The reaction mixture was concentrated in vacuo and
coevaporated with toluene (3 × 5 mL). The crude residue was
purified by flash chromatography (9:1 to 2:1, cyclohexane/ethyl
acetate) to afford mesylate 22L (494 mg, 93%) as a yellow oil: [α]25
Sodium borohydride (50 mg, 1.31 mmol) was added portionwise to
a solution of the bicyclic lactone 20L in ethanol (2 mL) and the
reaction stirred at rt for 16 h. Aqueous hydrochloric acid (2 M, 1.5
mL) and palladium (10% on C, 50 mg) were added to the reaction
mixture. The reaction vessel was evacuated and flushed with hydrogen
and stirred for 20 h. The reaction mixture was filtered through glass
microfiber (GF/B) and the filtrate concentrated to approximately 1
mL. This was loaded onto a short column of Dowex 50W-X8 (H+
form) and the pyrrolidine 2D liberated with 2 M aqueous ammonia.
The ammoniacal fractions were concentrated in vacuo to afford
D
+2.52 (c 0.45, CHCl3); νmax (thin film) 1178 (s, SO2), 1361 (s, SO2),
1801 (s, CO), 2102 (s, N3); δH (CD3CN, 400 MHz) 3.30 (3H, s,
SO2CH3), 3.44 (1H, dd, H6, J6,5 5.2, J6,6′ 10.5), 3.55 (1H, dd, H6′, J6′,5
2.8, J6′,6 10.5), 3.99 (1H, ddd, H5, J5,6′ 3.3, J5,6 5.3, J5,4 8.3), 4.40 (1H, d,
OCH2Ph, Jgem 11.6), 4.42 (1H, d, OCH2Ph, Jgem 11.6), 4.47 (1H, dd,
H3, J3,4 3.3, J3,2 4.6), 4.49 (1H, d, OCH2Ph, Jgem 11.6), 4.61 (1H, dd,
H4, J4,3 3.0, J4,5 9.1), 4.78 (1H, d, OCH2Ph, Jgem 11.6), 5.58 (1H, d,
H2, J2,3 4.6), 7.30−7.40 (10H, m, ArH); δC (CD3CN, 100 MHz); 39.7
(SO2CH3), 61.3 (C5), 69.1 (C6), 74.0, 75.1 (OCH2Ph), 76.5 (C3),
77.1 (C2), 80.4 (C4), 129.0, 129.1, 129.3, 129.4, 129.5, 129.6 (ArCH),
138.0, 138.9 (ArCC), 170.7 (C1); LRMS (ESI +ve) 484 (38, M +
Na+), 516 (100, M + MeOH + Na+), 945 (70, [2M + Na]+); HRMS
pyrrolidine 2D (26 mg, 80% over three steps) as a yellow oil: [α]25
D
+22.2 (c 1.18, H2O) [lit.68 [α]25D +26.1 (c 1.2, H2O)]; νmax (thin film)
3332 (br s, NH/OH); δH (D2O, 400 MHz) 3.52 (1H, ddd, H5, J5,4 3.5,
H
dx.doi.org/10.1021/jo301243s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(ESI +ve) found 484.1144 [M + Na+], C21H23N3NaO7S requires
484.1149.
a yellow oil. The crude triflate was reacted on without further
purification.
For the enantiomer 22D: [α]25 −1.54 (c 0.65, CHCl3).
Sodium trifluoroacetate (0.29 g, 2.11 mmol) was added portionwise
to a solution of crude triflate in DMF (6 mL) at rt under argon. The
reaction was stirred for 17 h, after which TLC analysis (2:1,
cyclohexane/ethyl acetate) indicated the complete consumption of
the starting material (Rf 0.55) and the formation of a major product
(Rf 0.29). The reaction mixture was partitioned between ethyl acetate
(10 mL) and saturated aqueous sodium bicarbonate (10 mL). The
phases were separated, and the aqueous layer was extracted with ethyl
acetate (2 × 10 mL). The combined organic fractions were washed
with a 1:1 brine/water solution (2 × 20 mL), dried (MgSO4), and
concentrated . The crude residue was purified by flash chromatography
(4:1, cyclohexane/ethyl acetate) to afford the lactone 26D (344 mg,
85%) as a white solid: [α]25 −41.2 (c 0.89, CHCl3) [lit.69 [α]25
D
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-L-gulitol
(23L). Sodium borohydride (41 mg, 1.08 mmol) was added
portionwise to a solution of lactone 22L (100 mg, 0.22 mmol) in
8:1 ethanol/1,4-dioxane (5 mL) at −30 °C under argon. The reaction
was stirred for 4 h, with the internal temperature rising to −15 °C,
after which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated
the partial consumption of the starting material (Rf 0.55) and the
formation of a major product (Rf 0.42). Further sodium borohydride
(41 mg, 1.08 mmol) was added at −30 °C and the reaction allowed to
warm to −15 °C. After 6 h, TLC analysis (2:1, cyclohexane/ethyl
acetate) indicated the complete consumption of the starting material
(Rf 0.55) and the major product (Rf 0.42). The reaction mixture was
neutralized with glacial acetic acid and concentrated in vacuo. The
crude residue was dissolved in ethyl acetate (30 mL) and washed with
saturated aqueous sodium bicarbonate (20 mL). The aqueous phase
was extracted with ethyl acetate (2 × 30 mL), and the organic fractions
were combined, dried (MgSO4), filtered, and concentrated in vacuo.
The crude residue was purified by flash chromatography (9:1 to 1:4,
cyclohexane/ethyl acetate) to afford diol 23L (83 mg, 82%) as a
D
D
−42.0 (c 0.5, CH2Cl2)]; mp 115−117 °C; νmax (thin film) 1790 (s,
CO), 2102 (s, N3) 3424 (br s, OH); δH (CDCl3, 400 MHz) 2.85
(1H, d, OH2, JOH,2 7.6), 3.79 (1H, dd, H6′, J6,5 5.6, J6,6′ 10.4), 3.93
(1H, br d, H6′, J6′,6 10.4), 3.98 (1H, m, H5), 4.38 (2H, m, H3, H4),
4.50 (1H, m, H2), 4.61 (2H, a-s, 2 × OCH2Ph), 4.78 (1H, d,
OCH2Ph, Jgem 10.8), 4.87 (1H, d, OCH2Ph, Jgem 10.8), 7.32 (10H, m,
ArH); δC (CDCl3, 100 MHz) 57.9 (C5), 69.1 (C6), 71.4 (C2), 73.6,
75.0 (OCH2Ph), 76.1 (C3), 76.4 (C4), 127.7, 127.9, 128.2, 128.4,
128.5, 128.6 (ArCH), 136.8, 137.4 (ArCC), 174.5 (C1); LRMS (ESI
+ve) 406 (100, M + Na+), 789 (83, 2M + Na+); HRMS (ESI +ve)
found 406.1362 [M + Na+], C20H21N3NaO5 requires 406.1373.
yellow oil: [α]25 +4.76 (c 0.48, CHCl3); νmax (thin film) 1172 (s,
D
SO2), 1336 (s, SO2), 2098 (s, N3), 3490 (br s, OH); δH (CD3OD, 400
MHz) 3.13 (3H, s, SO2CH3), 3.43 (1H, dd, H6, J6,5 6.6, J6,6′ 10.4), 3.55
(1H, dd, H6′, J6′,5 3.5, J6′,6 10.4), 3.63 (1H, ddd, H5, J5,6′ 3.5, J5,4 6.3,
J5,6 6.6), 3.84 (1H, dd, H4, J4,3 3.8, J4,5 6.3), 3.84 (1H, dd, H1, J1,2 6.8,
J1,1′ 12.7), 3.92 (1H, t, H3, J3,4 = J3,2 3.8), 4.05 (1H, dd, H1′, J1′,2 3.0,
J1′,1 12.7), 4.45 (1H, d, OCH2Ph, Jgem 11.6), 4.52 (1H, d, OCH2Ph,
Jgem 9.5), 4.55 (1H, d, OCH2Ph, Jgem 9.5), 4.76 (1H, d, OCH2Ph, Jgem
11.6), 4.85 (1H, m, H2), 7.30−7.36 (10H, m, ArH); δC (CD3OD, 100
MHz) 38.6 (SO2CH3), 61.8 (C1), 65.0 (C5), 70.1 (C6), 72.2 (C4),
74.5, 75.3 (OCH2Ph), 80.1 (C3), 85.9 (C2), 129.0, 129.1, 129.2,
129.6, 129.6 (ArCH), 139.3, 139.3 (ArCC); LRMS (ESI +ve) 488 (60,
M + Na+), 953 (100, 2M + Na+); HRMS (ESI +ve) found 488.1462
[M + Na+], C21H27N3NaO7S requires 488.1448.
For the enantiomer 26L: [α]20 +44.9 (c 0.52, CHCl3); mp 114−
D
116 °C.
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-D-man-
nono-1,4-lactone (27D). Methanesulfonyl chloride (0.09 mL, 1.17
mmol) was added dropwise to a solution of alcohol 26D (300 mg,
0.78 mmol) in pyridine (3 mL) at 0 °C under argon. The reaction was
stirred for 2 h, after which TLC analysis (1:1, cyclohexane/ethyl
acetate) indicated the complete consumption of the starting material
(Rf 0.67) and the formation of a major product (Rf 0.83). The reaction
was mixture was concentrated in vacuo, and the crude residue was
purified by flash chromatography (3:1, cyclohexane/ethyl acetate) to
For the enantiomer 23D: [α]25 −4.54 (c 0.50, CHCl3).
afford the mesylate 27D (358 mg, 99%) as a colorless oil: [α]25
D
D
2,5-Dideoxy-2,5-imino-L-iditol (4L). Palladium (10% on carbon, 32
mg) and sodium acetate (29 mg, 0.35 mmol) were added to a solution
of mesylate 23L (81 mg, 0.17 mmol) in 1,4-dioxane (4 mL). The
reaction vessel was evacuated, flushed with hydrogen, and stirred for
24 h. TLC analysis (2:1, cyclohexane/ethyl acetate) indicated the
complete consumption of the starting material (Rf 0.42) and the
formation of a major product (baseline). Aqueous hydrochloric acid (2
M, 1 mL) was added and the reaction vessel evacuated and flushed
with hydrogen and the reaction stirred for 16 h. The reaction mixture
was filtered through glass microfiber (GF/A), concentrated in vacuo,
dissolved in 2 M aqueous hydrochloric acid (4 mL), and loaded onto a
short column of Dowex 50W-X8 (H+ form). The product was
liberated with 2 M aqueous ammonia, and the ammoniacal fractions
were combined and concentrated in vacuo to afford the pyrrolidine 4L
−40.0 (c 1.3, CHCl3); νmax (thin film) 1178 (s, SO2), 1362 (s, SO2),
1802 (s, CO), 2103 (s, N3); δH (CDCl3, 400 MHz) 3.33 (3H, s,
SO2CH3), 3.76 (1H, dd, H6, J6,5 5.2, J6,6′ 10.4), 3.90 (1H, dd, H6′, J6′,5
2.2, J6′,6 10.4), 4.00 (1H, ddd, H5, J5,6′ 2.2, J5,6 5.2, J5,4 11.0), 4.44 (1H,
dd, H4, J4,3 3.0, J4,5 11.0), 4.52 (1H, dd, H3, J3,4 3.0, J3,2 4.5), 4.60 (2H,
a-s, OCH2Ph), 4.70 (1H, d, OCH2Ph Jgem 10.8), 4.94 (1H, d,
OCH2Ph, Jgem 10.8), 5.40 (1H, d, H2, J2,3 4.5), 7.36 (10H, m, ArH); δC
(CDCl3, 100 MHz) 39.9 (SO2CH3), 57.7 (C5), 68.8 (C6), 73.6, 74.9
(OCH2Ph), 75.1 (C3), 75.7 (C2), 76.7 (C4), 127.8, 127.9, 128.4,
128.4, 128.5, 128.5 (ArCH), 136.4, 137.3 (ArCC), 169.2 (C1); LRMS
(ESI +ve) 484 (50, M + Na+), 516 (71, M + MeOH + Na+), 945 (100,
2M + Na+); HRMS (ESI +ve) found 516.1413 [M + MeOH + Na+],
C22H27N3NaO8S requires 516.1411.
For the enantiomer 27L: [α]20 +29.8 (c 0.90, CHCl3).
D
(26 mg, 92%) as a yellow oil: [α]25D +7.25 (c 0.30, H2O) [lit.28 [α]25
D
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-D-manni-
tol (28D). Sodium borohydride (52 mg, 1.37 mmol) was added
portionwise to a solution of lactone 27D (0.13 g, 0.27 mmol) in 8:1
ethanol/1,4-dioxane (6 mL) at −30 °C under argon. The reaction
mixture was stirred for 4 h, with the internal temperature rising to −20
°C, after which TLC analysis (1:1, cyclohexane/ethyl acetate)
indicated the complete consumption of the starting material (Rf
0.83) and the formation of a major product (Rf 0.43). The reaction
mixture was neutralized with glacial acetic acid and concentrated in
vacuo. The crude residue was dissolved with ethyl acetate (30 mL) and
washed with saturated aqueous sodium bicarbonate (30 mL). The
aqueous phase was extracted with ethyl acetate (2 × 30 mL), and the
organic fractions were combined, dried (MgSO4), filtered, and
concentrated in vacuo. The crude residue was purified by flash
chromatography (3:1, cyclohexane/ethyl acetate) to afford the diol
+14.0 (c 1.0, H2O)]; νmax (thin film) 3347 (br s, NH/OH); δH (D2O,
400 MHz) 3.79 (1H, dd, H1, J1,2 6.6, J1,1′ 10.4), 3.80−3.84 (1H, m,
H2), 3.89 (1H, dd, H1′, J1′,2 6.8, J1′,1 10.4), 4.10 (1H, d, H3, J3,2 2.5);
δC (D2O, 100 MHz) 57.9 (C1), 63.4 (C2), 75.1 (C3); LRMS (ESI
+ve) 164 (100, M + Na+); HRMS (ESI +ve) found 164.0912 [M +
H+], C6H14NO4 requires 164.0917.
For the enantiomer 4D: [α]25 −8.11 (c 0.45, H2O).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-D-mannono-1,4-lactone (26D).
Trifluoromethanesulfonic anhydride (0.21 mL, 1.27 mmol) was added
dropwise to a solution of lactone 24D (0.405 g, 1.06 mmol) and
pyridine (0.21 mL, 2.64 mmol) in dichloromethane (4 mL) at −30 °C
under argon. The reaction was stirred for 2 h, after which TLC analysis
(2:1, cyclohexane/ethyl acetate) indicated the complete consumption
of the starting material (Rf 0.40) and the formation of a major product
(Rf 0.55). The reaction was diluted with dichloromethane (20 mL),
washed with 2 M aqueous hydrochloric acid (3 × 20 mL), dried
(MgSO4), filtered, and concentrated in vacuo to afford crude triflate as
28D (63 mg, 50%) as a pale yellow oil: [α]25 −45.4 (c 0.55,
D
methanol); νmax (thin film) 2106 (s, N3), 3375 (br s, OH); δH
(CD3OD, 400 MHz) 3.14 (3H, s, SO2CH3), 3.64 (2H, m, H4, H5),
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Featured Article
3.75 (1H, dd, H6, J6,5 6.4, J6,6′ 10.4), 3.87 (1H, dd, H1, J1,2 5.6, J1,1′
12.8), 3.96 (1H, dd, H6′, J6′,5 2.2, J6′,6 10.4), 4.10 (2H, m, H1′, H3),
4.58 (2H, a-s, 2 × OCH2Ph), 4.66 (1H, d, OCH2Ph, Jgem 11.2), 4.83
(2H, m, OCH2Ph, H2), 7.34 (10H, m, ArH); δC (CD3OD, 100 MHz)
38.7 (SO2CH3), 61.9 (C1), 63.1 (C5), 70.6 (C4), 71.8 (C6), 74.5,
75.9 (OCH2Ph), 78.4 (C3), 84.8 (C2), 128.9, 128.9, 129.2, 129.5,
129.6 (ArCH), 139.4, 139.6 (ArCC); LRMS (ESI +ve) 488 (67, M +
Na+), 953 (100, 2M + Na+); HRMS (ESI +ve) found 488.1455 [M +
Na+], C21H27N3NaO7S requires 488.1462.
(CH3)3), 27.2, 27.5 (C(CH3)2), 60.7 (C6), 64.2 (C5), 76.7 (C2), 78.7
(C4), 103.7 (C1), 114.4 (C(CH3)2), 207.5 (C3); LRMS (ESI +ve)
412 (75, M + MeOH + Na+), 801 (100, M + 2MeOH + Na+); HRMS
(ESI +ve) found 412.1870 [M + MeOH + Na+], C16H31N3NaO6Si
requires 412.1874.
For the enantiomer 30L: [α]25 −96.9 (c 0.92, CHCl3).
D
5-Azido-6-O-tert-butyldimethylsilyl-5-deoxy-1,2-O-isopropyli-
dene-α-D-allofuranose (31D). Sodium borohydride (847 mg, 22.4
mmol) was added portionwise to a solution of ketone 30D (8.00 g,
22.4 mmol) in ethanol (80 mL) at 0 °C under argon. The reaction was
stirred at 0 °C for 2 h, after which TLC analysis (2:1, cyclohexane/
ethyl acetate) indicated the complete consumption of the starting
material (Rf 0.23 streaking to Rf 0.67) and the formation of a major
product (Rf 0.47). The reaction was neutralized with glacial acetic acid
and concentrated in vacuo. The crude residue was dissolved with ethyl
acetate (500 mL) and washed with saturated aqueous sodium
bicarbonate (3 × 100 mL) and brine (100 mL). The organic phase
was dried (MgSO4), filtered, and concentrated in vacuo. The crude
residue was purified by flash chromatography (19:1 to 3:2,
cyclohexane/ethyl acetate) to afford alcohol 31D (7.48 g, 93%) as a
For the enantiomer 28L: [α]20 +42.6 (c 0.63, MeOH).
D
2,5-Dideoxy-2,5-imino-D-glucitol (2D). Palladium (10% on C, 25
mg) and sodium acetate (17 mg, 0.20 mmol) were added to a solution
of diol 28D (63 mg, 0.14 mmol) in 1,4-dioxane (2 mL). The reaction
vessel was evacuated and flushed with hydrogen and stirred for 16 h.
TLC analysis (1:1, cyclohexane/ethyl acetate) indicated the complete
consumption of starting material (Rf 0.43) and the formation of a
major product (baseline). Aqueous hydrochloric acid (2 M, 0.4 mL)
was added, and the reaction vessel was evacuated and flushed with
hydrogen and the reaction stirred for 24 h. The reaction mixture was
filtered through glass microfiber (GF/B) and concentrated in vacuo.
The crude residue was dissolved in 2 M aqueous hydrochloric acid and
loaded onto a short column of Dowex 5W-X80 (H+ form). The
product was liberated with 2 M aqueous ammonia, the ammoniacal
fractions combined and concentrated in vacuo to afford the pyrrolidine
2D (22.1 mg, quant) as a yellow oil.70
clear oil: [α]25 +19.9 (c 1.05, CHCl3); νmax (thin film) 2099 (s, N3),
D
3479 (br s, OH); δH (CDCl3, 400 MHz) 0.11 (6H, s, Si(CH3)2), 0.91
(9H, s, SiC(CH3)3), 1.37, 1.58 (2 × 3H, s, C(CH3)2), 3.14 (1H, d,
OH3, JOH,3 7.3), 3.80−3.83 (2H, m, H5, H6), 3.87−3.92 (1H, m,
H6′), 3.96 (1H, dd, H4, J4,5 3.7, J4,3 8.4), 4.09 (1H, ddd, H3, J3,2 4.9,
J3,OH 7.3, J3,4 8.4), 4.63 (1H, dd, H2, J2,1 3.6, J2,3 4.9), 5.81 (1H, d, H1,
J1,2 3.6); δC (CDCl3, 100 MHz) −5.6, −5.6 (Si(CH3)2), 18.2
(SiC(CH3)3), 25.7 (SiC(CH3)3), 26.4, 26.6 (C(CH3)2), 63.2 (C6),
63.5 (C5), 71.4 (C3), 79.2 (C2), 79.9 (C4), 103.8 (C1), 113.0
(C(CH3)2); LRMS (ESI +ve) 382 (85, M + Na+), 741 (100, 2M +
Na+); (ESI −ve) 358 (45, [M − H]−), 394 (30, M + 35Cl−), 396 (10,
M + 37Cl−), 717 (100, [2M − H]−); HRMS (ESI +ve) found
382.1769 [M + Na+], C15H29N3NaO5Si requires 382.1769.
5-Azido-6-O-tert-butyldimethylsilyl-5-deoxy-1,2-O-isopropyli-
dene-α-D-glucofuranose (29D). tert-Butyldimethylsilyl chloride (5.90
g, 38.5 mmol) was added to a solution of diol 9D (6.30 g, 25.7 mmol)
in pyridine (60 mL) at rt under argon. The reaction was stirred for 20
h, after which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated
the complete consumption of the starting material (Rf 0.19) and the
formation of a major product (Rf 0.52). The reaction was diluted with
ethyl acetate (500 mL), washed with 2 M aqueous hydrochloric acid
(3 × 150 mL), dried (MgSO4), filtered, and concentrated in vacuo.
The crude residue was purified by flash chromatography (39:1 to 4:1,
cyclohexane/ethyl acetate) to afford silyl ether 29D (8.50 g, 92%) as a
For the enantiomer 31L: [α]25 −21.7 (c 1.34, CHCl3).
D
5-Azido-5-deoxy-1,2-O-isopropylidene-α-D-allofuranose (32D).
Tetrabutylammonium fluoride (1 M in THF, 26 mL, 26.0 mmol)
was added to a solution of silyl ether 31D (7.48 g, 20.8 mmol) in THF
(75 mL) under argon. The reaction was stirred at rt for 1 h, after
which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated the
complete consumption of the starting material (Rf 0.47) and the
formation of a major product (Rf 0.19). The reaction was concentrated
in vacuo and purified by flash chromatography (1:1:0 to 0:9:1,
cyclohexane/ethyl acetate/methanol) to afford diol 32D (5.0 g, 98%)
colorless oil: [α]25 −23.1 (c 1.30, CHCl3); νmax (thin film) 2099 (s,
D
N3), 3458 (br s, OH); δH (CDCl3, 400 MHz) 0.11, 0.11 (2 × 3H, s,
Si(CH3)2), 0.92 (9H, s, SiC(CH3)3), 1.32, 1.49 (2 × 3H, s, C(CH3)2),
2.42 (1H, d, OH3, J3,OH 4.3), 3.74 (1H, ddd, H5, J5,6′ 3.2, J5,6 5.8, J5,4
8.1), 3.84 (1H, dd, H6, J6,5 5.8, J6,6′ 10.6), 4.03 (1H, dd, H6′, J6′,5 3.2,
J6′,6 10.6), 4.14 (1H, dd, H4, J4,3 2.8, J4,5 8.1), 4.31 (1H, dd, H3, J3,4 2.8,
J3,OH 4.3), 4.53 (1H, d, H2, J2,1 3.7), 5.94 (1H, d, H1, J1,2 3.7); δC
(CDCl3, 100 MHz) −5.6 (Si(CH3)2), 18.2 (SiC(CH3)3), 25.7
(SiC(CH3)3), 26.2, 26.7 (C(CH3)2), 60.9 (C5), 63.8 (C6), 75.2
(C3), 78.4 (C4), 84.9 (C2), 104.9 (C1), 111.9 (C(CH3)2); LRMS
(ESI +ve) 382 (95, M + Na+), 741 (100, 2M + Na+); (ESI −ve) 358
(10, [M − H]−), 394 (25, M + 35Cl−), 396 (10, M + 37Cl−), 717 (100,
[2M − H]−); HRMS (ESI +ve) found 382.1767 [M + Na+],
C15H29N3NaO5Si requires 382.1769.
as a white crystalline solid: [α]25D +50.1 (c 1.20, acetone) [lit.71 [α]25
D
+47.6 (c 1.0, CHCl3)]; mp 82−84 °C [lit.71 mp 82−83 °C]; νmax (thin
film) 2098 (s, N3), 3382 (br s, OH); δH ((CD3)2CO, 400 MHz) 1.31,
1.47 (2 × 3H, s, C(CH3)2), 3.71 (1H, dd, H6, J6,5 7.3, J6,6′ 11.9), 3.80
(1H, dd, H6′, J6′,5 3.8, J6′,6 11.9), 3.87 (1H, a-dt, H5, J5,4 = J5,6′ 3.8, J5,6
7.3), 4.00 (1H, dd, H4, J4,5 3.2, J4,3 8.6), 4.05 (1H, dd, H3, J3,2 4.3, J3,4
8.6), 4.61 (1H, a-t, H2, J2,1 = J2,3 3.9), 5.78 (1H, d, H1, J1,2 3.5); δC
((CD3)2CO, 100 MHz) 26.8, 27.0 (C(CH3)2), 62.3 (C6), 65.8 (C5),
72.4 (C3), 80.4 (C2), 80.5 (C4), 104.9 (C1), 113.1 (C(CH3)2);
LRMS (ESI −ve) 244 (100, [M − H]−), 489 (82, [2M − H]−);
HRMS (ESI +ve) found 268.0901 [M + Na+], C9H15N3NaO5 requires
268.0904.
For the enantiomer 29L: [α]25 +29.9 (c 0.90, CHCl3).
D
5-Azido-6-O-tert-butyldimethylsilyl-5-deoxy-1,2-O-isopropyli-
dene-α-D-ribo-hexofuranos-3-ulose (30D). Dess−Martin periodinane
(15.1 g, 35.5 mmol) was added to a solution of alcohol 29D (8.50 g,
23.6 mmol) in dichloromethane (90 mL) at 0 °C under argon. After
15 min, the reaction was allowed to warm to rt. After 18 h, TLC
analysis (2:1, cyclohexane/ethyl acetate) indicated the complete
consumption of the starting material (Rf 0.52) and the formation of
a major product (Rf 0.23 streaking to Rf 0.67). The reaction mixture
was diluted with ethyl acetate (450 mL) and washed with a saturated
aqueous sodium bicarbonate/sodium thiosulfate solution (400 mL, 2
× 100 mL). The organic phase was dried (MgSO4), filtered, and
concentrated in vacuo. The crude residue was purified by flash
chromatography (83:17 to 5:1, cyclohexane/ethyl acetate) to afford
ketone 30D (8.00 g, 95%) as a clear oil: [α]25D +93.5 (c 1.40, CHCl3);
νmax (thin film) 1775 (s, CO), 2106 (s, N3); δH (CDCl3, 400 MHz)
0.08 (6H, s, Si(CH3)2), 0.89 (9H, s, SiC(CH3)3), 1.44, 1.48 (2 × 3H, s,
SiC(CH3)2), 3.78−3.83 (3H, m, H5, H6, H6′), 4.41 (1H, dd, H2, J
1.0, J2,1 4.3), 4.52 (1H, br s, H4), 6.10 (1H, d, H1, J1,2 4.3); δC (CDCl3,
100 MHz) −5.5, −5.5 (Si(CH3)2), 18.3 (SiC(CH3)3), 25.8 (SiC-
For the enantiomer 32L: [α]25D −55.3 (c 1.12, acetone), mp 84−86
°C.
5-Azido-3,6-di-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-D-allo-
furanose (33D). Sodium hydride (60% min oil suspension, 2.50 g,
61.2 mmol) was added portionwise to a solution of diol 32D (5.00 g,
20.4 mmol) and benzyl bromide (7.30 mL, 61.2 mmol) in DMF (75
mL) at 0 °C under argon. The reaction mixture was allowed to warm
to rt and stirred for 18 h, after which TLC analysis (2:1, cyclohexane/
ethyl acetate) indicated the complete consumption of the starting
material (Rf 0.19) and the formation of a major product (Rf 0.68). The
reaction was quenched with methanol (10 mL), diluted with ethyl
acetate (600 mL), and washed with a 1:1 brine/water solution (3 ×
150 mL). The organic phase was dried (MgSO4), filtered, and
concentrated in vacuo. The crude residue was purified by flash
chromatography (99:1 to 1:1, cyclohexane/ethyl acetate) to afford
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Featured Article
dibenzyl ether 33D (7.61 g, 88%) as a colorless oil: [α]25 +58.3 (c
MHz) 61.9 (C5), 69.0 (C2), 70.3 (C6), 73.1, 74.1 (OCH2Ph), 75.9
(C3), 81.8 (C4), 128.8, 128.8, 129.0, 129.1, 129.5 (ArCH), 138.6,
139.0 (ArCC), 175.8 (C1); LRMS (ESI +ve) 789 (100, 2M + Na+);
HRMS (ESI +ve) found 406.1369 [M + Na+], C20H21N3NaO5
requires 406.1373.
D
1.25, CHCl3); νmax (thin film) 2099 (s, N3); δH (CDCl3, 400 MHz)
1.37, 1.59 (2 × 3H, s, C(CH3)2), 3.52 (1H, dd, H6, J6,5 9.1, J6,6′ 10.1),
3.62 (1H, dd, H6′, J6′,5 4.0, J6′,6 10.1), 3.90 (1H, dd, H3, J3,2 4.3, J3,4
8.6), 4.03 (1H, a-dt, H5, J5,4 = J5,6′ 3.5, J5,6 8.6), 4.17 (1H, dd, H4, J4,5
3.0, J4,3 8.6), 4.53 (2H, a-d, 2 × OCH2Ph, J 11.6), 4.55 (1H, a-t, H2,
J2,1 = J2,3 4.1), 4.56 (1H, d, OCH2Ph, Jgem 11.9), 4.72 (1H, d, OCH2Ph,
Jgem 11.6), 5.75 (1H, d, H1, J1,2 3.8), 7.31−7.39 (10H, m, ArH); δC
(CDCl3, 100 MHz) 26.5, 26.8 (C(CH3)2), 62.1 (C5), 69.4 (C6), 72.1,
73.3 (OCH2Ph), 77.4 (C2), 77.5 (C3), 77.8 (C4), 104.1 (C1), 113.2
(C(CH3)2), 127.7, 127.7, 128.1, 128.1, 128.4, 128.4 (ArCH), 137.1,
For the enantiomer 35L: [α]25 +20.5 (c 1.40, CHCl3).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-trifluoromethanesulfonyl-
D-allono-1,4-lactone (38D). Trifluoromethanesulfonic anhydride
(0.06 mL, 0.35 mmol) was added dropwise to a solution of lactone
35D (100 mg, 0.27 mmol) and pyridine (0.07 mL, 0.81 mmol) in
dichloromethane (1.0 mL) at −40 °C under argon. The reaction was
stirred for 1 h, after which TLC analysis (2:1, cyclohexane/ethyl
acetate) indicated the complete consumption of the starting material
(Rf 0.32) and the formation of a major product (Rf 0.63). The reaction
was diluted with dichloromethane (5 mL), washed with 2 M aqueous
hydrochloric acid (3 × 5 mL), dried (MgSO4), filtered, and
concentrated in vacuo. The crude residue was purified by flash
chromatography (19:1 to 4:1, cyclohexane/ethyl acetate) to afford
triflate 38D (108 mg, 80%) as a yellow oil, which crystallized on
standing: [α]25D −5.7 (c 1.06, CHCl3); mp 66−68 °C; νmax (thin film)
1808 (s, CO), 2125 (s, N3); δH (CDCl3, 400 MHz) 3.53−3.54 (2H,
m, H6, H6′), 3.94 (1H, ddd, H5, J 5.8, J 5.6, J5,4 3.0), 4.35 (1H, d, H3,
J3,2 5.7), 4.51 (1H, d, OCH2Ph, Jgem 11.6), 4.52 (1H, d, OCH2Ph, Jgem
11.6), 4.55 (1H, d, OCH2Ph, Jgem 11.9), 4.62 (1H, d, H4, J4,5 3.0), 4.66
(1H, d, OCH2Ph, Jgem 11.9), 5.52 (1H, d, H2, J2,3 5.7), 7.26−7.42
(10H, m, ArH); δC (CDCl3, 100 MHz) 61.2 (C5), 68.4 (C6), 73.0
(C3), 73.2, 73.9 (OCH2Ph), 76.5 (C2), 82.9 (C4), 127.8, 128.2, 128.4,
128.6, 128.7, 128.7 (ArCH), 135.8, 136.6 (ArCC), 166.7 (C1); LRMS
+
137.6 (ArCC); LRMS (ESI +ve) 443 (25, M + NH4 ), 448 (70, M +
Na+), 873 (100, 2M + Na+); HRMS (ESI +ve) found 448.1838 [M +
Na+], C23H27N3NaO5 requires 448.1843.
For the enantiomer 33L: [α]25 −63.4 (c 1.23, CHCl3).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-D-allofuranose (34D). p-Tolue-
nesulfonic acid (7.30 g, 39.3 mmol) was added to a solution of
isopropylidene-protected 33D (7.60 g, 17.9 mmol) in 7:1 1,4-dioxane/
water (40 mL) and heated to 80 °C. The reaction was stirred for 2 h,
after which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated
the complete consumption of the starting material (Rf 0.68) and the
formation of a major product (Rf 0.16). The reaction mixture was
allowed to cool to rt, diluted with ethyl acetate (600 mL) and
quenched with saturated aqueous sodium bicarbonate (250 mL). The
phases were separated, and the aqueous layer was extracted with ethyl
acetate (2 × 350 mL). The organic fractions were combined, dried
(MgSO4), filtered, and concentrated in vacuo to afford lactol 34D
(6.39 g, 93%) as a yellow oil, in an anomeric mixture (A:B, 2:1). Lactol
34D was reacted without further purification: [α]25 +12.0 (c 1.50,
+
(ESI +ve) 565 (38, M + MeOH + NH4 ), 570 (100, M + MeOH +
D
Na+); HRMS (ESI +ve) found 570.1127 [M + MeOH + Na+],
C22H24F3N3NaO8S requires 570.1128.
CHCl3); νmax (thin film) 2099 (s, N3), 3411 (br s, OH); δH (CDCl3,
400 MHz) 3.47 (1H, dd, H6A, J6,5 7.3, J6,6′ 10.0), 3.53 (1H, dd, H6B,
J6,5 8.2, J6,6′ 10.1), 3.61 (1H, dd, H6′A, J6′,5 4.0, J6′,6 10.1), 3.68−3.74
(2H, m, H5A, H6′B), 3.81 (1H, ddd, H5B, J5,6′ 3.3, J5,4 6.3, J5,6 8.2), 3.99
(1H, dd, H3A, J3,4 3.9, J3,2 5.7), 4.02 (1H, br d, H3B, J3,4 4.7), 4.07−4.11
(2H, m, H2A, H2B), 4.19 (1H, a-t, H4A, J4,3 = J4,5 4.0), 4.29 (1H, a-t,
H4B, J4,5 = J4,3 5.0), 4.52 (2H, a-d, 2 × OCH2PhB, J 12.1), 4.54−4.57
(2H, m, 2 × OCH2PhA), 4.58 (2H, a-d, 2 × OCH2PhA, J 11.9), 4.62
(2H, a-d, 2 × OCH2PhB, J 11.7), 5.26−5.27 (2H, m, H1A, H1B), 7.30−
7.39 (20H, m, ArHA, ArHB); δC (CDCl3, 100 MHz) 62.5 (C5A), 63.3
(C5B), 67.0 (C6A), 69.7 (C6B), 70.6 (C2A), 73.0, 73.5 (OCH2PhB),
73.0, 73.5 (OCH2PhA), 73.7 (C3B), 77.5 (C3A), 79.0 (C4B), 80.2
(C2B), 80.4 (C4A), 97.0 (C1A), 102.3 (C1B), 127.6, 127.8, 127.9,
128.2, 128.2, 128.4, 128.5, 128.5, 128.7 (ArCHA, ArCHB), 136.6, 136.6,
137.4, 137.5 (ArCCA, ArCCB); LRMS (ESI +ve) 408 (60, M + Na+),
793 (100, 2M + Na+); (ESI −ve) 769 (100, [2M − H]−), HRMS (ESI
+ve) found 408.1526 [M + Na+]; C20H23N3NaO5 requires 408.1530.
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-D-allono-
1,4-lactone (36D). Methanesulfonyl chloride (29 μL, 0.37 mmol) was
added dropwise to a solution of alcohol 35D (90 mg, 0.24 mmol) in
pyridine (1.0 mL) at 0 °C under argon. The reaction was stirred at 0
°C for 15 min, allowed to warm to rt, and stirred for a further 2 h, after
which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated the
complete consumption of the starting material (Rf 0.32) and the
formation of a major product (Rf 0.52). The reaction mixture was
concentrated in vacuo and coevaporated with toluene (3 × 3 mL). The
crude residue was purified by flash chromatography (19:1 to 3:1,
cyclohexane/ethyl acetate) to afford mesylate 36D (76 mg, 70%) as a
colorless oil: [α]25 +26.2 (c 1.00, CHCl3); νmax (thin film) 1178 (s,
D
SO2), 1365 (s, SO2), 1801 (s, CO), 2109 (s, N3); δH (CDCl3, 400
MHz) 3.31 (3H, s, SO2CH3), 3.47 (1H, dd, H6, J6,5 6.6, J6,6′ 10.1), 3.52
(1H, dd, H6′, J6′,5 4.9, J6′,6 10.1), 3.92 (1H, ddd, H5, J5,4 3.5, J5,6′ 4.9,
J5,6 6.6), 4.30 (1H, d, H3, J3,2 6.1), 4.51−4.55 (3H, m, 3 × OCH2Ph),
4.58 (1H, d, H4, J4,5 3.5), 4.76 (1H, d, OCH2Ph, Jgem 11.9), 5.50 (1H,
d, H2, J2,3 6.1), 7.30−7.40 (10H, m, ArH); δC (CDCl3, 100 MHz) 39.8
(SO2CH3), 61.3 (C5), 68.6 (C6), 73.1 (C2) 73.1, (C3), 73.3, 73.7
(OCH2Ph), 83.3 (C4), 127.8, 128.2, 128.3, 128.4, 128.6, 128.7
(ArCH), 136.4, 136.7 (ArCC), 169.8 (C1); LRMS (ESI +ve) 484 (24,
M + Na+), 516 (21, M + MeOH + Na+), 945 (100, 2M + Na+); (ESI
−ve) 352 (100), 496 (76, M + 35Cl−), 498 (32, M + 37Cl−); HRMS
(ESI +ve) found 516.1407 [M + MeOH + Na+], C22H27N3NaO8S
requires 516.1411.
For the enantiomer 34L: [α]25 −11.5 (c 1.20, CHCl3).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-D-allono-1,4-lactone (35D). Po-
tassium carbonate (4.94 mg, 35.7 mmol) and iodine (9.07 g, 35.7
mmol) were added to a solution of lactol 34D (6.39 g, 16.7 mmol) in
2-methyl-2-propanol (80 mL) at 100 °C. The reaction was stirred for 2
h, after which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated
the complete consumption of the starting material (Rf 0.16) and the
formation of a major product (Rf 0.32). The reaction mixture was
allowed to cool to rt and diluted with ethyl acetate (500 mL).
Saturated aqueous sodium thiosulfate (250 mL) was added slowly and
the biphasic mixture stirred until the iodine was visibly quenched. The
phases were separated, and the aqueous layer was extracted with ethyl
acetate (2 × 200 mL). The organic fractions were combined, dried
(MgSO4), filtered, and concentrated in vacuo. The crude residue was
purified by flash chromatography (9:1 to 1:1, cyclohexane/ethyl
For the enantiomer 36L: [α]25 −22.7 (c 1.15, CHCl3).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-D-allitol
(37D). Sodium borohydride (90 mg, 2.40 mmol) was added
portionwise to a solution of lactone 36D (101 mg, 0.22 mmol) in
8:1 ethanol/1,4-dioxane (6 mL) at −30 °C under argon. The reaction
was stirred for 6 h, with the internal temperature rising to −20 °C,
after which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated
the complete consumption of the starting material (Rf 0.52) and the
formation of a major product (Rf 0.05). The reaction was neutralized
with glacial acetic acid and concentrated in vacuo. The crude residue
was dissolved with ethyl acetate (40 mL) and washed with saturated
aqueous sodium bicarbonate (25 mL) and the aqueous layer extracted
with ethyl acetate (2 × 40 mL). The organic fractions were combined,
dried (MgSO4), filtered, and concentrated in vacuo. The crude residue
acetate) to afford lactone 35D (5.1 g, 79%) as a colorless oil: [α]25
D
−20.3 (c 1.50, CHCl3); νmax (thin film) 1789 (s, CO), 2104 (s, N3),
3434 (br s, OH); δH (CD3CN, 400 MHz) 3.62 (1H, dd, H6, J6,5 7.1,
J6,6′ 10.4), 3.71 (1H, dd, H6′, J6′,5 4.0, J6′,6 10.4) 3.77 (1H, d, OH2,
JOH,2 8.6), 3.94 (1H, ddd, H5, J5,6′ 4.0, J5,4 6.0, J5,6 7.1), 4.19 (1H, dd,
H3, J3,4 0.8, J3,2 5.8), 4.45 (1H, dd, H4, J4,3 0.8, J4,5 6.0), 4.54 (1H, d,
OCH2Ph, Jgem 12.1), 4.57 (1H, d, OCH2Ph, Jgem 12.1), 4.59 (1H, dd,
H2, J2,3 5.8, J2,OH 8.6), 4.61 (1H, d, OCH2Ph, Jgem 11.6), 4.65 (1H, d,
OCH2Ph, Jgem 11.6), 7.30−7.39 (10H, m, ArH); δC (CD3CN, 100
K
dx.doi.org/10.1021/jo301243s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
was purified by flash chromatography (9:1 to 1:1, cyclohexane/ethyl
acetate) to afford diol 37D (52 mg, 51%) as a yellow oil: [α]25D +12.1
(c 0.90, CHCl3); νmax (thin film) 1173 (s, SO2), 1339 (s, SO2), 2102
(s, N3), 3449 (br s, OH); δH (CDCl3, 400 MHz) 3.08 (3H, s,
SO2CH3), 3.58 (1H, dd, H6, J6,5 5.7, J6,6′ 10.1), 3.66 (1H, dd, H6′, J6′,5
3.4, J6′,6 10.1), 3.75 (1H, ddd, H5, J5,6′ 3.4, J5,4 4.5, J5,6 5.7), 3.83 (1H,
dd, H3, J3,2 2.3, J3,4 7.7), 3.92 (1H, dd, H4, J4,5 4.5, J4,3 7.7), 3.96 (1H,
dd, H1, J1,2 6.5, J1,1′ 12.9), 4.01 (1H, dd, H1′, J1′,2 4.1, J1′,1 12.9), 4.46
(1H, d, OCH2Ph, Jgem 11.9), 4.47 (1H, d, OCH2Ph, Jgem 11.1), 4.53
(1H, d, OCH2Ph, Jgem 11.9), 4.75 (1H, d, OCH2Ph, Jgem 11.1), 5.14
(1H, ddd, H2, J2,3 2.3, J2,1′ 4.1, J2,1 6.5), 7.29−7.39 (10H, m, ArH); δC
(CDCl3, 100 MHz) 38.5 (SO2CH3), 61.3 (C1), 61.4 (C5), 69.4 (C6),
71.4 (C4), 73.4, 73.7 (OCH2Ph), 79.2 (C3), 82.8 (C2), 127.9, 128.1,
128.3, 128.5, 128.6, 128.6 (ArCH), 136.8, 137.0 (ArCC); LRMS (ESI
+ve) 953 (100, 2M + Na+); HRMS (ESI +ve) found 488.1460 [M +
Na+], C21H27N3NaO7S requires 488.1462.
fractions were combined, dried (MgSO4), filtered and concentrated in
vacuo. The crude residue was purified by flash chromatography (49:1
to 1:1, cyclohexane/ethyl acetate) to afford the lactone 39D (3.80 g,
75%) as a white crystalline solid: [α]25 +37.1 (c 1.97, CHCl3); mp
D
121−123 °C; νmax (thin film) 1799 (s, CO), 2115 (s, N3), 3175 (br
s, OH); δH (CD3CN, 400 MHz) 3.54 (1H, dd, H6, J6,5 8.1, J6,6′ 10.2),
3.65 (1H, dd, H6′, J6′,5 4.0, J6′,6 10.2), 4.09 (1H, a-dt, H5, J5,4 = J5,6′ 4.0,
J5,6 8.1), 4.19 (1H, a-t, H3, J3,2 = J3,4 7.6), 4.24 (1H, br d, OH2, JOH,2
6.1), 4.33 (1H, dd, H4, J4,5 4.2, J4,3 7.5), 4.51 (1H, d, OCH2Ph, Jgem
12.1), 4.54 (1H, d, OCH2Ph, Jgem 12.1), 4.59 (1H, dd, H2, J2,OH 6.1,
J2,3 7.6), 4.61 (1H, d, OCH2Ph, Jgem 11.6), 4.79 (1H, d, OCH2Ph, Jgem
11.6), 7.29−7.38 (10H, m, ArH); δC (CD3CN, 100 MHz) 62.7 (C5),
69.8 (C6), 72.9, 73.9 (OCH2Ph), 75.1 (C2), 78.1 (C4), 81.2 (C3),
128.8, 129.0, 129.3, 129.5 (ArCH), 138.6, 139.1 (ArCC), 174.4 (C1);
LRMS (ESI +ve) 406 (100, M + Na+), 789 (60, 2M + Na+); HRMS
(ESI +ve) found 406.1369 [M + Na+], C20H21N3NaO5 requires
406.1373.
For the enantiomer 37L: [α]25 −8.5 (c 1.00, CHCl3).
D
For the enantiomer 39L: [α]25 −31.9 (c 2.00, CHCl3), mp 120−
2,5-Dideoxy-2,5-imino-D-altritol (5D). Palladium (10% on C, 60
mg) and sodium acetate (54 mg, 0.65 mmol) were added to a solution
of diol 37D (152 mg, 0.33 mmol) in 1,4-dioxane (10 mL). The
reaction vessel was evacuated and flushed with hydrogen and the
reaction stirred for 4 h. TLC analysis (3:7, cyclohexane/ethyl acetate)
indicated the complete consumption of the starting material (Rf 0.64)
and the formation of a major product (Rf 0.02). LRMS indicated the
absence of a peak corresponding to the diol 37D (m/z 488 [M +
Na+]) and the presence of a peak corresponding to the dibenzyl
pyrrolidine intermediate (m/z 344 [M + H+]). Aqueous hydrochloric
acid (2 M, 0.5 mL) was added, the reaction vessel evacuated and
flushed with hydrogen, and the reaction stirred for 19 h. LRMS
indicated the absence of a peak corresponding to dibenzylpyrrolidine
intermediate (m/z 344 [M + H+]) and the presence of a peak
corresponding to the pyrrolidine 5D (m/z 164 [M + H+]). The
reaction was filtered through glass microfiber (GF/B), concentrated in
vacuo, dissolved in 2 M aqueous hydrochloric acid (1 mL), and loaded
onto a short column of Dowex 50W-X8 (H+ form). The product was
liberated with 2 M aqueous ammonia. The ammoniacal fractions were
combined and concentrated in vacuo to afford the pyrrolidine 5D (53
mg, 99%) as a colorless oil: [α]25 +31.0 (c 1.10, H2O) [lit.52 [α]25
D
122 °C.
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-D-altro-
no-1,4-lactone (40D). Methanesulfonyl chloride (1.20 mL, 15.6
mmol) was added dropwise to a solution of alcohol 39D (3.99 g, 10.4
mmol) in pyridine (40 mL) at 0 °C under argon. After 10 min, the
reaction was allowed to warm to rt and stirred for a further 2 h. After
which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated the
complete consumption of the starting material (Rf 0.45) and the
formation of a major product (Rf 0.60). The reaction mixture was
concentrated in vacuo and coevaporated with toluene (2 × 25 mL)
and dichloromethane (2 × 25 mL). The crude residue was purified by
flash chromatography (47:3 to 3:2, cyclohexane/ethyl acetate) to
afford the mesylate 40D (4.04 g, 84%) as a clear oil: [α]25 +40.5 (c
D
2.40, CHCl3); νmax (thin film) 1178 (s, SO2), 1369 (s, SO2), 1803 (s,
CO), 2110 (s, N3); δH (CD3CN, 400 MHz) 3.29 (3H, s, SO2CH3),
3.56 (1H, dd, H6, J6,5 7.8, J6,6′ 10.2), 3.67 (1H, dd, H6′, J6′,5 4.5, J6′,6
10.2), 4.10 (1H, a-dt, H5, J5,4 = J5,6′ 4.0, J5,6 7.8), 4.48−4.56 (4H, m,
H3, H4, OCH2Ph × 2), 4.61 (1H, d, OCH2Ph, Jgem 11.0), 4.78 (1H, d,
OCH2Ph, Jgem 11.0), 5.59 (1H, d, H2, J2,3 6.8), 7.31−7.40 (10H, m,
ArH); δC (CD3CN, 100 MHz) 40.3 (SO2CH3), 62.2 (C5), 69.6 (C6),
73.4, 74.0 (OCH2Ph), 79.0, 79.2 (C3, C4), 81.0 (C2), 128.8, 128.8,
129.3, 129.5, 129.5, 129.6 (ArCH), 137.8, 139.0 (ArCC), 169.6 (C1);
LRMS (ESI +ve) 484 (56, M + Na+), 516 (100, M + MeOH + Na+),
945 (48, 2M + Na+); HRMS (ESI +ve) found 516.1406 [M + MeOH
+ Na+], C22H27N3NaO8S requires 516.1411.
D
D
+34.2 (c 0.83, H2O)]; νmax (thin film) 3283 (br s, NH/OH); δH (D2O,
400 MHz) 3.57 (1H, ddd, H5, J5,6′ 3.5, J5,6 5.8, J5,4 9.1), 3.68 (1H, ddd,
H2, J2,3 3.3, J2,1′ 5.3, J2,1 8.1), 3.77 (1H, dd, H6, J6,5 5.8, J6,6′ 12.6), 3.82
(1H, dd, H1, J1,2 8.1, J1,1′ 12.1), 3.89 (1H, dd, H6′, J6′,5 3.5, J6′,6 12.6),
3.92 (1H, dd, H1′, J1′,2 5.3, J1′,1 12.1), 4.19 (1H, dd, H4, J4,3 3.8, J4,5
9.1), 4.26 (1H, dd, H3, J3,2 3.3, J3,4 3.8); δC (D2O, 100 MHz) 58.0
(C1), 58.6 (C6), 62.2 (C5), 62.8 (C2), 70.6 (C3), 71.7 (C4); LRMS
(ESI +ve) 164 (100, M + Na+), 250 (38, M + 2MeOH + Na+); HRMS
(ESI +ve) found 186.0736 [M + Na+], C6H13NNaO4 requires
186.0737.
For the enantiomer 40L: [α]25 −35.6 (c 2.05, CHCl3).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-D-altritol
(41D). Sodium borohydride (205 mg, 5.42 mmol) was added
portionwise to a solution of mesylate 40D (500 mg, 1.08 mmol) in
8:1 ethanol/1,4-dioxane (24 mL) at −30 °C under argon. The reaction
was stirred for 1 h, with the internal temperature rising to −25 °C,
after which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated
the incomplete consumption of the starting material (Rf 0.60) and the
formation of a major product (Rf 0.18). Further sodium borohydride
(205 mg, 5.42 mmol) was added at −30 °C and the reaction allowed
to warm to −15 °C. After 3 h, TLC analysis indicated the complete
consumption of the starting material (Rf 0.60) and the major product
(Rf 0.18). The reaction was neutralized with glacial acetic acid and
concentrated in vacuo. The crude residue was dissolved with ethyl
acetate (200 mL) and washed with saturated aqueous sodium
bicarbonate (75 mL). The aqueous layer was extracted with ethyl
acetate (2 × 100 mL), and the organic fractions were combined, dried
(MgSO4), filtered, and concentrated in vacuo. The crude residue was
purified by flash chromatography (9:1 to 7:3, cyclohexane/ethyl
acetate) to afford the diol 41D (468 mg, 93%) as a pale yellow oil:
For the enantiomer 5L: [α]25 −25.5 (c 0.90, H2O).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-D-altrono-1,4-lactone (39D).
Trifluoromethanesulfonic anhydride (2.9 mL, 17.3 mmol) was added
dropwise to a solution of lactone 35D (5.1 g, 13.3 mmol) and pyridine
(3.2 mL, 39.9 mmol) in dichloromethane (60 mL) at −40 °C under
argon. The reaction was stirred for 1 h, with the internal temperature
rising to −25 °C, after which TLC analysis (2:1, cyclohexane/ethyl
acetate) indicated the complete consumption of the starting material
(Rf 0.32) and the formation of a major product (Rf 0.63). The reaction
was diluted with dichloromethane (250 mL), washed with 2 M
aqueous hydrochloric acid (3 × 250 mL), dried (MgSO4), filtered, and
concentrated in vacuo to afford crude triflate 38D. The crude triflate
38D was reacted on without further purification.
Sodium trifluoroacetate (3.62 g, 26.6 mmol) was added portionwise
to a solution of the crude triflate 38D in DMF (30 mL) at −30 °C
under argon. The reaction was allowed to warm to rt and stirred for 16
h, after which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated
the complete consumption of the starting material (Rf 0.63) and the
formation of a major product (Rf 0.45). The reaction mixture was
partitioned between ethyl acetate (250 mL) and saturated aqueous
sodium bicarbonate (150 mL). The phases were separated and the
aqueous layer extracted with ethyl acetate (3 × 250 mL). The organic
[α]25 +5.7 (c 0.91, CHCl3); νmax (thin film) 1171 (s, SO2), 1334 (s,
D
SO2), 2100 (s, N3), 3500 (br s, OH); δH (CD3CN, 400 MHz) 3.07
(3H, s, SO2CH3), 3.67 (1H, dd, H1 or H6, J 7.7, J 10.2), 3.77−3.89
(8H, m, H1 or H6, H1′, H3, H4, H5, H6′, OH1, OH4), 4.50 (1H, d,
OCH2Ph, Jgem 12.1), 4.54 (1H, d, OCH2Ph, Jgem 12.1), 4.60 (1H, d,
OCH2Ph, Jgem 11.1), 4.64 (1H, d, OCH2Ph, Jgem 11.1), 4.85 (1H, td,
H2, J 3.4, J 5.5, J 5.5), 7.29−7.38 (10H, m, ArH); δC (CD3CN, 100
L
dx.doi.org/10.1021/jo301243s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
MHz) 38.9 (SO2CH3), 61.8 (C1 or C6), 64.0, 70.7 (C1 or C6), 71.5,
73.9 (OCH2Ph), 75.0 (OCH2Ph), 78.8, 83.7 (C2), 128.7, 128.8, 128.9,
129.2, 129.4, 129.4 (ArCH), 139.0, 139.3 (ArCC); LRMS (ESI +ve)
488 (85, M + Na+), 953 (100, 2M + Na+); (ESI −ve) 929 (100, [2M
− H]−); HRMS (ESI +ve) found 488.1463 [M + Na+],
C21H27N3NaO7S requires 488.1462.
ethyl acetate (3 × 350 mL). The organic fractions were combined,
dried (MgSO4), filtered, and concentrated in vacuo. The crude residue
was purified by flash chromatography (7:3 to 1:1, cyclohexane/ethyl
acetate) to afford lactol 43L (6.0 g, 95%) as a colorless oil, in an
anomeric mixture (A:B, 3:2): [α]25 +66.8 (c 2.4, CHCl3); νmax (thin
D
film) 2100 (s, N3), 3422 (br s, OH); δH (CDCl3, 400 MHz) 2.59 (1H,
br s, OH2B), 2.93 (1H, br s, OH2A), 3.13 (1H, br s, OH1B), 3.49 (1H,
ddd, H5A, J5,4 2.8, J5,6 4.4, J5,6′ 8.2), 3.58 (1H, a-dt, H5B, J5,4 = J5,6 4.0,
For the enantiomer 41L: [α]25 −7.1 (c 1.05, CHCl3).
D
2,5-Dideoxy-2,5-iminoallitol (7). Palladium (10% on C, 180 mg)
and sodium acetate (160 mg, 1.94 mmol) were added to a solution of
diol 41D (450 mg, 0.97 mmol) in 1,4-dioxane (16 mL). The reaction
vessel was evacuated and flushed with hydrogen. The reaction was
stirred at rt for 4 h under hydrogen, after which TLC analysis (2:1,
cyclohexane/ethyl acetate) indicated the complete consumption of the
starting material (Rf 0.38) and the formation of a single product
(baseline). LRMS indicated the absence of a peak corresponding to
the diol 41D (m/z 488 [M + Na+]) and the presence of a peak
corresponding to the dibenzyl pyrrolidine intermediate (m/z 344 [M
+ H+]). Aqueous hydrochloric acid (2 M, 4 mL) was added, the
reaction vessel evacuated and flushed with hydrogen, and the reaction
stirred for 16 h. LRMS indicated the absence of a peak corresponding
to the dibenzylpyrrolidine intermediate (m/z 344 [M + H+]) and the
presence of a peak corresponding to the pyrrolidine 7 (m/z 164 [M +
H+]). The reaction was filtered through glass microfiber (GF/B),
concentrated in vacuo, dissolved in 2 M aqueous hydrochloric acid (1
mL), and loaded onto a short column of Dowex 50W-X8 (H+ form).
The product was liberated with 2 M aqueous ammonia, and the
ammoniacal fractions were combined and concentrated in vacuo to
afford the pyrrolidine 7 (150 mg, 95%) as a colorless oil: HRMS (ESI
J
5,6′ 8.0), 3.68 (1H, dd, H6B, J6,5 4.4, J6,6′ 10.1), 3.68 (1H, dd, H6A, J6,5
4.4, J6,6′ 9.9), 3.72 (1H, dd, H6′B, J6′,5 8.0, J6′,6 10.1), 3.74 (1H, dd,
H6′A, J6′,5 8.2, J6′,6 9.9), 3.88 (1H, br s, OH1A), 4.01 (1H, a-t, H3A, J3,2
= J3,4 5.6), 4.03 (1H, d, H2B, J2,3 3.9), 4.05 (1H, dd, H4B, J4,5 3.5, J4,3
7.1), 4.11 (1H, dd, H4A, J4,5 2.8, J4,3 5.3), 4.11−4.13 (1H, m, H2A),
4.29 (1H, dd, H3B, J3,2 4.0, J3,4 7.1), 4.53 (1H, d, OCH2PhB, Jgem 11.5),
4.62 (1H, d, OCH2PhB, Jgem 11.5), 4.54 (1H, d, OCH2PhA, Jgem 11.7),
4.56 (1H, d, OCH2PhA, Jgem 11.7), 4.59 (1H, d, OCH2PhB, Jgem 11.6),
4.65 (1H, d, OCH2PhB, Jgem 11.6), 4.60 (1H, d, OCH2PhA, Jgem 11.6),
4.68 (1H, d, OCH2PhA, Jgem 11.6), 5.27 (1H, s, H1B), 5.30 (1H, br s,
H1A), 7.29−7.43 (20H, m, ArH); δC (CDCl3, 100 MHz) 61.1 (C5A),
62.0 (C5B), 69.7 (C2A), 70.1 (C6A), 70.5 (C6B), 73.1, 73.5
(OCH2PhB), 73.4, 73.6 (OCH2PhA), 73.4 (C2B), 78.1 (C3A), 78.8
(C3B), 79.7 (C4A), 80.4 (C4B), 97.3 (C1A), 102.3 (C1B), 127.7, 127.8,
127.9, 127.9, 128.2, 128.5, 128.6, 128.7, 128.8 (ArCH), 136.7, 136.7,
137.5, 137.5 (ArCC); LRMS (ESI +ve) 408 (100, M + Na+), 793 (73,
2M + Na+); (ESI −ve) 384 (20, [M − H]−), 420 (25, M + 35Cl−), 422
(10, M + 37Cl−), 769 (100, [2M − H]−); HRMS (ESI +ve) found
408.1528 [M + Na+], C20H23N3NaO5 requires 408.1530.
For the enantiomer 43D: [α]25 −80.8 (c 2.00, CHCl3).
D
+ve) found 164.0919 [M + H+]; C6H14NO4 requires 164.0917; [α]25
5-Azido-3,6-di-O-benzyl-5-deoxy-L-talono-1,4-lactone (44L). Po-
tassium carbonate (1.98 g, 14.33 mmol) and iodine (3.64 g, 14.33
mmol) were added to a warm solution of lactol 43L (2.76 g, 7.17
mmol) in 2-methyl-2-propanol (30 mL) at 100 °C. The reaction was
stirred for 90 min, after which TLC analysis (1:1, cyclohexane/ethyl
acetate) indicated the complete consumption of the starting material
(Rf 0.40) and the formation of a major product (Rf 0.68). The reaction
was allowed to cool to rt and diluted with ethyl acetate (200 mL).
Saturated aqueous sodium thiosulfate (100 mL) was added slowly and
the biphasic mixture stirred until the iodine was visibly quenched. The
phases were separated, and the aqueous phase was extracted with ethyl
acetate (2 × 200 mL). The organic fractions were combined, dried
(MgSO4), filtered, and concentrated in vacuo. The crude residue was
purified by flash chromatography (17:3 to 1:1, cyclohexane/ethyl
D
0.0 (c 1.00, H2O); νmax (thin film) 3450 (br s, OH/NH); δH (D2O,
400 MHz) 3.61 (1H, a-q, H2, J2,1 = J2,1′ = J2,3 4.9), 3.73 (1H, dd, H1,
J1,2 5.8, J1,1′ 12.4), 3.82 (1H, dd, H1′, J1′,2 4.0, J1′,1 12.4), 4.11 (1H, d,
H3, J3,2 4.0); δC (D2O, 100 MHz) 58.5 (C1), 64.5 (C2), 71.0 (C3);
LRMS (ESI +ve) 164 (100, M + H+).
5-Azido-3,6-di-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-L-talo-
furanose (42L). Sodium hydride (60% mineral oil suspension, 2.2 g,
55.1 mmol) was added portionwise to a solution of diol 8L (4.50 g,
18.4 mmol) and benzyl bromide (6.55 mL, 55.1 mmol) in DMF (70
mL) at 0 °C under argon. The reaction mixture was allowed to warm
to rt and stirred for 19 h, after which TLC analysis (2:1, cyclohexane/
ethyl acetate) indicated the complete consumption of the starting
material (Rf 0.13) and the formation of a major product (Rf 0.73). The
reaction was quenched with methanol (2 mL), diluted in ethyl acetate
(200 mL) and washed with a 1:1 brine/water solution (3 × 100 mL).
The organic phase was dried (MgSO4), filtered, and concentrated in
vacuo. The crude residue was purified by flash chromatography (20:1
to 10:1, cyclohexane/ethyl acetate) to afford the dibenzyl ether 42L
acetate) to afford lactone 44L (2.20 g, 80%) as a clear oil: [α]25
D
+110.3 (c 1.25, CHCl3); νmax (thin film) 1790 (s, CO), 2112 (s,
N3), 3447 (br s, OH); δH (CDCl3, 400 MHz) 3.04 (1H, br s, OH2),
3.68−3.78 (3H, m, H5, H6, H6′), 4.15 (1H, dd, H3, J3,4 0.9, J3,2 6.2),
4.45 (1H, br s, H4), 4.54 (1H, d, OCH2Ph, Jgem 11.9), 4.59 (1H, d,
OCH2Ph, Jgem 11.9), 4.66 (1H, d, OCH2Ph, Jgem 11.6), 4.67 (1H, d,
H2, J2,3 6.2), 4.72 (1H, d, OCH2Ph, Jgem 11.9), 7.31−7.41 (10H, m,
ArH); δC (CDCl3, 100 MHz) 61.1 (C5), 67.8 (C2), 69.5 (C6), 73.1,
73.8 (OCH2Ph), 75.9 (C3), 80.9 (C4), 127.9, 128.1, 128.1, 128.6,
128.6, 128.8 (ArCH), 136.3, 137.0 (ArCC), 174.7 (C1); LRMS (ESI
+ve) 406 (45, M + Na+), 438 (40, M + MeOH + Na+), 789 (60, 2M +
Na+), 821 (63, 2M + MeOH + Na+), 853 (100, 2M + 2MeOH + Na+);
HRMS (ESI +ve) found 406.1365 [M + Na+], C20H21N3NaO5
requires 406.1373.
(7.73 g, 99%) as a colorless oil: [α]25 +122.0 (c 1.5, CHCl3); νmax
D
(thin film) 2098 (s, N3); δH (CDCl3, 400 MHz) 1.37, 1.58 (2 × 3H, s,
C(CH3)2), 3.70 (1H, ddd, H5, J5,4 2.3, J5,6 3.8, J5,6′ 9.1), 3.75 (1H, dd,
H6, J6,5 3.8, J6,6′ 10.1), 3.80 (1H, dd, H6′, J6′,5 9.1, J6′,6 10.1), 3.90 (1H,
dd, H3, J3,2 4.3, J3,4 8.8), 4.08 (1H, dd, H4, J4,5 2.3, J4,3 8.8), 4.56 (1H,
d, OCH2Ph, Jgem 11.6), 4.57−4.59 (1H, m, H2), 4.57 (1H, d,
OCH2Ph, Jgem 11.7), 4.62 (1H, d, OCH2Ph, Jgem 11.9), 4.79 (1H, d,
OCH2Ph, Jgem 11.9), 5.74 (1H, d, H1, J1,2 3.5), 7.29−7.42 (10H, m,
ArH); δC (CDCl3, 100 MHz) 26.4, 26.8 (C(CH3)2), 60.0 (C5), 70.8
(C6), 72.3, 73.4 (OCH2Ph), 77.0 (C2), 77.6 (C4), 77.9 (C3), 104.3
(C1), 113.3 (C(CH3)2), 127.7, 127.8, 128.1, 128.3, 128.5, 128.6
(ArCH), 137.2, 137.7 (ArCC); LRMS (ESI +ve) 448 (100, M + Na+),
464 (25, M + K+), 873 (100, 2M + Na+); HRMS (ESI +ve) found
448.1831 [M + Na+], C23H27N3NaO5 requires 448.1843.
For the enantiomer 44D; [α]25 −102.2 (c 1.30, CHCl3).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-trifluoromethanesulfonyl-
L-talono-1,4-lactone (47L). Trifluoromethanesulfonic anhydride (0.14
mL, 0.85 mmol) was added dropwise to a solution of alcohol 44L (250
mg, 0.65 mmol) and pyridine (0.16 mL, 1.96 mmol) in dichloro-
methane (3 mL) at −40 °C under argon. The reaction was stirred for
90 min, with the internal temperature rising to −25 °C, after which
TLC analysis (2:1, cyclohexane/ethyl acetate) indicated the complete
consumption of the starting material (Rf 0.38) and the formation of a
major product (Rf 0.71). The reaction was diluted with dichloro-
methane (20 mL), washed with 2 M aqueous hydrochloric acid (3 ×
20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The
crude residue was purified by flash chromatography (49:1 to 9:1,
cyclohexane/ethyl acetate) to afford triflate 47L (270 mg, 80%) as a
For the enantiomer 42D: [α]25 −138.4 (c 1.60, CHCl3).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-L-talofuranose (43L). p-Tolue-
nesulfonic acid (6.0 g, 36.7 mmol) was added to a solution of
isopropylidene-protected 42L (7.1 g, 16.7 mmol) in 7:1 1,4-dioxane/
water (40 mL) and heated to 50 °C for 2 h. TLC analysis (2:1,
cyclohexane/ethyl acetate) indicated the complete consumption of the
starting material (Rf 0.73) and the formation of a major product (Rf
0.24). The reaction mixture was allowed to cool to rt, quenched with
saturated aqueous sodium bicarbonate (350 mL), and extracted with
M
dx.doi.org/10.1021/jo301243s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
pale yellow oil: [α]25D +63.2 (c 1.25, CHCl3); νmax (thin film) 1808 (s,
CO), 2115 (s, N3); δH (CDCl3, 400 MHz) 3.69−3.78 (3H, m, H5,
H6, H6′), 4.32 (1H, dd, H3, J3,4 1.8, J3,2 6.1), 4.52−4.53 (1H, m, H4),
4.54 (1H, d, OCH2Ph, Jgem 11.6), 4.59 (1H, d, OCH2Ph, Jgem 11.6),
4.60 (1H, d, OCH2Ph, Jgem 11.6), 4.79 (1H, d, OCH2Ph, Jgem 11.6),
5.56 (1H, d, H2, J2,3 6.1), 7.32−7.43 (10H, m, ArH); δC (CDCl3, 100
MHz) 60.2 (C5), 69.1 (C6), 73.5, 73.8 (OCH2Ph), 74.6 (C3), 76.3
(C2), 81.8 (C4), 127.9, 128.2, 128.3, 128.6, 128.9 (ArCH), 135.6,
136.8 (ArCC), 166.6 (C1); LRMS (ESI +ve) 554 (95, M + K+), 570
(100, M + MeOH + Na+); HRMS (ESI +ve) found 570.1112 [M +
MeOH + Na+], C22H24F3N3NaO8S requires 570.1128.
HCOO−), 929 (41, [2M − H]−); HRMS (ESI +ve) found 488.1445
[M + Na+], C21H27N3NaO7S requires 488.1462.
For the enantiomer 46D: [α]25 −60.7 (c 1.20, CHCl3).
D
2,5-Dideoxy-2,5-iminogalactitol (6). Palladium (10% on carbon, 6
mg) and sodium acetate (11 mg, 0.13 mmol) were added to a solution
of diol 46L (30 mg, 0.06 mmol) in 1,4-dioxane (2 mL). The reaction
vessel was evacuated and flushed with hydrogen and stirred for 1 h.
TLC analysis (99:1, ethyl acetate/triethylamine) indicated the
complete consumption of the starting material (Rf 0.88) and the
formation of a major product (Rf 0.08). LRMS also indicated the
absence of a peak corresponding to the starting material 46L (m/z 488
[M + Na+]) and the formation of a peak corresponding to the amino
intermediate (m/z 440 [M + H+]). After a further 4 h, LRMS
indicated the absence of the amino diol intermediate (m/z 440 [M +
H+]) and the presence of a peak corresponding to the dibenzylated
pyrrolidine intermediate (m/z 344 [M + H+]). Aqueous hydrochloric
acid (2 M, 0.4 mL) was added and the reaction vessel evacuated,
flushed with hydrogen and stirred for 16 h. LRMS indicated the
absence of the dibenzylated pyrrolidine intermediate (m/z 344 [M +
H+]) and presence of a peak corresponding to the fully deprotected
pyrrolidine 6 (m/z 164 [M + H+]). The reaction mixture was filtered
through a glass microfiber (GF/A), concentrated in vacuo, dissolved in
2 M aqueous hydrochloric acid (1 mL), and loaded onto a short
column of Dowex 50W-X8 (H+ form). The product was liberated with
2 M aqueous ammonia and the ammoniacal fractions combined and
concentrated in vacuo to afford the pyrrolidine 6 (9.5 mg, 91%) as a
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-L-talono-
1,4-lactone (45L). Methanesulfonyl chloride (90 μL, 1.06 mmol) was
added to a solution of alcohol 44L (340 mg, 0.89 mmol) in pyridine
(3.5 mL) at 0 °C under argon. After 10 min, the reaction was allowed
to warm to rt and stirred for a further 90 min. TLC analysis (2:1,
cyclohexane/ethyl acetate) indicated the complete consumption of the
starting material (Rf 0.38) and the formation of a major product (Rf
0.50). The reaction mixture was concentrated in vacuo and
coevaporated with toluene (2 × 5 mL). The crude residue was
purified by flash chromatography (47:3 to 3:1, cyclohexane/ethyl
acetate) to afford mesylate 45L (390 mg, 95%) as a clear oil: [α]25
D
+106.6 (c 1.27, CHCl3); νmax (thin film) 1180 (s, SO2), 1455 (s, SO2),
1801 (s, CO), 2117 (s, N3); δH (CDCl3, 400 MHz) 3.30 (3H, s,
SO2CH3), 3.71 (1H, dd, H6, J6,5 6.5, J6,6′ 9.7), 3.74 (1H, dd, H6′, J6′,5
6.5, J6′,6 9.7), 3.82 (1H, td, H5, J5,4 1.9, J5,6 = J5,6′ 6.5), 4.30 (1H, dd,
H3, J3,4 1.4, J3,2 6.0), 4.55 (1H, d, OCH2Ph, Jgem 11.8), 4.55 (1H, a-t,
H4, J4,3 = J4,5 1.7), 4.59 (1H, d, OCH2Ph, Jgem 11.8), 4.60 (1H, d,
OCH2Ph, Jgem 11.8), 4.86 (1H, d, OCH2Ph, Jgem 11.8), 5.57 (1H, d,
H2, J2,3 6.0), 7.32−7.41 (10H, m, ArH); δC (CDCl3, 100 MHz) 39.7
(SO2CH3), 60.6 (C5), 69.4 (C6), 72.9 (C2), 73.6, 73.8 (OCH2Ph),
75.1 (C3), 82.5 (C4), 127.8, 128.2, 128.2, 128.5, 128.6, 128.7 (ArCH),
136.3, 136.9 (ArCC), 169.8 (C1); LRMS (ESI +ve) 484 (27, M +
Na+), 516 (100, M + MeOH + Na+), 945 (25, 2M + Na+), 977 (34,
2M + MeOH + Na+); HRMS (ESI +ve) found 516.1408 [M + MeOH
+ Na+], C22H27N3NaO8S requires 516.1411.
yellow oil: [α]25 0.0 (c 1.50, H2O); νmax (thin film) 3319 (br s, OH,
D
NH); δH (D2O, 500 MHz) 3.25 (1H, q, H2, J2,1 = J2,1′ = J2,3 5.7), 3.59
(1H, dd, H1, J1,2 5.7, J1,1′ 11.4), 3.70 (1H, dd, H1′, J1′,2 5.7, J1′,1 11.4),
4.21 (1H, d, H3, J3,2 5.7); δC (D2O, 125 MHz) 60.4 (C1), 60.5 (C2),
71.9 (C3); LRMS (ESI +ve) 164 (55, M + H+), 186 (85, M + Na+),
327 (100, 2M + H+); (ESI −ve) 162 (100, [M − H]−); HRMS (ESI
+ve) found 186.0743 [M + Na+], C6H13NNaO4 requires 186.0737.
5-Azido-3,6-di-O-benzyl-5-deoxy-L-galactono-1,4-lactone (48L).
Trifluoromethanesulfonic anhydride (0.30 mL, 1.75 mmol) and
pyridine (0.33 mL, 4.05 mmol) were added to a solution of lactone
44L (517 mg, 1.35 mmol) in dichloromethane (5 mL) at −40 °C
under argon. The reaction was stirred for 90 min, with the internal
temperature rising to −25 °C, after which TLC analysis (2:1,
cyclohexane/ethyl acetate) indicated the complete consumption of the
starting material (Rf 0.38) and the formation of a major product (Rf
0.71). The reaction was diluted with dichloromethane (150 mL),
washed with 2 M aqueous hydrochloric acid (3 × 50 mL), dried
(MgSO4), filtered, and concentrated in vacuo to afford the crude
triflate 47L as a yellow oil. The crude triflate 47L was reacted on
without further purification.
Sodium trifluoroacetate (370 mg, 2.70 mmol) was added
portionwise to a solution of the crude triflate 47L in DMF (10 mL)
at −30 °C under argon. The reaction was allowed to warm to rt and
stirred for 20 h, after which TLC analysis (2:1, cyclohexane/ethyl
acetate) indicated the complete consumption of the starting material
(Rf 0.71) and the formation of a major product (Rf 0.50). The reaction
mixture was partitioned between ethyl acetate (150 mL) and saturated
aqueous sodium bicarbonate (50 mL). The phases were separated, and
the aqueous layer was extracted with ethyl acetate (3 × 80 mL). The
organic fractions were combined, dried (MgSO4), filtered and
concentrated in vacuo. The crude residue was purified by flash
chromatography (49:1 to 1:1, cyclohexane/ethyl acetate) to afford the
lactone 48L (403 mg, 78% over two steps) as a pale yellow oil, which
crystallized on standing to form a white crystalline solid: [α]25D +99.8
(c 1.25, CH3Cl); mp 62−64 °C; νmax (thin film) 1793 (s, CO),
2104 (s, N3), 3423 (br s, OH); δH (CD3CN, 400 MHz) 3.70 (1H, dd,
H6, J6,5 8.3, J6,6′ 10.1), 3.76 (1H, dd, H6′, J6′,5 4.3, J6′,6 10.1), 3.83 (1H,
a-dt, H5, J5,4 = J5,6′ 3.8, J5,6 8.0), 4.19 (1H, a-t, H3, J3,2 = J3,4 7.6), 4.22
(1H, d, OH2, JOH,2 5.6), 4.25 (1H, dd, H4, J4,5 3.5, J4,3 7.8), 4.53 (1H,
d, OCH2Ph, Jgem 12.1), 4.56 (1H, d, OCH2Ph, Jgem 12.1), 4.57 (1H, dd,
H2, J2,OH 5.6, J2,3 7.6), 4.64 (1H, d, OCH2Ph, Jgem 11.6), 4.82 (1H, d,
OCH2Ph, Jgem 11.6), 7.29−7.41 (10H, m, ArH); δC (CD3CN, 100
MHz) 61.9 (C5), 70.5 (C6), 73.1, 74.0 (OCH2Ph), 74.8 (C2), 78.3
(C4), 81.8 (C3), 128.8, 129.1, 129.2, 129.5, 129.5 (ArCH), 138.8,
For the enantiomer 45D: [α]25 −96.3 (c 1.25, CHCl3).
D
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-L-talitol
(46L). Sodium borohydride (41 mg, 1.08 mmol) was added
portionwise to a solution of lactone 45L (100 mg, 0.217 mmol) in
8:1 ethanol/1,4-dioxane (9 mL) at −30 °C under argon. The reaction
was stirred for 2.5 h, with the internal temperature rising to −15 °C,
after which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated
the partial consumption of the starting material (Rf 0.50) and the
formation of a major product (Rf 0.11). Further sodium borohydride
(41 mg, 1.08 mmol) was added at −30 °C and the reaction allowed to
warm to −15 °C. After 2 h, TLC analysis indicated the complete
consumption of the starting material Rf 0.50) and the major product
(Rf 0.11). The reaction was neutralized with glacial acetic acid and
concentrated in vacuo. The crude residue was dissolved in ethyl
acetate (20 mL) and washed with saturated aqueous sodium
bicarbonate (6 mL) and the aqueous phase extracted with ethyl
acetate (2 × 20 mL). The organic fractions were combined, washed
with brine (6 mL), dried (MgSO4), filtered, and concentrated in
vacuo. The crude residue was purified by flash chromatography (9:1 to
0:1, cyclohexane/ethyl acetate) to afford the diol 46L (65 mg, 65%) as
a clear oil: [α]25 +63.5 (c 1.25, CHCl3); νmax (thin film) 1173 (s,
D
SO2), 1337 (s, SO2), 2104 (s, N3), 3484 (br s, OH); δH (CD3CN, 400
MHz) 3.09 (3H, s, SO2CH3), 3.27 (1H, t, OH6, JOH,6 = JOH,6′ 5.7),
3.58 (1H, d, OH3, JOH,3 6.8), 3.73−3.77 (4H, m, H1, H1′, H5, H3),
3.82−3.85 (3H, m, H4, H6, H6′), 4.54 (1H, d, OCH2Ph, Jgem 11.9),
4.56 (1H, d, OCH2Ph, Jgem 11.0), 4.58 (1H, d, OCH2Ph, Jgem 11.9),
4.80 (1H, d, OCH2Ph, Jgem 11.0), 5.06 (1H, ddd, H2, J 1.5, J 4.8, J 6.3),
7.28−7.39 (10H, m, ArH); δC (CD3CN, 100 MHz) 39.0 (SO2CH3),
61.4 (C1), 62.0, 70.8 (C4, C5), 71.5 (C6), 74.0, 74.5 (OCH2Ph), 80.6
(C3), 85.7 (C2), 128.8, 128.8, 129.0, 129.4, 129.5 (ArCH), 139.0,
139.3 (ArCC); LRMS (ESI +ve) 488 (45, M + Na+), 504 (100, M +
K+), 953 (15, 2M + Na+), 969 (10, 2M + K+); (ESI −ve) 464 (10, [M
− H]−), 500 (50, M + 35Cl−), 502 (22, M + 37Cl−), 510, (100, M +
N
dx.doi.org/10.1021/jo301243s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
139.1 (ArCC), 174.2 (C1); LRMS (ESI +ve) 484 (18, M + Na+), 516
(100, M + MeOH + Na+); HRMS (ESI +ve) found 406.1364 [M +
Na+], C20H21N3NaO5 requires 406.1373.
material (Rf 0.24) and the formation of a major product (Rf 0.08).
LRMS indicated the absence of a peak corresponding to the starting
material 50L (m/z 488 [M + Na+]) and the formation of a peak
corresponding to the amino intermediate (m/z 440 [M + H+]). After a
further 4 h, LRMS indicated the absence of the amino intermediate
(m/z 440 [M + H+]) and the formation of peak corresponding to the
dibenzylated pyrrolidine intermediate (m/z 344 [M + H+]). Aqueous
hydrochloric acid (2 M, 1.0 mL) was added, the reaction vessel
evacuated and flushed with hydrogen, and the reaction stirred for 16 h.
LRMS indicated the absence of the dibenzylated pyrrolidine
intermediate (m/z 344 [M + H+]) and the formation a peak
corresponding to the fully deprotected pyrrolidine 5L (m/z 164 [M +
H+]). The reaction mixture was filtered through glass microfiber (GF/
B) and concentrated in vacuo, and the residue dissolved in 2 M
aqueous hydrochloric acid (1 mL) and loaded onto a short column of
Dowex 50W-X8 (H+ form). The product was liberated with 2 M
aqueous ammonia, and the ammoniacal fractions were combined and
concentrated in vacuo to afford the pyrrolidine 5L (43 mg, 92%) as a
yellowish oil.72
For the enantiomer 48D: [α]25 −104.0 (c 1.40, CHCl3), mp 62−
D
64 °C.
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-L-galac-
tono-1,4-lactone (49L). Methanesulfonyl chloride (0.10 mL, 1.29
mmol) was added dropwise to a solution of alcohol 48L (330 mg,
0.861 mmol) in pyridine (4 mL) at 0 °C under argon. After 10 min,
the reaction mixture was allowed to warm to rt and stirred for 90 min.
TLC analysis (2:1, cyclohexane/ethyl acetate) indicated the complete
consumption of the starting material (Rf 0.50) and the formation of a
major product (Rf 0.65). The reaction mixture was concentrated in
vacuo, coevaporated with toluene (3 × 10 mL) and the crude residue
purified by flash chromatography (47:3 to 4:1, cyclohexane/ethyl
acetate) to afford the mesylate 49L (310 mg, 78%) as a clear oil:
[α]25D −99.9 (c 1.35, CHCl3); νmax (thin film) 1173 (s, SO2), 1363 (s,
SO2), 1801 (s, CO), 2107 (s, N3); δH (CD3CN, 400 MHz) 3.27
(3H, s, SO2CH3), 3.71 (1H, dd, H6, J6,5 8.1, J6,6′ 10.1), 3.77 (1H, dd,
H6′, J6′,5 4.3, J6′,6 10.1), 3.86 (1H, ddd, H5, J5,4 3.3, J5,6′ 4.3, J5,6 8.1),
4.43 (1H, dd, H4, J4,5 3.3, J4,3 7.6), 4.54 (1H, a-t, H3, J3,2 = J3,4 7.7),
4.55 (1H, d, OCH2Ph, Jgem 12.1), 4.56 (1H, d, OCH2Ph, Jgem 12.1),
4.65 (1H, d, OCH2Ph, Jgem 11.4), 4.81 (1H, d, OCH2Ph, Jgem 11.4),
5.56 (1H, d, H2, J2,3 7.8), 7.30−7.41 (10H, m, ArH); δC (CD3CN, 100
MHz) 40.2 (SO2CH3), 61.2 (C5), 70.3, 73.6 (OCH2Ph), 79.3 (C4),
79.4 (C3), 80.5 (C2), 128.8, 128.8, 129.4, 129.5, 129.6 (ArCH), 138.0,
139.0 (ArCC), 169.4 (C1); LRMS (ESI +ve) 484 (100, M + Na+), 516
(73, M + MeOH + Na+); HRMS (ESI +ve) found 516.1414 [M +
MeOH + Na+], C22H27N3NaO8S requires 516.1411.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: george.fleet@chem.ox.ac.uk; kato@med.u-toyama.ac.
■
For the enantiomer 49D: [α]25 +105.8 (c 1.32, CHCl3).
jp.
D
5-Azido-3,6-di-O-benzyl-5-deoxy-2-O-methanesulfonyl-L-galacti-
tol (50L). Sodium borohydride (80 mg, 2.11 mmol) was added
portionwise to a solution of lactone 49L (150 mg 0.325 mmol) in 8:1
ethanol/1,4-dioxane (4 mL) at −30 °C under argon. The reaction was
stirred for 90 min, with the internal temperature rising to −15 °C, after
which TLC analysis (2:1, cyclohexane/ethyl acetate) indicated the
incomplete consumption of the starting material (Rf 0.65) and the
formation of a major product (Rf 0.24). Further sodium borohydride
(80 mg, 2.11 mmol) was added at −30 °C and the reaction allowed to
warm to −15 °C. After 4 h, TLC analysis indicated the complete
consumption of the starting material (Rf 0.65) and the major product
(Rf 0.24). The reaction was neutralized with glacial acetic acid and
concentrated in vacuo. The crude residue was dissolved in ethyl
acetate (80 mL) and washed with saturated aqueous sodium
bicarbonate (40 mL). The aqueous phase was extracted with ethyl
acetate (2 × 80 mL), and the organic fractions were combined, dried
(MgSO4), filtered, and concentrated in vacuo. The crude residue was
purified by flash chromatography (9:1 to 3:7, cyclohexane/ethyl
acetate) to afford the diol 50L (134 mg, 89%) as a white, crystalline
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Newton Abraham Research
Fund (B.J.A.), Fundacion
■
́
Ramon
́
Areces (R.F.M.), and a
Grant-in-Aid for Scientific Research (C) (No. 23590127)
(A.K.) from the Japanese Society for the Promotion of Science
(JSPS).
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