Synthesis and biological evaluation of modified 2-deoxystreptamine dimers

Article abstract of DOI:10.1055/s-0030-1260033

Aminoglycosides are powerful antibiotics, but the emergence of resistant bacterial strains has prompted the search for analogues with better pharmacological profiles. The synthesis of 2-deoxystreptamine (2-DOS) dimers linked by polyamines and analogues based on furylcarbopeptoid skeletons is described. Potent and selective ligands for bacterial 16S rRNA were identified using microarray techniques by determining the affinity of these derivatives toward bacterial and human ribosomal RNAs. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260033

PAPER
1759
Synthesis and Biological Evaluation of Modified 2-Deoxystreptamine Dimers
2
-DO
S
D
imers and
é
A
nalogue
r
s
ald Coste,a Tim Horlacher,b Lidia Molina,c Antonio J. Moreno-Vargas,*c Ana T. Carmona,c Inmaculada Robina,c
Peter H. Seeberger,b,d Sandrine Gerber-Lemaire*a
a
Laboratory of Glycochemistry and Asymmetric Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale
de Lausanne, Batochime, 1015 Lausanne, Switzerland
Fax +41(21)6939355; E-mail: Sandrine.Gerber@epfl.ch
Department for Biomolecular Systems, Max-Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany
b
c
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Profesor García González 1, 41012 Sevilla, Spain
Fax +34(954)624960; E-mail: ajmoreno@us.es
Institute for Chemistry and Biochemistry, Frei Universität Berlin, Arnimallee 22, 14195 Berlin, Germany
d
Received 3 November 2010; revised 1 April 2011
Dedicated to Prof. Pierre Vogel on the occasion of his 65th birthday
DOS dimers as well as polyamine and aminopolyketide
Abstract: Aminoglycosides are powerful antibiotics, but the emer-
linked analogues.9,10
gence of resistant bacterial strains has prompted the search for ana-
logues with better pharmacological profiles. The synthesis of 2-
deoxystreptamine (2-DOS) dimers linked by polyamines and ana-
logues based on furylcarbopeptoid skeletons is described. Potent
and selective ligands for bacterial 16S rRNA were identified using
microarray techniques by determining the affinity of these deriva-
tives toward bacterial and human ribosomal RNAs.
Enhancement of the RNA binding affinities for dimeric
aminoglycosides may result from an increased overall
positive charge and from the possibility to target multiple
binding sites within large RNA molecules. In particular,
long and conformationally flexible spacers should allow
the resulting conjugates to search for several binding sites
by screening variable conformations.2a,6a While linkers
containing ether, thioether, amide, aromatic and disulfide
moieties have already been used to dimerize aminoglyco-
sides,6b–d we intended to combine both flexibility and en-
hanced cationic density through polyamine spacers.
Based on the variety of accessible polyamines, the prepa-
ration of 2-DOS dimers was thus envisaged through the
conjugation with diamino linkers 4–6 and with more com-
plex aminopolyketides 7 and 8 (Scheme 1). These differ-
Key words: antibiotics, 2-deoxystreptamine dimers, microarray,
ribosomal RNA, solid-phase synthesis
Many human diseases are associated with RNA process-
ing malfunction. At least 15% of all genetic disorders in-
volve aberrant mRNA processing.1 Despite some early
scepticism, RNA, in particular ribosomal RNA, has be-
come a well-established drug target. Aminoglycosides, a
large family of clinically used antibiotics, were the first
compounds to be recognized as effectors of RNA func-
tion.2 Despite their wide use for the treatment of entero-
coccal, mycobacterial, and severe Gram-negative
bacterial infections, aminoglycosides show ototoxicity
and cause renal damage.3 These side effects and the emer-
gence of aminoglycoside resistant strains4 have prompted
the development of aminoglycoside analogues. Several
approaches were based on the chemical modification of
the natural antibiotics.5 The affinity and specificity of
aminoglycosides for their viral or bacterial RNA targets
have been significantly enhanced by the formation of
dimers6 or conjugation to other binding molecules such as
aromatic structures and peptides.7 In view of the complex
synthesis of aminosugars and aminocyclitols, an appeal-
ing strategy is based on the generation of simpler structur-
al analogues that are amenable to straightforward
medicinal chemistry exploration. The central core of all
aminoglycosides, 2-deoxystreptamine (2-DOS), is a good
starting point for aminoglycoside analogues.8 Here, we re-
port on the preparation and RNA affinity evaluation of 2-
H2N
a
b, c
HO
HO
neomycin B
N3
NH2
77%
66%
OH
N3
meso-1
O
O
O
f, g
see Table 1
d, e
49%
O
N3
N3
OH
rac-2
O
CO2H
rac-3
linker
NH
H2N
NH2
HN
O
O
NH2
H2N
HO
O
O
HO
OH
OH
9–13
(relative configuration not assigned)
Scheme 1 Synthesis of 2-deoxystreptamine dimers. Reagents and
conditions: (a) HBr, 120 °C; (b) TfN3, CuSO4 (cat.), MeOH–PhH–
Et3N, 25 °C; (c) 2,2-dimethoxypropane, CSA (cat.), MeCN, 25 °C;
(d) NaH, BrCH2CO2Me, MeCN, 25 °C; (e) LiOH, THF–MeOH–
H2O, 25 °C; (f) 4–8, PyBOP, Et3N, CH2Cl2, 25 °C; (g) Method A: i)
CF3CO2H–MeOH–H2O, 25 °C, ii) H2 1 atm, Pd(OH)2/C (cat.),
MeOH, 25 °C. Method B: i) H2 1 atm, Pd(OH)2/C (cat.), AcOH, ii)
CF3CO2H–MeOH–H2O, 25 °C.
SYNTHESIS 2011, No. 11, pp 1759–1770
x
x.
x
x
.
2
0
1
1
Advanced online publication: 06.05.2011
DOI: 10.1055/s-0030-1260033; Art ID: T21510SS
© Georg Thieme Verlag Stuttgart · New York

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G. Coste et al.
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Table 1 Synthesis of 2-DOS Dimers
Linker
Method
A
Dimer
Yield (%, 3 steps)
50
9
H2N
NH2
4
H2N
N
H
NH2
A
A
10
11
42
19
5
H
N
NH2
H2N
N
H
6
B
B
12
13
10
23
NH2 OP
O
O
O
O
OP
NH2
7 (P = BOM)
PO
OP
O
O
O
O
H2N
NH2
8 (P = BOM)
ent spacers will give some insights in the influence of the the 13C NMR spectra (see Supporting Information) and
linker length and polarity on RNA affinity.
thus appeared as single isomers. Starting from optically
active diamines 7 and 8, the reverse order of deprotection
as well as stronger hydrogenolysis conditions were re-
quired for the cleavage of anti acetonides and BOM (ben-
zyloxymethyl) ethers to deliver 2-DOS conjugates 12 and
13 in modest overall yield. While several stereoisomers
could be produced, HPLC purification allowed the isola-
tion of the major products from this reaction sequence.
Following established procedures, diazido alcohol rac-2
was obtained by acidic degradation of neomycin B11 fol-
lowed by copper-mediated azide transfer12 and protection
of the remaining diol as an acetonide. SN2 displacement of
methyl bromoacetate by the corresponding alkoxide and
saponification of the resulting methyl ester afforded car-
boxylic acid rac-3 in 49% yield. Conjugation with various
diamines 4–8 (Table 1) was followed by different de- To test whether the 2-DOS RNA recognition element can
protection sequences. Starting from amines 4–6, acid- be replaced by other binding motifs, such as aromatic
mediated cleavage of the acetonide moieties and final hy- moieties, conjugates between furyl residues and 1,3-hy-
drogenolysis of the azido groups afforded dimers 9–11. droxyamine fragments were designed. Compounds 14b
Starting from rac-3, the formation of a meso-conjugate and 15 were prepared from furyl amino acids 17 and 18
and a threo-conjugate (mixture of 2 enantiomers) was ex- following the retrosynthetic analysis outlined in
pected. After purification by column chromatography, the Scheme 2. Compound 15 can be considered as an amino-
isolated dimers 9–11 displayed only one set of signals in polyketide with furyl moieties as spacers containing the
NH OH OH OH OH OH OH HN
NH2 OH OH OH OH OH OH
NH2
O
O
(+)-16
+
O
O
NHBoc
OH
RHN
NHR
OH
BocHN
COOBt
OH
HO
14a, R = Boc
14b, R = H
HO
O
OH
17
NHR
RHN
NH2
OH
NH2
OH
NHBoc
O
O
O
OH
H
N
OMe
FmocHN
COOBt
N
H
O
O
OH
O
NH2
OH
N
OH
18
N
Bt =
2
N
15
Scheme 2 Retrosynthetic analysis to furylcarbopeptoids
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2-DOS Dimers and Analogues
1761
structural motifs needed for potential interaction with lective tosylation followed by displacement with TMSN3/
RNA. The aromatic moieties could increase the binding TBAF gave 26. Saponification of 26 (LiOH/EtOH), fol-
affinity, as reported.7
lowed by reduction of the azido group and protection of
the resulting amino function with Fmoc, afforded the cor-
responding orthogonally protected diamino acid deriva-
tive, which was isolated as the benzotriazol-1-yl activated
ester 18 in 60% overall yield (Scheme 4). Both activated
esters 17 and 18 were purified by column chromatogra-
phy.
Synthesis of building blocks 17 and 18 started from readi-
ly available 19a and 19b (Scheme 3). Intermediate 19a
was obtained from D-glucose and benzyl acetoacetate fol-
lowing a high-yielding modified procedure of the García-
González reaction.13 The introduction of the azido moiety
at the benzylic position was carried out utilizing the pro-
cedure for the stereoselective synthesis of a-furfuryl-
amines.14 Regioselective tritylation of 19a (80% yield)
followed by reaction with thionyl chloride and triethyl-
amine afforded a mixture of cyclic sulfites, which were
not isolated. Subsequent SN2 displacement with trimeth-
ylsilyl azide, in the presence of TBAF, gave azide 21a in
70% yield from 19a. Removal of the p-methoxytrityl
group in 21a was successfully performed under mild
acidic conditions using triisopropylsilane as scavenger
(Scheme 3). As previously described,15 compound 22b
was obtained similarly but using ethyl acetoacetate as
starting material. Regioselective tosylation of benzyl ester
22a followed by nucleophilic displacement using tetrabu-
tylammonium azide afforded diazido derivative 23 in
58% overall yield (Scheme 4). Hydrogenation of 23 under
atmospheric pressure in methanol containing (Boc)2O fur-
nished the corresponding protected diamino acid deriva-
tive, which was isolated as the stable benzotriazol-1-yl
activated ester 17 by reaction with PyBOP and DIPEA in
50% overall yield. Hydrogenation of 22b in methanol
containing (Boc)2O afforded 24 in good yield. Regiose-
N3
OH
HO
a
COOR
O
OH
(for R = Bn)
(for R = Et)
c
22a, R = Bn
22b, R = Et
N3
OH
OH
NHBoc
N3
RO
COOBn
COOEt
O
OH
O
OH
23 (58%)
24, R = H (80%)
25, R = Ts (75%)
d
b
e
OH
NHBoc
BocHN
COOBt
NHBoc
OH
O
N3
OH
COOEt
17 (50%)
O
OH
26 (74%)
f
OH
OH
D-glucose
+
OH
NHBoc
R2O
c
a
COOR1
FmocHN
COOBt
O
O
O
OH
O
OH
OR1
R1 = Bn, Et
19a, R1 = Bn, R2 = H (78%)
19b, R1 = Et, R2 = H (76%)
18 (60%)
b
Scheme 4 Reagents and conditions: (a) (i) TsCl, Py, –15 to 0 °C,
(ii) Bu4NN3, THF, 50 °C, 2 h; (b) (i) H2 1 atm, Pd/C, (Boc)2O, MeOH,
(ii) PyBOP, DIPEA, DMF; (c) H2, 1 atm, Pd/C, (Boc)2O, MeOH; (d)
TsCl, Py, –15 to 0 °C; (e) TMSN3, TBAF, THF, 60 °C; (f) (i) LiOH,
EtOH, 50 °C, (ii) H2, 1 atm, Pd/C, EtOH, (iii) Fmoc-OSu, aq
NaHCO3, 1,4-dioxane, (iv) PyBOP, DIPEA, DMF, 60%.
20a, R1 = Bn, R2 = MeOTr (80%)
20b, R1 = Et, R2 = MeOTr (81%)
O
S
O
S
O
O
O
O
COOR1
+
MeOTrO
COOR1
Furyl carbopeptoids containing 1,3-hydroxyamine motifs
were prepared from building blocks 17 and 18 that are
protected furyldiamino acids activated for amido coupling
as stable benzotriazol-1-yl (Bt) esters. Acetonide hydrol-
ysis and hydrogenation of (+)-7 afforded aminopolyol
(+)-16, which was immediately coupled with 17 upon
treatment with DIPEA and DMF in 62% yield
(Scheme 5). Furyl carbopeptoid 14b was obtained after
removal of the Boc groups in quantitative yield.
O
O
OH
OH
OTrOMe
N3
OH
R2O
d
COOR1
O
OH
21a, R1 = Bn, R2 = MeOTr (70%)
21b, R1 = Et, R2 = MeOTr (76%)
e
On the other hand, orthogonally N-protected 18 was oli-
gomerized using solid-phase peptide synthesis methodol-
ogy (Fmoc strategy/HMBA-AM resin) (Scheme 6).
Fmoc-glycine was first attached to the hydroxyl resin to
facilitate the final cleavage of the furylcarbopeptoid from
the resin.16 Iterative couplings with excess 18 in the pres-
22a, R1 = Bn, R2 = H (80%)
22b, R1 = Et, R2 = H (80%)
Scheme 3 Reagents and conditions: (a) NaI, CeCl3, SiO2, 50 °C, 9
days; (b) MeOTrCl, Py; (c) SOCl2, CH2Cl2, 0 °C; (d) TMSN3, TBAF,
THF, r.t., 24 h; (e) 2% TFA–CH2Cl2, triisopropylsilane.
Synthesis 2011, No. 11, 1759–1770 © Thieme Stuttgart · New York

1762
G. Coste et al.
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NH2 OH OH OH OH OH OH NH2
(+)-16
+
OH NHBoc
BocHN
COOBt
O
OH
17
a
14a (62%)
14b (quant.)
b
Scheme 5 Reagents and conditions: (a) DIPEA, DMF; (b) 20%
TFA–CH2Cl2.
Figure 1 Structure of the 3¢-fluorescence-labeled rRNA mimics
(bacterial 16S rRNA analogue fluorescence label = tetramethylrhod-
amine, human 18S rRNA analogue fluorescence label = fluorescein)
ence of DIPEA in DMF, afforded the polymer-bound
compound, which was removed from the solid support by
treatment with MeOH–Et3N (2:1) overnight using DMF
as cosolvent. Due to the stability of the activated ester de-
rivative 18, excess of this compound was recovered from
the resin by washing with DMF and recycled to optimize
the overall yield. Final Boc deprotection with TFA
(20%)–CH2Cl2 gave furylcarbopeptoid 15 in 87% overall
yield.
printed onto amine-reactive microarray slides and incu-
bated with fluorescence-labeled RNA mimics (Figure 1).
Bacterial and human rRNA mimics bound well and in a
concentration dependent manner to several compounds on
the microarray, including neomycin, kanamycin, spermi-
dine, 9, 11, and (+)-16 (Figure 2 and Supporting Informa-
tion). Binding of some structures was even higher than to
the immobilized aminoglycosides. For instance, the bind-
ing level of the 16S rRNA mimic was higher for com-
pounds 9, 11, and (+)-16 than for streptomycin or
paranomycin. These long and flexible structures, as well
as spermidine, were recognized particularly well. Appar-
ently, the flexibility allows for improved interactions with
the rRNA mimics. However, no distinct structural feature
that is essential for rRNA binding could be determined.
Furthermore, no structure displayed any pronounced pref-
erence for binding bacterial versus human rRNA.
Fmoc
N
H
COOH
HO
HMBA-AM resin
O
a
H2N
O
NHBoc
OH
FmocHN
COOBt
b
O
OH
18
OH
NHBoc
O
O
H2N
O
N
N
N
H
Bt = N
The antibiotic properties of the compounds were analyzed
using a disc diffusion assay (data not shown). Aminogly-
cosides, 2-DOS dimers, analogues, or controls were added
to sterile filter plates that were placed on top agar plates
containing E. coli bacteria. Plates were incubated over-
night and checked for a zone of inhibition around the filter
plates. Standard aminoglycosides (neomycin, paranomy-
cin, streptomycin, and kanamycin A) inhibited bacterial
growth, while none of the 2-DOS dimers or their ana-
logues acted as inhibitors.
OH
O
2 x [18, b]
NHBoc
O
OH
OH
O
O
H
N
O
H2N
N
H
O
OH
O
NHBoc
OH
2
c
Several 2-DOS dimers and analogues interacted well with
rRNA in vitro, demonstrating their utility as scaffolds for
aminoglycoside analogues. However, the factors that are
responsible for binding specificity and in vivo antibiotic
activity remain elusive.
15 (87%, overall)
Scheme 6 Reagents and conditions: (a) (i) 2,6-dichlorobenzoyl
chloride, Py–DMF; (ii) 20% piperidine–CH2Cl2; (b) (i) DIPEA,
DMF, (ii) 20% piperidine–CH2Cl2; (c) (i) DMF, MeOH–Et3N (2:1),
(ii) 20% TFA–CH2Cl2.
In summary, we have synthesized 2-deoxystreptamine
dimers linked by naturally occurring polyamines or ami-
nofunctionalized polyketides.9 Some analogues contain-
ing substituted furyl moieties have been prepared from
furyl amino acid building blocks. Evaluation of the bind-
Binding of rRNA mimics to the 2-DOS dimers, ana-
logues, and aminoglycosides was analyzed using microar-
rays. The aminoglycosides, analogues, and controls were
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PAPER
2-DOS Dimers and Analogues
1763
formed by flash chromatography on silica gel (Merck No. 9385 sil-
ica gel 60, 240–400 mesh). 1H NMR spectra : Bruker spectrometers
at 300, 400, and 500 MHz. Chemical shifts in ppm relative to the
solvent’s residual 1H signal (MeOD: 3.34 ppm, CDCl3: 7.27 ppm,
1
C6D6: 7.30 ppm) as internal reference. H assignments were con-
firmed by 2D-COSY-45 spectra. Coupling constants J in Hz. 13C
NMR spectra: Same spectrometers as for 1H NMR spectra at 75.4,
100, and 125.7 MHz. Reference for solvent used as internal refer-
ence in ppm (MeOD: 49 ppm, CDCl3: 77 ppm, C6D6: 128.5 ppm).
Coupling constants J in Hz. IR spectra: Perkin-Elmer Paragon 1000
FT-IR spectrometer. Mass spectra: GC-MS spectrometer [Nermag
R-10-10C, chemical ionization (NH3) mode m/z]; MALDI-TOF
spectrometer (Axima-CFR+, Kratos, Manchester); ESI-Q spec-
trometer (Finnigan SSQ 710C, Thermoquest, UK); ESI-QT spec-
trometer (Ultima spectrometer, Micromass, Manchester); FAB
mass spectra were obtained using glycerol or 3-nitrobenzyl alcohol
as the matrix. Optical rotations were measured in a 1.0 cm or 1.0 dm
tube with a Perkin-Elmer 241MC spectropolarimeter.
Microarray Printing: Microarrays were fabricated according to
published methods.17 In brief, DOS dimers, analogues, aminoglyco-
sides and controls were dissolved in buffer (50 mM sodium phos-
phate, pH 8.5) and printed onto amine-reactive slides (CodeLink) in
concentrations ranging from 10 mM to 10 mM using an automated
arraying robot (Genetix). Spotted slides were incubated for 24 h in
a humidity chamber to complete the immobilization reaction and
stored under a dry atmosphere until usage.
Binding Experiments: Fluorescence-labeled human and bacterial
rRNA mimics were obtained from Biomers and were refolded by
incubation for 5 min at 60 °C in 20 mM Hepes, pH 7.4 and 200 mM
NaCl and slow cooling to r.t. Refolded rRNA mimics were incubat-
ed on the microarrays (500 pmol/slide with 40U RNAse inhibitor
(Invitrogen) in 20 mM Hepes pH 7.4 with 200 mM NaCl) for 1 h at
r.t. Slides were washed with buffer, centrifuged to dryness, and
scanned using a fluorescence microarray reader (Tecan). Spot inten-
sities were evaluated using the GeneSpotter software (MicroDis-
covery).
Figure 2 Binding of the bacterial 16S rRNA mimic or the human
18S rRNA mimic to aminoglycosides, 2-DOS dimers, and analogues.
Aminoglycosides, 2-DOS dimers, and analogues were printed onto
microarrays, incubated with rRNA analogues and evaluated as de-
scribed in the experimental section. Error bars show standard error.
Disc Diffusion Test: LB top agar plates containing E. coli [strain
BL21(DE3), Stratagene] bacteria were prepared. Sterile filter plates
were placed onto the agar and 10 mL of the test solution (aminogly-
cosides, analogues or controls, each 5 mM in H2O) was added to the
filters. Plates were incubated overnight at 37 °C and inhibition of
bacterial growth was assessed.
ing of rRNA mimics to these derivatives revealed high af-
finity of the flexible polyketide (+)-16. In addition, the
affinity of 2-deoxystreptamine dimers appeared to be de-
pendent on the length of the amino containing linker.
Spermine-derived dimer 11 bound well to rRNA mimics
but not selectively to bacterial rRNA. While furyl moi-
eties were expected to provide stacking interactions with
rRNA mimics, none of the furyl carbopeptoids displayed
high affinity toward rRNA fragments. These results high-
light that amino-functionalized derivatives may be used as
interesting scaffolds for the preparation of new aminogly-
coside mimics, but need to be further derivatized to im-
prove binding selectivity.
Coupling of Acid rac-3 with Diamines; General Procedure
To a solution of acid rac-3 (0.20 to 0.50 mmol, 2 equiv) in CH2Cl2
(0.15 to 0.1 M) were added Et3N (0.60 to 1.50 mmol, 6 equiv) and
PyBOP (0.22 to 0.55 mmol, 2.2 equiv) at 25 °C. Diamine (0.10 to
0.25 mmol, 1 equiv) was added to this mixture and the white sus-
pension was stirred for 2 h. The reaction mixture was concentrated
in vacuo. Purification of the residue by flash chromatography (4–10%
of MeOH in CH2Cl2) afforded diamides as colorless oils.
Deprotection of Dimers; General Procedures
Method A: Diamides obtained as above were dissolved in MeOH–
TFA–H2O (0.5:1:0.5, 2 to 4 mL) and stirred at 25 °C for 3 h. The
reaction mixture was concentrated in vacuo. Purification of the res-
idue by flash chromatography (2–10% of aq NH4OH in MeCN) af-
forded the corresponding azides as colorless oils. The intermediate
azides were dissolved in MeOH (2 to 4 mL) with a catalytic amount
of Pd(OH)2 on activated charcoal and stirred at 25 °C under 1 atm
of H2 for 3 h. The reaction mixtures were filtered through a pad of
Celite, the filtrates were concentrated in vacuo. Purification of the
residues by flash chromatography (40–60% of aq NH4OH in
MeCN) afforded products as white foams.
All commercially available reagents and solvents (Fluka, Aldrich,
Acros) were used without further purification. For reactions requir-
ing anhydrous conditions, anhydrous solvents were bought (Fluka)
or dried by filtration (Innovation Technology). Petroleum ether
(PE) used refers to the fraction boiling in the range 40–60 °C. Ex-
periments were carried out under argon atmosphere unless noted
otherwise. Reactions were monitored by TLC (Merck silica gel
60F254 plates). Detection by UV light, KMnO4, or Pancaldi reagent
[(NH4)6MoO4, Ce(SO4)2, H2SO4, H2O]. Purifications were per-
Method B: Diamides obtained as above were dissolved in AcOH (2
to 4 mL) and stirred with a catalytic amount of Pd(OH)2 on activated
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1764
G. Coste et al.
PAPER
charcoal at 25 °C under 1 atm of H2 for 5 h. The reaction mixtures
were filtered though a pad of Celite and the filtrates were concen-
trated in vacuo. The residues were dissolved in MeOH–TFA–H2O
(0.5:1:0.5, 2 to 4 mL) and stirred at 25 °C for 5 h. The reaction mix-
tures were concentrated in vacuo. Purification of the residues by
semi-preparative HPLC (0–100% of MeCN in H2O–TFA in 30 min
at 18 mL/min) afforded 2-DOS dimers as white foams.
mg, 64% yield based on recovered starting material). To a solution
of methyl ester (445 mg, 1.364 mmol) in THF (35 mL), MeOH (5
mL), and H2O (5 mL), a 1 M LiOH solution (20 mL, 20 mmol, 15
equiv) was added. The mixture was stirred at 25 °C for 15 h. THF
was removed in vacuo and the aqueous solution was saturated with
NaCl, the pH of the solution was adjusted to 4–5 with aq 2 M HCl
and extracted with EtOAc (4 × 50 mL). The combined organic lay-
ers were dried (MgSO4) and concentrated in vacuo. Purification of
the residue by flash chromatography (20% of MeOH in CH2Cl2) af-
forded rac-3 as a white foam; yield: 325 mg (76%).
(3aRS,4SR,5RS,7SR,7aRS)-5,7-Diazido-2,2-dimethylhexahy-
dro-1,3-benzodioxolo-4-ol (rac-2)
A solution of neomycin trisulfate (10.0 g, 11 mmol) in aq 48% HBr
(60 mL) was heated under reflux for 17 h. HBr was evaporated in
vacuo and the remaining black oil was dissolved in H2O (60 mL)
with activated charcoal. After mixing for 1 h, the black solution was
filtered though a pad of Celite and the filter was washed with H2O
(180 mL). The brown aqueous solution was concentrated in vacuo.
MeOH (60 mL) was added to the brown oil, which solidified upon
mixing. The white suspension was filtered and dried 12 h before be-
ing loaded on an anion resin exchanger column. Fractions with a ba-
sic pH were collected and lyophilized to obtain aminocyclitol meso-
1 as a white powder (1.37 g, 77%). To a solution of meso-1 (1.05 g,
6.474 mmol) in MeOH (64 mL) and Et3N (6.55 g, 9 ml, 65 mmol,
10 equiv) was added CuSO4 (52 mg, 0.324 mmol, 0.05 equiv). A 0.4
M solution of TfN3 in CH2Cl2 was added dropwise at 0 °C, the green
mixture was stirred for 24 h, and concentrated in vacuo. The green
oil was purified by flash chromatography (20% of pentane in
EtOAc then 20% of MeOH in EtOAc) affording diazide intermedi-
ate as a white solid (1.25 g, 90%). A solution of the intermediate
(1.25 g, 5.836 mmol) in MeCN (30 mL) and 2,2-dimethoxypropane
(30 mL) was treated with CSA (135 mg, 0.584 mmol, 0.1 equiv) at
25 °C for 5 h. The reaction mixture was poured into sat. aq NaHCO3
(50 mL) and extracted with EtOAc (3 × 50 mL). The combined or-
ganic layers were washed with brine (70 mL), dried (MgSO4), and
concentrated in vacuo. Purification of the residue by flash chroma-
tography (30% of EtOAc in pentane) afforded alcohol rac-2 as a
white solid (1.09 g, 73%). Preparation of the 0.4 M solution of TfN3
in CH2Cl2–Tf2O (5.19 g, 3.05 mL, 18.5 mmol, 0.2 equiv) was added
to a solution of NaN3 (6.01 g, 92.5 mmol) in CH2Cl2 (25 mL) and
H2O (15 mL). The mixture was stirred at 0 °C for 5 h. The aqueous
phase was extracted with CH2Cl2 (2 × 8 mL). The combined organic
layers were washed with sat. aq Na2CO3 (15 mL).
IR (film): 3215, 2920, 2500, 2355, 2100, 1730, 1595, 1450, 1060,
840, 785 cm–1.
1H NMR (400 MHz, MeOD): d = 4.31 (s, 2 H, H-2¢), 3.73 (ddd,
J = 4.7, 10.0, 11.7 Hz, 1 H, H-7), 3.68 (t, J = 8.4 Hz, 1 H, H-4), 3.64
(ddd, J = 4.7, 8.4, 9.2 Hz, 1 H, H-5), 3.55 (dd, J = 8.4, 9.2 Hz, 1 H,
H-3a), 3.44 (dd, J = 9.2, 10.0 Hz, 1 H, H-7a), 2.2 (dt, J = 4.7, 13.4
Hz, 1 H, H-6), 1.44, 1.43 (2 s, 6 H, CH3-2), 1.34 (dt, J = 11.7, 13.4
Hz, 1 H, H-6).
13C NMR (100 MHz, MeOD): d = 174.4 (s, C-1¢), 112.4 (s, C-2),
1
1
81.6 (d, JC,H = 155 Hz, C-4), 80.0, 79.9 (d, C3a,7a, JC,H = 147 Hz,
C-3a, C-7a), 68.1 (t, 1JC,H = 145 Hz, C-2¢), 60.9 (d, 1JC,H = 143 Hz,
C-5), 57.6 (d, JC,H = 145 Hz, C-7), 33.8 (t, JC,H = 134 Hz, C-6),
26.1, 25.9 (2 q, 1JC,H = 126 Hz, CH3-2).
1
1
MALDI-TOF-HRMS: m/z [M + Na]+ calcd for C11H16N6O5 + Na:
335.1080; found: 335.1080.
Anal. Calcd for C9H14N6O3 (312.28): C, 42.31; H, 5.16; N, 26.91.
Found: C, 42.50; H, 5.09; N, 26.75.
N,N¢-Pentane-1,5-diylbis(2-{[(1SR,2SR,3RS,4SR,6RS)-4,6-di-
amino-2,3-dihydroxycyclohexyl]oxy}acetamide) (9)
Name corresponding to the ( )-threo isomer. Starting from 1,5-di-
aminopentane (19 mL, 0.16 mmol), and following Method A, 9 (32
mg, 50% over 2 steps) was obtained as a white foam. The major
product isolated by flash chromatography appeared as a single ste-
reoisomer, which displayed a single set of signals in the 13C NMR
spectrum (see Supporting Information). No other isomer could be
isolated in sufficient amount for characterization.
IR (film): 3380, 2940, 2505, 2105, 1655, 1550, 1450, 1375, 1260,
1235, 1110, 840 cm–1.
IR (film): 3410, 2100, 1450, 1370, 1240, 1190, 1140, 1060, 960,
830, 780 cm–1.
1H NMR (400 MHz, MeOD): d = 3.80–3.65 (m, 1 H, H-7), 3.63 (dd,
J = 6.9, 6.8 Hz, 1 H, H-4), 3.46–3.40 (m, 5-H, H-3a, H-7a), 2.2 (dt,
J = 4.8, 13.4 Hz, 1 H, H-6), 1.45 (s, 6 H, 2-CH3), 1.34 (dt, J = 12.2,
13.4 Hz, 1 H, H-6).
1H NMR (400 MHz, D2O): d = 4.24, 4.14 (2 d AB, J = 15.3 Hz, 4
H, H-2¢), 3.59, 3.41 (2 t, J2,3 = 9.3 Hz, 4 H, H-2, H-3), 3.33 (t,
J = 9.3 Hz, 2 H, H-1), 3.26, 3.11 (td, J = 3.5, 9.3 Hz, 4 H, H-4, H-
6), 3.03 (t, J = 6.8 Hz, 4 H, H-1¢¢, H-5¢¢), 2.26 (dt, J = 3.5, 12.4 Hz,
2 H, H-5), 1.63 (d, J = 12.4 Hz, 2 H, H-5), 1.4–1.3 (m, 4 H, H-2¢¢,
H-4¢¢), 1.2–1.1 (m, 4 H, H-3¢¢).
13C NMR (100 MHz, D2O): d = 174.4 (s, C-1¢), 83.8 (d, 1JC,H = 148
13C NMR (100 MHz, MeOD): d = 113.1 (2 s, C-2), 81.1, 80.9 (2 d,
C-3a, C-7a), 75.2 (d, C-4), 64.3 (d, C-5), 58.9 (d, C-7), 34.8 (t, C-
6), 27.1, 26.9 (2 q, CH3-2).
1
Hz, C-1), 77.5, 74.8 (2 d, JC,H = 146, 141 Hz, C-2, C-3), 73.1 (t,
1
1JC,H = 146 Hz, C-2¢), 52.3 (d, JC,H = 143 Hz, C-4), 51.5 (d,
1
1JC,H = 147 Hz, C-6), 41.5 (t, JC,H = 139 Hz, C-1¢¢, C-5¢¢), 30.6 (t,
CI-MS: m/z = 255 [M + H]+.
1
1JC,H = 127 Hz, C-5), 30.5 (t, JC,H = 125 Hz, C-2¢¢, C-4¢¢), 25.9 (t,
1JC,H = 128 Hz, C-3¢¢).
Anal. Calcd for C9H14N6O3 (254.25): C, 42.52; H, 5.55; N, 33.05.
Found: C, 42.58; H, 5.52; N, 33.01.
ESI-HRMS: m/z [M + H]+ calcd for C21H42N6O8: 507.3142; found:
507.3145.
{[(3aRS,4SR,5RS,7SR,7aRS)-5,7-Diazido-2,2-dimethylhexahy-
dro-1,3-benzodioxolo-4-yl]oxy}acetic Acid (rac-3)
N,N¢-Pentane-1,5-diylbis(2-{[(3aRS,4SR,5RS,7SR,7aRS)-5,7-di-
azido-2,2-dimethylhexahydro-1,3-benzodioxolo-4-yl]oxy}acet-
amide)
Data for the intermediate, name corresponding to the ( )-threo iso-
mer.
To a solution of alcohol rac-2 (1.09 g, 4.267 mmol) in MeCN (20
mL) were added NaH (60% in mineral oil, 340 mg, 8.535 mmol, 2
equiv) and methyl bromoacetate (976 mg, 606 mL, 6.4 mmol, 1.5
equiv). The mixture was stirred at 25 °C for 2 h. The reaction mix-
ture was poured into sat. aq NH4Cl (50 mL) and extracted with
EtOAc (3 × 50 mL). The combined organic layers were washed with
brine (70 mL), dried (MgSO4), and concentrated in vacuo. Purifica-
tion of the residue by flash chromatography (20% of EtOAc in pen-
tane) afforded an intermediate methyl ester as a colorless oil (445
IR (film): 3380, 2940, 2505, 2105, 1655, 1550, 1450, 1375, 1260,
1235, 1110, 840 cm–1.
1H NMR (400 MHz, MeOD): d = 4.27, 4.18 (2 d AB, J = 15.6 Hz,
4 H, H-2¢), 3.79 (ddd, J = 4.7, 10.0, 11.4 Hz, 2 H, H-7), 3.73–3.66
Synthesis 2011, No. 11, 1759–1770 © Thieme Stuttgart · New York

PAPER
2-DOS Dimers and Analogues
1765
(m, 2 H, H-5), 3.60 (t, J = 8.6 Hz, 2 H, H-4), 3.58 (dd, J = 4.7, 8.6
Hz, 2 H, H-3a), 3.52 (dd, J = 4.7, 10.0 Hz, 2 H, H-7a), 3.40–3.35
(m, 4 H, H-1¢¢, H-5¢¢), 2.26 (dt, J = 4.7, 13.3 Hz, 2 H, H-6), 1.62–
1.52 (m, 4 H, H-2¢¢, H-4¢¢), 1.46, 1.45 (2 s, 12 H, CH3-2), 1.45–1.13
(m, 4 H, H-6, H-3¢¢).
N,N¢-[Butane-1,4-diylbis(iminopropane-3,1-diyl)]bis(2-
{[(1SR,2SR,3RS,4SR,6RS)-4,6-diamino-2,3-dihydroxycyclohex-
yl]oxy}acetamide) (11)
Name corresponding to the ( )-threo isomer. Starting from sper-
mine (46 mg, 0.229 mmol), and following Method A, 11 (40 mg,
19% over 3 steps) was obtained as a white foam. The major product
isolated by flash chromatography appeared as a single stereoisomer,
which displayed a single set of signals in the 13C NMR spectrum
(see Supporting Information). No other isomer could be isolated in
sufficient amount for characterization.
13C NMR (100 MHz, MeOD): d = 171.1 (s, C-1¢), 112.6 (s, C-2),
82.3 (d, 1JC,H = 155 Hz, C-4), 79.9, 79.5 (2 d, 1JC,H = 147, 148 Hz,
C-3a, C-7a), 70.0 (t, 1JC,H = 145 Hz, C-2¢), 61.4 (d, 1JC,H = 147 Hz,
C-5), 57.6 (d, 1JC,H = 144 Hz, C-7), 38.9, 38.8 (2 t, 1JC,H = 137 Hz,
1
C-1¢¢, C-5¢¢), 33.6 (t, 1JC,H = 134 Hz, C-6), 29.1 (t, JC,H = 121 Hz,
1
C-2¢¢, C-4¢¢), 26.1, 26.0 (2 q, JC,H = 126 Hz, CH3-2), 24.2 (t,
IR (KBr): 2965, 2790, 1650, 1590, 1455, 1005, 1290, 1195, 1145,
1100, 1060, 1005, 900 cm–1.
1JC,H = 125 Hz, C-3¢¢).
ESI-HRMS: m/z [M + H]+ calcd for C27H42N14O8: 691.3388; found:
691.3384.
1H NMR (400 MHz, D2O): d = 4.29, 4.20 (2 d AB, J = 15.4 Hz, 4
H, H-2¢), 3.5–3.25 (m, 8 H, H-1, H-2, H-4, H-5), 3.23–3.1 (m, 6 H,
H-3, H-1¢¢), 2.91 (br s, 8 H, H-3¢¢, H-1¢¢¢), 2.37–2.25 (m, 2 H, H-6),
1.83–1.72 (m, 4 H, H-2¢¢), 1.68 (dd, J = 12.4, 12.4 Hz, 2 H, H-5),
1.51 (br s, 4 H, H-2¢¢¢).
N,N¢-(Iminodipropane-3,1-diyl)bis(2-{[(1SR,2SR,3RS,4SR,6RS)-
4,6-diamino-2,3-dihydroxycyclohexyl]oxy}acetamide) (10)
Name corresponding to the ( )-threo isomer. Starting from 3,3¢-di-
aminopropylamine (27 mL, 0.192 mmol), and following Method A,
10 (32 mg, 42% over 3 steps) was obtained as a white foam. The
major product isolated by flash chromatography appeared as a sin-
gle stereoisomer, which displayed a single set of signals observed in
the 13C NMR spectrum (see Supporting Information). No other iso-
mer could be isolated in sufficient amount for characterization.
13C NMR (100 MHz, D2O): d = 172.5 (s, C-1¢), 82.6, 75.4, 72.7 (3
d, 1JC,H = 147, 146, 147 Hz, C-1, C-2, C-3), 71.0 (t, 1JC,H = 147 Hz,
C-2¢), 50.2, 49.3 (2 d, 1JC,H = 143, 147 Hz, C-4, C-6), 47.3, 45.5 (2
t, 1JC,H = 148 Hz, C-3¢¢, C-2¢¢¢), 28.4 (t, 1JC,H = 132 Hz, C-5), 26.2 (t,
1
1JC,H = 140 Hz, C-1¢¢), 25.9 (t, JC,H = 131 Hz, C-2¢¢), 23.2 (t,
1JC,H = 132 Hz, C-2¢¢¢).
ESI-HRMS: m/z [M + H]+ calcd for C26H54N8O8: 607.4143; found:
607.4147.
IR (film): 3320, 3095, 2940, 2105, 1670 1440, 1370, 1260, 1135,
1065, 840, 800 cm–1.
1H NMR (400 MHz, D2O): d = 4.30 (2 d AB, J = 15.4 Hz, 4 H, H-
2¢), 3.45–3.25 (m, 6 H, H-1, H-2, H-3), 3.26 (td, J = 3.8, 8.1 Hz, 2
H, H-4), 3.14 (t, J = 7.0 Hz, 4 H, H-3¢¢), 3.11 (td, J = 8.1, 3.8 Hz, 2
H, H-6), 2.87 (t, J = 7.0 Hz, 4 H, H-1¢¢), 2.26 (dt, J = 3.8, 12.5 Hz,
2 H, H-5), 1.76–1.65 (m, 4 H, H-4¢¢), 1.64 (2 H, d, J = 12.5 Hz, 2 H,
H-5).
N,N¢-[Butane-1,4-diylbis(iminopropane-3,1-diyl)]bis(2-
{[(3aRS,4SR,5RS,7SR,7aRS)-5,7-diazido-2,2-dimethylhexahy-
dro-1,3-benzodioxolo-4-yl]oxy}acetamide)
Data for the intermediate; name corresponding to the ( )-threo iso-
mer.
IR (film): 2930, 2105, 1670, 1550, 1535, 1450, 1380, 1230, 1105,
1050, 840, 750 cm–1.
13C NMR (100 MHz, D2O): d = 175.1 (s, C-1¢), 83.7 (d, 1JC,H = 143
1
Hz, C-1), 77.5, 74.8 (2 d, JC,H = 146, 149 Hz, C-2, C-3), 73.1 (t,
1H NMR (400 MHz, MeOD): d = 4.32, 4.22 (2 d AB, J = 15.5 Hz,
4 H, H-2¢), 3.81 (m, 4 H, H-5, H-7), 3.64, 3.59 (2 t, J = 9.4 Hz, 4 H,
H-3a, H-7a), 3.35 (2 t, J = 9.4 Hz, 2 H, H-4), 3.46–3.40, 3.33–3.28
(2 m, 4 H, H-1¢¢), 3.07–2.95 (m, 8 H, H-3¢¢, H-4¢¢¢), 2.27, 2.23 (dt,
J = 4.9, 13.3 Hz, 2 H, H-6), 1.97–1.88 (m, 4 H, H-2¢¢), 1.83–1.76
(m, 4 H, H-3¢¢¢), 1.45, 1.44 (2 s, 12 H, CH3-2), 1.43, 1.37 (2 d,
J = 13.3 Hz, 2 H, H-6).
1JC,H = 146 Hz, C-2¢), 52.3, 51.5 (2 d, 1JC,H = 143, 146 Hz, C-4, C-
1
1
6), 47.7 (t, JC,H = 142 Hz, C-1¢¢), 38.3 (t, JC,H = 140 Hz, C-3¢¢),
30.6 (t, 1JC,H = 134 Hz, C-5), 28.1 (t, 1JC,H = 130 Hz, C-2¢¢).
ESI-HRMS: m/z [M + H]+ calcd for C22H45N7O8: 536.3408; found:
536.3411.
N,N¢-(Iminodipropane-3,1-diyl)bis(2-{[(1SR,2SR,3RS,4SR,6RS)-
4,6-diazido-2,3-dihydroxycyclohexyl]oxy}acetamide)
Data for the intermediate; name corresponding to the ( )-threo iso-
mer.
13C NMR (100 MHz, MeOD): d = 172.3 (s, C-1¢), 112.6 (s, C-2),
82.4 (d,1JC,H = 145 Hz, C-3a), 80.0 (d, 1JC,H = 147 Hz, C-4), 79.5 (d,
1JC,H = 148 Hz, C-7a), 69.9 (t, 1JC,H = 145 Hz, C-2¢), 61.4, 57.6 (2 d,
1JC,H = 143 Hz, C-5, C-7), 47.4, 45.4 (2 t, 1JC,H = 138, 137 Hz, C-3¢¢,
C-4¢¢¢), 35.7 (t, 1JC,H = 138 Hz, C-1¢¢), 33.6 (t, 1JC,H = 133 Hz, C-6),
26.9 (t, 1JC,H = 125 Hz, C-2¢¢), 26.1 (q, 1JC,H = 127 Hz, CH3-2), 23.8
(t, 1JC,H = 126 Hz, C-3¢¢¢).
IR (film): 3320, 3095, 2940, 2105, 1670, 1440, 1370, 1260, 1135,
1065, 840, 800 cm–1.
1H NMR (400 MHz, MeOD): d = 4.30 (2 d AB, J = 3.1 Hz, 4 H, H-
2¢), 3.57 (ddd, J = 4.3, 9.4, 12.9 Hz, 2 H, H-4), 3.0–3.3 (m, 8 H, H-
2, H-6, H-3¢¢), 3.23 (t, J = 9.4 Hz, 2 H, H-1), 3.12 (t, J = 9.4 Hz, 2
H, H-3), 2.98 (t, J = 7.2 Hz, 4 H, H-1¢¢), 2.10 (dt, J = 4.3, 12.5 Hz,
2 H, H-5), 1.95–1.83 (m, 4 H, H-2¢¢), 1.28 (dd, J = 12.9, 12.5 Hz, 2
H, H-5).
ESI-HRMS: m/z [M + H]+ calcd for C32H54N16O8: 791.4389; found:
791.4393.
2-{[(1S,2S,3R,4S,6R)-4,6-Diamino-2,3-dihydroxycyclohex-
yl]oxy}-N-{(3R,5S,7R,9S, 11S,13R)-15-[({[(1S,2S,3R,4S,6R)-4,6-
diamino-2,3-dihydroxycyclohexyl]oxy}acetyl)amino]-
3,5,7,9,11,13-hexahydroxypentadecyl}acetamide (12)
Indication of the configurations of one possible isomer. Starting
from protected diamine 7 (85 mg, 0.129 mmol) and following meth-
od B, 12 (4 mg, 10% yield over 3 steps) was obtained as the major
product; white foam; [a]D25 –33 (c = 0.1, H2O).
13C NMR (100 MHz, MeOD): d = 173.0 (s, C-1¢), 85.5 (d,
1JC,H = 142 Hz, C-1), 76.7, 75.3 (2 d, 1JC,H = 142, 143 Hz, C-2, C-
1
1
3), 71.4 (t, JC,H = 146 Hz, C-2¢), 61.0, 60.8 (2 d, JC,H = 143, 143
Hz, C-4, C-6), 45.5 (t, 1JC,H = 143 Hz, C-1¢¢), 35.5 (t, 1JC,H = 135 Hz,
C-2¢¢), 32.1 (t, 1JC,H = 133 Hz, C-5), 26.5 (t, 1JC,H = 129 Hz, C-3¢¢).
MALDI-TOF-HRMS: m/z [M + H]+ calcd for C22H37N15O8:
640.3028; found: 640.3025.
IR (KBr): 3415, 2940, 1680, 1650, 1200, 1140, 840, 800, 670 cm–1.
1H NMR (400 MHz, D2O): d = 4.41–4.20 (m, 4 H, H-2¢, H-2¢¢¢),
4.05–3.72 (2 m, 6 H, H-3¢¢, H-5¢¢, H-9¢¢, H-11¢¢, H-13¢¢), 3.60–3.10
(3 m, 14 H, H-1, H-2, H-3, H-4, H-6, H-1IV, H-2IV, H-3IV, H-4IV, H-
Synthesis 2011, No. 11, 1759–1770 © Thieme Stuttgart · New York

1766
G. Coste et al.
PAPER
6IV, H-1¢¢, H-15¢¢), 2.55–2.30 (2 m, 2 H, H-5, H-5IV), 1.70–1.4 (m,
16 H, H-5, H-5IV, H-2¢¢, H-4¢¢, H-6¢¢, H-8¢¢, H-10¢¢, H-12¢¢, H-14¢¢).
30:1 → acetone, adding 1% of Et3N to the eluent) to afford 20a
(2.98 g, 80%) as a yellow oil; [a]D23 +16 (c = 0.9, CH2Cl2).
13C NMR (100 MHz, D2O): d = 140 (s, C-1¢, C-1¢¢¢), 81.7, 81.5, 81.4
(3 d, C-1, C-2, C-3, C-1IV, C-2IV, C-3IV), 75.2, 75.3 (2 t, C-1¢¢, C-
15¢¢), 72.4, 71.1 (t, C-2¢, C-2¢¢¢), 66.6, 66.5, 66.3, 66.1, 65.1, 65.0 (6
d, C-3¢¢, C-5¢¢, C-7¢¢, C-9¢¢, C-11¢¢, C-13¢¢), 59.2, 52.3, 52.1, 50.1,
49.8, 45.0, 44.9 (7 d, C-5, C-5IV, C-2¢¢, C-4¢¢, C-6¢¢, C-8¢¢, C-10¢¢, C-
12¢¢, C-14¢¢), 37.2, 33.2 (2 d, C-4, C-6, C-4IV, C-6IV).
IR (film): 3435 (OH), 2935, 1715 (C=O), 1610, 1510, 1445, 1250,
1075, 700 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.47–6.81 (m, 19 Harom), 6.50 (s,
1 H, H-4), 5.26 (s, 2 H, CH2Ph), 4.78 (d, J1¢,2¢ = 3.3 Hz, 1 H, H-1¢),
3.87–3.78 (m, 2 H, H-2¢, H-3¢), 3.76 (s, 3 H, OCH3), 3.26 (dd,
J4¢a,4¢b = 9.5 Hz, J4¢a,3¢ = 3.1 Hz, 1 H, H-4¢a), 3.14 (dd, J4¢b,3¢ = 5.9 Hz,
1 H, H-4¢b), 2.49 (s, 3 H, CH3).
13C NMR (75.4 MHz, CD3OD): d = 165.3 (CO2Bn), 160.2 (Carom),
160.0 (C-2), 155.1 (C-5), 150.1, 146.1, 138.4, 137.8, 136.9, 131.7,
129.7, 129.6, 128.7, 127.8, 125.6, 114.0 (23 C, Carom), 114.9 (C-3),
108.8 (C-4), 87.7 [(Ar)3C], 74.7 (C-2¢), 72.3 (C-3¢), 67.8 (C-1¢),
67.0 (CH2Ph), 66.6 (C-4¢), 55.7 (OCH3), 13.8 (CH3).
ESI-HRMS: m/z [M + H]+ calcd for C31H62N6O14: 743.4402;
743.4401.
2-{[(1S,2S,3R,4S,6R)-4,6-Diamino-2,3-dihydroxycyclohex-
yl]oxy}-N-{2-[(2S,4R,6R)-6-{(2R,4S)-5-[(2R,4R,6S)-6-{2-
[({[(1S,2S,3R,4S,6R)-4,6-diamino-2,3-dihydroxycyclohex-
yl]oxy}acetyl)amino]ethyl}-4-hydroxytetrahydro-2H-pyran-2-
yl]-2,4-dihydroxypentyl}-4-hydroxytetrahydro-2H-pyran-2-
yl]ethyl}acetamide (13)
MS (FAB): m/z (%) = 631 (4, [M + Na]+).
HRMS-FAB: m/z [M + Na]+ calcd for C37H36O8 + Na: 631.2308;
Indication of the configurations of one possible isomer. Starting
from protected diamine 8 (95 mg, 0.141 mmol), and following
method B, 13 (26 mg, 23% yield over 3 steps) was obtained as the
major product as a white foam; [a]D25 –18 (c = 0.2, H2O).
found: 631.2323.
Benzyl 5-(1-Azido-1-deoxy-4-O-methoxytrityl-D-ribotetritol-1-
yl)furan-3-carboxylate (21a)
To a solution of 20a (2.950 g, 5.4 mmol) and Et3N (2.43 g, 3.34 mL,
23.8 mmol) in anhyd CH2Cl2 (20 mL) cooled to 0 °C was slowly
added a solution of SOCl2 (1.62 g, 988 mL, 13.5 mmol) in anhyd
CH2Cl2 (5 mL). The solution was stirred at 0 °C for 30 min. The
mixture was diluted with Et2O (120 mL) and the Et2O layer was
washed with H2O and brine (3 × 40 mL), the organic phase was
dried (Na2SO4), filtered, and evaporated to dryness. The resulting
residue was dissolved in THF (10 mL), trimethylsilyl azide (1.96 g,
2.24 mL, 16.2 mmol) and TBAF (1 M in THF, 16.2 mL) were added
and the mixture stirred for 24 h. The solution was evaporated to dry-
ness and the resulting crude product purified by column chromatog-
raphy (Et2O–PE, 1:1, adding 1% of Et3N to the eluent) to afford 21a
(2.30 g, 70%) as a colorless oil; [a]D23 +42 (c = 1.33, CH2Cl2).
IR (KBr): 2940, 2855, 2810, 1600, 1455, 1360, 1305, 1270, 1115,
1070, 1005, 915, 865 cm–1.
1H NMR (400 MHz, D2O): d = 4.29, 4.21 (2 d AB, J = 15.3 Hz, 4
H, H-2¢), 4.17–3.75 (2 m, 12 H, H-2IV, H-4IV, H-6IV, H-2V, H-4V, H-
2VI, H-4VI, H-6VI, H-1¢¢, H-2¢¢¢), 3.47–3.28 (3 m, 6 H, H-1, H-2, H-
3), 3.27–3.13 (m, 4 H, H-4, H-6), 2.51–2.17 (2 m, 2 H, H-5), 2.07–
1.8 (2 m, 4 H, H-1V, H-5V), 1.83–1.70 (m, 2 H, H-5), 1.2–1.06 (m,
2 H, H-3V), 1.67–1.43 (m, 8 H, H-3IV, H-5IV, H-3VI, H-5VI).
13C NMR (100 MHz, D2O): d = 172.4 (s, C-1¢), 81.6, 75.5, 75.4,
72.7, 71.7 (5 d, C-1, C-2, C-3), 70.9, 70.7 (2 t, C-2¢), 67.4, 67.0,
65.9, 65.8, 63.9, 63.8 (6 d, C-2IV, C-4IV, C-6IV, C-2V, C-4V, C-2VI,
C-4VI, C-6VI), 57.1 (d, C-4, C-6), 50.1, 49.3 (2 t, C-1¢¢, C-2¢¢¢), 44.4
(t, C-3V), 42.7, 42.6 (2 t, C-1V, C-5V), 40.4, 39.8 (2 t, C-5IV, C-3IV),
37.0, 36.3 (2 t, C-3VI, C-5VI), 30.3, 30.0 (2 t, C-2¢¢, C-1¢¢¢), 28.5 (t,
C-5).
IR (film): 3480 (OH), 2935, 2100 (N3), 1715 (C=O), 1610, 1510,
1445, 1250, 1225 (N3), 1180, 1075, 830, 735, 700 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.48–6.83 (m, 19 Harom), 6.72 (s,
1 H, H-4), 5.28 (s, 2 H, CH2Ph), 4.62 (d, J1¢,2¢ = 4.5 Hz, 1 H, H-1¢),
3.96 (dd, J2¢,3¢ = 7.5 Hz, 1 H, H-2¢), 3.76 (s, 3 H, OCH3), 3.58 (m, 1
H, H-3¢), 3.35 (dd, J4¢a,4¢b = 9.7 Hz, J4¢a,3¢ = 3.4 Hz, 1 H, H-4¢a), 3.22
(dd, J4¢b,3¢ = 6.2 Hz, 1 H, H-4¢b), 2.55 (s, 3 H, CH3).
13C NMR (75.4 MHz, CD3OD): d = 165.1 (CO2Bn), 161.0 (Carom),
160.9 (C-2), 149.3 (C-5), 146.1, 137.7, 136.9, 131.7, 129.7, 129.6,
129.3, 128.7, 127.9, 114.0 (23 C, Carom), 115.1 (C-3), 111.8 (C-4),
87.8 [(Ar)3C], 74.7 (C-2¢), 72.5 (C-3¢), 67.1 (CH2Ph), 66.5 (C-4¢),
60.9 (C-1¢), 55.7 (OCH3), 13.9 (CH3).
ESI-HRMS: m/z [M + H]+ calcd for C35H66N6O14: 795.4715; found:
795.4720.
Benzyl 5-(d-arabinoTetritol-1-yl)-2-methylfuran-3-carboxylate
(19a)
Silica gel (2 g) was added to a mixture of CeCl3·7H2O (0.452 g, 1.2
mmol) and NaI (56 mg, 1.2 mmol) in MeCN (28 mL) and the mix-
ture was stirred overnight. Then, D-glucose (720 mg, 4 mmol) was
added to the mixture, and the suspension was stirred for 1 h. The
solvent was evaporated, benzyl acetoacetate (1.0 g, 0.9 mL, 5.2
mmol) was added to the mixture and the solvent-free mixture was
stirred for 9 days at 50 °C. After this period, MeOH was added to
the mixture, the resulting suspension was filtered over Celite and
the solid residue was washed several times with MeOH. The filtered
solution was evaporated to dryness and the resulting crude was pu-
rified by column chromatography (CH2Cl2–MeOH, 15:1 → 5:1) to
afford 19a (1.05 g, 78%) as a colorless oil. The analytical data were
in accord with the previously reported values.13
MS (FAB): m/z (%) = 656 (8, [M + Na]+).
HRMS-FAB: m/z [M + Na]+ calcd for C37H35N3O7 + Na: 656.2373;
found: 656.2371.
Anal. Calcd for C37H35O7N3: C, 70.13; H, 5.57; N, 6.63. Found: C,
69.82; H, 5.80; N, 6.16.
Benzyl 5-(1-Azido-1-deoxy-D-ribotetritol-1-yl)-2-methylfuran-
3-carboxylate (22a)
Compound 21a (2.25 g, 3.67 mmol) was dissolved in TFA–CH2Cl2
(2%, 45 mL) and triisopropylsilane (1.5 mL) was added. The mix-
ture was stirred for 1 h and then evaporated to dryness. The resulting
residue was purified by column chromatography (CH2Cl2–MeOH,
15:1) to afford 22a (1.06 g, 80%) as a colorless oil; [a]D23 +82
(c = 0.8, MeOH).
Benzyl 2-Methyl-5-[4-O-methoxytrityl-D-arabinoteritol-1-yl]fu-
ran-3-carboxylate (20a)
To a cooled solution of 19a (2.06 g, 6.12 mmol) in anhyd pyridine
(10 mL) was added p-methoxytrityl chloride (2.27 g, 7.34 mmol)
and the mixture stirred for 3 h at 25 °C. MeOH (2.5 mL) was added,
the solution stirred for further 15 min, and then evaporated to dry-
ness. The resulting residue was diluted with CH2Cl2 and the organic
layer was washed with H2O (2 × 40 mL) and brine (40 mL). The or-
ganic phase was dried (Na2SO4), filtered and evaporated. The crude
product was purified by column chromatography (CH2Cl2–acetone,
IR (film): 3415 (OH), 2925, 2105 (N3), 1715 (C=O), 1610, 1430,
1225 (N3), 1075, 775, 700 cm–1.
Synthesis 2011, No. 11, 1759–1770 © Thieme Stuttgart · New York

PAPER
2-DOS Dimers and Analogues
1767
1H NMR (300 MHz, CD3OD): d = 7.40–7.32 (m, 5 Harom), 6.80 (s,
1 H, H-4), 5.28 (s, 2 H, CH2Ph), 4.67 (d, J1¢,2¢ = 4.1 Hz, 1 H, H-1¢),
3.92 (dd, J2¢,3¢ = 8.3 Hz, 1 H, H-2¢), 3.74 (dd, J4¢a,4¢b = 11.3 Hz,
13C NMR (75.4 MHz, CD3OD): d = 164.5 (CO2Bt), 161.1 (2 C, CO
of Boc), 157.4 (C-2), 152.1 (C-5), 144.5, 130.3, 126.5, 120.8, 110.0
(6 C, Carom), 109.5 (C-3), 108.7 (C-4), 80.8, 80.4 [(CH3)3C], 75.4
(C-2¢), 72.2 (C-3¢), 51.4 (C-1¢), 44.7 (C-4¢), 28.7 [(CH3)3C], 14.2
(CH3).
J
4¢a,3¢ = 3.5 Hz, 1 H, H-4¢a), 3.60 (dd, J4¢b,3¢ = 5.8 Hz, 1 H, H-4¢b),
3.43 (ddd, J = 8.3, 5.8, 3.5 Hz, 1 H, H-3¢), 2.57 (s, 3 H, CH3).
13C NMR (75.4 MHz, CD3OD): d = 165.1 (CO2Bn), 160.9 (C-2),
149.4 (C-5), 137.7, 129.6, 129.3 (6 C, Carom), 115.1 (C-3), 111.8 (C-
4), 74.6 (C-2¢), 73.4 (C-3¢), 67.1 (CH2Ph), 64.5 (C-4¢), 60.9 (C-1¢),
13.8 (CH3).
MS (FAB): m/z (%) = 584 (52, [M + Na]+).
HRMS-FAB: m/z [M + Na]+ calcd for C26H35N5O9 + Na: 584.2332;
found: 584.2326.
MS (FAB): m/z (%) = 384 (16, [M + Na]+).
HRMS-FAB: m/z [M + Na]+ calcd for C17H19N3O6 + Na: 384.1172;
Ethyl 5-[1-N-(tert-Butoxycarbonyl)amino-1-deoxy-D-ribotetri-
tol-1-yl]-2-methylfuran-3-carboxylate (24)
To a solution of 22b (340 mg, 1.14 mmol) in absolute EtOH (20
mL) were added (Boc)2O (373 mg, 1.14 mmol) and Pd/C (catalytic
amount). The mixture was hydrogenated under atmospheric pres-
sure for 2 h. Et3N (175 mg, 240 mL, 1.71 mmol) was added and the
mixture was stirred for 30 min. The Pd/C was filtered over Celite
and washed with MeOH (20 mL). The filtered solution was evapo-
rated to dryness and the resulting residue was purified by column
chromatography (CH2Cl2–MeOH, 15:1) to afford 24 (328 mg, 77%)
as a colorless oil; [a]D20 +24 (c = 0.67, CH2Cl2).
found: 384.1171.
Benzyl 5-(1,4-Diazido-1,4-dideoxy-D-ribotetritol-1-yl)-2-meth-
ylfuran-3-carboxylate (23)
To a cooled solution of 22a (271 mg, 0.906 mmol) in anhyd pyri-
dine (5 mL) at –15 °C was added tosyl chloride (191 mg, 1.0 mmol)
and the mixture stirred for 3 h at –15–20 °C. H2O (0.3 mL) was add-
ed, the solution was stirred for 10 min, and the mixture evaporated
to dryness. The resulting residue was diluted with cold CH2Cl2 (60
mL), and the organic layer washed with aq 1 M HCl (30 mL), sat.
aq NaHCO3 (30 mL), and brine (30 mL). The organic phase was
dried (Na2SO4) and evaporated to dryness. The resulting crude
product was dissolved in THF (5 mL) and Bu4NN3 (284 mg, 1.0
mmol) was added to the solution. The mixture was heated at 60 °C
for 2 h. Then, the solvent was evaporated and the resulting residue
was purified by column chromatography (Et2O–PE, 1:3→1:1) to af-
ford 23 (203 mg, 58%) as a colorless oil; [a]D26 +89 (c = 1.54,
CH2Cl2).
IR (film): 3420 (OH), 2980, 2930, 1695 (CO), 1510, 1230, 1170,
1080, 780 cm–1.
1H NMR (300 MHz, CD3OD): d = 6.54 (s, 1 H, H-4), 5.00 (br s, 1
H, H-1¢), 4.26 (q, 3JH,H = 7.1 Hz, 2 H, CH2CH3), 3.77 (dd, J2¢,3¢ = 8.4
Hz, J2¢,1¢ = 3.7 Hz, 1 H, H-2¢), 3.73 (dd, J4¢a,4¢b = 11.4 Hz, J4¢a,3¢ = 3.3
Hz, 1 H, H-4¢a), 3.59 (dd, J4¢b,3¢ = 5.8 Hz, 1 H, H-4¢b), 3.41 (ddd,
J = 8.4, 5.8, 3.3 Hz, 1 H, H-3¢), 2.54 (s, 3 H, CH3), 1.44 [s, 9 H,
[CH3)3C], 1.33 (t, J = 7.1 Hz, 3 H, CH2CH3).
13C NMR (75.4 MHz, CD3OD): d = 165.7 (CO2Et)), 159.7 (C=O of
Boc), 157.4 (C-2), 152.3 (C-5), 115.1 (C-3), 109.4 (C-4), 80.7
[(CH3)3C], 74.8 (C-2¢), 73.2 (C-3¢), 64.7 (C-4¢), 61.3 (CH2CH3),
51.7 (C-1¢), 28.7 [(CH3)3C], 14.7 (CH2CH3), 13.8 (CH3).
1H NMR (300 MHz, CD3OD): d = 7.32–7.44 (m, 19 Harom), 6.79 (s,
1 H, 4-H), 5.28 (s, 2 H, CH2Ph), 4.66 (d, J = 3.9 Hz, 1 H, H-1¢), 3.90
(dd, J2¢,3¢ = 8.3 Hz, J2¢,1¢ = 3.9 Hz, 1 H, H-2¢), 3.53 (m, 1 H, H-3¢),
3.45 (dd, J4¢a,3¢ = 2.9 Hz, 1 H, H-4¢a), 3.36 (dd, J4¢b,4¢a = 12.8 Hz,
MS (CI): m/z (%) = 374 (6, [M + H]+), 257 (100, [M – BocNH]+).
HRMS-CI: m/z [M + H]+ calcd for C17H28NO8: 374.1815; found:
J4¢b,3¢ = 6.3 Hz, 1 H, H-4¢b), 2.56 (s, 3 H, CH3).
13C NMR (75.4 MHz, CD3OD): d = 165.0 (CO2Bn), 161.0 (C-2),
149.0 (C-5), 137.7, 129.6, 129.3 (6 C, Carom), 115.1 (C-3), 111.9 (C-
4), 74.2 (C-2¢), 72.4 (C-3¢), 67.2 (CH2Ph), 60.7 (C-1¢), 55.1 (C-4¢),
13.9 (CH3).
MS (FAB): m/z (%) = 409 (5, [M + Na]+).
HRMS-FAB: m/z [M + Na]+ calcd for C17H18N6O5 + Na: 409.1236;
374.1818.
Ethyl 5-[1-N-(tert-Butoxycarbonyl)amino-1-deoxy-4-O-tosyl-D-
ribotetritol-1-yl]-2-methylfuran-3-carboxylate (25)
To a cooled solution of 24 (697 mg, 1,32 mmol) in anhyd pyridine
(5 mL) was added tosyl chloride (763 mg, 3.96 mmol) and the mix-
ture was stirred for 2.5 h at –15 °C. H2O (0.3 mL) was added, the
solution was stirred for 10 min at –15 °C, and the mixture evaporat-
ed to dryness. The resulting residue was diluted with cold CH2Cl2
(70 mL), and the organic phase washed with aq 1 M HCl (2 × 40
mL), sat. aq NaHCO3 (40 mL), and brine (40 mL). The organic
phase was dried (Na2SO4), evaporated to dryness, and the resulting
crude product was immediately purified by column chromatogra-
phy (CH2Cl2–MeOH, 40:1) to afford 25 (525 mg, 75%) as a color-
less oil; [a]D21 +1 (c = 1.90, CH2Cl2).
found: 409.1245.
Benzotriazol-1-yl 5-[1,4-Di-N-(tert-butoxycarbonyl)amino-1,4-
dideoxy-D-ribotetritol-1-yl]-2-methylfuran-3-carboxylate (17)
To a solution of 23 (149 mg, 0.4 mmol) in absolute EtOH (6 mL),
Pd/C (catalytic amount) and (Boc)2O (134 mg, 0.6 mmol) were add-
ed. The mixture was hydrogenated for 3 h under atmospheric pres-
sure. Then, the catalyst was filtered and washed several times with
EtOH. The filtered solution was evaporated to dryness. To a solu-
tion of the resulting crude product in DMF (4 mL) were added Py-
BOP (215 mg, 0.4 mmol) and DIPEA (109 mg, 140 mL, 0.8 mmol)
and the mixture was stirred for 1 h. The solution was concentrated
to dryness. The resulting residue was dissolved in EtOAc (40 mL)
and the organic phase washed with aq 1 M HCl (20 mL), sat. aq
NaHCO3 (20 mL) and brine (20 mL). The organic phase was dried
(Na2SO4) and evaporated. The resulting residue was purified by col-
umn chromatography (Et2O–PE, 5:1) to afford 17 (111 mg, 50%) as
a colorless oil; [a]D23 –2 (c = 0.87, CH2Cl2).
IR (film): 3430 (OH), 2980, 1710 (C=O), 1510, 1365, 1230, 1175,
1080, 780 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.79 (d, J = 8.3 Hz, 2 Harom), 7.41
(d, J = 8.3 Hz, 2 Harom), 6.50 (s, 1 H, H-4), 4.94 (br s, 1 H, H-1¢),
3
4.25 (q, JH,H = 7.1 Hz, 2 H, CH2CH3), 4.17 (dd, J4¢a,4¢b = 10.1 Hz,
J4¢a,3¢ = 2.4 Hz, 1 H, H-4¢a), 4.02 (dd, J4¢b,3¢ = 6.4 Hz, 1 H, H-4¢b),
3.72 (dd, J2¢,3¢ = 8.4 Hz, J2¢,1¢ = 3.7 Hz, 1 H, H-2¢), 3.55 (ddd, J = 8.4,
6.4, 2.4 Hz, 1 H, H-3¢), 2.51 (s, 3 H, CH3), 2.44 (s, 3 H, CH3 of Ts),
1.42 [s, 9 H, (CH3)3C], 1.32 (t, J = 7.1 Hz, 3 H, CH2CH3).
1H NMR (300 MHz, CD3OD): d = 8.08–7.51 (m, 4 Harom), 6.88 (s,
1 H, H-4), 5.12 (br d, J1¢,2¢ = 3.5 Hz, 1 H, H-1¢), 3.70 (dd, J2¢,3¢ = 8.4
Hz, 1 H, H-2¢), 3.56–3.35 (m, 2 H, H-3¢, H-4¢a), 3.20 (dd,
J4¢b,4¢a = 14.0 Hz, J4¢b,3¢ = 6.3 Hz, 1 H, H-4¢b), 2.67 (s, 3 H, CH3),
1.46, 1.45 [2 s, 9 H each, 2 (CH3)3C].
13C NMR (75.4 MHz, CD3OD): d = 165.7 (CO2Et), 161.2 (C=O of
Boc), 156.1 (C-2), 146.4 (C-5), 146.2, 134.2, 131.0, 129.8, 129.1,
126.9 (6 C, Carom), 115.6 (C-3), 109.5 (C-4), 81.4 [(CH3)3C], 74.1
(C-2¢), 73.4 (C-4¢), 70.9 (C-3¢), 61.3 (CH2CH3), 51.8 (C-1¢), 28.7
[(CH3)3C], 21.6 (CH3 of Ts), 14.7 (CH2CH3), 13.8 (CH3).
Synthesis 2011, No. 11, 1759–1770 © Thieme Stuttgart · New York

1768
G. Coste et al.
PAPER
MS (FAB): m/z (%) = 550 (56, [M + Na]+).
HRMS-FAB: m/z [M + Na]+ calcd for C24H33NO10S + Na:
4¢a), 3.25 (dd, J4¢a,4¢b = 14.8 Hz, J4¢b,3¢ = 7.3 Hz, 1 H, H-4¢b), 2.66 (s,
3 H, CH3), 1.46 [s, 9 H, (CH3)3C].
550.1723; found: 550.1713.
13C NMR (75.4 MHz, CD3OD): d = 164.5 (CO2Bt), 161.1 (C-2),
159.5 (C-5), 157.4, 154.1 (C=O of Fmoc, C=O of Boc), 145.3,
144.5, 142.6, 130.3, 128.8, 126.5, 126.2, 120.9, 120.7, 109.9 (18 C,
Ethyl 5-[4-Azido-1-N-(tert-butoxycarbonyl)amino-1,4-dideoxy-
D-ribotetritol-1-yl]-2-methylfuran-3-carboxylate (26)
C
arom), 109.5 (C-3), 108.8 (C-4), 80.9 [(CH3)3C], 75.4 (C-2¢), 72.1
To a solution of 25 (447 mg, 0.85 mmol) in THF (3 mL) were added
trimethylsilyl azide (413 mg, 471 mL, 3.4 mmol) and a 1 M solution
of TBAF in THF (3.4 mL, 3.4 mmol). The mixture was heated at 60
°C and stirred for 4 h. The solution was evaporated to dryness and
the resulting residue was purified by column chromatography
(Et2O–PE, 2:1) to afford 26 (251 mg, 74%) as a colorless oil;
[a]D23 +22 (c = 1.11, CH2Cl2).
(C-3¢), 67.9 (CH2 of Fmoc), 51.4 (C-1¢), 48.2 (CH of Fmoc), 45.2
(C-4¢), 28.7 [(CH3)3C], 14.2 (CH3).
MS (FAB): m/z (%) = 706 (25, [M + Na]+).
HRMS-FAB: m/z [M + Na]+ calcd for C36H37N5O9 + Na: 706.2489;
found: 706.2443.
N-Protected Furylcarbopeptoid 14a
IR (film): 3425 (OH), 2980, 2930, 2105 (N3), 1690 (C=O), 1510,
1370, 1230 (N3), 1170, 1085, 870, 810, 780 cm–1.
To a solution of 17 (95.4 mg, 0.17 mmol) and aminopolyol (+)-16
(50 mg, 0.15 mmol) in DMF (8 mL) was added DIPEA (178 mg,
227 mL, 1.3 mmol) and the mixture was stirred overnight. Then, the
solution was evaporated to dryness. The resulting residue was puri-
fied by column chromatography (CH2Cl2–MeOH, 10:1 → 4:1) to
afford 14a (62.5 mg, 62%) as a colorless oil; [a]D22 +29 (c = 0.42,
MeOH).
1H NMR (500 MHz, CD3OD): d = 6.54 (s, 2 H, 2 H-4¢), 5.00 (br s,
2 H, 2 H-1¢¢), 4.04–3.89 (m, 6 H, H-3, H-5, H-7, H-9, H-11, H-13),
3.63 (dd, J2¢¢,3¢¢ = 8.2 Hz, J2¢¢,1¢¢ = 3.5 Hz, 2 H, 2 H-2¢¢), 3.54–3.35 (m,
8 H, H-1, H-15, 2 H-3¢¢, 2 H-4¢¢a), 3.16 (dd, J4¢¢b,4¢¢a = 14.1 Hz,
1H NMR (300 MHz, CD3OD): d = 6.54 (s, 1 H, H-4), 4.97 (br d,
3
J
1¢,2¢ = 3.9 Hz, 1 H, H-1¢), 4.26 (q, JH,H = 7.1 Hz, 2 H, CH2CH3),
3.75 (dd, J2¢,3¢ = 8.2 Hz, 1 H, H-2¢), 3.54 (m, 1 H, H-3¢), 3.45 (dd,
J4¢a,4¢b = 12.8 Hz, J4¢a,3¢ = 2.8 Hz, 1 H, H-4¢a), 3.34 (dd, J4¢b,3¢ = 6.7
Hz, 1 H, H-4¢b), 2.54 (s, 3 H, CH3), 1.44 [s, 9 H, [CH3)3C], 1.33 (t,
J = 7.1 Hz, 3 H, CH2CH3).
13C NMR (75.4 MHz, CD3OD): d = 165.7 (CO2Et), 159.8 (C=O of
Boc), 157.4 (C-2), 152.1 (C-5), 115.1 (C-3), 109.5 (C-4), 80.8
[(CH3)3C], 75.1 (C-2¢), 72.3 (C-3¢), 61.3 (CH2CH3), 55.2 (C-4¢),
51.5 (C-1¢), 28.7 [(CH3)3C], 14.7 (CH2CH3), 13.8 (CH3).
MS (FAB): m/z (%) = 421 (46, [M + Na]+).
HRMS-FAB: m/z [M + Na]+ calcd for C17H26N4O7 + Na: 421.1699;
J
4¢¢b,3¢¢ = 6.5 Hz, 2 H, 2 H-4¢¢b), 2.51 (s, 6 H, 2 CH3), 1.72–1.53 (m,
14 H, H-2, H-4, H-6, H-8, H-10, H-12, H-14), 1.45 [s, 36 H, 4
(CH3)3C].
13C NMR (125.7 MHz, CD3OD): d = 166.8 (2 C, 2 CONH), 159.2
(2 C, 2 C-2¢), 157.3, 157.0 (4 C, 4 CO of Boc), 151.8 (2 C, 2 C-5¢),
117.3 (2 C, 2 C-3¢), 108.0 (2 C, 2 C-4¢), 80.7, 80.4 [4 C, 4 (CH3)3C],
75.4 (2 C, 2 C-2¢¢), 72.3 (2 C, 2 C-3¢¢), 70.2, 68.3, 68.0, 67.2, 67.0,
66.1 (C-3, C-5, C-7, C-9, C-11, C-13), 51.4 (2 C, 2 C-1¢¢), 46.3,
46.2, 45.9, 45.8, 45.7 (C-4, C-6, C-8, C-10, C-12), 44.7 (2 C, 2 C-
4¢¢), 38.7 (2 C, C-2, C-14), 37.4 (2 C, C-1, C-15), 28.7 [12 C, 4
(CH3)3C], 13.6 (2 C, 2 CH3).
found: 421.1723.
Benzotriazol-1-yl 5-[1-N-(tert-Butoxycarbonyl)amino-1,4-
dideoxy-4-N-(fluorenylme-thoxycarbonyl)amino-D-ribotetritol-
1-yl]-2-methylfuran-3-carboxylate (18)
To a solution of 26 (153 mg, 0.38 mmol) in EtOH (3 mL) were add-
ed LiOH (74 mg, 3.4 mmol) and H2O (2 mL), and the mixture was
heated at 50 °C for 1.5 h. Aq 1 M HCl (3 mL) was added to the so-
lution to reach pH ~7. The mixture was evaporated to dryness. The
resulting residue was dissolved in EtOH (10 mL), Pd/C was added
and the mixture was hydrogenated under atmospheric pressure for
2 h. The Pd/C was filtered over Celite, washed with EtOH, and the
filtrate evaporated to dryness. The resulting crude product was dis-
solved in 1,4-dioxane (3 mL) and sat. aq NaHCO3 (6 mL) and a so-
lution of 9-fluorenylmethyloxycarbonylsuccinimide (158 mg, 0.46
mmol) in 1,4-dioxane (3 mL) were added. The mixture was stirred
for 3 h and then evaporated to dryness. The resulting residue was di-
luted with EtOAc (50 mL), and the organic phase washed with aq 1
M HCl (25 mL) and brine (25 mL). The organic phase was dried
(Na2SO4) and evaporated to dryness. To a solution of the crude
product in DMF (4 mL) were added PyBOP (204 mg, 0.38 mmol)
and DIPEA (104 mg, 133 mL, 0.76 mmol), and the mixture was
stirred for 2 h. The solution was evaporated, the residue diluted with
EtOAc (50 mL) and the organic phase washed with aq 1 M HCl (25
mL), sat. aq NaHCO3 (25 mL) and brine (25 mL). Purification by
column chromatography (Et2O–PE, 5:1) afforded 18 (155 mg, 60%)
as a colorless oil; [a]D24 +11 (c = 0.57, CH2Cl2).
MS (FAB): m/z (%) = 1214 (5, [M + Na]+), 813 (11, [M – 4 Boc +
Na]+).
HRMS-FAB: m/z [M + Na]+ calcd for C55H94N6O22 + Na:
1213.6319; found: 1213.6371,
Furylcarbopeptoid 14b
Compound 14a (30 mg, 0.025 mmol) was dissolved in TFA–
CH2Cl2 (20%, 1.5 mL) and the mixture was stirred for 20 min. Then,
the solvent was evaporated to afford 14b (19 mg, quant) as a yellow
oil; [a]D25 –0.9 (c = 0.97, MeOH).
1H NMR (500 MHz, CD3OD): d = 6.92 (s, 2 H, 2 H-4¢), 4.73 (d,
J1¢¢,2¢¢ = 3.3 Hz, 2 H, 2 H-1¢¢), 4.12–3.90 (m, 6 H, H-3, H-5, H-7, H-
9, H-11, H-13), 3.89 (dd, J2¢¢,3¢¢ = 9.2 Hz, 2 H, 2 H-2¢¢), 3.56 (ddd,
J = 9.1, 3.1, 2.5 Hz, 2 H, 2 H-3¢¢), 3.52–3.35 (m, 4 H, H-1, H-15),
3.23 (dd, J4¢¢a,4¢¢b = 13.2 Hz, J4¢¢a,3¢¢ = 3.1 Hz, 2 H, 2 H-4¢¢a), 2.94 (dd,
J
4¢¢b,3¢¢ = 2.51 Hz, 2 H, 2 H-4¢¢b), 2.56 (s, 6 H, 2 CH3), 1.99–1.50 (m,
14 H, H-2, H-4, H-6, H-8, H-10, H-12, H-14).
13C NMR (125.7 MHz, CD3OD): d = 165.9 (2 C, 2 CONH), 158.6
(2 C, 2 C-2¢), 145.8 (2 C, 2 C-5¢), 118.3 (2 C, 2 C-3¢), 111.8 (2 C, 2
C-4¢), 73.1 (2 C, 2 C-2¢¢), 69.5 (2 C, 2 C-3¢¢), 68.4, 68.2, 68.1, 67.4,
67.1, 66.2 (C-3, C-5, C-7, C-9, C-11, C-13), 51.6 (2 C, 2 C-1¢¢),
46.3, 46.2, 45.9, 45.8, 45.7 (C-4, C-6, C-8, C-10, C-12), 43.8 (2 C,
2 C-4¢¢), 38.6 (2 C, C-2, C-14), 37.6 (2 C, C-1, C-15), 13.6 (2 C, 2
CH3).
IR (film): 3390 (OH), 2920, 1795 (C=O), 1695 (C=O), 1160, 960,
740 cm–1.
1H NMR (300 MHz, CD3OD): d = 8.05 (d, J = 8.3 Hz, 1 Harom), 7.78
(d, J = 7.4 Hz, 2 Harom), 7.65 (d, J = 7.4 Hz, 2 Harom), 7.62 (d, J = 3.8
Hz, 2 Harom), 7.51 (m, 1 Harom), 7.38 (t, J = 7.4 Hz, 2 Harom), 7.30 (t,
J = 7.4 Hz, 2 Harom), 6.88 (s, 1 H, H-4), 5.14 (br s, 1 H, H-1¢), 4.43–
4.32 (m, 2 H, CH2 of Fmoc), 4.21 (m, 1 H, CH of Fmoc), 3.71 (dd,
MS (FAB): m/z (%) = 813 (1, [M + Na]+).
HRMS-FAB: m/z [M + Na]+ calcd for C35H62N6O14 + Na: 813.4222;
J2¢,3¢ = 8.3 Hz, J2¢,1¢ = 3.5 Hz, 1 H, H-2¢), 3.54–3.45 (m, 2 H, H-3¢, H-
found: 813.4240.
Synthesis 2011, No. 11, 1759–1770 © Thieme Stuttgart · New York

PAPER
2-DOS Dimers and Analogues
1769
Esterification of HMBA-AM Resin
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
A
mixture of HMBAAM resin (59 mg, 0.068 mmol,
substitution = 1.6 mmol/g) and Fmoc-glycine (81.5 mg, 0.274
mmol) in anhyd DMF (1.8 mL) was stirred for 15 min. Then a mix-
ture of pyridine (59 mg, 60 mL, 0.75 mmol) and 2,6-dichlorobenzoyl
chloride (93 mg, 64 mL, 0.274 mmol) was added and the resulting
solution was stirred for 12 h. The reaction mixture was filtered and
the resin washed with DMF (5 × 3 mL) and CH2Cl2 (3 × 3 mL). The
resin was dried under vacuum affording 80 mg of a solid residue
(100% substitution). The residue was treated with piperidine in
DMF (20%, 2 mL) and stirred for 10 min. The resin was collected
by filtration, washed with DMF (3 × 2 mL) and CH2Cl2 (4 × 2 mL),
and dried under vacuum to afford H-Gly-OResin (81 mg).
Acknowledgment
The Swiss National Science Foundation is gratefully acknowledged
for financial support. P.H.S. thanks the ETH Zürich and the Max-
Planck Society for generous financial support. The Ministerio de
Educación y Ciencia of Spain (CTQ2004-00649/BQU; CTQ2008-
01565/BQU) and the Junta de Andalucía (FQM-345) are also grate-
fully acknowledged for financial support.
References
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Units to H-Gly-OResin
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To H-Gly-OResin (81 mg, 0.068 mmol) in a reaction tube fitted
with a glass frit in the side arm was added a solution of 18 (116.6
mg, 0.171 mmol) in DMF (2 mL) and DIPEA (46 mg, 58.5 mL,
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Cleavage from the Resin and Final deprotection; Synthesis of 15
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1H NMR (500 MHz, CD3OD): d = 6.98, 6.95, 6.94 [3 s, 1 H each,
H-4(A, B, C)], 4.74 (d, J1¢A,2¢A = 3.3 Hz, 1 H, H-1¢A), 4.71, 4.70 [2
d, J1¢B,2¢B = J1¢C,2¢C = 3.4 Hz, 1 H each, H-1¢ (B, C)], 4.05 (s, 2 H, H-
2¢D), 3.88 (dd, J2¢A,3¢A = 9.2 Hz,
1 H, H-2¢A), 3.79 [dd,
J2¢B,3¢B = J2¢C,3¢C = 9.2 Hz, 2 H, H-2¢(B, C)], 3.74 (s, 3 H, OCH3),
3.61–3.54 [m, 5 H, H-3¢A, H-4¢a(B, C), H-4¢b(B, C)], 3.49–3.44 [m,
2 H, H-3¢(B, C)], 3.24 (dd, J4¢aA,4¢bA = 12.9 Hz, J4¢aA,3¢A = 3.5 HZ, 1
H, H-4¢aA), 2.95 (dd, J4¢bA,3¢A = 8.2 Hz, 1 H, H-4¢bA), 2.57 [s, 9 H,
CH3(A, B, C)].
13C NMR (125.7 MHz, CD3OD): d = 172.0 (C-1¢D), 167.2, 166.2 [3
C, CONH(A, B, C)], 159.3, 159.0 [3 C, C-2(A, B, C)], 146.4, 145.9
[3 C, C-5(A, B, C)], 117.7 [3 C, C-3(A, B, C)], 111.8, 111.5, 111.5
[C-4(A, B, C)], 73.1 (C-2¢A), 72.6, 72.5 [C-2¢(B, C)], 72.4, 72.4 [C-
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44.2, 44.0 [C-4¢(B, C)], 43.8 (C-4¢A), 41.8 (C-2¢D), 13.7, 13.6 [3 C,
CH3(A, B, C)].
MS (FAB): m/z (%) = 790 (15, [M + Na]+).
HRMS-FAB: m/z [M + Na]+ calcd for C33H49N7O14 + Na: 790.3235;
found: 790.3250.
Synthesis 2011, No. 11, 1759–1770 © Thieme Stuttgart · New York

1770
G. Coste et al.
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Synthesis 2011, No. 11, 1759–1770 © Thieme Stuttgart · New York