Major increases of the reactivity and selectivity in aminoglycoside O-alkylation due to the presence of fluoride ions

Article abstract of DOI:10.1016/j.tet.2011.10.102

Major increases of the selectivity and/or reactivity in aminosugar and sugar O-alkylation were observed in the presence of tetrabutylammonium fluoride (TBAF) in comparison to TBAI under phase-transfer conditions or in solution. The presence of TBAF allowe

Full text of DOI:10.1016/j.tet.2011.10.102

Tetrahedron 68 (2012) 737e746
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Major increases of the reactivity and selectivity in aminoglycoside O-alkylation
due to the presence of fluoride ions
a
a
a
a
a
Olivier Jackowski , Antoine Bussi eꢀ re , C eꢁ cile Vanhaverbeke , Isabelle Baussanne , Eric Peyrin ,
b
a,
*
Marie-Paule Mingeot-Leclercq , Jean-Luc D eꢁ cout
Universit ꢁe Joseph Fourier-Grenoble/CNRS, D ꢁe partement de Pharmacochimie Mol ꢁe culaire UMR 5063, ICMG FR CNRS 2607, F-38041 Grenoble, France
Universit ꢁe Catholique de Louvain, Louvain Drug Research Institute, LDRI, Unit ꢁe de Pharmacologie Cellulaire et Mol ꢁe culaire, FACM, Brussels, Belgium
a
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2011
Received in revised form 8 October 2011
Accepted 27 October 2011
Available online 3 November 2011
Major increases of the selectivity and/or reactivity in aminosugar and sugar O-alkylation were observed
in the presence of tetrabutylammonium fluoride (TBAF) in comparison to TBAI under phase-transfer
conditions or in solution. The presence of TBAF allowed the selective and rapid alkylation of the 6-
hydroxyl function of neamine and efficient preparation of protected intermediates useful in synthesis
and potent or potential antimicrobial O-alkylated derivatives of neamine and paromamine. In regard to
the observed strong effects of TBAF, the alkylation and acylation of carbohydrates merit to be studied in
the presence of TBAF under phase-transfer conditions.
Keywords:
Aminoglycosides
Neamine
Ó 2011 Elsevier Ltd. All rights reserved.
Paromamine
Alkylation
Phase transfer
Tetrabutylammonium fluoride
1. Introduction
5-position of ring I like in neomycin B 1 is an aminoglycoside of the
neomycin class, whereas amikacin 4 in which ring III is linked at the
The aminoglycosides, such as neomycin B 1, paromomycin 2,
kanamycin B 3 and amikacin 4 (Fig. 1) are pseudo-oligosaccharidic
antibiotic drugs active against a broad range of microorganisms.
Two main classes of aminoglycosides can be defined in regard to
the position of attachment of ring III to the 2-deoxystreptamine
ring I (Fig. 1). Paromomycin 2 in which ring III is attached at the
6-position of ring I like in kanamycin B 3 is an aminoglycoside of the
kanamycin class.
1
At physiological pH, these polycations strongly bind to the
bacterial 16S ribosomal RNA and then disturb bacterial protein
1
synthesis. The emergence of high level antibiotic resistances that
involve enzymatic modifications of aminoglycosides, reduction of
R
NH2
O
Ring II
H2N
O
HO
HO
R
HO
HO
4'
Ring I
5'
O
NH2
H2N
HO
HO
3'
H2N
O
NH2
1'
H2N
5
HO
NH2
O
O
5
NHR'
OH
2'
4
3
HO
2
O
2
H N
OH
6
O
OH
O
NH2
Ring III
HO
O
HO
Ring IV
H2N
3: R'= H, kanamycin B
4: amikacin, R'=
6 OH
NH2
OH
1
O
O
OH
5: R= NH2, neamine
6: R= OH, paromamine
OH
HO
NH2
1: R= NH2, neomycin B
2: R= OH, paromomycin
O
Fig. 1. Structure of antibiotic aminoglycosides and of neamine and paromamine.
the intracellular concentration through surexpression of efflux
pumps, alteration of the 16S ribosomal subunit target by
*
Corresponding author. Tel.: þ33 4 76 63 53 17; fax: þ33 4 76 63 52 98; e-mail
address: Jean-Luc.Decout@ujf-grenoble.fr (J.-L. D eꢁ cout).
0
040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.102

738
O. Jackowski et al. / Tetrahedron 68 (2012) 737e746
2
methylation of the aminoglycoside binding site has led to a re-
naissance of interest in the search for antibiotic agents through
NHTr
O
4
'
HO
1
HO
TrHN
chemical modifications of aminoglycosides. Aminoglycosides,
such as neomycin B (Fig. 1) also bind strongly to some HIV RNA
sequences in vitro and have appeared to be promising as antiviral
agents. They showed other interesting properties since that lipo-
philic aminoglycoside derivatives were proved to be potent in DNA
transfection in view of gene therapy and found to allow, via
binding to rRNA, the read-through of disease-causing nonsense
mutations by the translation complex and therefore the synthesis
3
'
NHTr
O
NHTr
7
HO
6
OH
3
a)
NHTr
O
NHTr
O
4'
4
HO
RO
RO
TrHN
+
RO
TrHN
3'
NHTr
3
'
NHTr
O
O
NHTr
a: R= PMB HO
9a: R= 2NM
NHTr
8
6
8b: R= PMB
9b: R= 2NM
HO
5
6
OR
of full-length active proteins.
OR
The neamine and paromamine cores incorporated in neomycin
B and paromomycin (rings I and II, Fig. 1), respectively, are the main
structural elements necessary for binding to the 16S subunit of ri-
bosomal RNA.6 Therefore, neamine 5, which can be prepared by
methanolysis of neomycin has appeared to be a very attractive
building block in the search for antibiotic and antiviral agents and
many works were developed to synthesise various derivatives
mainly modified at the 5- or 6-position in regard to the parent
classes of antibiotic aminoglycosides (neomycin class and kana-
b)
b)
NH2
O
NH2
O
4
'
HO
2NMO
2NMO
H2N
2NMO
H2N
HO
3'
NH2
3'
NH2
O
O
NH2
NH2
O2NM
HO
10b
10a
6
6
O2NM
Scheme 1. Previously reported alkylation of the tritylated derivative 7 with PMBCl and
-naphthylmethylene bromide (2NMBr) in the presence of NaH in DMF.
9,11h
2
(a) RX,
ꢁ
NaH, DMF, rt; (b) for 9a and 9b: TFA/DCM, anisole, 0 C.
1
mycin class, respectively). Long procedures of protection and
deprotection of the amine and hydroxyl functions have been gen-
erally used in order to alkylate neamine at position 6 for obtaining
analogues of amikacin and kanamycins.
were obtained from compound 7 in two steps (Scheme 1) through
alkylation with 2-methylnaphthalene bromide (2NMBr) in the
presence of NaH in DMF leading mainly to an about 50:50 mixture
7
In order to alkylate the hydroxyl functions of neamine and more
complex aminoglycosides, such as neomycin B, Wong and co-
workers inactivated the reactive amine functions by conversion to
0
0
0
of the tritylated 3 ,6-2NM (9a) and 3 ,4 ,6-tri2NM (9b) derivatives,
which were separated by chromatography on silica gel and
azido groups.8 In this fruitful approach
a
8bed
used, for example, in
deprotected with TFA.
11h
the preparation of neomycin analogues and 5,5-neamine dimers,
the main difficulties can be found in (i) the high cost of the triflic
azide reagent necessary for the conversion of the amine to azide
functions (excess of reagent and moderate yields), (ii) the low
solubility of the starting azidosugars in apolar solvents and (iii) the
lack of chromophore useful for easily monitoring the reaction
progress (UV detection in TLC).
In the search for bioactive aminoglycosides, the selective and
rapid alkylation of aminoglycosides, such as neamine remains
a challenge in regard to the number of carried hydroxyl groups. In
the new approach of the neamine O-alkylation reported here, we
were interested in the binding of fluoride ions to the hydroxyl
functions of sugars in aprotic polar solvents described in the
literature.
In regard to these difficulties, we have introduced trityl groups
for protecting the amine functions in neamine (compound 7,
Scheme 1) in order to: (i) obtain intermediates highly soluble in
apolar organic solvents, (ii) induce steric hindrance in the next O-
alkylation steps and (iii) deprotect the alkylated derivatives ob-
For example, the binding of KF to the OH functions of carbo-
hydrates in DMSO-d
6
leads to breaking of intra- and inter-
1
13
molecular H-bonds as observed by H and C NMR spectrome-
12a
try.
TBAF improves the solubility of cellulose in DMSO and has
a strong effect in its acetylation on the degree of substitution and
9
a
12b,c
tained in mild acidic conditions (TFA). Using this approach, we
the distribution of acetate groups.
0
ꢀ
have obtained in a nearly 50:50 mixture the N-tetratritylated 3 ,6-
The remarkable effects of organic and inorganic F as a base in
0
0
13a
diPMB (8a) and 3 ,4 ,6-triPMB (8b) neamine derivatives (Scheme 1),
synthesis have been reviewed. Such a basic character of fluorides
0
which were separated and selectively alkylated at the 4 - and/or 5-
in polar aprotic solvents has been used in a large range of reactions,
0
positions and then deprotected to lead for the first time to 4 -
such as alkylation, arylation, esterification, condensation and
9
a,b
13aec
neamine derivatives, which bind strongly to the HIV-1 TAR RNA.
b was recently described as an intermediate in the preparation of
elimination.
Fluoride ion assisted reactions are thought to
8
occur via strong H-bonding of the fluoride ion (the electron donor)
to the reactant protic molecule (the electron acceptor), with
resulting enhancement of the nucleophilicity of the protic com-
pound while at the same time the nucleophilicity of the fluoride is
a neamine thiol useful in dynamic combinatorial chemistry for the
identification of ligands for a pre-mRNA sequence, which is in-
volved in the onset of several tauopathies including dementia with
Parkinsonism.10
13a
ꢀ
reduced. More recently, a complex in which F is coordinated by
From 8a and 8b, we conjugated peptide nucleic acids (PNA) at the
H-bonds to four tert-butanol molecules has been prepared from
TBAF, crystallized and used as a highly effective fluorination agent.
0
14
4
- or 5-position of the neamine core in order to target the HIV-1 TAR
9
c,d
RNA through complementary base pairing.
The PNA conjugates
Here, we report on the study of the neamine alkylation in the
presence of tetrabutylammonium fluoride (TBAF) in toluene. Tol-
uene was chosen as an aprotic solvent in order to favour the H-
bonding of fluorides to NH and OH groups of the neamine core that
should modify the reactivity of the hydroxyl functions in the
presence of a strong base. Under these conditions, the H-bonding of
fluorides to OH groups should favour the deprotonation of partic-
ular hydroxyl functions and their reaction. Also, the H-bonding of
fluorides to tritylated NH groups and/or to undeprotonated OH
groups could induce strong conformational effects leading to
a modulation of the reactivity. In the presence of aq NaOH under
phase-transfer conditions (PTC) or in solution in the presence of
NaH, the presence of TBAF in toluene should strongly increase the
were able to strongly inhibit viral replication since the neamine core
permits the cellular uptake, whereas the PNA alone was not taken up
by the cells. We also showed that neamine derivatives carrying li-
0
9e
pophilic chains at the 4 - or 5-position are efficient as gene vectors
and in the separation of amino acid and nucleoside enantiomers by
9
f,g
chiral ligand-exchange chromatography.
Amphiphilic aminoglycosides have also shown interesting an-
tibacterial effects.11 We used the previously developed route for the
0
rapid preparation of amphiphilic 3 ,6-(2-(naphthyl)methylene)
0
0
0
(
3 ,6-di2NM) (10a) and 3 ,4 ,6-tri2NM (10b) neamines strongly
active against wild-type and resistant strains of Gram (ꢀ) and/or
11h,i
Gram (þ) bacteria (Scheme 1).
These antibacterial compounds

O. Jackowski et al. / Tetrahedron 68 (2012) 737e746
Table 1
739
reactivity of alkylation of carbohydrates, enhance their solubility
and could improve the selectivity.
0
0
0
Synthesis of the 3 ,6-di- and 3 ,4 ,6-trialkylated neamine derivatives through PTC.
Method A: TBAI (1.5 equiv), 30% aq NaOH/toluene, RX (3.6 equiv), 50 C; method B:
ꢁ
A remarkable shift in the selectivity and rate of O-alkylation of
N-tetratritylated neamine 7 was observed under PTC and in solu-
tion and was used for a more efficient preparation of the tritylated
key derivatives 8a and 8b. Analogues of the antibacterial neamine
derivatives 10a and 10b and similar derivatives of paromamine 6
were also prepared.
TBAF (1.5 equiv), 50% aq NaOH/toluene, RX (4 equiv), rt
0
0
0
Starting tritylated
aminoglycoside
RX
Method A: 3 ,
Method C: 3 ,4 ,
6-trialkylated
6-dialkylated
compound, yield %
compound, yield %
7
7
7
17
PMBCl
8a, 72 (þ8b, 9)
8b, 86 (þ8a, 6)
2NMBr
1-hexylBr
2NMBr
9a, 58 (þ9b, 14)
13a, 72 (þ13b, 20)
18a, 58 (þ18b, 21)
9b, 55 (þ9a, 28)
13b, 60 (þ13a, 20)
18b, 57 (þ18a, 30)
We also show here that TBAF allows the straightforward prep-
aration of 6-alkylated neamine derivatives, which was exploited in
two different approaches: (i) the rapid access after deprotection to
new potential antibacterial neamine derivative members of the
kanamycin class of aminoglycosides agents and (ii) the selective
Remarkably, in the presence of TBAF (1.5 equiv) under PTC at
room temperature (50% aq NaOH, 4 equiv PMBCl, method C), the
alkylation occurred much more rapidly in comparison to the ex-
0
0
11h
preparation of potential antibacterial 3 ,4 -dialkylated neamines
from the tritylated 6-monoPMB neamine derivative obtained in
good yield.
TBAF appeared to be a very interesting phase-transfer agent for
the alkylation of neamine 5 and paromamine 6 and we also studied
its effects in the benzylation of a glucose derivative.
ꢁ
periments conducted with TBAI (25 C: t1/2¼2.5 min and 35 h, re-
spectively; Fig. 2). The main product formed in the presence of an
0
0
excess of PMBCl appeared to be the 3 ,4 ,6-tri-O-PMB derivative 8b,
which was isolated in a high 86% yield (Scheme 2, Table 1). It has
been previously isolated in 32% yield using NaH/DMF. The yield
was strongly increased in the presence of TBAF and the 3 ,6-diPMB
derivative 8a was a minor product. The tetraPMB derivative
appeared to be difficult to form in the presence of TBAF under PTC,
whereas, in solution (NaH, DMF, excess PMBCl), it is rapidly formed.
Probably, fluoride ions bind strongly to the 5-hydroxyl function in
8b and prevent the corresponding alkylation.
9
a
0
2
2
. Results and discussion
.1. Alkylation of compound 7 with PMBCl in toluene and in
the presence of TBAI or TBAF
In the search for a simple procedure to prepare in a large scale
0
0
0
the 3 ,6-diPMB (8a) and 3 ,4 ,6-triPMB (8b) neamine derivatives,
which are key intermediates, the alkylation of 7 with para-
methoxybenzyl chloride (PMBCl) in excess was studied under
phase-transfer conditions (PTC) in the presence of aq NaOH at high
concentration (30e50%) and TBAF or TBAI. The reactions were
monitored by HPLC on C18 reversed phase.
By decreasing the amounts of PMBCl (2.5 equiv) and TBAF
(1 equiv), it was possible to isolate in 75% yield the 6-monoPMB
derivative 8d (Scheme 2, method D), which was characterized
0
0
through its 3 ,4 ,5-trimethylation and then deprotection to afford
compound 12. The HPLC analysis in the course of the alkylation
showed that 8d reacts to lead to 8b but the corresponding reaction
rate appeared to be slower than the rate of the first 6-
monoalkylation step (kinetic profiles B in Fig. 2). Thus, re-
markably, it was possible to prepare rapidly in good yield the 6-
monoPMB derivative 8d.
At room temperature in the presence of 30% aq NaOH, TBAI
(
(
1.5 equiv) and PMBCl (3 equiv), the alkylation did not proceed
neither in the absence of TBAI) and appeared to be slow using 50%
ꢁ
aq NaOH. In the presence of 50% aq NaOH at 50 C, the conversion
appeared to be limited by the decomposition of the TBA cation.
However, using 30% aq NaOH, TBAI (1.5 equiv) and PMBCl (3 equiv)
Therefore, the nature of the TBA halide affects strongly the
course of the alkylation (Scheme 2): (i) in the presence of TBAI, the
ꢁ
0
0
0
0
at 50 C, the 3 ,6-diPMB derivative 8a (Scheme 2, method A) could
3 -monoPMB (8c) and 3 ,6 -diPMB (8a) derivatives can be prepared
ꢁ
be prepared in a good 72% yield (Table 1).
and the reaction is slow (preparation at 50 C), (ii) in the presence
NHTr
O
HO
HO
TrHN
a) Method A
2%
c) Method C
86%
TrHN
8a
O
8b
7
HO
NHTr
7
OH
b) Method B
8%
d) Method D
75%
3
NHTr
O
NH2
O
NH2
O
NHTr
O
e) 60%
HO
e) 70%
H3CO
3
H CO
HO
HO
PMBO
HO3
'
TrHN
3
H CO
H2N
3'
TrHN
2
H N
TrHN
2
H N
H2N
O
TrHN
O
NHTr
O
O
NH2
NH2
OCH3
HO
8c (mainly)
NHTr
OPMB
H3CO
HO
3
H CO
11
OH
8d
6
12
6
OH
Scheme 2. Alkylation of the tritylated neamine derivative 7 under phase-transfer conditions in the presence of TBAI or TBAF. (a) Method A: TBAI (1.5 equiv), 30% aq NaOH/toluene,
ꢁ
ꢁ
PMBCl (3.6 equiv), 50 C, 24 h, 72%; (b) method B: TBAI (1.5 equiv), 30% aq NaOH/toluene, PMBCl (2 equiv), 50 C, 4 days, 38%; (c) method C: TBAF (1.5 equiv), 50% aq NaOH/toluene,
PMBCl (4 equiv), rt, 4 h, 86%; (d) method D: TBAF (1 equiv), 50% aq NaOH/toluene, PMBCl (2.5 equiv), rt, 1 h, 75%; (e) two steps: (i) NaH (6 equiv), MeI (3.5 equiv), DMF, rt, 2 h; (ii)
2 2
TFA/CH Cl , anisole, rt; 11: 60% and 12: 70%.
0
0
0
0
Either in the presence of 30% and 50% aq NaOH, the 3 ,4 ,6-triPMB
derivative 8b was detected as a minor product (kinetic profiles A in
Fig. 2). By decreasing the amount of PMBCl, it was possible to isolate
of TBAF, the 6-monoPMB (8d) and the 3 ,4 ,6-triPMB (8b) de-
rivatives can be prepared in high yields and (iii) the presence of
fluorides induces the drastic increase of the reaction rate in com-
parison to iodides especially the rate of the first monoalkylation
step (Fig. 2).
0
the 3 -monoPMB derivative 8c in 38% yield (Scheme 2, method B).
HPLC analysis showed that the 3 -monoPMB product can be con-
verted to the 3 ,6-diPMB derivative 8a by adding more PMBCl. The
structure of 8c was determined through NMR experiments with
0
0
The reactions of 7 with PMBCl were also studied by HPLC in
toluene using NaH as a base in the presence of TBAF or TBAI and in
the absence of TBA halide (Supplementary data). The rate and the
selectivity of the reactions in toluene were compared to those
0
compound 11 obtained through 4 ,5,6-tri-O-methylation (NaH/
3
DMF, CH I) and deprotection with TFA (Scheme 2).

740
O. Jackowski et al. / Tetrahedron 68 (2012) 737e746
ꢁ
Fig. 2. Kinetic profiles of alkylation of compound 7 with PMBCl (4 equiv) at 25 C under phase-transfer conditions (PTC) with 50% aq NaOH/toluene. Surfaces of peaks in arbitrary
0
0
0
0
units (254 nm) as a function of time: 7 (B), 3 -monoPMB 8c (C), 6-monoPMB 8d (;), 3 ,6-diPMB 8a (7), 3 ,4 ,6-triPMB 8b (,).A: TBAI (1.5 equiv)B; TBAF (1.5 equiv).
observed in DMF. In DMF, in the absence or in the presence of TBAI
or TBAF, the reactions appeared to be rapid and unselective. A
constitutes a very short route for preparing 6-alkylated neamine
derivatives in the search for antibacterial agents as analogues of the
natural antibiotic aminoglycosides kanamycins. Evaluated against
0
0
0
7
mixture of 6-mono- (8c), 3 ,6-di- (8a), 3 ,4 ,6-tri-PMB (8b) and also
tetraPMB derivatives was rapidly formed. In toluene, the results
obtained were similar to those obtained under PTC with 50% aq
NaOH: (i) no reaction in the absence of TBA halide, (ii) in the
presence of TBA halide, slower reactions than in DMF and much
stronger increase of the reaction rate in the presence of TBAF in
comparison to TBAI, especially of the monoalkylation step with the
same selectivity leading mainly to 8b with TBAF and 8a with TBAI.
Gram (þ) and Gram (ꢀ) bacteria, the 6-(3-aminopropyl) neamine
derivative 16d showed an interesting minimum inhibitory con-
centration (MIC) of 4 mg/mL against wild-type Staphylococcus au-
reus ATCC 25923.
2.3. Alkylation of compound 7 with PMBCl and TBA hydrogen
4
sulfate (TBAHSO ) in toluene under PTC
1
7a,b
TBA hydrogen sulfate is used as a phase-transfer agent
instance in the alkylation of sugars
for
2
.2. Preparation of 6-monoalkylated neamine derivatives
17b
and therefore we compared
analogues of kanamycin B
by HPLC the rates of the para-methoxybenzylation of the tetra-
tritylated neamine derivative 7 under PTC at room temperature
Previously, we have reported the obtention of tritylated 6-
monoalkylated neamine derivatives in low yields (10e20%)
through reaction of 7 with NaH in DMF/THF (50:50), for example,
the 6-mono2NM neamine derivative 9d (Scheme 3, method D) has
4
with TBAHSO and TBAF (1.5 equiv of phase-transfer agent, 4 equiv
PMBCl). The rate of the first alkylation step appeared to be much
lower with TBAHSO
4
than with TBAF (in the disappearance of 7 at
11h
ꢁ
0
25
C t1/2z6 h and 3 min, respectively). First, the 3 -monoPMB
been obtained in 12% yield.
derivative 8c was mainly formed like with TBAI but less selectively
NHR1
O
0
due to the concomitant formation of the 6-isomer 8d and 3 ,6-
HO
HO
diPMB derivative 8a. However with TBAHSO
4
, after the mono-
a)
R1HN
alkylation step, which appeared to be the rate limiting step, the
7
R1HN
O
3
0
0
,4 ,6-triPMB derivative 8b was mainly formed at room tempera-
NHR1
HO
6
ture after 24 h and was isolated (50% yield). This result confirms the
great interest of TBAF for preparing the 6-monoPMB derivative 8d
and to strongly increase the rate of the alkylation leading to the
OR2
1
1
1
0d: R1= H, R2= 2NM, 77%
9d: R1= Tr, R2= 2NM, 45%
13d: R1= Tr, R2= hexyl, 50%
14d: R1= Tr, R2= (CH2)3NHBoc, 35%
b)
5d: R1= H, R2= hexyl, 80%
6d: R1= H, R2= (CH2)3NH2, 87%
0
0
3
,4 ,6-triPMB derivative 8b.
Scheme 3. Alkylation of 7 under phase-transfer conditions in the presence of TBAF and
preparation of kanamycin analogues. (a) Method D: TBAF, 50% aq NaOH/toluene, RX, rt;
0
0
0
2
.4. Preparation of new 3 ,6-di- and 3 ,4 ,6-tri-alkylated
(
2 2
b) TFA/CH Cl , anisole.
neamine and paromamine derivatives in toluene in the
presence of TBAF or TBAI
In regard to the selective obtention of the tritylated 6-monoPMB
derivative 8d in 75% yield from 7, 9d was also prepared from 7 and
NMBr under PTC in the presence of TBAF and was isolated in 43%
yield.
It appears to be possible to alkylate selectively 7 in toluene
In regard to the antimicrobial effects of 10a and 10b,11h,i their
2
synthesis was achieved under PTC. In the presence of TBAF, the
0
0
tritylated 3 ,4 ,6-2NM neamine intermediate 9b previously ob-
11h
under PTC at room temperature in the presence of TBAF (1.5 equiv)
with the non-benzylic alkylating agents 1-bromohexane and N-
tained in 38% yield was prepared in 55% yield from 7 and 2NMBr
Scheme 4, method C, Table 1). The 3 ,6-di2NM derivative 9a was
0
(
(tert-butoxycarbonyl)-3-bromopropylamine. The new 6-alkylated
also isolated in 28% yield. Here, alkylation with 2NMBr more re-
active than PMBCl is less selective. In addition, a side reaction of
neamine derivatives 13d and 14d (Scheme 3) were obtained in 50
and 35% yields, respectively. The reaction appeared to be totally
regioselective, it was limited by an unexplained stop in the con-
version leading to a mixture of only the starting derivative 7 and
the 6-alkylated product, which were easily separated. Addition of
TBAF and/or alkylbromide and/or increase of the temperature were
inefficient to improve the conversion ratios.
2
NM bromide with TBAF leading to 2NM fluoride was observed by
1
H NMR under the conditions used. In the presence of TBAI, 9a and
9b were isolated in 58% and 14% yields, respectively (Scheme 4,
method A, Table 1).
The reaction of 7 with 1-bromohexane in the presence of TBAI at
ꢁ 0
0 C under PTC (30% aq NaOH/toluene) led to the 3 ,6-dihexyl
derivative 13a in 68% yield and to the 3 ,4 ,6-trihexyl derivative
3b in 20% yield (Scheme 4, method A, Table 1). As expected with
5
The tritylated 6-monoalkylated products 13d and 14d were
treated with TFA/anisole for obtaining compounds 15d and 16d in
0
0
1
8
0% and 87% yields, respectively (Scheme 3). This method
0
0
TBAF under PTC at room temperature (50% aq NaOH), the 3 ,4 ,6-

O. Jackowski et al. / Tetrahedron 68 (2012) 737e746
741
R1
The NMR study was performed under phase-transfer conditions
with 50% aq NaOH/toluene-d /TBAF, in the absence of the alkylat-
O
HO
HO
8
RHN
HO
ing agent at the concentrations and [TBAF]/[7] molar ratio used in
the performed synthesis (method C). The toluene phase was ana-
lyzed after decantation.
NHR
O
7
: R1= NHTr, R= Tr
7: R1= OTr, R= Tr
NHR
RHN
1
OH
In the presence of 7, the signal corresponding to the TBA cations
a) Method A
b) Method C
1
were detected in toluene-d
8
by H NMR but were not observed in
R1
R1
O
the absence of 7. The presence of the corresponding fluoride ions in
O
4'
HO
19
R2O
the toluene phase could not be directly observed by F NMR.
R2O
RHN
HO
R2O
3'
However, their presence was confirmed after extraction of the
NHR
3'
O
RHN
O
19
NHR
NHR
toluene phase with water and analysis by F NMR of the resulting
6
HO
OR2
6
aqueous phase (signal at ꢀ120 ppm). The fluoride ions in toluene in
OR2
19
equilibria with 50% aq NaOH appeared difficult to be detected by
F
9
1
1
a: R= Tr, R1= NHTr, R2= 2NM
3a: R= Tr, R1= NHTr, R2= hexyl
8a: R= Tr, R1= OTr, R2= 2NM
9b: R= Tr, R1= NHTr, R2= 2NM
13b: R= Tr, R1= NHTr, R2= hexyl
18b: R= Tr, R1= OTr, R2= 2NM
NMR spectrometry neither in the presence nor in the absence of 7
(very weak and large signals).
c)
c)
Clearly, these experiments demonstrate that the presence of
1
1
1
0a: R= H, R1= NH2, R2= 2NM
5a: R= H, R1= NH2, R2= hexyl
9a: R= H, R1= OH, R2= 2NM
10b: R= H, R = NH , R = 2NM
þ
1
2
2
fluorides and TBA in toluene is related to the presence of com-
pound 7 and suggest the strong TBAF-7 affinity.
15b: R= H, R = NH , R = hexyl
1
2
2
19b: R= H, R = OH, R = 2NM
1
2
To get more information about the aminoglycoside-TBAF bind-
ing, titrations were performed in toluene by F and H NMR
spectrometry.
0
0
0
Scheme 4. Synthesis of the 3 ,6-di- and 3 ,4 ,6-trialkylated neamine derivatives
19
1
through PTC. (a) Method A: TBAI (1.5 equiv), 30% aq NaOH/toluene, R
2
X (3.6 equiv),
X (4 equiv), rt,
ꢁ
50
C, 24 h; (b) method C: TBAF (1.5 equiv), 50% aq NaOH/toluene, R
Cl , anisole.
2
24 h; (c) TFA/CH
2
2
The titration of 7 by TBAF in toluene-d
8
showed the progressive
appearance of three F NMR signals, a broad signal at around
20 ppm and two narrow minor signals at nearly ꢀ126 and
74 ppm, the latter being very weak (Fig. 3). The intensity of the
19
1
ꢀ
trihexyl derivative 13b was obtained in 60% yield with isolation of
3a in 20%. The deprotection of 13a and 13b in TFA led to 15a and
5b, respectively.
This methodology was applied to the N-tetratritylated de-
rivative of paromamine 17 (Scheme 4, Table 1), which was treated
with 2NMBr under PTC. In the presence of TBAF at room temper-
1
1
two main signals increased with the TBAF concentration and the
broad signal appeared to be progressively and strongly shifted
downfield from ꢀ121 to ꢀ116 ppm with the increase of the TBAF/7
molar ratio from 0.2 to 2, respectively. This broad signal was
assigned to the free fluorides according to the broad signal detected
0
ature, alkylation of 17 led to the tritylated 3 ,6-di2NM (18a, 30%)
and 3 ,4 ,6-tri2NM (18b, 57%) derivatives, which gave separately
0
0
at nearly ꢀ114 ppm for TBAF alone in toluene-d
8
.
after treatment with TFA 19a and 19b. In the presence of TBAI at
ꢁ
5
0 C, 18a and 18b were obtained in 58 and 21% yields, respectively.
0
0
2
.5. An access to 3 ,4 -dialkylated neamine derivatives
In another illustration of the methodology described here, the
tritylated 6-monoPMB derivative 8d was alkylated with 1NM
0
0
chloride under PTC in the presence of TBAF to lead to the 3 ,4 -
di1NM-6-PMB derivative (61%, Scheme 5). After deprotection in
0
0
TFA, the 3 ,4 -di1NM derivative 20 was obtained in good 60% yield
in regard to its sensitivity to acidic conditions. The antimicrobial
activity of 20 against S. aureus strains will be interesting to compare
0
0
to the strong antibacterial effects observed with its 3 ,4 -di2NM
isomer obtained previously in 51% yield through the careful treat-
0
0
11h
ment with TFA of the 3 ,4 ,6-tri2NM derivative 10b.
NHTr
O
NH2
O
4
'
HO
HO
1NMO
1NMO
a), b)
NHTr
TrHN
H2N
NHTr
3' NH2
O
O
NH2
HO
HO
8
d
6
20
OPMB
OH
Fig. 3. 19F NMR spectra (282 MHz, 28 ꢁC) of 7 (A) at a concentration of 77 mM in
toluene-d and upon titration by a 0.386 M TBAF solution in toluene-d , at the molar
ratios ([TBAF]/[7]) of 0.2 (B), 0.5 (C), 1 (D), 1.25 (E), 1.5 (F) and 2 (G). Inset: enlargement
of the region between ꢀ126.6 and ꢀ125.6 ppm.
0
0
Scheme 5. Preparation of the 3 ,4 -di1NM neamine derivative 20 from the 6-
monoPMB neamine derivative 8d under PTC with TBAF as a phase-transfer agent. (a)
8
8
TBAF (2 equiv), 50% aq NaOH/toluene, 1NMCl (3 equiv), rt, 5 h, 61%; (b) TFA/CH
2
Cl
2
,
ꢁ
anisole, 0 C, 60%.
With the increase of TBAF/7 ratio, the major sharp signal in-
creased in intensity and was progressively weakly shifted down-
field (Fig. 3). It was assigned to the fluoride ions bound to 7. The
2
7
.6. Study by NMR spectrometry of the binding of compound
to fluorides
8
titration of TBAF by 7 in toluene-d led to the same conclusion. In
In order to confirm that the observed strong effects of TBAF on
regard to the shape of the signals and their varying positions, it
the rate and selectivity of alkylation of compound 7 are related to
the H-binding of F to the neamine core, we investigated by NMR
spectrometry the expected interactions between fluoride ions and
compound 7.
appeared difficult to quantify the fluoride binding to 7.
ꢀ
ꢀ
The interactions between F and 7 were also confirmed upon
1
the titration by H NMR spectrometry (Figs. 4 and 5). Most of proton
signals of 7 were strongly shifted by fluoride addition. The larger

742
O. Jackowski et al. / Tetrahedron 68 (2012) 737e746
Fig. 6. Dissolution of 21 (75.7 mmol) during progressive addition of TBAF in toluene.
a): starting mixture; from (b) to (f): mixtures of 21 and TBAF at ([TBAF]/[21]) molar
(
ratios of 0.5, 1, 1.5, 2.5 and 3, respectively.
comparison to TBAI (Supplementary data) in the presence of which
21 appeared to be weakly soluble (3 equiv). Any regioselectivity
was observed as well as in the para-methoxybenzylation of 21.
The observed stoichiometric solubilization of 21 confirms the
strong binding of fluorides to the hydroxyl groups of carbohydrates
in toluene.
Fig. 4. 1H NMR spectra (300 MHz, 28 C) of 7 (A) at a concentration of 77 mM in
toluene-d and upon titration by a 0.386 M TBAF solution in toluene-d , at the molar
ꢁ
8
8
ratios ([TBAF]/[7]) of 0.2 (B), 0.5 (C), 1 (D), 1.25 (E), 1.5 (F) and 2 (G). Only the region
from 3.8 to 4.3 ppm is represented.
2.8. First results obtained with another aminoglycoside: O-
alkylation of ribostamycin 23 (see Supplementary data)
In order to O-alkylate ribostamycin 23 made of rings I, II and III
of neomycin B 1 (Fig. 7), pentatritylribostamycin 25 was prepared
by tritylation of the free base. The alkylation of 25 with 1NMCl
(6 equiv) under PTC led mainly after detritylation with TFA to an O-
tetra1NM derivative in the presence of TBAF, whereas in the pres-
ence of TBAI a mono1NM derivative 24 was isolated. The 1NM
00
group in the latter compound appeared to be carried by the 2 -
oxygen atom of the ribose ring. In regard to the lack of antibacterial
activity of 24, we did not continue in this approach. These pre-
liminary experiments again point out the increased reactivity of the
hydroxyl groups of aminoglycosides in the presence of TBAF in
comparison to TBAI.
NH2
O
NHTr
O
HO
HO
HO
HO
H2N
TrHN
O
NH2
O
TrHN
O
NH2
O
NHTr
HO
O
TrO
Fig. 5. Variations of the 1H NMR chemical shifts of 7 at a concentration of 77 mM in
OH
O
OH
1"
2
"
toluene-d
8
upon titration by a 0.386 M TBAF solution in toluene-d
8
. For each proton,
23: R= H, ribostamycin
24: R= 1NM
OH OR
OH OH
the difference (Dd) between the chemical shifts in presence and absence of TBAF is
displayed as a function of the molar ratios ([TBAF]/[7]).
25
Fig. 7. Structure of ribostamycin and of the corresponding prepared derivatives.
0
0
downfield shifts were observed for H3, H6, H3 , H5 and for the
0
trityl protons attached to the 2 -nitrogen atom, whereas upfield
0
shifts were detected for H1 , H4 and H5.
3. Conclusion
These experiments suggest that in toluene fluoride ions bind
strongly to the neamine core probably through the formation of
hydrogen bonds with the hydroxyl and the amine functions.
However, the corresponding signals of the hydroxyl functions could
To the best of our knowledge, here, we report for the first time
on the major increases of the selectivity and/or reactivity of car-
bohydrates in the presence of fluorides associated to a strong base
in an apolar aprotic solvent. The corresponding methodology in-
volving TBAF in toluene and aq NaOH under phase-transfer con-
ditions or NaH offers prospects of selectivity in the modification of
carbohydrates and polyols through a simple procedure. It provides
selectivity and rapidity for preparing aminoglycosides of medicinal
1
not be identified in the complex H NMR spectra observed.
2
.7. Alkylation of a monosaccharide in toluene in the
presence of TBAI or TBAF
0
0
0
interest especially the 3 ,6-diPMB (8a) and 3 ,4 ,6-triPMB (8b)
The 6-O-tritylated methylglucopyranoside 21 (Fig. 6) was pre-
pared for alkylation under PTC (50% aq NaOH/toluene) in the
presence of TBAF or TBAI. Compound 21 appeared to be insoluble in
toluene and remarkably the addition of TBAF (3 equiv) allowed
dissolution (Fig. 6). The dissolution of 21 appeared to be complete
with 3 equiv of TBAF that corresponds to one fluoride ion for one
hydroxyl group. In the presence of benzyl bromide (4 equiv) at
room temperature, a rapid and complete benzylation was observed
to lead to the tribenzyl derivative 22 (Fig. 6) in 70% yield. The rate of
benzylation appeared to be strongly increased by TBAF addition in
neamine derivatives, which are key intermediates in the prepara-
0
0
tion of 4 -, 5- and 4 ,5-neamine derivatives. This procedure also
allows the selective preparation of the tritylated 6-monoPMB
neamine derivative 8d useful for the preparation of potential an-
0
0
tibacterial 3 ,4 -neamine derivatives, such as 20. Using PTC in tol-
uene and TBAF as a phase-transfer agent, 6-monoalkylated
neamine derivatives, which can be seen as analogues of the anti-
biotic aminoglycosides kanamycins, were rapidly and selectively
prepared.

O. Jackowski et al. / Tetrahedron 68 (2012) 737e746
743
In conclusion, TBAF can be advantageously used as a phase-
transfer agent for the alkylation in toluene at room temperature of
aminosugars and sugars, which bind to fluoride ions through H-
bonds. Experiments performed in the para-methoxylation of the
tetratritylated neamine derivative 7 under PTC showed that TBAF can
be replaced by the TBA hydroxide/NaF mixture cheaper than TBAF.
compound 7 (1 g, 1 equiv) in toluene (30 mL) were added
TBAF$3H O (1.5 equiv), the halide (4 equiv) and an aqueous so-
lution of NaOH (50% w/w, 15 mL). The resulting mixture was
stirred vigorously for 4e24 h at room temperature. The organic
solution was extracted, diluted with ethyl acetate, then washed
twice with an aq saturated ammonium chloride solution before
2
4
being dried over MgSO , filtrated and concentrated under reduced
4
4
. Experimental section
pressure. The trialkylated product was purified by chromatogra-
phy on alumina or silica gel neutralized with triethylamine eluting
with a gradient of toluene/ethyl acetate or cyclohexane/ethyl
acetate.
.1. General procedures
General: H NMR (400 MHz) and 13C NMR (100 MHz) spectra
1
were recorded with a BRUKER AVANCE 400 spectrometer using the
residual solvent signal as internal standard. LRMS were achieved
with a NERMAG spectrometer for the FAB, DCI and EI techniques,
with an AUTOFLEX BRUKER spectrometer for the MALDI and with
a ZQ WATERS for the ESI. HRMS were obtained from the Mass
Spectrometry Service, CRMPO, at the University of Rennes I, France,
using a MICROMASS ZABSPEC-TOF spectrometer and a VARIAN
MAT311 spectrometer. Melting points were determined with
a BUCHI 510 apparatus. Thin layer chromatographies were per-
formed on silica gel (Alugram Sil G/UV254) or Alumina gel (Alu-
gram Alox N/UV254) from MachereyeNagel and spots were
detected either by UV-absorption, by using a cerium-molybdate
stain or by charring with ninhydrin. Columns chromatography
were performed on alumina gel (MP Ecochrom Biomedicals, Act II-
III acc. to Brockman), on silica gel (MN Kieselgel 60, 0.063e0.2 mm/
4.1.4. Method D: general procedure used for the 6-mono-O-alkylation
of the tetra-N-tritylated neamine derivative 7. To a solution of
compound 7 (1 g, 1 equiv) in toluene (30 mL) were added
2
TBAF$3H O (1 equiv), the halide (1.2e2.5 equiv) and an aqueous
solution of NaOH (50% w/w, 15 mL). The resulting mixture was
ꢁ
stirred vigorously for 1e24 h at room temperature (25 C). The
organic solution was extracted, diluted with ethyl acetate and
washed twice with an aq saturated ammonium chloride solution
before being dried over MgSO , filtrated and concentrated under
4
reduced pressure. The monoalkylated product was purified by
chromatography on alumina or silica gel neutralized with trie-
thylamine eluting with a gradient of toluene/ethyl acetate or cy-
clohexane/ethyl acetate.
4.1.5. Method E: general procedure for the deprotection of the tetra-
7
(
0e230 mesh, MachereyeNagel) or on C18 reversed phase
MachereyeNagel polygoprep 60-50C18). All starting materials
were obtained from suppliers and used without further purification
unless otherwise noted. DMF was distilled in the presence of CaH
N-tritylated neamine derivative. The protected compound was dis-
ꢁ
solved at 0 C or at room temperature in CH
2
Cl
2
/TFA (1/1, v/v) in the
presence of anisole (0.1 mL/mL). After 2 h stirring, the solvents were
evaporated under reduced pressure. H O and Et O were added and
the aqueous phase was washed twice with Et O before being
concentrated and poured on a C18 reversed phase column. The
2
,
2
2
THF over sodium with benzophenone and stored under argon at-
mosphere prior to use. Compound 7 was synthezised as previously
described.9
2
a
2
compound was eluted with a H O/MeOH gradient and obtained
pure as the TFA salt.
0
4
.1.1. Method A: general procedure used for the 3 ,6-di-O-alkylation
of the tetra-N-tritylated neamine derivative 7. To a solution of
compound 7 (1 g, 1 equiv) in toluene (30 mL) were added TBAI
4.2. Synthesis and characterization
0
(
(
1.5 equiv), the halide (3 equiv) and an aqueous solution of NaOH
30% w/w, 15 mL). The resulting mixture was heated at 50 C and
4.2.1. 3 ,6-Di-O-(4-methoxybenzyl)-tetra-N-trityl neamine derivative
ꢁ
(8a). Compound 8a was obtained from 7 (1 g) and 4-
stirred vigorously. After 5 h, another portion of halide (0.6 equiv)
was added to the reacting mixture. After 24 h, the organic solution
was extracted, diluted with ethyl acetate and washed twice with an
aq saturated ammonium chloride solution before being dried over
methoxybenzyl chloride with 72% yield (854 mg) following the
method A and after a purification by chromatography on silica gel
with a gradient of toluene/ethyl acetate (v/v: 100/0 to 90/10) with
triethylamine (0.2%) as eluent. The NMR and mass spectra were in
9
a
MgSO
4
, filtrated and concentrated under reduced pressure. The
agreement with those obtained for 8a previously described.
dialkylated product was purified by chromatography on alumina or
silica gel neutralized with triethylamine eluting with a gradient of
toluene/ethyl acetate or cyclohexane/ethyl acetate.
0
4.2.2. 3 -Mono-O-(4-methoxybenzyl)-tetra-N-trityl neamine de-
rivative (8c). Compound 8c was obtained from 7 (1 g) and 4-
methoxybenzyl chloride with 38% yield (416 mg) following the
method B and after a purification by chromatography on silica gel
eluting with a gradient of toluene/ethyl acetate (v/v: 100/0 to 50/
0
4
.1.2. Method B: general procedure used for the 3 -mono-O-alkyl-
ation of the tetra-N-tritylated neamine derivative 7. To a solution of
compound 7 (1 g, 1 equiv) in toluene (30 mL) were added TBAI
þ
þ
50) with triethylamine (0.2%). HRMS (ESI ): [MþH] m/z calculated
þ
(
(
1.5 equiv), the halide (1.2 equiv) and an aqueous solution of NaOH
30% w/w, 15 mL). The resulting mixture was heated at 50 C and
1411.6888, found 1411.6906, [MþNa] m/z calculated 1433.6707,
ꢁ
found 1433.6722. The identification was done via the synthesis of
11 due to the difficulty of interpretation of the NMR spectra of 8c.
stirred vigorously. Two other portions of halide (2ꢂ0.4 equiv) were
added to the reacting mixture after 1 day and then 3 days. After 4
days, the organic solution was extracted, diluted with ethyl acetate
and washed twice with an aq saturated ammonium chloride so-
0
4.2.3. 4 ,5,6-Tri-O-methyl-neamine derivative (11). To a solution of
compound 8c (230 mg, 0.16 mmol) in dry DMF (5 mL) under argon
were added sodium hydride (60%, 6 equiv) and after 30 min stirring
at room temperature, iodomethane (2.3 equiv). The resulting
mixture was stirred for 2 h at room temperature before the addition
of ethanol (5 mL). The solution was concentrated under reduced
pressure. The crude product was diluted with ethyl acetate and
4
lution before being dried over MgSO , filtrated and concentrated
under reduced pressure. The monoalkylated product was purified
by chromatography on alumina or silica gel neutralized with trie-
thylamine eluting with a gradient of toluene/ethyl acetate or cy-
clohexane/ethyl acetate.
4
then washed with water and brine before being dried over MgSO ,
filtrated and concentrated under reduced pressure. The trimethy-
0
0
4
.1.3. Method C: general procedure used for the 3 ,4 ,6-tri-O-alkyl-
ation of the tetra-N-tritylated neamine derivative 7. To a solution of
lated compound obtained was enough pure to be deprotected

744
O. Jackowski et al. / Tetrahedron 68 (2012) 737e746
directly following the method E. After purification on a C18 re-
deprotection was achieved following the method E to give 10b with
versed phase column eluting with water, the compound was ob-
tained as trifluoroacetic acid salt. Compound 11: 60% (80 mg), H
65% yield (83 mg).The NMR and mass spectra were in agreement
with those obtained for 10b previously described.
1
11h
NMR (400 MHz, CD
H), 3.62 (s, 3H), 3.56 (s, 3H), 3.51e3.17 (m, 8H), 2.45 (m, 1H), 1.97
m, 1H); 13C NMR (100 MHz, CD
OD) 163.8, 163.5, 163.2 and 162.8
CO TFA), 122.6, 119.7, 116.8 and 113.9 (CF3), 94.7, 86.2, 84.1, 81.1,
3
OD) d 5.71 (d, 1H), 4.23e4.10 (m, 3H), 3.65 (s,
3
(
(
4.2.9. 6-Mono-O-naphthyl neamine derivative (10c). Compound
10c was synthesised following the method C from 7 (250 mg) and
2-(bromomethyl)naphthalene (1.2 equiv) for 1.5 h. The protected
derivative 9c was obtained with 45% yield (134 mg). The depro-
tection of 9c (94 mg) was achieved following the method E to give
10c with 77% yield (38 mg). The NMR and mass spectra were in
3
d
7
7.1, 72.2, 69.0, 61.4, 60.9, 60.5, 54.6, 50.7, 50.3, 41.2, 29.7; HRMS
þ
(
[
ESIþ): [MþH] m/z calculated 365.2400, found 365.2403,
þ
MþNa] m/z calculated 387.2220, found 387.2207.
11h
agreement with those obtained for 10c previously described.
0 0
.2.4. 3 ,4 ,6-Tri-O-(4-methoxybenzyl)-tetra-N-trityl neamine de-
4
0
rivative (8b). Compound 8b was obtained from 7 (1 g) and 4-
methoxybenzyl chloride with 86% yield (1.10 g) following the
method C and after a purification on silica gel with a gradient of
toluene/ethyl acetate (v/v: 100/0 to 95/5) and triethylamine (0.2%).
The NMR and mass spectra were in agreement with those obtained
4.2.10. 3 ,6-Di-O-hexyl neamine derivative (15a). Compound 15a
was obtained following the method A from 7 (200 mg) and 1-
bromohexane (3 equiv) and after the addition of another portion
of halide (3 equiv) and stirring for 16 h more. Protected derivative
13a was obtained with 72% yield (163 mg). The deprotection of 13a
9
a
for 8b previously described.
(285 mg) was achieved following the method E. Compound 15a:
1
5
7% (106 mg), H NMR (400 MHz, CD3OD)
d
5.94 (d, J¼3.6 Hz, 1H),
4.2.5. 6-Mono-O-(4-methoxybenzyl)-tetra-N-trityl neamine de-
4.07e3.89 (m, 4H), 3.84 (dd, J¼8.5, 10.3 Hz, 1H), 3.75e3.62 (m, 3H),
3.45e3.37 (m, 3H), 3.33e3.19 (m, 3H), 3.10 (dd, J¼8.7, 13.3 Hz, 1H),
2.44 (m, J¼4.1, 12.3 Hz, 1H), 2.00 (m, J¼12.5 Hz, 1H), 1.72e1.61 (m,
rivative (8d). The compound 8d was obtained from 7 (2 g) and 4-
methoxybenzyl chloride with 75% yield (1.64 g) following the
method D for 2 h. Yet, the crude product was not purified by
chromatography, instead, the yellow solid gum was dissolved in
13
3
4H), 1.34 (br s, 12H), 0.91 (m, 6H); C NMR (100 MHz, CD OD)
d
97.0, 82.4, 79.0, 77.7, 77.6, 75.2, 74.8, 73.5, 71.8, 54.6, 50.7, 50.2,
CH
solid was triturated in Et
give the pure compound as a white powder in 86% yield. HRMS
2
Cl
2
and the solvent removed under reduced pressure, then the
41.8, 33.0, 31.2, 31.0, 30.1, 26.8, 26.7, 23.8, 14.5 (2 CH
3
); HRMS
þ
þ
2
O, filtrated, washed with H O and dried to
2
(ESIþ): [MþH] m/z calculated 491.3809, found 491.3815, [MþNa]
m/z calculated 513.3628, found 513.3631.
þ
þ
(
[
ESI ): [MþH] m/z calculated 1411.6888, found 1411.6898,
þ
0
0
MþNa] m/z calculated 1433.6707, found 1433.6689. The identi-
4.2.11. 3 ,4 ,6-Tri-O-hexyl neamine derivative (15b). Compound 13b
was synthesised following the method C from 7 (250 mg) and 1-
bromohexane (4 equiv) for 4 h. Protected derivative 13b was ob-
tained with 60% yield (182 mg). The deprotection of 13b (40 mg)
fication was done via the synthesis of 12 due to the difficulty of
interpretation of the NMR spectra of 8d.
0
0
4
.2.6. 3 ,4 ,5,-Tri-O-methyl-neamine derivative (12). To a solution of
was achieved following the method E. Compound 15b: 52% (14 mg),
1
compound 8d (250 mg, 1 equiv) in dry DMF (5 mL) under argon
were added sodium hydride (60%, 6 equiv) and after 30 min stirring
at room temperature, iodomethane (2.3 equiv). The resulting
mixture was stirred for 2 h at room temperature before the addition
of ethanol (5 mL). The solution was concentrated under reduced
pressure. The crude product was diluted with ethyl acetate and
H NMR (400 MHz, CD
3
OD)
d
5.89 (d, J¼3.4 Hz, 1H), 4.14 (m, J¼9.2,
2.4 Hz, 1H), 4.03e3.58 (m, 9H), 3.44e3.15 (m, 7H), 2.43 (m, J¼4.0,
12.4 Hz, 1H), 1.99 (dd, J¼12.4 Hz, 1H), 1.75e1.58 (m, 6H), 1.36 (br s,
13
3
18H.), 0.94 (m, 9H); C NMR (100 MHz, CD OD) d 96.9, 82.5, 81.0,
79.9, 77.9, 77.7, 75.2, 74.8, 74.5, 71.3, 54.7, 50.9, 50.1, 41.6, 33.1
(3CH ), 31.5, 31.2, 31.1, 30.4, 27.0, 26.9, 26.7, 23.8 (3 CH ), 14.5 (3
CH
2
2
þ
þ
þ
then washed with water and brine before being dried over MgSO
4
,
3
); HRMS (ESI ): [MþH] m/z calculated 575.4748, found
filtrated and concentrated under reduced pressure. The trimethy-
lated compound obtained was enough pure to be deprotected di-
rectly following the method E. After purification on a C18 reversed
phase column with water, the compound was obtained as the tri-
fluoroacetic acid salt, which was converted to the chlorhydrate salt
575.4748, [MþNa] m/z calculated 597.4567, found 597.4566,
[MþK]þ m/z calculated 613.4306., found 613.4311.
4.2.12. 6-Mono-O-hexyl neamine derivative (15d). Compound 13d
was synthesised following the method D from 7 (250 mg) and 1-
bromohexane (1.5 equiv). After 6 h, another portion of halide
(1.5 equiv) was added and the mixture was stirred 16 h more.
Protected derivative 13d was obtained with 50% yield (134 mg). The
1
with an ion exchange resin. 12: 70% (102 mg), H NMR (400 MHz,
CD
3
OD)
d 5.76 (d, 1H), 4.32 (dd, 1H), 4.21 (m, 1H), 4.08 (m, 1H), 3.70
(
3
s, 3H), 3.69 (s, 3H), 3.59 (s, 3H), 3.66e3.57 (m, 2H), 3.50 (dd, 1H),
13
.43 (dd, 1H), 3.40e3.22 (m, 4H), 2.41 (ddd, 1H), 2.05 (ddd, 1H);
OD) 94.5, 86.2, 81.6, 78.3, 75.7, 74.8, 71.4, 60.9,
0.7, 60.6, 53.8, 51.4, 50.4, 41.2, 29.5; HRMS (ESI ): [MþH] m/z
C
deprotection of 13d (94 mg) was achieved following the method E
1
NMR (100 MHz, CD
6
3
d
to lead to 15d: 80% (38 mg), H NMR (400 MHz, CD
3
OD)
d
5.94 (d,
þ
þ
J¼3.8 Hz, 1H), 4.07e3.88 (m, 4H), 3.72 (dd, J¼9.2 Hz, 1H), 3.65 (m,
1H), 3.48e3.38 (m, 2H), 3.37e3.19 (m, 4H), 3.11 (dd, J¼8.4, 13.3 Hz,
1H), 2.46 (m, J¼4.1, 12.4 Hz, 1H), 2.01 (m, J¼12.5 Hz, 1H), 1.72e1.62
þ
calculated 365.2400, found 365.2398, [MþNa] m/z calculated
3
87.2220, found 387.2211.
13
(
3
m, 2H), 1.32 (br s, 6H), 0.91 (m, 3H); C NMR (100 MHz, CD OD)
0
4
.2.7. 3 ,6-Di-O-[(2-naphthyl)methyl] neamine derivative (10a). Com-
d 97.3, 82.3, 79.1, 77.6, 75.8, 73.3, 71.1, 69.6, 55.5, 50.6, 50.1, 42.0,
þ
þ
pound 10a was prepared following the method A from 7 (250 mg)
and 2-(bromomethyl)naphthalene. The protected derivative 9a was
obtained with 58% yield (177 mg). The deprotection was achieved
following the method E to give 10a with 70% yield (83.2 mg). The
NMR and mass spectra were in agreement with those obtained for
33.0, 31.0, 29.8, 26.6, 23.7, 14.4; HRMS (ESI ): [MþH] m/z calcu-
þ
lated 407.2864, found 407.2861, [MþNa] m/z calculated 429.2684,
found 429.2683, [MþK]þ m/z calculated 445.2423, found 445.2418.
4.2.13. 6-Mono-O-(3-amino)propyl neamine derivative (16d). Com-
pound 14d was synthesised following the method D from 7 (250 mg)
and 1-bromo-N-Boc-propylamine (1.5 equiv). After 2 h, another
portion of halide (1.5 equiv) was added and the mixture was stirred
16 h more. The protected derivative 14d was obtained with 35% yield
11h
10a previously described.
0
0
4
.2.8. 3 ,4 ,6-Tri-O-[(2-naphthyl)methyl]
neamine
derivative
(10b). Compound 10b was synthesised following the method C
from 7 (250 mg) and 2-(bromomethyl)naphthalene. The protected
derivative 9b was obtained with 55% yield (182 mg). The
(96 mg). The deprotection of 14d (91 mg) was achieved following the
1
method E to lead to 16d: 87% (55 mg), H NMR (400 MHz, CD
3
OD)

O. Jackowski et al. / Tetrahedron 68 (2012) 737e746
745
d
6.01 (d, J¼3.7 Hz, 1H), 4.04e3.89 (m, 4H), 3.87e3.74 (m, 2H),
.46e3.33 (m, 4H), 3.32e3.21 (m, 3H), 3.15e3.05 (m, 3H), 2.43 (m,
toluene to give a pale yellow gum in 61% yield (730 mg). The
3
deprotection was achieved following the procedure E. Compound
13
1
J¼4.2, 12.5 Hz, 1H), 2.10e1.87 (m, 3H); C NMR (100 MHz, CD
3
OD)
20: 60% (274 mg), H NMR (400 MHz, CD
3
OD)
d
7.88e7.60 (m, 7H),
d
97.1, 83.2, 79.1, 77.5, 73.4, 71.6, 71.1, 70.1, 55.6, 50.6, 50.3, 42.1, 38.8,
7.45e7.20 (m, 7H), 6.01 (d, J¼3.5 Hz, 1H), 5.40 (d, J¼12.4 Hz, 1H),
5.20 (d, J¼12.4 Hz, 1H), 5.02 (d, J¼12.0 Hz, 1H), 4.90 (m br, 1H and
solvent), 4.44 (dd, J¼7.8, 9.4 Hz, 1H), 4.28 (m, J¼3.0, 8.4, 9.8 Hz, 1H),
þ
3
3
0.5, 29.0; HRMS (ESIþ): [MþH] m/z calculated 380.2504, found
þ
80.2503, [MþNa] m/z calculated 402.2323, found 402.2323.
4
.06 (dd, J¼9.3, 10.1 Hz, 1H), 3.68e3.57 (m, 3H), 3.53e3.42 (m, 2H),
0
0
4
1
.2.14. 1,3,2 ,6 -Tetra-N-trityl paromamine derivative (17). Compound
3.21 (m, J¼4.3, 10.3, 12.5 Hz, 1H), 2.98 (m, 2H), 2.48 (m, J¼4.2,
13
7 was obtained under the conditions used previously for the
12.4 Hz, 1H), 2.02 (dd, J¼12.4 Hz, 1H); C NMR (100 MHz, CD
135.2e132.2 (6C-naphtyl), 130.0e124.1 (14CH-naphtyl), 96.3,
79.6, 79.2, 77.9, 77.3, 74.4, 74.0, 73.6, 71.6, 54.4, 51.6, 50.3, 41.5, 29.9;
3
OD)
9a
15
preparation of 7. A solution of paromamine tetrahydrochloride 6
2.5 g, 1 equiv) in DMF/triethylamine (60:8 mL) under argon atmo-
d
(
þ
þ
sphere was stirred at room temperature for 1 h. Then a solution of
trityl chloride (13.6 g, 48.6 mmol) in DMF/triethylamine (130:8 mL)
and DMAP (0.2 equiv) were added. After 4 h at room temperature,
dichloromethane (100 mL) was added. The resulting solution was
HRMS (ESI ): [MþNa] m/z calculated 625.3002, found 625.3002,
[MþK]þ m/z calculated 641.2741, found 641.2744; HPLC: method C.
4.2.18. Methyl-6-O-trityl-2,3,4-tri-O-benzy
L
-
a
-
D
-glucopyranoside
16a
washed with water (2ꢂ100 mL), dried over Na
2 4
SO and evaporated.
derivative (22) . Compound 22 was prepared with 70% yield fol-
16
The residue was precipitated in pentane and then chromatographed
on alumina gel eluting with toluene/ethyl acetate (v/v: 100/0 to 50/
lowing method B from 21 (1 g) and benzyl bromide (718 mg). The
NMR and mass spectra were in agreement with those obtained for
22 previously described.
5
0) to obtain the tetratritylated derivative 17 with 77% yield (7.7 g).
1
3
3
C NMR (100 MHz, CDCl ) d 146.3e143.2 (CPh),129.7e125.9 (CHPh),
9
6
9.8 (CH), 86.7 (CH), 76.9 (CH), 75.6 (CH), 71.4 (C), 70.9 (CH), 69.7 (C),
4
.3. Kinetic studies by HPLC
5.9 (CH
2
), 57.8 (CH), 54.3 (CH), 52.8 (CH), 21.3 (CH
2
); LRMS (MALDI,
þ
þ
þ
DHB) m/z: 1332 [MþK] , 1316 [MþNa] , 1292 [MþH] , 1089
Kinetic studies were performed by HPLC with an Agilent 1100
þ
þ
þ
þ
[
[
MꢀTrþK] , 1073 [MꢀTrþH] , 1047 [MꢀTrþH] ; HRMS (ESI ):
series HPLC machine with a diode array detector using a C18 re-
versed phase column (Nucleosil C18 column, MachereyeNagel,
5
þ
MþNa] m/z calculated 1314.5967, found 1314.5976.
mm particle size, 250ꢂ4.6 mm) and MeOH as a mobile phase.
0
4.2.15. 3 ,6-Di-O-[(2-naphthyl)methyl]
paromamine
derivative
(
19a). Compound 19a was synthesised following the method A
4
.4. NMR study of fluoride binding to compound 7
from 17 (1 g) and 2-(bromomethyl)naphthalene (3 equiv). Pro-
tected derivative 18a was obtained with 58% yield (705 mg). The
deprotection was achieved following the procedure E. Compound
1
7
2
In the NMR study of phase transfer experiments, TBAF$3H O
(
12.2 mg, 38.7 mmol) were dissolved in toluene (1 mL) and 50% aq
NaOH (0.5 mL) in the presence or in the absence of 7 (33.3 mg,
5.8 mmol). The mixture was stirred at room temperature for 2 h.
The toluene phase was extracted with 1 mL of distilled water.
00 L of this aqueous phase were introduced in an NMR tube
together with 50 L of D O.
For the titration of 7 by TBAF, a 500
pared at 77 mM in toluene-d . The 7/TBAF binding was studied by
direct addition of aliquots of a concentrated solution of TBAF in
toluene-d (typically 0.386 M) to the solution of 7.
For the titration of TBAF by 7, a 500 L solution of TBAF$3H
was prepared at 39 mM in toluene-d . The 7/TBAF binding was
studied by direct addition of aliquots of a concentrated solution of 7
1
9a: 44% (187 mg), H NMR (400 MHz, CD
3
OD)
d
7.93e7.83 (m, 8H),
.60e7.55 (m, 2H), 7.51e7.43 (m, 4H), 5.55 (d, J¼3.5 Hz, 1H), 5.24 (d,
2
J¼11.1 Hz, 1H), 5.00e4.83 (m, J¼11.2 Hz, 3H), 4.04e3.94 (m, 3H),
3
3
1
1
7
.89e3.85 (m, 2H), 3.71 (dd, J¼9.0, 11.7 Hz, 1H), 3.70e3.60 (m, 2H),
5
m
.56e3.47 (m, 2H), 3.37 (m, 1H), 2.49 (m, 1H), 1.87 (m, J¼12.4 Hz,
m
2
13
3
H); C NMR (100 MHz, CD OD) d 136.9e134.6 (6C-naphthyl),
mL solution of 7 was pre-
29.1e127.1 (14CH-naphthyl), 98.7, 84.1, 81.3, 78.4, 77.0, 76.9, 76.1,
8
þ
þ
6.0, 71.9, 61.9, 54.7, 50.6, 50.4, 30.1; HRMS (ESI ): [MþH] m/z
þ
calculated 604.3017, found 604.3013, [MþNa] m/z calculated
8
6
26.2837, found 626.2830.
m
2
O
8
0 0
.2.16. 3 ,4 ,6-Tri-O-[(2-naphthyl)methyl] paromamine derivative
4
(19b). Compound 19b was synthesised following the method C from
in toluene-d
8
(typically 0.157 M) to the NMR TBAF sample.
NMR spectra were recorded at 28 C, on Bruker Avance 300 and
00 MHz spectrometers. To follow the proton chemical shift vari-
1
7 (1 g) and 2-(bromomethyl)naphthalene (4 equiv). Protected de-
ꢁ
rivative 18b was obtained with 57% yield (755 mg). The deprotection
4
was achieved following the method E. Compound 19b: 32% (153 mg),
ations in 7 upon binding to fluoride, chemical shifts of 7 in the
absence and in the presence of TBAF at a ([TBAF]/[7]) molar ratio of
1
1
H NMR (400 MHz, CD
3
OD)
d
7.93e7.30 (m, 21H), 5.60 (d, J¼3.2 Hz,
1
3
H), 5.24 (d, J¼11.1 Hz, 1H), 5.05e4.82 (m, 5H), 4.18e4.13 (m, 2H),
were assigned using COSY, HMQC, HMBC experiments.
.92e3.80 (m, 4H), 3.72e3.60 (m, 3H), 3.48 (m,1H), 3.37 (m,1H), 2.48
13
(
m, J¼4.1, 12.4 Hz, 1H), 1.85 (m, J¼12.7 Hz, 1H); C NMR (100 MHz,
CD OD) 136.8e134.6 (9C-naphthyl), 129.4e126.7 (21CH-naphthyl),
8.0, 83.4, 81.5, 78.5, 78.1, 77.3, 76.6, 76.2, 75.9, 75.6, 61.4, 54.5, 50.6,
Acknowledgements
3
d
9
5
This work was supported by the French National Research
Agency (ANR ‘Physique et Chimie du Vivant’) which is gratefully
acknowledged.
þ
þ
0.5, 30.1; HRMS (ESI ): [MþH] m/z calculated 744.3643, found
þ
7
44.3639, [MþNa] m/z calculated 766.3463, found 766.3449.
0
0
4
.2.17. 3 ,4 -Di-O-[(1-naphthyl)methyl] neamine derivative (20). To
Supplementary data
a solution of 8d (1 g) in toluene (30 mL) were added TBAF$3H
2
O
(
2 equiv), 1-(chloromethyl)naphthalene (3 equiv) and an aqueous
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.10.102.
solution of NaOH (50% w/w, 15 mL). The resulting mixture was
stirred vigorously for 5 h at room temperature. The organic solution
was extracted, diluted with ethyl acetate then washed twice with
an ammonium chloride aqueous saturated solution before being
References and notes
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