Synthesis of 4′-deoxy-4′-fluoro neamine and 4′-deoxy-4′-fluoro 4′-epi neamine

Article abstract of DOI:10.1039/c4md00072b

The syntheses of 4′-deoxy-4′-fluoro neamine and 4′-deoxy-4′-fluoro 4′-epi neamine from the readily available neamine and paromamine are described. Different approaches for the introduction of fluorine such as the use of DAST, sulfonic esters displacement,

Full text of DOI:10.1039/c4md00072b

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CONCISE ARTICLE
Synthesis of 40-deoxy-40-fluoro neamine and
40-deoxy-40-fluoro 40-epi neamine†
Cite this: Med. Chem. Commun., 2014,
5, 1166
*
Stephen Hanessian, Oscar M. Saavedra, Miguel A. Vilchis-Reyes and Ana M. Llaguno-
Rueda
The syntheses of 40-deoxy-40-fluoro neamine and 40-deoxy-40-fluoro 40-epi neamine from the readily
available neamine and paromamine are described. Different approaches for the introduction of fluorine
such as the use of DAST, sulfonic esters displacement, and epoxide ring opening by fluoride anion were
studied. Examples of anchimeric assistance and ring contraction in the aminoglycoside series are
highlighted.
Received 20th February 2014
Accepted 26th March 2014
DOI: 10.1039/c4md00072b
www.rsc.org/medchemcomm
Despite their potent bactericidal activity, the widespread use
of aminoglycosides is limited because of dose-dependent
nephrotoxicity and ototoxicity.6 For this reason, their use is
Introduction
Aminoglycosides containing the 2-deoxystreptamine unit are
important antibiotics agents. Since the discovery of the antibi-
otic streptomycin, several members of this class of pseudo
oligosaccharides have been used in clinical practice.1 Neomycin
which is used topically,2 and paromomycin widely used in India
as an injectable drug against leishmaniasis3 and against other
enteric parasites4 are among the oldest known (Fig. 1). The
common target site of aminoglycosides is found at the decoding
center of bacterial 16S ribosomal RNA with the 2-deoxystrept-
amine ring acting as the anchoring scaffold.5
limited to intra-hospital environments. The toxicity of amino-
glycosides has been linked to the number of amino groups
present in the molecule although the mechanism implied is
complex and not well understood.7 For example, the C-40
deoxygenation of neamine slightly lowered its toxicity when
compared to the parental compound, while the tetradeoxy
derivative generated a compound having twice the level of
toxicity.8 The replacement of the C-60 amine by a hydroxyl group
in butirosin A reduced the toxicity relative to the parent anti-
biotic.8 Likewise, the deoxygenation of kanamycin A in position
C-30 appreciably increases its toxicity.8 A derivative of neamine
bridged with a methylidene group between position C-30 and
C-40 (NB23) was less toxic than the parental compound.9 In
contrast, the deoxygenated derivative at C-30 and C-40 (gent-
amine C1A) was more toxic, and this effect was directly linked to
the basicity of the C-20 amino group.9
Deoxyuorination of aminoglycoside antibiotics is known to
lower toxicity relative to the parent compound, as shown for
uoro derivatives of sporaricin,10 kanamycin B,11 and 1-N-[(S)-4-
amino-2-hydroxybutanoyl] derivatives of kanamycin B.12 The
observed lower toxicity was correlated with a diminution in the
basicity of the amine group adjacent the uorine atom.12,13
Fluorination of a compound nearby an amino group is
well known to diminish the basicity of the amine.14 This
modication also improves metabolic stability, bioavail-
ability, and induces conformational and stereoelectronic
changes that could inuence the binding of the drug to the
receptor.14a,c
Fig. 1 Structure of the 2-deoxystreptamine (ring II) aminoglycosides
paromomycin (1) and neomycin (2). The aminoglycosides paromamine
(3) and neamine (4) comprise rings I and II of paromomycin and
neomycin respectively.
Herein we report the synthesis of 40-deoxy-40-uoro neamine
and 40-deoxy-40-uoro 40-epi neamine by SN2 displacement
reactions of sulfonate esters as well as epoxide opening reac-
tions, intended to be prototypical models for further applica-
tion to neomycin.15
´
´
Department of Chemistry, Universite de Montreal, P.O. Box 6128, Station Centre-Ville,
Montreal, Quebec H3C 3J7, Canada. E-mail: stephen.hanessian@umontreal.ca; Fax:
+1 (514) 343-5728; Tel: +1 (514) 343-6738
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4md00072b
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Results and discussion
Studies regarding the synthesis of 40-deoxy-40,40-diuoro nea-
mine using per-N-Boc protected neamine16 and previous work
done in our laboratory using per-N-Cbz aminoglycosides17
showed that 40-deoxyuorination is in general not satisfactory.
We therefore decided to use azides as masked amino groups.
We rst studied the deoxyuorination reaction on a model
compound that mimics ring I of neamine (4). The synthesis
started by treatment of 5 (ref. 18) with benzaldehyde dimethy-
lacetal in the presence of 10-camphorsulfonic acid (CSA)
followed by benzylation of the free hydroxyl group to afford 6 in
a 76% yield (Scheme 1). Cleavage of the benzylidene protecting
group under acidic conditions, followed by selective tosylation
of the resulting primary hydroxyl and displacement with
sodium azide afforded 7 in a 72% overall yield. Treatment of 7
with diethylaminosulfur triuoride (DAST) in CH2Cl2 gave a
complex mixture from which methyl 2,6-diazido-3-O-benzyl-
2,4,6-trideoxy-4-uoro-a-D-galactopyranoside 8 and methyl 2,6-
diazido-3-O-benzyl-2,4,6-trideoxy-4-uoro-a-D-glucopyranoside
9 were identied by the characteristic splitting patterns of their
uorine signals in 19F NMR in a 1.1 : 1 ratio respectively.
However, the reaction could not be optimized under a variety of
conditions and this approach was not pursued further. We then
resorted to classical SN2 displacement reactions of 4-sulfonate
esters with uoride anion.
Scheme 1 Reagents and conditions: (a) benzaldehyde dimethylacetal,
(CH2)2Cl2, CSA, reflux, 2 h, 99%; (b) NaH, BnBr, DMF, room tempera-
ture, overnight, 77% (c) AcOH : THF : H2O 4 : 1 : 1, 60 ꢀC, overnight,
98%; (d) TsCl, pyridine, room temperature, 18 h, 83%; (e) NaN3, DMF,
70 ꢀC, overnight, 89%; (f) DAST, CH2Cl2, room temperature, overnight;
(g) Tf2O, pyridine, 0 ꢀC, 30 min; (h) NaH, DMF, 0 ꢀC, 30 min then 1,10-
sulfonyldiimidazole, ꢁ40 ꢀC, 30 min, 90%; (i) TBAF, THF, 60 ꢀC, 2.5 h
from 10: 84%, from 11: 82%, from 13: 78%; (j) THF, MeOH, HCl, Pd/C,
H2 (1 atm), for 12: 77%, for 14: 70%; (k) TBAAc, THF, 60 ꢀC, 2 h, 76%; (l)
MeONa, MeOH, room temperature, quantitative.
Reaction of 4-triate 10 or the imidazylate ester 11 with tet-
rabutylammonium uoride (TBAF) afforded 8 as single product
in good yield (Scheme 1). The synthesis of the 4-epimeric
compound 13 required a double inversion at C-4 of 10 with
tetrabutylammonium acetate (TBAAc) followed by deprotection
of the resulting acetate with sodium methoxide. The resulting
methyl 2,6-diazido-3-O-benzyl-2,6-dideoxy-a-D-galactopyrano-
side 13, was converted to corresponding triate, and the latter
Scheme 2 Reagents and conditions: (a) benzaldehyde dimethylacetal, CSA, DCE, reflux, 2 h, 92%; (b) NaH, THF, 0 ꢀC, 1 h, then BnBr, TBAI, room
temperature, overnight, 96%; (c) AcOH : H2O : THF (4 : 1 : 1), 60 ꢀC, overnight, 77%; (d) TsCl, pyridine, CH2Cl2, room temperature, overnight,
91%; (e) NaN3, DMF, 50 ꢀC, overnight, 85%; (f) DAST, CH2Cl2, room temperature, overnight, for 18: 32%, for 19: 33%; (g) Tf2O, pyridine, CH2Cl2,
0 ꢀC 30 min then room temperature 1 h; (h) TBAAc, THF, 2 h, 60 ꢀC, 79%; (i) MeONa, MeOH, room temperature, overnight, 94%; (j) TBAF, THF,
30 min, 50 ꢀC, for 18: 82%, for 19: 66%; (k) PMe3, NaOH, THF, H2O, 50 ꢀC, 1 h, 96% from 18, 94% from 19; (l) Pd(OH)2/C, MeOH/1 N HCl, H2 (1 atm),
10 h, for 20: 91%, for 22: 90%.
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characterized by NMR. The formation of 19 with retention of
conguration can be explained by anchimeric assistance of the
benzyl group15f,20 prior to the introduction of the uorine atom
at C-40 (Scheme 3). In contrast to the results obtained with the
monosaccharide model 7, treatment of 17 with DAST afforded
18 and 19 in reasonable yields although scale-up proved to be
challenging. Once again we resorted to the displacement of
triic esters (Scheme 2). Thus, the C-40 triate from 17 was
reacted with TBAF to afford the deoxyuoro derivative 18 in
good yield. The azido groups were reduced using the Staudinger
reduction21 and the benzyl groups were removed by hydro-
genolysis to obtain 40-deoxy-40-uoro 40-epi neamine (20) in 38%
overall yield from 15. For the synthesis of the D-gluco-analogue
22 (Scheme 2), the stereocenter at C-40 in 17 was inverted via the
displacement of the triate with TBAAc. Further reaction of the
resulting 40-epi acetate with sodium methoxide in methanol
afforded 21 in 74% overall yield. The 40-epi alcohol 21 was
subjected to the same process as above affording 19 with an
overall yield of 66%. Finally, 40-deoxy-40-uoro neamine (22) was
obtained in 85% yield by reduction of the azide group under
Scheme 3 Plausible mechanism to obtain 19 from 17 using DAST.
was treated with TBAF in THF affording 9 in good yield. Finally,
catalytic hydrogenation of 8 and 9 afforded 12 and 14 respec-
tively in reasonable yields.
Encouraged by these results, we undertook the synthesis of
the 40-uorinated derivatives of neamine using two general
approaches. In the rst approach we used perazido parom-
amine 15 (Scheme 2) and in the second, perazido neamine as
starting materials (Schemes 4 and 5).
Table 1 Regioselective outcome as a function of solvent and basicity
for epoxide 27
We adapted the procedure developed for the synthesis of 7 to
the synthesis of 1,3,20,60-tetraazido-5,6,30-tri-O-benzyl neamine
17 (Scheme 2). Thus, perazido paromamine 15 (ref. 19) gave 16
in 88% overall yield. The synthesis of 17 was also straightfor-
ward and proceeded in a 60% overall yield from 16. Treatment
of 17 with DAST gave two isolable monouorinated compounds:
Entry
Reaction conditionsa
28
30
1
2
3
4
TBAF, DMF, 50 ꢀC, 3 days
12%
36%
51%
—
70%
36%
28%
90%
TBAF, THF, 50 ꢀC, 3 days
TBAF, toluene, 50 ꢀC, 3 days
DMF, NaH, 0 ꢀC to room temp, overnight
1,3,20,60-tetraazido-5,6,30-tri-O-benzyl-40-deoxy-40-uoro
40-epi
a
Under the same reaction conditions reported for entries 1, 2 and 3
compound 27 did not react when TBAF was changed by TBACl, TBABr
or TBAI.
neamine 18 and 1,3,20,60-tetraazido-5,6,30-tri-O-benzyl-40-deoxy-
40-uoro neamine 19 in a 1 : 1 ratio and 65% yield which were
Scheme 4 Reagents and conditions: (a) TIPSOTf, 2,4,6-collidine, CH2Cl2, 0 ꢀC, 15 min, then room temperature, overnight, 68%; (b) Ac2O,
pyridine, room temperature, overnight, for 25: 52%, for 29: 43%; (c) MsCl, 2,4,6-collidine, CH2Cl2, room temperature, overnight, 68%; (d) TBAF,
THF, room temperature, overnight, 76%. (e) TBAF, toluene, 50 ꢀC, 3 days, for 28: 51%, for 30: 28%; (f) HCl in MeOH, 0 ꢀC 30 min then room
temperature 1 h; (g) PMe3, NaOH, water, THF, room temperature, overnight then HCl, 68% from 28.
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Table 2 Observed NOE interactions, chemical shift assignment, and
coupling constants for contracted ring compound 33 and 34
d/ppm
J/Hz
J/Hz
Protond
33a
34b
33a
4.4
4.4
2.1
6.6
6.6
34b
33a,c
Scheme
5 Reagents and conditions: (a) DAST, CH2Cl2, room
H-10
H-20
H-30
H-40
H-5a0
H-5b0
H-60
5.65
2.75
5.19
4.41
3.56
3.65
5.70
7.00
—
J1 ,2
—
—
3.4
4.5
4.5
J1 ,F6
1.8
11.0
54.1
28.6
53.3
0
0
0
0
0
0
0
0
0
0
temperature, 2 days, for 31: 34%, for 33: 22%; (b) Ac2O, pyridine, 72%;
(c) AcOH : dioxane : H2O, reflux, 18 h; (d) PMe3 (exc), NaOH, H2O, THF,
room temperature, 2 h, 88% from 31; (e) PMe3 (1 equiv.), THF, ꢁ78 ꢀC
15 min to room temperature, then aqueous NaOH, room temperature,
2 h, 34%.
0
0
J2 ,3
J2 ,F6
0
0
6.51
5.34
3.41
3.65
9.81
J3 ,4
J6 ,F6
0
0
0
J4 ,5a
J2 ,F3
0
0
0
J4 ,5b
J3 ,F3
0
0
0
0
J5a ,5b
12.7
13.2
J4 ,F3
28.1
a
300 MHz, CDCl3. b 400 MHz, CDCl3; 4J1 ,4 ¼ 1.5 Hz (W coupling), 4J1 ,3
0
0
0
0
¼ 0.7 Hz (allylic coupling). c JH–F coupling constants measured in proton
Staudinger conditions,21 and cleavage of the benzyl groups by
catalytic hydrogenation in 22% yield from 15.
We also explored an alternative approach to 20 and 22
starting with the neamine derivative 23 (ref. 9) (Schemes 4
and 5).
d
spectra. For other protons see experimental procedures and Table S1
in ESI.
Removal of protecting groups in 31 afforded 40-deoxy-40-uoro
40-epi neamine (20) (30% overall from 23). This is amenable to
scale-up and the short number of steps compensates for the low
yield observed in the uorination step (Scheme 5).
The synthesis of epoxide 27 by selective protection of 23 (ref.
9) with tri-isopropylsilyltriate (TIPSOTf) afforded 24 in 68%
yield. The reaction proceeded with complete regiocontrol
affording the 30 silyl ether selectively. The assignment was
conrmed by NMR where a displacement to lower eld of C-40
proton chemical shi was observed in the acetate 25 as
compared with the shi observed for C-40 proton in the case of
24 (Table 3).
Treatment of 24 with methanesulfonyl chloride afforded 26.
As expected, the cleavage of the silyl moiety of 26 with TBAF was
followed by the internal displacement of the 30-O-mesyl group
affording 27 in moderate yield. Opening of the epoxide with
TBAF led to the intended 40-deoxy-40-uoro neamine derivative
28 (51% yield). However, the vinyl azide 30 was also formed as a
signicant by-product (28% yield). The ratio of 28 to 30 in the
epoxide ring opening reaction varied with the solvent (Table 1).
The best result for uorination was obtained in toluene.
Treatment of 27 with base gave vinyl azide 30 as a sole product
in excellent yield (Table 1 entry 4). Vinyl azides in the carbo-
hydrate series resulting from b-elimination are rare.22
Removal of the cyclohexylidene acetal in 28 under acidic
conditions, followed by reduction of the azide groups as
described above afforded 40-deoxy-40-uoro neamine 22 in 68%
yield (14% overall from 23) (Scheme 2).
Treatment of 23 with DAST for longer reaction times affor-
ded ring-contracted product 33 as the major product (Scheme
5). Ring contraction had proceeded with retention of congu-
ration at C-20 as evidenced by NMR analysis and by a NOE
interaction between C-20 proton and C-40 proton (Table 2). This
stereochemical outcome is analogous to others described for
similar systems,22a,23 and is most likely the result of a rare
example of anchimeric assistance by the azido group15c,22a,b,24
prior to rearrangement (Scheme 6). Treatment of 33 with one
equivalent of PMe3,21 followed by aqueous basic workup25
afforded the a,b-unsaturated aldehyde 34 as the only detectable
product.
Scheme
6 Anchimeric assistance by the azido group to afford
The synthesis of 40-deoxy-40-uoro 40-epi neamine starting
from neamine derivative 23 was accomplished as shown in
Scheme 5. Treatment of 23 (ref. 9) with DAST in CH2Cl2 at room
temperature for 2 days afforded the mono uoro derivative 31
(34%), and the ring contracted diuorinated compound 33
compound 33.
Conclusion
(22%) (Scheme 5). The deoxyuorination at C-40 on 23 with We developed synthetic routes that allow for the synthesis of 40-
DAST proceeded with inversion of conguration, as evidenced deoxy-40-uoro neamine 22 and 40-deoxy-40-uoro 40-epi nea-
by NMR analysis of the acetylated derivative 32 (Table 3). mine 20 from paromamine and neamine as starting materials.
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The uorinated compounds are being studied by NMR to
determine the variation of pKa due to replacement by uorine of
the 40-OH with retention or inversion of conguration. In the
course of these synthetic studies, we encountered interesting
by-products resulting from anchimeric assistance and ring
contraction. Vinyl azide 30 and the aldehyde 34 are versatile
functionalized derivatives of neamine that may nd utility in
further synthetic efforts. We are currently adapting the meth-
odology developed in this study to the synthesis of 40-deoxy-40-
uoro neomycin and its 40-epi variant.
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Table 3 Chemical shift assignments for selected compounds. Ring I
onlya,e
d/ppm, J/Hz
32b
25b
5.67
29b
5.56
22c
5.27
20d
5.38
5 (a) E. Jin, V. Katritch, W. K. Olson, M. Kharatisvili,
R. Abagyan and D. S. Pilch, J. Mol. Biol., 2000, 298, 95–110;
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H-10
H-20
H-30
H-40
H-50
H-6a0
H-6b0
5.65
3.75
5.33
4.91
4.33
3.39
3.63
3.5
11.3
2.5
—
3.30
4.19
4.85
4.04
3.35
3.66
3.7
9.8
8.8
10.1
3.18
5.60
4.46
4.34
3.51
3.64
3.6
10.9
8.9
9.8
2.84
3.85
4.23
3.97
2.82
2.99
3.5
10.5
8.7
9.8
3.10
3.85
4.84
4.09
2.91
2.95
3.9
11.0
2.5
—
R.
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Morgan-Warren,
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0
0
0
0
0
J1 ,2
6 (a) K. Tabuchi, B. Nishimura, M. Nakamagoe, K. Hayashi,
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335–345.
0
J2 ,3
0
J3 ,4
0
J4 ,5
0
0
J5 ,6a
7.7
5.5
12.8
—
3.0
6.9
13.5
—
4.7
2.4
13.5
2.8
6.8
3.2
13.8
3.5
5.2
7.9
13.5
—
0
0
J5 ,6b
0
0
J6a ,6b
0
J1 ,F
0
J2 ,F
—
—
1.0
nd
0.8
0
J3 ,F
26.6
50.8
29.2
—
—
—
—
—
13.8
50.0
4.7
14.7
51.1
3.2
30.0
51.1
30.9
—
0
J4 ,F
0
J5 ,F
0
J6a ,F
1.4
nd
0
J6b ,F
—
—
1.5
2.2
1.0
a
b
7 C. R. S. R. E. Craig, Modern pharmacology with clinical
applications, Lippincott Williams & Wilkins, Philadelphia,
2004.
JH–F coupling constants measured in proton spectra. 400 MHz,
c
d
e
CDCl3. 400 MHz, D2O, free base. 500 MHz, D2O, free base. For
other protons see experimental procedures and Table S1 in ESI.
8 K. Fujisawa, T. Hoshiya and H. Kawaguchi, J. Antibiot., 1974,
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Acknowledgements
We thank NSERC for nancial assistance. We thank CONACyT
for supporting the postdoctoral stay of M. A. Vilchis-Reyes and
for a fellowship for A. M. Llaguno-Rueda. We thank the spec-
´
´
troscopic and spectrometric staff of Universite de Montreal for
NMR and mass spectrometry services.
11 (a) Y. Kobayashi, T. Tsuchiya, T. Ohgi, N. Taneichi and
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