Synthesis of 2-deoxy-2-C-alkyl glycal and glycopyranosides from 2-hydroxy glycal ester

Article abstract of DOI:10.1021/jo202240f

A method to convert 2-hydroxy glycal ester to the corresponding 2-deoxy-2-C-alkyl glycal in a facile manner, through key reactions including (i) C-allylation at C-1, (ii) Wittig reaction, and (iii) Cope rearrangement of a 1,5-diene derivative, is reported. The α-anomer of the 1,5-diene derivative underwent Cope rearrangement to afford 2-deoxy-2-C-glycal derivative, whereas the β-anomer was found to be unreactive. Employing this sequence, 3,4,6-tri-O-benzyl-2-O-acetyl-1,5-anhydro-d-arabino-hex-1-enitol was transformed to 3,4,6-tri-O-benzyl-2-deoxy-2-C-alkyl-1,5-anhydro-d-arabino-hex-1-enitol. 2-Deoxy-2-C-alkyl glycal derivative is a suitable glycosyl donor to prepare 2-deoxy-2-C-alkyl glycosides, mediated through haloglycosylation and a subsequent dehalogenation. A number of 2-deoxy-2-C-alkyl glycosides, with both glycosyl and nonglycosyl moieties at the reducing end, are thus prepared from the glycal.

Full text of DOI:10.1021/jo202240f

Article
pubs.acs.org/joc
Synthesis of 2-Deoxy-2-C-alkyl Glycal and Glycopyranosides from
2-Hydroxy Glycal Ester
Gour Chand Daskhan and Narayanaswamy Jayaraman*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
S
* Supporting Information
ABSTRACT: A method to convert 2-hydroxy glycal ester to the
corresponding 2-deoxy-2-C-alkyl glycal in a facile manner,
through key reactions including (i) C-allylation at C-1, (ii) Wittig
reaction, and (iii) Cope rearrangement of a 1,5-diene derivative, is
reported. The α-anomer of the 1,5-diene derivative underwent
Cope rearrangement to afford 2-deoxy-2-C-glycal derivative, whereas the β-anomer was found to be unreactive. Employing this
sequence, 3,4,6-tri-O-benzyl-2-O-acetyl-1,5-anhydro-D-arabino-hex-1-enitol was transformed to 3,4,6-tri-O-benzyl-2-deoxy-2-C-alkyl-1,5-
anhydro-D-arabino-hex-1-enitol. 2-Deoxy-2-C-alkyl glycal derivative is a suitable glycosyl donor to prepare 2-deoxy-2-C-alkyl glycosides,
mediated through haloglycosylation and a subsequent dehalogenation. A number of 2-deoxy-2-C-alkyl glycosides, with both glycosyl
and nonglycosyl moieties at the reducing end, are thus prepared from the glycal.
and several carbohydrate mimetics.17,18 From a synthetic
perspective, development of methods to prepare 2-deoxy-2-C-
INTRODUCTION
Unsaturated sugars are excellent synthetic equivalents for synthetic
■
branched sugars relied primarily on either glycals19−21 or
cyclopropanated adducts of glycals22−26 as the precursors or
Wittig homologation of 2-ketoglycosides.27 In contrast, the
presence of an oxygen functionality at C-2 in oxyglycals provides
an advantage for subsequent synthetic manipulations. With this
perspective, we undertook an effort to transform oxyglycals to
2-deoxy-2-C-alkyl glycals that upon activation form precursors for
the synthesis of 2-deoxy-2-C-alkyl glycopyranosides. Syntheses of
2-deoxy-2-C-alkyl glycals and the corresponding glycopyranosides
are described herein.
transformations in general.1−3 The particular class of unsaturated
sugars, namely, 2-hydroxy glycals or oxyglycals, which differ from
1,2-unsaturated sugars or glycals by the presence of an oxygen
functionality at C-2, undergo reactions to provide synthetic
intermediates that offer diverse reaction possibilities. The synthetic
value of oxyglycals is illustrated elegantly, for example, (i) to
synthesize reactive 1-halo-2-uloses,4 (ii) to implement allylic
rearrangements so as to prepare 2,3-unsaturated glycosides,5−8
(iii) to conduct addition across the vinyl ether functionality,9 and
(iv) to synthesize unnatural seven-membered septanosides through
an insertion-ring-opening reaction sequence.10−12 By far the
greatest utilization of oxyglycals can be traced to the synthesis of
1-halo-2-ulose sugars by Lichtenthaler and co-workers and the
diversified reaction possibilities arising from such uloses.13 The
presence of oxygen functionality at C-2 leads to altered reactivities
of intermediates derived from oxyglycals, as opposed to those
derived from glycals. An example is the reactivity differences and,
thus, altered product formation profiles of cyclopropane adducts
derived from glycals and oxyglycals. A cyclopropane adduct in the
case of glycals leads to the formation of 2-C-branched sugars;14 on
the other hand, a similar adduct derived from oxyglycal affords
seven-membered oxepine systems,10 both under base-promoted
conditions.
RESULTS AND DISCUSSION
■
The conversion of oxyglycal to 2-deoxy-2-C-alkyl glycal was
initiated as shown in Figure 1, for which implementation of a
Cope rearrangement was planned as a key step.
In Figure 1, utilization of 2-hydroxy glycal ester relies on the
possibility of facile in situ generation of vinyl oxide anion under
a base-promoted condition. The vinyl oxide anion, in turn, is
susceptible to an O- or C-alkylation in the presence of an
acceptor alkyl moiety. This anticipation was realized readily
when oxyglycal 1, prepared through an orthoester method,28
was reacted with allyl bromide in the presence of NaH/aq
DMF (Scheme 1). The reaction led to the formation of
C-allylated (2) and O-allylated (3) products. The presence of
NMR signals corresponding to ketone functionality and C-1 of
the glycal moiety indicated the formation of 2 and 3,
respectively. The presence of 3, along with 2, was inferred
In further efforts to expand the scope of reactions, we under-
took an effort to transform oxyglycals to the corresponding
2-deoxy-2-C-alkyl glycals. As a consequence of the presence of
C-1−C-2 unsaturation, such 2-C-alkylated glycals would be
subjected to activation of the double bond and subsequent
reactions, as is well-known for glycals so far.15,16 Thus, developing
a synthetic methodology to transform oxyglycals to 2-deoxy-2-
C-alkyl glycals would, in principle, offer an alternative route to
prepare 2-deoxy-2-C-branched sugars. 2-Deoxy-2-C-branched
sugars are prominent moieties in natural products, antibiotics,
1
from the H NMR spectrum, wherein anomeric proton of 3
was observed at 6.26 ppm as a singlet and CH2CHCH2 of 2
at 2.34−2.66 ppm as a multiplet; the ratio of these two nuclei of
Received: October 31, 2011
Published: January 25, 2012
© 2012 American Chemical Society
2185
dx.doi.org/10.1021/jo202240f | J. Org. Chem. 2012, 77, 2185−2191

The Journal of Organic Chemistry
Article
Figure 1. Synthetic plan to prepare 2-deoxy-2-C-glycal from 2-hydroxy glycal ester.
Scheme 1
2:3 was found to be 9:1. The C- (2) and O-allylated (3)
products were an inseparable mixture, which was mitigated
through heating the mixture at 165 °C in a sealed tube. The
thermal rearrangement led to the disappearance of 3 and
exclusive formation of 2 in an overall moderate yield of 63%
from oxyglycal 1.
The C-glycoside 2 was an anomeric mixture, and the
anomers could not be separated in a facile manner. Whereas a
C-alkylation at C-1 retained with keto-functionality at C-2 is
achieved from an oxyglycal precursor in the present work,
preparation of either anomer of 2 was reported previously by
Zou and co-workers through oxidation of the C-2 hydroxyl
group on stereochemically pure α- and β-C-glycosides.29 The
ratio of anomeric mixture of alkyl C-2-ulosides 2 in our
protocol was determined on the basis of the observed distinct
resonances of anomeric proton for each anomer and in
conjecture with the above report. The presence of triplet at
4.25 ppm corresponding to H-1 of α-anomer and a multiplet at
4.02−4.07 ppm, corresponding to H-1of the β-anomer,
facilitated determination of the ratio to be 55:45%.
with β-anomeric configuration, showed a strong cross peak
between H-1 and H-3 and a weak cross peak between H-2 and
allylic CH2 protons. Additional cross peaks within the ring, as
well as with benzylic groups, were also observed.
The installation of a methylene moiety at C-2 generated 1,5-
diene functionalities in 4 and 5 that are amenable for a thermal
rearrangement. Thus, when α-C-alkyl glycoside 4 in diphenyl
ether was heated at 240 °C for ∼25 min, in a sealed tube, a Cope
rearrangement occurred to afford 2-deoxy-2-(but-3-enyl) glycal
6, in 72% yield (Scheme 3). Formation of 6 was confirmed by
the appearance of C-1 resonance at 140.6 ppm and C-2
resonance at 111.5 ppm in 13C NMR spectrum, and in place of
a resonance at 78.2 ppm for the same nucleus in 4. Whereas
the reaction was facile with α-anomer 4, attempts to subject
β-anomer 5 for a similar thermal rearrangement were not
successful, and only the starting material was recovered.
Possible conformations of 4 and 5, agreeing with NOESY
analyses (vide supra), are shown also in Scheme 3. Further, the
observation that none of the β-anomer 5 underwent rearrange-
ment indicated that the transition state of this anomer did not
encounter ring-flipping or interconversion which would initiate
the rearrangement.
Implementation of Cope rearrangement completed the
formal transformation of oxyglycal to 2-deoxy-2-C-alkyl glycal.
The utility of Claisen rearrangement of 1,5-dienes originating
from varied carbons of a sugar is known previously. For
example, Fraser-Reid and co-workers demonstrated30 an “out-
of-ring” oxy-Cope rearrangement to produce C-2 and C-3 gem-
disubstituted pyranosides, with exclusive stereoselectivities.
Curran and Suh31 demonstrated stepwise mono- and bis-
Claisen rearrangements of glycals, equipped with appropriate
bis(ketene silyl)acetal moieties to afford functionalized C-glycosyl
compounds. On the other hand, elegant examples of Claisen
rearrangements are the conversion of carbohydrates to func-
tionalized cyclohexanes, as demonstrated by Nagarajan and
Sudha,32 and cyclooctanes, by Thiem and co-workers.33
In efforts to utilize 2-C-glycal 6 for subsequent elaboration as
a donor in glycosylations, reaction at the terminal double bond
was undertaken first. A hydration across the double bond
through a hydroboration-oxidation was exercised. Thus, diene
6 was reacted with 9-BBN in THF, followed by treatment
with H2O2 (30%)−aq NaOH (3 N) solution (Scheme 4).
With the inability to separate the anomeric mixture of 2, the
synthesis was proceeded to install the methylene moiety at C-2
in 2. A Wittig methylenation of 2 afforded C-2-methylene
C-glycosides 4 and 5 (Scheme 2). The anomers were separated
Scheme 2
and identified by the observation of a set of multiplets at 2.34−
2.44 ppm and 2.53−2.60 ppm for CH2CHCH2 nuclei of the
α-anomer 4 and an triplet at 2.55 ppm of the corresponding nuclei
of β-anomer 5. The newly introduced methylene moiety at C-2 in 4
resonated at 5.24, 5.02 ppm and that for 5 resonated at 5.31,
5.10 ppm. Further, evidence for the assignments of 4 comes
through the presence of strong cross peaks of H-3 and H-5
with allylic CH2 protons and a weak cross peak between C-2
methylene and allylic CH2 protons in the NOESY spectrum.
The spectrum did not exhibit a cross peak between H-1 and
H-3. On the other hand, the NOESY spectrum of 5, assigned
Scheme 3
2186
dx.doi.org/10.1021/jo202240f | J. Org. Chem. 2012, 77, 2185−2191

The Journal of Organic Chemistry
Article
Scheme 4
Table 1. List of 2-Iodo-2-C-alkyl Glycosides 9−14 and 15, Formed through Iodoglycosylation of 8 and 7, Respectively, and
a
2-Deoxy-2-C-glycosides 16 and 17, Formed from 13 and 15, Respectively
a
Isolated yields are given in parentheses.
The reaction led to a hydration at the terminal double bond
and afforded alcohol 7.
axial configuration in 9−14 and an equatorial configuration in
15 of iodide at C-2 were inferred.
Subsequent to iodoglycosylation, a deiodination reaction was
undertaken with few glycosides. Reaction of glycosides 13 and
15 with Bu3SnH/AIBN, followed by treatment with NaOMe/
MeOH, in the case of 13, led to a facile deiodination and
O-deacetylation to afford 2-deoxy-2-(n-butyl) glycosides 16 and
17 in 81 and 88% yields, respectively. In order to assess the
anomeric configuration, a NOESY experiment was performed
on 17, from which cross peaks of H-1 with H-3 and H-5
protons were observed, in addition to the C1 resonance at
102.04 ppm in the corresponding 13C NMR spectrum. In the
case of 16, having two α-anomeric carbons, both C1 resonances
were seen at 96.3 and 97.8 ppm. These comparisons led to
assign a β-anomeric configuration to 17. The examples studied
herein showed not only a facile iodoglycosylation but also
subsequent deiodination in order to realize 2-C-branched
2-deoxy-2-C-alkyl glycosides.
Reactivities of 2-deoxy-2-C-alkyl glucal 7 were explored
further by subjecting it to a haloglycosylation.15,16 Toward this,
alcohol 7 was protected as an acetate 8 (Ac2O/pyridine) and
subjected to haloglycosylation using N-iodosuccinimide (NIS)
in the presence of acceptor alcohols, including sugars. The
reaction in CH2Cl2 at room temperature led to the formation of
haloglycosylation products 9−14 (Table 1) in good yields. We
infer from previous reports that haloglycosylation generally
has a very high propensity for 1,2-trans diaxial addition pattern
of substituents.34,35 Observing that anomeric carbon resonates
at around 101 ppm for compounds 9−14, we assign these
compounds an α-anomeric configuration. Trans-addition being
predominant in haloglycosylation, we are tempted to assign an
axial configuration to the iodo-group at C-2. Whereas the
intermolecular haloglycosylation led to α-anomeric glycosides
in 9−14, wherein C-1 appeared at ∼101 ppm, an intra-
molecular reaction with glycal 7 afforded the oxepine derivative
15, for which the anomeric carbon appeared at 107.1 ppm in
the 13C NMR spectrum, which we assign to a β-anomeric
configuration. The conformational constraints appeared to be
dominating in the formation of 15 with β-anomeric linkage, as
opposed to α-anomeric linkage with 9−14 predominated by
the kinetic anomeric effect. On the basis of of anti-addition, an
CONCLUSION
■
A synthetic method to transform 2-hydroxy glycal ester,
namely, oxyglycal to the corresponding 2-deoxy-2-C-alkyl glycal
was developed by involving (i) C-alkylation at anomeric carbon
of an oxyglycal to afford C-alkyl-2-uloside, (ii) Wittig methy-
lenation to 1,5-diene, namely, 2-C-methylenyl-C-alkyl glycal,
2187
dx.doi.org/10.1021/jo202240f | J. Org. Chem. 2012, 77, 2185−2191

The Journal of Organic Chemistry
Article
Ha-6), 3.54 (dd, J = 3.6, 10.8 Hz, 1 H, Hb-6), 3.48 (dd, J = 4.8, 8.0 Hz,
1 H, H-4), 2.55 (t, J = 6.9 Hz, 2 H, CH2CHCH2); 13C NMR (100
MHz, CDCl3) δ 143.9 (C-2), 138.3−138.1 (aromatic), 135.0 (−CH
CH2), 128.3−127.4 (aromatic), 116.6 (−CHCH2), 107.7 (methy-
lene C), 84.5 (C-3), 80.3 (C-4), 79.1 (C-5), 76.9 (C-1), 74.6 (PhCH2),
73.3 (PhCH2), 72.9 (PhCH2), 69.3 (C-6), 35.9 (CH2CHCH2); ES-MS
m/z C31H34O4Na calcd 493.2355, found 493.2353.
and (iii) a Cope rearrangement on 2-C-methylenyl-
C-alkyl glycal. The presence of glycal functionality and a
terminal olefin functionality in the exo-cyclic alkyl substituent
provided feasibility to conduct reactions separately. Thus,
whereas the terminal olefin was subjected to a hydration, the
glycal functionality was utilized to an iodoglycosylation and
deiodination reactions, leading to the formation of a series of
2-deoxy-2-C-alkyl glycosides, with nonglycosyl and glycosyl
substituents. A bicyclic sugar−oxepine fused ring derivative
was also obtained through an intramolecular glycosylation on
2-deoxy-2-C-alkyl glycal.
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-(but-3-enyl)-D-
arabino-hex-1-enitol (6). The reaction tube was deacidified by
soaking in 1,1,1,3,3,3-hexamethyldisilazane overnight. A solution of 4
(0.37 g, 0.78 mmol) in diphenyl ether (3 mL) was sealed and heated at
240 °C for ∼25 min and purified (SiO2) (hexane/EtOAc = 10:1) to
afford 6 (0.27 g, 72%) as a colorless oil: Rf = 0.25 (hexane/EtOAc =
1
9:1); [α]D +49.0 (c 2, CHCl3); H NMR (CDCl3, 400 MHz) 7.35−
EXPERIMENTAL SECTION
7.26 (band, 15 H, aromatic), 6.28 (s, 1 H, H-1), 5.80−5.71 (m, 1 H, −
CHCH2), 5.0−4.94 (m, 2 H, −CHCH2), 4.75−4.48 (m, 6 H,
PhCH2), 4.16−4.12 (m, 1 H, H-5), 4.06 (d, J = 4.8 Hz, 1 H, H-3), 3.96
(dd, J = 4.8, 6.8 Hz, 1 H, H-4), 3.80 (dd, J = 5.6, 10.4 Hz, 1 H, Ha-6),
3.72 (dd, J = 3.6, 10.4 Hz, 1 H, Hb-6), 2.20−1.94 (m, 4 H, −
CH2CH2CHCH2); 13C NMR (100 MHz, CDCl3) δ 140.6 (C-1),
138.4 (−CHCH2) 138.3−138.0 (aromatic), 128.4−127.7 (aro-
matic), 114.7 (−CHCH2), 111.5 (C-2), 76.1 (C-5), 75.6 (C-3),
73.8 (C-4), 73.4 (PhCH2), 72.8 (PhCH2), 71.3 (PhCH2), 68.2 (C-6),
32.5 (−CH2CH2CHCH2), 28.2 (−CH2CH2CHCH2); ES-MS
m/z C31H34O4Na calcd 493.2352, found 493.2357.
■
3-C-(3′,4′,6′-Tri-O-benzyl-α/β-D -arabino-hex-2-
ulopyranosyl)propene (2). Allyl bromide (0.33 mL, 3.79 mmol)
was added to a solution of 128 (0.9 g, 1.89 mmol) in DMF (10 mL)
at 0 °C. NaH (0.095 g, 2.37 mmol, 60% in mineral oil) and H2O
(100 μL) in DMF (1 mL) were added slowly to the reaction mixture
for over 5−10 min. The reaction mixture was diluted with water
(50 mL), extracted with Et2O (3 × 50 mL), washed with aq NH4Cl (2 ×
50 mL), dried (Na2SO4), and filtered, solvents were removed in vacuo,
and the crude product was purified (SiO2) (EtOAc/pet ether = 1:19),
1
to afford a mixture of 2 and 3. H NMR (400 MHz, CDCl3): 2.34−
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-(4-hydroxybu-
tyl)-D-arabino-hex-1-enitol (7). 9-BBN (2 M in THF) (0.34 mL,
0.69 mmol) was added dropwise to a solution of 6 (0.26 g, 0.55 mmol)
in THF (10 mL) under argon atmosphere and at room temperature
and stirred for 2 h. The reaction mixture was cooled to 0 °C, and aq
NaOH (3 N) (0.4 mL) and aq H2O2 (30%) (0.5 mL) were added
dropwise. The reaction mixture was stirred for 2 h, diluted with H2O
(100 mL), extracted with Et2O (3 × 70 mL), dried (Na2SO4), filtered,
concentrated in vacuo, and purified (SiO2) (hexane/EtOAc = 4:1) to
afford 7 (0.22 g, 82%): gum; Rf = 0.37 (hexane/EtOAc = 2:1); [α]D +
2.66 ppm (m, CH2CHCH2 of 2); 6.26 ppm (s, H-1 of 3), ratio
of 2:3 = 9:1. The O-allyl product 3 in toluene (4 mL) was heated at
165 °C in a sealed tube for over 45 min, and solvents were removed in
vacuo to afford 2 (0.56 g, 63%) (α/β = 1.2:1) as an oil: IR 1738 cm−1.
1H NMR (400 MHz, CDCl3) δ 7.39−7.21 (band, 33.3 H), 5.90−5.72
(m, 2.22 H), 5.15−5.01 (m, 4.44 H), 4.96 (d, J = 11.6 Hz, 1.22 H),
4.87−4.76 (m, 2.44 H), 4.62−4.58 (m, 3.22 H), 4.51 (d, J = 11.6 Hz,
2.44 H), 4.43−4.38 (m, 4 H), 4.27 (t, J = 6.8 Hz, 1.22 H), 4.05−4.02
(m, 1 H), 3.93−3.89 (m, 2 H), 3.83−3.58 (m, 8.88 H), 3.50−3.47 (m,
1 H), 2.66−2.58 (m, 2 H), 2.47 (t, J = 6.4 Hz, 2.44 H); 13C NMR (100
MHz, CDCl3) δ 207.8, 201.9, 138.7−137.5, 133.6, 132.3, 128.6−127.6,
118.4, 117.2, 86.7, 84.4, 79.9, 78.3, 76.2, 75.5, 75.3, 74.4, 74.2, 73.9,
73.7, 73.4, 72.8, 72.2, 69.8, 68.2, 34.8, 32.9; ES-MS m/z C30H32O5Na
cslcd 495.2147, found 495.2154.
1
47.1 (c 1, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.33−7.25 (band,
15 H, aromatic), 6.26 (s, 1 H, H-1), 4.72−4.44 (m, 6 H, PhCH2), 4.13
(dd, J = 5.6, 10.8 Hz, 1 H, H-5), 4.02 (d, J = 4.8 Hz, 1 H, H-3), 3.93
(app. t, J = 5.6 Hz, 1 H, H-4), 3.78 (dd, J = 6.0, 10.8 Hz, 1 H, Ha-6),
3.70 (dd, J = 3.6, 10.8 Hz, 1 H, Hb-6), 3.57 (t, J = 6.4 Hz, 2 H, −
CH2OH), 2.14−2.07 (m, 1 H, −CH2CH2OH), 1.91−1.84 (m, 1 H, −
CH2CH2OH), 1.54−1.30 (m, 4 H, −CH2CH2CH2CH2OH); 13C
NMR (100 MHz, CDCl3): δ 140.4 (C-1), 138.3−137.9 (aromatic),
128.4−127.6 (aromatic), 111.7 (C-2), 75.9 (C-5), 75.2 (C-3), 73.6
(C-4), 73.3 (PhCH2), 72.7 (PhCH2), 71.2 (PhCH2), 68.2 (C-6), 62.7
(−CH2OH), 32.2 (−CH2CH2OH), 28.5 (−CH2CH2CH2CH2OH),
24.0 (−CH2CH2CH2OH);ES-MS m/z C31H36O5Na calcd 511.2460,
found 511.2458.
3-C-(3′,4′,6′-Tri-O-benzyl-2-deoxy-2-C-methylene-α/β-D-arab-
ino-hexopyranosyl)propene (4 and 5). nBuLi (1.6 M hexane)
(1.47 mL, 2.36 mmol) was added dropwise to a solution of Ph3PMeI
(1.2 g, 2.96 mmol) in THF (10 mL) at 0 °C. After ∼20 min, a solution
of 2 (0.56 g, 1.18 mmol) in THF (20 mL) was added dropwise and
stirring continued for 2 h. The reaction mixture was diluted with H2O
(150 mL), extracted with CHCl3 (3 × 50 mL), dried (Na2SO4),
filtered, concentrated in vacuo, and purified (SiO2) (hexane/EtOAc =
7:1) to afford 4 and 5. 4: 0.19 g (55%); gum; Rf = 0.24 (hexane/
1
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-(4-acetoxybu-
tyl)-D-arabino-hex-1-enitol (8). Acetic anhydride (0.09 mL, 0.9
mmol) was added to a solution of 7 (0.22 g, 0.04 mmol) in pyridine
(4 mL) at 0 °C and stirred for 6 h at room temperature. The reaction
mixture was diluted with water (50 mL), extracted with CHCl3 (3 ×
50 mL), washed with aq HCl (2 N) and aq NaHCO3 (2 × 50 mL),
dried (Na2SO4), filtered, concentrated in vacuo, and purified (SiO2)
(hexane/EtOAc = 9:1) to afford 8 (0.22 g, 92%): gum; Rf = 0.33
EtOAc = 9:1); [α]D +9.7 (c 0.7, CHCl3); H NMR (CDCl3, 400
MHz) 7.36−7.15 (band, 15 H, aromatic), 5.79−5.69 (m, 1 H, −CH
CH2), 5.24 (br. s, 1 H, methylene H), 5.08−5.04 (m, 2 H, −CH
CH2), 5.02 (br. s, 1 H, methylene H), 4.83 (d, J = 10.8 Hz, 1 H,
PhCH2), 4.74−4.58 (band, 3 H, PhCH2), 4.51−4.48 (band, 2 H,
PhCH2), 4.38 (t, J = 7.2 Hz, 1 H, H-1), 4.22 (d, J = 8.4 Hz, 1 H, H-3),
3.85−3.81 (m, 1 H, H-5), 3.70 (dd, J = 3.6, 10.8 Hz, 1 H, Ha-6), 3.63
(dd, J = 2.4, 10.8 Hz, 1 H, Hb-6), 3.55 (t, J = 8.4 Hz, 1 H, H-4), 2.60−
2.53 (m, 1 H, −CH2CHCH2), 2.44−2.34 (m, 1 H, −CH2CH
CH2); 13C NMR (100 MHz, CDCl3) δ 143.4 (C-2), 138.2−138.1
(aromatic), 134.0 (−CHCH2), 128.4−127.5 (aromatic), 117.1
(−CHCH2), 110.2 (methylene C), 81.0 (C-3), 80.3 (C-4), 78.2
(C-1), 74.1 (PhCH2), 73.4 (PhCH2), 73.3 (PhCH2), 73.1 (C-5), 69.3
(C-6), 35.6 (−CH2CHCH2); ES-MS m/z C31H34O4Na calcd
493.2355, found 493.2353.
1
(hexane/EtOAc = 9:1); [α]D +26.0 (c 1, CHCl3); H NMR (CDCl3,
400 MHz) δ 7.33−7.25 (band, 15 H, aromatic), 6.26 (s, 1 H, H-1),
4.72−4.44 (m, 6 H, PhCH2), 4.15−4.12 (m, 1 H, H-5), 4.01−3.98
(band, 3 H, H-3, −CH2OAc), 3.94 (dd, J = 5.6, 12.8 Hz, 1 H, H-4),
3.78 (dd, J = 5.6, 10.4 Hz, 1 H, Ha-6), 3.70 (dd, J = 3.6, 10.4 Hz, 1 H,
Hb-6), 2.12−2.06 (m, 1 H, −CH2CH2OAc), 2.01 (s, 3 H, Me), 1.91−1.81
(m, 1 H, −CH2CH2OAc), 1.63−1.50 (band, 4 H, −CH2CH2CH2OAc +
H2O), 1.40−1.23 (m, 2 H, −CH2CH2CH2CH2OAc); 13C NMR (100
MHz, CDCl3) δ 171.1 (−COCH3), 140.5 (C-1), 138.2−137.9 (aromatic),
128.4−127.6 (aromatic), 111.5 (C-2), 75.9 (C-5), 75.2 (C-3), 73.6 (C-4),
73.4 (PhCH2), 72.8 (PhCH2), 71.2 (PhCH2), 68.2 (C-6), 64.3 (−CH2−
OAc), 28.4 (−CH2CH2OAc), 28.0 (−CH2CH2CH2CH2OAc), 24.3
(−CH2CH2CH2OAc), 20.9 (−COCH3); ES-MS m/z C33H38O6Na
calcd 553.2566, found 553.2561.
5: 0.15 g (45%); gum; Rf = 0.28 (hexane/EtOAc = 9:1); [α]D +28.0
1
(c 1, CHCl3); H NMR (CDCl3, 400 MHz) 7.38−7.15 (band, 15 H,
aromatic), 5.93−5.86 (m, 1 H, −CHCH2), 5.31 (br s, 1 H,
methylene H), 5.14−5.05 (m, 2 H, −CHCH2), 5.10 (br s, 1 H,
methylene H), 4.84 (d, J = 10.8 Hz, 1 H, PhCH2), 4.74 (d, J = 11.6 Hz,
1 H, PhCH2), 4.65−4.47 (m, 4 H, PhCH2), 4.02 (d, J = 8.0 Hz, 1 H,
H-3), 3.76−3.69 (m, 2 H, H-1, H-5), 3.63 (dd, J = 4.8, 10.8 Hz, 1 H,
2188
dx.doi.org/10.1021/jo202240f | J. Org. Chem. 2012, 77, 2185−2191

The Journal of Organic Chemistry
Article
Methyl 3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-(2-C-(4-acetoxy-
butyl))-α-D-arabino-hexopyranoside (9). N-Iodosuccinimide
(0.06 g, 0.25 mmol) and methanol (10 μL, 0.34 mmol) were added
to a solution of 8 (0.09 g, 0.17 mmol) in CH2Cl2 (10 mL) under argon
atmosphere and at room temperature, stirred for 2 h, diluted with
water (50 mL), extracted with CH2Cl2 (3 × 50 mL), washed with aq
Na2S2O3 solution (5%) (2 × 20 mL) and brine (2 × 20 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The crude product was
purified (SiO2) (hexane/EtOAc = 6:1) to afford 9 (0.1 g, 86%):
colorless oil; Rf = 0.31 (hexane/EtOAc = 5.5:1); [α]D +23.7 (c 1,
(C-3), 79.6 (C-4), 75.2 (PhCH2), 73.4 (PhCH2), 72.2 (PhCH2), 68.8
(C-5), 67.7 (C-6), 64.3 (−CH2OAc), 63.0 (−CH2OH), 62.4
(−OCH2CH2CH2CH2OH), 39.8 (C-2), 30.0 (−CH2CH2OAc), 29.5
(−CH2CH2CH2OH), 28.3 (−CH2CH2CH2CH2OAc), 25.8 (−CH2-
CH2OH), 22.3 (−CH2CH2CH2OAc), 20.9 (CH3); ES-MS m/z
C37H47O8INa calc 769.2213, found 769.2217.
2-(Phenylethyl)-3,4,6-tri-O-benzyl-2-deoxy-2-iodo-(2-C-(4-
acetoxybutyl))-α-D-arabino-hexopyranoside (12). N-Iodosuccin-
imide (0.038 g, 0.17 mmol) and 2-phenylethanol (28 μL, 0.23 mmol)
were added to a solution of 8 (0.06 g, 0.11 mmol) in CH2Cl2 (10 mL)
under argon atmosphere and at room temperature and stirred for 2 h,
and the reaction was followed further as described for 9. The crude
product was purified (SiO2) (hexane/EtOAc = 6:1) to afford 12
(0.068 g, 77%): gum; Rf = 0.36 (hexane/EtOAc = 9:1); [α]D +3.0 (c 1,
1
CHCl3); H NMR (CDCl3, 400 MHz) δ 7.37−7.25 (band, 14 H,
aromatic), 7.15−7.13 (m, 1 H, aromatic), 5.02 (d, J = 11.6 Hz, 1 H,
PhCH2) 4.90 (s, 1 H, H-1), 4.79−4.71 (m, 3 H, PhCH2), 4.63−4.49 (m,
2 H, PhCH2), 4.15−4.09 (m, 1 H, H-5), 4.04−3.99 (m, 2 H, CH2−OAc),
3.83−3.69 (m, 3 H, H-4, -H-6a,b), 3.33 (s, 3 H, OMe), 2.86 (d, J = 8.4 Hz,
1 H, H-3), 2.02 (s, 3 H, −COCH3), 1.74−1.70 (m, 2 H, −CH2CH2OAc),
1.60−1.46 (m, 2 H, −CH2CH2CH2OAc), 1.35−1.27 (m, 2 H, −CH2-
CH2CH2CH2OAc); 13C NMR (100 MHz, CDCl3) δ 171.0 (−COCH3),
138.5−137.9 (aromatic), 128.3−127.3 (aromatic), 102.9 (C-1), 83.2
(C-3), 79.5 (C-4), 75.2 (C-5), 75.0 (PhCH2), 73.3 (PhCH2), 72.0
(PhCH2), 68.8 (C-6), 62.9 (−CH2OAc), 55.0 (OMe), 39.8 (C-2), 28.3
(−CH2CH2OAc), 22.1 (−CH2CH2CH2OAc), 20.9 (−CH2CH2CH2-
CH2OAc), 20.8 (−COCH3); ES-MS m/z C34H41O7INa calcd 711.1795,
found 711.1794.
1
CHCl3); H NMR (CDCl3, 400 MHz) δ 7.38−7.24 (band, 15 H,
aromatic), 7.20 (d, J = 11.6 Hz, 1 H, aromatic), 7.16−7.14 (band, 4 H,
aromatic), 5.02 (d, J = 11.8 Hz, 1 H, PhCH2), 4.94 (s, 1 H, H-1), 4.87
(m, 2 H, PhCH2), 4.77 (d, J = 11.2 Hz, 1 H, PhCH2), 4.71 (d, J = 11.8 Hz,
1 H, PhCH2), 4.51 (d, J = 11.2 Hz, 1 H, PhCH2), 4.12 (app t, J =
9.2 Hz, 1 H, H-4), 3.92−3.83 (m, 2 H, −CH2OAc), 3.75−3.73 (m, 1
H, H-5), 3.65 (d, J = 9.6 Hz, 1 H, Ha-6), 3.51 (dd, J = 9.6, 16.4 Hz, 1
H, Hb-6), 2.87−2.80 (m, 3 H, H-3, −OCH2CH2Ph), 2.01 (s, 3 H, −
COCH3), 1.90−1.80 (m, 2 H, −OCH2CH2Ph), 1.74−1.66 (m, 2 H, −
CH2CH2OAc), 1.59−1.52 (m, 1 H, −CH2CH2CH2OAc), 1.42−1.25
(m, 2 H, −CH2CH2CH2CH2OAc), 1.0−0.9 (m, 1 H, −CH2CH2-
CH2CH2OAc); 13C NMR (100 MHz, CDCl3) δ 170.3 (-COCH3),
138.3−138.0 (aromatic), 128.8−127.4 (aromatic), 101.8 (C-1), 82.9
(C-5), 79.5 (C-4), 75.0 (C-3), 74.2 (PhCH2), 73.3 (PhCH2), 72.1
(PhCH2), 68.7 (C-6), 64.1 (−CH2OAc), 63.0 (-OCH2−CH2Ph), 35.9
(C-2), 32.3 (−OCH2CH2Ph), 28.2 (−CH2CH2OAc), 21.4
(−CH2CH2CH2OAc), 20.9 (−CH3), 19.9 (−CH2CH2CH2CH2OAc);
ES-MS m/z C41H47O7INa calcd 801.2264, found 801.2263.
Butyl 3,4,6-Tri-O-benzyl-2-deoxy-(2-iodo)-(2-C-(4-acetoxy-
butyl))-α-D-arabino-hexopyranoside (10). N-Iodosuccinimide
(0.04 g, 0.17 mmol) and n-butanol (17 μL, 0.22 mmol) were added
to a solution of 8 (0.06 g, 0.11 mmol) in CH2Cl2 (10 mL) under argon
atmosphere and stirred for 2 h at room temperature, and the reaction
was followed further as described for 9. The crude product was
purified (SiO2) (hexane/EtOAc = 5.6:1) to afford 10 (0.07 g, 85%):
1
gum; Rf = 0.39 (hexane/EtOAc = 9:1); [α]D +26.0 (c 1, CHCl3); H
NMR (CDCl3, 400 MHz) δ 7.37−7.28 (band, 14 H, aromatic), 7.26−
7.13 (m, 1 H, aromatic), 5.03 (d, J = 11.6 Hz, 1 H, PhCH2), 4.99 (s,
1 H, H-1), 4.8−4.72 (m, 3 H, PhCH2), 4.55−4.51 (m, 2 H, PhCH2),
4.14 (app t, J = 9.2 Hz, 1 H, H-4), 4.03−4.0 (m, 2 H, −CH2OAc),
3.86−3.78 (m, 2 H, H-5, Ha-6), 3.69−3.65 (m, 2 H, Hb-6, −OCH2-
CH2CH2CH3), 3.35−3.29 (m, 1 H, −OCH2CH2CH2CH3), 2.89 (d,
J = 8.8 Hz, 1 H, H-3), 2.02 (s, 3 H, −COCH3), 1.88−1.82 (m, 1 H, −
CH2CH2CH3), 1.74−1.68 (m, 2 H, CH2CH2CH3), 1.55−1.51 (m,
5 H, −CH2CH2CH2OAc, −OCH2CH2CH2CH3), 1.37−1.32 (m, 2 H, −
CH2CH2CH2CH2OAc), 0.91 (t, J = 7.6 Hz, 3 H, −CH3); 13C NMR
(100 MHz, CDCl3) δ 171.0 (-COCH3), 138.3−137.9 (aromatic),
128.4−127.4 (aromatic), 101.9 (C-1), 83.3 (C-5), 79.5 (C-4), 75.2
(C-3), 75.1 (PhCH2), 73.3 (PhCH2), 72.1 (PhCH2), 68.8 (C-6), 64.2
(−CH2OAc), 63.3 (−OCH2CH2CH2CH3), 39.8 (C-2), 32.3 (−CH2-
CH2OAc), 31.4 (−CH2CH2CH2OAc), 28.4 (−CH2CH2CH2CH2-
OAc), 22.3 (CH2CH2CH3), 20.9 (−COCH3), 19.3 (−CH2CH3),
13.7 (−CH3); ES-MS m/z C37H47O7INa calcd 753.2264, found
753.2259.
4-Hydroxybutyl 3,4,6-Tri-O-benzyl-2-deoxy-(2-iodo)-(2-C-(4-
acetoxybutyl))-α-D-arabino-hexopyranoside (11). N-Iodosucci-
nimide (0.05 g, 0.22 mmol) and 1,4-butanediol (7 μL, 0.07 mmol)
were added to a solution of 8 (0.08 g, 0.15 mmol) in CH2Cl2 (15 mL)
under argon atmosphere and stirred for 6 h at room temperature, and
the reaction was followed further as described for 9. The crude
product was purified (SiO2) (hexane/EtOAc = 5.6:1) to afford 11
(0.090 g, 80%): gum; Rf = 0.37 (hexane/EtOAc = 4:1); [α]D +28.4
(c 1, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.38−7.29 (band, 14 H,
aromatic), 7.26−7.13 (m, 1 H, aromatic), 5.03 (d, J = 12.2 Hz, 1 H,
PhCH2), 5.01 (s, 1 H, H-1), 4.79−4.70 (m, 3 H, PhCH2), 4.58−4.50
(m, 2 H, PhCH2), 4.13 (app t, J = 9.2 Hz, 1 H, H-4), 4.05−3.98 (m,
2 H, −CH2OAc), 3.84 (dd, J = 3.6, 10.8 Hz, 1 H, H-5), 3.78 (dd, J = 4.8,
10.8 Hz, 1 H, Ha-6), 3.74−3.68 (m, 1 H, Hb-6), 3.62 (app t, J = 7.2 Hz,
2 H, −CH2OH), 3.53 (app t, J = 6.0 Hz, 2 H, −OCH2CH2CH2-
CH2OH), 2.88 (d, J = 8.8 Hz, 1 H, H-3), 2.0 (s, 3 H, −COCH3),
1.73−1.69 (m, 2 H, −OCH2CH2CH2CH2OH), 1.63−1.51 (m, 6 H,
CH2CH2CH2OAc, CH2CH2CH2OH), 1.37−1.30 (m, 2 H, −CH2CH2-
CH2CH2OAc); 13C NMR (100 MHz, CDCl3) δ 171.1 (−COCH3),
138.3−137.8 (aromatic), 128.4−127.5, (aromatic) 102.0 (C-1), 83.3
3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-(2-C-(4-acetoxybutyl))-α-
D-arabino-hexopyranosyl-(1→6)-α-D-1,2:3,4-di-O-isopropylidene-
α-D-glucopyranose (13). N-Iodosuccinimide (0.05 g, 0.22 mmol) and
1,2:3,4-diisopropylidene-α-D-galactopyranoside (0.1 g, 0.37 mmol)
were added to a solution of 8 (0.08 g, 0.15 mmol) in CH2Cl2 (15 mL)
under argon atmosphere and at room temperature. The reaction
mixture was stirred for 6 h, and the reaction was followed further as
described for 9. The crude product was purified (SiO2) (hexane/
EtOAc = 4:1) to afford 13 (0.115 g, 83%): gum; Rf = 0.39 (hexane/
EtOAc = 4:1); [α]D −5.0 (c 1, CHCl3); 1H NMR (CDCl3, 400 MHz)
δ 7.39−7.25 (band, 14 H, aromatic), 7.14−7.13 (m, 1 H, aromatic),
5.50 (d, J = 5.2 Hz, 1 H, HR-1), 5.08 (s, 1 H, HNR-1), 5.03 (d, J = 12.0 Hz,
1 H, PhCH2), 4.76 (m, 3 H, PhCH2), 4.61 (dd, J = 2.6, 8.0 Hz, 1 H,
HR-3), 4.55−4.51 (m, 2 H, PhCH2), 4.32 (dd, J = 2.4, 5.2 Hz, 1 H, HR-
2), 4.20 (app t, J = 9.2 Hz, 1 H, HNR-4), 4.12 (dd, J = 2.4, 8.0 Hz, 1 H,
HR-4), 4.06−3.92 (band, 2 H, −CH2OAc), 3.93 (m, 1 H, HR-5), 3.86−
3.82 (m, 1 H, HNR-5), 3.80 (app d, J = 4.4 Hz, 1 H, HNR-6a), 3.78−
3.69 (band, 2 H, HNR-6b, HR-6a), 3.61 (dd, J = 6.4, 10.4 Hz, 1 H, HR-6b),
2.89 (d, J = 8.8 Hz, 1 H, HNR-3), 2.07−2.04 (m, 1 H, −CH2CH2OAc),
2.02 (s, 3 H, −COCH3), 1.60−1.57 (m, 1 H, −CH2CH2OAc), 1.55−1.48
(m, 4 H, −CH2CH2CH2OAc + H2O), 1.53 (s, 3 H, Me), 1.42 (s, 3 H,
Me), 1.33 (s, 3 H, Me), 1.31 (app s, 4 H, Me, −CH2CH2CH2CH2OAc),
1.26−1.23 (m, 1 H, −CH2CH2CH2CH2OAc); 13C NMR (100 MHz,
CDCl3) δ 170.0 (−COCH3), 138.3−137.9 (aromatic), 128.3−127.3
(aromatic), 109.3, 108.6, 101.3 (CNR-1), 96.2 (CR-1), 83.1 (CNR-3),
79.4 (CNR-4), 75.2 (PhCH2), 75.1 (PhCH2), 73.3 (PhCH2), 72.3
(CNR-5), 70.9 (CR-4), 70.6 (CR-3), 70.4 (CR-2), 68.5 (CNR-6), 65.0
(CR-6), 64.2 (CR-5), 63.3 (−CH2OAc), 39.7 (CNR-2), 28.4
(−CH2CH2OAc), 26.1 (Me), 25.9 (Me), 24.8 (Me), 24.5
(−CH2CH2CH2OAc), 22.1 (−CH2CH2CH2CH2OAc), 20.9
(−CH3); ES-MS m/z C45H57O12INa calcd 939.2792, found
939.2793.
Methyl 3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-(2-C-(4-acetoxy-
butyl))-α-D-arabino-hexopyranosyl-(1→6)-α-D-2,3,4-tri-O-
benzyl-α-D-glucopyranoside (14). N-Iodosuccinimide (0.063 g,
0.28 mmol) and methyl 1,2,3-tri-O-benzyl-α-D-glucopyranoside (0.18 g,
0.38 mmol) were added to a solution of 8 (0.10 g, 0.19 mmol) in
CH2Cl2 (15 mL) under argon atmosphere and at room temperature.
2189
dx.doi.org/10.1021/jo202240f | J. Org. Chem. 2012, 77, 2185−2191

The Journal of Organic Chemistry
Article
The reaction mixture was stirred for 6 h, and the reaction was followed
further as described for 9. The crude product was purified (SiO2)
(hexane/EtOAc = 4:1) to afford 14 (0.174 g, 82%): gum; Rf = 0.36
(hexane/EtOAc = 4:1.5); [α]D +29.0 (c 1, CHCl3); 1H NMR (CDCl3,
400 MHz) δ 7.37−7.24 (band, 28 H, aromatic), 7.13−7.11 (m, 2 H,
aromatic), 5.02 (s, 1 H, HNR-1), 5.01−4.98 (band, 2 H, PhCH2), 4.93
(d, J = 11.2 Hz, 1 H, PhCH2), 4.82−4.74 (m, 4 H, PhCH2), 4.68−4.64
(m, 2 H, PhCH2), 4.59−4.50 (band, 3 H, HR-1, PhCH2), 4.44 (d, J =
12.0 Hz, 1 H, PhCH2), 4.14 (app. t, J = 9.2 Hz, 1 H, HNR-4), 4.02−3.93
(band, 3 H, HR-5, −CH2OAc), 3.86 (dd, J = 4.4, 11.2 Hz, 1 H, HR-6a),
3.77 (dd, J = 2.8, 11.2 Hz, 1 H, HNR-5), 3.67 (dd, J = 4.4, 11.2 Hz, 2 H,
HR-3, HNR-6a), 3.57 (dd, J = 1.6, 11.2 Hz, 1 H, HNR-6b), 3.50 (dd, J = 1.6,
11.2 Hz, 1 H, HR-6b), 3.44−3.39 (m, 2 H, HR-2, HR-4), 3.34 (s, 3 H,
OMe), 2.83 (d, J = 8.8 Hz, 1 H, HNR-3), 2.04−1.99 (band, 4 H,
−CH2CH2OAc, −COCH3), 1.67−1.62 (m, 1 H, −CH2CH2OAc), 1.50−
1.39 (m, 2 H, −CH2CH2CH2OAc), 1.35−1.25 (m, 2 H,
−CH2CH2CH2CH2OAc); 13C NMR (100 MHz, CDCl3) δ 170.9
(-COCH3), 138.6−138.0 (aromatic), 128.5−127.4 (aromatic), 102.7
128.3−127.6 (aromatic), 109.3, 108.6, 97.8 (CNR-1), 96.3 (CR-1), 81.8
(CNR-3), 79.5 (CNR-5), 75.4 (PhCH2), 74.8 (PhCH2), 73.5 (PhCH2),
71.0 (CR-4), 70.9 (CR-3), 70.6 (CR-2), 70.5 (CR-5), 68.6 (CNR-6), 64.9
(CNR-4), 64.8 (CR-6), 62.5 (−CH2OH), 46.0 (CNR-2), 33.1
(−CH2CH2OH), 26.8 (−CH2CH2CH2OH), 26.1 (Me), 25.9 (Me),
24.8 (Me), 24.4 (Me), 22.6 (−CH2−); ES-MS m/z C43H56O11Na
calcd 771.3720, found 771.3721.
(4R,5S,5aS,6R,9aR)-6-Benzyloxymethyl-4,5-dibenzyloxyocta-
hydrooxepino[2,3-b]pyran (17). Bu3SnH (72 μL, 0.24 mmol) and
AIBN (0.5 mg) were added to a stirring solution of 15 (0.1 g, 0.16 mmol)
in benzene (3 mL). The reaction mixture was refluxed at 75 °C for 2 h
under argon atmosphere. The solution was concentrated in vacuo.
Purified with hexane/EtOAc = 9:1 to afford 17 (0.07 g, 88%): gum;
Rf = 0.39 (hexane/EtOAc = 9:1); [α]D +61.8 (c 1, CHCl3); 1H NMR
(CDCl3, 400 MHz) δ 7.35−7.25 (band, 14 H, aromatic), 7.17 (d, J =
6.4 Hz, 1 H, aromatic), 4.91 (d, J = 3.6 Hz, 1 H, H-1), 4.90 (d, J =
11.2 Hz, 1 H, PhCH2), 4.79 (d, J = 11.2 Hz, 1 H, PhCH2), 4.64 (d, J =
14.0 Hz, 2 H, PhCH2), 4.53 (t, J = 12.4 Hz, 2 H, PhCH2), 3.99−3.95
(m, 2 H, H-4, Ha-6), 3.75 (ddd, J = 2.4, 6.0, 16.8 Hz, 2 H, H-3, Hb-6),
3.68 (dd, J = 4.8, 9.2 Hz, 1 H, H-5), 3.65−3.59 (m, 2 H, −CH2O),
2.13−2.09 (m, 1 H, H-2), 1.87−1.80 (m, 1 H, −CH2CH2O), 1.67−
1.61 (m, 2 H, −CH2CH2O, −CH2CH2CH2O), 1.49−1.41 (m, 1 H, −
CH2CH2CH2O), 1.36−1.25 (m, 2 H, −CH2CH2CH2CH2O); 13C
NMR (100 MHz, CDCl3) δ 138.6−138.0 (aromatic), 128.3−127.5
(aromatic), 102.0 (C-1), 81.7 (C-3), 79.5 (C-5), 75.2 (PhCH2), 74.5
(PhCH2), 73.4 (PhCH2), 72.4 (C-4), 69.2 (C-6), 68.7 (−CH2O), 45.3
(C-2), 32.0 (−CH2−CH2−O), 27.8 (−CH2CH2CH2O), 21.5
(−CH2CH2CH2CH2O); ES-MS m/z C31H36O5Na calcd 511.2460,
found 511.2459.
(CNR-1), 97.8 (CR-1), 82.5 (CNR-3), 81.9 (CR-5), 80.1 (CR-2), 79.5 (CNR
-
4), 77.7 (CR-4), 75.7 (PhCH2), 75.1 (PhCH2),75.0 (PhCH2), 74.9
(PhCH2), 73.3 (PhCH2), 73.1 (PhCH2), 72.4 (CNR-5), 69.6 (CR-3), 68.6
(CNR-6), 66.6 (CR-4), 64.1 (−CH2OAc), 62.5 (CR-6), 55.1 (OMe), 39.9
(CNR-2), 28.4 (−CH2CH2CH2CH2OAc), 23.5 (−CH2CH2CH2OAc),
22.2 (−CH2CH2CH2CH2OAc), 20.9 (−COCH3); ES-MS m/z
C61H69O12INa calcd 1143.3731, found 1143.3734.
(4R,5S,5aS,6R,9aR)-6-Benzyloxymethyl-4,5-dibenzyloxy-5a-
iodooctahydrooxepino[2,3-b]pyran (15). N-Iodosuccinimide
(0.07 g, 0.3 mmol) was added to a solution of 7 (0.1 g, 0.2 mmol)
in CH2Cl2 (10 mL) under argon atmosphere and at room
temperature, stirred for 1.5 h, diluted with water (30 mL), extracted
with CH2Cl2 (3 × 25 mL), washed with aq Na2S2O3 (5%) (2 ×
15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The
crude product was purified (SiO2) (hexane/EtOAc = 20:1) to afford
15 (0.10 g, 79%): colorless oil; Rf = 0.47 (hexane/EtOAc = 49:1);
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental method and H and 13C NMR spectra of all new
1
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
[α]D +41.5 (c 1, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.39−7.25
(band, 14 H, aromatic), 7.25−7.13 (m, 1 H, aromatic), 5.19 (s, 1 H,
H-1), 5.04 (d, J = 11.6 Hz, 1 H, PhCH2), 4.83−4.71 (m, 3 H, PhCH2),
4.57−4.52 (m, 2 H, PhCH2), 4.09−4.03 (band, 3 H, H-4, −CH2O),
3.77 (dd, J = 3.2, 10.8 Hz, 1 H, Ha-6), 3.69 (app d, J = 10.8 Hz, 1 H, Hb-
6), 3.64−3.58 (m, 1 H, H-5), 2.83 (d, J = 8.0 Hz, 1 H, H-3), 2.66 (dd, J =
8.8, 15.2 Hz, 1 H, −CH2CH2CH2CH2O), 2.16 (dd, J = 8.8, 16.0 Hz, 1 H,
−CH2CH2CH2CH2O), 1.75−1.68 (b, 2 H, −CH2CH2O), 1.62−1.53 (b,
2 H, −CH2CH2CH2O); 13C NMR (100 MHz, CDCl3) δ 138.4−138.1
(aromatic), 128.3−127.4 (aromatic), 107.1 (C-1), 83.3 (C-3), 79.6 (C-4),
75.1 (PhCH2), 74.8 (PhCH2), 73.7 (−CH2O), 73.4 (PhCH2), 70.9 (C-5),
68.8 (C-6), 62.1 (C-2), 44.3 (−CH2CH2CH2CH2O), 31.0
(−CH2CH2O), 20.8 (−CH2CH2CH2O); ES-MS m/z C31H35O5INa
calcd 637.1427, found 637.1431.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jayaraman@orgchem.iisc.ernet.in.
ACKNOWLEDGMENTS
■
We thank the Department of Biotechnology, New Delhi, for
financial support of the work. G.C.D. thanks the Council of
Scientific and Industrial Research, New Delhi, for a research
fellowship.
3,4,6-Tri-O-benzyl-2-deoxy-2-C-(4-hydroxybutyl)-α-D-arabi-
no-hexopyranosyl-(1→6)-α-D-1,2:3,4-di-O-isopropylidene-α-D-
glucopyranose (16). Bu3SnH (57 μL, 0.19 mmol) and AIBN (1 mg)
was added to a solution of 13 (0.12 g, 0.13 mmol) in benzene (3 mL)
under argon atmosphere and refluxed at 75 °C for 2 h. The solution
was concentrated in vacuo, dissolved in MeOH (10 mL), admixed with
NaOMe in MeOH (0.3 mL, 0.5 M), stirred for 4 h, and neutralized
with Amberlite IR-120 resin (H+), and solvents were evaporated in
vacuo. The crude product was purified (SiO2) (hexane/EtOAc =
2.5:1) to afford 16 (0.08 g, 81%): colorless oil; Rf = 0.34 (hexane/
EtOAc = 2:1); [α]D +32.7 (c 1, CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 7.35−7.26 (band, 14 H, aromatic), 7.15−7.13 (m, 1 H, aromatic),
5.53 (d, J = 5.0 Hz, 1 H, HR-1), 4.90−4.87 (m, 2 H, HNR-1, HR-4),
4.78 (d, J = 12.0 Hz, 1 H, PhCH2), 4.67−4.60 (m, 3 H, PhCH2),
4.52−4.49 (m, 2 H, PhCH2), 4.32 (app. d, J = 2.4, 5.0 Hz, 1 H, HR-2),
4.21 (d, J = 8 Hz, 1 H, HR-3), 3.97 (app t, J = 7.5 Hz, 1 H, HNR-4),
3.79−3.75 (m, 3 H, HNR-5, −CH2OH), 3.70−3.59 (m, 6 H, HNR-3,
HNR-6a,b, HR-6a,b, HR-5), 2.35−2.28 (m, 1 H, −CH2CH2OH), 2.06−
1.98 (m, 1 H, −CH2CH2OH), 1.87−1.83 (m, 1 H, HNR-2), 1.68−1.58
(m, 2 H, −CH2CH2CH2OH), 1.53 (s, 3 H, Me), 1.43 (s, 3 H, Me),
1.33 (s, 3 H, Me), 1.25 (s, 3 H, Me), 0.89 (app t, J = 7.5 Hz, 2 H,
−CH2−); 13C NMR (125 MHz, CDCl3) δ 138.6−138.0 (aromatic),
REFERENCES
■
(1) Fraser-Reid, B.; Lopez, J. C. Curr. Org. Chem. 2009, 13, 532−553.
(2) Ferrier, R. J. Top. Curr. Chem. 2001, 215, 153−175.
(3) Collins, P.; Ferrier, R. Monosaccharides: Their Chemistry and Their
Roles in Natural Products; John Wiley & Sons Ltd.: Chichester, 1995;
pp 316−334.
(4) Lichtenthaler, F. W.; Schwidetzky, S.; Nakamura, K. Tetrahedron
Lett. 1990, 31, 71−74.
(5) Ferrier, R. J.; Zubkov, O. A. Org. React. 2003, 62, 569−736.
(6) Ferrier, R. J.; Prasad, N.; Sankey, G. H. J. Chem. Soc. C 1968,
974−7.
(7) Varela, O.; De Fina, G. M.; De Lederkremer, R. M. Carbohydr.
Res. 1987, 167, 187−196.
(8) Gupta, P.; Kumari, N.; Agarwal, A.; Vankar, Y. D. Org. Biomol.
Chem. 2008, 6, 3948−3956.
(9) Lichtenthaler, F. W.; Weimer, T.; Immel, S. Tetrahedron:
Asymmetry 2004, 15, 2703−2709.
(10) Ganesh, N. V.; Jayaraman, N. J. Org. Chem. 2007, 72, 5500−
5504.
(11) Ganesh, N. V.; Jayaraman, N. J. Org. Chem. 2009, 74, 739−746.
2190
dx.doi.org/10.1021/jo202240f | J. Org. Chem. 2012, 77, 2185−2191

The Journal of Organic Chemistry
Article
(12) Ganesh, N. V.; Sonti, R.; Raghothama, S.; Jayaraman, N. J. Org.
Chem. 2010, 75, 215−218.
(13) Lichtenthaler, F. W. Chem. Rev. 2011, 111, 5569−5609.
(14) Hewitt, R. J.; Harvey, J. E. J. Org. Chem. 2010, 75, 955−958.
(15) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am.
Chem. Soc. 1975, 97, 4056−4062.
(16) Thiem, J.; Karl, H.; Schwentner, J. Synthesis 1978, 696−698.
(17) Kirschning, A.; Bechthold, A. F.-W.; Rohr, J. Top. Curr. Chem.
1997, 188, 1−84.
(18) Hanessian, S. Total Synthesis of Natural Products: The “Chiron”
Approach; Pergamon Press: Oxford, 1983; pp 40−183.
(19) Schmidt, R. R.; Kast, J. Tetrahedron Lett. 1986, 27, 4007−4010.
(20) Ramesh, N. G.; Balasubramanian, K. K. Tetrahedron Lett. 1991,
31, 3875−3878.
(21) Linker, T.; Sommermann, T.; Kahlenberg, F. J. Am. Chem. Soc.
1997, 119, 9377−9384.
(22) Beyer, J.; Skaanderup, P. R.; Madsen, R. J. Am. Chem. Soc. 2000,
122, 9575−9583.
(23) Shao, H.; Ekthawatchai, S.; Wu, S.-H.; Zou, W. Org. Lett. 2004,
6, 3497−3499.
(24) Tian, Q.; Xu, L.; Ma, X.; Zou, W.; Shao, H. Org. Lett. 2010, 12,
540−543.
(25) Sridhar, P. R.; Ashalu, K. C.; Chandrasekaran, S. Org. Lett. 2004,
6, 1777−1779.
(26) Scott, R. W.; Heathcock, C. H. Carbohydr. Res. 1996, 291, 205−
208.
(27) Wong, G.; Fraser-Reid, B. Can. J. Chem. 1994, 72, 69−74.
(28) Lichtenthaler, F. W.; Schneider-Adams, T. J. Org. Chem. 1994,
59, 6728−6734.
(29) Zou, W.; Wang, Z.; Lacroix, E.; Wu, S.-H.; Jennings, H. J.
Carbohydr. Res. 2001, 334, 223−231.
(30) Tulshian, D. B.; Tsang, R.; Fraser-Reid, B. J. Org. Chem. 1984,
49, 2347−2355.
(31) Curran, D. P.; Suh, Y.-G. Carbohydr. Res. 1987, 171, 161−191.
(32) Sudha, A. V. R. L.; Nagarajan, M. Chem. Commun. 1998, 925−
926.
(33) Jurs, S.; Werschkun, B.; Thiem, J. Eur. J. Org. Chem. 2006,
̈
4451−4462.
(34) Lafont, D.; Descotes, G. Carbohydr. Res. 1987, 166, 195−209.
(35) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380−1419.
2191
dx.doi.org/10.1021/jo202240f | J. Org. Chem. 2012, 77, 2185−2191