A convenient synthesis of orthogonally protected 2-deoxystreptamine (2-DOS) as an aminocyclitol scaffold for the development of novel aminoglycoside antibiotic derivatives against bacterial resistance

Article abstract of DOI:10.1039/b804784g

The development of new aminoglycoside analogues to reduce the emergence of bacterial resistance has become a topic of high interest. We describe here a rapid and facile access to orthogonally protected 2-deoxystreptamine (2-DOS), a meso-diaminocyclitol known to be a pivotal component of most active aminoglycosides. Our synthetic approach started from highly protected methyl α-d-glucopyranoside which in turn was converted by a Ferrier rearrangement into an enantiopure polyfunctionalized cyclohexane ring. Finally, two different N-protected groups were successively introduced. The first one was inserted as an oximino benzylether followed by a diastereofacial hydride reduction, working with Me₄NBH(OAc)₃ only in TFA at low temperature rather than in AcOH as usual. The second group was introduced by displacement of a hydroxyl group through a Mitsunobu reaction using a DPPA-DIAD-Ph₃P system for azide transfer. The Royal Society of Chemistry.

Full text of DOI:10.1039/b804784g

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A convenient synthesis of orthogonally protected 2-deoxystreptamine
(2-DOS) as an aminocyclitol scaffold for the development of novel
aminoglycoside antibiotic derivatives against bacterial resistance†
Claude Bauder*
Received 20th March 2008, Accepted 19th May 2008
First published as an Advance Article on the web 20th June 2008
DOI: 10.1039/b804784g
The development of new aminoglycoside analogues to reduce the emergence of bacterial resistance has
become a topic of high interest. We describe here a rapid and facile access to orthogonally protected
2-deoxystreptamine (2-DOS), a meso-diaminocyclitol known to be a pivotal component of most active
aminoglycosides. Our synthetic approach started from highly protected methyl a-D-glucopyranoside
which in turn was converted by a Ferrier rearrangement into an enantiopure polyfunctionalized
cyclohexane ring. Finally, two different N-protected groups were successively introduced. The first one
was inserted as an oximino benzylether followed by a diastereofacial hydride reduction, working with
Me4NBH(OAc)3 only in TFA at low temperature rather than in AcOH as usual. The second group was
introduced by displacement of a hydroxyl group through a Mitsunobu reaction using a
DPPA–DIAD–Ph3P system for azide transfer.
gentamicin, apramycin. . . are based on a central diaminocyclitol
Introduction
core named 2-deoxystreptamine (2-DOS) that is O-substituted at
Aminoglycosides constitute a large family of small molecules
the 4, 5 and/or 6-position by an additional carbohydrate unit
that display a powerful antibacterial drug activity by causing a
(Fig. 1). This recurring presence of 2-DOS core scaffold suggests
miscoding in protein biosynthesis and consequently the death of
an important role for its recognition at the bacterial rRNA
a bacterial cell.1 In this regard they are widely used as clinically
important antibacterial agents. Indeed, their antibiotic activity
takes place specifically in the aminoacyl tRNA decoding site (A-
site) located in a well defined region of the 16S rRNA (ribosomal
RNA) within the 30S subunit of the bacterial ribosome.2 Thus,
these aminoglycosides, connected to particular oligonucleotides
of the rRNA, disturb the fidelity of mRNA translation, leading to
a misreading of bacterial protein elongation.
Unfortunately, during the last few decades, more and more
resistant strains develop1b,d,3 enzymes that modify these natural
aminoglycosides, which thus become ineffective in the treatment
of various infections. Faced with this increasing emergence of
bacterial resistance to multiple antibiotics, the access to novel
active aminoglycoside antibiotic derivatives will therefore repre-
sent a major goal.3d To this end, a library of numerous analogues
of antibiotics has been obtained, by chemical modifications,
from their parent aminoglycosides (often neamine or paromanine
subunits). The main drawbacks, limiting this option of structural
modifications, lie in problems of regiospecificity of protection–
deprotection (for further incorporation of various substitutes),
multi-step reactions, low solubility, difficulties in purification and
tedious NMR characterization.
target.1d,4 In this way, a highly functionalized 2-DOS becomes an
interesting polyvalent entity with the advantage of more flexibility
in the elaboration and development of a suitable range of modified
antibiotics able to mimic the aminoglycosides’ potency.5
Syntheses of minimally protected or naked 2-deoxystreptamine
have been performed by degradations of natural antibiotic
sources6 requiring further desymmetrization of the 2-DOS meso
compound.1d,7 Alternatively, it is more convenient to build
polyprotected 2-DOS by modifications and successive incorpo-
ration of different protecting groups starting from an existing
carbohydrate derivative precursor,8 or from a chiral pool like
D-allylglycine.9 However, the few given literature examples are
often low-yielding, multi-step syntheses that require separation
of diastereomers. For all these reasons, we chose to investigate an
efficient and convenient orthogonally protected 2-DOS synthesis.
We reporthereintwoinexpensive approaches towards thesynthesis
of highly functionalized meso 2-deoxystreptamine (2-DOS) in 7
and 11 steps respectively.
Results and discussion
Our objective was to minimize the number of steps and to use
procedures for which each protected intermediate would be readily
obtained by simple crystallization in very good yields and on
a large scale. The orthogonal protection should allow for the
regioselective introduction of different substituents in order to give
access to a range of new mimetic antibiotics. Thus the starting
point was the readily available methyl a-D-glucopyranoside10
which can be transformed to a pentahydroxylated cyclohexane
(quercitol) by a Ferrier carbocyclization rearrangement.11
Notably, a majority of aminoglycosides such as kanamycin,
neomycin, tobramycin, paromomycin, amikacin, ribostamycin,
Institut de Chimie, UMR 7177 associe´ au CNRS - Universite´ de Strasbourg,
1 rue Blaise Pascal, BP 296 R8, 67008, Strasbourg Cedex, France.
E-mail: cbauder@chimie.u-strasbg.fr
† Electronic supplementary information (ESI) available: Experimental
procedures for 1, 2, 4, 5, 9, 10, 11, 11a, 11b and spectroscopic data for
all products reported herein. See DOI: 10.1039/b804784g
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Fig. 1 Structures of selected common aminoglycoside antibiotics containing the meso-diaminocyclitol (2-DOS) unit.
Our strategy began by the known one-step protection of methyl
a-D-glucopyranoside to isolate compound 1 in 92% yield by
simple crystallization in MeOH (Scheme 1).12 As depicted in
Scheme 1, the tosyl group on the C-6 primary alcohol was then
easily substituted to give, in very good yield, either the iodide
212a (NaI, Ac2O, 93%) or the azide 3 (NaN3, dioxane, 95%) as
crystalline products. Compound 3 is a useful precursor for the
synthesis of the aminoglucosides kanamycin A or D bearing
the 2-DOS unit, or for applications in click chemistry13a to link
two carbohydrate moieties through a triazole ring as recently
published.13b–c Dehydroiodination of 2 was cleanly performed (68%
yield) in toluene with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)14
instead of silver fluoride as described earlier to give the expected
enopyranoside 4.12a Enone 4 was then subjected to the Ferrier
carbocyclic ring-closure in the presence of Hg(OAc)2 in a refluxing
mixture of acetone–H2O–AcOH to give 512a,15 in 69% yield after
recrystallization from CH2Cl2 (Scheme 2). This compound was
isolated as a single epimeric b-hydroxy-cyclohexanone where the
hydroxyl group has an axial orientation as shown by vicinal
coupling (J2,1 = 2.5 Hz).
Scheme 2 Reagents and conditions: (e) ref. 12a, Hg(OAc)2, acetone, H2O,
AcOH, 70 ◦C, 2.5 h (69%); (f) BnONH2·HCl, EtOH, pyridine, RT, 6 h
(93%); (g) 7a from 5: Me4NBH(OAc)3, AcOH, 0 ◦C, 1.5 h (80%); 7b from
6: Me4NBH(OAc)3, TFA, 0 ◦C, 2 h (93%); 7c from 6: DPPA, DBU, RT,
10 h (71%); (h) from 7b: DPPA, Ph3P, DIAD, RT, 7 h (65%).
formation of a six-membered boron complex intermediate, prior
to reduction.18,19
In our case, the oximino benzyl ether function is located on a
rigid cyclohexane unit. The axial b-hydroxyl group should play
an essential role in the hydride reduction to participate in a
neighboring group effect via coordination to the boron group
of TABH, thereby allowing control of diastereofacial selectivity
(see Scheme 3). With this in mind, we expected the asymmetric
reduction of b-hydroxy oximinobenzyl ether 6 with this mild and
selective reducing TABH agent to provide the optically active trans
1,3-benzyloxyamino alcohol 7b (Scheme 3).
Scheme 1 Reagents and conditions: ref. 12a for (a) and (b), 92% and 93%
respectively; (c) NaN3, dioxane–H2O, 110 ◦C, 48 h (95%); (d) from 2: DBU,
PhMe, 80 ◦C, 15 h (68%).
Now the first amino group was introduced at the carbonyl po-
sition through an oxime precursor using O-benzylhydroxylamine
hydrochloride in EtOH–pyridine to afford the crystalline benzy-
loxime 6 in 93% yield without further purification (on the basis
of NMR analysis). For the next step, the asymmetric reduction of
this oximino ether has to be discussed.
=
Generally, the reduction of an imino (C N) bond with
Scheme 3 Treatment with AcOH instead of TFA gave exclusively starting
material 6 (see text).
borane or aluminium hydride reagents results in an isomeric
mixture and/or the corresponding free amine after N–O bond
cleavage.8c,e,f ,16 Literature precedents17 show that tetramethylam-
monium triacetoxyborohydride (TABH)18 can undergo a stereo-
controlled reduction of acyclic b-hydroxy oximino benzyl ether
to give trans 1,3-amino alcohols. More typically, TABH is used
in the diastereoselective reduction of acyclic b-hydroxy ketones
to provide trans 1,3-diols. The latter is proposed to involve the
Surprisingly, the typical treatment on 6 (TABH in MeCN–
AcOH) failed and exhibited only starting material as summarized
in Table 1 (entries 4, 5). However, applying identical conditions
to the b-hydroxyketone 5 (entries 1–3) furnished the expected
quercitol 7a.20 This quercitol, named (+)-viburnitol,21 was rapidly
formed and isolated in good yield (80%). We were able to assign
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Table 1 Reduction conditions of ketone 5 or oximes 6 and 17 with TABH in the presence of AcOH or TFAa
Entry
Ketone and oxime
Acid (equiv.)
Time/h
Yield (%) of benzyloxyamine
1
2
3
4
5
6
7
8
9
5
AcOH (560)
AcOH (530)
AcOH (518)
AcOH (441)
AcOH (774)
TFA (473)
TFA (415)
TFA (152)
TFA (76)
0.5
1
0.5
84
80
65
0b
5
5
6
6
c
6
0b
6
1.5
1
2
30
2.5
65
66
93
89
69
6
6
6
10
17
TFA (151)
a All the experiments were performed with 10 to 11 equiv. of TABH (Me4NBH(OAc)3). For entries 1–5, standard conditions were used (TABH, MeCN,
AcOH) and in entries 6–11, AcOH was replaced by TFA. b Exclusively starting material was observed. c Only starting material was present even after 5 h
at room temperature and then 48 h at 55 ◦C.
unambiguously its absolute configuration. The configuration of
the newly generated hydroxyl group at C-5 was determined by
NMR spectroscopy. The large coupling constants, J4,5 (9.7 Hz)
and J5,6ax (14.2 Hz) as well as J5,6eq (4.7 Hz), revealed that the new
hydroxyl group in 7a was oriented in an equatorial position.
Nevertheless, neither excess of AcOH nor increasing the time
of reaction, even by heating for 48 h, produced any effect on
the reduction of the oximinium intermediate (entries 4, 5 in
Table 1). Gratifyingly, slightly modified conditions such as the use
of the stronger acid TFA (trifluoroacetic acid) instead of AcOH,
furnished cleanly the desired optically pure benzyloxyamino
alcohol 7b in 94% yield after only 2 h at low temperature and with
at least 152 equivalents of TFA (entry 8). Moreover, no cleavage
of the N–O bond and no dehydratation to enoxime were observed
under these conditions. If less TFA was used (entry 9), more time
was required for the reaction to reach completion.
Finally, the next strategy was the use of diphenylphosphoryl
azide (DPPA) as an azide transfer reagent to convert the axial
hydroxyl group at C-1 directly into an equatorial azide functional
group, which acts as an amine precursor. In this way, Mitsunobu
type conditions were used for the incorporation of the azide,
following the procedure described in the literature.22 Thus, reac-
tion of alcohol 7b with triphenylphosphine (Ph3P), diisopropyl
azodicarboxylate (DIAD), and DPPA provided the azide 8 in
good yield (65%) resulting in complete stereocontrol for the overall
conversions. The stereochemistry of 8 was confirmed by 1H NMR
spectroscopy: J6ax,1 = J6ax,5 13.3 Hz and J6eq,1 = J6eq,5 4.4 Hz, as
well as by NOESY analysis (see Experimental part). Attempts
to apply a modification of this Mitsunobu azidation (DPPA and
DBU) according to Thompson’s procedure23 was ineffective and
yielded only the formation of the phosphate ester 7c (71%).24
This completes the synthesis of a 2-DOS derivative with two
differentiated amine functionalities.
Alternatively, it was also interesting and attractive to envisage
the synthesis of orthogonally protected 2-DOS starting from
methyl 4,6-O-benzylidene-a-D-glucopyranoside 9 (Scheme 4). This
new approach has the advantage of locking simultaneously and
selectively the primary and the secondary alcohols at C-6 and C-4
to avoid, in this way, the double benzoyl protection at C-3 and C-4
of the above method.
Again, the stereochemistry of 7b was fully characterized by
NMR spectroscopic analysis that indicated that the amino group
was only equatorial. The large coupling between H-4 and H-5
(J4,5 = 10.0 Hz), as well as between H-6ax and H-5 (J6ax,5
12.2 Hz), shows that all these protons have an axial position,
while the relatively small coupling between H-6eq and H-5 (J6eq,5
=
=
4.0 Hz) suggests that the amino group in 7b adopts an equatorial
orientation.
Scheme 4 Reagents and conditions: (a) PhCH(OMe)2, pTsOH, DMF, 84 ◦C, 1.5 h (73%); (b) pTsCl, Bu2SnO (82%) or Ts·Im, MeONa (56%); (c) BaO,
Ba(OH)2·8H2O, BnBr, DMF, 0 ◦C to RT, 8 h (87%); (d) DMSO, NaBH4, 0 ◦C then 160 ◦C, 3d (78%); (e) PMBCl, NaH, DMF, RT, 3 h (50%); (f) MeOH,
pTsOH, RT, 4.5 h (98%); (g) I2, PPh3, Imd, PhMe, 70 ◦C, 1 h (93%); (h) BzCl, RT, Py, 12 h (96%); (i) NBS, CaCO3, CCl4, (43%); (j) DBU, PhMe, 96 ◦C,
15 h (60%).
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Compound 9 was readily available in 73% yield from methyl
a-D-glucopyranoside by acid catalyzed acetal exchange with a,a-
dimethoxytoluene in DMF.25 Subsequent regioselective monoto-
sylation at C-2 with either Bu2SnO26 (82% after chromatographic
purification) or with tosylimidazole and MeONa27 (56% after
recrystallization of the crude product) gave 10,28 which was ben-
zylated to afford 1129a as a white crystalline solid (87%). Attempts
to directly introduce a PMB (p-methoxybenzyl) protecting group
on the C-2 hydroxy group of 9, followed by benzylation at C-3
gave a mixture of regioselective protection with PMBCl. Instead,
a stepwise approach had to be used, involving removal of tosyl
group of 11 with NaBH4 in DMSO29a (78% yield for 11a29b), and
then introduction of a p-methoxybenzyl group to yield 11b30 in
50%. Due to the low yield of the stepwise route, we chose to use
the tosylated product 11 in further reactions.
Next, we needed a halogen group at C-6 to prepare the enone 15
(Scheme 4) for a Ferrier reaction leading to a cyclohexane skeleton.
Initially, we submitted benzylidene 11 to Hannessian’s protocol
(NBS, BaCO3, CCl4)31 to provide directly the bromine analogue
14a having a benzoyl group at C-4 in one step (Scheme 4). After
conventional dehydrobromination of 14a, the resulting enone 15
would be suitable to furnish cyclitol 16 by a Ferrier reaction.
Unfortunately, product recovery was not efficient since chromato-
graphic purification caused extensive losses and compound 14a
could be isolated in 43% yield only (Scheme 4).
Consequently, an alternative route to 15 was achieved by
removing first the temporary benzylidene group of 11 with
pTsOH in MeOH.32 The resulting diol 12 was then submitted
to selective iodination at the less hindered primary hydroxyl
group using PPh3–I2–Im, according to the procedure of Garegg
and Samuelsson,33 to synthesize 13 which was benzoylated to
compound 14 (87.2% yield for the three steps).
Dehydrohalogenation of 14 (or 14a) followed by a Ferrier
rearrangement with Hg(OAc)2 (Scheme 5) led to the b-hydroxycy-
clohexanone 16 (40% yield for the two steps). This last step needed
a facile purification to separate the two epimers a and b. The axial
orientation of the hydroxyl group in 16 was elucidated through
the coupling constant between H-2 and H-1 (J2,1 = 2.5 Hz).
benzylether function in 17 was achieved with TABH in TFA (entry
10), giving trans 1,3-benzylhydroxylamine 18 as the only detectable
isomer in 69.7% yield (Scheme 5). The assignment of the absolute
configuration of the newly created center at C-5 was done by 1H
NMR (J5,6a = 14.3 Hz and J5,6e = 3.9 Hz). Reaction of compound
18 under Mitsunobu conditions (DPPA, PPh3, DIAD) for the
azide incorporation at C-1, gave the fully orthogonal protected
2-deoxystreptamine 19 (98% yield). Vicinal coupling constants
between H-1, H-6 and H-5 (J6ax,1 = J6ax,5 13.3 Hz and J6eq,1 = J6eq,5
2.4 Hz) account for the fact that H-1 and H-5 are both axially
orientated. Thus, we have unambiguously confirmed the absolute
stereochemistry of 19.
In summary, we have developed an efficient and convenient
inexpensive method to access a versatile diaminocyclitol unit
present in aminoglycosides. It is now widely important to target
a library of new type aminoglycoside antibiotics against drug-
resistant bacteria. With the idea that 2-deoxystreptamine is a com-
mon component for most active aminoglycosides, we have focused
on its straightforward synthesis with orthogonal protection. This
will allow selective deprotection for further linkage with different
substituents. Consequently, we have successfully investigated two
short and efficient routes for the synthesis of highly polyprotected
2-deoxystreptamine derivatives (8 and 19), in only 7 steps (23%
overall yield) and 11 steps (10.1% yield) respectively, with total
control of the stereochemistry. These versatile and flexible entities
can be prepared on a large scale and would be interesting scaffolds
for the construction of novel molecular designs with improved
antibacterial activity. Besides, in the course of our investigations
into stereoselective hydride reduction of oximino benzylether with
TABH, we have shown that the use of TFA instead of the usual
AcOH was a necessary modification. Furthermore, the polyva-
lent units 8 and 19 could also be useful intermediates for the prepa-
ration of novel bioactive cyclitols, which are actually being studied.
Experimental
General experimental
Reactions were carried out in flame-dried glassware under an
argon atmosphere, unless otherwise noted. All solvents used were
of reagent grade. Tetrahydrofuran (THF) was freshly distilled
from sodium–benzophenone under argon immediately prior to
use. Unless otherwise noted, reactions were magnetically stirred
and monitored by thin layer chromatography (TLC) with 0.25 mm
Merck pre-coated silica gel plates. Spots were detected under
UV (254 nm) and/or by staining with acidic ceric ammonium
molybdate unless otherwise noted. Flash chromatography was
performed with silica gel 60 (particle size 0.040–0.063 mm)
supplied by Merck, Geduran. Yields refer to chromatographically
and spectroscopically pure compounds, unless otherwise stated.
1H NMR, 13C NMR, COSY, NOESY, HMQC as well as HMBC
spectra were measured on a Bruker Avance-300 spectrometer
using an internal deuterium lock at ambient temperature. If not
otherwise noted, CDCl3 (7.26 ppm relative to residual CHCl3) was
the solvent for all NMR experiments. Multiplicities are described
using the following abbreviations: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad, ABX = an ABX
system. Chemical shifts are given in ppm and coupling constants
are presented in Hz. 13C NMR spectra were calibrated from the
Scheme 5 Reagents and conditions: (k) Hg(OAc)2, acetone, H2O, AcOH,
72 ◦C, 4 h (66%); (l) BnONH2·HCl, EtOH, pyridine, RT, 2 h (82%); (m)
Me4NBH(OAc)3, TFA, 0 ◦C to RT, 2.5 h (70%); (n) DPPA, Ph3P, DIAD,
RT, 2.5 h (98%).
Synthesis of benzyloxime 17 was accomplished from 16 in 82%
yield, by using O-benzylhydroxylamine hydrochloride in EtOH–
pyridine. Once more, taking advantage of the axial position of the
b-hydroxyl group at C-1, stereoselective reduction of the oximino
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central triplet peak, to 77.0 ppm for CDCl3. Optical rotations
[a] were recorded on a Polarimeter Model 341 (Perkin Elmer)
at a wavelength of 589 nm and are reported as follows: [a]D,
concentration (c in g/100 mL) and solvent. Elemental analysis
were collected at the Service de microanalyse of the University
Louis Pasteur of Strasbourg (France).
Ar), 80.5 (CH-2), 76.6 (OCH2Ph), 71.3 (CH-4), 69.9 (CH-3), 67.4
(CH-1), 27.3 (CH2-6), 21.6 (Me–Ar).
Preparation of the diol (7a). A precooled (0 ◦C) solution of
Me4NBH(AcO)3 (1.379 g; 10.2 equiv.) in MeCN (1.6 mL) and
AcOH (6.6 mL) was added dropwise to the b-hydroxyketone 5
(0.270 g; 0.514 mmol) dissolved in MeCN (3 mL) and AcOH
(9 mL) at 0 ◦C. The reaction was left at ambient temperature for
1.5 h, water (30 mL) and diethyl ether (30 mL) were added and
stirring was continued for 1 h. The aqueous layer was extracted
with diethyl ether (2 × 15 mL) and the combined organic layers
were washed with water (3 × 20 mL), sat. aq. NaHCO3 (3 ×
10 mL), water (2 × 20 mL), brine (15 mL) dried (MgSO4), filtered
and then concentrated under reduced pressure to afford a white
solid (217 mg; 80.2%). The crude product was pure enough for the
next step, but it can be purified with a chromatography column
on silica gel (AcOEt–cyclohexane; 1 : 1)◦to give the desired diol
7a as a crystalline white solid. Mp = 206 C. [a]2D0 = −14.6 (c 1.08
in CHCl3). Elemental analysis for C27H26O9S (526.554): Calcd. C,
61.59; H, 4.98. Found: C, 61.48; H, 5.15%. 1H NMR (300 MHz,
CDCl3), d (ppm) = 7.86–7.84 (m, 2 H, Ar), 7.63–7.60 (m, 2 H, Ar),
7.55 (d, 2 H, J = 8.4 Hz, pTs), 7.48–7.40 (m, 2 H, Ar), 7.30–7.23
Methyl 3,4-di-O-benzoyl-6-deoxy-6-azido-2-O-tosyl-a-D-gluco-
pyranoside (3). The glucopyranoside 1 (6.517 g; 9.17 mmol) and
NaN3 (4.256 g; 7.1 equiv.) were dissolved in dioxane (155 mL) and
water (50 mL). The reaction was stirred at 110 ◦C for 48 h until all
starting product had disappeared (tlc: AcOEt–hexane 1 : 1). The
solvents were evaporated under reduced pressure and the white
solid residue was then diluted with CH2Cl2 (100 mL) and water
(50 mL). The aqueous layer was extracted with CH2Cl2 (2 × 25 mL)
and the combined organic extracts were washed with water (3 ×
50 mL), brine (30 mL), dried (MgSO4), filtered and concentrated
in vacuo to afford a white solid of 3 (5.096 g; 95.5%). Mp = 172 ◦C.
[a]2D0 = +54.3 (c 1.1 in CHCl3). Elemental analysis for C28H27N3O9S
(581.593): Calcd. C, 57.82; H, 4.68; N, 7.22. Found: C, 57.52; H,
4.64; N, 6.79%. 1H NMR (300 MHz, CDCl3), d (ppm) = 7.9–6.9
(m, 14 H, Ar), 5.89 (dd, 1 H, J3–2 = J3–4 = 9.7 Hz, H-3), 5.32 (dd,
1 H, J4–3 = J4–5 = 9.7 Hz, H-4), 5.11 (d, 1 H, J1–2 = 3.6 Hz, H-1 b
anomeric), 4.60 (dd, 1 H, J2–1 = 3.6 Hz, J2–3 = 10 Hz, H-2), 3.99
(ddd, Hx of ABX, 1 H, J5–4 = 10 Hz, J5–6a = 5.9 Hz, J5–6b = 3.6 Hz,
H-5), 3.53 (s, 3 H, MeO), 3.39–3.37 (AB part on a degenerated
ABX system, 2 H, H-6), 2.19 (s, 3 H, CH3 of pTs). 13C NMR
(75 MHz, CDCl3), d (ppm) = 165.2 (CO), 164.9 (CO), 144.9 (Cq
Ar), 133.6 (CH Ar), 133.1 (CH Ar), 132.7 (Cq Ar), 129.8 (CH Ar),
129.7 (2 × CH Ar), 128.8 (Cq Ar), 128.4 (CH Ar), 128.3 (Cq Ar),
128.1 (CH Ar), 127.6 (CH Ar), 97.8 (CH anomeric), 76.5 (CH-2),
69.9 (CH-4), 69.3 (CH-3), 68.8 (CH-5), 56.2 (MeO), 50.9 (CH2-6),
21.6 (Me of pTs).
(m, 4 H, Ar), 6.86 (d, 2 H, J = 8.3 Hz, pTs), 5.88 (dd, 1 H, J3–4
=
J3–2 = 10.0 Hz, H-3), 5.28 (dd, 1 H, J4–5 = J4–3 = 9.7 Hz, H-4), 4.72
(dd, 1 H, J2–3 = 10.0 Hz, J2–1 = 2.8 Hz, H-2), 4.53 (m, 1 H, H-1),
4.37 (ddd, 1 H, J5–6ax = 14.2 Hz, J5–4 = 9.7 Hz, J5–6eq = 4.7 Hz,
H-5), 2.57 (br s, 2 H, 2 × OH), 2.47 (ddd, 1 H, J6eq-6ax = 14.2 Hz,
J6eq-5 = J6eq-1 = 4.6 Hz, H-6eq), 2.13 (s, 3 H, Me–Ar), 1.77 (ddd,
1 H, J6ax-6eq = J6ax-5 = 14.2 Hz, J6ax-1 = 2.3 Hz, H-6ax). 13C NMR
(75 MHz, CDCl3), d (ppm) = 166.6 (CO), 165.1 (CO), 144.9 (Cq
Ar), 133.3 (CH Ar), 133.0 (CH Ar), 132.7 (Cq Ar), 129.8 (CH Ar),
129.7 (2 × CH Ar), 128.9 (Cq Ar), 128.8 (Cq Ar), 128.3 (CH Ar),
128.1 (CH Ar), 127.5 (CH Ar), 82.0 (CH-2), 77.1 (CH-4), 69.5
(CH-3), 67.7 (CH-1), 66.8 (CH-5), 35.0 (CH2-6), 21.6 (Me–Ar).
Preparation of the benzyloxime ether (6). Distilled pyridine
(2.5 mL) was added to a solution of the hydroxyketone 512a (1 g;
0.0019 mole) and O-benzylhydroxylamine hydrochloride (352 mg;
1.16 equiv.) in dry ethanol (17 mL) at room temperature. The
mixture was stirred for 6 h and then the solvents were evaporated
under reduced pressure. The residue was dissolved in CH2Cl2
(30 mL) and water (30 mL). The organic layer was washed with
a solution of HCl 2% (3 × 35 mL), water (2 × 30 mL), brine
(10 mL), dried (MgSO4) and filtered before being concentrated
under reduced pressure to afford a white solid (1.123 g; 93.5%).
The crude product was pure enough for the next step, but it was
purified, for elemental analysis, with a chromatography column
on silica gel (AcOEt–cyclohexane; 1 : 1) to give the desired oxime
Preparation of the benzylamine (7b). A cold solution (0 ◦C)
of Me4NBH(AcO)3 (4.79 g; 10.2 equiv.) and TFA (12 mL) in
acetonitrile (11 mL) was added to a solution of the benzyl oximine
6 (1.122 g; 1.78 mmole) in acetonitrile (20 mL) and TFA (8 mL) at
0 ◦C. The reaction mixture was then stirred at room temperature
for 2 h and then poured into a vigorously stirred ice cold solution
(0 ◦C) of water (50 mL) and diethyl ether (60 mL). The aqueous
layer was neutralized with an aqueous solution of KOH. The
organic layer was washed with water (3 × 50 mL), brine, dried
(MgSO4) and concentrated under reduced pressure to give a white
solid of the title compound 7b (1.055 g; 93.7%). This crude product
was pure enough for the next step, but it can be purified with a
chromatography column on silica gel (AcOEt–cyclohexane; 4 :
6) to give the desired amine 7b as a crystalline white solid, or
recrystallized with CH2Cl2–diethyl ether (1 : 10), in 89.1%. Mp =
161 ◦C (diethyl ether). [a]2D0 = +34.4 (c 1.06 in CHCl3). Elemental
analysis for C34H33NO9S (631.692): Calcd. C, 64.65; H, 5.27; N,
◦
6 as a crystalline white solid (92%). Mp = 152 C. [a]2D0 = −15.1
(c 1.04 in CHCl3). Elemental analysis for C34H31NO9S (629.676):
Calcd. C, 64.85; H, 4.96; N, 2.22. Found: C, 64.38; H, 5.01; N,
2.15%. 1H NMR (300 MHz, CDCl3), d (ppm) = 7.97–6.94 (m, 19
H, Ar), 5.90 (dd, 1 H, J3–4 = J3–2 = 8.4 Hz, H-3), 5.66 (d, 1 H,
1
J = 8.4 Hz, H-4), 5.03 (s, 2 H, OCH2Ph), 4.89 (dd, 1 H, J2–3
=
2.22. Found: C, 64.86; H, 5.29; N, 1.99%. H NMR (300 MHz,
8.5, J2–1 = 2.7 Hz, H-2), 4.46 (m, 1 H, H-1), 2.97 (AB part of an
ABX system, 2 H, J6a-6b = 15.3 Hz, J6a-1 = 5.4 Hz, J6b-1 = 3.3 Hz,
Dm = 15.3 Hz, H-6), 2.5 (broad s, 1 H, OH), 2.20 (s, 3 H, Me–Ar).
13C NMR (75 MHz, CDCl3), d (ppm) = 165.2 (CO), 164.5 (CO),
147.8 (Cq), 145.1 (Cq), 137.2 (Cq), 133.2 (CH Ar), 132.8 (Cq),
129.9 (CH Ar), 129.8 (CH Ar), 129.1 (Cq), 128.8 (Cq), 128.5 (CH
Ar), 128.3 (CH Ar), 128.2 (CH Ar), 127.9 (CH Ar), 127.6 (CH
CDCl3), d (ppm) = 7.83–6.84 (m, 19 H, Ar), 5.86 (dd, 1 H, J3–4 =
J3–2 = 9.9 Hz, H-3), 5.62 (dd, 1 H, J4–5 = J4–3 = 10.0 Hz, H-4),
4.70 (s, 2 H, OCH2Ph), 4.65 (dd, 1 H, J2–3 = 9.9 Hz, J2–1 = 2.7 Hz,
H-2), 4.56 (m, 1 H, H-1), 3.74 (m, 1 H, H-5), 2.88 (br s, 2 H, OH
and NH), 2.38 (ddd, 1 H, J6eq-6ax = 14.4 Hz, J6eq-5 = J6eq-1 = 4.0 Hz,
H-6eq), 2.12 (s, 3 H, Me–Ar), 2.03 (ddd, 1 H, J6ax-6eq = 14.5 Hz,
J6ax-5 = 12.2 Hz, J6ax-1 = 2.2 Hz, H-6ax). 13C NMR (75 MHz,
2956 | Org. Biomol. Chem., 2008, 6, 2952–2960
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CDCl3), d (ppm) = 165.8 (CO), 165.1 (CO), 144.8 (Cq Ar), 136.1
(Cq Ar), 133.3 (CH Ar), 133.0 (CH Ar), 132.7 (Cq Ar), 129.7 (CH
Ar), 129.6 (CH Ar), 128.9 (Cq Ar), 128.8 (Cq Ar), 128.7 (CH Ar),
128.4 (CH Ar), 128.3 (CH Ar), 128.0 (CH Ar), 127.5 (CH Ar), 81.8
(CH-2), 76.6 (OCH2Ph), 71.0 (CH-4), 70.5 (CH-3), 67.6 (CH-1),
55.9 (CH-5), 30.3 (CH2-6), 21.5 (Me–Ar).
(CH-3 or CH-4), 71.0 (CH-3 or CH-4), 59.5 (CH-1), 58.0 (CH-5),
30.7 (CH2-6), 21.5 (Me of pTs).
Methyl 3-O-benzyl-2-O-tosyl-a-D-glucopyranoside (12). The
benzylidene 11 (1.579 g, 2.99 mmol) was left in suspension in
MeOH (35 mL) with pTsOH (160 mg, 0.8 mmol). The solution,
which gradually became homogeneous, was stirred for 4.5 h and
then treated with aq. sat. NaHCO3 (10 mL). The mixture was
concentrated under reduced pressure, diluted with water (20 mL)
and AcOEt (60 mL). The aqueous layer was extracted with AcOEt
(20 mL). Then the combined organic extracts were washed with
water (2 × 20 mL), brine (10 mL), dried (MgSO4), filtered and
concentrated under vacuum to afford white crystals of 12 (1.28 g;
97.6%). This product was pu◦re enough and can be used like that
for the next step. Mp = 140 C. [a]2D0 = +51.7 (c 1.08 in CHCl3).
Elemental analysis for C21H26O8S (438.491): Calcd. C, 57.52; H,
Preparation of the phosphate ester (7c). To a cold solution
(0 ◦C) of the amino alcohol 6 (160 mg; 0.253 mmole) in dry
THF (1 mL) were added successively DPPA (0.1 mL; 1.8 equiv.)
and DBU (0.1 mL; 2.64 equiv.). The reaction mixture was stirred
at room temperature for 10 h until no more starting material
was detected by tlc. The heterogeneous solution was diluted with
AcOEt (10 mL) and water (10 mL) and the organic layer was
washed with water (2 × 10 mL), aq. HCl 1 M (5 mL), water
(10 mL), brine (5 mL), dried (MgSO4), filtered and evaporated
under vacuum to afford a crude product of 7c, which was
1
5.98. Found: C, 57.93; H, 5.93%. H NMR (300 MHz, CDCl3),
◦
recrystallized in diethyl ether (155 mg; 71%). Mp = 138–140 C
d (ppm) = 7.82–7.20 (m, 9 H, Ar), 4.81 (d, 1 H, J1–2 = 3.6 Hz,
H-1), 4.64 and 4.47 (AB system, 2 H, J = 11.5 Hz, Dm = 50.6 Hz,
PhCH2O), 4.38 (dd, 1 H, J2–3 = 9.6 Hz, J2–1 = 3.6 Hz, H-2), 3.75
(m, 3 H, H-3 and H-6), 3.56 (m, 2 H, H-4 and H-5), 3.34 (s, 3 H,
MeO), 2.40 (s, 3 H, Me of pTs), 2.27 (d, 1 H, J OH-4 = 2.8 Hz, OH),
1.88 (dd, 1 H, JOH-6 = 5.7 Hz, OH). 13C NMR (75 MHz, CDCl3), d
(ppm) = 145.1 (Cq Ar), 137.9 (Cq Ar), 133.5 (Cq Ar), 129.8 (CH
Ar), 128.6 (CH Ar), 128.0 (CH Ar), 127.9 (CH Ar), 127.8 (CH
Ar), 97.7 (CH-1), 79.5 (CH-2), 78.9 (CH-3), 75.1 (OCH2-Ph), 70.6
(CH-4 or CH-5), 70.4 (CH-4 or CH-5), 62.0 (CH2-6), 55.5 (MeO),
21.7 (Me of pTs).
(diethyl ether). [a]2D0 = +44.8 (c 1 in CHCl3). Elemental analysis for
C46H42NO12PS (863.863): Calcd. C, 63.96; H, 4.90; N, 1.62. Found:
C, 63.49; H, 4.99; N, 1.62%. 31P NMR (121.5 MHz, CDCl3), d
1
(ppm) = −11.8. H NMR (300 MHz, CDCl3), d (ppm) = 7.86–
6.86 (m, 29 H, Ar), 5.85 (dd, 1 H, J3–4 = J3–2 = 9.9 Hz, H-3), 5.63
(dd, 1 H, J4–5 = J4–3 = 9.9 Hz, H-4), 5.31 (m, 1 H, H-1), 4.74 (ddd,
4
1 H, J2–3 = 10.0 Hz, J2–1 = J2-P = 2.9 Hz, H-2), 4.62 (s, 2 H,
OCH2Ph), 3.38 (m, 1 H, H-5), 2.49 (ddd, 1 H, J6eq-6ax = 15.2 Hz,
J6eq-5 = J6eq-1 = 3.9 Hz, H-6eq), 2.17 (s, 3 H, Me–Ar), 2.07 (m, 1
H, H-6ax). 13C NMR (75 MHz, CDCl3), d (ppm) = 165.6 (CO),
165.1 (CO), 150.5 (Cq Ar), 150.4 (Cq Ar), 144.8 (Cq Ar), 133.3
(CH Ar), 133.0 (CH Ar), 132.8 (Cq Ar), 129.9 (CH Ar), 129.8
(CH Ar), 129.7 (CH Ar), 129.1 (Cq Ar), 129.0 (Cq Ar), 128.6 (CH
Ar), 128.4 (CH Ar), 128.3 (CH Ar), 128.1 (CH Ar), 128.0 (CH
Ar), 127.7 (CH Ar), 125.6 (CH Ar), 125.5 (CH Ar), 120.5 (CH
Ar), 120.4 (CH Ar), 120.3 (CH Ar), 78.1 (CH-2, JC–P = 6 Hz), 76.8
(OCH2Ph), 75.7 (CH-1, JC–P = 9 Hz), 71.0 (CH-4), 70.1 (CH-3),
56.1 (CH-5), 30.5 (CH2-6), 21.6 (Me–Ar).
Methyl 3-O-benzyl-6-deoxy-6-iodo-2-O-tosyl-a-D-glucopyrano-
side (13). Dry toluene (52 mL) was poured at room temperature
into a mixture of the diol 12 (2.017 g; 4.59 mmole), imidazole
(941 mg; 3 equiv.) and triphenylphosphine (1.35 g; 1.1 equiv.).
Iodine (1.29 g; 1.1 equiv.) was then added and the deep orange
solution was heated at 70 ◦C with vigorous stirring during 1 h. The
clear reaction mixture was left at room temperature for 30 min and
was then treated with aq. NaHCO3 (40 mL). The organic layer was
washed with water (2 × 50 mL), brine (30 mL), dried (MgSO4) and
concentrated under reduced pressure. The resulting oily residue
was purified on a silica gel chromatography column (diethyl ether–
light petroleum ether, 1 : 1 and then AcOEt–cyclohexane, 1 : 1)
to furnish the title compound 13 (2.36 g; yield 93.5%) as a white
sticky solid. [a]2D0 = +52.4 (c 1.06 in CHCl3). Elemental analysis for
C21H25IO7S (548.388): Calcd. C, 45.99; H, 4.60. Found: C, 45.67;
Preparation of the azide (8). To a cold solution (0 ◦C) of
the alcohol 7b (185 mg; 0.292 mmole) and triphenylphosphine
(176 mg; 2.29 equiv.) in dry THF (3 mL) were successively added
the DIAD (0.13 mL; 2.25 equiv.) and DPPA (0.14 mL; 2.21 equiv.).
The mixture was stirred during 7 h at room temperature and then
concentrated under reduced pressure to give a yellow liquid, which
was purified by silica gel chromatography (AcOEt–cyclohexane
1 : 1) to afford the corresponding◦ product 8 as a white solid
(125 mg; 65.2%). Mp = 141–143 C. [a]2D0 = +19.93 (c 1.5 in
CHCl3). Elemental analysis for C34H32N4O8S (656.704): Calcd. C,
1
H, 4.66%. H NMR (300 MHz, CDCl3), d (ppm) = 7.84–7.80
and 7.37–7.20 (m, 9 H, Ar), 4.76 (d, 1 H, J1–2 = 3.6 Hz, H-1 b
anomeric), 4.69 and 4.44 (AB system, 2 H, J = 11.5 Hz, Dm =
71.4 Hz, PhCH2O), 4.41 (dd, 1 H, J2–3 = 9.5 Hz, J2–1 = 3.6 Hz,
H-2), 3.77 (dd, 1 H, J3–2 = J3–4 = 9.6 Hz, H-3), 3.36 (s, 3 H, MeO),
3.35 (m, 4 H, H-4, H-5 and H-6), 2.41 (s, 3 H, Me of pTs), 2.13 (d,
1 H, JOH-4 = 2.8 Hz, OH). 13C NMR (75 MHz, CDCl3), d (ppm) =
145.2 (Cq Ar), 137.8 (Cq Ar), 133.6 (Cq Ar), 129.9 (CH Ar), 128.7
(CH Ar), 128.2 (CH Ar), 128.0 (CH Ar), 127.9 (CH Ar), 97.5
(CH-1), 79.5 (CH-2), 78.5 (CH-3), 75.2 (OCH2-Ph), 73.8 (CH-4),
69.6 (CH-5), 55.7 (MeO), 21.7 (Me of pTs), 6.3 (CH2-6).
1
62.18; H, 4.91; N, 8.53. Found: C, 62.39; H, 4.79; N, 8.52%. H
NMR (300 MHz, CDCl3), d (ppm) = 7.8–7.7 (m, 4 H, arom.), 7.63
(A of AAꢀBBꢀ, 2 H, pTol, JAB = 8.3 Hz), 7.5–7.2 (m, 6 H, arom.),
6.97 (A of AAꢀBBꢀ, 2 H, pTol, JAB = 8.3 Hz), 5.57–5.47 (m, 2 H,
H-3 and H-4), 4.84 (m, 1 H, H-2), 4.64 (s, 2 H, CH2Ph), 3.64 (m,
1 H, H-1), 3.22 (m, 1 H, H-5), 2.42 (ddd, 1 H, J6eq-6ax = 13.5 Hz,
J6eq-1 = J6eq-5 = 4.4 Hz, H-6eq), 2.17 (s, 3 H, Me of Ts), 1.83 (ddd
as an apparent q, 1 H, J6ax-6eq = J6ax-1 = J6ax-5 = 13.3 Hz, H-6ax).
13C NMR (75 MHz, CDCl3), d (ppm) = 165.5 (CO), 165.2 (CO),
144.9 (Cq Ar), 136.9 (Cq Ar), 134.0 (Cq Ar), 133.3 (CH Ar), 133.1
(CH Ar), 129.9 (CH Ar), 129.7 (CH Ar), 129.5 (CH Ar), 128.9 (Cq
Ar), 128.7 (CH Ar), 128.4 (CH Ar), 128.3 (CH Ar), 128.1 (CH Ar),
128.0 (CH Ar), 127.5 (CH Ar), 81.3 (CH-2), 77.0 (CH2Ph), 71.9
Methyl 4-O-benzoyl-3-O-benzyl-6-deoxy-6-iodo-2-O-tosyl-a-D-
glucopyranoside (14). Benzoyl chloride (0.5 mL; 1.07 equiv.) was
added at room temperature to a solution of the alcohol 13 (2.204 g;
4.02 mmole) in pyridine (10 mL) and stirred for 12 h. Diethyl ether
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(60 mL) was then added and stirring was continued for 20 min.
The precipitate was filtered and thoroughly washed with diethyl
ether, diluted in CH2Cl2 (20 mL), washed with water (2 × 15 mL) to
eliminate the pyridinium salt, dried over MgSO4 and concentrated
under reduced pressure to afford a first crop of 14 (1.351 g; 51.5%)
as a white powder, which was clean enough according the NMR
analysis and needed no more purification. The previous combined
ether layers were washed with water (20 mL), diluted HCl 10%
(4 × 25 mL), water (2 × 25 mL), brine (15 mL), dried (MgSO4),
filtered and concentrated under reduced pressure to leave a pale
yellow solid, which was diluted in some CH2Cl2 and recrystallized
in diethyl ether to give a second crop of colourless prisms (1.16 g;
44.2%) The total yield of the two crops was 2.51 g; 95.6%. Mp =
(15 mL), dried (MgSO4), filtered and evaporated in vacuo to give
a viscous orange oil. This crude material was purified with a
chromatography column on silica gel (AcOEt–cyclohexane, 1 :
3) to yield a white powder of the enone 15 (0.516; 60%). Mp =
127–128 ◦C. [a]D20 = −20.9 (c 1 in CHCl3). Elemental analysis for
C28H28O8S (524.582): Calcd. C, 64.11; H, 5.38. Found: C, 63.99;
1
H, 5.41%. H NMR (300 MHz, CDCl3), d (ppm) = 8.00–6.94
(m, 14 H, H-arom), 5.60 (ddd, 1 H, J4–3 = 9.3 Hz, J4–6a = J4–6b
=
2.1 Hz, H-4), 5.05 (d, 1 H, J1–2 = 3.4 Hz, H-1), 4.74 (dd, 1 H,
J6a-6b = J6a-4 = 2.1 Hz, H-6a), 4.55 (dd, 1 H, J6b-6a = J6b-4 = 1.9 Hz,
H-6b), 4.53 (dd, 1 H, J2–3 = 9.5 Hz, J2–1 = 3.4 Hz, H-2), 4.46 (s,
2 H, CH2Ph), 4.09 (dd, 1 H, J3–4 = J3–2 = 9.4 Hz, H-3), 3.47 (s, 3
H, MeO), 2.35 (s, 3 H, Me of Ts). 13C NMR (75 MHz, CDCl3), d
(ppm) = 164.9 (CO), 150.3 (Cq C-5), 145.2 (Cq arom.), 137.3 (Cq
arom.), 133.5 (CH arom.), 132.9 (Cq arom.), 129.9 (CH arom.),
129.1 (Cq arom.), 128.5 (CH arom.), 128.1 (CH arom.), 128.0
(CH arom.), 127.8 (CH arom.), 127.6 (CH arom.), 98.5 (C-1),
97.6 (C-6), 78.9 (C-2), 76.4 (C-3), 75.0 (CH2Ph), 71.4 (C-4), 56.0
(MeO), 21.7 (Me of Ts).
◦
165 C. [a]2D0 = −2.40 (c 1.04 in CHCl3). Elemental analysis for
C28H29IO8S (652.494): Calcd. C, 51.54; H, 4.48. Found: C, 52.51;
H, 4.57%. 1H NMR (300 MHz, CDCl3), d (ppm) = 8.17–6.9 (m,
14 H, Ar), 5.09 (dd, 1 H, J4–3 = J4–5 = 9.3 Hz, H-4), 4.97 (d, 1 H,
J1–2 = 3.6 Hz, H-1 b anomeric), 4.45 (dd, 1 H, J2–3 = 9.5 Hz, J2–1
=
3.6 Hz, H-2), 4.48 and 4.39 (AB system, 2 H, J = 11.1 Hz, Dm =
26 Hz, PhCH2O), 4.07 (dd, 1 H, J3–2 = J3–4 = 9.3 Hz, H-3), 3.86
(X of ABX, H-5), 3.49 (s, 3 H, OMe), 3.19 (AB part of an ABX
system, 2 H, J6a-6b = 10.9 Hz, J6a-1 = 8.8 Hz, J6b-1 = 2.5 Hz, Dm =
35 Hz, H-6), 2.35 (s, 3 H, Me-Ts). 13C NMR (75 MHz, CDCl3),
d (ppm) = 165.1 (CO), 145.1 (Cq Ar), 137.2 (Cq Ar), 133.6 (CH
Ar), 133.1 (Cq Ar), 129.9 (CH Ar), 129.8 (CH Ar), 128.9 (Cq
Ar), 128.5 (CH Ar), 128.1 (CH Ar), 128.0 (CH Ar), 127.8 (CH
Ar), 127.5 (CH Ar), 97.6 (CH-1), 79.4 (CH-2), 76.0 (CH-3), 75.2
(CH2Ph), 73.9 (CH-4), 69.4 (CH-5), 56.1 (OMe), 21.7 (Me), 3.8
(CH2-6).
Preparation of the cyclohexanone (16). To a solution of the
enone 15 (335 mg; 0.638 mmol) in acetone (19 mL) and water
(8 mL) were added Hg(OAc)2 (348 mg;◦1.7 equiv.) and AcOH
(2 mL). The reaction was refluxed at 72 C during 4 h and then
the solvents were evaporated. The residue was dissolved in CH2Cl2
(50 mL) and water (10 mL). The organic layer was washed with
water (2 × 10 mL), sat. NaHCO3 (2 × 5 mL), water (10 mL), brine
(5 mL), dried over MgSO4, filtered on Celite and concentrated
under reduced pressure to afford a white solid as a mixture of
two products (tlc: AcOEt–cyclohexane, 1 : 1). Purification was
accomplished by chromatography on a silica gel column (AcOEt–
cyclohexane 1 : 1) to get the desired hydroxyketone 16 (216 g;
66.3%). Mp = 212–213 ◦C. [a]D20 = −74 (c 1 in CHCl3). Elemental
analysis for C27H26O8S (510.555): Calcd. C, 63.52; H, 5.13. Found:
C, 63.54; H, 5.22%. 1H NMR (300 MHz, CDCl3), d (ppm) = 7.9–
6.9 (m, 14 H, arom.), 5.51 (d, 1 H, J4–3 = 9.9 Hz, H-4), 4.87 (dd, 1
H, J2–3 = 9.4 Hz, J2–1 = 2.5 Hz, H-2), 4.65 (m, 1 H, H-1), 4.57 and
4.45 (AB system, 2 H, J = 11.1 Hz, Dm = 33 Hz, PhCH2O), 4.31
(dd, 1 H, J3–4 = J3–2 = 9.6 Hz, H-3), 2.80 (dd, 1 H, J6a-6b = 15.2 Hz,
J6a-1 = 3.8 Hz, H-6a), 2.71 (m, 2 H, H-6b and OH), 2.36 (s, 3 H, Me
of pTs). 13C NMR (75 MHz, CDCl3), d (ppm) = 197.1 (CO), 165.3
(COOBz), 145.4 (Cq arom.), 137.1 (Cq arom.), 133.5 (CH arom.),
132.9 (Cq arom.), 130.0 (CH arom.), 128.9 (Cq arom.), 128.4 (CH
arom.), 128.2 (CH arom.), 128.0 (CH arom.), 127.7 (CH arom.),
83.3 (C-2), 79.0 (C-4), 77.2 (C-3), 75.3 (CH2Ph), 67.5 (C-1), 42.6
(CH2–6), 21.7 (Me of Ts).
Methyl 4-O-benzoyl-3-O-benzyl-6-deoxy-6-bromo-2-O-tosyl-a-
D-glucopyranoside (14a). Compound 14a was synthesized fol-
lowing Hanessian’s protocol.31 The crude product was purified
on a silica gel chromatography column (◦AcOEt–cyclohexane, 4 :
6) to afford 14a in 43% yield. Mp = 142 C. [a]2D0 = −7.2 (c 2.2 in
CHCl3). Elemental analysis for C28H29BrO8S (605.494): Calcd. C,
55.54; H, 4.83. Found: C, 56.58; H, 5.19%. 1H NMR (300 MHz,
CDCl3), d (ppm) = 7.9–6.9 (m, 14 H, H-arom), 5.11 (dd, 1 H,
J4–3 = J4–5 = 9.6 Hz, H-4), 4.98 (d, 1 H, J1–2 = 3.6 Hz, H-1), 4.48
and 4.38 (AB system, 2 H, J = 11.0 Hz, Dm = 26 Hz, PhCH2O),
4.44 (dd, 1 H, J2–3 = 9.7 Hz, J2–1 = 3.7 Hz, H-2), 4.07 (dd, 1 H,
J3–2 = J3–4 = 9.4 Hz, H-3), 4.02 (ddd, H part of an ABX system, 1
H, J5–4 = 10.2 Hz, J5–6a = 7.6 Hz, J5–6b = 2.6 Hz, H-5), 3.47 (s, 3
H, MeO), 3.39 (AB part of an ABX system, 2 H, JAB = 11.4 Hz,
JAX = 7.6 Hz, JBX = 2.7 Hz, Dm = 19.4 Hz, H-6), 2.36 (s, 3 H, Me
of pTs). 13C NMR (75 MHz, CDCl3), d (ppm) = 165.1 (CO), 145.1
(Cq Ar), 137.2 (Cq Ar), 133.6 (CH Ar), 133.1 (Cq Ar), 129.9 (CH
Ar), 128.9 (CH Ar), 128.5 (CH Ar), 128.0 (CH Ar), 127.8 (CH
Ar), 127.5 (CH Ar), 97.6 (CH-1), 79.3 (CH-2), 76.3 (CH-3), 75.2
(OCH2-Ph), 72.8 (CH-4), 69.2 (CH-5), 55.9 (MeO), 29.7 (CH2-6),
21.6 (Me of pTs).
Preparation of the benzyloxime ether (17). To a stirred solution
of the ketol 16 (222 mg; 0.43 mmol) and O-benzylhydroxylamine
hydrochloride (84 mg; 1.2 equiv.) in dry EtOH (5 mL) was
added dry pyridine (0.51 mL). The mixture, which became slowly
homogeneous, was concentrated under reduced pressure after 2 h
(no more starting material on tlc; AcOEt–cyclohexane 1 : 1). The
crude product was dissolved in CH2Cl2 (20 mL), washed with
water (10 mL), dil. HCl 2% (3 × 5 mL), water (10 mL), brine
(5 mL), dried (MgSO4), filtered and evaporated in vacuo to give
a white solid (263 mg), which needed a further purification on
a silica gel chromatography column (ether–light petroleum 4 : 1)
to afford the title compound 17 (218 mg; 81.6%). Mp = 137–
Methyl 4-O-benzoyl-3-O-benzyl-6-deoxy-2-O-tosyl-a-D-xylo-
hex-5-enopyranoside (15). A solution of the iodoglucopyra-
noside 14 (1.072 g; 1.64 mmol) and DBU (1.9 mL; 7.7 equiv.) was
heated in dry PhMe (10 mL) during 15 h at ca. 96 ◦C. The mixture
was then left for decantation at room temperature and the upper
layer was concentrated and diluted with AcOEt (30 mL). The
organic layer was washed with water (2 × 50 mL), an aqueous
solution of thiosulfate (1.6 M; 10 mL), water (100 mL), brine
◦
138 C (diethyl ether–petroleum ether 4 : 1). [a]2D0 = −24.9 (c 1.1
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in CHCl3). Elemental analysis for C34H33NO8S (615.692): Calcd.
C, 66.33; H, 5.40; N, 2.27. Found: C, 66.14; H, 5.46; N, 2.28%.
1H NMR (300 MHz, CDCl3), d (ppm) = 7.99–7.06 (m, 19 H,
aromatics), 5.55 (d, 1 H, J4–3 = 6.0 Hz, H-4), 5.05 (s, 2 H, N-
OCH2Ph), 4.72 (dd, 1 H, J2–3 = 6.3 Hz, J2–1 = 2.8 Hz, H-2), 4.65
and 4.48 (AB system, 2 H, J = 11.5 Hz, Dm = 50.9 Hz, PhCH2O),
4.29 (m, 1 H, H-1), 4.09 (dd, 1 H, J3–4 = J3–2 = 6.2 Hz, H-3), 2.91
(AB part of an ABX system, 2 H, JAB = 14.5 Hz, JAX = 7.8 Hz,
JBX = 4.1 Hz, Dm = 57.1 Hz, H-6), 2.34 (s, 3 H, Me of pTs), 2.33
(d, 1 H, J = 4.1 Hz, OH). 13C NMR (75 MHz, CDCl3), d (ppm) =
165.1 (CO), 149.6 (C-5), 145.1 (Cq arom.), 137.2 (Cq arom.), 137.1
(Cq arom), 133.2 (CH arom.), 132.8 (Cq arom.), 129.9 (CH arom.),
129.8 (CH arom.), 129.5 (Cq arom.), 128.4 (CH arom.), 128.3 (CH
arom.), 128.2 (CH arom.), 127.9 (CH arom.), 127.8 (CH arom.),
127.7 (CH arom.), 81.4 (C-2), 76.5 (N-OCH2Ph), 76.1 (C-3), 74.0
(OCH2Ph), 71.7 (C-4), 66.4 (C-1), 27.0 (CH2–6), 21.6 (Me of pTs).
Elemental analysis for C34H34N4O7S (642.721): Calcd. C, 63.54;
H, 5.33; N, 8.72. Found: C, 61.05; H, 5.44; N, 9.18%. H NMR
1
(300 MHz, CDCl3), d (ppm) = 7.97–6.84 (m, 19 H, aromatics), 5.35
(dd, 1 H, J4–3 = J4–5 = 9.8 Hz, H-4), 4.65 (dd, 1 H, J2–1 = J2–3
=
9.6 Hz, H-2), 4.58 (s, 2 H, PhCH2O), 4.50 and 4.35 (AB system, 2
H, J = 11 Hz, Dm = 44 Hz, PhCH2O), 3.63 (dd, 1 H, J3–2 = J3–4
=
9.3 Hz, H-3), 3.45 (m, 1 H, H-1), 3.08 (m, 1 H, H-5), 2.36 (ddd,
1 H, J6eq-6ax = 13.4 Hz, J6eq-1 = J6eq-5 = 2.4 Hz, H-6eq), 2.33 (s, 3
H, Me of Ts), 1.68 (ddd as an apparent q, 1 H, J6ax-6eq = J6ax-1
=
J6ax-5 = 13.3 Hz, H-6ax). 13C NMR (75 MHz, CDCl3), d (ppm) =
165.3 (CO), 149.8 (Cq arom.), 144.6 (Cq arom.), 137.1 (Cq arom.),
137.0 (Cq arom.), 134.6 (Cq arom.), 133.3 (CH arom.), 130.1 (CH
arom.), 129.7 (CH arom.), 129.6 (CH arom.), 128.7 (CH arom.),
128.4 (CH arom.), 128.3 (CH arom.), 128.0 (CH arom.), 127.9 (CH
arom.), 127.7 (CH arom.), 127.4 (CH arom.), 126.2 (CH arom.),
120.3 (CH arom.), 120.2 (CH arom.), 83.8 (C-2), 79.9 (C-3), 76.9
(OCH2Ph), 75.2 (OCH2Ph), 72.8 (C-4), 59.6 (C-1), 58.3 (C-5), 30.8
(CH2-6), 21.6 (Me of pTs).
Preparation of the benzylamine (18). A cold solution (0 ◦C)
of Me4NBH(AcO)3 (799 mg; 11.3 equiv.) and TFA (1 mL) in
acetonitrile (3 mL) was added to a solution of the benzyl oximine
17 (165 mg; 0.267 mmole) in acetonitrile (4 mL) and TFA
(2 mL) at 0 ◦C. The reaction mixture was then stirred at room
temperature for 2.5 h and then poured into a vigorous stirred ice
cold solution (0 ◦C) of water (20 mL) and diethyl ether (15 mL).
The aqueous layer was neutralized with an aqueous solution of
KOH (2.6g/15 mL). The organic layer was washed with water
(2 × 10 mL), brine, dried (MgSO4), filtered and concentrated under
reduced pressure to give a white solid (305 mg). This crude product
was purified with a chromatography column on silica gel (AcOEt–
cyclohexane; 1 : 2) to afford a crystalline white solid of the amine
18, which was recrystallized in die◦thyl ether to give white needles
(115 mg; 69.7%). Mp = 119–120 C (diethyl ether). [a]2D0 = +9.5
(c 1.1 in CHCl3). Elemental analysis for C34H35NO8S (617.708):
Calcd. C, 66.11; H, 5.71; N, 2.27. Found: C, 65.95; H, 5.89; N,
2.19%. 1H NMR (300 MHz, CDCl3), d (ppm) = 7.97–6.84 (m, 19
Notes and references
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10.0 Hz, H-4), 4.60 and 4.56 (AB system, 2 H, J = 12 Hz, Dm =
2.7 Hz, PhCH2O), 4.48 (m, 1 H, H-1), 4.47 (m, 1 H, H-2), 4.35 (s,
2 H, OCH2Ph), 4.01 (dd, 1 H, J3–4 = J3–2 = 9.2 Hz, H-3), 3.45 (m,
1 H, H-5), 2.63 (broad s, 1 H, OH), 2.31 (s, 3 H, Me of pTs), 2.22
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arom.), 129.7 (CH arom.), 128.4 (CH arom.), 128.3 (CH arom.),
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(CH arom.), 127.5 (CH arom.), 127.3 (CH arom.). 84.7 (C-2), 77.5
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(C-5), 30.9 (CH2–6), 21.6 (Me of pTs).
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2960 | Org. Biomol. Chem., 2008, 6, 2952–2960
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